Practical

Algorithms in
Pediatric
Nephrology
Editors
Israel Zelikovic, Haifa
Israel Eisenstein, Haifa

56 graphs, 1 figure and 10 tables, 2008

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Basel Freiburg Paris London New York Bangalore
Bangkok Shanghai Singapore Tokyo Sydney

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 Contents
1 Contributors Urinary tract disease/tubulointerstitial Hypertension
II
nephropathy 50 Neonatal hypertension
2 Preface 22 Urinary tract infection S. Turi; A.L. Friedman
Z. Hochberg R. Adelman; S. Hulton
52 Pediatric hypertension
3 Introduction 24 Dilated/obstructed urinary tract S. Turi; A.L. Friedman
I. Zelikovic; I. Eisenstein S. Hulton; R. Adelman

26 Fetal hydronephrosis
Tubular disease
J.-P. Guignard; R.N. Fine
Glomerular and vascular disease
54 Aminoaciduria
28 Vesicourethral reflux
4 Hematuria I. Eisenstein; P. Goodyer; I. Zelikovic
R. Adelman; S. Hulton
A.L. Friedman; S. Turi
30 Dysfunctional voiding 56 Cystinuria
6 Acute nephritic syndrome P. Goodyer; I. Eisenstein; I. Zelikovic
S. Hulton; R. Adelman
F. Santos; S.P. Makker
32 Loin pain with hematuria 58 Glycosuria
8 Proteinuria I. Eisenstein; P. Goodyer; I. Zelikovic
J. Smith; F.B. Stapleton
F. Santos; S.P. Makker
34 Renal trauma 60 Renal tubular acidosis
10 Nephrotic syndrome in the first year I. Eisenstein; P. Goodyer; I. Zelikovic
R. Adelman; S. Hulton
of life
36 Tubulointerstitial nephritis 62 Proximal tubulopathy
F. Santos; S.P. Makker
A.L. Friedman; S. Turi (Fanconi syndrome)
12 Nephrotic syndrome in the child and P. Goodyer; I. Eisenstein; I. Zelikovic
adolescent 64 Polyuria
S.P. Makker; F. Santos Structural/congenital abnormalities P. Goodyer; I. Eisenstein; I. Zelikovic
14 Rapidly progressive 38 Single kidney (renal agenesis) 66 Hypouricemia
glomerulonephritis G. Rizzoni ; M.A. Linshaw J. Smith; F.B. Stapleton
S.P. Makker; F. Santos
40 Renal hypoplasia-dysplasia 68 Hyperuricemia
16 Chronic nephritic syndrome G. Rizzoni ; M.A. Linshaw F.B. Stapleton; J. Smith
S.P. Makker; F. Santos
42 Nephromegaly 70 Rickets
18 Vasculitis M.A. Linshaw; G. Rizzoni G. Ariceta; B. Hoppe; C.B. Langman
W. Proesmans; U.S. Alon
44 Hyperechoic kidney
20 Hemolytic uremic syndrome M.A. Linshaw; G. Rizzoni
W. Proesmans; U.S. Alon

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46 Cystic kidneys
G. Rizzoni ; M.A. Linshaw

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48 Renal mass

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M.A. Linshaw; G. Rizzoni
 Fluid/electrolyte/acid base balance Divalent ion metabolism Renal failure
72 Hyponatremia 92 Hypocalcemia 106 Oliguria/anuria
S. Watkins; D. Okamura; J. Rodrguez Soriano G. Ariceta; B. Hoppe; C.B. Langman J.-P. Guignard; R.N. Fine

74 Hypernatremia 94 Hypercalcemia 108 Neonatal acute renal failure

S. Watkins; D. Okamura; J. Rodrguez Soriano B. Hoppe; G. Ariceta; C.B. Langman J.-P. Guignard; R.N. Fine

76 Hypochloremia 96 Hypophosphatemia 110 Acute renal failure (child/adolescent)

J. Rodrguez Soriano; D. Okamura; S. Watkins C.B. Langman; G. Ariceta; B. Hoppe R.N. Fine; J.-P. Guignard

78 Hyperchloremia 98 Hyperphosphatemia 112 Chronic renal failure

D. Okamura; J. Rodrguez Soriano; S. Watkins C.B. Langman; G. Ariceta; B. Hoppe R.N. Fine; J.-P. Guignard

80 Hypokalemia 100 Hypomagnesemia 114 Renal osteodystrophy

D. Okamura; J. Rodrguez Soriano; S. Watkins I. Eisenstein; P. Goodyer; I. Zelikovic R.N. Fine; J.-P. Guignard

82 Hyperkalemia 102 Hypercalciuria

J. Rodrguez Soriano; D. Okamura; S. Watkins F.B. Stapleton; J. Smith
116 Index of Signs and Symptoms
84 Metabolic acidosis 104 Nephrolithiasis/urolithiasis
U.S. Alon; W. Proesmans F.B. Stapleton; J. Smith 120 Abbreviations

86 Metabolic alkalosis
U.S. Alon; W. Proesmans

88 Hypovolemia
U.S. Alon; W. Proesmans

90 Edema
W. Proesmans; U.S. Alon

III

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IV
Library of Congress Cataloging-in-Publication Data
Practical algorithms in pediatric nephrology / editors, Israel Zelikovic,
Israel Eisenstein.
p. ; cm. -- (Practical algorithms in pediatrics)
Includes bibliographical references and index.
ISBN 978-3-8055-8539-2 (soft cover : alk. paper)
1. Pediatric nephrology--Handbooks, manuals, etc. 2. Medical
protocols--Handbooks, manuals, etc. I. Zelikovic, Israel. II. Eisenstein,
Israel, 1964- III. Series.
[DNLM: 1. Kidney Diseases--diagnosis. 2. Adolescent. 3. Child. 4.
Decision Trees. 5. Diagnosis, Differential. WS 320 P895 2008]
RJ476.K5P73 2008
618.9261--dc22
2008019859
Disclaimer. The statements, options and data contained in this publi-
cation are solely those of the individual authors and contributors and
not of the publisher and the editor(s). The appearance of advertise-
ments in the book is not a warranty, endorsement, or approval of the
products or services advertised or of their effectiveness, quality or
safety. The publisher and the editor(s) disclaim responsibility for any
injury to persons or property resulting from any ideas, methods, in-
structions or products referred to in the content or advertisements.
Drug Dosage. The authors and the publisher have exerted every effort
to ensure that drug selection and dosage set forth in this text are in
accord with current recommendations and practice at the time of pub-
lication. However, in view of ongoing research, changes in government
regulations, and the constant flow of information relating to drug ther-
apy and drug reactions, the reader is urged to check the package insert
for each drug for any change in indications and dosage and for added
warnings and precautions. This is particularly important when the rec-
ommended agent is a new and/or infrequently employed drug.
All rights reserved. No part of this publication may be translated into
other languages, reproduced or utilized in any form or by any means,
electronic or mechanical, including photocopying, recording, micro-
copying, or by any information storage and retrieval system, without
permission in writing from the publisher.
Copyright 2008 by S. Karger AG, P.O. Box, CH4009 Basel
(Switzerland)
Printed in Switzerland on acid-free and non-aging paper (ISO 9706)
by Reinhardt Druck, Basel
ISBN 9783805585392
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 Contributors
Raymond Adelman, MD Bernd Hoppe, MD Juan Rodrguez Soriano, MD
Department of Pediatrics University Childrens Hospital Division of Pediatric Nephrology
Phoenix Childrens Hospital Division of Pediatric Nephrology Department of Pediatrics
Phoenix, AZ, USA Cologne, Germany Hospital de Cruces and Basque University
School of Medicine
Uri S. Alon, MD Sally Hulton, MD Baracaldo, Vizcaya, Spain
Section of Pediatric Nephrology Department of Pediatric Nephrology
The Childrens Mercy Hospital and Clinics The Birmingham Childrens Hospital Fernando Santos, MD
University of Missouri NHS Trust Division of Pediatric Nephrology
Kansas City, MO, USA Birmingham, United Kingdom Hospital Central de Asturias
University of Oviedo
Gema Ariceta, MD Craig B. Langman, MD Oviedo, Asturias, Spain
Division of Pediatric Nephrology Feinberg School of Medicine
Hospital de Cruces Northwestern University Jodi Smith, MD
Baracaldo, Vizcaya, Spain Kidney Diseases, Childrens Memorial Hospital Division of Pediatric Nephrology
Chicago, IL, USA Childrens Hospital and Regional Medical Center
Israel Eisenstein, MD University of Washington
Michael A. Linshaw, MD Seattle, WA, USA
Pediatric Nephrology
Rambam Medical Center Division of Pediatric Nephrology
Faculty of Medicine Technion Massachusetts General Hospital F. Bruder Stapleton, MD
Haifa, Israel Boston, MA, USA Department of Pediatrics
Childrens Hospital and Regional Medical Center
Richard N. Fine, MD Sudesh Paul Makker, MD University of Washington
Seattle, WA, USA
School of Medicine Pediatric Nephrology
State University of New York at Stony Brook UC Davis Medical Center
Stony Brook, NY, USA Sacramento, CA, USA Sandor Turi, MD
Department of Pediatrics and Child Health Center
Aaron L. Friedman, MD Daryl Okamura, MD University of Szeged
Szeged, Hungary
Department of Pediatrics Division of Pediatric Nephrology
University of Minnesota Childrens Hospital and Regional Medical Center
Minneapolis, MN, USA University of Washington Sandra Watkins, MD
Seattle, WA, USA Division of Pediatric Nephrology
Paul Goodyer, MD Childrens Hospital and Regional Medical Center
Willem Proesmans, MD University of Washington
Division of Pediatric Nephrology
Seattle, WA, USA
The Montreal Childrens Hospital Renal Unit, Department of Pediatrics
McGill University University Hospital Gasthuisberg
Montreal, Quebec, Canada Leuven, Belgium Israel Zelikovic, MD
1 Pediatric Nephrology
Jean-Pierre Guignard, MD Gianfranco Rizzoni , MD Rambam Medical Center
Faculty of Medicine Technion
Division of Pediatric Nephrology Division of Nephrology
Haifa, Israel
Department of Pediatrics Childrens Hospital and

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Lausanne University Medical School Research Institute Bambino Gesu
Lausanne, Switzerland Rome, Italy

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The term algorithm is derived from the
2
name of the ninth century Arabic mathe-
matician Algawrismi, who also gave his
name to algebra. His algorismus, indi-
cated a well-defined procedure for step-by-
step logical approach to mathematical
problem-solving. In reading the final prod-
uct, written by some of the finest pediatric
nephrologists in the world and edited by
my friends Drs. Israel Zelikovic and Israel
Eisenstein, it is obvious that the spirit of the
algorismus has been utilized in its best.
The algorithm input are physical symptoms
and signs, or laboratory results, which lead
to a number of effective steps, and pro-
duces the diagnoses for an output.
Preface
Practical Algorithms in Pediatric Ne- This is the third in the Series of Practical
phrology is meant as a pragmatic text to be Algorithms in Pediatrics, following Practi-
used at the patients bedside. The experi- cal Algorithms in Pediatric Endocrinology
enced practitioner applies step-by-step and Practical Algorithms in Pediatric Hema-
logical problem-solving for each patient tology-Oncology. Hopefully, this volume
individually. Decision trees prepared in ad- will provide residents, fellows, general pe-
vance have the disadvantage of unac- diatricians and family practitioners some
quaintedness with the individual patient. important clinical tools in understanding
Yet, for the physician who is less experi- their patients.
enced with a given problem, a prepared
algorithm would provide a logical, concise,
cost-effective approach prepared by a spe- Zeev Hochberg, MD, PhD
cialist who is experienced with the given Series Editor
problem.
Thirty years after completing my pedi-
atric residency, I discover that Pediatric
Nephrology has become a sophisticated
specialty with solid scientific background,
of which I know so little. I would still refer
my patients to a specialist with many of the
diagnoses, symptoms and signs discussed
here. But, with the help of this outstanding
algorithms and text, I would refer them af-
ter an educated initial workup, and would
be better equipped to follow the specialists
management.
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 Introduction
Practical Algorithms in Pediatric Ne- understanding of the physiology and During the production process of this
phrology is a pragmatic text which classi- pathophysiology of renal function in health book, it has been our privilege to interact
fies common clinical symptoms, signs, and disease. Hence, special emphasis has and work with some of the leading clini-
laboratory abnormalities and issues of been given in this book to the novel knowl- cians and teachers in the field of pediatric
management as they present themselves edge that has accumulated on the molecu- nephrology in the world. It has been a very
in daily practice. Aimed at an audience of lar pathophysiology and molecular genet- enriching and gratifying experience for us,
general and family practitioners, pediatri- ics of various kidney diseases and urinary the editors, for which we thank all the
cians and trainees who are not exposed to tract abnormalities, in order to deepen and authors. A final note we have been very
pediatric nephrology problems on a day-to- strengthen the practical approach to com- saddened by the recent passing of Prof.
day basis, it provides a rational, stepwise mon problems occurring in pediatric ne- Gianfranco Rizzoni, a prominent pediatric
and as noninvasive as possible approach phrology. Indeed, many of the algorithms nephrologist from Rome, Italy, who con-
from which they can profit and acquire in this book, written by leading investiga- tributed several excellent algorithms to this
medical reasoning. tors in the area of pediatric nephrology, book. We send our deep condolences to
incorporate and exemplify this bench to his family and friends.
In the past decade, remarkable prog- patient approach which has become a
ress has been made in our understanding characteristic of modern medicine. Israel Zelikovic, MD
of the molecular pathogenesis of heredi- Israel Eisenstein, MD
tary kidney diseases and congenital urinary It is the Editors hope that the algorith-
tract abnormalities. Studies in molecular mic, logical and stepwise approach to the
genetics and molecular biology have led to diagnosis and management of various he-
the identification of numerous kidney dis- reditary and acquired kidney diseases,
ease-causing mutations, provided impor- fluid and electrolyte abnormalities, aberra-
tant insights into the defective molecular tions in mineral balance, and other impair-
mechanisms underlying various kidney ments in kidney function, will equip the
diseases and structural abnormalities of practitioner, inexperienced in the field of
the kidney, and have greatly increased our pediatric nephrology, with the tools and
ability to successfully confront and man-
age, at least at their initial stages, clinical
problems which have always been notori-
ous for their complexity and which have
been left, from the outset, to specialists in
3
the area.

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 Glomerular and vascular disease A.L. Friedman S. Turi Hematuria

/
Hematuria
4

Microscopic hematuria 0 Macroscopic (gross) hematuria

Exclude myo-/hemoglobinuria or red urine without hematuria 3

Transient 1 Persistent 2 () Nephritic syndrome 4 (+) Nephritic syndrome :

Hx PHE Laboratory/imaging Hx PHE Laboratory

Urinary symptoms Edema, fever Urine: microscopy, culture, protein, Recurrent/new onset ? Blood pressure, Urine: microscopy, protein,
Stones/urinary sediment Abdominal/loin metabolic profile of stones Postinfectious respiratory rate, eosinophils
Abdominal/loin pain mass or tenderness Serum: creatinine and BUN, electrolytes, Ca2+, Rash, arthritis/arthralgia pallor, edema, Serum: CBC + reticulocytes,
Weight loss Eye/ear examination phosporus, uric acid, CBC + reticulocytes, Hemoptysis rash, petechia, creatinine, BUN, electrolytes,
Hearing impairment Diaper/underwear blood gases, LDH, C3, C4, ANA, ANCA Respiratory symptoms arthritis/arthralgia, AST, ALT, albumin,
Eye anomalies sediment Hepatitis B, C serology Weight loss, fever lung examination hepatitis B, C serology,
(+)Family Hx of stones/ Bruises/hematomas Imaging: plain abdominal film, Drugs (NSAID, antibiotics) C3, C4, ANA, ANCA
hearing impairment/hematuria/ renal/abdominal Doppler US, Kidney biopsy
bleeding disorder/ abdominal CT, angiography, kidney biopsy
hypercoagulability

Fever Glomerular disease 5 Urinary tract diseases 8 Immune-mediated disease ; Vasculitides < Miscellaneous =
Strenuous exercise Alport syndrome Urinary tract infection Postinfectious glomerulonephritis HSP RPGN
Benign familial hematuria Nephro-/urolithiasis Other glomerulonephritides Wegner's granulomatosis HUS
IgA nephropathy Hypercalciuria (shunt GN, SBE, cryoglobulinemia) Churg-Strauss syndrome TIN
Postinfectious glomerulonephritis Loin pain hematuria syndrome MPGN Microscopic polyangiitis
Persistent asymptomatic hematuria Hematologic diseases 9 IgA nephropathy (microscopic PAN)
Anatomic malformation 6 Coagulopathies Lupus nephritis Polyarteritis nodosa (classic PAN)
Hydronephrosis Renal vein thrombosis Anti-GBM glomerulopathy
Polycystic kidney disease Sickle cell disease (Goodpasture syndrome)
Tumors 7 Nutcracker syndrome
Wilms tumor AV malformation

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 1 RBCs in the urine.
2 Microscopic hematuria is defined as >23
RBCs/high power field or >5 RBCs/l.
3 Transient hematuria is observed in children
with intercurrent infection (which is the most common
cause of microscopic hematuria in children) and
during strenuous exercise. This type of hematuria is
asymptomatic, resolves within a few days and does
not warrant further evaluation.
4 The presence of RBCs in 3 consecutive urine
samples obtained over a 3-week period is defined as
persistent hematuria.
5 Damage to muscle tissue or RBCs causes a
release of myoglobin or hemoglobin, respectively.
Both molecules are filtered in the glomerulus and lead
to red, blood-like urine, with a positive heme test on
dipstick but no RBCs on urinary microscopy. Various
drugs and food derivatives can cause red-colored
urine without hematuria.
6 The differential diagnosis of gross hematuria
includes conditions with or without features of
nephritic syndrome (see below). It is important to
emphasize that most conditions outlined below
(sections 711) can lead to gross as well as micro-
hematuria. The workup of the child with hematuria
should be rational, sequential, disease-oriented
and as noninvasive as possible.
7 Glomerular diseases can cause a spectrum of
clinical manifestations ranging from asymptomatic
microscopic hematuria to rapidly progressive glomer-
ulonephritis and severe renal impairment.
Alport syndrome is an inherited x-linked, autosomal-
recessive, or rarely autosomal-dominant disorder,
which is caused by a defect in collagen type IV, an
essential component of the basement membrane. The
clinical picture of Alport syndrome includes hearing
impairment, eye abnormalities and renal disease man-
ifested as hematuria, (microscopic or recurrent macro-
scopic), progressive proteinuria and deteriorating GFR
culminating in ESRD. Benign familial hematuria (thin
5 can result in glomerulopathy leading to microscopic
basement membrane disease) is another genetically
transmitted disease that is caused by alterations in
collagen type IV. The cardinal manifestation of this
Glomerular and vascular disease
mostly benign disease is asymptomatic microscopic
hematuria. Although the clinical presentation of IgA
nephropathy and postinfectious glomerulonephritis
can be asymptomatic microscopic hematuria, these
diseases are more likely to present with macroscopic
hematuria with or without nephritic syndrome (see
below). Persistent asymptomatic hematuria, a clini-
cally insignificant condition, is a diagnosis made after
excluding all other causes of hematuria.
8 Anatomic malformations can cause hematu-
ria, which is either microscopic or macroscopic. The
features of polycystic kidney disease (either autosomal
dominant or autosomal recessive), a leading cause of
ESRD, include (among other manifestations) hematu-
ria (see Cystic kidneys).
9 Tumors of the kidneys or the urinary tract will
cause either microhematuria or, more commonly,
gross hematuria.
10 Urinary tract infections may lead (in addition
to the typical urinary manifestations) to microhematu-
ria. Hemorrhagic cystitis, a condition caused by viral
infections (mostly adenovirus), radiation or cyclophos-
phamide administration will manifest with gross
hematuria. Hypercalciuria, the most common cause of
nephrolithiasis/urolithiasis in children, can cause either
isolated microscopic hematuria or gross hematuria.
Most of these children will have idiopathic hyper-
calciuria (see Hypercalciuria). Loin pain hematuria
syndrome is a rare and enigmatic disorder, observed
mostly in young women (see Loin pain with hematu-
ria).
11 Hematologic disorders will manifest usually
with microscopic hematuria without urinary symp-
toms. Conditions that increase the risk of renal vein
thrombosis include intravascular volume depletion
and hypercoagulability. It is also observed in infants
of diabetic mothers. Nutcracker syndrome is a condi-
tion caused by a compression of the left renal vein
between the abdominal aorta and superior mesenteric
artery leading to intermittent gross hematuria and
left flank pain. Diagnosis is made by abdominal
Doppler sonogram or angiography. Sickle cell disease
hematuria or renal papillary necrosis which will cause
gross hematuria.
A.L. Friedman S. Turi
12 Nephritic syndrome is a condition character-
ized by gross hematuria with urinary casts (RBCs,
granular), proteinuria, hypertension and variable
degrees of decreased renal function.
13 Immune-mediated GN comprises the major-
ity of diseases that cause nephritic syndrome in chil-
dren, and usually present with gross hematuria. For
details, see appropriate algorithms.
14 Vasculitides, a group of disorders that cause
inflammation of blood vessels, usually presents with
gross hematuria. See appropriate algorithms.
15 RPGN, or crescentic GN, usually manifest
with gross hematuria in addition to the rapid decline
in GFR (for details, see appropriate algorithms). Hemo-
lytic uremic syndrome (HUS) and tubulointerstitial
nephritis are additional important causes of gross
hematuria (see appropriate algorithms).
Selected reading
Bergstein J, Leiser J, Andreoli S: The clinical signifi-
cance of asymptomatic gross and microscopic
hematuria in children. Arch Pediatr Adolesc Med
2005;159:353355.
Diven SC, Travis LB: A practical primary care
approach to hematuria in children. Pediatr Nephrol
2000;14:6572.
Hudson BG, Tryggvason K , Sundaramoorthy M,
Neilson EG: Alports syndrome, Goodpastures
syndrome, and type IV collagen. N Engl J Med
2003;348:25432556.
Pan CG: Evaluation of gross hematuria. Pediatr Clin
North Am 2006;53:401412.
Shin JI, Park JM, Lee SM, Shin YH, Kim JH, Lee JS,
Kim MJ: Factors affecting spontaneous resolution
of hematuria in childhood nutcracker syndrome.
Pediatr Nephrol 2005;20:609613.
Yadin O: Hematuria in children. Pediatr Ann 1994;23:
474478, 481485.
Youn T, Trachtman H, Gauthier B: Clinical spectrum
of gross hematuria in pediatric patients. Clin Pediatr
2006;45:135141.
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Hematuria
 Glomerular and vascular disease F. Santos S.P. Makker Acute nephritic syndrome

/
Acute nephritic syndrome Macroscopic hematuria, oliguria, acute renal failure,
salt retention (hypertension and edema), proteinuria

6 Initial diagnostic work-up 0

History and physical examination
Culture of throat and/or cutaneous lesion
Serum creatinine, BUN, electrolytes and albumin levels
Urinalysis + microscopy
Serum C3, C4 levels, antistreptolysin O titers, hepatitis B and C serology, ANA levels
Renal ultrasound, chest X-ray

Hypocomplementemia 1 Normocomplementemia 3 Rapidly declining renal function

Transient Persistent 3

Renal biopsy Renal biopsy

Acute postinfectious GN 2 Membranoproliferative GN 4 IgA GN 5 RPGN 7

Lupus nephritis HSP
Endocarditis Polyarteritis nodosa

Antibiotics, if indicated Supportive treatment (regardless of etiology) 6 Methylprednisolone pulse therapy

Salt, potassium, fluid restriction Cytotoxic drugs
Furosemide Plasmapheresis
Antihypertensive drugs
Dialysis therapy

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 1 Acute GN often manifests as an ANS. The main features of
this syndrome are: (a) hematuria, usually gross hematuria of sudden
onset; it is sometimes associated with the presence of RBC casts
in urinary sediment, which is diagnostic of glomerular bleeding;
(b) oliguric acute renal failure of variable severity; oliguria is defined
as urine volume less than 1214 ml/m2/h in children and below 0.6
0.8 ml/kg/h in neonates and infants; (c) hypertension and edema are
mainly produced by salt retention that is not only secondary to de-
creased glomerular filtration rate but also to increased reabsorption
of sodium chloride in the collecting duct. This tubular hyperabsorp-
tion of sodium chloride probably results from hyperactivity of the
Na+/K+ ATPase pump located on the basolateral membrane of the
collecting duct cells; (d) proteinuria of variable intensity; although
urinary protein excretion in children with ANS is characteristically
below the nephrotic range.
2 Initial diagnostic approach to a child who presents with
manifestations suggestive of ANS should focus on: (a) confirmation
of ANS by measuring GFR and amount of protein lost in urine as well
as potential detection of RBC casts in urine sediment; (b) search for
evidence of infectious causal agent, mainly group A beta-hemolytic
streptococcus, by cultures of throat and skin lesions, if any, and
serum determination of antistreptolysin O titer; (c) exclusion of sys-
temic diseases, such as HSP syndrome, systemic lupus erythemato-
sus, endocarditis or idiopathic GN (MPGN, IgA nephropathy) by
detailed anamnesis, meticulous physical examination and laboratory
tests which include serum C3 and C4 levels, hepatitis B and C serol-
ogy and levels of ANA. No specific findings of ANS may be found in
renal ultrasound which usually will show a loss of the normal corti-
comedullary differentiation; however, the absence of other abnormal
findings is useful to rule out chronic nephro-urologic disorders; if
respiratory symptoms are present, a chest X-ray film is mandatory
since pulmonary edema may be a presenting manifestation of ANS.
3 Measurement of serum C3 levels is important in the evalua-
tion of the child presenting with ANS. Hypocomplementemia is a
major diagnostic criteria of postinfectious acute GN. Serum levels of
C3 are usually markedly depressed when clinical and biochemical
manifestations of ANS become apparent. The degree of depression
of C3 does not correlate with the severity of the disease or have any
prognostic significance. Serum C3 concentrations tend to normalize
progressively and persistence of hypocomplementemia beyond 8
weeks after presentation should alert the clinician to the possibility
of MPGN or lupus nephritis.
4 Poststreptococcal GN is representative of a larger group of
7 postinfectious GNs in which acute glomerular injury results from
immune events triggered by a variety of bacterial, viral, and proto-
zoal infections. Poststreptococcal GN predominantly affects children
between 2 and 10 years and usually follows a benign course with full
recovery being the rule. Kidney biopsy, which is not indicated in typi-
cal cases, will show diffuse GN with endocapillary proliferation and
Glomerular and vascular disease
abundance of polymorphonuclear cells, positive immunoflorescence
Selected reading
for C3 and IgG and subepithelial electron-dense deposits or humps.
Poststreptococcal acute GN must be treated with penicillin as Appel GB, Cook HT, Hageman G, Jennette JC, Kashgarian M,
though an active infection by group A streptococcus is present. Kirschfink M, Lambris JD, Lanning L, Lutz HU, Meri S, Rose NR,
Salant DJ, Sethi S, Smith RJ, Smoyer W, Tully HF, Tully SP,
5 The finding of normal serum C3 concentrations or Walker P, Welsh M, Wurzner R, Zipfel PF: Membranoproliferative
persistent hypocomplementemia must raise the suspicion of other glomerulonephritis type II (dense deposit disease): an update.
diagnostic options mentioned above and lead to kidney biopsy. J Am Soc Nephrol 2005;16:13921403.
Delos Santos NM, Wyatt RJ: Pediatric IgA nephropathies:
6 MPGN is a chronic GN rarely seen before 10 years of age. clinical aspects and therapeutic approaches. Semin Nephrol 2004;
This entity is divided into 3 subtypes by histopathologic features 24:269286.
termed MPGN I, II and III. MPGN can be idiopathic or associated with Hricik DE, Chung-Park M, Sedor J: Glomerulonephritis. N Engl J
systemic diseases (suppurative infections, hepatitis B and C infec- Med 1998;339:888889.
tion, cryoglobulinemia and malignancies). Lupus nephritis is more Jucos LI: Intrarenal mechanisms of salt and water retention in
often found in adolescent girls with elevated titers of antinuclear the nephritic syndrome. Kidney Int 2002;61:11821195.
antibodies and multisystemic involvement. The renal lesions are Kurtzman NA: Nephritic edema. Semin Nephrol 2001;21:257261.
divided into 5 types based on the WHO classification of histologic Lee BS, Cho HY, Kim EJ, Kang HG, Ha IS, Cheong HI, Kim JG,
findings: type 1 normal glomeruli; type 2 mesangial changes; type Lee HS, Choi Y: Clinical outcomes of childhood lupus nephritis:
3 focal proliferative GN; type 4 diffuse proliferative GN (the most a single centers experience. Pediatr Nephrol 2007;22:222231.
common and most severe form), and type 5 membranous GN. Madaio MP, Harrington JT: The diagnosis of glomerular diseases:
Long-term prognosis of the severe forms of lupus nephritis (types 3 acute glomerulonephritis and the nephrotic syndrome.
and 4) is poor and, therefore, treatment regimens are aggressive and Arch Intern Med 2001;161:2534.
include IV pulses of methylprednisolone and cyclophosphamide.
7 IgAN is the most common GN worldwide with especially
high prevalence in certain areas (south-east Asia, Pacific rim) in
contrast to low rates among blacks. Although the exact etiology is
unknown, there are certain predisposing genetic and environmental
factors that are associated with IgAN. The pathogenesis of IgAN is
complex and it involves mesangial deposition of IgA molecules,
circulating IgA complexes as well as abnormal IgA glycosylation.
The typical histological findings include mesangial proliferation with
mesangial IgA staining on immunofluorescence. Although the long-
term prognosis is usually good, hypertension, heavy proteinuria
and/or reduced GFR are bad prognostic factors and aggressive ther-
apy should be instituted which includes combinations of steroids,
fish-oil, azathioprine, dipyridamole and heparin/warfarin. Vasculitis
can lead to ANS with normocomplementemia. This picture is espe-
cially seen in HSP and polyarthritis nodosa.
8 Patients with ANS require close monitoring to prevent com-
plications. Physical activity as well as salt, potassium, and fluid
intake must be restricted during the acute period of the disease. Oral
or intravenous furosemide is often needed for a few days to treat
oliguria and hypertension. Other drugs used to treat hypertension
include calcium channel blockers, - and -blockers, various vaso-
dilators, and, occasionally, ACE inhibitors.
9 RPGN is diagnosed by an abrupt and progressive deteriora-
tion of glomerular filtration rate along with the presence of epithelial
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crescents in more than 60% of glomeruli. For details, see Rapidly
progressive glomerulonephritis.
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 Glomerular and vascular disease F. Santos S.P. Makker Proteinuria

/
Proteinuria
8

Transient 0 Persistent 1

Tubular Glomerular 4

Isolated 4 Associated with

Tubular disorders 2 Overload proteinuria 3 Nephritic syndrome 5 Nephrotic syndrome 5 Chronic renal disease 6

No additional studies ACE or angiotensin receptor antagonists 7

No treatment

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 1 Minimal amounts of proteins can be physi-
ologically found in urine. Pathologic proteinuria can be
detected by dipstick, which is especially sensitive to
albumin. A rough estimation of the intensity of pro-
teinuria may be drawn from the dipstick: trace, 1+, 2+,
3+, 4+ approximately correspond to 1015, 30, 100, 300
and >1,0002,000 mg/dl, respectively. A more accurate
quantitation of proteinuria requires timed urine collec-
tion of measurement of the protein (mg/dl)/creatinine
(mg/dl) ratio in an isolated urine sample, preferably the
first one of the morning. A urinary protein to creatinine
ratio 60.2 in children beyond infancy is considered
abnormal. In infants, higher ratios (up to 0.5) are still
considered normal. The 24-hour urine collection is
the best test for the estimation of protein excretion.
Values above 4 mg/m2/h are pathologic and values
above 40 mg/m2/h are in the nephrotic range.
2 Prevalence of proteinuria in a single urine
specimen in children varies between 5% and 15%.
Transient proteinuria is not indicative of underlying
renal disease. This type of proteinuria is often found in
association with fever, exercise, stress or dehydration
and the only study required is to confirm its disappear-
ance once the intercurrent factor has worn off. Ortho-
static proteinuria is diagnosed when urinary protein
is elevated when the subject is upright but normalizes
during recumbency. It occurs most commonly in
school-aged children, its intensity is usually below the
nephrotic range, and its outcome is generally consid-
ered to be benign, so no additional diagnostic studies
or therapeutic measures are necessary.
3 Proteinuria detected in repeated urine sam-
ples over time is always an index of renal or systemic
abnormality and should be further investigated.
4 Decreased reabsorption of normally filtered
low-molecular-weight proteins (molecular weight
below 40,000 Da) by the renal proximal tubules leads
to tubular proteinuria. Dipstick testing is less sensitive
to detect tubular proteins than albumin. 2-Microglob-
ulin and retinol-binding protein are the low-molecular-
weight proteins measured most frequently. Normal
reference values for these proteins in children beyond
6 months of age and adults are as follows: urinary
9 2-microglobulin = 6.040.7 g/mmol creatinine; plas-
ma 2-microglobulin 1.02.4 mg/l; urinary retinol-bind-
ing protein ~124.5 g/mmol creatinine. In infants,
these concentrations tend to be higher. Measurement
Glomerular and vascular disease
of 2-microglobulin requires monitoring of urine pH
Selected reading
because of its instability in samples with pH below 6.5.
From the diagnostic point of view, the finding of tubu- Adelman RD, Restaino IG, Alon US, Blowey DL:
lar proteinuria is seen in the setting of a more general- Proteinuria and focal segmental glomerulosclerosis
ized proximal tubular disorder, usually congenital or in severely obese adolescents. J Pediatr 2001;138:
primary, that produces aminoaciduria, phosphaturia, 481485.
glucosuria and/or bicarbonaturia, or as an acquired Chandar J, Abitbol C, Montane B, Zilleruelo G: An-
alteration secondary to interstitial nephropathy (acute giotensin blockade as sole treatment for proteinuric
pyelonephritis, reflux nephropathy, obstructive kidney disease in children. Nephrol Dial Transplant
nephropathy, administration of aminoglycosides, etc.) 2007;22:13321337.
Hogg RJ, Portman RJ, Milliner D, Lemley KV, Eddy A,
5 Systemic overproduction of low-molecular- Ingelfinger J: Evaluation and management of
weight proteins may give rise to proteinuria because proteinuria and nephrotic syndrome in children:
of excessive amounts of these proteins in the glomeru- recommendations from a pediatric nephrology
lar filtrate which overwhelms the maximum reabsorp- panel established at the National Kidney Founda-
tive capacity of the tubule. Thus, low-molecular- tion conference on proteinuria, albuminuria, risk,
weight proteinuria may be a manifestation of multiple assessment, detection, and elimination (PARADE).
myeloma (light chains), leukemia (lysozyme), rhabdo- Pediatrics 2000;105:12421249.
myolysis (myoglobin) or hemolysis (hemoglobin). Litwin M, Grenda R, Sladowska J, Antoniewicz J:
Add-on therapy with angiotensin II receptor 1
6 With a negative personal history of renal dis- blocker in children with chronic kidney disease
ease, persistent glomerular proteinuria even under the already treated with angiotensin-converting
nephrotic range (between 4 and 40 mg/m2/h) requires enzyme inhibitors. Pediatr Nephrol 2006;21:
clinical evaluation (family and personal history, edema, 17161722.
blood pressure) laboratory work-up (urinalysis, renal Tomlinson PA: Low molecular weight proteins in
function, serum lipid profile, serum complement, anti- children with renal disease. Pediatr Nephrol
nuclear antibodies, hepatitis and HIV diagnostic tests) 1992;6:565571.
and abdominal ultrasound to rule out associated renal
dysfunction. If these complementary studies are
normal, renal biopsy to identify the underlying kidney
lesion may be necessary.
7 For details on nephritic and nephrotic syn-
dromes, see corresponding algorithms.
8 High pressure and glomerular hyperfiltration
in chronic renal disease may lead to proteinuria
induced by glomerulosclerosis as found in diabetic
nephropathy, reduced functioning renal mass, arterial
hypertension, severe obesity, etc.
9 ACE inhibitors and angiotensin II receptor
antagonists are increasingly used in adult patients
with chronic renal disease because of their potential
renoprotective, antihypertensive and antiproteinuric
actions. Although few data are available in children,
accumulating evidence seems to confirm the benefi-
cial effect of these therapies on proteinuria of pediatric
patients with different types of chronic renal disease.
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 Glomerular and vascular disease F. Santos S.P. Makker Nephrotic syndrome in the first year of life

/
Nephrotic syndrome in the first year of life
10

Congenital NS 0 Infantile NS 0

Finnish type NS 1 Secondary NS 2 DMS 3 FSGS 4 Others 5

Particularly frequent in Finns Intrauterine infections Isolated or Denys-Drash syndrome Resistant to

Early-onset massive proteinuria Congenital syphilis Early progression to renal failure immunomodulatory drugs
Prematurity and large placenta Toxoplasmosis Characteristic renal pathology Early progression to renal failure
No renal insufficiency Rubella Mutations in WT1 gene Usually podocin gene mutations
Microcystic kidneys CMV
Mutations in NPHS1 gene HIV

MCD
MGN
SLE

Nephrectomy 7 Supportive therapy 6 Treatment of primary disease

Dialysis Nutritional supplementation Immunomodulatory treatment
Early transplantation Albumin infusions + furosemide
Thyroid hormone replacement
Anticoagulation

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Aggressive treatment of infections

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Antiproteinuric agents

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 1 NS is characterized by massive proteinuria,
estimated by urinary protein elimination equal to or
greater than 40 mg/m2/h and/or urinary protein/creati-
nine ratio >23 mg/mg, resulting in hypoalbuminemia
of less than 3 g/dl, edema and hyperlipidemia. Al-
though minimal change nephropathy is by far the lead-
ing cause of NS in childhood, when NS presents in the
first year of life, other underlying diseases must be
considered.
2 The term congenital NS is classically used to
describe a NS of onset within the first 3 months of life
(and has become synonymous with Finnish type NS).
Infantile NS usually applies to NS of later onset, until
1 year of age.
3 Finnish-type NS may be found worldwide
although it is more frequent in Finland where its inci-
dence is approximately 1/10,000 newborns. A typical
clinical picture includes premature delivery, placenta
weighing more than 25% of the birth weight, develop-
ment of generalized edema, massive proteinuria and
hypoalbuminemia at birth or within the first days of
life. In untreated cases, the natural course of the dis-
ease leads to early death secondary to infection and/or
malnutrition in the presence of normal glomerular
filtration rate. Proteinuria may be detected prenatally
by increased concentrations of alfa-fetoprotein in
amniotic fluid. Microscopically, NS of Finnish type is
characterized by irregular pseudocystic dilatation of
proximal tubules which is typically seen after the first
36 months of life. The disease follows an autosomal-
recessive transmission and is caused by mutations in
the gene NPHS1. The gene is localized to 19q13.1 and
encodes a protein named nephrin which is essential in
the formation of the normal zipper-looking structure
in the slit diaphragm that joins the interdigitating pro-
cesses of podoctytes. Abnormal nephrin results in a
massive leak of proteins through the glomerular basal
membrane.
4 Neonatal infections, such as syphilis and less
frequently toxoplasmosis, cytomegalovirus or hepati-
tis can cause nephrotic syndrome. These causes must
be excluded by the associated clinical manifestations
and proper immunologic or serologic tests. In these
11 cases, specific treatment of the primary disorder usu-
ally leads to remission of the NS.
5 DMS is responsible for early-onset NS either
as an isolated disease or as part of Denys-Drash
syndrome in which DMS is associated with male
Glomerular and vascular disease
pseudohermaphroditism and Wilms tumor. Incom-
Selected reading
plete forms of the syndrome have been reported. DMS
causes ESRD in the first 2 years of life. The pathologi- Holmberg C, Tryggvason K, Kestila MK, Jalanko HJ:
cal picture is characteristic and consists of mesangial Congenital nephrotic syndrome; in Avner ED,
matrix expansion, thickened glomerular basal mem- Harmon WE, Niaudet P (eds): Pediatric Nephrology,
brane, tuft contraction and tubular dilatation. Muta- ed 5. Philadelphia, Lippincott-Williams & Wilkins,
tions in the WT1 gene, which is expressed in podo- 2004, pp 503516.
cytes and epithelial cells of the Bowmans capsule of Kestila M, lenkkeri U, Mannikko N, Lamerdin J,
postnatal kidney, have been found in nearly all Mc Cready P, Putaaala H, Ruotsalinen V, Morita T,
patients affected with Denys-Drash syndrome and in Nissinen M, Herva R, Kashtan DE, Peltonen L,
many cases of isolated DMS. Holmberg C, Olsen A, Tryggvason K: Positionally
cloned gene for a novel glomerular protein neph-
6 Although FSGS is usually diagnosed in older rin is mutated in congenital nephrotic syndrome.
children or adults, it can present in the first year of life. Mol Cell 1998;1:575582.
These cases are usually due to mutations in the gene Niaudet P, Gubler MC: WT1 and glomerular
encoding podocin, a protein which is essential in the diseases. Pediatr Nephrol 2006;21:16531660.
formation and structure of the slit diaphragm. Two Tryggvason K, Patrakka J, Wartiovaara J: Hereditary
additional genes encoding the proteins alfa-actinin-4 proteinuria syndromes and mechanisms of protein-
and TRPC6 are known to cause FSGS when mutated, uria. N Engl J Med 2006;354:13871401.
usually in older children. These genetic defects do not
respond to treatment with glucocorticoids or other
immunomodulatory drugs and no disease recurrence
after transplantation (which is common in idiopathic
FSGS) is expected.
7 NS in infants younger than 1 year may be
secondary to SLE, minimal-change nephropathy or
membranous nephropathy. These cases are rare and
for details on these disorders, see the appropriate
algorithms.
8 The management of an infant with persistent
NS is complex and must be done in a highly special-
ized childrens hospital. It includes active nutritional
support, control of edema by repeated administration
of intravenous albumin in association with furosemide,
hormone replacement, prevention of thromboembolic
complications, and prompt and aggressive treatment
of infections. Administration of indomethacin, ACE
inhibitors, angiotensin II-type I receptor blockers to
reduce glomerular filtration rate, and, subsequently,
proteinuria may facilitate the control of the patient.
9 In spite of the above measures, infants with
massive proteinuria often require early nephrectomy
and dialysis to place the patient in proper metabolic
and nutritional conditions for a successful renal trans-
plantation. Bilateral nephrectomy and chronic perito-
neal dialysis have been recommended in Finnish type
NS when the infant weighs 7 kg. The effectiveness of
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unilateral nephrectomy in association with antiprotein-
uric drugs is a matter of controversy.
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Nephrotic syndrome in the child and adolescent
12 History 01
Physical examination
Laboratory tests

Gross hematuria () 2 Gross hematuria (+) Microhematuria (+) Microhematuria (+) Microhematuria (+) Microhematuria ()
Microhematuria () BPM or N, GFRmor N BPM or N BPMor N BPM or N BPM or N
BP-N MASLO GFRm or N GFRmor N GFRmor N GFRmor N
GFR-N mC3, C4-N ANA (+) C3, C4-N ASLO-N C3, Cr-N, occasionallym
C3, C4-N ANA () C3, C4m mC3 ANA ()
ANA () Group A B-streptococcus in C4mor N ASLO-N
throat or skin () () ANA

Anti DsDNA (+)

Most likely Possibly Most likely PSGN SLE IgAGN 8: MPGN

MCD FSGS, MGN MGN
FSGS
Other chronic GN
Trial with steroids 3 Supportive teatment 9 Including HSP, RPGN

Renal biopsy Renal biopsy Renal biopsy

Urine Protein () Urine protein (+) 6

Steroids and Steroids 78 Steroids 78
Cyclophosphamide/ Other immunosuppressive agents
Azathioprine/MMF 78
Relapse Renal biopsy

Permanent Frequent relapses Steroid dependent HepB Abs (+) HepC Ab(+) ANCA (+) HIV (+) ;
remission 4

MCD MGN 78 HepB GN ; HepC GN ; Wegener's GN

FSGS Polyangiitis

Cyclophosphamide 5 Steroids Steroids Steroids and

Chlorambucil Chlorambucil Chlorambucil other immunosuppressive agents

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Cyclosporine A Cyclophosphamide Cyclosporine
Cyclosporine A

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FK 506

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 1 NS is a clinical condition that consists of edema, heavy pro-
teinuria, hypoalbuminemia and hyperlipidemia with or without the
accompanying hypertension and/or renal failure. Nephrotic range
(heavy) proteinuria is defined as protein excretion of 640 mg/h/m2
obtained on a timed urine collection. It is usually evident on a routine
urinalysis with dipstick test as 3 to 64 (300 to 61,000) mg/dl protein.
A random spot urine tested for protein and creatinine often will show
a protein/creatinine ratio of 1 or greater and ratios of 10 or greater
are not uncommon in NS.
2 History and physical examination provide important clues
about the etiology of NS. Traditionally NS has been classified into
primary or idiopathic and secondary types. Since the etiology in the
primary type is not known, it is further classified based on histo-
pathology into MCD, FSGS, MPGN, MGN and various proliferative
glomerulonephritides including IgA nephropathy and RPGN.
Secondary NS may result from infections (group A streptococci,
hepatitis B and C, HIV, infected ventriculoatrial shunts, syphilis,
malaria, etc.), vasculitis (SLE, HSP, Wegeners GN and polyarteritis),
systemic disorders (diabetes mellitus, amyloidosis), certain medi-
cations (captopril, penicillamine, NSAIDs), and occasionally a
neoplasm (Hodgkin lymphoma). Although MCD accounts for nearly
75% of all cases of NS in children, symptoms and signs associated
with conditions producing secondary NS should be elicited during
history and examination. For example, antecedent of sore throat or
impetigo with group A streptococci would suggest PSGN, and
arthritis and facial rash would suggest SLE and a family history of
Alport syndrome would suggest that as the diagnosis. Presence/
absence of hypertension provides an important clue. Blood pressure
is normal in MCD but may be elevated in other entities.
3 In the initial laboratory work-up, urine is tested for routine
protein/creatinine ratio and serum for electrolytes, creatinine, BUN,
total proteins, albumin, cholesterol, C3 and C4, ANA, ASLO and
serology for hepatitis B, hepatitis C and HIV. In addition, a renal
sonogram must be performed in every child with NS. These tests
establish the diagnosis, determine if renal failure (elevated serum
creatinine) is present and provide useful information about the
etiology of NS.
4 Gross hematuria can occur with any of the glomerular
diseases producing NS but is not seen in MCD. The gross hematuria
when seen is painless and brown tea colored. Microhematuria
detected as occult blood on dipstick test or greater than 5 RBC/HPF
on microscopic examination of urine sediment is almost always
present at some time during the course of a glomerulonephritis and
13
may be present at onset in 1520% of patients with MCD. Persistent
microhematuria, however, is not usually seen in MCD.
5 Prednisone is given daily in a single morning dose or 34
divided doses at 2 mg/kg at a maximum dose of 60 mg/day. Various
schedules for the continuation of prednisone after the urine
Glomerular and vascular disease
becomes negative for protein have been used but the superiority of
any one schedule is not established though recent data suggest that
longer treatment (6 months) may reduce the frequency of subse-
quent relapses. In general, the same dose is continued for 24 weeks
and then tapered to zero over several weeks.
6 About 15% of patients with MCD achieve a permanent
remission but the remainder relapse. The relapses usually occur with
common upper respiratory infections and may continue for years.
Relapses are treated with prednisone as above but once urine
becomes negative for protein, prednisone is given as a single dose
every other morning and continued for 12 months and then tapered
gradually to zero over the subsequent 12 months. Once again,
several schedules for the administration of prednisone exist but the
superiority of any one schedule is not established.
7 Patients who relapse frequently, i.e. 34 times/year, or who
become steroid-dependent, i.e. require a certain dose of prednisone
at all times to stay in remission, are prone to develop side effects of
prednisone (hypertension, cushigoid habitus, reduced bone mass,
stunting of height, mood changes, gastrointestinal bleeding, etc.).
These patients will generally achieve remission with the addition of
cyclophosphamide (2.5 mg/kg) or chorambucil (0.15 mg/kg) given
concurrently with the tapering down of prednisone. Blood counts
are monitored weekly and the drug discontinued if the WBC count
drops to ^3,500/l. Patients receiving cyclophosphamide can
develop alopecia and or hemorrhagic cystitis and should be encour-
aged to drink plenty of fluids. Although these two drugs appear safe
at the above-recommended doses, the long-term safety for gonadal
toxicity and possible future malignancy is not established and,
therefore, these drugs should only be used with the full consent of
the patient. In children in whom cytotoxic drugs are to be avoided
(puberty) or in those who continue to relapse, cyclosporine should
be used. See previous section for details.
8 Patients who continue to have proteinuria after a course of
48 weeks of daily prednisone are considered steroid resistant.
Some of these patients show a partial response in that the quantita-
tive proteinuria decreases and some improvement may also be
noted in serum albumin concentration and edema. Steroid-resistant
NS showing MCD or FSGS on renal biopsies may also be treated
with cyclophosphamide or chlorambucil, and some patients may
respond by going into a complete (urine negative for protein) or an
incomplete (urine positive for protein but reduction of proteinuria
and improvement or resolution of edema) remission. Cyclosporine
or tacrolimus may also achieve similar results in some patients;
however, the exact dosages and duration of treatment are not yet
established. Doses of 150200 mg/m2/day or 46 mg/kg/day of
cyclosporine have been used successfully. Both cyclosporine and
tacrolimus are nephrotoxic. In general, patients who show a partial
response to the initial course of steroids are more likely to benefit
further with any of the above than those who showed no response at
all to steroids.
S.P. Makker F. Santos Nephrotic syndrome in the child and adolescent
9 All other glomerulonephrides producing NS are generally
first treated with prednisone which is usually started at 2 mg/kg/day
(maximum 60 mg) dose. Usually after 46 weeks, the dose is
switched to every other morning dose to reduce the side effects of
prednisone. The durations of daily and alternate day prednisone
administration are quite variable and not established. Various immu-
nosuppressive agents some old (azathioprine, cyclophosphamide,
chlorambucil) and some newer (cyclosporine, tacrolimus, mycophe-
nolate motetil, sirolimus) have been and are being used in conjunc-
tion with prednisone, but there is little control data in children for
specific recommendations.
10 ACE inhibitors and angiotensin II receptor antagonists can
be used in all NS associated with chronic glomerular diseases except
steroid-responsive MCD and/or PSGN for their renoprotective
effects. Also, lipid-lowering drugs (statins) may be used in such
patients with chronic hyperlipidemia for their lipid lowering and
renoprotective effects.
11 NS associated with PSGN resolves on its own, and support-
ive therapy is sufficient. Generally, progressive improvement over
days is seen in NS, hypertension and renal failure.
12 Patients with NS secondary to IgA nephropathy are occa-
sionally treated additionally with fish oil (Max FPA) 24 g three times
a day.
13 Hepatitis-associated NS, particularly with MPGN or MGN
histology, may resolve spontaneously. Patients in whom the renal
disease does not resolve may be treated with interferon- or anti-
viral agents (lamivudine). HIV is treated with standard antiviral and
protease inhibitors.
Selected reading
Eddy AA, Symons JM: Nephrotic syndrome in childhood.
Lancet 2003;23:629639.
Filler G, Young E, Geier P, Carpenter B, Drukker A, Feber J:
Is there really an increase in non-minimal change nephrotic
syndrome in children? Am J Kidney Dis 2003;42:11071113.
Gipson DS, Gibson K, Gipson PE, Watkins S, Moxey-Mims M:
Therapeutic approach to FSGS in children. Pediatr Nephrol
2007;22:2836.
Grimbert P, Audard V, Remy P, Lang P, Sahali D: Recent
approaches to the pathogenesis of minimal-change nephrotic
syndrome. Nephrol Dial Transplant 2003;18:245248.
Niaudet P: Steroid-resistant nephrotic syndrome in children; in
Avner ED, Harmon WE, Niaudet P (eds): Pediatric Nephrology, ed 5.
Philadelphia, Lippincott-Williams & Wilkins, 2004, pp 557574.
198.143.33.65 - 8/6/2015 3:20:41 PM
Niaudet P: Steroid-sensitive nephrotic syndrome in children; in
Avner ED, Harmon WE, Niaudet P (eds): Pediatric Nephrology, ed 5.
Univ. of California San Diego
Philadelphia, Lippincott-Williams & Wilkins, 2004, pp 543556.
Ray PE, Xu L, Rakusan T, Liu XH: A 20-year history of childhood
HIV-associated nephropathy. Pediatr Nephrol 2004;19:10751092.
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 Glomerular and vascular disease S.P. Makker F. Santos Rapidly progressive glomerulonephritis

/0
Rapidly progressive glomerulonephritis
14 Renal biopsy

Immunofluorescence microscopy 1

Linear staining for IgG along the GBM 2 No staining or minimal staining 3 Granular staining along capillary loops
Negative staining for albumin and/or mesangium 4

ANA (), C3, C4Nm

Immune deposit-mediated GN
Serum for anti-GBM Ab, lung hemorrhage

Pauci-immune GN
Group A B-streptococci, ANA, C3, C4, ANCA
Anti-GBM disease
ANCA

Throat/skin culture (+) ANA (+), C3, C4 ANA (), C3m ANA ()
Lung hemorrhage (+) Lung hemorrhage () for group A B-streptococci mor N C4mor N C3, C4N
Anti-GBM Ab () Anti-GBM Ab ANCA (+) ANCA () ASLOM, anti-DNAaseBM ANCA () ANCA ()

Goodpasture syndrome Necrotizing glomerulonephritis Renal biopsy Renal biopsy Renal biopsy Renal biopsy
Wegener's granulomatosis consistent with consistent with consistent with consistent with
Churg-Strauss syndrome PSGN SLE MPGN IgAGN, HSP,
Miscoscopic polyangiitis Chronic GN

Steroids 5 Steroids 5 Supportive treatment 5 Steroids 5

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Immunosuppressive agents Immunosuppressive agents Immunosuppressive agents
Plasmapheresis plasmapheresis

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 1 RPGN is a term used to describe proliferative
glomerulonephritides with rapidly deteriorating renal
function and renal biopsy findings showing diffuse
epithelial crescents in greater than 60% of the glom-
eruli. Because of the presence of crescents, this entity
is also called crescentic glomerulonephritis. Of note,
several renal disorders can lead to a clinical picture
similar to RPGN but without the typical histologic find-
ings. These disorders include conditions such as tubu-
lointerstitial nephritis and acute tubular necrosis.
2 History and physical examination can pro-
vide valuable clues towards the type of RPGN. By defi-
nition these patients have hematuria, proteinuria,
abnormal cellular casts in urine sediment, and renal
failure (elevated serum creatinine). Frequently, they
also have gross hematuria (brown tea color urine)
and/or hypertension and/or NS. These clinical and
laboratory features by themselves are not very helpful
in uncovering the underlying etiology of RPGN.
Previous throat or skin infection (impetigo) with group
A -streptococci, typical rash of HSP, clinical features
of SLE (joint pain, skin rash, fever, etc.), hemoptysis
(Goodpasture syndrome), and chronic sinusitis
(Wegeners) are helpful leading clues.
3 A renal biopsy is performed and the tissue is
processed for histology using HE, PAS, and Jones
stains for light microscopy, and for immunofluores-
cence and transmission electron microscopy. For
immunofluoresence, frozen sections are stained with
fluorescein-labeled antibodies to human immuno-
globulins (IgG, IgM, IgA), complement components
(C3, C4 C1q), fibrinogen and albumin. All these studies
are necessary for making an accurate diagnosis.
Additional laboratory tests including serum ANA,
ANCA, AGBMAb, C3 and C4 complement, and tests
for group A -streptococcal infection provide useful
leads into the etiology of RPGN.
4 Anti-GBM disease is a rare disorder, espe-
cially in children. It is caused by circulating antibodies
(mainly IgG) against GBM in the lungs and kidney
glomeruli. Clinical features include RPGN with or
without pulmonary hemorrhage (called in the past
Goodpasture syndrome and Goodpasture disease,
15 respectively). Typical laboratory findings include
reduced renal function, anemia and serum anti-GBM
antibodies. Renal biopsy reveals crescentic GN with
linear staining for IgG along the GBM. For treatment
Glomerular and vascular disease
modalities, see section (6). The prognosis, which was are continued until these antibodies disappear from
devastating before the plasmapheresis era, has the serum. In most cases of pauci-immune RPGN,
improved dramatically but still the rates of chronic plasmapheresis is added to the treatment regimen.
renal sequelae, ESRD and mortality are high. The value of plasmapheresis in immune-mediated
RPGN is not certain, but it is often used as a last effort
5 A subset of children and adults with RPGN in refractory cases.
will not show either immune deposits or anti-GBM
antibodies on renal biopsy. This entity, termed pauci-
immune GN, will be accompanied in approximately Selected reading
8090% of the cases by a positive test for ANCA in
their sera. ANCA(+) RPGN may be associated with Dillon MJ: Crescentic glomerulonephritis; in
small vessel vasculitidies (Wegeners granulomatosis, Avner ED, Harmon WE, Niaudet P (eds): Pediatric
Churg-Strauss syndrome and microscopic polyangi- Nephrology, ed 5. Philadelphia, Lippincott Williams
itis) or may be idiopathic with neocrotizing glomerulo- & Wilkins, 2004, pp 655662.
nephritis on biopsy. Fischer EG, Lager DJ: Anti-glomerular basement
The antigen specificity of ANCA may be for proteinase membrane glomerulonephritis: a morphologic
3 or myeloperoxidase. The former produces C-ANCA study of 80 cases. Am J Clin Pathol 2006;125:
and the latter P-ANCA staining. 8090% of ANCA 445450.
found in Wegeners granulomatosis are C-ANCA. Jennette JC, Thomas DB: Crescentic glomerulo-
P-ANCA are more often seen in necrotizing glomerulo- nephritis. Nephrol Dial Transplant 2001;16
nephritis and polyangiitis. For treatment modalities, (suppl 6):8082.
see section (5). Kallenberg CG: Antineutrophil cytoplasmic auto-
antibody-associated small-vessel vasculitis.
Curr Opin Rheumatol 2007;19:1724.
6 RPGN resulting from PSGN, despite its
Morgan MD, Harper L, Williams J, Savage C:
severity, resolves spontaneously and does not require Anti-neutrophil cytoplasm-associated glomerulo-
immunosuppressive agents or plasmapheresis. nephritis. J Am Soc Nephrol 2006;17:12241234.
Patients with PSGN, however, may require dialysis
for a few days. For details on other immune-mediated
diseases leading to RPGN (SLE, MPGN, IgAN,
HSP, etc.), see the appropriate algorithms.
7 Immunosuppression is generally started
with a high dose of intravenous methyl prednisolone
(pulse therapy). Common dosages are 1530 mg/kg
(maximum 1,000 mg) given once a day as an infusion
in 50100 ml of 5% dextrose over 12 h. Usually, 3 dos-
es are given but 56 doses have also been given safely.
This is followed by 2 mg/kg/day oral prednisone given
in 34 divided doses. Cyclophosphamide may be
added as an adjunct to therapy and can be given orally
at a dosage of 2 mg/kg/day or intravenously at a dose
of 500 mg/m2 according to the schedule used by the
NIH to treat diffuse proliferative glomerulonephritis of
SLE. The duration of prednisone and cyclophospha-
mide therapy is variable and is often individualized
depending on the initial response. Plasmapheresis is
generally added to the regimen of the above immuno-
suppression in RPGN resulting from anti-GBM disease
particularly if autoantibodies to the GBM are present
in serum. In general, the plasmapheresis treatments
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S.P. Makker F. Santos Rapidly progressive glomerulonephritis
 Glomerular and vascular disease S.P. Makker F. Santos Chronic nephritic syndrome

/
Chronic nephritic syndrome
16 History and examination 0

Laboratory tests 1

Urinalysis, urinalysis on family members, C3, C4,

ANA, ANCA, HepCAb, HepBsAg, HIV, renal US

Hematuria/proteinuria ANA (+) ANA () ANA () ANA ()

in family members C3, C4m C3, C4 N C3mN, C4m ANCA ()
ANCA () ANCA () C3, C4 Nm
Hep B and C ()

ds DNA Ab (+)

Alport syndrome SLE IgAGN MPGN Hep BsAg (+) Hep C ab (+) HIV (+)
Thin basement membrane disease HSP
Nail-patella syndrome MGN
Chronic GN

Hearing test Renal biopsy Renal biopsy Renal biopsy (types I, II, III) Renal biopsy
Ophthalmologic exam (WHO classification)
Bone film (in nail-patella syndrome)

Renal biopsy

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 1 Chronic nephritic syndrome is defined as a 3 Initial laboratory tests to be obtained in all
Selected reading
clinical condition resulting from a chronic GN that con- patients with chronic GN are urinalysis including urine
sists of persistent hematuria, proteinuria and abnor- sediment examination, spot urine for protein/creati- Balow JE: Clinical presentation and monitoring of
mal cellular casts in urine sediment with or without nine ratio, serum electrolytes, BUN, creatinine, total lupus nephritis. Lupus 2005;14:2530.
accompanying hypertension and/or renal failure. He- protein, albumin, serum complement C3, C4, ANA, Barratt J, Feehally J: Treatment of IgA nephropathy.
maturia without proteinuria may be present in some ANCA and serologic tests for hepatitis B, hepatitis C Kidney Int 2006;69:19341938.
patients and occasionally (particularly in IgA nephrop- and HIV. Hematuria, proteinuria and RBC casts in the Bongers EM, Gubler MC, Knoers NV: Nail-patella
athy) the hematuria may be intermittent. Renal failure urine sediment essentially clinch the diagnosis of glo- syndrome: overview on clinical and molecular
may include the presence of edema and chronic ne- merulonephritis. If hereditary disorder is suspected findings. Pediatr Nephrol 2002;17:703712.
phritic syndrome may coexist with NS. (positive family history, hearing impairment, skeletal Kashtan CE: Familial hematurias: what we know and
pathology, etc.) and/or other etiologies are not appar- what we dont. Pediatr Nephrol 2005;20:10271035.
2 All entities other than MCD and FSGS listed ent, urines on all immediate family members should
in the algorithm for NS and those listed in the algo- be tested and hearing test, ophthalmologic examina-
rithm for RPGN can produce chronic nephritic syn- tion and bone film should be performed.
drome. Other conditions to be considered in the differ-
ential diagnosis of chronic GN include: Alport syn-
drome, thin basement membrane disease, nail-patella 4 For details on therapy, see Nephrotic syn-
syndrome, subacute bacterial endocarditis, hemolytic drome, Rapidly progressive glomerulonephritis, and
uremic syndrome, chronic renal transplant rejection, Acute nephritic syndrome.
other collagen vascular diseases besides SLE, and oth-
er infections such as filaria, leprosy and schistosomia-
sis. Symptoms and signs associated with the above
conditions and those mentioned in the NS algorithm
should be elicited during history and physical exami-
nation and would be helpful in guiding towards the
etiology. Painless gross hematuria (brown, tea color) is
common in chronic nephritic syndrome and is fre-
quently precipitated by upper respiratory infections
including a sore throat with group A streptococci.
A helpful feature differentiating chronic nephritic syn-
drome from acute PSGN is the fact that in chronic
nephritic syndrome the gross hematuria occurs in the
classic case at the time of sore throat but in PSGN it
occurs after a lag period of 12 weeks.

17

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Glomerular and vascular disease S.P. Makker F. Santos Chronic nephritic syndrome
 Glomerular and vascular disease W. Proesmans U.S. Alon Vasculitis

/
Vasculitis
Exclude systemic lupus erythematosus 0

18 Modified Chapel Hill Classification 1

Large vessel vasculitis Medium vessel vasculitis Small vessel vasculitis Other vasculitides ;

Angiography Cardiac US, angiography, skin biopsy Complement, ANCA, renal biopsy incl. IF

Stenoses of aorta Coronary artery Hepatic, renal Skin nodules Granulomatous Nongranulomatous
and branches aneurysm artery aneurysms

cANCA (+) asthma ANCA () pANCA (+) ANCA ()

Pauci-immune ANCA (+) IgA (+) Compl low
deposits Eosinophilia Compl nl

Takayasu arteritis 2 Kawasaki syndrome 3 PAN 4 CPA 5 Wegeners Churg-Strauss HSP 8 MPA 9 HUV :
granulomatosis 6 syndrome 7

Steroids Aspirin Steroids Steroids Steroids Steroids Steroids? Steroids Steroids

Methotrexate IVIG CYP NSAID CYP CYP CYP? CYP CYP
Stenting iloprost AZA AZA IVIG
TAP methotrexate MMF
Surgery

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 1 Systemic vasculitides are a heterogeneous group of disor-
ders that are relatively rare in childhood. They are characterized by
inflammation, necrosis and thrombosis of blood vessel walls with
deposition of fibrin and platelets. Microvasculitis is often the domi-
nant feature which affects the skin, the articulations, the kidneys, the
lungs and the gut.
2 SLE is not a vasculitis strictly speaking but an autoimmune
systemic disorder that mimics any rheumatic disease and has simi-
larities with many forms of vasculitis. SLE is a chronic, remitting and
relapsing inflammatory, febrile, multisystem disorder. It involves
skin, joints, kidneys and serosal membranes. Characteristic hemato-
logical anomalies are leukopenia, thrombocytopenia, hemolytic ane-
mia and increased ESR. Except for a few patients with drug-induced
SLE, the etiology is unknown. The pathophysiology is thought to
be a failure of the regulatory mechanisms of the autoimmune sys-
tem that sustain self-tolerance. There are a series of autoantibodies
present especially antibodies against double-stranded DNA which
are pathognomonic. Furthermore, serum total complement and C3
levels are decreased and gammaglobulins increased.
3 Classification of the vasculitides is difficult, arbitrary and
not completely satisfactory. The Chapel Hill nomenclature is based
on the size of the vessels involved. From a pediatric perspective, it
has proved unsatisfactory. Therefore, an attempt was recently made
to develop a general classification for vasculitis as seen in children.
A consensus was reached at an international conference held in
Vienna in June 2005. It was decided to modify the Chapel Hill classifi-
cation and this document is based on this modified classification.
4 Takayasu arteritis is characterized by inflammation fol-
lowed by progressive obliteration and stenosis of the aorta and its
branches. Clinical findings depend on the artery involved: lesions of
the carotid arteries leads to ischemia of the brain (syncope, transient
hemiplegia, retinal atrophy), of the subclavian arteries to loss of puls-
es in the arm(s), of the renal arteries to macroscopic hematuria and
flank pain and renal infarction with arterial hypertension and eventu-
ally renal failure, and of the distal aorta to claudication. Angiography
conventional, CT or MRI shows irregular vessel walls and/or nar-
rowing of the aorta and its branches. The etiology is unknown but in
some parts of the world, tuberculosis is believed to play a role.
5 Kawasaki syndrome (mucocutaneous lymph node disease):
this possibly (post)infectious disease is seen mainly in children
below the age of 5 years and is characterized by high fever for at
19
least 5 days, bilateral conjunctival injection, changes of the lips, the
oral or pharyngeal mucosa, cervical adenopathies and a polymor-
phous exanthema followed by desquamation of the fingers and the
toes. The main complication is aneurysms of the coronary arteries.
Glomerular and vascular disease
6 PAN (also known as macroscopic polyangiitis) is a form of
systemic, necrotizing vasculitis involving the medium-sized arteries
with signs and symptoms resulting from infarction and scarring of
the affected organ(s). The following findings are hallmarks of the dis-
ease: skin rash, purpura and nodules (which correspond to affected
peripheral arteries), myalgia, systemic hypertension, neuropathy
and arthralgia. The vasculitis leads to arterial aneurysms or occlu-
sion. Angiography of the abdominal great vessels shows character-
istic aneurysms located at the bifurcation points of the hepatic and
renal arteries. Patchy renal lesions can sometimes be documented
by DMSA scanning. Laboratory investigation shows anemia, signs of
inflammation and circulating immune complexes. The etiology is
unknown; the association with hepatitis B is common mainly in adult
patients.
7 CPA is a more benign form of polyarteritis with limited
involvement of the skin, the joints and the muscles. It is a chronic,
relapsing disorder and there is frequently an association with
streptococcal infections. The skin has red, painful, edematous
nodules at the extremities and the trunk and fever is frequent.
Fingers and toes can display ischemia, the Raynaud phenomenon
and, exceptionally, gangrene. Biopsies show small and medium-
sized vessels with fibrinoid necrosis.
8 Wegeners granulomatosis is a multisystem disease
characterized by necrotizing granulomatous vasculitis involving
the upper and lower respiratory tract, the lungs and the kidneys.
The diagnosis requires three of the following six manifestations:
(1) granulomas on biopsy material, (2) naso-sinus inflammation,
(3) subglottis or tracheal stenosis, (4) abnormal chest X-ray, (5) renal
manifestations such as hematuria, proteinuria and decreased GFR,
and (6) presence of c-ANCA, mainly anti-PR3. Renal biopsy typically
shows crescentic glomerulonephritis with pauci-immune deposits.
9 Churg-Strauss syndrome is a rare form of systemic necro-
tizing vasculitis characterized by asthma, hypereosinophilia and
extravascular granulomas. It affects lungs, skin, peripheral nerves,
gut, heart and kidneys. Laboratory findings consist of leukocytosis
with eosinophilia, elevated ESR and in the majority of patients ANCA
are positive mostly of the anti-MPO type. Renal involvement is not
the rule but not exceptional either and consists of glomerulonephri-
tis with hypertension and renal insufficiency.
10 HSP is the most common vasculitis in childhood. It is a form
of nonthrombocytopenic purpura due to leukoclastic vasculitis of
unknown origin. The hallmarks are diffuse abdominal pain, arthral-
gia and arthritis, palpable purpura concentrated mainly on the
buttocks and the ankles and renal manifestations (hematuria, pro-
teinuria, hypertension, renal failure). Skin and renal biopsies show
IgA deposits. The disease is self-limiting and only a small percent-
age of HSP patients develop serious renal complications.
W. Proesmans U.S. Alon Vasculitis
11 Microscopic polyangiitis is another systemic disease with
many similarities to Wegeners granulomatosis and polyarteritis
nodosa. It differs from Wegeners granulomatosis by the presence of
P-ANCA, mainly anti-MPO and the absence of granuloma formation
of the respiratory tract despite pulmonary hemorrhage. It differs
from PAN by the presence of extensive glomerular involvement.
MPA invariably affects the kidneys. Renal abnormalities vary but
rapidly progressive glomerulonephritis is the most serious complica-
tion.
12 HUV vasculitis is a rare form of vasculitis that is often mis-
diagnosed as HSP; the more so since skin biopsy shows leukoclastic
vasculitis. The main characteristics are skin manifestations urti-
caria, angioedema associated with arthritis and arthralgia. Serum
total complement as well as C1q, C3 and C4 levels are low due to
complement activation via the classical pathway. In 50% of the
patients there is glomerulonephritis membranoproliferative or
crescentic and obstructive lung disease is equally frequent.
13 In a number of patients, vasculitis cannot be ascribed to
any of the above-mentioned categories. It is the case for, among
others, malignancy-associated vasculitis and drug-related hyper-
sensitivity as well as isolated vasculitis of the central nervous sys-
tem. Finally, there is Behet disease, a special form of vasculitis. It is
a chronic inflammatory disorder involving the small blood vessels
and is of unknown origin. It is characterized by recurrent aphthous
ulceration of the oral and pharyngeal mucous membranes and the
genitalia, skin lesions, uveitis and retinal vasculitis and sometimes
optic atrophy. It frequently also involves the joints, gut and central
nervous system.
Selected reading
Bakkakoglu M: Takayasu arteritis in children: preliminary
experience with cyclophosphamide induction and corticosteroids
followed by methotrexate. J Pediatr 2007;150:7276.
Copo R, Andrulli S, Amore A, Gianoglio B, Conti G, Peruzzi L,
Licatelli F, Cagnoli L: Predictors of outcome in Henoch-Schnlein
nephritis in children and adults. Am J Kidney Dis 2006;47:
9931003.
Dillon MJ, Ozen S: A new international classification of childhood
vasculitis. Pediatr Nephrol 2006;21:12191222.
Hattori M, Kurayama H, Koitabashi Y, Japanese Society for
Pediatric Nephrology: Antineutrophil cytoplasmatic autoantibody-
associated glomerulonephritis in children. J Am Soc Nephrol
2001;12:14931500.
Savage COS, Harper L, Adu D: Primary systemic vasculitis.
Lancet 1997;349:553558.
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 Glomerular and vascular disease W. Proesmans U.S. Alon Hemolytic uremic syndrome

/
Hemolytic uremic syndrome
20
Diarrhea 0 No diarrhea 3

Stx (+) 1 Stx () 2 Stx () 4

S. dysenteriae Yersinia
EHEC Campylobacter
Pneumococci 5 HIV/AIDS 6 Cancer 7 Glomerulonephritis 8 Inf. ()
C. Freundii Salmonella
Cancer ()
GN ()

Classical HUS ? Pneumonia HIVN Drugs Acute

Typical Meningitis TBI Chronic
HUS BMT

Supportive Supportive Antibiotics Specific drugs Supportive Supportive

Exchange transfusion

Complement vWF protease S-homocysteineM Familial Pregnancy Quinine None

dysregulation deficiency U-methylmalonic acidM HUS / TTP Puerperium OKT3
Calcineurin inhibitor

FH/FI/MCP deficient TTP : Genetic cobalamin C Autosomal-recessive, PP-associated Drug-associated Unclassified

HUS 9 defect ; autosomal-dominant HUS = HUS > HUS ?
HUS <

Plasma Plasma Vitamin B12 PE Supportive Stop drug

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 1 The diagnostic term HUS represents a heterogeneous
group of disorders with variable etiology, clinical expression and
severity. Common features are acute, acquired hemolytic anemia,
thrombocytopenia and renal dysfunction. Renal manifestations
can range from a mild disease consisting of only minimal urinary
findings (hematuria and proteinuria) to acute renal failure with oligo-
anuria and arterial hypertension necessitating dialysis. The histo-
logical substrate is referred to as thrombotic microangiopathy. HUS
is among the most frequent causes of acute renal failure in child-
hood. The outcome depends on the severity and the causative agent.
2 Diarrhea-associated HUS (D(+)HUS). In the great majority of
children with HUS, there is prodromal diarrhea with the characteris-
tics of colitis, i.e. mucous diarrhea often with blood in the stool. This
postcolitis HUS is called classical or typical or D(+)HUS. 9 Cancer-associated HUS is rare especially in children. There
3 Classical HUS is caused by Shigella dysenteriae in develop-
ing countries and by members of the enterohemorrhagic Escherichia
coli family and Citrobacter freundii in industrialized parts of the world.
The most frequent Stx-producing serotype is E. coli O157H7; other
strains are O26, O111 and O103. Two shigatoxins have been well
defined in terms of structure and biological activity: Stx1 and Stx2.
HUS is mostly caused by Stx2-producing strains. There are several
techniques to diagnose Stx-associated HUS (but none are 100%
percent sensitive and specific): (1) bacterial culture of S. dysenteriae,
Stx-producing E. coli and Citrobacter, (2) isolation of Stx from the
stools, and (3) serum antibodies to specific species known to pro-
duce Stx. It is noteworthy that diarrhea can be absent in patients
with proven Stx-associated HUS. Therapy in all types of D(+)HUS is
supportive.
4 Several case reports mention D(+)HUS with Yersinia entero-
colitica, Campylobacter jejuni or Salmonella and without isolation of
Stx. There is, however, no proof of a causal relationship.
5 HUS not associated with diarrhea (D()HUS). In a minority
of children and a majority of adults with HUS, there is no prodromal
diarrhea. To distinguish it from classical HUS, the term D()HUS has
been introduced. The term comprises an extremely heterogeneous
group of rare disorders for many of which specific causes have
recently been established.
6 The association of D() and Stx()HUS necessitates
thorough investigation for specific causes of HUS such as pneumo-
cocci-associated, HIV-associated, cancer-associated HUS and
HUS superimposed on several forms of glomerulonephritis.
21
7 Streptococcus pneumoniae-associated HUS can be ob-
served in patients with pneumonia or meningitis. Typical features
are febrile illness, respiratory or neurological signs and symptoms
and a positive Coombs test. The traditional pathophysiological
hypothesis is that neuraminidase secreted by pneumococci exposes
the TFA on erythrocytes, platelets and glomerular structures,
Glomerular and vascular disease
resulting in features common to all forms of HUS. Early recognition
is crucial for prognosis. Antibiotics and exchange transfusion are
indicated but the administration of fresh plasma containing anti-TFA
antibodies is contraindicated. The outcome is worse than in
classical D(+)HUS both in terms of acute mortality and long-term
renal function.
8 HIV positivity and AIDS are risk factors for renal complica-
tions, referred to as HIVN. HUS is part of the spectrum of HIVN. It is
assumed that the virus directly affects the endothelium. In the
largest study published so far, it occurred in one third of HIV-infected
adult patients and was the most frequent cause of rapidly progres-
sive renal failure.
however, needs to be elicited.
are several ways in which cancer can lead to HUS: besides some
drugs (such as mitomycin), total body irradiation and bone marrow
transplantation have been implicated. There is no accepted therapy
and the outcome is poor.
10 Children as well as adults with acute or chronic forms of
GN more specifically acute poststreptococcal GN and membrano-
proliferative GN have been described with hemolysis, thrombo-
cytopenia and accelerated hypertension. This exceptional condition
is known as HUS superimposed on GN.
11 Abnormalities of the complement system have been found
in a relatively large number of patients with D(), familial or recurrent
HUS. Complement dysfunction is mainly genetic in origin. Mutations
in the genes of FH, FI and MCP also known as CD46 have been
documented to be associated with HUS. FH is a potent regulator of
complement activation and FI is its co-factor. MCP, a membrane-
bound regulator is a co-factor for FI and is expressed in glomerular
endothelium. The diagnosis of complement dysregulation requires
special expertise. Low plasma levels of C3, FH and FI are diagnostic
but are present only in a minority of patients. In exceptional patients,
complement dysregulation is acquired due to autoantibodies to FH.
12 TTP which is mainly seen in adults has many similarities
with HUS. Hemolysis and thrombocytopenia are accompanied by
fever and varying neurological manifestations whereas renal
involvement is rather limited. Diffuse platelet-rich microthrombi elic-
ited by large multimeric forms of vWF in the circulation, are present
in small blood vessels of several organs. TTP is a relapsing disorder
caused by a deficiency of vWF-cleaving protease, ADAMTS13. The
inherited forms of TTP are caused by mutations in the ADAMTS13
gene, the acquired nonfamilial TTP is due to autoantibodies inhibit-
ing the protease. In some patients this acquired TTP is associated
with the platelet inhibitors ticlopedine or clopidogrel.
13 A very rare autosomal-recessive and life-threatening
condition with elements of HUS is caused by defects in the intra-
cellular cobalamine metabolism. It has been observed mainly in
W. Proesmans U.S. Alon Hemolytic uremic syndrome
newborns and young infants with systemic manifestations including
central nervous system, cardiac and respiratory signs and symp-
toms. It is characterized biochemically by increased plasma levels of
homocysteine and urinary methylmalonic aciduria. Early recognition
and treatment with vitamin B12 can be life-saving.
14 In some families, no defects in the above-mentioned
genetic defects can be found. In their absence, the diagnosis of either
dominant or recessive forms of HUS can be made. New underlying
genetic defects are likely to be detected in the years to come.
15 Pregnancy and/or puerperium-associated HUS is a quite
common disorder in the literature. It has been speculated that
hormonal disturbances are at its origin. The precise mechanism,
16 Several drugs are suspected to be implicated in the devel-
opment of HUS/TTP. Besides the already mentioned mitomycin and
the platelet inhibitors ticlopedine and clopidrogel, there is evidence
for a role for some immunosuppressive drugs of the calcineurin
inhibitors family used after solid organ transplantation such as ciclo-
sporin A and tacrolimus but OKT3 has also been implicated. Quinine
is another suspected culprit as are several contraceptive hormonal
preparations.
17 In large series of D()HUS patients, no etiology can be
found at present. Therefore, there is a need for a temporary category
of unclassified HUS patients.
Selected reading
Besbas N, Karpman D, Landau D, et al: A classification of hemo-
lytic uremic syndrome and thrombotic thrombocytopenic purpura
and related disorders. Kidney Int 2006;70:423431.
Dragon-Durey MA, Frmaux-Bacchi V, Loirat C, et al: Heterozygous
and homozygous factor H deficiencies associated with hemolytic
uremic syndrome or membranoproliferative glomerulonephritis:
report and genetic analysis of 16 cases. J Am Soc Nephrol
2004;15:787795.
Furlan M, Robles R, Galbusera M, et al: von Willebrand factor
cleaving protease in thrombotic thrombocytopenic purpura
and the hemolytic uremic syndrome. N Engl J Med 1998;339:
15781584.
George JN: Thrombotic thrombocytopenic purpura. N Engl J Med
2006;354:19271935.
Moake JL: Thrombotic microangiopathies. N Engl J Med
2002;347:589600.
Zimmerhackl LB, Besbas N, Jungraithmayer T, et al: Epidemiology,
clinical presentation and pathophysiology of atypical and
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 Urinary tract disease/tubulointerstitial nephropathy R. Adelman S. Hulton Urinary tract infection

Urinary tract infection

22
History, signs, symptoms /

Urinalysis 0

LE, nitrate negative LE, nitrate positive Pyuria Bacteriuria Bacteriuria and pyuria

Send urine culture 1

Culture negative 2 Culture positive

Treatment Evaluation 6

Nonspecific pyuria
False negative
Trauma
Tuberculosis

Asymptomatic Uncomplicated UTI 3 Complicated UTI 4 Adjunctive U/S 7 VCUG 8 Radionuclide IVP :

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 1 The clinical manifestations of UTI vary
according to the age of the child. In infants under 2
years of age, UTI may present with failure to thrive,
feeding problems, screaming, irritability, diarrhea,
vomiting, and fever. In children older than 2 years, UTI
may present with fever, frequency, dysuria, enuresis,
acute urinary retention, and abdominal or flank pain.
Similarly, the physical findings might be none, tender-
ness in the flank, suprapubic or abdominal area, fever,
pallor, enlargement of the bladder or kidneys, a meatal
abnormality, abnormal stream, and hypertension.
Often unrecognized is the association of palpable fecal
masses reflecting constipation, especially in children
with recurrent UTI. Except in the first 6 months of life,
UTIs are much more common in females.
2 A urinalysis that demonstrates pyuria or is
positive for leukocyte esterase or nitrite probably indi-
cates a UTI. However, a positive dipstick with or with-
out microscopic pyuria has a sensitivity of only 80%;
in 20% of UTI, these tests are negative. The presence
of bacteriuria in an unspun urine specimen is associ-
ated with a high likelihood of greater than 105 colony
counts in urine culture.
3 The diagnosis of UTI depends upon docu-
mentation of significant bacteriuria, i.e. greater than
105/ml, usually of a single organism in a midstream
specimen, >103/ml, usually of a single organism in a
catheterized specimen, and any growth in a suprapu-
bic specimen. Escherichia coli is the most common
organism. Urine cultures from urinary bags are fre-
quently contaminated. A negative culture from a bag
sample is reliable as a screening test but false-positive
results have been recorded in up to about 40% of sam-
ples taken from infants. Remember, one may have py-
uria without a UTI and UTI without pyuria. Adoles-
cents with the triad of dysuria, frequency and pyuria
may have colony counts <105.
4 When a urine culture is negative in a patient
with UTI symptoms, it is important to rule out false-
negatives due to dilute urine specimens, prior use
of antibiotic therapy, tuberculosis, or, rarely, acute
obstruction. With dysuria and frequency in the pres-
ence of a negative culture, one must consider chemi-
23 cal or mechanical trauma to the urethra which may
include child abuse.
Urinary tract disease/tubulointerstitial nephropathy
5 An uncomplicated UTI is acute cystitis or
asymptomatic bacteriuria. Acute cystitis may be treat-
ed with amoxicillin and clavulanate, cefixime, sulfon-
amide, TMP/SMX, usually for a duration of 57 days.
Asymptomatic bacteriuria is not treated in the older
child unless the patient has usually developed symp-
tomatic infections in such settings.
6 Complicated infections include neonatal UTI,
pyelonephritis, and urinary tract obstruction. These
patients are usually treated with intravenous antibiot-
ics and, when afebrile and stable, changed to a narrow
spectrum oral antibiotic to which the organism is sen-
sitive. The duration of therapy is usually 10 days. In
stable children acute pyelonephritis may also be treat-
ed successfully with oral antibiotics.
7 Nonpharmacologic therapy may be helpful in
the patient with UTI, including encouragement to take
fluids to assist in bladder emptying. Acidifying agents,
such as cranberry juice, may be helpful. A patient
should be encouraged to empty his bladder complete-
ly, often using double voiding techniques. Constipa-
tion, if present, should be vigorously treated. Both
mechanical and chemical urethral trauma should be
avoided. Children should avoid bubble bath and chem-
ical irritants and should be counseled on avoiding self-
injury. Therapeutic delay increases the incidence of
renal scaring significantly; patients with UTI should be
treated promptly.
8 The evaluation of UTI would include a renal
and bladder ultrasound, cystorethrogram, a radio-
nuclide scan (DMSA), or intravenous pyelogram. The
indications for such studies include pyelonephritis, a
first UTI in a boy, a first UTI in a girl <5 years of age, or
a first UTI in a child with an abnormal voiding pattern,
hypertension, poor growth or a family history of UTI or
structural abnormality of the urinary tract.
9 Renal ultrasound is easy to perform and is
used in detecting obstructions, masses, calculi, and
renal swelling, but has a low sensitivity for scars.
Renal ultrasound is not an adequate method for the
detection of vesicoureteral reflux, even severe reflux.
10 Voiding cystorethrogram is used to evaluate
for vesicoureteral reflux, which, when severe, tends to
be associated with secondary complications such as
scarring and hypertension. Mild-to-moderate vesico-
ureteral reflux tends to resolve over time. Severe reflux
has about a 50% chance of resolving over 510 years.
R. Adelman S. Hulton
11 Radionuclide scan is the most reliable meth-
od for detecting acute pyelonephritis and renal scars.
The detection of renal scars is important because of
the association between unilateral and bilateral renal
scars and the development of hypertension; vesico-
ureteral reflux alone without scars is associated with a
low incidence of hypertension. Studies using DMSA
scanning show little or no risk of renal scars develop-
ing in children age 4 years or older.
12 Intravenous pyelogram is rarely indicated in
the evaluation of UTI unless one is looking for a duplex
kidney or a small ureteral calculus.
Selected reading
Bachur R, Harper MB: Reliability of the urinalysis for
predicting urinary tract infections in young febrile
children. Arch Pediatr Adolesc Med 2001;155:6065.
Chang SL, Shortliffe LD: Pediatric urinary tract
infections. Pediatr Clin North Am 2006;53:379400.
Hansson S, Jodal U: Urinary tract infection; in
Avner ED, Harmon WE, Niaudet P (eds): Pediatric
Nephrology, ed 5. Philadelphia, Lippincott Williams
& Wilkins, 2004, pp 10071026.
Mahant S, Friedman J, MacArthur C: Renal
ultrasound findings and vesicoureteral reflux in
children hospitalised with urinary tract infection.
Arch Dis Child 2002;86:419420.
Smellie JM, Barratt TM, Chantler C, Gordon I,
Prescod NP, Ransley PG, Woolf AS: Medical versus
surgical treatment in children with severe bilateral
vesicoureteric reflux and bilateral nephropathy:
a randomized trial. Lancet 2001;357:13291333.
Verrier Jones K: Time to review the value of imaging
after urinary tract infection in infants. Arch Dis Child
2005;90:663664.
Walsh TJ, Hsieh S, Grady R, Mueller BA: Antenatal
hydronephrosis and the risk of pyelonephritis
hospitalization during the first year of life. Urology
2007;69:970974.
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Urinary tract infection
 Urinary tract disease/tubulointerstitial nephropathy S. Hulton R. Adelman Dilated/obstructed urinary tract

/
Dilated/obstructed urinary tract
24 Abnormal US

Infants 0 Older children 0

VCUG If thick-walled UTI/female

bladder consider
PUV 6

VCUG

VUR VUR Mild dilatation Moderate/severe dilatation

No UTI

Yes No Yes No MAG3/ DTPA renal scan 2

MAG3/DTPA renal scan 2

Obstructed 3
Obstructed 3

No Yes
No Yes

If severe, drainage

Prophylactic Repeat US Consider surgical relief 5 Suprapubic/urethral Prophylactic antibiotics Repeat US If severe, drainage
antibiotics 36 months 4 catheter drainage 36 months 4

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DMSA renal scan 1 Cystourethroscopy and valve DMSA renal scan 1 Consider surgical

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fulguration/ablation relief 5

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 1 Dilatation of the urinary tract is considered
when there is dilatation of the renal pelvis (hydrone-
phrosis) with or without a dilated ureter. The clinical
features of a dilated/obstructed urinary tract depend
upon whether the obstruction is acute or chronic,
partial or complete, and on whether complications
such as infection are present. The two commonest
causes of dilatation of the urinary tract are VUR and
obstruction. VUR presents usually with UTI or it can be
asymptomatic. A history of oligohydramnios (occa-
sionally polyhydramnios) during pregnancy may be
noted. Acute obstruction usually presents with pain,
depending on the site of the obstruction. Hematuria is
present when calculi are found. Hypertension can
occur in patients with acute obstruction. Polyuria due
to the inability to concentrate the urine may result
from acute bilateral partial obstruction.
In chronic obstruction, a full bladder or enlarged kid-
ney may be palpable. The inability to conserve sodium
is a common feature and may lead to salt wasting
and hyponatremia. In the case of severe obstruction,
once satisfactory drainage has been established, it is
imperative to send the urine for culture and to treat
infection aggressively. Monitoring of body weight, se-
rum electrolytes levels, acid base and fluid balance is
required. Hyperkalemic acidosis is commonly noted
and close attention must be paid to postobstructive
diuresis.
2 The management of a child with a dilated uri-
nary tract depends on the age of the child, the degree
of dilatation, the presence or absence of a dilated
ureter and whether there is a history of UTI. Age is an
additional important factor in determining how to
proceed with the evaluation. In infants, females and,
in the case of UTI, a VCUG is usually the first test. In
older children, the degree of hydronephrosis and the
parenchymal appearance dictates if a renal scan is
needed.
3 DMSA radionuclide scan is the most reliable
test for detecting renal scars. The detection of renal
scars is important because of the association between
unilateral and bilateral renal scars and the develop-
ment of hypertension and renal failure later in life. It is
indicated in children with UTI and high-grade VUR and
25
if the renal US shows signs of renal injury (small or
hyperechogenic kidneys).
Urinary tract disease/tubulointerstitial nephropathy
4 A dynamic renal scan using radiotracers such
Selected reading
as MAG3 or DTPA in conjunction with a diuretic agent,
e.g. intravenous furosemide, is the preferred test to Belarmino JM, Kogan BA: Management of neonatal
investigate the dilated urinary tract. Estimation of hydronephrosis. Early Hum Dev 2006;82:914.
drainage of the urinary tract and differential renal Fefer S, Ellsworth P: Prenatal hydronephrosis.
function will indicate the severity of the obstruction. Pediatr Clin North Am 2006;53:429447.
This scan, however, is best performed after the first Greenbaum LA, Mesrobian HG: Vesicoureteral
month of life, when renal function is more mature. reflux. Pediatr Clin North Am 2006;53:413427.
Hubert KC, Palmer JS: Current diagnosis and
5 Causes of obstruction: management of fetal genitourinary abnormalities.
Urol Clin North Am 2007;34:89101.
UPJ/UVJ obstruction Onen A, Jayanthi VR, Koff SA: Long-term follow up
Intrinsic of prenatally detected severe bilateral newborn
External compression hydronephrosis initially managed nonoperatively.
Prolapsing ureterocoele (female) J Urol 2002;168:11181120.
Hydrocolpos (female) Piepsz A, Ham HR: Pediatric applications of renal
Pelvic mass (e.g. Wilms tumor, abscess, nuclear medicine. Semin Nucl Med 2006;36:1635.
ectopic kidney)
UPJ obstruction is seen more commonly than UVJ
obstruction.
Bladder outlet obstruction
Posterior urethral valves (male)
Stone
Rhabdomyosarcoma
Meatal polyp/stenosis
Prolapsed ureterocele
External compression
Pelvic tumor
Spinal tumor
6 If renal function is stable and the child is
asymptomatic, observation of the child is appropriate.
Progression of the hydronephrosis on ultrasound may
indicate a repeat diuretic renogram to demonstrate
increasing obstruction.
7 There is considerable debate about the indi-
cations for and timing of surgery for UPJ obstruction.
Proponents of early surgery claim that pyeloplasty
should be performed before function is allowed to
deteriorate. There is evidence, however, that many
neonates managed conservatively will demonstrate
improvement in function without intervention.
8 Posterior urethral valves are the commonest
cause of lower urinary tract obstruction in male in-
fants. 3040% of children presenting with posterior
urethral valves will also have renal dysplasia. Cystic
dysplastic changes in an individual kidney may be
associated with ipsilateral VUR.
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S. Hulton R. Adelman Dilated/obstructed urinary tract
 Urinary tract disease/tubulointerstitial nephropathy J.-P. Guignard R.N. Fine Fetal hydronephrosis

Fetal hydronephrosis
26 Antenatal US /

US at 37 days

Urinary tract dilatation 0

RPD <10 mm RPD 10 mm

US at 1 month Antibiotic prophylaxis 1

RPD <5 mm RPD 5 mm VCUG at 1 month 2

No reflux

Dynamic renal scan at 6 weeks 4

VUR 3 Obstructive uropathy 5

Notify pediatric urologist and nephrologist

US at 1 year Antibiotic prophylaxis, serial US

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Conservative treatment 5 Surgery

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 1 Most renal abnormalities are detected at
1820 weeks. Persistent postnatal abnormalities are
usually seen when the RPD is >6 mm at 20 weeks;
>8 mm at 2030 weeks and >10 mm at >30 weeks of
gestation. While antenatal resolution of hydronephro-
sis may occur, the patient must still undergo postnatal
investigation as the hydronephrosis can recur. The
overall incidence of prenatal hydronephrosis is 1:100
to 1:500 of maternal-fetal US studies.
2 At birth, hydronephrosis is defined by a
RPD >5 mm. RPD 510 mm: mild hydronephrosis; RPD
1020 mm: moderate hydronephrosis; RPD >20 mm:
severe hydronephrosis. As much as 50% of renal
abnormalities detected in utero disappear after birth.
Obstructive and nonobstructive conditions can dilate
the urinary tract. Obstructive causes include: obstruc-
tion of the UPJ (45%) and of the UVJ (20%), posterior
urethral valves (10%) or ureterocele/ureteral ectopia.
Nonobstructive causes include VUR (15%), transient
hydronephrosis and physiological hydronephrosis.
3 Prophylaxis should be started if significant
hydronephrosis (RPD >10 mm) is seen on renal US.
Drugs commonly used include:
First month of life:
amoxycillin 1030 mg/kg/day (in 2 doses)
16 months:
cotrimoxazole 34 mg/kg/day (in 2 doses)
>6 months:
nitrofurantoin 2 mg/kg/day (in 2 doses) or
cotrimoxazole as above
4 Whether to recommend VCUG in all infants
with persistent postnatal hydronephrosis remains
controversial. We recommend performing a VCUG in
these conditions: RPD above 10 mm, significant ante-
natal hydronephrosis, a thick-walled bladder or ure-
teric dilatation, and in cases of bilateral hydronephro-
sis.
5 VUR is detected postnatally in ~10% of neo-
nates with antenatal hydronephrosis. VUR is most
severe and most frequent in males (34 M:1 F). In
males, renal scarring (dysgenesis) is often present at
birth. In patients with VUR, antibiotic prophylaxis
27 should be continued as well as serial renal sonogram
follow-up. For further details, see appropriate algo-
rithm.
Urinary tract disease/tubulointerstitial nephropathy
6 After ruling out VUR, radiotracers such as
Selected reading
MAG3, DTPA or hippuran can be used to investigate
the dilated urinary tract. Estimation of drainage of the Asku N, Yavascan O, Kangin M, Kara OD, Avdin Y,
urinary tract and differential renal function will indi- Erdogan H,Tuncel TC, Cetinkaya E,Ozbay E,
cate the severity of the obstruction. Re-ascent of the Sandikcioglu TG: Postnatal management of infants
radioactive agent from bladder to kidney may indirect- with antenatally detected hydronephrosis.
ly suggest the presence of VUR. Unilateral renal func- Pediatr Nephrol 2005;20:12531259.
tion <35% of total bilateral function suggests that the De Bruyn R, Gordon I: Postnatal investigation of fetal
kidney may be at risk of obstructive damage. Whether renal disease. Prenat Diagn 2001;21:984991.
such a kidney will benefit from early relief of obstruc- Ismaili K, Avni FE, Wissing KM, Hall M; Brussels
tion is still debated. Dynamic renal scan is best per- Free University Perinatal Nephrology Study Group:
formed after the first month of life, when renal func- Long-term clinical outcome of infants with mild and
tion is more mature. moderate fetal pyelectasis: validation of neonatal
ultrasound as a screening tool to detect significant
7 The obstruction of the urinary tract can be nephrouropathies. J Pediatr 2004;144:759765.
located at the UPJ junction, the UVJ or in the urethra Lee RS, Cendron M, Kinnamon DD, Nguyen HT:
(posterior urethral valves). Antenatal hydronephrosis as a predictor of
UPJ obstruction: Conservative management of UPJ postnatal outcome: a meta-analysis. Pediatrics
anomalies is justified in most infants, provided that 2006;118:586593.
the pelvic dilatation does not increase on repeated US, Martini S, Guignard JP: Diagnostic et prise en
and that on isotopic studies the relative function of the charge des dilatations des voies urinaires dpistes
affected kidney does not deteriorate. The indication in intero. Rev Med Suisse Rom 2002;122:619624.
and the best time for pyeloplasty remains ill-defined. Woodward M, Frank D: Postnatal management of
UVJ obstruction: Megaureters are the results of abnor- antenatal hydronephrosis. BJU Int 2002;89:149156.
mal or dysfunctional UVJ. Spontaneous improvement
of megaureters is common, so that conservative
management is recommended when renal function
and dilatation remains stable. Ureteric reimplantation
may be performed when dilatation increases and
renal function deteriorates.
Posterior urethral valves: The most common cause of
congenital bladder outlet obstruction, occurring only
in males; its incidence is approximately 1:8,000. The
bladder outlet obstruction leads to a trabeculated,
thick-walled bladder, and to damage to the renal
parenchyma. Clinical presentation can range from
severe obstruction in utero leading to fetal demise, to
hydronephrosis with normal kidney function diag-
nosed in late childhood. Transurethral incision of the
valves is the treatment of choice.
Ureterocele: Occurs in 1:5,000 neonates with M:F ratio
of 1:35. Ureteroceles are frequently associated with
duplicated collecting system (8090%), are bilateral in
1020% of patients, and associated with ectopic inser-
tion of the ureter into bladder in up to 75% of cases.
A large ureterocele may result in bilateral ureteral
obstruction. Transurethral endoscopic punction of the
ureterocele is often used as an initial intervention.
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J.-P. Guignard R.N. Fine Fetal hydronephrosis
 Urinary tract disease/tubulointerstitial nephropathy R. Adelman S. Hulton VUR

/
Vesicourethral reflux
28

Evaluation 0 Treatment 2

US, repeat VCUG, or indirect CUG DTPA or MAG3 1

Negative Positive

Age <5 Age >5

Continue prophylaxis Antibiotic prophylaxis 1

Review 0 Consider surgery 3

(reimplantation of ureters or deflux injection) for
Bilateral grade IVV
plus

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Severe, recurrent pyelonephritis or
Severe loin pain

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 1 Approximately 35% of patients with UTI have
VUR. The incidence is lower, however, amongst Afri-
can-Americans. Approximately 30% of patients with
VUR develop renal scars, placing them at greater risk
for developing hypertension and, less commonly,
ESRD. These complications are greater with severe
VUR.
2 VUR tends to clear with time. Most mild VUR
(grades 12) will cease within 5 years of diagnosis.
Even with severe VUR (grades 35), up to 50% will
have cleared completely upon 10 years of follow-up.
3 Repeated VCUG should be done in patients
with VUR every 1824 months. When VUR has disap-
peared or the patient is 5 years or older, prophylaxis
can be stopped. VUR can be assessed by either con-
trast VCUG or a radionuclide VCUG (indirect CUG),
which is less invasive and associated with lower radia-
tion exposure.
4 Children under the age of 5, especially under
age 2, with VUR are at greatest risk for scarring associ-
ated with acute urinary infections. Infections should
be diagnosed and treated promptly; scarring is more
likely with delayed therapy. Most experts recommend
use of prophylactic antibiotics, TMP/SMX (TMP 2 mg/
kg + SMX 10 mg/kg at night) or nitrofurantoin (12 mg/
kg at night) until reflux clears or the patient reaches 5
years of age when new scarring is uncommon.
Selected reading
Canning DA: Deflux for vesicoureteral reflux:
pro the case for endoscopic correction. Urology
2006;68:239241.
Gil Rushton H Jr: Urinary tract infection; in Avner ED,
Harmon WE, Niaudet P (eds): Pediatric Nephrology,
ed 5. Philadelphia, Lippincott Williams & Wilkins,
2004, pp 10271048.
Greenbaum LA, Mesrobian HG: Vesicoureteral
reflux. Pediatr Clin North Am 2006;53:413427.
Lorenzo AJ, Khoury AE: Endoscopic treatment of
reflux: management pros and cons. Curr Opin Urol
2006;16:299304.
Perez-Brayfield M, Kirsch AJ, Hensle TW, Koyle MA,
Furness P, Scherz HC: Endoscopic treatment with
dextranomer/hyaluronic acid for complex cases of
vesicoureteral reflux. J Urol 2004;172:16141616.
Smellie JM, Jodal U, Lax H, Mobius TT, Hirche H,
Olbing H; Writing Committee, International Reflux
Study in Children (European Branch): Outcome at
10 years of severe vesicoureteric reflux managed
medically: Report of the International Reflux Study
in Children. J Pediatr 2001;139:656663.

5 Surgery of VUR, with ureteral reimplantation,

is rarely indicated with mild-to-moderate VUR. Sur-
gery for severe VUR, grade 35, is usually successful
in curing reflux. However, antireflux surgery has not
been shown to be better than conservative medical
management in such outcomes as renal scarring, re-
nal growth, renal function or incidence of secondary
complications such as hypertension and chronic renal
failure. Surgery may be indicated in isolated cases of
recurrent severe pyelonephritis or severe loin pain or
parental concerns about medical management such
as long-term use of antibiotics. An alternative surgical
approach is the STING procedure, injection of deflux
at the vesicoureteral junction.
29

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Urinary tract disease/tubulointerstitial nephropathy R. Adelman S. Hulton VUR
 Urinary tract disease/tubulointerstitial nephropathy S. Hulton R. Adelman Dysfunctional voiding

/
Dysfunctional voiding
30
Detailed voiding history and Physical examination 2 Urine dipstix
Clinical history 0
3-day-frequency voiding diary 1 Serum creatinine
Renal US

Problems in infancy UTI Growth

Age of toilet training Urinary incontinence Blood pressure
Family history Frequency, urgency Abdomen for loaded colon
Psychological stress Dysuria Lower back/spine hair tufts, dimple, lipoma, sinus
Exclude organic factors Infrequent voiding Neurology lower limb reflexes, anal reflex
(e.g. epilepsy, diabetes) Incomplete emptying Genitalia
Voiding maneuver (squat, crossed legs)
Constipation, soiling

Primary nocturnal enuresis*

UTI 3 Continuous Giggle/stress Urge/frequency/incomplete/ Constipation > Lazy bladder

incontinence/drip 4 incontinence 5 delayed bladder emptying

VCUG IVP Pelvic floor exercises U/S (renal/bladder) and Laxatives A -Blocker
urodynamic flow rates 6 No (Prazocin) <

Follow protocol Ectopic ureter

(30% have VUR) Anticholinergic drugs :
Incomplete bladder Overactive bladder 7 Lazy bladder 8 Oxybutynin 0.4 mg/kg/day, b.d. or t.d.s.
emptying

Ongoing biofeedback training ;

Double voiding Bladder training 9
Chemoprophylaxis
TMP or nitrofurantin 12mg/kg
nocte x 36 months Response No response
Review
Review at 8 weeks Video urodynamics

Response
Non-neuropathic Intermittent bladder
neuropathic bladder catheterization

198.143.33.65 - 8/6/2015 3:20:52 PM

(Hinman) =

Univ. of California San Diego

Stop antibiotics Yes
Mitroffanoff last resort

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 1 Enuresis is defined as normal voiding, occurring at an inap-
propriate time, or involuntarily in a socially unacceptable setting.
Enuresis is most commonly nocturnal, although it is not uncommon
for nocturnal enuretics to have episodes of diurnal enuresis.
Diurnal enuresis is usually linked with the term dysfunctional voiding
which can be categorised into neuropathic and non-neuropathic
voiding disorders. Functional neuropathic voiding disorders include
spina bifida, transverse myelitis and spinal cord trauma. This review
focuses on the non-neuropathic voiding dysfunction.
2 The majority of children have acquired an adult voiding pat-
tern by 45 years of age and investigations for dysfunctional voiding
should not be undertaken in children under 5 years.
3 The 3-day frequency voiding diary is particularly helpful to
provide more detailed information about the childs voiding pattern.
The information does not have to cover consecutive days, and week-
ends may give better opportunity for the parent to document the
information. The diary must include the record of bowel action.
4 Inspection of the genitalia in boys should exclude a meatal
stenosis and in girls look for labial adhesions, which can impede
urinary flow. Voiding dysfunction and urinary symptoms have been
described with sexual abuse and attention needs to be directed
towards examination of the genitalia for any scarring, tearing or
signs of trauma. This obviously needs to be performed carefully and
sensitively.
5 Children with dysfunctional voiding are at risk of recurrent
UTIs. Both reflux and UTIs are observed in 3040% of children at the
time of dysfunctional voiding and resolve with the attainment of a
normal voiding pattern. Bladder instability with high intravesical
pressures are observed in children with VUR. High voiding detrusor
pressures have also been observed in infants presenting with symp-
tomatic urinary tract infections who do not have VUR.
6 A history of continuous urinary incontinence, particularly in
a young girl, is suggestive of an ectopic ureter. If intravenous uro-
gram fails to demonstrate this, careful examination of the introitus by
a trained urologist may identify the opening of the ectopic ureter.
7 Giggling and laughter associated with embarrassing wet-
ting episodes is more commonly seen in girls and is usually self-lim-
iting. Anticholinergic agents may be helpful. Postvoid dribbling may
occur in girls (commonly obese) where the urine accumulates in the
lower vagina.
31
8 US is very useful to image the upper urinary tract to demon-
strate abnormalities such as duplex kidney, dilatation of the collecting
system and gross reflux. A thickened bladder wall with trabeculation
may be observed. This will depend on the expertise of the ultraso-
nographer. Postmicturition bladder volumes are considered signifi-
cant when they represent, on repeated occasions, volumes of >20 ml
Urinary tract disease/tubulointerstitial nephropathy
or more than 10% of the normal bladder capacity for age. Noninva-
sive urodynamics, using a graphic recording of urinary flow rate dur-
ing voiding, is becoming a more standard office procedure. Flow pat-
terns and rates need to be consistent to allow for appropriate evalua-
tion and sometimes several recordings are necessary. Invasive proce-
dures should only be done following the results of the noninvasive
tests where there is a suspicion of a neuropathic bladder sphincter
dysfunction and should only be performed in specialist centers.
9 Common between 5 and 7 years of age, present with
hyperactivity or instability of the bladder, with urgency and small
frequent voids. This may follow an initial episode of painful voiding,
e.g. following UTI or urethritis.
10 Characterized by large capacity hypotonic bladder with
infrequent voiding every 812 h and incontinence between voiding.
Sensation of bladder fullness is reduced. Incontinence is due to
overflow and the urinary stream is poor with incomplete voiding.
Such bladder decompensation may occur as a result of previous
posterior urethral valves in infancy and can be associated with
myogenic detrusor failure.
11 Bladder training involves frequent voiding, initially 2 hourly,
later 4 hourly on a regular basis with advice to relax the pelvic floor
when voiding, e.g. by whistling. Low-dose prophylactic antibiotics
are useful in children who have a history of urinary tract infections
without reflux. The antibiotics can be used for a short period of time,
usually not longer than 6 months.
12 Oxybutynin is the most commonly used anti-cholinergic
drug. It is usually initiated at a low dose once or twice daily and is
gradually titrated to a maximum dose over 68 weeks. Side effects
are common and include facial flushing, constipation and dry mouth.
Occasionally headache and palpitations are reported. Approximately
20% of patients have to stop medication because of these side
effects. The management of constipation is essential and needs
particular vigilance in patients on anticholinergic treatment.
13 Biofeedback training is very useful in children over 8 years
of age. This involves psychological support, learning to void using
a flowmeter, ultrasound scanning to check for complete bladder
emptying, the use of alarms to detect wetness and regular charting
of voiding activities. Follow-up by a dedicated incontinence adviser
is essential. Such behavior modification programmes will cure 50%
of children within 6 months and 75% within 1 year. Pharmacological
intervention may speed up this process for some patients but good
voiding behavior is the key to success.
14 Alpha-adrenergic blockade may be useful to improve
bladder emptying in some patients. Prazosin or Doxazosin 0.451 mg
at night may be used. Treatment is generally well tolerated but hypo-
tension may be observed.
S. Hulton R. Adelman Dysfunctional voiding
15 Non-neuropathic bladder (Hinman syndrome) represents
the extreme of the spectrum and will only be diagnosed by exclusion
of all other identifiable treatable conditions. MRI scanning of the lum-
bar spine is necessary to exclude an underlying undiagnosed neuro-
logical disorder. In Hinman syndrome there is no physical neurologi-
cal deficit; however, the bladder behaves in a neuropathic fashion.
This occurs primarily in boys as an acquired voiding disorder charac-
terised by inappropriate voluntary contraction of the striated urinary
sphincter during the process of micturition. This results in functional
urinary obstruction that over time is associated with urinary tract
infection, myogenic bladder failure, hydronephrosis and even renal
insufficiency. Ochoa syndrome has the same clinical features at
Hinman syndrome but is known as urofacial syndrome because of
facial grimace instead of smile and is inherited in an autosomal-dom-
inant pattern. If the patient is not found to have Hinman syndrome
but is still not responding to treatment one must consider other con-
ditions such as congenital bladder neck insufficiency or ectopic ure-
teroceles.
16 The management of constipation is imperative in all
patients. It is due to the inability to relax the pelvic floor musculature.
* Primary nocturnal enuresis is a prevalent disorder with a complex mode of
inheritance. It appears to be associated with a deficiency of inhibitory signal
processing in the brain stem which underlies the deficient pre-path inhibition of
micturition, as well as the inability to inhibit micturition at night. A low nocturnal
arginine vasopressin production may be present, and the role of melatonin in this,
as well as the regulation of sleep/wake cycle, is currently under review. These
children may respond to Desmopressin (DDAVP 2040 g intranasally). This
should not be used for prolonged periods as water intoxication is a serious
adverse side effect. DDAVP should be used along with other treatment modalities,
such as bed wetting alarms, dry bed training and behavioural treatment. It is
important to distinguish nocturnal enuresis from diurnal enuresis or daytime
wetting. It is not uncommon for bed wetters to wet their underclothes during the
day or for day wetters to wet the bed. They should be viewed as two separate
problems. Diurnal enuresis is linked with the term dysfunctional voiding.
Dysfunctional voiders exhibit poor co-ordination between the bladder and
bladder outlet which results in inefficient bladder emptying and is termed
dyssynergia.
Selected reading
Akbal C, Genc Y, Burgu B, Ozden E, Tekgul S: Dysfunctional voiding
and incontinence scoring system: quantitative evaluation of incon-
tinence symptoms in pediatric population. Urol 2005;173:969973.
Austen PF, Ritchey ML: Dysfunctional voiding. Paediatr Rev
2000;21:336340.
Feldman AS, Bauer SB: Diagnosis and management of dysfunc-
tional voiding. Curr Opin Pediatr 2006;18:139147.
Nrgaard JP, van Gool JD, Hjalmas K, Djurhuus JC: Standardiza-
tion and definitions in lower urinary tract dysfunction in children.
Br J Urol 1998;81(suppl 3):116.
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Schulman SL: Voiding dysfunction in children. Urol Clin North Am
2004;31:481490.
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 Urinary tract disease/tubulointerstitial nephropathy J. Smith F.B. Stapleton Loin pain with hematuria

/
Loin pain with hematuria
32 History and physical examination

Urinalysis

Red blood cells White blood cells Red blood cell casts Crystals Blood tests including Renal angiogram
No casts Bacteria Protein electrolytes, calcium, BUN,
Urine culture creatinine, blood gases

Normal Abnormal
Pyelonephritis Glomerulonephritis Consider urolithiasis Renal arteriovenous fistula
Normal Abnormal Nutcracker syndrome
Ultrasound of kidneys and bladder with Doppler 0 Glomerulopathy
(e.g. IgA nephropathy)
Hypercalcemia
(e.g. hyperparathyroidism) Renal biopsy 4
Normal Abnormal Renal tubular acidosis
Urolithiasis
Obstructive uropathy
Polycystic kidney disease Normal Abnormal
Pyelonephritis Intravenous pyelogram 2 Glomerulopathy
Renal vein thrombosis (e.g. IgA nephropathy)
Tumor Thin basement membrane disease
Nutcracker syndrome
Normal Abnormal
Medullary sponge kidney
Tumor
Further urine evaluation 1 Cyst Loin pain hematuria syndrome 5
24-hour collection of calcium, protein, sodium, citrate,
cystine, oxalate, uric acid, creatinine

Cystoscopy 3

Normal Abnormal
Proteinuria
Hypercalciuria Normal Abnormal Psychiatric evaluation 6
Hypocitraturia Bladder lesion
Cystinuria
Hyperoxaluria

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Hyperuricosuria

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 1 Evaluation of loin pain associated with
hematuria (microscopic or gross) is best approached
in a staged manner depending on the duration and
severity of symptoms.
2 Ultrasound of kidneys and Doppler is recom-
mended to exclude possible etiologies of loin pain and
hematuria including urolithiasis, obstructive uropathy,
polycystic kidney disease, pyelonephritis, renal
vein thrombosis, tumor, or evidence of nutcracker
syndrome (left renal vein entrapment).
3 Urinary concentrations of protein, calcium,
uric acid, oxalate and cystine are typically normal in
loin pain hematuria syndrome. Normal urinary values
for school-age children: calcium <4 mg/kg/day or
calcium/creatinine (mg/mg) <0.2; citrate >400 mg/g
creatinine; uric acid <0.56 mg/dl GFR; oxalate <50 mg/
1.73 m2/day; cystine <60 mg/1.73 m2/day.
4 Depending on severity and duration of symp-
toms, further investigations are indicated. An IVP can
identify the uncommon diagnoses, medullary sponge
kidney which can lead to pain, and hematuria due to
the passage of microcalculi.
5 Cystoscopy should be performed to deter-
mine if hematuria is unilateral or bilateral and to
exclude a bladder lesion that could be causing pain
and hematuria.
33
Urinary tract disease/tubulointerstitial nephropathy
6 To exclude significant pathology, such as
Selected reading
IgA nephropathy or thin basement membrane disease,
a renal biopsy is recommended. Descriptions of renal Burke JR, Hardie IR: Loin pain haematuria syndrome.
pathology in loin pain hematuria syndrome (see Pediatr Nephrol 1996;10:216220.
below) vary markedly. Reported abnormalities include Chin JL, Kloth D, Paulter SE, Mulligan M: Renal
mesangial proliferation, interstitial fibrosis, and arte- autotransplantation for the loin pain-hematuria
riolar and arterial hyalinosis. Immunofluorescence syndrome: long-term follow-up of 26 cases. J Urol
may show arteriolar C3 deposits as well as IgM and 1998;160:12321235.
IgA in the mesangium. Hebert LA, Betts JA, Sedmark DD, Cosio FG,
Bay WH, Carlson S: Loin pain-hematuria syndrome
7 The definition of loin pain hematuria syn- associated with thin glomerular basement
drome is based upon hematuria, gross or microscopic, membrane and hemorrhage into renal tubules.
associated with recurrent episodes of loin pain, unilat- Kidney Int 1996;49:168173.
eral or bilateral. Pain may radiate across the abdomen Weisburg LS, Bloom PB, Simmons RL, Viner ED:
or toward the groin. Patients are mainly young women Loin pain haematuria syndrome. Am J Nephrol
and older children. Diagnosis of loin pain hematuria 1993;13:229237.
is a diagnosis of exclusion. Patients must have normal Winearls CG, Bass C: The loin pain hematuria
renal function and a normal genito-urinary system. syndrome. Nephrol Dial Transplant 1994;9:
There must be no evidence of infection, malignancy, 15371539.
calculi or hypercalciuria. Management of loin pain syn-
drome presents a challenge and is best addressed by
a multidisciplinary team. Analgesic therapy is the
mainstay of therapy. Most patients inevitably require
narcotic analgesia for pain relief. A variety of other
interventions have been reported including biofeed-
back, transcutaneous nerve stimulation and regional
nerve blocks. Renal auto-transplantation has been the
most successful surgical intervention.
8 Evaluation should include a detailed psychi-
atric examination including patients perception of
pain, history of physical or sexual abuse, and family
psychiatric history. There is a strong correlation with
somatoform pain disorder. The possibility of factitious
disorder should also be considered.
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J. Smith F.B. Stapleton Loin pain with hematuria
 Urinary tract disease/tubulointerstitial nephropathy R. Adelman S. Hulton Renal trauma

/01
Renal trauma
34

Gross hematuria or microscopic hematuria with No gross hematuria or microscopic hematuria with
RBC >20/HPF RBC <20/HPF

CT scan 2
(usually CT angio)

Renal contusion Diagnosis unclear (ex. neoplasm)

Mild-to-moderate laceration 345 Severe renal bleeding
Pedicle injury
Ureteropelvic avulsion
Large or pulsatile retroperitoneal hematoma
Bladder rupture 6

Observe Surgery Observe

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 1 The kidney is the most commonly injured
abdominal organ as well as the most often injured part
of the genitourinary system.
2 Blunt trauma accounts for 90% of renal
injuries.
3 Physical findings compatible with renal
trauma include an abdominal mass or tenderness,
flank tenderness or ecchymoses, rib fracture,
abdominal distention, hypertension or hypotension.
4 Computerized tomography (usually a CT
angio) is the imaging of choice and indicated for rapid
deceleration injury such as a fall or motor vehicle
accident, a penetrating injury, presence of physical
findings, gross hematuria, or microscopic hematuria
>20 RBCs/HPF.
Selected reading
Buckley JC, McAninch JW: The diagnosis,
management, and outcomes of pediatric renal
injuries. Urol Clin North Am 2006;33:3340.
Christensen R: Invasive radiology for pediatric
trauma. Semin Pediatr Surg 2001;10:711.
Heyns CF: Renal trauma: indications for imaging and
surgical exploration. BJU Int. 2004;93:11651170.
Patel HP, Bissler JJ: Hematuria in children.
Pediatr Clin North Am 2001;48:15191537.
Puig S, Schaefer-Prokop C, Mang T, Prokop M:
Single- and multi-slice spiral computed tomography
of the paediatric kidney. Eur J Radiol 2002;43:
139145.

5 Most renal injuries are contusions which

require no therapy.

6 Most renal lacerations, even those that

are moderate to severe, heal with nonoperative
intervention.

7 Pre-existing renal anomalies occur in

1520% of children presenting with renal trauma and
hematuria.

8 Bladder rupture is diagnosed with a cysto-

urethrogram. It is frequently associated with gross
hematuria, pelvic fracture, but may be seen in
child abuse. Most extraperitoneal rupture responds
to bladder drainage; otherwise, surgery is usually
indicated.

35

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Urinary tract disease/tubulointerstitial nephropathy R. Adelman S. Hulton Renal trauma
 Urinary tract disease/tubulointerstitial nephropathy A.L. Friedman S. Turi Tubulointerstitial nephritis

/
Tubulointerstitial nephritis
36 Renal insufficiency/ failure
Tubular dysfunction

Fever, hematuria (gross/microscopic) Polyuria, polydipsia, metabolic acidosis glycosuria,

proteinuria, pyuria, eosinopholia, eosinophiluria, flank pain, rash, high urine pH, sterile pyuria, non-nephrotic range proteinuria,
arthralgia, polyuria, eye symptoms, history of recent drug intake insidious onset (months to years)

AIN Chronic TIN 6

Urine: microscopy, eosinophils 0 , culture Urine: microscopy, pH, osmolarity, electrolytes,

Serum: CBC + reticulocytes, creatinine, BUN, protein electrophoresis, organic acids
electrolytes, bicarbonate, ASLO, ANA Serum: creatinine, BUN, electrolytes, bicarbonate, CBC, ANA,
Imaging: renal US, ophthalmologic examination ceruloplasmin, WBC cystine
Renal biopsy 1 Imaging: renal US, VCUG, nuclear scan
Renal biopsy 7

Immune-mediated 2 Infectious 3 Idiopathic 4 Anatomic malformation 8 Inflammatory 9 Hereditary/metabolic : Hematologic

Drug-induced Direct infection Reflux nephropathy SLE Cystinosis Sickle cell disease
SLE, other GN Reactive TIN Obstructive nephropathy Vasculitis Wilson
TINU Dysplasia/hypoplasia Other GN Hyperoxaluria

Therapy 5

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 1 The interstitium gives structural support for
the nephrons and the renal vascular bed. The tubulo-
interstitium comprises approximately 80% of the renal
parenchyma. TIN is a distinct entity that should not be
confused with GN.
2 The presence of more than 1% eosinophils of
the total WBC in the urine is considered significant and
it is a sensitive (although not specific) marker of AIN.
3 Findings on renal biopsy typical of AIN
include interstitial edema and cellular infiltrate as well
as tubulitis. Renal biopsy, when indicated, is essential
in distinguishing glomerular from tubulointerstitial
injury.
4 Immune-mediated conditions are the leading
cause of AIN in children. Drugs/toxins associated with
AIN include, for example:
Penicillins (methicillin, ampicillin, penicillin G)
Ciprofloxacin
Sulfonamide
Rifampin
NSAID including aspirin
Phenytoin
Furosemide
Allopurinol
H2 blockers
Combinations of the above-listed drugs appear to lead
to more significant toxicity or greater likelihood of
developing AIN. SLE may lead to AIN with or without
GN. The AIN in SLE patients is due to immune depos-
its found in the tubulointerstitium. In general, any
condition leading to GN can be associated with tubu-
lointerstitial involvement. TINU is a rare disorder of
unknown etiology seen mostly in adolescent females.
Causes of this disorder include infections, drugs
(NSAID) and auto-immune disorders. The renal
disease in TINU usually resolves spontaneously
whereas the uveitis requires aggressive immuno-
suppressive therapy.
37
Urinary tract disease/tubulointerstitial nephropathy
5 A host of infectious agents including bacteria,
Selected reading
viruses, fungi as well as rickettsia can lead to AIN
either due to a direct invasion of the pathogen to the Alon US: Tubulointerstitial nephritis; in Avner ED,
interstitium, or secondary to a reactive immunologic Harmon WE, Niaudet P (eds): Pediatric Nephrology,
process during which no infectious agent is isolated ed 5. Philadelphia, Lippincott Williams & Wilkins,
from the renal parenchyma. 2004, pp 817831.
Clarkson MR, Giblin L, OConnell FP, OKelly P,
6 Idiopathic AIN is a diagnosis of exclusion and Walshe JJ, Conlon P, DAmico G, Ferrario F,
it is rarely seen in children. Rastaldi MP: Tubulointerstitial damage in glomerular
diseases: its role in the progression of renal dam-
7 The data for the use of glucocorticoids in AIN age. Am J Kidney Dis 1995;26:124132.
is primarily anecdotal. Pulse methylprednisolone or Krause I, Cleper R, Eisenstein B, Davidovits M:
brief oral courses of glucocorticoids in patients whose Acute renal failure, associated with non-steroidal
renal function fails to improve within 13 weeks after anti-inflammatory drugs in healthy children.
stopping presumed inciting agent may be of benefit. Pediatr Nephrol 2005;20:12951298.
OMeara Y, Dormon A, Campbell E, Donohoe J:
8 The differential diagnosis of CTIN is broad. Acute interstitial nephritis: clinical features and
AIN from any cause, may lead to CTIN. response to corticosteroid therapy. Nephrol Dial
Transplant. 2004;19:27782783.
9 The main histologic findings of CTIN include: Vohra S, Eddy A, Levin AV, Taylor G, Laxer RM:
interstitial fibrosis, tubular atrophy, mild lymphocyte Tubulointerstitial nephritis and uveitis in children
infiltrate and glomerular drop-out. Potential findings and adolescents: four new cases and a review of
depending on underlying etiology include: tubular the literature. Pediatr Nephrol 1999;13:426432.
pigment, casts, crystals, inclusion, etc.
10 CTIN due to congenital anatomic malforma-
tion is the leading cause of end stage renal disease
in children. These malformations include: obstructive
nephropathy (the most common cause of CTIN in
children), aplastic/hypoplastic/dysplastic kidneys or
reflux nephropathy.
11 All types of GN, if severe and prolonged, may
lead to tubulointerstitial damage and CTIN.
12 Hereditary disorders causing either tubular
and/or interstitial damage may lead to CTIN. Both Wil-
son disease and cystinosis lead to Fanconi syndrome
(see algorithm), and when the metabolic abnormalities
of these disorders are uncontrolled and long-lasting,
they will lead to chronic and irreversible interstitial
damage as well. Primary hyperoxaluria (see algorithm
on Nephrolithiasis) is another genetically transmitted
disease in which excessive production of oxalate leads
to accumulation of calcium oxalate stones in the renal
tubulointerstitium.
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A.L. Friedman S. Turi Tubulointerstitial nephritis
 Structural/congenital abnormalities G. Rizzoni M.A. Linshaw Single kidney (renal agenesis)

/
Single kidney (renal agenesis)
38
Association of nonurological malformations 0

Clinical evaluation 1
US 2
VCUG 3
DMSA renal scan 4

Single kidney compensatory hypertrophy Urinary tract abnormalities 3

Normal urinary tract

Annual follow-up in outpatient clinic 5 Investigations and treatment according to

the specific malformation found

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 1 Absence of a kidney is usually asymptomatic:
this condition is discovered incidentally on prenatal
ultrasound, during evaluation of UTI, during screening
for hip luxation or for associated congenital abnor-
malities, or in adult during work-up for a possible
donation of a kidney.
2 Genital, skeletal, cardiac, gastrointestinal and
chromosomal abnormalities have been found to be
more frequent in children with single kidney than in
the general population. In addition, maternal use of
cocaine and maternal diabetes can lead to renal agen-
esis.
3 Clinical evaluation is aimed to exclude the
presence of hypertension and/or UTI and to ascertain
that the single kidney has normal glomerular filtration
rate, concentrating capacity and microalbuminuria
excretion.
4 Sonogram of the urinary tract should aim to
exclude direct or indirect signs of other urinary tract
malformations, to ascertain that the single kidney is
clearly hypertrophied (calculated with the centiles),
and to check whether the renal parenchyma is nor-
mally and uniformly thick with normal echogenicity.
39
Structural/congenital abnormalities
5 Unilateral renal agenesis may be the end
result of regression of a multicystic dysplastic kidney
during gestation. Associated urological anomalies
have been found in approximately 3545% of these
cases. The majority of these malformations are VUR
(hence, voiding cystourethrography is recommended
in infants with single kidney), but ureteropelvic junc-
tion stenosis and ureterovesical junction obstruction
are also found.
6 DMSA renal scan should be done to check
the function of the kidney and to confirm that there is
no ectopic functioning renal tissue, possibly missed by
US.
7 Renal sonogram should be periodically
performed to follow the hypertrophic growth of the
kidney. If no UTI occurs, no microalbuminuria appears
and BP is normal, it is not necessary to monitor GFR
and concentrating capacity closely. Follow-up exami-
nation should include an annual measurement of BP
and urinalysis. Periodic measurements of urinary
protein excretion and GFR are also indicated because,
in the long term, these patients may have an increased
incidence of proteinuria, hypertension and renal
insufficiency. Although the American Academy of
Pediatrics recommended in the past that children with
a solitary kidney do not participate in contact sports,
recent studies show that there is no increased risk for
a major renal trauma for children engaging in these
activities.
G. Rizzoni M.A. Linshaw
Selected reading
Dursun H, Bayazit AK, Buyukcelik M, Soran M,
Noyan A, Anarat A: Associated anomalies in
children with congenital solitary functioning kidney.
Pediatr Surg Int 2005;21:456459.
Johnson B, Christensen C, Dirusso S, Choudhury M,
Franco I: A need for reevaluation of sports participa-
tion recommendations for children with a solitary
kidney. J Urol 2005;174:686689.
Matsukura H, Toyoshima S, Inaba S, Miyanaki T,
Miyamoto M: Vesicoureteral junction obstruction
associated with unilateral renal agenesis. Urol Int
2003;71:329330.
Parikh CR, McCall D, Engelman C, Schrier RW:
Congenital renal agenesis: case-control analysis of
birth characteristics. Am J Kidney Dis 2002;39:
689694.
Woolf AS, Hillman KA: Unilateral renal agenesis
and the congenital solitary functioning kidney:
developmental, genetic and clinical perspectives.
BJU Int 2007;99:1721.
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Single kidney (renal agenesis)
 Structural/congenital abnormalities G. Rizzoni M.A. Linshaw Renal hypoplasia-dysplasia

/
Renal hypoplasia-dysplasia
40 Assessment of renal function 0
US
VCUG
DMSA renal scan

Multicystic dysplasia 1 Hypoplasia/dysplasia with Hypoplasia-dysplasia without Oligomeganephronia 3

urinary tract malformation 2 urinary tract malformation 2

Appropriate decisions according to

the urinary tract malformations
found in the contralateral kidney

Nephrological follow-up

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 1 True renal hypoplasia is defined as a reduc-
tion in the number of nephrons that have developed
and differentiated normally. Pure hypoplasia is rare.
Approximately 2.5% of the childrens autopsies show
the presence of small kidneys without evident clinical
problems. The majority of hypoplastic kidneys are also
dysplastic because their parenchyma is structurally
disorganized and contains undifferentiated tissue,
with primitive ducts and/or focal areas of cartilaginous
metaplasia of the blastema. Other features like cysts
and primitive tubules and ductules may be present.
For this reason, a reliable diagnosis of renal dysplasia
is dependent on histological examination. From the
practical point of view, renal hypoplasia and dysplasia
always mean a reduction in the number of functioning
nephrons. The entity of this reduction cannot, how-
ever, be precisely assessed by standard examinations
such as US because the renal volume in this case is
not necessarily proportional to the number of func-
tioning nephrons.
2 The kidney and urinary tract contralateral to a
hypoplastic-dysplastic kidney may be abnormal in a
substantial proportion of patients (2075%). For this
reason, US and VCUG should always be performed to
evaluate the degree of compensatory hypertrophy of
the healthy kidney and to ascertain or exclude the
presence of urinary tract malformations. In addition,
DMSA renal scan should be done to assess renal func-
tion. Renal function (glomerular filtration rate, concen-
trating capacity, microalbuminuria and proteinuria)
must be carefully evaluated and checked periodically.
41
Structural/congenital abnormalities
3 A MCDK represents the most common
expression of renal dysplasia: the overall structure of
the kidney is abnormal, no pelvis and no typical lobar
organization is recognized. Microscopically, only
dysplastic tissue is present, without normal nephronic
structures. Only a few primitive glomeruli may be
present. In most cases, the associated ureter is atretic
and renal function is absent. The incidence of MCDK is
about 1 in 4,300 livebirths. The diagnosis of MCDK is
done antenatally by the finding of a unilateral flank
mass in a newborn or, by chance, in coincidence with
an abdominal US.
4 Hypoplasia can be unilateral (1 in 500 adults)
or bilateral. In unilateral hypoplasia, if the controlateral
kidney is normal it must be clearly hypertrophic. In
this case, the renal prognosis is good and only the risk
of hypertension and proteinuria over time should be
kept in mind; if the contralateral kidney is not hypertro-
phic, it probably means that both kidneys are, to a dif-
ferent degree, abnormal. If hypoplasia is bilateral, the
possibility of the development of chronic renal failure
must be kept in mind.
5 Oligomeganephronic renal dysplasia is
characterized by a low number of nephrons (2025%
of normal), very enlarged glomeruli (twice the normal
volume) and hypertrophic tubules as well as by the
absence of urinary tract malformations. At the histo-
logical level, the precocious arrest of the development
of the metanephric renal blastema is the most likely
cause of oligomeganephronia. The majority of report-
ed cases are not associated with a genetic disorder.
G. Rizzoni M.A. Linshaw
Selected reading
Dziarmaga A, Quinlan J, Goodyer P: Renal
hypoplasia: lessons from Pax2. Pediatr Nephrol
2006;21:2631.
Hubert KC, Palmer JS: Current diagnosis and
management of fetal genitourinary abnormalities.
Urol Clin North Am 2007;34:89101.
Kalyoussef E, Hwang J, Prasad V, Barone J:
Segmental multicystic dysplastic kidney in children.
Urology 2006;68:1121.
Palmer LS: Pediatric urologic imaging. Urol Clin
North Am 2006;33:409423.
Salomon R, Tellier AL, Attie-Bitach T, Amiel J,
Vekemans M, Lyonnet S, Dureau P, Niaudet P,
Gubler MC, Broyer M: PAX2 mutations in oligome-
ganephronia. Kidney Int 2001;59:457462.
Selected reading for Nephromegaly,
pages 42 and 43
Ahmed HU, Arya M, Levitt G, Duffy PG, Mushtaq I,
Sebire NJ: Part I. Primary malignant non-Wilms
renal tumours in children. Lancet Oncol 2007;8:
730737.
Becker A, Baum M: Obstructive uropathy. Early Hum
Dev 2006;82:1522.
Chou JY, Matern D, Mansfield BC, Chen YT:
Type I glycogen storage diseases: disorders of the
glucose-6-phosphatase complex. Curr Mol Med
2002;2:121143.
Driscoll K, Isakoff M, Ferrer F: Update on pediatric
genitourinary oncology. Curr Opin Urol 2007;17:
281286.
Karadeniz C, Oguz A, Ataoglu O, Citak C, Buyan N,
Pinarli G, Ozkaya O, Kapucu O: Primary renal lym-
phoma and xanthogranulomatous pyelonephritis
in childhood. J Nephrol 2002;15:597600.
Zugor V, Schott GE, Labanaris AP: Xanthogranulo-
matous pyelonephritis in childhood: a critical
analysis of 10 cases and of the literature. Urology
2007;70:157160.
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Renal hypoplasia-dysplasia
 Structural/congenital abnormalities M.A. Linshaw G. Rizzoni Nephromegaly

/
Nephromegaly
42
Normal/minor anomaly Pathological Pseudoenlargement, transient nephromegaly 1
Physiological response 0

Hypertrophy Tamm-Horsfall protein

Duplex kidney Pararenal mass
Column of Bertin Splenic compression
Fetal lobulation Perirenal urinoma
Perirenal hematoma
Renal angioplasty
After lithotripsy
Pseudotumor-sarcoid

Obstructive 2 Cystic 3 Metabolic 4 Inflammatory, Hematologic 6 Oncologic 7 Miscellaneous

toxic, anoxic 5

With hydronephrosis Diabetes mellitus Sickle cell Beckwith-Weidemann

Ureteropelvic junction obstruction Glycogen storage disease Thalassemia Congenital hemihypertrophy
Ureterovesical junction obstruction type 1 Hemophilia Sjogren
Posterior urethral valves Hereditary tyrosinemia Myelofibrosis Renal amyloidosis
Vesicoureteral reflux Fabrys disease RVT Radiocontrast nephropathy
Prune belly syndrome Acromegaly
Polycystic kidney disease Acute tubulointerstitial nephritis Wilms tumor
Other (stone, tumor, clot)
Autosomal dominant Glomerulonephritis Nephroblastomatosis
Without hydronephrosis
Autosomal recessive Pyelonephritis Mesoblastic nephroma
Myoglobinuria
Glomerulocystic kidney disease Abscess-intra-/perirenal Clear cell sarcoma
Hemoglobinuria
Tuberous sclerosis Renal malakoplakia Neuroblastoma
Acute urate nephropathy
Multicystic dysplastic kidney Nephrotic syndrome Malignant rhabdoid
Acute tubular necrosis Cystic nephroma
Acute lymphoblastic leukemia
Hodgkin/non-Hodgkin lymphoma
Angiomyolipoma

US, MAG-3 diuretic scan, US, CT, syndromic Specific labs Urinalysis, culture, CBC, smear, Radiographic study; Specific syndromes,
VCUG, CT, cystoscopy, IVP findings, tissue CBC, urine eosinophils, Hb electrophoresis, bone marrow or tissue, history, labs
Urine-pigmented casts, urinary protein, bone marrow, tissue for diagnosis

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myoglobin, uric acid crystals renal function, lipids, coagulation, US, CT,
Blood-hemolysis, CPK, reticulocytes biopsy as needed, proteinuria, fibrin products

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BUN, creatinine, uric acid

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 1 Nephromegaly is noted by palpation of an abdominal/flank
mass or by radiographic study. The degree of renomegaly is unrelated
to disease severity, histological pattern or prognosis. History and phys-
ical examination with laboratory and radiological studies may allow
diagnosis without biopsy/surgery.
2 Renomegaly from renal hypertrophy occurs in response to
congenital/acquired solitary kidney or unilateral reduction in renal
function. Hypertrophy starts minutes after loss of a healthy kidney and
takes months to complete. Benign nephromegaly includes duplex kid-
ney seen on abdominal US or CT. Two benign conditions may resemble
a mass. Palpable persistent fetal lobulation in a child is clarified by US.
A prominent Bertin column is differentiated from tumor by US (with
agents to enhance vascularity) or CT.
3 Pseudo-renal enlargement may reflect splenic left renal com-
pression, posterior pararenal mass, perirenal hematoma or urinoma.
Traumatic intra-/extrarenal hematoma and traumatic/obstructive urin-
oma are seen by US or CT. Transient renomegaly may follow angio-
plasty for renal artery stenosis or ESWL and occurs with sarcoid granu-
lomatous infiltration that distorts renal contour and mimics tumor. A
notable cause in neonates/older children, Tamm-Horsfall proteinuria,
may present as renal masses. US shows large, hyperechoic kidneys
resembling ARPKD, RVT, dysplasia or intrarenal obstruction. Oliguria
and ARF may occur, but usually reverse in a few days or weeks.
4 Urinary tract obstruction may present as a flank/abdominal
mass or distended bladder in infancy or may be found at evaluation of
UTI, abdominal/flank pain or hematuria. UPJ obstruction, the most
common cause of hydronephrosis/renomegaly in newborns, can be
seen antenatally by US, can present as an abdominal mass and often
resolves spontaneously in 612 months. Other causes of hydronephro-
sis/renomegaly include UVJ obstruction, VUR and PUV. PUV, mucosal
cusps that appose during voiding, can obstruct urine flow. If mild, they
may present after many years with incontinence, polyuria, nocturia or
UTI. If severe, infants have an enlarged, trabeculated bladder, weak
stream, renal dysplasia, severe hydronephrosis and hydroureter (not
always bilateral) and may have urosepsis. Diagnosis is best made by
VCUG. If hydroureter/nephrosis is unilateral, check for urethral obstruc-
tion as well as high ureteral lesions with IVP or antegrade pyelogram.
In Prune-Belly syndrome (mostly in males), in utero prostatic urethral
obstruction or urethral hypoplasia may be causative in many cases.
Features include oligohydramnios, hydronephrosis, renomegaly, di-
lated prostatic urethra and ureters, VUR, bilateral cryptorchidism, lax/
wrinkled nonresistant abdominal wall (hypoplastic lower abdominal
muscles) and renal dysplasia and is suspected by finding cystomegaly
on US as early as 1214 weeks gestation. Nephrolithiasis is the most
43 common acquired cause of childhood hydronephrosis/renomegaly.
Intrarenal obstruction with no hydronephrosis occurs when pigmented
casts/crystals occlude tubule lumens. With dehydration and acidic
urine, hemoglobinuria/myoglobinuria and hyperuricosuria can cause
ARF and large, echoic kidneys, resembling ARPKD, RVT or dysplasia,
but this usually reverses in days to weeks (prognosis of large echoic
kidneys is not always bad).
Structural/congenital abnormalities
5 ARPKD may present in utero with large, hyperechoic kidneys,
oligohydramnios, no bladder visualization and negative family history.
Most affected children progress to renal failure in childhood, but mild
disease can be undiagnosed for years. Neonatal ADPKD can cause
large, hyperechoic kidneys with/without visible cysts. Cysts may ini-
tially be unilateral. Patients can be asymptomatic early in the disease
with cysts noted on US performed because a parent is affected. Cysts
may present as abdominal pain, mass, hematuria, hypertension or UTI.
Extrarenal problems include mitral valve prolapse, cysts in liver, ovary,
spleen and pancreas, hernias and cerebral aneurysms. MCDK, a severe
renal dysgenesis, is the most common cause of neonatal abdominal
mass. The MCDK has an atretic or non patent ureter and no identifiable
renal sinus or functioning renal parenchyma. Contralateral anomalies,
e.g. VUR, UPJ obstruction, are common. VCUG and nuclear scan can
confirm lack of VUR and function. Tuberous sclerosis (autosomal-domi-
nant neurocutaneous hamartomatosis) affects skin, heart, retina, cen-
tral nervous system and kidney. Renal lesions include angiomyolipo-
mas (~50% of patients) that are often bilateral and best evaluated with
CT, and large cysts (~20% of patients) resembling ADPKD. GCKD in-
cludes entities with glomerular (not tubular) cysts that are typically di-
lated Bowmans capsules with an aborted/primitive glomerulus. Cysts
are cortical, not medullary, in contrast to other cystic diseases. Infants
may have abdominal masses (cystic kidneys by US) and renal insuf-
ficiency. Mild disease can present later in life with hypertension or flank
pain.
6 In diabetes mellitus, renomegaly becomes prominent in pu-
berty, especially with reduced renal function. Glomerular hypertrophy,
proximal tubular hyperplasia and hypertrophy may relate to increased
growth hormone and insulin-like growth factor. Careful glycemic con-
trol reduces renal hyperfiltration and high GFR, but may not reduce
renomegaly. Glycogen storage disease type 1 can present at 34
months of age with hepatomegaly or hypoglycemic seizures when
food intake decreases (acute illness or night feeding is stopped). Renal
problems include renomegaly from accumulated glycogen, hyperfiltra-
tion, proteinuria, FSGS, nephrocalcinosis, stones and Fanconi-like syn-
drome. Hereditary tyrosinemia type 1 causes liver and renal tubular
dysfunction with renomegaly and uniform thickness of renal cortex.
Fabrys disease shows nephromegaly in the 3rd decade from accumu-
lation of glycosphingolipid. Acromegaly causes nephromegaly prob-
ably from increased tubule mass rather than increased glomerular size.
Other causes of renomegaly include Perlman, Sjogren, Beckwith-
Wiedemann syndromes, renal amyloidosis, intravenous hyperalimen-
tation/protein loading (usually bilateral and reversible) and in convales-
cent burn patients, perhaps from higher renal workload (high therapeu-
tic salt/fluid/protein intake and catabolism).
7 Nephromegaly may occur with acute postinfectious or vascu-
litic glomerulonephritis (can be unilateral with flank pain) and with NS
(with no relation to histology or steroid response). Loin pain may relate
to fluid retention and a response to diuretics often relieves pain. Pa-
tients with acute TIN typically have renal tenderness, pyuria, urinary
WBC casts and renomegaly on US. Acute bacterial infections with re-
nomegaly may be intrarenal (pyelonephritis, abscess) or perirenal (ab-
M.A. Linshaw G. Rizzoni Nephromegaly
scess). Nephromegaly is usually not palpable and resolves about 2
weeks after starting therapy. In renal malakoplakia/xanthogranuloma-
tous pyelonephritis, a form of chronic interstitial nephritis, patients
have recurrent UTI, sometimes massive renomegaly and a non-func-
tioning avascular mass. Destroyed renal parenchyma is replaced by
yellowish-brown soft infiltrate of bacteria, inflammatory cells, lipid-lad-
en histiocytes and calculi. The lesion resembles malignancy and histo-
logical diagnosis is needed. ATN, toxic or hypoxic, often causes reno-
megaly. By contrast, hypoxic injury causes acute cortical necrosis and
renal infarction does not. This may relate to ongoing renal arterial flow
during tubular necrosis whereas severe arterial compromise sufficient
to necrose glomeruli is associated with reduced renal blood flow. Cell
swelling and consequent renomegaly are unlikely if blood flow is insuf-
ficient to deliver more fluid into the kidney.
8 Sickle cell disease may induce renomegaly by sickling of red
blood cells, oxidative stress, medullary congestion and vaso-occlusive
disease. A similar process may occur in thalassemia. RVT causes neph-
romegaly and gross hematuria. In older nephrotic children, CT may
show renal vein or inferior vena caval thrombus, pericapsular venous
collaterals or opacification of renal parenchyma. In neonates or older
infants, look for diffusely enlarged, hyperechoic kidneys with ill-de-
fined central-echo complexes and poor venous Doppler flow. Inferior
vena caval or main renal vein thrombus is usually absent.
9 Wilms tumor (nephroblastoma) is the most common tumor
causing renomegaly in children. Work-up includes laboratory data, US,
chest film, skeletal survey, abdominal/chest CT. Radiological study may
miss contralateral renal tumors and renal surgical exploration may be
needed. Nephroblastomatosis (residual metanephrogenic tissue in a
mature kidney) causes renomegaly. This can regress to fibrous tissue,
mature to glomeruli and tubules, or become malignant (e.g. Wilms tu-
mor), but the usual course of nephroblastomatosis is regression before
malignancy. Other renal tumors are usually unilateral and solid. Con-
genital mesoblastic nephroma (leiomyomatous hamartoma) is usually
benign and tends to present in infants <3 months of age. Neuroblas-
toma is usually solid, may have calcifications or cysts and must be dif-
ferentiated from primary renal tumor. Clear-cell sarcoma typically pres-
ents in a 3- to 5-year-old child, tends to metastasize to bone and brain
and has a poor prognosis. Work-up includes brain MRI, bone scan, skel-
etal survey and abdominal/chest CT. Malignant rhabdoid tumor is usu-
ally large, originates in the central hilar area, replaces the whole kidney,
metastasizes to lung, brain, liver and has median presenting age at
around 11 months. Abdominal and chest CT and brain MRI are needed.
Multilocular cystic nephroma usually presents from 3 to 24 months of
age as benign multilocular cyst or as cystic lesion with stroma contain-
ing partially differentiated blastema cells. The latter may have Wilms
tumor nodules and is indistinguishable from cystic Wilms tumor with-
out biopsy. Hematologic malignancies, e.g. acute lymphoblastic leuke-
mia or lymphoma, cause diffuse unilateral or bilateral nephromegaly
from renal infiltration or discrete intrarenal/hilar mass lesions. Rare
causes of renomegaly include renal adenomatosis, histiocytic medul-
198.143.33.65 - 8/6/2015 3:20:59 PM
lary reticulosis, Castleman disease and renal cell carcinoma.
Univ. of California San Diego
Selected reading, see page 41.
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/
Hyperechoic kidney
44

Cortical 0 Medullary 0

Diffuse 1 Focal 4 Nephrocalcinosis 5

Large kidney 2 Small-normal size kidney 3

Cystic kidney diseases Chronic renal failure Pyelonephritis Hypercalciuria Cushing syndrome 6
Interstitial nephritis Nephronophthisis Tumors Hyperoxaluria Corticosteroid therapy
Acute tubular necrosis Dysplasia with hypoplasia Xanthinuria Fat deposition
Acute glomerulonephritis Ischemia Medullary sponge kidney Renal candidiasis
Nephrotic syndrome Cortical necrosis Vascular congestion
Malignancy Chronic glomerulonephritis Urate nephropathy
Infections Tamm-Horsfall protein precipitation
Metabolic storage diseases
Renal vein thrombosis

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Neonatal hyperechoic kidney with normal GFR

Univ. of California San Diego

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 1 Kidneys on US are normally hypoechoic
compared to the liver and spleen. In neonates, the kid-
neys are generally isoechoic to these organs, but not
hyperechoic. The relative increase in echotexture of
the infant kidney cortex has been ascribed to the rela-
tively increased density of glomeruli/cortical area. Glo-
merulogenesis ceases after 3436 weeks of gestation.
Thereafter, although there is increase in glomerular
size, increase in cortical mass is largely a reflection of
tubular growth. Echogenicity decreases as tubular
growth expands, more filtrate fills the larger tubules,
tubules further separate glomeruli, and tissue inter-
faces that reflect sound waves become more spread
apart. Echogenicity gradually decreases until ~6
months of age at which point virtually all normal kid-
neys are hypoechoic to liver and spleen except for the
renal sinus area. Fat is normally echogenic. In contrast
to the adult, the neonatal central renal sinus has little
fat and its area of echogenicity is much smaller. The
medullary pyramids are hypoechoic, prominent in the
newborn kidney and help define corticomedullary
differentiation.
The appearance of pathologic hyperechogenicity on
renal US reflects a temporary or permanent patho-
logic state, but the echoic pattern is not diagnostic of
any specific disease.
2 The hyperechoic kidney requires follow-up of
renal structure and function with therapy directed
toward the specific illness. History and physical exam
usually point to the diagnosis. Hyperechoic kidneys
may be small, normal-sized or large. In addition,
hyperechogenicity may be cortical or medullary and
can be focal or diffuse. Edematous, infectious and
infiltrative states should improve with specific therapy,
but hyperechoic kidneys due to scarring/fibrosis will
not recover.
3 Diffuse cortical hyperechogenicity, in con-
trast to medullary involvement, is rare in infants, but
not uncommon in older children. It can be categorized
by kidney size (large or small-to-normal).
4 Large hyperechoic kidneys in the infant occur
with autosomal recessive or dominant forms of poly-
cystic kidney disease, glomerulocystic disease, and
45
diffuse cystic renal dysplasia. In ARPKD and medullary
cystic kidney disease, the hyperechogenicity may
actually be more prominent in the medulla. Large
hyperechoic kidneys are seen in acute TIN and in acute
tubular necrosis (myoglobinuria, hemoglobinuria).
Other relatively common renal diseases such as acute
Structural/congenital abnormalities
GN and NS (especially in congenital nephrotic syn-
drome) may cause hyperechoic renal enlargement.
Infiltrative diseases such as leukemia, infectious pro-
cess (candida, tuberculosis), glycogen storage disease
type 1 (Von Gierke) and tyrosinemia may lead to large
hyperechogenic kidneys.
RVT causes a large congested, hemorrhagic, edema-
tous, echogenic kidney that may calcify. Edema and
hemorrhage give an early hyperechoic appearance
and cause nephromegaly.
We occasionally see large hyperechoic kidneys in ill
neonates without renal dysfunction that normalize
over several weeks to months by sonography. Thus,
it is appropriate to be patient and avoid immediate
prediction of future renal problems to parents.
5 In general, hyperechoic small kidneys are
scarred and fibrotic. Diseases include chronic glomer-
ulonephritis or pyelonephritis, Alport syndrome, cysti-
nosis, nail-patella syndrome, nephronophthisis, HUS,
renal dysplasia, and ESRD. Clinical history or physical
or laboratory findings help define the diagnosis. Corti-
cal necrosis and malignant hypertension may lead to a
small, hyperechoic kidney. In the infant, small hyper-
echoic kidneys are seen in dysplastic renal disease
associated with hypoplasia and in renal ischemic corti-
cal and medullary necrosis. Cortical echogenicity does
not correlate with the severity or type of glomerular
lesions on biopsy, but does correlate with the severity
of interstitial lesions.
6 Focal areas of cortical hyperechogenicity
may occur with tumors (e.g. angiomyolipoma,
mesoblastic nephroma, rhabdoid tumor of kidney) or
infection (pyelonephritis).
7 Diffusely hyperechogenic renal pyramids
generally indicate medullary nephrocalcinosis. Nor-
mal size and corticomedullary architecture is usually
maintained in these kidneys. Ultrasonography is more
sensitive than plain film radiography for detecting
renal calcifications and nephrocalcinosis. High-resolu-
tion computed tomography without contrast is even
more sensitive than sonography. Karlowicz and Adel-
man provide a convenient way to categorize nephro-
calcinosis in infants, depending on whether the patient
is normo- or hypercalcemic and normo- or hypercal-
ciuric. Hereditary disorders leading to hypercalciuria
with or without hypercalcemia include William, Bartter,
Liddle and Lowe syndromes, primary hyperoxaluria
types 1 and 2, distal renal tubular acidosis with neuro-
sensory deafness and Dents disease. Other causes
M.A. Linshaw G. Rizzoni
are furosemide toxicity, particularly in premature or
newborn infants, distal renal tubular acidosis, vitamin
D and A toxicity and hyperparathyroidism. In medul-
lary sponge kidney, hypercalciuria is not typical, but
does occur. In general, nephrocalcinosis occurs with
hypercalciuria or hypercalcemia in the presence of
factors favoring urinary or tissue Ca precipitation.
Medullary calcification usually starts in the fornices at
the tip of the pyramid and then spreads throughout the
pyramid. Hyperechoic pyramids with calcifications are
brighter than other causes of hyperechogenicity.
8 Medullary hyperechogenicity not related to
nephrocalcinosis is seen with Cushing syndrome and
steroid therapy, from fat deposition, renal candidiasis,
vascular congestion (papillary necrosis, sickle-cell
anemia), medullary infection and fibrosis. Urate
nephropathy causes hyperechoic kidneys with distal
nephron urate deposition, but echogenicity is not
limited to the medulla. A non-nephrocalcinotic cause
of medullary hyperechogenicity is precipitation of
Tamm-Horsfall protein, usually in dehydrated neo-
nates. Acute renal insufficiency may occur, but is
usually quickly reversible (as is the hyperechogenicity)
and not likely to require dialysis or cause renal dam-
age. Echogenic kidneys with urate or Tamm-Horsfall
protein deposition are usually enlarged.
Selected reading
Cheidde L, Ajzen SA, Tamer Langen CH,
Christophalo D, Pfeferman Heilberg I: A critical
appraisal of the radiological evaluation of
nephrocalcinosis. Nephron Clin Pract 2007;106:
c119c124.
Karlowicz MG, Adelman RD: What are the possible
causes of neonatal nephrocalcinosis? Semin
Nephrol 1998;18:364367.
Kasap B, Soylu A, Turkmen M, Kavukcu S:
Relationship of increased renal cortical echogenicity
with clinical and laboratory findings in pediatric
renal disease. J Clin Ultrasound 2006;34:339342.
Makhoul IR, Soudack M, Smolkin T, Sujov P,
Epelman M, Eisenstein I, Magen D, Zelikovic I:
Neonatal transient renal failure with renal medullary
hyperechogenicity: clinical and laboratory features.
Pediatr Nephrol 2005;20:904949.
Marks SD, Massicotte MP, Steele BT, Matsell DG,
Filler G, Shah PS, Perlman M, Rosenblum ND,
198.143.33.65 - 8/6/2015 3:20:59 PM
Shah VS: Neonatal renal venous thrombosis: clinical
outcomes and prevalence of prothrombotic
Univ. of California San Diego
disorders. J Pediatr 2005;146:811816.
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Hyperechoic kidney
 Structural/congenital abnormalities G. Rizzoni M.A. Linshaw Cystic kidneys

/
Cystic kidneys
46

Polycystic kidney disease 0 Glomerulocystic kidney disease 3 Hereditary Medullary cystic disease
malformation syndrome 6

Autosomal-dominant Autosomal-recessive Non syndromal 4 With malformation syndrome 5 Juvenile nephronophthisis Medullary sponge
polycystic kidney disease 1 polycystic kidney disease 2 Medullary cystic disease 7 kidney 8

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Univ. of California San Diego
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 1 Cystic kidneys may be found in numerous clinicopathologi-
cal entities which are very different from each other. Once cystic
kidneys are found, usually by sonography, the following information
and clinical data must be carefully obtained: complete family and
personal history; physical examination and BP measurement; renal
function (glomerular and tubular) evaluation; renal and liver US in
the child and in the parents. The most important renal cystic disor-
ders are PKD, GCKD, cystic kidneys with a hereditary malformation
and medullary cystic disease. It is often difficult to distinguish
between the various cystic disorders, especially if family history is
unremarkable and US is normal in the parents. Multiple large bilat-
eral cysts will orientate toward ADPKD; very enlarged hyperecho-
genic kidneys in an infant with chronic renal failure and/or arterial
hypertension will suggest ARPKD; a significant concentrating defect
with or without chronic renal failure with non enlarged kidneys and
no hypertension may be suggestive of GCKD or of medullary cystic
disease.
2 PKD is an inheritable cystic disorder involving both kidneys
and without dysplasia. Both ADPKD and ARPKD can be found in
infants and children; clinical presentation may often be very similar
and, therefore, it may not be easy to differentiate the two entities
especially if no renal or liver abnormalities are found in the parents
or grandparents. In this case, liver or kidney histology should be
examined. An exact diagnosis is also important for an appropriate
genetic counseling.
3 In ADPKD, cysts arise from all segments of the nephron and
their size is often >2 cm. Renal involvement may be asymmetrical.
The prevalence is very high (1/200 to 1/1,000). Two genes are involved
in ADPKD: PKD1, which encodes for the polycystin-1 protein, is
responsible for approximately 85% of cases. PKD2 encodes for poly-
cystin-2. ADPKD due to mutation in PKD2 show a milder clinical
picture with later onset. Prenatal ultrasound can show, in a minority
of cases, enlarged hyperechogenic kidneys, with or without cysts.
Postnatally, in rare cases, there is severe clinical involvement at birth
or in infancy; most often, ADPKD is suspected when bilateral renal
cysts are found on US in an asymptomatic child. Extrarenal manifes-
tations (liver, pancreas or ovarian cysts, cardiac valvular abnormali-
ties, cerebral aneurysms) are very rare in the pediatric age. If renal
and liver ultrasound in the parents (older than 30) is normal, the pos-
sibility of ADPKD due to a de-novo mutation should be considered
(this is the case in approximately 5% of the patients with ADPKD).
Asymptomatic children should be checked annually (physical exami-
nation, blood pressure measurement, urinalysis) keeping in mind the
possible complications of urinary tract infectious and renal calculi.
47
4 In ARPKD, renal cysts arise only from the collecting ducts; a
varying degree of periportal fibrosis and biliary dysgenesis is always
present. The great majority of cases are diagnosed in the pediatric
age but a very small proportion can also be found in adults. ARPKD
is much rarer than APKD (1:10,000 to 1:40,000). In very severe forms,
Structural/congenital abnormalities
antenatal ultrasound can show enlarged hyperechogenic kidneys
with oligo- or anhydramnios. Cysts are normally very small (<2 mm)
but, with increasing age, may become larger, usually <2 cm. Portal
fibrosis is always present and, with time, may lead to the clinical pic-
ture of portal hypertension. The gene responsible for ARPKD called
PKHD1, identified on chromosome 6 p 21, encodes fibrocystin, a
transmembrane protein. Severe cases (neonatal and infantile form)
map to the same region as milder forms who survive; the major
problems are declining renal function, severe arterial hypertension
and portal hypertension.
5 Bilateral GCKD is a rare disorder characterized by glomeru-
lar cysts, i.e. dilated Bowmans spaces with normal tubules; GCKD is
a heterogeneous group of entities which may be isolated (nonsyn-
dromal) or associated with malformation syndromes. The diagnosis
can only be obtained histologically.
6 Primary, nonsyndromic GCKD can be transmitted as an
autosomal-dominant disease or can be sporadic. There are two
genetically transmitted entities that lead to GCKD: the renal cysts
and diabetes syndrome that is associated with mutations in the
hepatocyte nuclear factor-1b gene, and GCKD with hyperuricemia
and isosthenuria caused by mutations in the gene encoding uro-
modulin also known as Tamm-Horsfall glycoprotein.
7 GCKD can be syndromal and part of syndromes such as
Zellweger, short rib polydactyly, oral-facial-digital type I, trisomy 13,
brachymesomelia.
8 Cystic kidneys may be found frequently in the presence of
tuberous sclerosis, Jeune asphyxiating thoracic dysplasia, von
Hippel-Lindau syndrome and in those syndromes already mentioned
for GCKD.
9 In medullary cystic disease cysts are exclusively situated in
the medulla and, especially, at the corticomedullary junction and
arise from the convoluted distal and collecting tubules. Despite the
name, in many cases cysts may not be found on ultrasound or may
only be detected later in life. The nephronophthisis-medullary cystic
disease (NPH-MCKD) complex is characterized by polyuria, polydip-
sia, anemia, growth retardation, chronic renal failure, corticomedul-
lary cysts as well as interstitial fibrosis with thickening and thinning
of the tubular basement membrane. Juvenile NPH is an autosomal
recessive disease and can occur with ocular, liver, skeletal and cer-
ebellar abnormalities; it is due to mutations in at least three different
loci: NPHP1 in chromosome 2, NPHP2 in chromosome 9 and NPHP3
in chromosome 3 (adolescent NPH). MCKD is inherited as an autoso-
mal-dominant trait, causes chronic renal failure at a later age (3060
years of age) and may be associated with hyperuricemia and gout.
Two separate genes, MCKD1-MCKD2, on chromosome 1 and chro-
mosome 16, respectively, can cause the disease. Renal histology is
indistinguishable from that in NPH. Recently, the gene for FJHN
G. Rizzoni M.A. Linshaw Cystic kidneys
which is an autosomal dominant disorder with chronic interstitial
nephritis, medullary cysts, marked thickening of tubular basement
membrane, was mapped. This gene encodes to the uromodulin pro-
tein. Mutations in this gene lead to FJHN as well as to MCKD2 and to
GCKD with hyperuricemia and isosthenuria. In fact, it is now sug-
gested that FJHN and MCKD type 2 are facets of the same disease.
10 MSK consists of the dilatation of collecting ducts (sponge-
like appearance). Most cases are sporadic and the prevalence in the
general population, although unknown, is estimated to be from
1:5,000 to 1:20,000. MSK is often an asymptomatic and benign condi-
tion, but hematuria, urinary tract infection and nephrolithiasis may
be present. Concentrating and acidification defects and hypercalci-
uria may be present. MSK can be diagnosed by intravenous pyelog-
raphy which shows dilated collecting tubules (brush-like pattern).
Selected reading
Gambaro G, Feltrin GP, Lupo A, Bonfante L, DAngelo A,
Antonello A: Medullary sponge kidney (Lenarduzzi-Cacchi-Ricci
disease): a Padua Medical School discovery in the 1930s.
Kidney Int 2006;69:663670.
Lens XM, Banet JF, Outeda P, Barrio-Luca V: Novel pattern of
mutation in uromodulin disorders: autosomal dominant medullary
cystic kidney disease type 2, familial juvenile hyperuricemic
nephropathy, and autosomal dominant glomerulocystic kidney
disease. Am J Kidney Dis 2005;46:5257.
Rossetti S, Harris PC: Genotype-phenotype correlations in
autosomal dominant and autosomal recessive polycystic kidney
disease. J Am Soc Nephrol 2007;18:13741380.
Simons M, Walz G: Polycystic kidney disease: cell division without
a c(l)ue? Kidney Int 2006;70:854864.
Wilson PD: Polycystic kidney disease. N Engl J Med 2004;350:
151164.
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 Structural/congenital abnormalities M.A. Linshaw G. Rizzoni Renal mass

/
Renal mass
48

Normal/physiological 0 Fluid collection, infection 1 Renal anomaly Renal anomaly Tumor 4 Cystic lesion 5
no hydronephrosis 2 hydronephrosis 3

Prominent fetal lobulation Abscess (intrarenal/extrarenal) Duplex kidney UPJ obstruction Wilms ARPKD
Column of Bertin Hematoma Horseshoe kidney UVJ obstruction Mesoblastic nephroma ADPKD
Renal hypertrophy Urinoma Pelvic kidney PUV Malignant rhabdoid MCDK
Xanthogranulomatous/ Crossed, ectopia Prune-belly syndrome Clear-cell sarcoma Cystic nephroma
renal malakoplakia Angiomyolipoma GCKD
Renal cell carcinoma Lymphangiectasis

Confirm: US or CT US, CT, culture, antibiotics, Abdominal CT; US, VCUG, MAG-3 diuretic Radiographic study; Abdominal CT, DMSA
surgery, fluid (creatinine), nuclide scan to confirm and DMSA scans, CT abdomen/chest, scan for function, tissue
tissue, observation as needed ectopic kidney; VCUG for UTI antegrade pyelogram; brain MRI, abdominal US, for accurate diagnosis
or later hydronephrosis cystoscopy, IVP IVP, bone scan skeletal survey;

198.143.33.65 - 8/6/2015 3:20:59 PM

tissue diagnosis

Univ. of California San Diego

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 1 Renal mass is noted by palpation of an abdominal/flank mass
or by radiographic study. Most renal masses cause renomegaly and
are easier to feel in infants. History and physical examination with labo-
ratory and radiological studies may allow diagnosis without biopsy/
surgery in many cases. Radiographic studies include renal/bladder US,
CT, MRI, VCUG, nuclear scan-MAG-3 with/without furosemide and
DMSA. IVP and magnetic resonance urography help define complex
anatomic problems associated with tumors, anomalies or obstruction.
IVP is still useful when one needs to limit radiation exposure from CT.
US shows if the mass is unilateral or bilateral, cystic or solid, and if re-
nal contour is normal or distorted. A MAG-3 furosemide scan with ure-
thral catheter helps identify functional obstruction. VCUG is used to
view bladder and urethral anatomy and VUR.
2 Renomegaly from renal hypertrophy occurs in response to
congenital/acquired solitary kidney or unilateral reduction in renal
function. Hypertrophy starts minutes after loss of a healthy kidney and
takes months to complete. Two benign conditions may resemble a
mass. Palpable persistent fetal lobulation in a child is clarified by US.
A prominent Bertin column is differentiated from tumor by US (with
agents to enhance vascularity) or CT.
3 Acute bacterial infections with nephromegaly may be classi-
fied as intrarenal (pyelonephritis, abscess) or perirenal (abscess). Acute
renal infection may be classified from CT findings as (1) pyelonephritis
(large kidney with global decreased parenchymal enhancement), (2)
bacterial nephritis (striated or wedge-shaped zones or ill-defined areas
of low attenuation), or (3) renal abscess (well-defined noncystic area of
low attenuation that may have a fibrous capsule). All may be unilateral
or bilateral. One expects a good response to antibiotics for acute pyelo-
nephritis or type A bacterial nephritis. Bacterial nephritis type B is likely
to be associated with a protracted response to antibiotics and may lead
to abscess formation. A renal/perirenal abscess will likely require surgi-
cal drainage. In renal malakoplakia/xanthogranulomatous pyelonephri-
tis, a form of chronic interstitial nephritis, patients have recurrent UTI,
sometimes massive renomegaly and a nonfunctioning avascular mass.
Destroyed renal parenchyma is replaced by yellowish-brown soft infil-
trate of bacteria, inflammatory cells, lipid-laden histiocytes and calculi.
Clinical findings include fever, night sweats, loin pain, abdominal mass,
fatigue, weight loss, anemia, hematuria, and leukocytosis. US shows
multiple anechoic or hypoechoic corticomedullary masses and
contracted renal pelvis. CT may reveal a staghorn calculus obscured
sonographically by peripelvic fibrosis. The lesion can be diffuse,
segmental or focal. Surgery is often needed as the lesion resembles
malignancy and histological diagnosis is essential.
4 Anomalies that may present as a mass and are generally not
49 associated with hydronephrosis include duplex kidney, horseshoe kid-
ney, pelvic kidney and crossed (fused or nonfused) ectopic kidney.
These conditions are seen on abdominal US or CT. While they are usu-
ally benign, problems such as abdominal/pelvic discomfort, UTI,
kinked ureter or hydronephrosis can occur over time and periodic im-
aging with US is useful.
Structural/congenital abnormalities
5 Urinary tract obstruction may present as a flank/abdominal
mass or distended bladder in an infant or may be found at evaluation
for UTI, abdominal or flank pain or hematuria. UPJ obstruction is the
most common cause of hydronephrosis and nephromegaly in the new-
born. It can be seen antenatally by US, usually presents as a palpable
abdominal mass and often resolves spontaneously in 612 months.
Other etiologies leading to hydronephrosis with nephromegaly in chil-
dren include ureterovesical junction obstruction; VUR and posterior
urethral valves. Prune-belly syndrome occurs mostly in males. In utero
prostatic urethral obstruction or urethral hypoplasia may be causative
in a majority of cases. Features include oligohydramnios, hydronephro-
sis, renomegaly, dilated and tortuous ureters, dilated prostatic urethra,
VUR, bilateral cryptorchidism and hypoplastic lower abdominal mus-
cles. Bladder is large and atonic and abdominal wall lax, wrinkled and
offers no resistance to palpation. The syndrome is suspected antena-
tally by finding cystomegaly on US as early as 1214 weeks of gesta-
tion. Renal dysplasia is common. Nephrolithiasis is the most common
acquired condition leading to hydronephrosis and renomegaly in chil-
dren. Intrarenal obstruction without hydronephrosis occurs when pig-
mented casts or crystals occlude tubule lumens. With dehydration and
acidic urine, hemoglobinuria, myoglobinuria and hyperuricosuria all
can cause acute renal failure and renomegaly. Work-up is designed to
look for functional obstruction and VUR. It is important to check for
posterior urethral valves that can cause unilateral hydroureter and hy-
dronephrosis and to rule out higher, unsuspected ureteral lesions with
IVP or antegrade pyelogram.
6 Renal mass is common in tumors. Wilms tumor (nephroblas-
toma), ~85% of renal tumors, is the most common tumor leading to
nephromegaly in children. In addition to laboratory data, work-up in-
cludes US, chest film, skeletal survey and abdominal/chest CT.
Radiological study may miss contralateral renal tumors. Thus, surgical
exploration of contralateral kidney may be needed. Nephroblastomato-
sis (residual metanephrogenic tissue in a mature kidney) causes reno-
megaly. These can regress to fibrous tissue, mature to tubules and
glomeruli, or become malignant (e.g. Wilms tumor) although the usual
course of nephroblastomatosis is regression before malignancy. Other
renal tumors are usually unilateral and solid. Congenital mesoblastic
nephroma (leiomyomatous hamartoma), the most common solid tu-
mor of newborns, is usually benign and tends to present in infants un-
der 3 months of age. Neuroblastoma is usually solid, may have calcifi-
cations or cysts and must be differentiated from primary renal tumor.
Clear-cell sarcoma typically presents in a 3- to 5-year-old child, has a
poor prognosis and tends to metastasize to bone and brain. Work-up
includes brain MRI, bone scan, skeletal survey and abdominal/chest CT.
Malignant rhabdoid tumor is usually large, originates in the central hilar
area, replaces the whole kidney, metastasizes mainly to lung, brain, liv-
er and has median presenting age ~11 months. Chest/abdominal CT
and brain MRI are needed. Multilocular cystic nephroma presents as
benign multilocular cyst or as a cystic lesion with stroma containing
partially differentiated blastema cells. The latter may have Wilms tu-
mor nodules and is indistinguishable from cystic Wilms tumor without
biopsy. Most children present these tumors from 324 months of age.
In addition to the tumors mentioned above, hematologic malignancies
M.A. Linshaw G. Rizzoni Renal mass
such as acute lymphoblastic leukemia and lymphoma may lead to dif-
fuse unilateral or bilateral nephromegaly from renal infiltration or dis-
crete intrarenal or hilar mass lesions. Rare causes of renomegaly in-
clude renal adenomatosis, histiocytic medullary reticulosis, Castleman
disease and renal cell carcinoma.
7 Renomegaly occurs in several cystic diseases. ARPKD may
present in utero with large, hyperechoic kidneys, oligohydramnios, no
bladder visualization and negative family history. Most affected chil-
dren progress to renal failure in childhood although mild disease can
be undiagnosed for years. Neonatal ADPKD can cause large, hyper-
echoic kidneys with/without visible cysts. Cysts may initially be unilat-
eral. Patients are often asymptomatic early in the disease with cysts
noted on an US done because a parent is affected. Cysts may present
as abdominal pain, mass, hematuria, hypertension or UTI. Extrarenal
problems include mitral valve prolapse, cysts in liver, ovary, spleen and
pancreas, hernias and cerebral aneurysms. MCDK, a severe renal dys-
genesis, is the most common cause of neonatal abdominal mass. In
MCDK, there is no renal sinus or functioning parenchyma and there is
an atretic or nonpatent ureter. Contralateral anomalies, e.g. VUR and
UPJ, are common. VCUG and nuclear scan can confirm lack of VUR and
function. Tuberous sclerosis, an autosomal-dominant neurocutaneous
hamartomatosis, involves skin, heart, retina, central nervous system
and kidney. Renal lesions include angiomyolipomas (~50% of patients)
with fat, smooth muscle, and abnormal vessels that are often bilateral
and best evaluated with CT, and large cysts (~20% of patients) resem-
bling ADPKD. Glomerulocystic disease includes entities with glomeru-
lar (not tubular) cysts that are typically dilated Bowmans capsules with
an aborted/primitive glomerulus. Cysts are cortical, not medullary, a
finding differentiating this from other cystic diseases. Infants may pre-
sent with abdominal masses (cystic kidneys by US) and renal insuf-
ficiency. The disease can be sporadic or inherited and mild or present
later in life with hypertension or flank pain.
Selected reading
Ahmed HU, Arya M, Levitt G, Duffy PG, Mushtaq I, Sebire NJ:
Part I: Primary malignant non-Wilms renal tumours in children. Lan-
cet Oncol 2007;8:730737.
Avner ED, Sweeney WE Jr: Renal cystic disease: new insights for the
clinician.
Becker A, Baum M: Obstructive uropathy. Early Hum Dev 2006;
82:1522. Curr Opin Urol 2007;17:281286.
Driscoll K, Isakoff M, Ferrer F: Update on pediatric genitourinary on-
cology. J Nephrol 2002;15:597600.
Karadeniz C, Oguz A, Ataoglu O, Citak C, Buyan N, Pinarli G,
Ozkaya O, Kapucu O: Primary renal lymphoma and xanthogranulo-
matous pyelonephritis in childhood. Pediatr Clin North Am
2006;53:889909.
Zugor V, Schott GE, Labanaris AP: Xanthogranulomatous
pyelonephritis in childhood: a critical analysis of 10 cases and of the
198.143.33.65 - 8/6/2015 3:20:59 PM
literature. Urology 2007;70:157160.
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 Hypertension S. Turi A.L. Friedman Neonatal hypertension

/0
Neonatal hypertension
50 Clinical Features

Accutely ill neonate Less acutely ill neonate

Congestive heart failure Unexplained irritability
Cardiogenic shock Failure to thrive 5
Intracranial hemorrhage
Life-threatening conditions

History Physical examination

Case and family histories Dysmorphic features, heart murmur, cyanosis, dyspnea/tachypnea,
Medical procedures (e.g. umbilical artery catheterization) tachycardia, hepatosplenomegaly

Generally useful Useful in selected infants

Serum: CBC, BUN, creatinine, electrolytes, calcium Serum: PRA, cortisol, thyroid studies, aldosterone
Urine: urinalysis ( culture) Urine: catecholamines
Imaging: chest X-ray, echocardiogram renal sonogram and Doppler study Imaging: abdominal/pelvic sonogram, voiding cystourethrography,
CT angiogram, nuclear scan (DTPA/Mag-3/DMSA)

Renal Renovascular 1 Cardio-pulmonary 2 Endocrine Drugs 3 Neurologic 4 Tumors Miscellaneous

Congenital Thromboembolism Coarctation of aorta Congenital adrenal Glucocorticoids Pain Wilms tumor TPN
PKD (AD, AR) Renal artery stenosis BPD hyperplasia Theophylline Elevated intracranial Mesoblastic Hypercalcemia
MCDK Mid-aortic coarctation Hyperthyroidism Caffeine pressure (intracranial nephroma Postclosure of
Obstructive uropathy RVT Gordon syndrome Vitamin D intoxication hemorrhage, Neuroblastoma abdominal wall defect
Acquired Congenital rubella syndrome Maternal drug abuse hydrocephalus, etc.) ECMO
Acute tubular necrosis (cocaine, heroin) Seizures

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 1 BP is low at birth. It increases with age, by 90 Upper 95% CI
80 Selected reading
1 mm Hg per day within the period of 38 days. It rises

Systolic BP (mm Hg)

70
by about 1 mm Hg per week between ages 5 and 6 Brewer ED: Evaluation of hypertension in childhood
60
weeks. At a later age, systolic BP is around 95 10 mm diseases; in Avner ED, Harmon WE, Niaudet P (eds):
50
Hg. Hypertension is a rare condition in the neonate. 40 Lower 95% CI
Pediatric Nephrology, ed 5. Philadelphia, Lippincott
Neonates with hypertension are at a high risk of devel- 30 Williams & Wilkins, 2004, pp 11791198.
oping cardiorespiratory failure and cerebral distress. 20 Cordero L, Timan CJ, Waters HH, Sachs LA: Mean
In a neonate or infant, the BP is considered to be 10 arterial pressures during the first 24 hours of life in
elevated if it is above the 95th percentile for infants of 0 < or = 600-gram birth weight infants. J Perinatol
similar gestational or postconceptual age and size. 22 24 26 28 30 32 34 36 38 40 42 2002;22:348353.
For older infants (112 months), hypertension could be Gestational age (weeks) Flynn JT: Neonatal hypertension: diagnosis and
defined as blood pressure elevation above the 95th 70 management. Pediatr Nephrol 2000;14:332341.
percentile for infants of similar age, size and gender. 60 Upper 95% CI
Friedman AL, Hustead VA: Hypertension in babies

Diastolic BP (mm Hg)

50
following discharge from a neonatal intensive care
2 The actual incidence of hypertension in unit. Pediatr. Nephrol 1987;1:3034.
40
neonates is between 0.2 and 3%. As opposed to older Lee J, Rajadurai VS, Tan KW: Blood pressure
30 standards for very low birth weight infants during
children in whom hypertension is most commonly Lower 95% CI
caused by renal or endocrine disorders, in neonates 20 the first day of life. Arch Dis Child Fetal Neonatal Ed
the common causes of hypertension are renovascular 10 1999;81:168170.
disease, cardiac malformations, as well as broncho- 0 Zubrow AB, Hulman S, Kushmer H, Falkner B:
pulmonary dysplasia. 22 24 26 28 30 32 34 36 38 40 42 Determinants of blood pressure in infants admitted
Gestational age (weeks) to neonatal intensive care units: a prospective
3 Umbilical artery catheter is the most com- multicenter study. J Perinatol 1995;15:470479.
mon cause of hypertension in neonates. The catheter
may lead to thrombus formation. The thrombi may
embolize to the kidneys, causing areas of infarction
and increased release of renin, which, in turn, elevates
blood pressure. RVT is a relatively common cause of
hypertension in asphyxiated or hypovolemic infants, Table. Commonly used drugs for the treatment of neonatal hypertension
infants with coagulopathies, as well as in infants of
Drug Class Dose Route Comments
diabetic mothers.
Diazoxide vasodilator 25 mg/kg per dose rapid bolus injection slow injection ineffective, duration
4 Coarctation of the aorta is the most common (arteriolar) unpredictable, use with caution, may cause
rapid hypotension
heart malformation that leads to hypertension in neo-
nates. The hypertension in this condition is found in Enalaprilat ACE inhibitor 528 g/kg/day i.v. injection over may cause prolonged hypotension and
the upper extremities. 510 min acute renal insufficiency
The etiology of hypertension in BPD is probably
multifactorial and includes prolonged glucocorticoid
Esmolol -blocker drip: 100300 g/kg i.v. infusion very short-acting constant infusion
administration and chronic hypoxia. per min necessary

Hydralazine vasodilator bolus: 0.150.6 mg/kg i.v. bolus or tachycardia frequent side effect;
5 Various drugs may cause hypertension in (arteriolar) per dose infusion must administer q 4 h when given i.v. bolus
neonates, either by direct administration to the sick drip: 0.755.0 g/kg
neonate (glucocorticoids, theophylline), or due to per min
maternal drug abuse that leads to hypertension in their
Labetalol - and -blocker 1.203.0 mg/kg per h i.v. bolus or heart failure, BPD relative contraindications
infant child (e.g. heroin, cocaine).
constant infusion
51
6 A common cause of hypertension in prema- Nicardipine Ca2+ channel blocker 13 g/kg per min constant infusion may cause reflex tachycardia
ture infants is intracranial hemorrhage.
Sodium vasodilator 0.510 g/kg per min constant infusion thiocyanate toxicity can occur with

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venous)

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Hypertension S. Turi A.L. Friedman Neonatal hypertension
 Hypertension S. Turi A.L. Friedman Pediatric hypertension

/0
Pediatric hypertension
Evaluation 1
52

Hx and physical examination, ABPM 2

Urinalysis, CBC, serum creatinine and BUN
Serum electrolytes, Ca2+, bicarbonate and uric acid
Renal sonogram, ECG, ophthalmologic examination

Renal 3 Renovascular 4 Endocrine/metabolic 5 Cardiac 6 CNS 7 Drugs Essential 8

Renal sonogram
Voiding cystourethrography
Renal nuclear scan
(DTPA/MAG-3, DMSA)
Renal biopsy
PRA Serum: aldosterone, cortisol,
Renal Doppler sonogram PRA, TSH, FT4
CT angio./angiography Urine: cathecholamines, cortisol
Imaging: abdominal sonogram,
MIBG scan
ECG, Echocardiogram Fundus examination Positive family Hx
Cardiac catheterization Brain CT/MRI Normal physical examination
Lumbar puncture and workup

PRAM

Anatomic malformations RVT Low plasma renin Coarctation of aorta Brain trauma Glucocorticoids Positive genetic analysis
Reflux/obstructive Renal artery stenosis Cushing syndrome Brain tumor Vitamin D (in selected cases)
nephropathy (fibromuscular dysplasia, Primary hyperaldosteronism CNS bleeding Cyclosporin A
Renal trauma neurofibromatosis, etc.) Liddle syndrome Pseudotumor cerebri Oral contraceptives
Renal tumors Umbilical artery catheter Gordon syndrome Guillain-Barr syndrome Sympathomimetics
No anatomic malformations (in neonate) Apparent mineralocorticoid excess Familial dysautonomia Amphetamines
Pyelonephritis Takayasu arteritis Glucocorticoid-remediable aldosteronism Cocaine
Hemolytic-uremic syndrome Moyamoya disease Congenital adrenal hyperplasia Heavy metal poisoning
Glomerulonephritides (hypertensive forms)
Vasculitides Normal plasma renin
Pheochromcytoma
Hyperthyroidism
Hypercalcemia

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Treatment 9

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 1 Hypertension in children is an overlooked and relatively
common condition. Its prevalence is
1.213% depending on the studied population of children. Pediatric
hypertension is a leading risk factor for cardiovascular disease, renal
disease, and stroke later in life.
Blood pressure values in children are defined and classified as fol-
lows:
Normal BP: Average systolic or diastolic BP below the 90th percentile
for age, gender, and height.
Borderline hypertension: Average systolic or diastolic BP between
the 90th and 95th percentiles for age, gender, and height.
Hypertension: Average systolic or diastolic BP greater than the 95th
percentile for age, gender, and height.
Hypertensive emergency: Markedly elevated BP accompanied by
acute end-organ damage (seizures, encephalopathy, heart failure,
etc.).
White-coat hypertension: Elevated BP measurements in the presence
of health care professionals but normotension at other times.
For BP values by age, gender and height see reference below [Pediat-
rics 2004;114:555576].
BP should be routinely measured in high-risk infants from birth, and
in all children from age 3 years on. Measurement of BP should be
performed by a trained person on a quiet, relaxed child, using an ap-
propriate-size cuff. The fifth Korotkoff phase should be used for de-
termination of diastolic BP. Repeated BP measurements in the office
and at home are necessary to confirm the diagnosis of systemic hy-
pertension.
2 It is beyond the scope of this text to elaborate on all causes
of hypertension in children. Hence, only selected diseases will be
discussed. For discussion of other disorders, see the appropriate al-
gorithms. Of note, the younger the child and the higher the BP, the
more likely a secondary cause will be found and an earlier and more
extensive evaluation should be pursued.
3 History and physical examination of the child with hyper-
tension should include the following systems: Cardiovascular: Palpa-
tion of femoral pulses, auscultation of murmurs and search for evi-
dence of congestive heart failure. BP must be measured in all 4 ex-
tremities to rule out coarctation of the aorta.
Abdomen: The presence of enlarged kidneys, masses or bruits.
Endocrine: Flushing, sweating, weight changes; physical examination
should search for thyromegaly, virilization or cushingoid habitus.
Cutaneous: The presence of caf-au-lait spots, rash, purpura or neu-
rofibromas.
The workup of the child with hypertension should be rational, se-
53
quential, disease- oriented and as noninvasive as possible. The initial
evaluation of the hypertensive child should include all the tests out-
lined in this section. Additional tests should be reserved for the sub-
sequent evaluation depending on the suspected condition (as out-
lined in the algorithm).
Hypertension
4 ABPM is the measurement of BP values over a 24-hour pe-
riod preferably at home while the child maintains his ordinary activi-
ties. ABPM is recommended when there are large fluctuations in BP
values, for follow-up after changes in treatment, or when white-coat
hypertension is suspected.
5 Renal diseases are the most common causes of secondary
hypertension in children (see appropriate algorithms for details).
6 The combination of elevated BP with the laboratory find-
ings of hypokalemia, metabolic alkalosis, and elevated plasma renin
and aldosterone levels in children is most commonly due to renovas-
cular disease. The most common etiologies of renovascular diseases
are renovascular changes secondary to umbilical artery catheter in
newborn infants and fibromuscular dysplasia in older children. Other
less common causes of renovascular hypertension are listed in this
algorithm.
7 Endocrine/metabolic disorders leading to hypertension are
subclassified according to PRA and serum aldosterone levels. For
detailed discussion, see algorithms on Hypokalemia, Hypochlore-
mia and Metabolic alkalosis. Pheochromocytoma is a (usually be-
nign) tumor of the chromaffin cells in the adrenal gland or the sym-
pathetic nervous system which secretes excessive amounts of cat-
echolamines and can lead to severe hypertensive attacks.
8 Coarctation of aorta is the most common heart malforma-
tion that leads to hypertension in children. The hypertension in this
condition is found in the upper extremities.
9 Any condition leading to increased intracranial pressure
will cause systemic hypertension, sometimes accompanied by bra-
dycardia and widened pulse pressure (Cushing triad).
10 It is increasingly believed that essential (primary) hyperten-
sion, the most common cause of hypertension in adolescents and
adults, has its roots in early childhood. Family studies have demon-
strated that about 2040% of the BP variance observed in the popula-
tion is determined genetically. However, in most cases, the segrega-
tion of BP in families does not follow a Mendelian or single-gene pat-
tern, but it seems to be under the influence of a variety of genetic,
demographic, and environmental factors. Several genes have been
shown to affect BP (angiotensinogen, renin, ACE, AT1 receptor, nitric
oxide synthase genes, etc.). The significance and the contribution of
specific polymorphisms as well as variations in function of each of
these genes to final regulation of BP are the subject of current re-
search.
S. Turi A.L. Friedman Pediatric hypertension
11 For children and adolescents with essential hypertension,
nonpharmacologic therapies (diet, salt restrictions and physical ac-
tivity) are usually effective in reducing BP. However, because of ei-
ther end-organ involvement (particularly left ventricular hypertro-
phy) or unwillingness to change lifestyle, antihypertensive medica-
tions are often needed. Severe hypertension should be promptly
treated, pharmacologically or later, if indicated, surgically. Blood
pressure should not be normalized immediately but initially lowered
to a safe level.
The therapy of secondary hypertension includes the treatment of the
basic disease as well as the hypertension itself. Often multiple class-
es of drugs must be used. Major classes of antihypertensive drugs
commonly used in children include: calcium channel blockers, diuret-
ics, -blockers, vasodilators and ACE inhibitors. For dosage, side ef-
fects and contraindications see Selected reading.
Selected reading
Bender UJ, Bonilla-Felix MA, Portman RJ: Epidemiology of hyper-
tension; in Avner ED, Harmon WE, Niaudet P (eds): Pediatric Ne-
phrology, ed 5. Philadelphia, Lippincott Williams & Wilkins, 2004,
pp 11251152.
Ingelfinger JR: The molecular basis of pediatric hypertension. Pe-
diatr Clin North Am 2006;53:
10111028.
Lifton RP, Gharavi AG, Geller DS: Molecular mechanisms of human
hypertension. Cell 2001;23:545556.
Pappadis SL, Somers MJG: Hypertension in adolescents: a review
of diagnosis and management. Curr Opin Pediatr 2003;15:370378.
Soergel M, Kirschstein M, Busch C, Danne T, Gellermann J, Holl R,
Krull F, Reusz GS, Rascher W: Oscillometric twenty-four hour am-
bulatory BP values in healthy children and adolescents: a multi-
center trial including. J Pediatr 1997;130:178184.
Stephens SE, Dillon MJ: The investigation and management of hy-
pertension. Curr Paediatr 2002; 12:561568.
The 4th Report on the Diagnosis, Evaluation, and Treatment of High
Blood Pressure in Children and Adolescents: National High Blood
Pressure Education Program Working Group on High Blood Pres-
sure in Children and Adolescents. Pediatrics 2004;114:555576.
Yagil Y, Yagil C: The search for the genetic basis of hypertension.
Curr Opin Nephrol Hypertens 2005; 14:141147.
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 Tubular disease I. Eisenstein P. Goodyer I. Zelikovic Aminoaciduria

/
Aminoaciduria
54

Generalized AA 0 Overflow AA 0 Isolated hereditary AA 1

Cationic AA 2 Neutral AA 3 Imminoaciduria and Dicarboxylic AA 5

glycinuria 4

Fanconi syndrome Inborn errors of Classic cystinuria (types I, II, III) Hartnup disease Imminoglycinuria Dicarboxylic AA
Prematurity amino acid metabolism Lysinuric protein intolerance Methioninuria Isolated glycinuria
Isolated cystinuria Histidinuria
Hyperdibasic AA type I
Isolated lysinuria

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 1 Free amino acids circulating in the blood are
derived from dietary protein hydrolization, intracellular
peptides catabolism and from de novo synthesis with-
in cells. These free amino acids are filtered through the
renal glomeruli and, under normal conditions, more
than 99% are reabsorbed by the renal tubule, mainly in
the proximal tubule (PT). There are several amino ac-
ids transport mechanism in the PT that are character-
ized by their Na+ dependency vs. independency, by the
electroneutrality of the transport mechanism or by
their specificity to certain amino acids.
2 Generalized AA is seen in Fanconi syndrome
(see appropriate algorithm) and in the urine of prema-
ture newborn infants because of the immaturity of the
tubular transport mechanisms. In addition, overflow
AA is due to inborn errors of amino acid metabolism.
3 Hereditary AAs are a group of disorders in
which a single or a group of amino acids are excreted
in excessive amounts in the urine. These disorders are
categorized into 5 major groups according to the trans-
port pathway affected. Of note, in the algorithm only 4
groups are depicts. The fifth, -AA, is found only in
animals.
4 Cationic AA is divided into 5 disorders. The
most common disease, classic cystinuria, is discussed
in detail in the appropriate algorithm.
In LPI, a rare autosomal-recessive disorder, excessive
urinary excretion of dibasic amino acids (especially
lysine) is accompanied by poor intestinal absorption of
these amino acids. Typical clinical pictures of children
with LPI include protein malnutrition, FTT, vomiting,
diarrhea, hepatosplenomegaly, hyperammonemia,
hypotony and seizures. LPI is caused by a defect in the
gene encoding one of the subunits of system y+L, re-
sponsible for the efflux of dibasic amino acids from
the tubular cells to the blood. Treatment of patients
with LPI includes protein restriction as well as oral
supplements of arginine, ornithine and citrulline.
Isolated cystinuria, isolated lysinuria and hyperdibasic
AA type I are very rare disorders. Each one of these
diseases has been reported in only few children world-
wide.
55
Tubular disease
5 Hartnup disease, the most common disorder
of the neutral AA group, is an autosomally recessive
inherited disease. It is characterized by intestinal mal-
absorption, and massive hyperexcretion of the neutral
monoamino monocarboxylic amino acids (alanine,
phenylalanine, serine, theronine, valine, leucine, iso-
leucine, tryptophan, tyrosine, histidine, glutamine and
asparagine). Clinical features usually appear in adoles-
cence or adulthood and they resemble those of pella-
gra (photosensitive rash, ataxia and psychiatric mani-
festations). The disease is caused by mutations in the
gene SLC6A19 which encodes a sodium-dependent
neutral amino acid transporter, expressed in kidneys
and intestine. Methioninuria and histidinuria are ex-
tremely rare disorders reported in very few cases
worldwide.
6 Imminoglycinuria is a benign, autosomal-
recessive disorder characterized by urinary excretion
of excessive amounts of proline, hydroxyproline and
glycine. Its incidence is 1:15,000 live births. Patients
are usually asymptomatic. The genetic defect has not
been identified yet but it is believed to involve the
transport system, located on the brush-border mem-
brane of the proximal tubule that is responsible for the
reabsorption of the amino acids proline, hydroxypro-
line and glycine. Isolated glycinuria is an extremely
rare condition described in only a few patients so far.
7 Dicarboxylic AA is another benign, autoso-
mal-recessive disorder caused by hyperexcretion in
the urine of glutamate and aspartate. The incidence of
this disorder is 1:29,000 live births and although be-
nign in nature, there are rare reports of hypoglycemia
in patients with dicarboxylic AA, which is corrected by
the administration of glutamate and aspartate. The
genetic defect is not known but the candidate gene is
the gene encoding EAAC1, an anionic amino acid
transporter expressed in the kidney and the intestine.
I. Eisenstein P. Goodyer I. Zelikovic
Selected reading
Bergeron M, Goodyer PR, Gougoux A, et al:
Pathophysiology of renal hyperaminoacidurias and
glucosuria; in Seldin DW, Giebisch G (eds): The
Kidney: Physiology and Pathophysiology, ed 5.
Philadelphia, Lippincott Williams & Wilkins, 2000:
22112233.
Broer A, Cavanaugh JA, Rasko JE, Broer S:
The molecular basis of neutral aminoacidurias.
Pflugers Arch 2006;451:511517.
Palacin M, Bertran J, Chillaron J, Estevez R,
Zorzano A: Lysinuric protein intolerance: mecha-
nisms of pathophysiology. Mol Genet Metab
2004;81(suppl 1):S2737.
Seow HF, Broer S, Broer A, Bailey CG, Potter SJ,
Cavanaugh JA, Rasko JE: Hartnup disorder is
caused by mutations in the gene encoding the
neutral amino acid transporter SLC6A19. Nat Genet
2004;36:10031007.
Zelikovic I: Aminoaciduria and glycosuria; in
Avner ED, Harmon WE, Niaudet P (eds): Pediatric
Nephrology, ed 5. Philadelphia, Lippincott
Williams & Wilkins, 2004, pp 701729.
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Aminoaciduria
 Tubular disease P. Goodyer I. Eisenstein I. Zelikovic Cystinuria

/
Cystinuria
(hexagonal crystals in urine; urine cystine >100 mol/g creatinine)

56

Broad aminoaciduria Elevated cystine, ornithine, arginine and lysine 0

Age >2 years Newborn

Persistent cystinuria Partial resolution

>1,200 mol/g creatinine <1,200 mol/g creatinine

Fanconi syndrome Recessive/recessive Dominant/dominant 1 Mixed type Heterozygote (dominant/N)

Nephrolithiasis 2

Passage of stone Persistent stone Multiple stones Obstructive stones

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Conservative measures MPG or penicillamine
(high fluid intake) Lithotripsy, endoscopic surgery

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 1 Children with cystinuria may be identified in
screening programs, during evaluation of familial
nephrolithiasis or when they present with renal calculi.
The incidence of cystinuria worldwide is estimated to
be about 1:10,000 but may be higher in specific popu-
lations (1:2,000 among newborns in England, 1:2,500
in Libyan Jews). Normally, >98% of filtered amino
acids is reabsorbed by transport mechanisms in the
luminal membrane of proximal tubular cells. However,
in patients who inherit one or more of the cystinuria
genes, the specific transport mechanism shared by
cystine, artinine, ornithine and lysine is defective. The
only clinical consequence is cystine nephrolithiasis.
Cystinuria should be distinguished from a broader
Fanconi pattern of aminoaciduria, accompanied
by variable degrees of glucosuria, proteinuria and
phosphaturia.
2 At birth, renal tubular reabsorption of amino
acids is not fully mature. There is little effect on nor-
mal infants but children who are carriers of one par-
tially dominant (type II or type III) cystinuria gene may
excrete cystine at exaggerated levels, appearing to be
homozygotes. Final diagnosis should be delayed;
urine cystine quantification should be repeated at
about 2 years of age.
3 Cystinuria has now been attributed to two
principal genes. SLC 7A9 encodes the luminal cystine
transporter, itself, and is transmitted as a dominant
urinary phenotype. If both parents excrete cystine
above the normal range (>100 mol/g creatinine), but
less than the stone-forming range (>1,200 mol/g cre-
atinine), the child has inherited two dominant SLC 7A9
mutations. By contrast, the SLC3A1 gene encodes a
subunit of the transporter and is transmitted as a
recessive urinary phenotype. If both parents excrete
cystine in the normal range, the child has most likely
57
Tubular disease
inherited two mutant SLC3A1 genes. Both types of
Selected reading
cystinuria have a high risk of recurrent nephrolithiasis
and usually excrete cystine in the range of 2,5005,000 Goodyer PR, Saadi J, Ong P, Elkas G, Rozen R:
mol/g creatinine. High fluid intake (about 2.5 l/m2) Cystinuria subtype and the rest of nephrolithiasis.
should be advised; this can be individualized by mea- Kidney Int 1998;54:5661.
suring the amount of cystine excreted per day and cal- International Cystinuria Consortium: Functional
culating the amount of fluid needed to dilute the cys- analysis of mutations in SLC7A9, and genotype/
tine to <1,200 mol/l. Patients who frequently exceed phenotype correlation in non-type I cystinuria.
this theoretic limit of urinary cystine solubility in acidic Hum Mol Genet 2001;10:305316.
urine should take 0.52.0 mEq/kg/day of NaHCO3 or Palacin M, Goodyer P, Nunes V, Gasparini P:
potassium citrate to bring urine pH to >7.5, especially Cystinuria; in Scriver C, Beaudet A, Sly W, Valle D
overnight when urine is most concentrated and acidic. (eds): The Metabolic and Molecular Basis of
Yearly ulrasonography is warranted after age 5 years. Inherited Disease. New York, McGraw-Hill, 2001,
On the other hand, children who inherit one recessive vol III, pp 49094932.
and one dominant gene from their parents have the Rogers A, Kalakish S, Desai RA, Assimos DG:
mixed type of cystinuria and have much lower risk of Management of cystinuria. Urol Clin North Am
stone formation, requiring less intense monitoring. 2007;34:347362.
Zelikovic I: Aminoaciduria and glycosuria; in
4 Pure cystine calculi are radio-opaque and Avner ED, Harmon WE, Niaudet P (eds): Pediatric
often incorporate variable amounts of calcium; they Nephrology, ed 5. Philadelphia, Lippincott
may be identified by ordinary radiography or by ultra- Williams & Wilkins, 2004, pp 701728.
sonography. About 4050% of stones recovered from
cystinuria patients contain substantial amounts of
calcium. Prior to starting an alkalinizing agent, hyper-
calciuria should be ruled out. Individual risk of nephro-
lithiasis cannot be predicted by urine cystine level
alone. If multiple or obstructive stones are identified,
cystine chelating agents such as MPG (1015 mg/kg/
day) or penicillamine (30 mg/kg/day) may be intro-
duced, monitoring carefully for side effects such as
fever, rash, elevation of liver enzymes and proteinuria.
Partial dissolution may allow the stone to pass, but
most will require lithotripsy or surgical stone removal.
Long-term prophylaxis with these agents (vs. high
fluid intake plus urinary alkalinization) should be indi-
vidualized based on compliance, drug tolerance and
severity of recurrent stone disease.
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 Tubular disease I. Eisenstein P. Goodyer I. Zelikovic Glycosuria

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Glycosuria
58

Hyperglycemia 0 Generalized proximal tubular dysfunction Hereditary renal glycosuria 2

Fanconi syndrome ISHG 3 Glucose-galactose malabsorption 4 Fanconi-Bickel syndrome 5

Extreme prematurity 1

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 1 Under normal conditions, the reabsorption of
filtered glucose by the renal tubule is almost complete.
Most filtered glucose is reabsorbed in the proximal
convoluted tubule and the rest by proximal straight
tubule, the loop of Henle, and, to some extent, by the
collecting duct. Reabsorption of glucose across the
proximal tubular cells occurs by an active, carrier-
mediated, Na+-dependent process in the apical mem-
brane and a Na+-independent, facilitated glucose
transporter resides in the basolateral membrane. The
evaluation of glycosuria should include determination
of blood glucose levels and the evaluation of proximal
tubular dysfunction (see algorithms on Fancony syn-
drome and Renal tubular acidosis).
2 The human kidney is characterized by a lim-
ited capacity to reabsorb D-glucose. Beyond a certain
level of blood glucose level, a maximal rate of renal
glucose reabsorption is achieved and glucose will
appear in the urine. Thus, glycosuria is seen in any
condition leading to hyperglycemia such as diabetes
mellitus, stress-induced and drug-induced hyperglyce-
mia.
3 Glycosuria is observed in generalized proxi-
mal tubular dysfunction (Fanconi syndrome). For
details see appropriate algorithm. Glycosuria is often
seen in premature newborn infants because of the
immaturity of the tubular transport mechanisms.
4 Hereditary renal glycosuria is an abnormality
in which variable amounts of glucose are excreted
in the urine at normal blood glucose concentration.
Several genetic disorders are known to cause this
abnormality (see below).
59
Tubular disease
5 ISHG is a benign condition in which the
glycosuria is the only abnormality, and there is no
increase in the urinary excretion of other sugars. This
disorder is caused by a genetic defect in the SGLT2- a
Na+-glucose cotransporter which is located in the
luminal membrane of the proximal convoluted tubule.
ISHG is transmitted in an autosomally recessive
fashion. Of note, some of these children have massive
aminoaciduria in addition to the renal glycosuria.
6 Glucose-galactose malabsorption is an auto-
somal-recessive genetic disease which is potentially
lethal. The disorder is caused by a genetic defect in
SGLT1, another Na+-glucose cotransporter, which is
found in the intestine and kidney. The typical clinical
picture of glucose-galactose malabsorption is severe
watery diarrhea starting in the neonatal period. The
diarrhea ceases once glucose and galactose are
removed from the diet.
7 Fanconi-Bickel syndrome is an autosomal-
recessive disorder characterized by Fanconi syndrome
and hepatomegaly due to glycogenesis of the liver and
kidneys. The disease is caused by mutation in the
gene encoding the facilitated glucose transporter
GLUT2. Glycosuria is a prominent feature of this disor-
der but unlike the disorders outlined above, it is not
the sole renal manifestation, and other proximal tubu-
lar dysfunctions exist.
I. Eisenstein P. Goodyer I. Zelikovic
Selected reading
Bergeron M, Goodyer PR, Gougoux A, et al:
Pathophysiology of renal hyperaminoacidurias and
glucosuria; in Seldin DW, Giebisch G (eds): The
Kidney: Physiology and Pathophysiology, ed 3.
Philadelphia, Lippincott Williams & Wilkins, 2000,
pp 22112233.
Kleta R, Stuart C, Gill FA, Gahl WA: Renal glucosuria
due to SGLT2 mutations. Mol Genet Metab
2004;82:5658.
Magen D, Sprecher E, Zelikovic I, Skorecki K: A novel
missense mutation in SLC5A2 encoding SGLT2
underlies autosomal-recessive renal glucosuria and
aminoaciduria. Kidney Int 2005;67:3441.
Wright EM, Turk E, Martin MG: Molecular basis for
glucose-galactose malabsorption. Cell Biochem
Biophys 2002;36:115121.
Zelikovic I: Aminoaciduria and glycosuria;
in Avner ED, Harmon WE, Niaudet P (eds):
Pediatric Nephrology, ed 5. Philadelphia, Lippincott
Williams & Wilkins, 2004, pp 701729.
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 Tubular disease I. Eisenstein P. Goodyer I. Zelikovic Renal tubular acidosis

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Renal tubular acidosis
60 History and physical examination 0
Serum creatinine, Na+, K+, Ca2+, P, HCO3, plasma aldosterone, renin
Urine-urinalysis, osmolarity, Cl, Na+, K+, Ca2+, pH
Renal US

Negative urinary anion gap 1 Positive urinary anion gap 13

[Cl >Na+ + K+] [Cl <Na+ + K+]
Urine pH <5.5
Hypokalemia

Urine pH >5.5 Urine pH <5.5

Hyperkalemia

RTA type 2 (PRTA) 2 RTA type 1 (DRTA) 4 RTA type 4 5

Hypokalemia Hyperkalemia

Inherited causes Secretory or gradient defect Voltage-dependent defect Aldosterone deficiency

Cystinosis Inherited causes Obstructive uropathy Addison disease
Dent disease Marfan syndrome Sickle cell disease Congenital adrenal hypoplasia
Mitochondriopathies Ehlers-Danlos syndrome SLE CAH (salt-losing types)
Fanconi-Bickel glycogenosis Wilson disease Marked volume depletion CMO deficiency type I and II
Tyrosinemia Primary-genetic Amiloride administration Hyporeninemic hypoaldosteronism
Wilson disease Autoimmune disorders Diabetes mellitus
Lowe syndrome Sjogren syndrome Interstitial nephritis
Galactosemia SLE Gordon syndrome (PHA type II)
Hereditary fructose intolerance Chronic active hepatitis Aldosterone resistant
Glycogen storage disease type 1 Primary biliary cirrhosis Pseudohypoaldosteronism
Primary-genetic Rheumatoid arthritis Obstructive uropathy
Drugs Drugs Chronic tubulointerstitial damage
Chemotherapy (cisplatin/ifosfamide) Amphotericin B Drugs (spironolactone, cyclosporin, heparin, amiloride)
Valoproic acid Ifosfamide
Outdated tetracyclines Lithium
Glue sniffing Toluene
Heavy metal poisoning Analgesic abuse
Aminoglycosides

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Vitamin D deficiency

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 1 The kidney is the major organ responsible for acid-base
homeostasis. This homeostasis is maintained by the renal tubule in
two ways: (1) reabsorption of the filtered HCO 3 (mainly by the proxi-
mal tubule), and (2) excretion of the H+ produced by the human body
in the distal tubule. When one of these processes is defected RTA
ensues. There are 3 major types of RTA: type 1 (DRTA), type 2 (PRTA)
and type 4.
2 The evaluation of the child with RTA includes obtaining his-
tory regarding abnormal growth pattern, polyuria, recurrent vomit-
ing, pathologic fractures, psychomental retardation, family history of
genetic diseases, intrauterine fetal demise or fetal uropathy and drug
administration. Physical examination includes weight and height
measurement, signs of rickets (bowing, frontal bossing, etc.), dys-
morphic features and signs of hepato-/splenomegaly. Laboratory
evaluation includes serum levels of creatinine, BUN, electrolyte lev-
els, calcium, inorganic phosphorus, bicarbonate as well as plasma
aldosterone levels and PRA. Urine should be obtained for urinalysis,
pH, osmolarity, Ca2+ and electrolyte levels (Cl , Na+ and K+). In addi-
tion, renal US should be performed in every child with suspected
RTA.
3 A primary means by which the renal tubule handles an acid
load is by production of ammonia (NH3). When combined with H+ in
the distal tubular lumen, NH3 is converted to ammonium ion (NH4+)
which is lipid-insoluble and therefore cannot be reabsorbed.
Because a direct measurement of urinary ammonium excretion is
cumbersome, urinary anion gap [Na+ + K+ Cl] serves as an indirect
index of urinary ammonium excretion and hence of distal acidifica-
tion ability. This index is based on the fact that any change in urinary
ammonium excretion will be accompanied by a parallel change
in urinary chloride excretion in order to maintain electroneutrality.
A negative urinary anion gap (Cl > Na+ + K+) signifies normal
ammonium production/secretion whereas a positive urinary anion
gap (Cl < Na+ + K+) represents decreased ammonium production/
secretion.
4 HCMA accompanied by negative urinary anion gap repre-
sents an intact distal acidification mechanism. Besides gastrointesti-
nal bicarbonate loss due to diarrhea, PRTA, also known as RTA type
2, is the most common cause of HCMA with a negative urinary anion
gap. In addition to negative urinary anion gap, PRTA is characterized
by hypokalemia and urinary pH < 5.5 in the face of systemic acidosis.
PRTA can be isolated or can be a part of generalized proximal tubu-
lopathy (Fanconi syndrome) which leads to hypophospatemic rickets,
hypouricemia, glycosuria and aminoaciduria. For details on Fanconi
61
syndrome, see appropriate algorithm. Major causes of PRTA/Fanconi
syndrome include: hereditary disorders (cystinosis, galactosemia,
tyrosinemia, hereditary fructose intolerance, mitochondrial cytopa-
thies and Wilson disease), drugs (aminoglycosides, ifosfamide, out-
dated tetracyclines and carbonic anhydrase inhibitors) and heavy
metal poisoning. Several genetic defects in specific proximal tubule
Tubular disease
transporters leading to primary isolated RTA have been recognized
in the last years. Autosomal-recessive PRTA associated with ocular
abnormalities, short stature and mental retardation is caused by a
genetic defect in the Na+/HCO 3 cotransporter NBC1 located in the
basolateral membrane of the proximal tubular cell. An additional
entity leading to autosomal-recessive PRTA and osteopetrosis is due
to mutations in the gene encoding carbonic anhydrase II, a cyto-
plasmatic enzyme responsible for the generation of HCO 3 and H+
from H2O and CO2. The genetic defect in this enzyme, which operates
in both the proximal and distal tubule, can lead to combined distal
and proximal RTA (previously known as RTA type 3).
5 RTA types 1 and 4 are characterized by a positive urinary
anion gap which is due to impaired tubular NH+4 production or
secretion.
6 DRTA is characterized by an impaired distal H+ secretion and,
hence, a failure to lower urine pH in the presence of acidosis. Several
different mechanisms are responsible for this type of RTA:
Secretory defect a defect in the H+-ATPase pump of the inter-
calated cell in the CCD. This abnormality can be a primary-genetic
disorder, or secondary to autoimmune diseases (SLE, Sjogren
syndrome).
Gradient defect an increase in membrane permeability causing
backleak of luminal H+ in CCD cells. This condition is observed for
example in children treated with amphotericin B.
Voltage-dependent defect a reduction in CCD Na+ reabsorption
which diminishes the luminal electronegativity, thus impairing the
ability to secrete H+. This type of DRTA is accompanied by hyperka-
lemia and is seen in markedly volume-depleted children and sec-
ondary to amiloride treatment.
A cardinal feature of DRTA is nephrolithiasis/nephrocalcinosis
caused by calcium- phosphate complexes. The reason for this abnor-
mality is the combination of the acidic urine and hypocitraturia pro-
moting Ca-phosphorus precipitation. Mutations in the gene encod-
ing the anion exchanger AE1 located in the -intercalated cells in the
CCD lead to both autosomal-dominant and autosomal-recessive
DRTA. In the milder, autosomal-dominant type, the disease can man-
ifest as mild metabolic acidosis in older children or even adults,
whereas in the recessive type, which is seen mainly in the southeast
Asian population, the clinical picture includes DRTA with hemolytic
anemia. Autosomal-recessive DRTA coupled with sensorineural
hearing loss is caused by a genetic defect in the B1 subunit of the
H+-ATPase transporter.
7 The primary pathogenic mechanism of RTA type IV is
aldosterone deficiency or resistance. In this type of RTA, the ability
to acidify the urine is intact but NH+4 excretion and thus net acid
excretion is reduced. Hyperkalemia is a main feature of this type of
RTA. Low plasma aldosterone levels with elevated PRA is generally
observed in endocrine disorders such as congenital adrenal hypo-
plasia, salt-losing forms of CAH or in rare inherited defects of aldo-
I. Eisenstein P. Goodyer I. Zelikovic Renal tubular acidosis
sterone biosynthesis called CMO deficiency types I and II. Adrenal
cortical failure is observed in Addison disease and in adrenoleuko-
dystrophy, which is very rare in children.
Hyporeninemic hypoaldosteronism is observed in patients with dia-
betic nephropathy or chronic tubolointerstitial disorders. Although
considered rare in children, hyporeninemic hypoaldosteronism is
probably more common in this age group than previously thought.
Gordon syndrome, also called pseudohypoaldosteronism type 2, is a
hereditary, autosomal-dominant disorder caused by gain of function
mutations in the genes encoding WNK1 or WNK4 kinases. The con-
sequence of the mutation is increased NaCl reabsorption in the distal
convoluted tubule which results in hypervolemia, hypertension,
hyporeninemic hypoaldosteronism, hyperkalemia and type 4 RTA.
Aldosterone resistance with elevated plasma levels of aldosterone, is
observed in PHA 1. This hereditary disorder presents clinically with
renal sodium wasting, hyperkalemia and metabolic acidosis. There
are two forms of PHA 1: in the renal, autosomal-dominant form, the
aldosterone resistance is limited to the kidney and is due to muta-
tions in the gene encoding the mineralocorticoid receptor. In the
autosomal-recessive multiple-end-organ form, the aldosterone
resistance is present in many organs (kidney, colon, lung, sweat and
salivary glands) and is due to mutations in one of the -, -, or -sub-
units of the epithelial Na+ channel. There is also a secondary form
of aldosterone resistance, called PHA type 3, frequently observed in
infants with obstructive uropathy and/or urinary tract infection.
Selected reading
Fry AC, Karet FE: Inherited renal acidosis. Physiology 2007;22:
202211.
Herrin TH: Renal tubular acidosis; in Avner ED, Harmon WE,
Niaudet P (eds): Pediatric Nephrology, ed 5. Philadelphia,
Lippincott Williams & Wilkins, 2004, pp 757776.
Nicoletta JA, Schwartz GJ: Distal renal tubular acidosis. Curr Opin
Pediatr 2004;16:194198.
Rodrguez Soriano J: Renal tubular acidosis: the clinical entity.
J Am Soc Nephrol 2002;13:21602170.
Rose BD, Post TW: Clinical Physiology of Acid-Base and Electrolyte
Disorders, ed 5. New York, McGraw-Hill, 2001, pp 612627.
Scheinman SJ, Guay-Woodford LM, Thakker RV, Warnock DG:
Genetic disorders of renal electrolyte transport. N Engl J Med
1999;340:11771187.
Zelikovic I: Molecular pathophysiology of tubular transport
disorders. Pediatr Nephrol 2001;16:919935.
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Proximal tubulopathy (Fanconi syndrome)
62

Isolated transport defect / Broad proximal tubular dysfunction 0

Cystinuria Phosphaturia (TRP <85% with low serum PO4)

Lysinuric protein intolerance PRTA (bicarbonate therapy >3 mEq/kg/day)
Hypophosphatemic rickets Aminoaciduria (quantitative urine amino acids)
ISHG Tubular proteinuria (B2-microglobulinuria)
PRTA Glucosuria
Potassium wasting (TTKG >12)
Salt wasting (FENa >1% with elevated renin)

Drugs 1 Inherited causes 2 Hyperparathyroidism 3

Chemotherapy (cisplatin/ifosfamide) Cystinosis
Valproic acid Dent disease
Outdated tetracyclines Mitochondriopathies
Glue sniffing Fanconi-Bickel glycogenosis
Heavy metal poisoning Tyrosinemia
Aminoglycosides Wilson disease
Lowe syndrome
Galactosemia
Hereditary fructose intolerance
Idiopathic Fanconi syndrome

Therapeutic strategies 4
Fluids, NaCl, KCl, NaHCO3 , PO4 , calcitrol, carnitine, specific therapy,

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 1 Fanconi syndrome should always be distin-
guished from diseases associated with an isolated
defect in renal proximal tubular transport. In cystinuria,
amino acid wasting is restricted to cystine, ornithine,
lysine and artinine. In hereditary hypophosphatemia,
proximal tubular reabsorption of phosphate is de-
pressed but aminoaciduria is absent. For details, see
algorithms on Rickets and Hypophosphatemia. ISHG,
a relatively benign condition, is caused by a genetic
defect in the Na+-glucose cotransporter, SGLT2.
2 In the early 1930s, Fanconi (Switzerland),
DeToni (Italy) and Debre (France) described a renal
tubular syndrome in children characterized by massive
urinary wasting of electrolytes, glucosuria and pro-
teinuria, causing acidosis, rickets and severe failure to
thrive. In retrospect, it is evident that these patients
had cystinosis (see below) and exhibited broad dys-
function of the proximal tubule. The defect in phos-
phate reabsorption may be assessed by calculating
the tubular reabsorption of phosphate: 1 (urine PO4/
serum PO4) (serum creatinine/urine creatinine); val-
ues of less than 0.85, in the face of hypophosphatemia,
demonstrate the defect. proximal tubular losses of
bicarbonate may be massive with acidosis requiring
replacement of 1020 mEq/kg/day; losses of this mag-
nitude in the face of a nonanion gap acidosis indicate
proximal RTA. Aminoaciduria may be quantified on an
automated analyzer and normalized for urine creati-
nine; all amino acid transport systems are affected.
LMW proteins are normally filtered through the glom-
erulus and reabsorbed (>95%) by endocytosis; in Fan-
coni syndrome there may be several grams of LMW
protein excreted per day; this is best proven by mea-
suring the 24-hour excretion of 2-microglobulin or
retinol binding protein. Glucosuria may be detected by
standard dipsticks or by direct quantification. There is
no simple test for salt wasting which distinguishes a
proximal tubular defect from dysfunction at more
distal sites, but Fanconi syndrome is associated with
NaCl losses of >1% of the filtered load in the face of
volume contraction: fractional excretion of sodium =
(urine Na/serum Na) (serum creatinine/urine creati-
nine) 100%. Potassium wasting is identified by cal-
culating the trans-tubular potassium gradient (TTKG)
>12. TTKG = (urine K) 300/urine osmolarity); normal
63
range = 46. Some of the patients with Fanconi syn-
drome also have hypercalciuria.
3 In adults, the most common cause of Fanconi
syndrome is drug toxicity and this should also be con-
sidered in children; it may be noted following chemo-
Tubular disease
therapy with ifosfamide or cisplatin. Heavy metal
poisoning, glue sniffing, and other drugs have also
been reported to cause proximal tubular dysfunction.
4 Most pediatric referrals for Fanconi syn-
drome involve a hereditary disease; proximal tubular
dysfunction may involve all transport mechanisms or
may affect only a few (partial Fanconi syndrome).
Cystinosis nearly always causes a complete Fanconi
syndrome and the diagnosis is confirmed by measure-
ment of leukocyte cystine on an automated amino acid
analyzer or by slip lamp identification of corneal crys-
tals. Cystinosis is due to mutations of the cystinosin
gene on chromosome 17p13, encoding a lysosomal
membrane protein which selectively permits cystine
to exit from the lysosome into the cytoplasm. Mechan-
ical disruption of lysosomes or interference with the
endocytotic membrane recycling pathway causes a
broad, severe disturbance of proximal tubule transport
functions. Dent disease is X-linked and caused by mu-
tations of a chloride channel gene (CLCN5) which dis-
rupts normal endocyctotic mechanisms; most patients
with Dent disease are characterized by hypercalciuria,
massive LMW proteinuria and chronic renal failure.
Proximal tubule dysfunction is quite variable depend-
ing on the mutation. Mitochondriopathies are occa-
sionally associated with lactic acidosis and may be
maternally inherited (mitochondrial genes) or due to
autosomal-recessive (nuclear genes) defects in the
electron transport chain. The mitochondriopathies
often have neuromuscular manifestations, may have
episodes of rapid deterioration during intercurrent ill-
ness and usually require tissue diagnosis. In Fanconi-
Bickel syndrome, children present with hepatomegaly
due to glycogenosis of the liver and kidneys; The syn-
drome is caused by mutations in the facilitated GLUT2.
Massive glucosuria is a prominent feature in addition
to other proximal tubule dysfunctions. Proximal tubule
dysfunction is often incomplete in Wilson disease and
tyrosinemia where it can fluctuate with metabolic cri-
sis. In glactosemia, hereditary fructose intolerance
and Lowe syndrome there are usually characteristic
extrarenal features which bring the patient to medical
attention.
5 Aminoaciduria and phosphaturia may be
seen in hyperparathyroidism states, but this is uncom-
mon in children.
6 In general, the strategy for supportive thera-
py of Fanconi syndrome is to replace fluid and the
inorganic solutes lost in the urine. Amino acids, LMW
P. Goodyer I. Eisenstein I. Zelikovic
proteins and glucose do not usually deplete metabolic
pools as long as adequate nutrition is maintained. On
the other hand, NaCl supplementation (28 mEq/kg/
day) to avoid chronic volume contraction often im-
proves growth failure. Dose may be titrated to plasma
renin if there is no growth improvement. The bicar-
bonate requirement may vary from 2 to 20 mEq/kg/day
depending on the severity of tubular dysfunction; this
may also be conveniently supplied as Na/K citrate (ci-
trate consumes H+ when metabolized in the Krebs cy-
cle). Oral phosphate supplements (25100 mg elemen-
tal phosphate/kg divided in 34 doses/day) are adjust-
ed to assure that serum phosphate comes into the nor-
mal range 4560 min after each dose. The aim is to
provide adequate serum phosphate for bone mineral-
ization and linear growth. However, phosphate serves
as an oral calcium binder, stimulating PTH release.
Since proximal tubular synthesis of 1,25(OH)2 vitamin
D may also be affected, oral calcitriol 1040 ng/kg/day
in 2 divided doses is usually needed to avoid hyper-
parathyroidism, under close monitoring of urine cal-
cium levels, and periodic renal sonogram to prevent
hypercalciuria and nephrolithiasis. Depending on the
underlying disease, specific therapy (such as cysta-
mine in cystinosis) is indicated.
Selected reading
Fanconi G: Die nicht diabetischen Glykosurien und
Hyperglykmien des lteren Kindes. Jahrb Kinder-
heilk 1931;133:257300.
Forman JW: Cystinosis and Fanconi syndrome;
in Avner ED, Harmon WE, Niaudet P (eds): Pediatric
Nephrology, ed 5. Philadelphia, Lippincott
Williams & Wilkins, 2004, pp 789806.
Gahl WA, Theoene JG, Schneider J: Cystinosis.
N Engl J Med 2002;347:111121.
Hsu SY, Tsai IJ, Tsau YK: Comparison of growth in
primary Fanconi syndrome and proximal renal
tubular acidosis. Pediatr Nephrol 2005;20:460464.
Kuwertz-Broking E, Koch HG, Marquardt T, Rossi R,
Helmchen U, Muller-Hocker J, Harms E, Bulla M:
Renal Fanconi syndrome: first sign of partial
respiratory chain complex IV deficiency. Pediatr
Nephrol 2000;14:495498.
Santer R, Steinmann B, Schaub J: Fanconi-Bickel
syndrome: a congenital defect of facilitative glucose
transport. Curr Mol Med 2002;2:213227.
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Proximal tubulopathy (Fanconi syndrome)
 Tubular disease P. Goodyer I. Eisenstein I. Zelikovic Polyuria

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Polyuria
64

Renal salt wasting Renal free water loss 3

FENa+ >1% FENa+ <1%

Urine osm = 200400 mosm/l Urine osm <200 mosm/l

Fanconi syndrome 0 Primary NDI Central DI

salt-losing states 1

Urinary tract obstruction X-linked Congenital

Nephronophthisis Autosomal recessive Acquired
Bartter syndrome Drug-induced
Gitelman syndrome Hypercalcemia
Pseudohypoaldosteronism Hypokalemia
Adrenogenital syndrome

Salt and water replacement 2 Water replacement 4 DDAVP

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 1 Polyuria is divided into conditions where high
urine volume reflects renal tubular salt wasting and
those in which there is primary free water loss. To
make this distinction, the patient must be in a state of
relative volume contraction (may be confirmed by el-
evated plasma renin; avoid assessment during rapid
intravenous fluid infusions). Under these conditions,
a fractional excretion of sodium (FENa+) >1% indicates
a salt-losing state. FENa+ = [Urine sodium/serum
sodium] [serum creatinine/urine creatinine] 100%.
If FENa+ is <1% under these conditions, the next goal is
to determine whether polyuria is due to an osmotic
solute such as glucose or mannitol; urine osmolarity
less than 150 mosm/l suggests dysfunction of the col-
lecting duct and free water loss.
2 Children with polyuria due to the renal Fan-
coni syndrome are readily identified by tests of proxi-
mal tubular dysfunction (tubular reabsorption of phos-
phate, proximal RTA, aminoaciduria, LMW proteinuria,
etc.). For details, see algorithm on Faconi syndrome.
3 Obstructive uropathy damages the distal
nephron causing polyuria from defective reabsorption
of both salt and water in collecting duct. Polyuria is
also characteristic of several inherited salt-losing con-
ditions (exposure to diuretic drugs should be excluded
by history). Nephronophthisis (medullary cystic dis-
ease complex) is a group of autosomal-recessive dis-
eases caused by mutations in several genes. In over
90% of the cases of juvenile nephronophthisis (NPHS1)
polyuria is noted in childhood well before progressive
renal insufficiency becomes evident between 10 and
20 years. In Europe, NPH1 accounts for 1015% of chil-
dren with ESRD. While FENa+ may reflect salt-wasting,
urine is usually dilute, implying that polyuria may also
reflect free water losses from collecting duct dysfunc-
tion associated with characteristic medullary cysts
and interstitial disease. Bartter syndrome is caused by
mutations in various genes involved in salt reabsorp-
tion by the thick ascending limb of the loop of Henle;
the syndrome is mimicked by furosemide and associ-
ated with striking hypercalciuria. In Gitelman syn-
drome, the gene for sodium/chloride reabsorption in
the distal convoluted is mutated, but salt losses are
modest and often only mild polyuria exists; hypocalci-
65
uria is a characteristic finding. Pseudohypoaldosteron-
ism and adrenogenital syndrome are easily distin-
guished by the presence of acidosis and/or hyperkale-
mia.
Tubular disease
4 In many of the conditions associated with
salt wasting, the principal of therapy is replacement of
fluids and electrolyte losses in the urine.
5 Children who present with polyuria due to
renal free water losses, must first be distinguished
from those with psychogenic polydipsia. Since any
form of chronic polyuria washes out the renal medul-
lary concentrating gradient, the initial response to
water deprivation or vasopressin may be blunted;
most fluid restriction daily intranasal or subcutane-
ous DDAVP (0.52 g) for 23 days may sometimes be
needed to demonstrate a completely normal renal
response. Classical NDI is an X-linked disease (females
are asymptomatic or mildly affected) caused by inacti-
vating mutations of the vasopressin receptor in the
renal collecting duct. A rare autosomal-recessive form
of NDI is due to mutations of the aquaporin II gene,
preventing water flux through the collecting tubule.
Important conditions leading to secondary NDI include
hypercalcemia, hypokalemia, sickle cell disease,
chronic renal failure and drugs (lithium, demeclocy-
cline). In infant males, polyuria and urine osmolarity of
50100 mosm/l are evident in the first days of life, but
water loss increases rapidly in the postnatal period
and should be diagnosed as quickly as possible to
avoid brain injury from dehydration. Whenever pos-
sible, urgent molecular diagnosis is advisable. A short
water deprivation test is also diagnostic, but great care
must be taken to avoid excessive dehydration; body
weights are taken every 30 min. Water is withheld until
urine osmolarity reaches a plateau as indicated by an
hourly increase of <30 mosm/l for 3 successive hours
or until body weight drops by 3%. DDAVP (0.52 g) is
then administered subcutaneously and urine osmolar-
ity is measured 60 minutes afterward. In children with
CDI, urine osmolarity is low (<200 mosm/l) but rises by
>50% following DDAVP. CDI may be congenital or
secondary to pituitary ablation by trauma or tumors.
In children with inherited NDI, urine osmolarity is
also low (50150 mosm/l) and there is no significant
increase (<20%) after DDAVP. Intermediate results may
reflect partial CDI or mild NDI mutations.
6 The distinction between salt-wasting states
and diabetes insipidus is crucial since the approaches
to therapy are quite different. In NDI, the strategy is to
create mild volume contraction with hydrochlorothia-
zide (12 mg/kg/day) and restricted renal solute load;
P. Goodyer I. Eisenstein I. Zelikovic
naprosyn (510 mg/kg/day in divided doses) may then
be used to blunt the compensatory production of
renal prostaglandin. The combination of these effects
enhances proximal tubular fluid reabsorption. Con-
versely, the use of a diuretic in Bartter syndrome may
be life-threatening, since marked volume contraction
already exists. The strategy here is to introduce
naprosyn plus oral salt supplements (48 mEq/kg/day);
naprosyn again blunts prostaglandin production, re-
ducing intraglomerular pressure and, thus, the filtered
load of salt. Doses are adjusted to bring plasma renin
to 23 times normal. Therapy of other conditions in
this algorithm involves additional considerations, but
replacement of salt or free water is important in each
one.
Selected reading
Bichet DG, Fijiwara TM: Nephrogenic diabetes
insipidus; in Sciver C, Beaudet A, Sly W, Valle D
(eds): The Metabolic and Molecular Bases of Inher-
ited Disease. New York, McGraw-Hill, 2001, vol III,
pp 49094932.
Pinelli JM, Symington AJ, Cunningham KA, Paes BA:
Case report and review of the prenatal implications
of maternal lithium use. Am J Obstet Gynecol 2002;
187:245249.
Robben JH, Knoers NV, Deen PM: Cell biological
aspects of the vasopressin type-2 receptor and
aquaporin 2 water channel in nephrogenic diabetes
insipidus. Am J Physiol Renal Physiol 2006;291:
F257F270.
Saunier S, Salomon R, Antignac C: Nephronoph-
thisis. Curr Opin Genet Dev 2005;15:324331.
Saxena A, Hanukogulu I, Saxena D, Thompson RJ,
Gardiner RM, Hanukoglu A: Novel mutations
responsible for autosomal recessive multisystem
pseudohypoaldosteronism and sequence variants
in epithelial sodium channel alpha-, beta-, and
gamma-subunit genes. J Clin Endocrinol Metab
2002;87:33443350.
Zelikovic I: Hypokalaemic salt-losing tubulopathies:
an evolving story. Nephrol Dial Transplant 2003;
18:16961700.
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Polyuria
 Tubular disease J. Smith F.B. Stapleton Hypouricemia

Hypouricemia
66 Serum uric acid <2 mg/dl

Determine urinary uric acid excretion /

Normal or decreased uric acid excretion Increased uric acid excretion

(urinary uric acid <0.34 mg/dl GFR*) (urinary uric acid >0.57 mg/dl GFR**)
* Mean uric acid excretion for children older than 2 years ** Mean +2 SD for children older than 2 years

Medications 0 Medications 3
Ex. allopurinol Idiopathic renal hypouricemia 4
Metabolic disorders 1 Generalized proximal tubular defect 5
Xanthinuria 2 SIADH, extracellular volume expansion 6

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 1 Urinary uric acid concentration is determined
by glomerular filtration of uric acid as well as by a
complex array of reabsorption and secretion process-
es of this substance in the renal tubule. Uric acid
excretion (in a urine sample) is expressed as uric acid
(Ua) excretion per deciliter of GFR which is calculated
according to the formula (UUa SCr/UCr), where Cr is
creatinine and U and S are concentrations in mg/dl in
urine and serum, respectively.
2 The table lists some of the medications that
are associated with hypouricemia. Allopurinol, a com-
petitive inhibitor of the enzyme xanthine oxidase, is
the most commonly implicated medication which
leads to hypouricemia by decreased uric acid produc-
tion.
3 Persistent hypouricemia has been associated
with deficiencies of enzymes such as nucleoside phos-
phorylase and PP-ribose-P-synthetase.
4 Xanthinuria is an autosomal-recessive dis-
order caused by a deficiency of the enzyme xanthine
dehydrogenase (and, in some cases, also aldehyde
oxidase) and characterized by xanthine urolithiasis,
myopathy, and polyarthritis.
5 Hypouricemia and uric acid stones may
develop due to administration of drugs that inhibit
tubular reabsorption or increase tubular secretion of
uric acid (table).
6 Idiopathic renal hypouricemia is an inherited
disorder caused by a defect in the proximal tubular
urate/anion exchanger URAT1 which leads to renal
urate wasting. The disease is characterized by exer-
cise-induced acute renal failure and nephrolithiasis.
7 Generalized defects in proximal tubular func-
tion may lead to renal urate wasting. Examples include
idiopathic Fanconi syndrome, cystinosis, Wilson dis-
ease and galactosemia. Hodgkin disease and paren-
teral alimentation are also associated with uricosuria
and hypouricemia.
8 In SIADH, antidiuresis results in expansion of
the extracellular fluid compartment, which then leads
to increased urinary excretion of uric acid.
9 The development of hyperglycemia, glucos-
uria and osmotic diuresis is associated with decreased
urate reabsorption in the proximal tubule.
Selected reading
Baldree LA, Stapleton FB: Uric acid metabolism in
children. Pediatr Clin N Am 1990;37:391418.
Cameron JS, Moro F, Simmonds HA: Gout, uric acid
and purine metabolism in paediatric nephrology.
Pediatr Nephrol 1993;7:105118.
Hediger MA, Johnson RJ, Miyazaki H, Endou H:
Molecular physiology of urate transport. Physiology
2005;20:125133.
Icihida K, Hosoyamada M, Hisatome I, Enomoto A,
Hikita M, Endou H, Hosoya T: Clinical and molecular
analysis of patients with renal hypouricemia in
Japan: influence of URAT1 gene on urinary urate
excretion. J Am Soc Nephrol 2004;15:164173.
Stapleton FB, Linshaw MA, Hassansein K: Uric acid
excretion in normal children. J Pediatr 1978;92:911.

Table. Selected medications associated with hypouricemia

Decreased uric acid production

Allopurinol
Azouridine
Orotic acid
Oxypurinol
Increased uric acid secretion
Ascorbic acid (high dose)
Citrate
Dicumarol
Most diuretics (acutely, before extracellular volume contraction)
Estrogens
Glycerol guaiacholate
Glycine
Halofenate
Outdated tetracyclines (Fanconi syndrome)
Iopanoic acid (radiocontrast agent)
67 Meglumine iodipamide
Phenylbutazone
Phenol sulfophthalein
p-Nitrophenylbutazone
Probenecid

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Salicylates (high dose)
Sodium diatrizoate (radiocontrast agent)

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Tubular disease J. Smith F.B. Stapleton Hypouricemia
 Tubular disease F.B. Stapleton J. Smith Hyperuricemia

/
Hyperuricemia
68
Elevated serum uric acid level (table 1)

Complete medical and family history

Positive medication history / Negative family history Positive family history

(e.g. diuretics)

Examine extracellular fluid volume status

Normal ECF volume Increased ECF volume Decreased ECF volume Increased uric acid excretion* Decreased uric acid excretion*

Cell lysis Acute renal failure 4 Diarrhea 5 Genetic diseases 2 Uromodulim disorders 3
Hemolysis Congestive heart failure Nephrogenic diabetes insipidus HGPRT deficiency FJHN
Polycythemia (Lesch-Nyhan syndrome) MCKD2
Leukemia/lymphoma PRPS overactivity GCKD
Tumor lysis syndrome G6P deficiency
Exercise, acidosis/alkalosis 0 (glycogen storage disease type 1)
Hypertension 1
Hereditary/metabolic conditions 23
Miscellaneous conditions
Hypothyroidism
Hypoparathyroidism
Psoriasis
Sarcoidosis
Obesity
Starvation
Down syndrome

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* see Hypouricemia, for values of urinary acid excretion

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 1 There are numerous medications that alter
the metabolism of uric acid. Diuretics are the class of
drugs most commonly associated with hyperuricemia
(table 2). They initially cause a uricosuric response
which is followed by decreased renal urate excretion.
The antiuricosuric response is due to the extracellular
fluid volume depletion induced by the diuretics and
can be abolished by replacing urinary sodium losses.
2 The lactic acidemia induced by exercise
reduces uric acid excretion. Respiratory acidosis and
diabetic ketoacidosis have been associated with
reduced uric acid excretion. Metabolic alkalosis (espe-
cially if associated with extracellular volume contrac-
tion) can promote uric acid retention.
3 Hyperuricemia is a common finding in
untreated hypertensive patients. It has been shown
that uric acid affects vascular smooth muscle cells
and endothelial cell proliferation and hyperuricemia
has been implicated in the pathogenesis of hyper-
tension and vascular disease.
4 These are examples of genetic diseases
which are associated with hyperuricemia. HGPRT defi-
ciency (Lesch-Nyan syndrome) is an X-linked reces-
sive disorder in males. It is characterized by clinical
gout, hyperuricemia, nephrolithiasis, and a neurologic
syndrome of cerebral palsy, mental retardation, and
obsessive destructive and self-mutilating behavior.
The disease can be diagnosed by demonstrating low
HGPRT level in erythrocytes of affected patients. PRPS
overactivity disorder is a heterogeneous X-linked
disorder associated with hyperuricemia, gout and
nephrolithiasis frequently presenting in children less
than 10 years of age. G6P deficiency (glycogen storage
69 Table 1. Normal serum values (mean + SD) for uric acid in neonates and children
2933 weeks 3437 weeks 3840 weeks Male
34 years
Serum uric acid, 7.71 + 2.65 6.04 + 2.19 5.19 + 2.65
mg/dl
Tubular disease
disease type 1) is an autosomal-recessive enzymatic
Selected reading
defect. Patients usually display hyperuricemia during
infancy and gout later in life. In this disease there is Baldree LA, Stapleton FB: Uric acid metabolism in
increased uric acid production due to depletion of children. Pediatr Clin N Am 1990;37:391418.
intracellular high energy phosphates and diffusion of Cameron JS, Moro F, Simmonds HA: Gout, uric acid
adenosine out of the cell. and purine metabolism in paediatric nephrology.
Pediatr Nephrol 1993;7:105118.
5 FJHN, autosomal-dominant medullary cystic Cameron JS, Simmonds HA: Hereditary hyperurice-
kidney disease type 2 (MCKD2) and autosomal-domi- mia and renal disease. Semin Nephrol 2005;25:918.
nant GCKD constitute a group of hereditary renal dis- Scolari F, Caridi G, Rampoldi L, et al: Uromodulin
eases that share an autosomal dominant pattern of storage diseases: clinical aspects and mechanisms.
transmission as well as hyperuricemia/gout and pro- Am J Kidney Dis 2004;44:987999.
gressive renal damage that may cause end-stage renal Stapleton FB, Linshaw MA, Hassansein K: Uric acid
disease. Histologically, FJHN and MCKD2 are charac- excretion in normal children. J Pediatr 1978;92:911.
terized by chronic interstitial nephritis with thickening
of the tubular basement membrane and corticomedul-
lary cysts, while GCKD is characterized by diffuse glo-
merular cysts caused by marked dilatation of Bowman
space in most glomeruli. These three diseases are
caused by mutations in the gene encoding uromodu-
lim (Tamm-Horsfall protein), a protein which is exclu-
sively expressed in the thick ascending limb of the
loop of Henle and the distal convoluted tubule. Lack of
uromodulim function is associated with impairment of
the urine-concentrating process, resulting in water
depletion and hyperuricemia.
6 In acute renal failure, there is a decrease in
the filtered load of uric acid presented to the renal Table 2. Selected medications associated with hyperuricemia
tubules. In addition, there may be increased uric acid
synthesis secondary to catabolism. Increase uric acid production
Vitamin B12 (acute administration)
Cytotoxic drugs
7 Diarrhea-induced volume contraction Ethanol
diminishes urinary uric acid excretion and leads to 2-Ethylamoni-1,3,4-thiadiazole
hyperuricemia. Fructose
Nicotinic acid
Pancreatic extract
Decrease uric acid excretion
Diuretics (indirectly when ECF volume is diminished)
Acetazolamide
Amiloride
Chlorthalidone
Furosemide
Organomercurials
Thiazides
Triamterene
Ethambutol
Ethanol
Laxative abuse (alkalosis)
Female Male Female Male Female Levodopa
34 years 59 years 59 years 1014 years 1014 years Methoxyflurane
Nicotinic acid
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3.45 + 1.01 3.44 + 0.80 3.63 + 1.04 3.71 + 0.92 4.28 + 1.19 4.09 + 1.20 Pyrazinamide
Salicylates (low dose)
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F.B. Stapleton J. Smith Hyperuricemia
 Tubular disease G. Ariceta B. Hoppe C.B. Langman Rickets

/
Rickets
70 Serum total [Ca] 0

Normal Elevated Lowered

PTH 1 Jansen syndrome @ PTH 1

Vitamin D intoxication
Malignancy

Elevated Normal Normal Elevated

25(OH)D 2 Serum [P] 9 25(OH)D 2

Lowered Normal Normal Lowered Lowered Elevated

1,25(OH)2D 2

Vitamin D depletion 3 Chronic kidney disease 6 Pseudorickets : X-linked hypophosphatemic Disease not Vitamin D depletion 3 Lowered Elevated
Malabsorption 4 Early vitamin D treatment 7 rickets ; identified yet 8 Malabsorption 4
Liver diseases 5 Disease not identified yet 8 Autosomal dominant Liver diseases 5
hypophosphatemic rickets <
Tumor-induced osteomalacia = Chronic kidney Vitamin D-resistant
Hypophosphatemic rickets with disease 6 rickets B
hypercalciuria > 1A-Hydroxylase Dietary Ca deficiency

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 1 Rickets is the clinical expression of undermineralization of
osteoid, produced at the epiphysis of growing bones, leading to disor-
dered endochondral bone formation. It represents not a single disease,
but a process with wide heterogeneity. Clinical expression may occur
in the skull, chest, pelvis, upper and lower extremities, with palpable,
knobby-like enlargements. Skeletal deformity may result in a knock-
kneed or bowed appearance of the lower extremities. Dental develop-
ment may be impaired in primary and secondary dentition as well. Ra-
diographically, the most characteristic changes are in the epiphyses,
with widening, and an irregular, frayed, and cupped appearance. The
cortices are thin, and the bone appears with reduced density.
2 Serum total calcium [Ca] is an easy differential point to begin
the evaluation of rickets. Normal ranges have been established for age.
Its value may be lowered with concomitant hypoalbuminemia, or
raised with concomitant hyperproteinemia. Thus blood ionized calcium
indicates if there is a real calcium disturbance.
3 Serum PTH refers to an immunometric assay measurement
to detect 1-84 PTH. While controversy exists as to the meaning of first
generation assays that may detect other N-terminal fragments, and
thereby elevate the total PTH level, it is not clear that the newer assays
offer better discrimination for rachitic diseases. PTH value must be in-
terpreted with respect to either serum total Ca or ionized Ca.
4 Measurement of circulating vitamin D metabolites is useful in
the differential diagnosis. 25(OH)D is produced in the liver, and repre-
sents the major substrate of the vitamin D. Its level defines sufficiency
of the vitamin. Despite some ethnic differences 25(OH)D levels <5 ng/
ml are considered deficient. Values between 5 and 15 ng/ml should be
interpreted carefully with respect to the presence or absence of rickets.
Circulating levels of 1,25(OH)2D, produced in the kidney proximal tu-
bule, but with some minor extrarenal production too, are often prob-
lematic to interpret, except in the few circumstances noted in this algo-
rithm. The normal range is 2080 pg/ml.
5 Vitamin D depletion is a common cause of rickets. Depletion
is caused by a dietary lack of the parent compound, and/or insufficient
sunlight exposure to have dermal conversion of precursors into vita-
min D. After restoration of body vitamin D stores the rachitic bone
heals completely with no long-term consequences generally.
6 Malabsorption may produce functional vitamin D deficiency
due to its solubility. Processes that impair fat absorption (sprue, inflam-
matory bowel diseases, cystic fibrosis, etc.) will lead to lowered vita-
min D body stores and reduced conversion to the 25(OH)D substrate.
71 7 25(OH)D is produced in hepatocytes by a cytosolic mixed
function P450 enzyme, whose gene has been cloned and sequenced. Al-
terations in hepatic production leading to substrate deficiency include
hepatic mass reduction, alterations in P450 enzyme activity, xenobiotics
(antibiotics, anti-epileptics, etc.), or enterohepatic circulation (cystic
fibrosis), since nearly 80% of daily production of 25(OH)D is salvaged
by this route. To date, there are no well-described cases of absence of
the hepatic vitamin-D-25-hydroxylase enzyme in a child with rickets.
Tubular disease
8 CKD refers to declining glomerular filtration rates, and is
staged from 1 to 5. The inability to produce 1,25(OH)2D may appear in
CKD advanced stages (4 and 5) from the absence of sufficient kidney
mass, or related to hyperphosphatemia. In earlier CKD stages (2, 3)
children may suffer metabolic acidosis that suppresses 1,25(OH)2D pro-
duction also.
9 During vitamin D repletion, there are dys-synchronous tem-
poral changes with elevation of PTH remaining for several weeks to
months after restoration of circulating levels of 25(OH)D.
10 Disease not identified yet (DNIY). The clinician should be criti-
cal in these circumstances. While new diseases, or explanations for
existing diseases, arise continually, it is often misleading information,
or misguided assays, that result in the disease not indentified yet clas-
sification.
11 Serum phosphorus (P) varies with age, time of day, and state
of acid-base balance. Normative values have been established. Re-
duced P interpretation needs concomitant evaluation of P kidney han-
dling (see algorithm for Hypophosphatemia).
12 Pseudorickets refers to other metabolic, genetic, or structural
diseases in which the radiographic appearance more commonly than
the clinical appearance resembles rickets. They include intrinsic bone
disorders (chondrodysplasias), mucopolysaccharidoses, sex steroid
hormonal insufficiency disorders, vitamin C deficiency, osteogenesis
imperfecta, hypophosphatasia, osteopetrosis, craniometaphyseal dys-
plasia, and others.
13 X-linked hypophosphatemic rickets (XLH) is an X-linked,
dominant disease caused by Phex gene (Phosphate regulating with
Homologies to Endopeptidases on the X chromosome) mutations. The
condition is associated with inappropriate phosphaturia. Levels of
1,25(OH)2D, that should be stimulated by hypophosphatemia, are often
in the normal range, suggesting a second defect in the vitamin D
system too. Phenotype-genotype relationships await clarification.
14 XLH expression is mimicked by autosomal-dominant hypo-
phosphatemic rickets, produced by mutations in the gene encoding
FGF-23, a potent phosphaturic agent.
15 Some primitive, ectodermally derived tumors may produce a
substance leading to inappropriate phosphaturia, hypophosphatemia,
and rickets (in children) or osteomalacia (in adults). Hence, tumor-in-
duced osteomalacia denomination has been applied to both conditions.
Removal of the tumor results in complete correction of the rachitic
state, although the presence of the tumor may be difficult to demon-
strate.
16 Two inheritance patterns, autosomal dominant or recessive,
have been described for hereditary hypophosphatemia with renal hy-
percalciuria. In both, the hypophosphatemia is accompanied by supra-
physiologic levels of 1,25(OH)2D. The genetic abnormality in hereditary
hypophosphatemia with renal hypercalciuria (HHRH) is due to muta-
G. Ariceta B. Hoppe C.B. Langman Rickets
tions in the gene encoding NaPi IIc, a Na-P cotransporter of the proxi-
mal tubule. Any patient with hereditary hypophosphatemic rickets
should be referred to an experienced center or practitioner in the nu-
ances of its care.
17 Children with idiopathic, or syndromic Fanconi syndrome
(see specific Algorithm chapter) commonly present with rickets. Fac-
tors for its presence include chronic metabolic acidosis, hypophospha-
temia with insufficient production of 1,25(OH)2D, and/or CKD (see foot-
note 14).
18 These diseases may resemble rickets. For details see algo-
rithm on Hypercalemia.
19 Autosomal-recessive, inherited absence of the proximal tu-
bule 25-hydroxyvitamin D-1-hydroxylase has been referred to previ-
ously as vitamin D-dependent rickets, type 1. Currently this disease
entity should be referred as 1-hydroxylase deficiency. It responds to
physiologic replacement doses of the active hormone, 1,25(OH)2D.
20 End-organ resistance to 1,25(OH)2D may occur in presence of
mutated intracellular vitamin D receptor (VDR) resulting in a hypofunc-
tional or absent receptor. The disease has been called vitamin D-de-
pendent rickets, type 2 in the past. The highest blood levels of
1,25(OH)2D in humans are seen here, with values often above 400 pg/ml
(normal, 1580). Any patient with this disorder should be referred to an
experienced center or practitioner in the nuances of its care.
21 Primary dietary calcium deficiency may produce a picture of
rickets in the presence of adequate vitamin D. This picture has been
described in preterm neonates, and young infants and older children in
rural South Africa.
Selected reading
Cho HY, Lee BH, Kang JH, Ha IS, Cheong HI, Choi Y: A clinical and
molecular genetic study of hypophosphatemic rickets in children.
Pediatr Res 2005;58:329333.
Hochberg Z: Vitamin-D-dependent rickets type 2. Horm Res 2002;
58:297302.
Holick MF: Resurrection of vitamin D deficiency and rickets.
J Clin Invest. 2006;116:20622072.
Klein GL, Soriano H, Shulman RJ, Levy M, Jones G, Langman CB:
Hepatic osteodystrophy in chronic cholestasis: evidence for a
multifactorial etiology. Pediatr Transplant 2002;6:136140.
Langman CB: Disorders of phosphorus, calcium and vitamin D;
in Avner ED, Harmon WE, Niaudet P (eds): Pediatric Nephrology, ed 5.
Philadelphia, Lippincott Williams & Wilkins, 2004, pp 237254.
Thacher TD, Fischer PR, Pettifor JM: Rickets: vitamin D and calcium
deficiency. J Bone Miner Res 2007;22:638.
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 Fluid/electrolyte/acid base balance S. Watkins D. Okamura J. Rodrguez Soriano Hyponatremia

/
Hyponatremia
(Serum Na+ <130 mEq/l)

72
Exclude pseudohyponatremia or hypertonic hyponatremia /

Hypovolemia 01 Euvolemia/mild volume excess 01 Hypervolemia 01

Urine sodium (mEq/l) Urine Sodium (mEq/l) Urine sodium (mEq/l)

Variable 8
[Na+] >20 [Na+] <20 [Na+] <20 29 [Na+] >20

Renal losses 2 Extrarenal losses 67

Diuretics Vomiting Glucocorticoid deficiency Cirrhosis Renal failure 2:

Salt-losing nephropathy 3 Diarrhea Hypothyroidism Heart failure
Metabolic alkalosis 4 Burns Primary polydipsia Nephrotic syndrome
Ketonuria Pancreatitis SIADH
Osmotic diuresis Cystic fibrosis
Cerebral salt wasting 5

Sodium and water replacement ; Water restriction ; Sodium and water restriction ;

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 1 It is important to exclude pseudohyponatremia (secondary
to hyperlipidemia or hyperproteinemia) and to exclude hypertonic
hyponatremia (elevated serum osmolality secondary to hyperglyce-
mia or mannitol infusion).
2 Serum sodium will be diminished in the setting of body
water excess, sodium depletion or a combination of the two. A thor-
ough clinical evaluation of the child to determine his volume status is
therefore vital in order to proceed with the work-up: (1) History:
Changes in weight, intake and output (urinary, gastric, stool), medi-
cation history. (2) Examination: Weight, skin changes (edema, turgor),
fontanelle changes, blood pressure/orthostatics, mucous mem-
branes, cardiac gallop.
3 Once fluid status is assessed, patients work-up can be
appropriately directed. Determination of urine Na+ concentration is
essential for narrowing the differential diagnosis. It should be
emphasized that there is no correlation between urinary Na+ level
(which is normally determined by the ECF volume status) and serum
Na+ concentration.
4 Renal etiology: Kidney disease can cause both fluid reten-
tion and excess sodium losses.
5 Salt-losing nephropathies include any form of renal disease
that cause an impairment in sodium reabsorbtion and hence free wa-
ter excretion. Etiologies include: Bartters syndrome and Gitelmans
syndrome, renal tubular acidosis, TIN, pyelonephritis and hypo- or
pseudohypoaldosteronism. Hypoaldosteronism (aldosterone defi-
ciency) will result in high urine sodium and water losses and its main
causes are immune-mediated diseases (polyglandular or isolated),
salt-losing forms of CAH and adrenoleukodystrophy. Pseudohypo-
aldosteronism is caused by primary or acquired diseases character-
ized by end organ resistance to aldosterone. Laboratory investiga-
tion of salt-losing nephropathies includes: Serum and urine osmolar-
ity, serum BUN, creatinine, electrolytes, acid-base status, plasma
aldosterone levels, urinary electrolyte levels and renal sonogram.
6 In metabolic alkalosis (as well as in some forms of RTA)
the hyponatremia is due to urinary losses of Na+ that accompany the
bicarbonaturia.
7 The features of cerebral salt wasting are similar to those of
SIADH except for volume depletion which is a feature of the former.
Cerebral salt wasting is characterized by excessive urinary sodium
losses in patients with intracranial disease. The exact mechanism is
73
unknown but it has been speculated that the Na+ loss is due to the
release of a natriuretic factor, probably from the injured brain.
8 Gastrointestinal Na+ losses: Gastrointestinal disease can
result in sodium losses with or without fluid losses, as well as fluid
retention. Vomiting and diarrhea can result in losses of sodium and
water. In the setting of gastrointestinally driven hyponatremia, se-
rum aldosterone levels and sodium avidity of the kidneys are high.
Fluid/electrolyte/acid base balance
9 Skin Na+ losses: Observed in the setting of cystic fibrosis
and loss of skin barrier, such as burns. As with gastrointestinal
losses, renal sodium avidity is high.
10 The main mechanism of hyponatremia in this condition is
water retention. In cortisol deficiency (primary or secondary), the
hyponatremia is due to a combination of excessive ADH release and
urinary Na+ losses. In hypothyroidism, hyponatremia is caused by
impaired water excretion due to ADH release and diminished water
delivery to the diluting segments of the renal tubule. Primary poly-
dipsia is rare in children and most patients will have normal levels of
serum sodium unless water intake significantly exceeds urine output.
SIADH is a common cause of hyponatremia in children and is due to
a combination of water excess and excessive urinary Na+ excretion
leading to the euvolemic state. SIADH can be seen in a variety of situ-
ations including infections, neuropsychiatric diseases, neoplasms,
lung diseases and secondary to drugs (table). Laboratory investiga-
tion includes: Serum and urine osmolarity, electrolytes, serum BUN,
creatinine, plasma aldosterone, cortisol levels and thyroid function
tests.
11 The hyponatremia in hypervolemic/edematous states is
characterized by high total body sodium content due to avid renal
sodium retention. In these conditions, the hyponatremia is primarily
due to water retention. In the setting of liver failure and nephrotic
syndrome, intravascular volume depletion and hypoalbuminemia
contribute to urinary sodium retention leading to hypervolemia.
12 In renal failure, the combination of water retention and de-
creased tubular ability to reabsorb sodium causes hyponatremia and
elevated urinary sodium concentration.
13 Management of hyponatremia: In the stable patient, serum
sodium levels should be normalized slowly to prevent central pon-
tine myelinolysis. The amount of sodium to be replaced in hypovole-
mic hyponatremia can be assessed by the formula:
Na+ deficit = (serum Na+ concentration desired
serum Na+ concentration present) TBW,
where TBW (total body water) = 0.6 body weight (kg). Correction of
serum Na+ levels should be done cautiously and should not exceed
10 mEq/l/day. Diuretics hypertonic saline should be only considered
in the patient with neurologic changes (seizure, coma), and should
only be done in the pediatric intensive care unit setting. Of note, loop
diuretics, but not thiazides, should be used since the former augment
excretion of electrolyte free water. In the setting of cortisol deficiency
or hypothyroidism, treatment with thyroid replacement or glucocor-
ticoid therapy is indicated. If true hypoaldosteronism or cerebral salt
wasting is diagnosed, treatment with mineralocorticoids is indicated.
S. Watkins D. Okamura J. Rodrguez Soriano
Selected reading
Avner ED: Clinical disorders of water metabolism: hyponatremia
and hypernatremia. Pediatr Ann 1995;24:2330.
Moritz ML, Ayus JC: Preventing neurological complications from
dysnatremias in children. Pediatr Nephrol 2005;20:16871700.
Rose BD, Post TW: Clinical Physiology of Acid-Base and Electrolyte
Disorders, ed 5. New York, McGraw-Hill, 2001, pp 703712.
Sakarcan A, Bocchini J Jr: The role of fludrocortisone in a child
with cerebral salt wasting. Pediatr Nephrol 1998;12:769771.
Trachtman H: Sodium and water; in Avner ED, Harmon WE,
Niaudet P (eds): Pediatric Nephrology, ed 5. Philadelphia,
Lippincott Williams & Wilkins, 2004, pp 125145.
Table. Causes of SIADH
I. Increased hypothalmic production of ADH
Neuropsychiatric disorders
1. Infections: meningitis (tuberculous or bacterial), encephalitis, abscess,
herpes zoster 2. Vascular: thrombosis, subarachnoid or subdural hemorrhage,
cavernous sinus thrombosis, cerebrovascular accident 3. Neoplasm:
primary or metastatic 4. Skull fracture, head injury 5. Psychosis, delirium
tremens 6. Other: Guillain-Barr syndrome, acute intermittent porphyria,
autonomic neuropathy, hypothalamic sarcoidosis, postpituitary surgery,
multiple sclerosis, epilepsy, hydrocephalus, lupus erythematosus, peripheral
neuropathy, spinal cord lesions
Drugs
1. Intravenous cyclophosphamide (increased sensitivity may also
contribute) 2. Carbamazepine (though increased sensitivity is probably
important) 3. Vincristine or vinblastine 4. Psychiatric drugs
5. Bromocriptine 6. Clofibrate 7. General anesthesia 8. Narcotics, opiate
derivatives
Pulmonary disease
1. Pneumonia: viral, bacterial, fungal 2. Tuberculosis 3. Lung abscess,
empyema 4. Acute respiratory failure 5. Positive pressure ventilation
6. Other: asthma, COPD, atelactasis, pneumothorax, cystic fibrosis
Miscellaneous
Postoperative patient, severe nausea, pain, infection with HIV, idiopathic
II. Ectopic (nonhypothalamic) production of ADH
1. Ewing sarcoma 2. Hodgkin disease, leukemia 3. Pulmonary tuberculosis
III. Potentiation of ADH effect
1. Chlorpropamide 2. Carbamazepine 3. Psychosis 4. Intravenous
cyclophosphamide 5. Prostaglandin synthesis inhibitors (salicylates,
NSAIDS)
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IV. Exogenous administration of ADH
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 Fluid/electrolyte/acid base balance S. Watkins D. Okamura J. Rodrguez Soriano Hypernatremia

/
Hypernatremia
(Serum Na+ >150 mEq/l)

74

Hypovolemia / Euvolemia / Hypervolemia /

Urine Na+ (mEq/l) 0 Urine Na+ (mEq/l) 0 Urine Na+ (mEq/l) 0

[Na+] variable [Na+] >20 7

[Na+] >20 1 [Na+] <20 2 Urine osmolality (mosm/kg) 3

>800 <300

Renal losses Extrarenal losses Insensible losses DI Improperly mixed formula

Renal dysplasia Diarrhea Skin NaHCO3/NaCl administration
Postobstruction Sweating Lungs Mineralocorticoid excess
Osmotic diuresis Fever Hypodipsia
Diuretics (loop, osmotic) Burns

Water deprivation test 4

(response to DDAVP)

Yes No

CDI 5 NDI 6

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Hypotonic fluid replacement 8 Hypotonic fluid replacement 8 Water replacement 8 Water replacement 8 Water replacement 8 Water replacement 8
DDAVP Thiazide/potassium- Diuretics, dialysis

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 1 Serum sodium will be elevated in the setting of sodium ex-
cess or water losses. A thorough clinical evaluation of the child to
determine his volume status is therefore vital in order to proceed
with the work-up: (1) History: Information from patient/family on
weight changes, intake and output (urinary, gastric, stool), medica-
tion history. (2) Examination: Weight, skin changes (edema, turgor),
fontanelle changes, blood pressure/orthostatics, mucous mem-
branes, cardiac gallop. Due to the fact that in hypernatremic dehydra-
tion the ECF volume may be preserved, the classic signs of dehydra-
tion (sunken eyes and fontanelle, reduced skin turgor, hypotension)
may be absent.
2 Once fluid status is assessed, patients work-up can be ap-
propriately directed. Determination of urine Na+ concentration is es-
sential for narrowing the differential diagnosis. It should be empha-
sized that there is no correlation between urinary Na+ level (which is
normally determined by the ECF volume status), and serum Na+ con-
centration.
3 In renal conditions causing hypernatremia, there are usually
both water and sodium losses, but the water losses exceed the so-
dium losses. The water loss is usually secondary to the reduced uri-
nary concentrating ability present in these patients.
4 Diarrhea is the most common cause of hypernatremic de-
hydration in children, especially in infants. Other causes of extrarenal
hypernatremic dehydration in children such as losses from skin are
much less common in children.
5 The normal response to the elevated plasma osmolarity is
secretion of ADH resulting in renal water reabsorption and hence
elevated urine osmolality, usually above 800 mosm/kg. Thus, in the
hypernatremic patient, the urine osmolality determines whether
there is a urinary concentrating defect.
6 Water deprivation test should be done in a hospital setting
with close observation of vital signs and urine output. Monitor
weight, blood pressure, heart rate, electrolytes, serum and urinary
osmolality every hour for 4 h. Give DDAVP intranasally if patient is
polyuric or urine osm/serum osm <1.5. After 1 h, if patient is still
polyuric or urine osm/serum osm <1.5, replace urine output ml for ml
for 2 h then recheck weight and electrolyte levels. Test is completed
after 7 h. If the patient responded to ADH with increased urine osmo-
lality, decreased urine output and decreased serum osmolality, liber-
alize fluids cautiously. Watch input closely to avoid water intoxica-
tion. If patient did not respond to ADH, then patient has NDI and lib-
75
eralize fluids ad libitum.
7 CDI is caused by impaired production or secretion of ADH.
Common causes of CDI include craniopharyngioma, trauma, malig-
nancies or infiltrative diseases (e.g. histiocytosis X).
Fluid/electrolyte/acid base balance
8 NDI is a congenital or acquired disorder in which hypotha-
lamic function and ADH production and secretion are normal but
there is a lack of renal responsiveness to ADH. Congenital NDI is in-
herited in an X-linked, autosomal-recessive or, rarely, autosomal-
dominant fashion. The X-linked disease is due to different mutations
in the ADH (V2) receptor gene. The autosomal-recessive and autoso-
mal-dominant forms are caused by mutations in the H2O channel
(AQP2) gene. Major causes of acquired NDI include lithium adminis-
tration, hypercalcemia, hypokalemia and osmotic diuresis associated
with uncontrolled diabetes mellitus.
9 Sodium excess can be due to exogenous administration of
sodium (improperly mixed formulas or NaCl or NaHCO3 administra-
tion). Infants are especially susceptible to sodium overload. For ex-
ample, the administration of only 1 tablespoon of NaCl to a newborn
infant can raise the plasma Na by as much as 70 mEq/l. Sodium ex-
cess can also be secondary to mineralocorticoid excess. In this con-
dition, the hypernatremia is usually mild or even absent, and the
main electrolyte abnormalities are hypokalemia and hypochloremia
(see, Hypokalemia and Hypochloremia).
10 Rapid correction of hypernatremia can induce cerebral ede-
ma, seizures, permanent neurologic damage and death. These com-
plications are a result of rapid reduction in ECF osmolality causing
entry of water into cells in the brain and cerebral edema. To minimize
this risk, the plasma sodium level should be slowly reduced unless
the patient has symptomatic hypernatremia. The rate at which the
sodium concentration should be lowered is no more than 0.5 mEq/l
per hour or 12 mEq/l per day. Since most cases of hypernatremia are
due to water loss, gradual correction requires calculation of free wa-
ter deficit [Water deficit = 0.6 weight (kg) (plasma Na/140 1)]. Fre-
quent monitoring of electrolyte levels is necessary to assure gradual
reduction of hypernatremia. In CDI, treatment involves careful use of
DDAVP at minimum dose needed to maintain an adequate urine out-
put. Treatment of NDI may involve use of a thiazide diuretic (which
decreases ECF volume thereby increasing H2O reabsorption) and po-
tassium-sparing diuretic such as amiloride.
S. Watkins D. Okamura J. Rodrguez Soriano
Selected reading
Avner ED: Clinical disorders of water metabolism: hyponatremia
and hypernatremia. Pediatr Ann 1995;24:2330.
Moritz ML, Ayus JC: Preventing neurological complications from
dysnatremias in children. Pediatr Nephrol 2005;20:16871700.
Rose BD, Post TW: Clinical Physiology of Acid-Base and Electrolyte
Disorders, ed 5. New York, McGraw-Hill, 2001, pp 750758.
Trachtman H: Sodium and water; in Avner ED, Harmon WE,
Niaudet P (eds): Pediatric Nephrology, ed 5. Philadelphia,
Lippincott Williams & Wilkins, 2004 pp 125145.
Table. Causes of SIADH
I. Increased hypothalmic production of ADH
Neuropsychiatric disorders
1. Infections: meningitis (tuberculous or bacterial), encephalitis, abscess,
herpes zoster 2. Vascular: thrombosis, subarachnoid or subdural hemorrhage,
cavernous sinus thrombosis, cerebrovascular accident 3. Neoplasm:
primary or metastatic 4. Skull fracture, head injury 5. Psychosis, delirium
tremens 6. Other: Guillain-Barr syndrome, acute intermittent porphyria,
autonomic neuropathy, hypothalamic sarcoidosis, postpituitary surgery,
multiple sclerosis, epilepsy, hydrocephalus, lupus erythematosus, peripheral
neuropathy, spinal cord lesions
Drugs
1. Intravenous cyclophosphamide (increased sensitivity may also
contribute) 2. Carbamazepine (though increased sensitivity is probably
important) 3. Vincristine or vinblastine 4. Psychiatric drugs
5. Bromocriptine 6. Clofibrate 7. General anesthesia 8. Narcotics, opiate
derivatives
Pulmonary disease
1. Pneumonia: viral, bacterial, fungal 2. Tuberculosis 3. Lung abscess,
empyema 4. Acute respiratory failure 5. Positive pressure ventilation
6. Other: asthma, COPD, atelactasis, pneumothorax, cystic fibrosis
Miscellaneous
Postoperative patient, severe nausea, pain, infection with HIV, idiopathic
II. Ectopic (nonhypothalamic) production of ADH
1. Ewing sarcoma 2. Hodgkin disease, leukemia 3. Pulmonary tuberculosis
III. Potentiation of ADH effect
1. Chlorpropamide 2. Carbamazepine 3. Psychosis 4. Intravenous
cyclophosphamide 5. Prostaglandin synthesis inhibitors (salicylates,
NSAIDS)
IV. Exogenous administration of ADH
Vasopressin, desmopressin, oxytocin
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Hypernatremia
 Fluid/electrolyte/acid base balance J. Rodrguez Soriano D. Okamura S. Watkins Hypochloremia

/
Hypochloremia
(Serum Cl <100 mEq/l)

76

Hypovolemia 0 Euvolemia/volume excess 0

Urine Cl 1 Hypertension
Urine Cl >10 mEq/l
PRAm6

<10 mEq/l 0 >10 mEq/l

Plasma aldosterone levels

Decreased Cl intake Renal Cl losses 5

Yes 2 No

Gastrointestinal Cl losses 3 Cutaneous Cl losses 4 Low/normal 7 High 8

Dietary chloride deficiency Vomiting Cystic fibrosis Bartter syndrome Liddle syndrome Glucocorticoid-remediable aldosteronism
in neonates (maternal vomiting) Pyloric stenosis, psychogenic Excessive sweating Gitelman syndrome AME Primary hyperaldosteronism
Prebiliary obstruction Burns Diuretics Licorice ingestion
Intracranial hypertension Gluco- or mineralocorticoid
Gastric drainage administration

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Chloride diarrhea
Congenital, sporadic

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 1 Hypochloremia is usually associated with
metabolic alkalosis. It is often difficult to establish
which of these two laboratory findings is the primary
phenomenon. Hypokalemia is also frequently present.
2 Patient assessment: Hypochloremia can be
accompanied by either hypovolemia or euvolemia/
volume excess. A thorough clinical evaluation of the
child to determine his volume status is therefore vital
in order to proceed with the work-up: (1) History: Infor-
mation from patient/family of weight changes, intake
and output (urinary, gastric, stool), medication history.
(2) Examination: Weight, skin changes (edema, turgor),
fontanelle changes, blood pressure/orthostatics, mu-
cous membranes, cardiac gallop.
3 In a hypovolemic patient, determination of
urine Cl concentration is essential for narrowing the
differential diagnosis.
4 Decreased intake of Cl is a rare cause of
hypochloremia. Dietary chloride deficiency has been
described in infants fed soy or regular formulas with
low Cl content due to a manufacture mistake. This
syndrome may be also rarely observed in breast fed
infants due to low C content of the human milk.
5 Hypochloremia due to gastrointestinal Cl
losses is a prominent feature of persistent vomiting or
gastric drainage. It is characteristically observed in
infants with pyloric stenosis, and more rarely follow-
ing other conditions associated with persistent vomit-
ing such as prebiliary obstruction, intracranial hyper-
tension or psychogenic vomiting. Congenital hypo-
chloremia of the newborn infant may occur due to pro-
fuse vomiting of the mother prior to delivery. Congeni-
tal chloride diarrhea is caused by an inherited defect of
intestinal Cl transport due to mutations in the gene
encoding the intestinal Cl/HCO3 exchanger. This disor-
der should be suspected when an infant presents with
watery diarrhea since birth and a fecal Cl concentra-
tion above 90 mEq/l.
6 Increased cutaneous losses of Cl may be
caused by excessive sweating during exercise or heat
stress. This is a common phenomenon in patients with
77
cystic fibrosis. Infants with cystic fibrosis may present
with a clinical picture of failure to thrive associated
with hypochloremic and hypokalemic metabolic alka-
losis which mimics Bartter syndrome. However, a dif-
ferential feature is the very low value of urinary Cl in
cystic fibrosis.
Fluid/electrolyte/acid base balance
7 Increased urinary losses of Cl are observed
in some inherited tubular disorders such as Bartter
and Gitelman syndromes or following prolonged ther-
apy with loop or thiazide diuretics.
8 The combination of hypertension, hypochlo-
remic metabolic alkalosis, urinary chloride wasting,
hypokalemia and hyporeninemia is characteristic of
hyperaldosteronism (with high plasma aldosterone
levels) or pseudohyperaldosteronism (with low/nor-
mal plasma aldosterone levels) .
9 Liddle syndrome is a rare hereditary autoso-
mal-dominant disease characterized by low renin level,
volume expansion and hypertension due to excessive
and unregulated NaCl reabsorption in the distal neph-
ron. This situation is due to gain of function mutation
in the genes encoding the subunits or of the epithe-
lial Na+ channel. AME is caused by inactivating muta-
tions in the gene encoding renal 11-hydroxysteroid
dehydrogenase type 2. The defective enzyme fails to
inactivate cortisol, which in turn binds to the mineralo-
corticoid receptor to cause Na+ retention, hyperten-
sion and hypokalemia. Ingestion of licorice which
inhibits 11-hydroxysteroid dehydrogenase type 2,
may cause similar abnormalities.
10 Glucocorticoid-remediable aldosteronism is
an inherited, autosomal-dominant disease, which is a
result of formation of a chimeric gene that possesses
the 5-11-hydroxylase and the 3-aldosterone syn-
thase sequences. In this situation, aldosterone secre-
tion is under the influence of ACTH instead of angio-
tensin II and is completely suppressed by dexametha-
sone administration. The diagnosis of primary hyper-
aldosteronism (Conn disease) is rarely made in chil-
dren.
J. Rodrguez Soriano D. Okamura S. Watkins
Selected reading
Rodrguez Soriano J, Vallo A, Castillo G, Oliveros R,
Cea JM, Balzategui MJ: Biochemical features of
dietary chloride deficiency syndromes: a compara-
tive study of 30 cases. J Pediatr 1982;103:209214.
Rodrguez Soriano J: Bartter and related syndromes:
The puzzle is almost solved. Pediatr Nephrol 1998;
12:315327.
Rodrguez Soriano J: Tubular disorders of
electrolyte regulation; in Avner ED, Harmon WE,
Niaudet P (eds): Pediatric Nephrology, ed 5.
Lippincott Williams & Wilkins, 2004, pp 729756.
Rose BD, Post TW: Clinical Physiology of
Acid-Base and Electrolyte Disorders, ed 5.
New York, McGraw-Hill, 2001, pp 555557.
Scheinman SJ, Guay-Woodford LM, Thakker RV,
Warnock DG: Genetic disorders of renal electrolyte
transport. N Engl J Med 1999;340:11771187.
Sojo A, Rodrguez Soriano J, Vitoria JC, Vzquez C,
Ariceta G, Villate A: Chloride deficiency as a
presentation or complication of cystic fibrosis.
Eur J Pediatr 1994;153:825828.
Zelikovic I: Molecular pathophysiology of tubular
transport disorders. Pediatr Nephrol 2001;16:
919935.
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 Fluid/electrolyte/acid base balance D. Okamura J. Rodrguez Soriano S. Watkins Hyperchloremia

/
Hyperchloremia
(Serum Cl >110 mEq/l)

78

Metabolic acidosis (normal anion gap) /

No Yes

Urine anion gap 1

[Na+ + K+ Cl]

Negative 2 Positive 3

Bromide poisoning 0 Intestinal HCO3 losses RTA type I (distal RTA)

RTA type II (proximal RTA) RTA type IV
Acetazolamide administration
Exogenous acid administration
TPN

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Ureterosigmoidostomy

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 1 Calculation of the serum anion gap [Na+
HCO 3 Cl] (normal value 1012 mEq/l) is essential for
the evaluation of MA. Hyperchloremic metabolic aci-
dosis, in which hyperchloremia compensates for the
loss of bicarbonate, is therefore a normal anion gap
MA. In contrast, in high anion gap MA (characterized
by the presence of anions other than bicarbonate), the
serum chloride level remains within normal limits.
2 Bromide poisoning can lead to pseudohyper-
chloremia (because standard laboratory tests can not
make the distinction between these two anions) and
negative serum anion gap. Some bromide products
also cause mental status changes.
3 A primary means by which the renal tubule
handles an acid load is by production of ammonia
(NH3). When combined with H+ in the distal tubular
lumen, NH3 is converted to ammonium ion (NH4+)
which is lipid-insoluble and therefore can not be
reabsorbed. Because a direct measurement of urinary
ammonium excretion is cumbersome, urinary anion
gap [Na+ + K+ Cl] serves as an indirect index of
urinary ammonium excretion and hence of distal
acidification ability. Any change in urinary ammonium
excretion will be accompanied by a parallel change
in urinary chloride excretion in order to maintain
electroneutrality.
4 HCMA accompanied by negative urinary
anion gap represents an intact distal acidification
mechanism. Gastrointestinal bicarbonate loss due to
diarrhea is the most common cause of HCMA in
children. Proximal RTA (RTA type II) does not usually
interfere with urinary ammonium excretion. Proximal
RTA can be isolated or can be a part of generalized
proximal tubulopathy (Fanconi syndrome) which leads
to hypophospatemic rickets, hypouricemia, glycosuria
and aminoaciduria. Major causes of proximal RTA/
79
Fluid/electrolyte/acid base balance
Fanconi syndrome include: hereditary disorders (cysti-
Selected reading
nosis, galactosemia, tyrosinemia, hereditary fructose
intolerance, mitochondrial cytopathies and Wilson Herrin TH: Renal tubular acidosis; in Avner ED,
disease), drugs (aminoglycosides, ifosfamide, outdat- Harmon WE, Niaudet P (eds): Pediatric Nephrology,
ed tetracyclines), heavy metal poisoning, and genetic ed 5. Philadelphia, Lippincott Williams & Wilkins,
defects in specific proximal tubule transporters lead- 2004, pp 757776.
ing to primary isolated RTA. Acetazolamide is an in- Rodrguez Soriano J: Renal tubular acidosis:
hibitor of carbonic anhydrase, an enzyme which has a the clinical entity. J Am Soc Nephrol. 2002;13:
major role in tubular bicarbonate regeneration. Inhibi- 21602170.
tion of this enzyme will cause HCMA. Other causes of Rose BD, Post TW: Clinical Physiology of Acid-Base
HCMA with a negative urinary anion gap are rare in and Electrolyte Disorders, ed 5. New York,
children. McGraw-Hill, 2001, pp 612627.
Scheinman SJ, Guay-Woodford LM, Thakker RV,
5 RTA types I and IV are characterized by a pos- Warnock DG: Genetic disorders of renal electrolyte
itive urinary anion gap which is due to impaired tubu- transport. N Engl J Med 1999;340:11771187.
lar NH+4 production or secretion. Zelikovic I: Renal tubular acidosis. Pediatr Ann 1995;
RTA type I (distal RTA) is characterized by an impaired 24:4854.
distal H+ secretion and hence, a failure to lower urine
pH in the presence of acidosis. Several different mech-
anisms are responsible for this type of RTA:
Secretory defect: A defect in the H+-ATPase pump of
the intercalated cell in the CCD. This abnormality
can be a primary genetic disorder, or secondary to
autoimmune diseases (SLE, Sjogren syndrome).
Gradient defect: An increase in membrane permeabil-
ity causing backleak of luminal H+ in CCD cells. This
condition is observed for example in children treated
with amphotericin B.
Voltage-dependent defect: A reduction in CCD Na+
reabsorption which diminishes the luminal electro-
negativity, thus impairing the ability to secrete H+.
This type of distal RTA is accompanied by hyperkale-
mia and is seen in markedly volume depleted children
and secondary to amiloride treatment.
The primary pathogenic mechanism of RTA type IV is
aldosterone deficiency or resistance. In this type of
RTA, the ability to acidify the urine is intact but NH+4
excretion and thus net acid excretion is reduced.
Hyperkalemia is a main feature of this type of RTA (for
further details, see Hyperkalemia).
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D. Okamura J. Rodrguez Soriano S. Watkins Hyperchloremia
 Fluid/electrolyte/acid base balance D. Okamura J. Rodrguez Soriano S. Watkins Hypokalemia

/
Hypokalemia
(Plasma K+ <3.5 mEq/l)

80
Urine K+

<20 mEq/l >20 mEq/l

Decreased K+ intake Blood pressure

Yes 0 No Normal/low 4 High

PRA

Parenteral fluids
Protein-calorie malnutrition

Low 5 High 8

Plasma aldosterone level Renovascular disease

Renin-secreting tumor
Gastrointestinal K losses 1
+
Cutaneous K losses 2
+
Altered K distribution 3
+

Associated with alkalosis Cystic fibrosis Metabolic alkalosis Postobstructive diuresis Low/normal 6 High 7
Vomiting, gastric drainage Excessive sweating Insulin administration Recovery from ARF
Congenital chloride diarrhea Burns B2-Agonists administration RTA type 1
Associated with acidosis Barium poisoning Fanconi syndrome
Profuse or prolonged diarrhea Familial hypokalemic Bartter syndrome Liddle syndrome Glucocorticoid-remediable
Malabsorption, biliary/intestinal fistula periodic paralysis Gitelman syndrome AME aldosteronism
Enterostomy losses, ureterosigmoidostomy Diuretics Licorice ingestion Primary hyperaldosteronism
Unpredictable acid-base abnormality Gluco- or mineralocorticoid

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Laxative or enema abuse administration
Villous adenoma

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 1 Plasma K+ level is indicative of the total intra-
cellular content of K+. The relationship between the
reduction in plasma K+ and the deficit in intracellular K+
is curvilinear: when the plasma K+ decreases from
3.5 to 2.5 mEq/l, the deficit in cell K+ is still small, but
becomes more and more significant (up to 30%) when
the plasma K+ level decreases below 2.0 mEq/l.
2 Decreased intake of K+ is a rare cause of
hypokalemia in the Western world. However, primary
protein-calorie malnutrition, complicated by gastro-
enteritis, is the most common cause of hypokalemia in
underdeveloped countries.
3 Gastrointestinal K+ losses may be accompa-
nied by metabolic alkalosis or acidosis. Hypokalemic
metabolic alkalosis is a prominent feature of persistent
vomiting (as observed in pyloric stenosis), and of con-
genital chloride diarrhea (an entity caused by an inher-
ited defect in intestinal chloride transport). Although
there is some K+ loss via the gastrointestinal tract,
most K+ losses in these settings are due to urinary K+
losses. The kaliuria is caused by a combination of
hyperaldosteronism, secondary to hypovolemia, and
increased distal tubular reabsorption of Na+, which
accompanies the HCO3 delivered to this nephron seg-
ment. Diarrhea can lead to gastrointestinal K+ losses
associated with metabolic acidosis.
4 Increased cutaneous losses of K+ and Cl lead-
ing to secondary hypokalemia may be caused by
excessive sweating during exercise or heat stress. This
is a common phenomenon in patients with cystic
fibrosis. Infants with cystic fibrosis may present with
a clinical picture of failure to thrive and electrolyte
abnormalities mimicking Bartter syndrome.
5 Altered K+ distribution, with a shift of K+ from
the extracellular to the intracellular compartment, is a
common cause of hypokalemia. It may occur after in-
sulin administration during treatment of diabetic coma,
or as a complication of bronchodilator therapy with
2-agonists. Familial hypokalemic periodic paralysis
is an inherited disorder caused by mutations in
the pore-forming 1S-subunit of the skeletal muscle
T-tubule calcium-entry channel.
81
6 Increased urinary losses of K+ with normo- or
hypotension are often observed as a result of the mas-
sive polyuria that follows release of acute urinary tract
Fluid/electrolyte/acid base balance
obstruction or recovery from ARF. It is also character-
Selected reading
istically observed in some inherited tubular disorders
such as distal RTA, Bartter syndrome and Gitelman Kamel S, Quaggin S, Halperin ML: Disorders of
syndrome or following prolonged therapy with loop or potassium homeostasis: an approach based on
thiazide diuretics. pathophysiology. Am J Kidney Dis 1994;24:597613.
Rodrguez Soriano J: Bartter and related syndromes:
7 The combination of hypertension, hyperkaliu- the puzzle is almost solved. Pediatr Nephrol 1998;12:
ric hypokalemia, metabolic alkalosis and hyporenin- 315327.
emia is characteristic of hyperaldosteronism (with high Rodrguez Soriano J: Potassium homeostasis and its
plasma aldosterone levels) or pseudohyperaldosteron- disturbances in children. Pediatr Nephrol 1995;9:
ism (with low/normal plasma aldosterone levels). 364374.
Rodrguez Soriano J: Tubular disorders of electro-
8 Liddle syndrome is a rare hereditary autoso- lyte regulation; in Avner ED, Harmon WE, Niaudet P
mal-dominant disease characterized by low renin, vol- (eds): Pediatric Nephrology, ed 5. Philadelphia,
ume expansion and hypertension due to excessive Lippincott Williams & Wilkins, 2004, pp 729756
and unregulated NaCl reabsorption in the distal neph- Scheinman SJ, Guay-Woodford LM, Thakker RV,
ron. This situation is due to gain of function mutation Warnock DG: Genetic disorders of renal electrolyte
in the genes encoding the subunits or of the epithe- transport. N Engl J Med 1999;340:11771187.
lial Na+ channel. AME is caused by inactivating muta- Zelikovic I: Molecular pathophysiology of tubular
tions in the gene encoding renal 11-hydroxysteroid transport disorders. Pediatr Nephrol 2001;16:
dehydrogenase type 2. The defective enzyme fails to 919935.
inactivate cortisol, which in turn binds to the mineralo-
corticoid receptor to cause Na+ retention, hyperten-
sion and hypokalemia. Ingestion of licorice which
inhibits 11-hydroxysteroid dehydrogenase type 2,
may cause similar abnormalities.
9 Glucocorticoid-remediable aldosteronism is
an inherited, autosomal-dominant disease, which is a
result of formation of a chimeric gene that possesses
the 5-11-hydroxylase and the 3-aldosterone syn-
thase sequences. In this situation, aldosterone secre-
tion is under the influence of ACTH instead of angio-
tensin II and is completely suppressed by dexametha-
sone administration. The diagnosis of primary hyper-
aldosteronism (Conn disease) is rarely made in chil-
dren.
10 The combination of hyperkaliuric hypokale-
mia, metabolic alkalosis, elevated blood pressure and
elevated plasma renin and aldosterone levels in chil-
dren is almost always due to renovascular disease.
Major etiologies include: renovascular changes sec-
ondary to umbilical artery catheter in newborn infants,
arteritis secondary to Takayasu or Moyamoya disease,
fibromuscular dysplasia (idiopathic or secondary to
neurofibromatosis type I), or extrinsic compression of
the renal artery due to a tumor, hematoma or fibrosis.
Renin-secreting tumor is rarely diagnosed in children.
198.143.33.65 - 8/6/2015 3:21:53 PM
Univ. of California San Diego
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D. Okamura J. Rodrguez Soriano S. Watkins Hypokalemia
 Fluid/electrolyte/acid base balance J. Rodrguez Soriano D. Okamura S. Watkins Hypokalemia

/
Hyperkalemia
(Plasma K+ >5.2 mEq/l)

82
Exclude spurious hyperkalemia or pseudohyperkalemia 0

Urine K+

>20 mEq/l <20 mEq/l

Exogenous K+ administration Low GFR 3 Normal GFR 4

Yes 1 No Normal plasma Low plasma High plasma

aldosterone 5 aldosterone aldosterone 8

PRA

Endogenous K+ source Altered K+ distribution 2

High 6 Low 7

Acute hemolysis Metabolic acidosis Acute renal failure Defective renal secretion CAH Hyporeninemic hypoaldosteronism PHA type 1 and 3
GI bleeding Insulin deficiency Chronic renal failure Sickle cell disease, SLE, Salt-losing CAH Gordon syndrome (PHA type 2)
Rhabdomyolysis, exercise Drugs obstructive uropathy Adrenocortical failure
Infection B 2-Blockers therapy RTA type 1 (hyperkalemic form) CMO deficiency type 1 and 2
Burns Digoxin overdose Drugs
Surgery Succinylcholine Spironolactone, triamterene, amiloride,
Prematurity ACE inhibitors, heparin, cyclosporine A,
Hyperosmolality NSAID, trimethoprim
Diet Familial hyperkalemic
Oral or i.v. K+ load periodic paralysis
Transfusions

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Univ. of California San Diego
Downloaded by:
 1 Severe hyperkalemia is a life-threatening
condition. An electrocardiogram must be obtained
promptly to test for changes such as prolonged PR
interval, widened QRS complex or ventricular fibrilla-
tion. If these changes are observed, or plasma K+ con-
centration rises above 7 mEq/l, immediate therapy for
hyperkalemia should be initiated. This includes: Intra-
venous (IV) administration of calcium gluconate,
NaHCO3 and/or glucose with insulin, administration of
a 2-agonist aerosol, or dialysis therapy, if necessary.
Mild hypokalemia (<6 mEq/l) without EKG changes can
be managed by decreasing dietary K+ intake and by
oral or rectal administration of a cation exchange resin
(Kayexalate).
2 Spurious hyperkalemia is due to the libera-
tion of K+ from cellular elements of muscle during
blood drawing or from erythrocytes during in vitro
hemolysis, In pseudohyperkalemia, K+ is elevated in
serum but not in plasma due to its liberation from
platelets and leukocytes during clot retraction in indi-
viduals with thrombocytosis or leukocytosis or in a
rare entity called familial pseudohyerkalemia.
3 Increased intake of K+ rarely induces hyperka-
lemia unless there is reduced renal function, as occurs
in preterm newborn infants or in patients with chronic
renal failure. Transfusions of aged or irradiated blood
products may also induce hyperkalemia.
4 Altered K+ distribution, with release of K+
from the intracellular to the extracellular compartment,
is not rare. In metabolic acidosis H+ moves into the
cells, and causes shift of intracellular K+ to the extracel-
lular fluid. However, only very severe degree of meta-
bolic acidosis due to retention of fixed acids will be
accompanied by hyperkalemia. In organic acidemia
(lactic acidosis, ketoacidosis, hereditary organic acido-
sis), on the other hand, the organic anion is able to fol-
low the H+ into the cells, thus alleviating the need for K+
redistribution. Hyperkalemia may be seen in sick pre-
term newborn infants even without impaired renal
function or metabolic acidosis and as a consequence
of administration of several drugs. Familial hyperkale-
mic periodic paralysis (Garmstrop disease) is a very
rare disorder caused by mutations of the gene encod-
83
ing the -subunit of the skeletal Na+ channel.
5 Decreased excretion of K+ is frequently seen
in both acute and chronic renal failure. Hyperkalemia
develops in oliguric acute renal failure even in the ab-
sence of excessive K+ intake because of tissue catabo-
Fluid/electrolyte/acid base balance
lism. In mild-to-moderate chronic renal failure, signifi-
cant hyperkalemia is uncommon unless a state of
hyporeninemic hypoaldosteronism exists (see below).
6 The combination of hyperkalemia, low uri-
nary potassium concentration and normal GFR is usu-
ally the result of aldosterone deficiency or resistance.
An estimate of aldosterone activity in the distal and
collecting tubule is given by the so-called transtubular
potassium gradient, as calculated by the formula:
[UK /(Uosm/Posm)]
. Normal value 64.0.
Plasma K
7 Defective renal secretion of K+ with normal
plasma aldosterone level with or without mild renal
failure, may be observed in acute or chronic interstitial
nephropathies (obstructive uropathy, SLE, sickle cell
disease). In the hyperkalemic form of RTA type 1 (also
known as voltage-type distal RTA), there is a reduction
in Na+ reabsorption in the cortical collecting duct,
which diminishes the tubular lumen electronegativity,
thus impairing distal K+ secretion. Defective renal
secretion of K+ is more frequently seen as a conse-
quence of administration of various drugs. These
drugs should be used with extreme caution in the
presence of preexisting renal disease.
8 Hypokaliuric hyperkalemia due to aldoste-
rone deficiency with elevated PRA is generally
observed in endocrine disorders such as congenital
adrenal hypoplasia, salt-losing forms of CAH or in rare
inherited defects of aldosterone biosynthesis called
CMO deficiency types 1 and 2. Adrenal cortical failure
is observed in Addison disease and in adrenoleuko-
dystrophy.
9 Hyporeninemic hypoaldosteronism is ob-
served in patients with diabetic nephropathy or chron-
ic tubolointerstitial disorders. Although considered
rare in children, hyporeninemic hypoaldosteronism is
probably more common in this age group than previ-
ously thought. Gordon syndrome, also called pseudo-
hypoaldosteronism type 2, is a hereditary, autosomal-
dominant disorder caused by loss of function muta-
tions in the gene encoding WNK4 or gain of function
mutations in the gene encoding WNK1 kinase. The
consequence of the mutation is increased NaCl reab-
sorption in the distal convoluted tubule which results
in hypervolemia, hypertension, hyporeninemic hy-
poaldosteronism, hyperkalemia and type 4 RTA.
J. Rodrguez Soriano D. Okamura S. Watkins
10 Aldosterone resistance with elevated plasma
levels of aldosterone, is observed in PHA type 1.
This hereditary disorder presents clinically with renal
sodium wasting, hyperkalemia and metabolic acidosis.
There are two forms of PHA type 1: In the renal, auto-
somal-dominant form, the aldosterone resistance is
limited to the kidney and is due to mutations in the
gene encoding the mineralocorticoid receptor. In the
autosomal-recessive multiple-end-organ form, the
aldosterone resistance is present in many organs (kid-
ney, colon, lung, sweat and salivary glands) and is due
to mutations in one of the genes encoding the -, -, or
-subunits of the epithelial Na+ channel. There is also a
secondary form of aldosterone resistance, called PHA
type 3, frequently observed in infants with obstructive
uropathy and/or urinary tract infection.
Selected reading
Kamel S, Quaggin S, Halperin ML: Disorders of
potassium homeostasis: an approach based on
pathophysiology. Am J Kidney Dis 1994;24:597613.
Rodrguez Soriano J: Bartter and related syndromes:
the puzzle is almost solved. Pediatr Nephrol 1998;12:
315327.
Rodrguez Soriano J: Potassium homeostasis and its
disturbances in children. Pediatr Nephrol 1995;9:
364374.
Rodrguez Soriano J: Tubular disorders of electro-
lyte regulation; in Avner ED, Harmon WE, Niaudet P
(eds): Pediatric Nephrology, ed 5. Philadelphia,
Lippincott Williams & Wilkins, 2004, pp 729756.
Scheinman SJ, Guay-Woodford LM, Thakker RV,
Warnock DG: Genetic disorders of renal electrolyte
transport. N Engl J Med 1999;340:11771187.
Zelikovic I: Molecular pathophysiology of tubular
transport disorders. Pediatr Nephrol 2001;16:
919935.
198.143.33.65 - 8/6/2015 3:21:53 PM
Univ. of California San Diego
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Hypokalemia
 Fluid/electrolyte/acid base balance U.S. Alon W. Proesmans Metabolic acidosis

/
Metabolic acidosis
84 Renal failure 0

No Yes

Normal (1012 mEq/l) Blood anion gap 1 Increased < Blood lactate

Urine anion gap 2

Elevated Normal

Cl >Na++K+ 3 Cl <Na++K+ 4
Blood glucose

Urine pH High Normal/low

Urine ketones
>5.8 <5.8
Elevated Negative
Serum K+
RTA type 4 7
Hypoglycemic Toxicology
syndromes
Low High PRA Fasting Negative

Positive
High Low
Distal RTA Hyperkalemic
(type 1) 5 distal RTA (type 1) 6
Blood pressure
Plasma aldosterone
Diabetes mellitus Acute failure Chronic failure
High Normal Nondiabetic causes
Low High

Plasma cortisol

Renal US
Normal Low

198.143.33.65 - 8/6/2015 3:21:53 PM

Univ. of California San Diego
Intestinal HCO3 losses Primary PHA type 1 8 Gordon Hyporeninemic Liver failure Salicylates Examine:
RTA type 2 (proximal RTA) hypoaldosteroidism syndrome : hypoaldosteronism ; Leukemia Ethylene glycol Carnitine (blood)

Downloaded by:
Acetazolamide administration (PHA type 2) Solid tumors Methanol Urine for reducing substances,
Exogenous acid administration Salicylates organic and amino acids
 TPN Muscle hyperactivity
Ureterosigmoidostomy Tissue hypoperfusion
and hypoxia
Addison disease PHA type 3 Inherited and
Congenital adrenal (vesicoureteral reflux, obstructive uropathy, metabolic disorders
hyperplasia pyelonephritis) 9 Diabetes mellitus

1 MA is characterized by low blood HCO3 level as well as by
low pCO2 level caused by compensatory hyperventilation.
2 MA in renal failure is usually associated with increased se-
rum anion gap [Na+ HCO3 CI ] due to accumulation of acids in the
blood. However, due to tubular damage, a component of normal an-
ion gap acidosis is often added, resulting in a mixed picture.
drase, an enzyme which has a major role in tubular bicarbonate re-
generation. Inhibition of this enzyme will cause HCMA. Other causes
of HCMA with a negative urinary anion gap are rare in children.
6 RTA types 1 and 4 are characterized by a positive urinary
anion gap [Cl < Na+ + K+] which is due to impaired tubular NH4+ pro-
duction or secretion.
12 Gordons syndrome, also called pseudohypoaldostreonism
type 2, is a hereditary, autosomal-dominant disorder caused by gain
of function mutation in the genes encoding WNK1 or WNK4 kinases.
The consequence of the mutation is increased NaCl reabsorption in
the distal convoluted tubule which results in hypervolemia, hyper-
tension, hyporeninemic hypoaldosteronism, hyperkalemia and type
4 RTA.

3 Calculation of the serum anion gap [Na+ HCO3 Cl ] is es-
sential for the evaluation of MA. In normal anion gap MA, hyperchlo-
remia compensates for the loss of bicarbonate. In contrast, in high
anion gap MA (characterized by the presence of anions other than
bicarbonate), the serum chloride level remains within normal limits.
4 A primary means by which the renal tubule handles an acid
load is by production of ammonia (NH3). When combined with H+ in
the distal tubular lumen, NH3 is converted to ammonium ion (NH4+)
which is lipid-insoluble and therefore cannot be reabsorbed. Be-
cause a direct measurement of urinary ammonium excretion is cum-
bersome, urinary anion gap [Na+ + K+ Cl] serves as an indirect in-
dex of urinary ammonium excretion and hence of distal acidification
ability. Any change in urinary ammonium excretion will be accompa-
nied by a parallel change in urinary chloride excretion in order to
maintain electroneutrality. Anions like ketone bodies and certain an-
tibiotics may interfere with calculation of the urine anion gap. Fur-
thermore, NH4+ excretion decreases in the face of hypovolemia and
avid tubular Na reabsorption (urine Na <20 mEq/l).
5 HCMA accompanied by negative urinary anion gap [Cl >
Na+ + K+] represents an intact distal acidification mechanism. Gastro-
intestinal bicarbonate loss due to diarrhea is the most common
cause of HCMA in children. Proximal RTA (RTA type 2) does not usu-
ally interfere with urinary ammonium excretion. Proximal RTA can
be isolated or can be a part of generalized proximal tubulopathy
(Fanconi syndrome) which leads to hypophosphatemic rickets,
hypouricemia, glycosuria and aminoaciduria. Major causes of proxi-
85 mal RTA/Fanconi syndrome include: hereditary disorders (cystinosis,
galactosemia, tyrosinemia, hereditary fructose intolerance, mito-
chondrial cytopathies and Wilson disease), drugs (aminoglycosides,
ifosfamide, outdated tetracyclines), heavy metal poisoning, and ge-
7 RTA type 1 (distal RTA) is characterized by an impaired distal 13 Hyporeninemic hypoaldosteronism can be caused by vari-
H+ secretion and, hence, a failure to lower urine pH in the presence of
acidosis. Several different mechanisms are responsible for this type
of RTA:
Secretory defect a defect in the H+-ATPase pump of the interca-
lated cell in the CCD. This abnormality can be a primary-genetic dis-
order, or secondary to autoimmune diseases (SLE, Sjogren syn-
drome).
Gradient defect an increase in membrane permeability causing
backleak of luminal H+ in CCD cells. This condition is observed for
example in children treated with amphotericin B.
8 Hyperkalemic distal (type 1) RTA is seen mainly in associa-
tion with obstructive uropathy in markedly volume-depleted children
and secondary to amiloride treatment. In this type of distal RTA (also
known as voltage-type distal RTA), there is a reduction in Na+ reab-
sorption in the cortical collecting duct, which diminishes the tubular
lumen electronegativity, thus impairing distal H+ and K+ secretion.
9 RTA type 4 is characterized by hyperkalemia and decreased
ability to secrete NH4+.
10 11 PHA types 1 and 3 are characterized by hyponatremia,
hypernatriuria, hyperkalemia and metabolic acidosis. There are two
forms of PHA 1: in the renal, autosomal-dominant form, the aldoste-
rone resistance is limited to the kidney and is due to mutations in the
gene encoding the mineralocorticoid receptor. In the autosomal-re-
cessive, multiple-end-organ form, the aldosterone resistance is
present in many organs (kidney, colon, lung, sweat and salivary
glands) and is due to mutations in one of the -, - or -subunits of
the epithelial Na+ channel. There is also a secondary form of aldoste-
rone resistance called PHA type 3, frequently observed in infants
ous conditions including:
interstitial nephritis, sickle cell nephropathy, amiloride administra-
tion, diabetes mellitus, obstructive uropathy and others. Although
considered rare in children, hyporeninemic hypoaldosteronism is
probably more common in this age group than previously thought.
14 Increased serum anion gap indicates that an unmeasured
anion is added to the blood, either endogenously (lactate, ketone
bodies, organic acids) or exogenously (salicylates, ethelene glycol,
methanol). For details on the various disorders leading to high anion
gap MA in children see appropriate references.
Selected reading
Batlle D, Moorthi KM, Schlueter W, Kurtzman N: Distal renal tubular
acidosis and the potassium enigma. Semin Nephrol 2006;26:
471478.
Hanna JD, Scheinman JI, Chan JCM: The kidney in acid-base
balance. Pediatr Clin N Am 1995;42:1365.
Herrin TH: Renal tubular acidosis; in Avner ED, Harmon WE,
Niaudet P (eds): Pediatric Nephrology, ed 5. Philadelphia,
Lippincott Williams & Wilkins, 2004, pp 757776.
Krapf R, Seldin DW, Alpern RJ: Clinical syndromes of metabolic
acidosis; in Seldin DW, Giebisch G (eds): The Kidney:
Physiology and Pathophysiology, ed 3. Philadelphia, Lippincott
Williams & Wilkins, 2000, pp 20732130.
Nicoletta JA, Schwartz GJ: Distal renal tubular acidosis.
Curr Opin Pediatr 2004;16:194198.
Rodrguez Soriano J: Renal tubular acidosis: the clinical entity.
J Am Soc Nephrol 2002;13:21602170.

198.143.33.65 - 8/6/2015 3:21:53 PM

netic defects in specific proximal tubule transporters leading to pri- with obstructive uropathy and/or urinary tract infection. Zelikovic I: Renal tubular acidosis. Pediatr Ann 1995; 24:4854.
mary isolated RTA. Acetazolamide is an inhibitor of carbonic anhy-

Univ. of California San Diego

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Fluid/electrolyte/acid base balance U.S. Alon W. Proesmans Metabolic acidosis
 Fluid/electrolyte/acid base balance U.S. Alon W. Proesmans Metabolic alkalosis

/
Metabolic alkalosis
86 Urine chloride

High (>20 mEq/l) 0 Variable 5 Low (<20 mEq/l) 6

Blood pressure Special diet/formula Yes

No Low Cl intake
Normal High

Chronic diuretic therapy Yes

Diuretics (recent) Plasma renin

No Loop, thiazides

Yes No 1 High 2 Low Gastric loss Yes

Plasma aldosterone No Vomiting, nasogastric suction

Diarrhea Yes
High 3 Low 4

No Congenital CI diarrhea
Colonic adenoma

Other causes of hypovolemia Yes

Hereditary potassium- Glucocorticoid-remediable Gastrocystoplasty
losing tubulopathies aldosteronism Excessive alkali administration
(Bartter, Gitelman syndrome) Primary Hypoparathyroidism
No Contraction alkalosis
hyperaldosteronism Glucose ingestion after starvation
Large dose of penicillin
Severe K or Mg depletion
Sweat test Abnormal

Loop Renal artery stenosis Liddle syndrome

Thiazides Renin-secreting tumors Apparent mineralocorticoid excess Normal Cystic fibrosis

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11A-Hydroxylase deficiency
Gluco-/mineralocorticoid administration

Univ. of California San Diego

Licorice ingestion Post hypercapnia

Downloaded by:
 1 Metabolic alkalosis is characterized by elevat-
ed serum HCO3 and pCO2 levels. The latter is caused
by compensatory hypoventilation. Metabolic alkalosis
is usually associated with hypochloremia and it is of-
ten difficult to establish which of these two laboratory
findings is the primary phenomenon. Metabolic alkalo-
sis can be accompanied by either hypovolemia or eu-
volemia/volume excess. A thorough clinical evaluation
of the child to determine his volume status is therefore
vital in order to proceed with the work-up:
I. History: Information from patient/family of weight
changes, intake and output (urinary, gastric, stool),
medication history.
II. Examination: Weight, skin changes (edema, turgor),
fontanelle changes, blood pressure/orthostatics,
mucous membranes, cardiac gallop.
2 Most conditions that lead to metabolic alkalo-
sis and are associated with high urine chloride level
and are regarded as chloride-resistant.
3 As a rule of thumb, the earlier the age of pre-
sentation of hereditary potassium-losing nephropa-
thies, the more severe the presentation. When pre-
sented in early childhood, it is often associated with
severe urinary losses of Na and Cl and failure to thrive
(Bartter syndrome). In later childhood, presentation is
milder, at times with tetany due to hypomagnesemia/
hypocalcemia (Gitelman syndrome). These syndromes
mimic the pictures seen when either loop diuretics or
thiazides are used, with reduction in NaCl reabsorp-
tion in the loop of Henle (Bartter syndrome) or the dis-
tal tubule (Gitelman syndrome), respectively. Bartter
syndrome is characterized by urinary calcium losses
whereas Gitelman syndrome by increased urinary
magnesium losses.
4 The combination of hyperkaliuric hypokale-
mia, metabolic alkalosis, elevated blood pressure and
elevated plasma renin and aldosterone levels in chil-
dren is almost always due to renovascular disease.
Major etiologies include: renovascular changes sec-
ondary to umbilical artery catheter in newborn infants,
arteritis secondary to Takayasu or Moyamoya disease,
fibromuscular dysplasia (idiopathic or secondary to
neurofibromatosis type 1), or extrinsic compression of
87 the renal artery due to a tumor, hematoma or fibrosis.
Although the gold standard for the diagnosis of renal
artery stenosis is selective renal angiogram, currently
CT angiography is the preferred mode of imaging. Re-
nin-secreting tumor is rarely diagnosed in children.
Fluid/electrolyte/acid base balance
5 Glucocorticoid-remediable aldosteronism is
Selected reading
an inherited, autosomal-dominant disease, which is a
result of formation of a chimeric gene that possesses Galla JH: Metabolic alkalosis. J Am Soc Nephrol
the 5-11-hydroxylase and the 3-aldosterone syn- 2000;11:369375.
thase sequences. In this situation, aldosterone secre- Laski ME, Sabatini S: Metabolic alkalosis, bedside
tion is under the influence of ACTH instead of angio- and bench. Semin Nephrol 2006;26:404421.
tensin II and is completely suppressed by dexametha- Oh MS, Carroll HJ: Mechanism of chloride deficit in
sone administration. The diagnosis of primary hyper- the maintenance of metabolic alkalosis. Nephron
aldosteronism (Conn disease) is rarely made in chil- 2002;91:379382.
dren. Rodrguez Soriano J: Tubular disorders of electro-
lyte regulation; in Avner ED, Harmon WE, Niaudet P
6 Liddle syndrome is a rare hereditary autoso- (eds): Pediatric Nephrology, ed 5. Philadelphia,
mal-dominant disease characterized by low renin, vol- Lippincott Williams & Wilkins, 2004, pp 729756.
ume expansion and hypertension due to excessive Wesson DE, Alpern RJ, Seldin DW: Clinical
and unregulated NaCl reabsorption in the distal neph- syndromes of metabolic alkalosis; in Seldin DW,
ron. This situation is due to gain of function mutation Giebisch G (eds): The Kidney: Physiology and
in the genes encoding the - or -subunits of the epi- Pathophysiology, ed 3. Philadelphia, Lippincott
thelial Na+ channel. AME is caused by inactivating mu- Williams & Wilkins, 2000, pp 20552072.
tations in the gene encoding renal 11-hydroxysteroid Zelikovic I: Molecular pathophysiology of tubular
dehydrogenase type 2. The defective enzyme does not transport disorders. Pediatr Nephrol 2001;16:
inactivate cortisol, which in turn binds to the mineralo- 919935.
corticoid receptor to cause Na+ retention, hyperten-
sion and hypokalemia. Ingestion of licorice which in-
hibits 11-hydroxysteroid dehydrogenase type 2, may
cause similar abnormalities.
7 In the majority of these conditions urine chlo-
ride level is expected to be low.
8 The combination of metabolic alkalosis and
low urine Cl level is observed in conditions caused
either by low chloride intake or extrarenal losses of
this ion, through the gastrointestinal tract or the skin.
These disorders are characterized by volume depletion
and low urinary chloride concentration and are regard-
ed as chloride responsive. For details on these condi-
tions, see sections on Hypokalemia and Hypochlore-
mia.
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U.S. Alon W. Proesmans Metabolic alkalosis
 Fluid/electrolyte/acid base balance U.S. Alon W. Proesmans Hypovolemia

/
Hypovolemia
88 Trauma, bleeding Normal/high 9
Environmentally induced hypovolemia

Serum Na
No

Urine volume Low/normal High

(renal Na + H2O losses) (renal H2O losses)

Low 0 Glucosuria Diabetes insipidus

Response to ADH
Yes No
CNS Respiratory GI tract losses 3 Skin Third spacing

Pharmacotherapy Yes No
Toxicology
Serum albumin
Metabolic Metabolic Central Renal
alkalosis acidosis
Yes No

Low 6 Normal GFR

Ascites
Anasarca Acute Vascular Normal Low
abdomen 8 pathology

Urine protein Urinary

salt wasting Improving Stable

High Negative
Serum

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aldosterone

Univ. of California San Diego

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 Insensible Melena Excessive Renal Pleural Bleeding Diuretics Low Normal/high Postobstructive Chronic renal
losses 2 sweating 4 disease effusion 7 Rupture Osmotic uropathy failure
Obstruction diuresis
Blood pressure

Adipsia 1 Gastric Intestinal Insensible Malnutrition Intestinal Diabetes

Pancreatic losses 5 Malabsorption obstruction mellitus
Biliary Burns Protein-losing Pancreatitis Proximal
Normal High
enteropathy Peritonitis tubulopathy
Liver disease
Hypoaldosteronism Salt-losing Hyponatremic
Hypoadrenalism nephropathy : hypertensive
syndrome ;

1 Hypovolemia is characterized by rapid heart rate, decreased
tissue perfusion and at times lowered blood pressure. A thorough
clinical evaluation of the hypovolemic child is vital in order to pro-
ceed with the work-up:
I. History: Information from patient/family on weight changes, intake
and output (urinary, gastric, stool), medication history.
II. Examination: Weight, skin changes (edema, turgor), fontanelle
changes, heart rate, blood pressure/orthostatics, mucous mem-
branes, cardiac gallop, capillary refill time.
2 Hypovolemia accompanied by low urine volume (below 1
ml/kg/h) usually indicates that the ability of the kidneys to conserve
water is intact and that the cause of the hypovolemia is extrarenal.
3 Patients with adipsia/hypodipsia often have additional CNS
manifestations. As some of them may also have partial ADH defi-
ciency, urine volume may vary. Typically, these patients are at risk to
develop hyperosmolar dehydration.
4 Loss of water through the respiratory system may be in-
creased especially during mechanical ventilation.
8 Although massive proteinuria often results in hypovolemia,
some patients remain euvolemic. The volume status can be assessed
by measuring FENa, which is very low in hypovolemic states, or in
conditions characterized by low effective circulatory volume (e.g. NS,
congestive heart failure, etc.).
9 A large pleural effusion, especially when continuously
drained, can result in hypovolemia.
10 Some of these conditions, if becoming long-standing, can
result in hypoalbuminemia.
11 The combination of hypovolemia with high urine output
indicates that there is an impairment in renal water reabsorption,
either due to an intrinsic renal defect or secondary to an osmotic
substance in the urine that interferes with normal renal concentrat-
ing mechanisms.
12 Salt-losing nephropathies include any form of renal disease
that causes an impairment in sodium reabsorption and hence free
water excretion. For further details, see Hyponatremia.
Selected reading
Bockenkamp B, Vyas H: Understanding and managing acute fluid
and electrolyte disturbances. Curr Paediatr 2003;13:520528.
Boluyt N, Bollen CW, Bos AP, Kok JH, Offringa M: Fluid resuscita-
tion in neonatal and pediatric hypovolemic shock: a Dutch
Pediatric Society evidence-based clinical practice guideline.
Intens Care Med 2006;32:9951003.
Finberg L: Dehydration in infancy and childhood. Pediatr Rev
2002;23:277282.
Nicholls MG: Unilateral renal ischemia causing
the hyponatremic hypertensive syndrome in children more
common than we think? Pediatr Nephrol 2006;21:887890.
Rose BD, Post TW: Clinical Physiology of
Acid-Base and Electrolyte Disorders, ed 5.
New York, McGraw-Hill, 2001, pp 415446.
Trachtman H: Sodium and water homeostasis. Pediatr Clin N Am
1995;42:1343.

5 GI tract losses may result in hypo-, iso- or hyperosmolar
dehydration.
6 In a patient with excessive sweating, one needs to rule out
89
cystic fibrosis.
7 Insensible losses of water through the skin are more com-
mon in the newborn due to the higher skin surface area to body mass
13 The hyponatremic hypertensive syndrome is a rare disor-
der seen mainly in infants and young children. It is caused by severe
primary or secondary hyperreninemia, severe hypertension and
consequently pressure diuresis. Once the patient becomes severely
dehydrated, urine volume declines. Losses of sodium and water stop
when the hypertension is corrected.

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ratio. Especially prone to hypovolemia are preterm infants under
radiant warmers.

Univ. of California San Diego

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Fluid/electrolyte/acid base balance U.S. Alon W. Proesmans Hypovolemia
 Fluid/electrolyte/acid base balance W. Proesmans U.S. Alon Edema

/
Edema
90
Symmetrical Localized/unilateral

Hypoalbuminemia
Angioedema A Venous B Lymphatic C Infectious C

Yes No

Albuminuria TSHMT4m

No Yes No Yes

Malnutrition 0 Protein-losing Hepatic Hydrops Renal CHF ? Myxedema @

enteropathy 1 failure 2 fetalis 3

Serum creatinineM

No Yes

Idiopathic NS Systemic manifestations 8

Hematuria
No Yes

No Yes

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Minimal-change NS 4 FSGS 5 MGP 6 IgAN 7 MPGN 9 AGN : HUS ; ICGN < SLE = Vasculitis >

Univ. of California San Diego

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 1 Presence of abnormally large amounts of fluid in the intercel-
lular spaces of the body. Clinically, edema is characterized by demon-
strable accumulation of excessive fluid in subcutaneous tissues. The fol-
lowing forms of edema can be distinguished (1) edema due to increased
transudation of fluid as in NS resulting in pitting edema, (2) edema
due to increased protein concentration in the interstitium as in lymph-
edema resulting in nonpitting, rubbery edema, and (3) edema due to
increased interstitial gel formation as in myxedema resulting in non-
compressible or brawny edema. Edema can be localized or generalized,
the latter is known as anasarca or, in the newborn, hydrops.
2 Nutritional edema is the consequence of a longstanding diet
deficiency of protein and is marked by ascites or anasarca. It is mainly
seen in the third world due to famine or war. Kwashiorkor is the more
common name for the syndrome produced by severe protein deficiency,
characterized by growth retardation, changes in the skin and hair pig-
ments, edema, mental apathy, anemia and low serum albumin. Maras-
mic kwashiorkor is a condition in which deficiency of both calories and
protein is present.
3 This is a nonspecific term referring to a series of conditions as-
sociated with excessive enteric loss of plasma protein. It occurs a.o in
inflammatory bowel disease, giant hypertrophic gastritis (Mntrier dis-
ease) and in congenital or acquired intestinal lymphangiectasies. It is
noteworthy that cardiac patients having undergone the Fontan proce-
dure can develop intestinal protein losing.
4 A large number of diseases can affect the liver to cause hepatic
insufficiency which is characterized by defective synthesis of a number
of proteins including albumin. Low albumin causes reduced oncotic pres-
sure leading to ascites and edema of the legs or to anasarca.
5 This is a life-threatening syndrome characterized by severe hy-
poalbuminemia and ascites or anasarca before birth. In terms of patho-
physiology, there are two categories of patients: (1) patients with circula-
tory failure, and (2) fetuses with primary hypoproteinemia. Etiologies of
the first category are a.o. erythroblastosis fetalis, congenital heart de-
fects, cardiac arrythmias, obstruction of the cava inferior, etc. Etiologies
of the second category are intrauterine infections, inborn errors of me-
tabolism and congenital nephrotic syndrome.
6 In childhood, the most frequent form of the idiopathic nephrotic
syndrome is an acquired illness of unknown etiology which presents be-
tween the age of 18 months and 12 years and is histologically character-
ized by minimal glomerular lesions. It comprises massive proteinuria,
hypoalbuminemia and hypercholesterolemia but, usually, not accompa-
nied by hematuria, hypertension or increased serum creatinine. Over
91 90% of these patients go into complete remission when given 60 mg/m
of predniso(lo)ne but recurrence is common.
7 FSGS. This term refers to a nonspecific glomerular lesion
which can be observed in patients with idiopathic nephrotic syndrome
accompanied by hematuria and not responsive to steroids. The lesions
are focal (touching only part of the glomeruli) and segmental (involving
parts of the glomerular capillaries). The abnormal segment adheres to
Bowmans capsule, has little cells, increased fibrous tissue and lipid
Fluid/electrolyte/acid base balance
droplets. Roughly one third of these patients do not respond to any treat-
ment and have a relentless progressive course towards end-stage renal
failure. In some patients, the underlying cause is genetic (see Nephrotic
syndrome).
8 MGP is the most common cause of NS in adults but it is uncom-
mon in childhood. There is proteinuria and hematuria and sometimes
hypertension. Histologically, the GBM is thickened by the presence of
immune deposits on the epithelial side and spikes which are extrusions
of membrane-like material. Immunofluorescence demonstrates granular
deposits of IgG and C3 to be located on the epithelial side of the GBM.
Half of the children are carrying the hepatitis B virus. MGP resolves spon-
taneously in the majority of children.
9 IgA nephropathy is the most frequent chronic glomerulopathy
in the world. It manifests itself by recurrent macroscopic hematuria, mi-
croscopic hematuria plus proteinuria, the nephrotic syndrome and only
exceptionally as chronic renal insufficiency. Histology shows a spectrum
of lesions from minimal segmental mesangial proliferation to diffuse
crescentic glomerulonephritis. Immunofluorescence demonstrates the
presence of IgA and C3, sometimes IgG and IgM as well, in the mesan-
gium of all glomeruli.
10 The term used here should be interpreted as widely as possible
but does not include arterial hypertension. It comprises skin lesions (urti-
caria, redness, vasculitis), arthritis and arthropathies, abdominal and
muscle pain, vomiting and diarrhea, headache and neurologic deficit.
11 MPGN is a prototypical form of chronic glomerulonephritis
characterized by proteinuria, hematuria, hypertension, some degree of
renal failure and hypocomplementemia. From the histological point of
view, 3 different types have been identified; type 2 is mainly referred to
as dense deposit disease. The prognosis of this glomerulopathy is rather
poor with a high incidence of recurrence after transplantation especially
in type 2. There is no uniformly accepted and efficient therapy.
12 The classical poststreptococcal acute GN presents with gross
hematuria, mild edema, oliguria and hypertension, some days to weeks
after a streptococcal infection of the skin or amygdalae. It is a self-limit-
ing disorder with an almost 100% cure rate.
13 HUS is the commonest cause of primary acute renal failure in
childhood (see Hemolytic uremic syndrome).
14 Diffuse crescentic GN is the morphologic substrate of rapidly
progressive GN. This clinicopathologic entity can be seen with a variety
of well-defined glomerular and systemic diseases or may be due to a
glomerular disease that does not fit into any of these conditions and is
therefore referred to as idiopathic crescentic GN (ICGN) (see Rapidly
progressive glomerulonephritis).
15 SLE is an immune complex-mediated disorder which has an
autoimmune basis. Multiple organ involvement is caused by deposition
of circulating IC; if IC localize in the glomeruli, lupus nephritis develops
(see Vasculitis).
W. Proesmans U.S. Alon Edema
16 Vasculitis is a term used to describe a vascular lesion character-
ized by inflammation and necrosis of the blood vessels walls as can be
observed in a heterogeneous group of disorders (see Vasculitis).
17 CHF leads to cardiac edema. Rapidly occurring deficiency in
cardiac output is marked by venocapillary congestion, hypertension,
edema and often lung edema. CHF is further clinically characterized by
reduced excercise capacity and dyspnea.
18 Myxedema is a condition characterized by dry, waxy swelling
of the skin with abnormal deposits of glycosaminoglycans in the skin and
other tissues. It is caused by hypothyroidism, a deficiency is thyroid ac-
tivity. Hypothyroidism can be congenital or acquired and sometimes he-
reditary.
19 Angioedema, also called Quincke edema, is a vascular reaction
involving the deep dermis, representing localized edema caused by dila-
tation and increased permeability of the capillaries. Clinically, angioede-
ma is characterized by the development of giant, urticarial wheals. There
is eosinophilia and deficiencies in the complement system. Besides spo-
radic angioedema, which can be elicited by a large number of antigens,
there is also hereditary angioedema which is due to a deficit in C1 inhibi-
tor. Angioedema is localized in the majority of cases; occasional patients
can display a more diffuse form of the disorder.
20 Localized edema can be caused by venous obstruction as in
varices, venous thrombosis, thrombophlebitis and accidental venous
cutting. Klippel-Trenaunay-Weber syndrome is a congenital, nonheredi-
tary disorder comprising macular vascular nevus in combination with
bony and soft tissue hypertrophy and venous varicosities.
21 Edema caused by obstruction of the lymph drainage from an ar-
ea in the body is of rubbery consistence. Acquired lymphedema may result
from inflammatory processes or from surgical or radiological obliteration
of lymph nodes or lymph channels. Congenital lymphedema of both legs
due to chronic lymphatic obstruction is referred to as Milroy disease.
22 Infections of the subcutaneous tissues can lead to edema
which is accompanied by redness and pain. A classical example is erysip-
elas, an acute form of superficial cellulitis usually caused by an infection
with group A streptococci. The lesion is hot, bright red, edematous and
sharply circumscribed with a raised border.
Selected reading
Bukowski R, Saade GR: Hydrops fetalis. Clin Perinatol 2000;27:10071031.
Franceschini P, Licata D, Rapello G, et al: Prenatal diagnosis of
Nonne-Milroy lymphedema. Ultrasound Obstet Gynecol 2001;8:182183.
Haycock GB: Sodium and body fluids; in Barratt TM, Avner A,
Harmon WE (eds): Pediatric Nephrology, ed 4. Baltimore, Lippincott
Williams & Wilkins, 1999, chap 8, pp 133153.
198.143.33.65 - 8/6/2015 3:21:53 PM
Katz MA: Interstitial space: the forgotten organ. Med Hypotheses
1980;6:885898.
Univ. of California San Diego
Witt C, Ottesen EA: Lymphatic filariasis: an infection of childhood.
Trop Med Int Health 2001;6:584606.
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 Divalent ion metabolism G. Ariceta B. Hoppe C.B. Langman Hypocalcemia

/
Hypocalcemia Symptoms 0

92 mSerum PO4
MSerum alkaline phosphase

Yes No

PTHMand radiological signs Serum Mgm

Calcipenic rickets 1 No

Serum PTH
Serum 25(OH)D3

Elevated Low

Absent/low Normal
Serum creatinineM

Vitamin D-deficient Genetic disorders in Hypomagnesemia 4

rickets 2 vitamin D metabolism 3 No Yes

Serum 1,25(OH)2D3 PHP ; Hypoparathyoroidism 5

cAMP increase in PTH testing < Fam. Hypoparathyroidism 6

Absent/low Elevated DiGeorge syndrome 7
Other syndromes 8
Low Normal Secondary forms 9

PHP type 1 =

Gs A-protein reduced in
red blood cells

Yes No

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1-A hydroxylase Vitamin D-resistant PHP type 1a PHP type 1c PHP type 1b PHP type 2 > Renal osteodystrophy :

Univ. of California San Diego

deficiency rickets

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 1 When serum albumin is normal, hypocalcemia is defined as
a decrease in serum Ca concentration <2.1 mmol/l or 8.4 mg/dl, or as
a decrease in ionized [Ca2+] <1.1 mmol/ or 4.4 mg/dl. If serum albumin
levels are low, serum total calcium might be low as well, but ionized
Ca2+ values will still be in the normal range. Ionized Ca2+ levels are
dependent on the blood pH, with a decrease in [Ca2+] in alkalosis and
an increase in acidosis (0.21 mmol/l change per 0.1 unit pH change).
2 Clinical symptoms of hypocalcemia are protean and in-
clude: neuromuscular changes (tetany), central nervous system
manifestations (generalized or focal seizures, psychological distur-
bances, intracranial Ca deposits), bradyarrthmias, ocular involve-
ment (cataracts), dental abnormalities as well as skin changes (xero-
dermatosis, alopecia).
3 In patients with calcipenic rickets, additional biochemical
findings are hypophosphatemia, elevated levels of serum alkaline
phosphatase and secondary hyperparathyroidism. Examining serum
levels of vitamin D metabolites [25(OH)D and 1,25(OH)2D3] are impor-
tant in the work-up of the child with hypocalcemic rickets. Hereditary
forms of hypophosphatemic rickets are not associated with distur-
bances in serum calcium levels.
4 If serum 25(OH)D levels are low, vitamin D-deficient rickets
is suspected. The differential diagnosis includes vitamin D-poor diet,
insufficient exposure to sunlight (especially in dark-skinned infants),
malabsorption secondary to gastrointestinal or hepatobiliary dis-
eases and due to medications that alter normal 25(OH)D metabolism.
5 When serum 25(OH)D levels are normal, genetic disorders
in vitamin D metabolism are suspected. This form of rickets [previ-
ously known as vitamin D-dependent rickets (VDDR)] can be further
differentiated by measuring serum levels of 1,25(OH)2D3. In 1- hy-
droxylase deficiency (called in the past VDDR type 1) serum levels of
1,25(OH)2D3 are low or absent due to a mutation in the gene encoding
the enzyme 1-hydroxylase which converts 25(OH)D to 1,25(OH)2D3
in the kidney. Administration of an active vitamin D analogue is the
therapy of choice. In vitamin D-resistant rickets (originally termed
VDDR type 2) serum levels of 1,25(OH)2D3 are high. This rare entity is
caused by end-organ resistance (often associated with alopecia) to
vitamin D actions due to mutations in the vitamin D receptor gene.
Therapy consists of high dose of 1,25(OH)2D3 as well as calcium sup-
plements.
6 Severe hypomagnesemia, via its effect on the Ca2+/Mg2+
sensing receptor (CaSR), can lead to hypocalcemia through both a
93
decrease in PTH production or secretion and end organ resistance to
this hormone.
Divalent ion metabolism
7 Hypocalcemia (usually associated with hyperphosphate-
mia) may be due to transient or permanent hypoparathyroidism.
Transient hypoparathyroidism is seen in neonates and is typically
categorized to early and late forms. The early form appears in the
first few days of life, it usually presents with asymptomatic hypocal-
cemia, and is seen most commonly in preterm and low-birth-weight
infants or in children of diabetic mothers. The late form is seen after
the 1st week of life, it may present with seizures and tetany, and it is
caused most commonly by high phosphate content in milk.
8 Familial hypoparathyroidism may be autosomal recessive,
autosomal dominant or x-linked. In the autosomal-dominant type,
there is a gain of function mutation in the CaSR, leading to hypocal-
cemic hypercalciuria. Although serum PTH levels can be within the
normal range, they are inappropriate for the degree of hypocalcemia.
9 Aplasia/hypoplasia of the parathyroid glands is often found
in DiGeorge anomaly, which includes, in addition to parathyroid hy-
poplasia, thymic hypoplasia, cardiac abnormalities (all of which are
related to the structures arising from the 3rd and 4th brachial arches),
facial dysmorphism, and often, a gene deletion in 22 q11. Velocardio-
facial syndrome, or other isolated 22q11 gene mutations may pro-
duce hypoparathyroidism as well. The hypocalcemia in these syn-
dromes may disappear spontaneously in young children, although it
may return later in life.
10 Hypoparathyroidism may occur in various syndromes in-
cluding Kerns Sayre syndrome and other mitochondrial cytopathies,
auto-immune endocrinopathy type 1 (associated with systemic can-
didiasis and Addison disease), Kenney-Caffey syndrome (small stat-
ure, tubular long bones, osteosclerosis) and others.
11 Secondary hypoparathyroidism is seen most commonly
after (para)-thyroidectomy. Other reasons of secondary hypopara-
thyroidism include infiltrative lesions such as tumors, hemosiderosis
(thalassemia) and copper deposition (Wilson disease).
12 The combination of hypocalcemia, hyperphosphatemia and
elevated serum creatinine concentration suggests the presence of
secondary hyperparathyroidism secondary to chronic kidney dis-
ease. For details see Renal osteodystrophy.
13 PHP also known as Albright hereditary osteodystrophy is
characterized by hypocalcemia and hyperphosphatemia despite a
normal or even elevated serum levels of PTH. There are several
types of this genetic disorder which are caused by defects in the ad-
enylate cyclase system necessary for the PTH-receptor normal func-
tion in end organs. PHP is usually a part of the McCune-Albright he-
reditary osteodystrophy the main clinical features of which are short
stature, psychomotoric and mental retardation, brachydactyly and
subcutaneous Ca deposits adjacent to the joints.
G. Ariceta B. Hoppe C.B. Langman Hypocalcemia
14 To accurately define the types of PHP, urinary cAMP levels
following a PTH infusion test should be measured. In normal sub-
jects, cAMP levels obtained it this test will be elevated.
15 In PHP type 1, urinary cAMP elevation after PTH infusion is
reduced compared to normal. Three subtypes are further differenti-
ated. Types 1a and 1c appear phenotypically as McCune-Albright
osteodystrophy with hypothyroidism and hypogonadotropism. The
difference between the two forms is in Gs- protein levels in red
blood which is reduced in type 1a and normal in type 1c. Type 1b is
characterized by a normal phenotype and abnormal biochemical
tests.
16 PHP type 2 is characterized by markedly increased PTH
levels with urinary cAMP levels elevated both before and after PTH
infusion.
Selected reading
Al-Jenaidi F, Makitie O, Grunebaum E, Sochett E: Parathyroid gland
dysfunction in 22q11.2 deletion syndrome. Horm Res 2007;67:
117122.
Gelfand IM, Eugster EA, DiMeglio LA: Presentation and clinical
progression of pseudohypoparathyroidism with multi-hormone
resistance and Albright hereditary osteodystrophy: a case series.
J Pediatr 2006;149:877880.
Hochberg Z: Vitamin-D-dependent rickets type 2. Horm Res 2002;
58:297302.
Holick MF: Resurrection of vitamin D deficiency and rickets.
J Clin Invest 2006;116:20622072.
Langman CB: Disorders of phosphorus, calcium and vitamin D; in
Avner ED, Harmon WE, Niaudet P (eds): Pediatric Nephrology, ed 5.
Philadelphia, Lippincott Williams & Wilkins, 2004, pp 237254.
Thacher TD, Fischer PR, Pettifor JM: Rickets: vitamin D and calcium
deficiency. J Bone Miner Res 2007;22:638.
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 Divalent ion metabolism B. Hoppe G. Ariceta C.B. Langman Hypercalcemia

/
Hypercalcemia Symptoms 0

94 Serum PTH 1

Low Normal/increased

Serum vitamin D metabolites

(25(OH)D and 1,25(OH)D)
Urine calciumM Urine calciumm

No Increased

Tumor

PTHrpM

No Yes

Syndromatic features

No Yes

Phosphate depletion 2 Jansen osseous dysplasia : Tumor hypercalcemia ; Vitamin D intoxication < Primary/tertiary Familial hypocalciuric
Vitamin A intoxication 3 Williams syndrome hyperparathyroidism = hypercalcemia >
High-dose hydrochlorothiazide therapy 4 Infantile idiopathic hypercalcemia
Adrenal insufficiency 5
Hypo-/hyperthyroidism 5
Immobilization 6
Hypophosphatasia 7

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Transient neonatal hypercalcemia 8
Sarcoidosis 9

Univ. of California San Diego

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 1 Hypercalcemia is defined as an increase in
serum Ca concentration >2.65 mmol/l or 10.6 mg/dl or
as an increase in ionized Ca2+ >1.4 mmol/l or 5.6 mg/dl.
Acid-base changes may affect the levels of ionized cal-
cium in the blood (see Hypocalcemia).
2 Clinical symptoms of hypercalcemia include
anorexia, weight loss, vomiting, psychological distur-
bances, hypertension, extraosseous Ca deposits,
urine-concentrating defect, polydypsia and nephrocal-
cinosis. In hyperparathyroidism, bone pain and radio-
logical signs such as subperiosteal defects at the ra-
dial side of the middle phalanges might be present.
3 In children with hypercalcemia, serum PTH
level is an important diagnostic tool. Low or sup-
pressed PTH levels suggest a normal response of the
parathyroid glands to hypercalcemia. If, on the other
hand, serum PTH level is elevated, primary or tertiary
hyperparathyroidism or familial hypocalciuric hyper-
calcemia are suspected.
4 Low phosphorus intake, especially in preterm
infants will lead to hypercalcemia. Chronic hypophos-
phatemia leads to hypercalcemia through increase in
the levels of 1,25(OH)2D3 and by reducing bone mineral
content. Breast-milk feeding without phosphate sup-
plementation can also lead to hypercalcemia by a simi-
lar mechanism.
5 Vitamin A intoxication, administrated in the
same preparations as vitamin D, can lead to hypercal-
cemia.
6 Overdose of thiazide diuretics may lead to
hypercalcemia by increasing urinary calcium reab-
sorption.
7 Although rare, endocrine disorders such as
hypothyroidism, hyperthyroidism and adrenal insuf-
ficiency, may lead to hypercalcemia.
8 Prolonged Immobilization may lead to en-
hanced bone Ca resorption, and, often, to hypercalce-
mia and hypercalciuria.
95
9 Infantile hypophosphatasia (an inherited de-
fect in alkaline phosphatase activity) may lead to hy-
percalcemia. Typical laboratory findings include nor-
mal serum phosphorus level and low alkaline phos-
phatase level. Bone films demonstrate typical findings
of rickets.
Divalent ion metabolism
10 Transient neonatal hypercalcemia is found in
newborns of mothers with hypocalcemia (usually due
to maternal hypoparathyroidism). The maternal hypo-
calcemia leads to excessive fetal PTH production that,
in turn, causes hypercalcemia after birth.
11 Granulomatous diseases such as sarcoidosis
or tuberculosis might lead to hypercalcemia through
an increased ectopic production of 1,25(OH)2D.
12 In the infant with hypercalcemia and dysmor-
phic features few disorders should be excluded:
Jansen osseous dysplasia is a rare hereditary disorder
belonging to the chondroplasia group of diseases.
It is caused by a mutation in the gene encoding the
PTH/PTHR1 receptor. Williams-Beuren syndrome is a
genetic disorder caused by sporadic mutations in the
gene encoding the elastin protein. Typical clinical fea-
tures include peculiar, elfin-like facies, failure to thrive,
mild mental retardation with a cheerful, loveable
personality and heart malformations (mostly supra-
valvular aortic stenosis). Infrequently, hypercalcemia
accompanies this syndrome. Infantile idiopathic
hypercalcemia is a rare disorder characterized by
musculoskeletal abnormalities, hypertension, strabis-
mus and hyperacusis. Although usually transient in
nature, serum calcium levels can be extremely high.
13 In children with hematologic or solid organ
malignancies (mostly carcinomas), hypercalcemia may
be due to skeletal metastasis or to an increase in PTH-
related protein levels, a gene product distinct from PTH.
14 Vitamin D intoxication can lead to hypercal-
cemia and hypercalciuria. Conditions leading to this
entity include overdosage of vitamin D given for pro-
phylaxis or of vitamin D given as a supplementation to
formula preparations. Of note, vitamin D excess can
also result from an ectopic production of this hormone
in various disorders (granulomatous diseases, malig-
nancies).
15 The laboratory findings of hyperparathyroid-
ism include, in addition to hypercalcemia, hypophos-
phatemia and hypercalciuria. Conditions leading to
primary hyperparathyroidism include adenoma of the
parathyroid glands. This condition can be isolated or a
part of more generalized disorders of hyperplasia/neo-
plasia of endocrine glands called MEN. MEN type 1
consists of primary hyperparathyroidism, endocrine
pancreatic hyperplasia and prolactinoma whereas
MEN type 2 includes, in addition to primary hyper-
B. Hoppe G. Ariceta C.B. Langman
parathyroidism, medullary carcinoma of thyroid and
bilateral pheochromocytoma. Tertiary hyperparathy-
roidism is the result of long-standing secondary hy-
perparathyroidism which leads to hyperplasia of the
parathyroid gland with autonomous, uncontrolled se-
cretion of PTH.
16 The combination of hypercalcemia, elevated
serum PTH levels and hypocalciuria is seen in FHH.
This rare autosomal-dominantly inherited disease usu-
ally presents clinically with asymptomatic hypercalce-
mia. The genetic defect in FHH is an inactivating muta-
tion in the Ca-sensing receptor. Most children affected
are asymptomatic and thus no specific therapy is
needed.
Selected reading
Huang J, Coman D, McTaggart SJ, Burke JR: Long-
term follow-up of patients with idiopathic infantile
hypercalcaemia. Pediatr Nephrol 2006;21:16761680.
Raue F, Haag C, Schulze E, Frank-Raue K: The role of
the extracellular calcium-sensing receptor in health
and disease. Exp Clin Endocrinol Diab 2006;114:
397405.
Kollars J, Zarroug AE, van Heerden J, Lteif A,
Stavlo P, Suarez L, Moir C, Ishitani M, Rodeberg D:
Primary hyperparathyroidism in pediatric patients.
Pediatrics 2005;115:974980.
Langman CB: Disorders of phosphorus, calcium and
vitamin D; in Avner ED, Harmon WE, Niaudet P (eds):
Pediatric Nephrology, ed 5. Philadelphia, Lippincott
Williams & Wilkins, 2004, pp 237254.
Menegazzi JJ: Williams-Beuren syndrome. Science
2006;311:1552.
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Hypercalcemia
 Divalent ion metabolism
Hypophosphatemia
96
P redistribution 1
Glucose infusion
TPN
Refeeding
Respiratory alkalosis
Drugs (insulin, glucagon,
androgens, B-agonists)
C.B. Langman G. Ariceta B. Hoppe
Normal/low
Nonselective renal P wasting 3
Fanconi syndrome
Relief to obstructive uropathy
Metabolic acidosis
Drugs (glucocorticoids, diuretics)
Hypophosphatemia
/
Symptoms 0
P depletion
Urine P 2
Increased Reduced
PTH
High
Selective renal P wasting 4 Hyperparathyroidism 5 P deprivation 6
Hypophosphatemic rickets (X-linked, Reduced absorption
autosomal dominant, autosomal recessive, with hypercalciuria) Intestinal disorders
Vitamin D related rickets (deficiency, dependent rickets types I Phosphate binders
[absence of kidney 25(OH)D-1-A-OHase] and II Alcoholism
[mutations in VDR], and genetic absence of Hungry bone syndrome
liver vitamin D-25-OHase enzyme activity) Miscellaneous
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 1 Serum P level is continuously declining with
age, and thus the definition of hypophosphatemia is
age-dependent. Hypophosphatemia in adolescents
and adults is defined as a serum P level <2.5 mg/dl.
Normal values in other age groups include: infants:
mean 6.5 mg/dl, range 4.87.4; toddlers: mean
5.0 mg/dl, range 4.55.8 mg/dl; children: mean 4.4 mg/
dl, range 3.55.5 mg/dl.
2 Hypophosphatemia may be asymptomatic or
associated with various symptoms. Symptoms result
from decreased intracellular ATP level and impaired
oxygen delivery to tissues, and may include anorexia,
vomiting, muscle dysfunction (paraesthesias, hypore-
flexia, proximal myopathy), rickets or osteomalacia as
well as hematologic disorders. Severe P deficit associ-
ated with acute shift of P into the cells can lead to life-
threatening events: cardiac failure with ventricular ar-
rhythmias, hypotension, rhabdomyolysis, respiratory
failure, or coma.
3 More than 99% of P is found in the intracel-
lular compartment and only less than 1% is extracel-
lular. Most P content in the body is in bone. Acute
shifts from extra- to intracellular space may reduce
serum P leading to hypophosphatemia. Increased
carbohydrate intake stimulates insulin release which,
in turn, leads to P shift into cells. Thus, infusion of glu-
cose, fructose, lactate or amino acid salts (especially
during refeeding malnourished patients or in diabetic
ketoacidosis) may lead to hypophosphatemia. Respira-
tory alkalosis, as a result of acute hyperventilation (e.g.
anxiety) or in a variety of respiratory disorders, may
lead to hypophosphatemia. Various drugs such as in-
sulin, glucagon, androgens and -adrenergic agonists
have a similar effect.
4 With a normal dietary intake of P, 1520% of
the filtered P is excreted in the final urine. Total body P
deficit, in the presence of a normal functioning kidney,
will maximally increase tubular reabsorption of this
mineral and will reduce P excretion to nil.
97
Divalent ion metabolism
5 In generalized proximal tubulopathy (termed
Fanconi syndrome), excessive phosphaturia may be
associated with glycosuria, aminoaciduria, and bicar-
bonaturia. For details, see Faconi syndrome and Meta-
bolic Acidosis. After the relief of obstructed kidneys,
excessive urinary losses of water and minerals includ-
ing P, can be observed (postobstructive diuresis). A
similar phenomenon might be seen during the diuretic
phase of acute tubular necrosis. High P excretion in
urine can also be observed after the administration of
drugs such as glucocorticoids and diuretics (acetazol-
amide, thiazides).
6 Selective urinary P wasting is seen in several
genetic disorders collectively called hypophospha-
temic rickets. XLH is characterized by reduced recla-
mation of filtered phosphorus by the proximal tubule,
and normal levels of 1,25(OH)2D which are inappropri-
ate for the degree of hypophosphatemia. XLH is
caused by mutations in the PHEX gene. Autosomal
dominant hypophosphatemic rickets result from muta-
tions in the gene encoding FGF-23, a potent phospha-
turic agent. This mutation renders the FGF-23 resistant
to normal proteolytic cleavage and hence, exagger-
ates its phosphaturic action, and that of reducing the
25(OH)D-1--OHase activity in the proximal nephron
mitochondria, too. Autosomal recessive XLH has re-
cently been described to be due to mutations in DMP-1,
and seemingly, elevations in FGF23 level as well. In
HHH, the genetic abnormality is due to mutations in
the gene encoding NaPi IIc, a Na-P cotransporter of
the proximal tubule. In contrast to XLH and autosomal-
dominant or -recessive hypophosphatemic rickets, se-
rum levels of 1,25(OH)2D in HHH are elevated, leading
to hypercalciuria. All of these disorders, if left untreat-
ed in children, will lead to rickets and short stature.
Various forms of vitamin D related rickets lead to hypo-
phosphatemia. In oncogenic osteomalacia, there is
excessive production of FGF-23 by various tumors
leading to hypophosphatemia. Phosphaturia and hy-
pophosphatemia may occur in 70% of patients follow-
ing renal transplantation within the first year, and be
either transient or permanent. Persistent secondary
hyperparathyroidism, corticosteroid therapy and in-
trinsic tubular dysfunction of the graft are possible
factors involved in this abnormality. Persistence of el-
evated levels of FGF23 after kidney transplantation
may be responsible for persistent hypophosphatemia.
C.B. Langman G. Ariceta B. Hoppe
7 For details on hyperparathyroidism, see Hy-
percalcemia and Renal osteodystrophy. Of note, after
long-standing hyperparathyroidism is resolved there
is an increased avidity of bone for Ca and P, termed
hungry bone syndrome (see below).
8 Any condition leading to P deprivation may
lead to hypophosphatemia with low urinary P concen-
tration. In addition, intestinal disorders leading to mal-
absorption will show the same abnormalities in P level.
Calcium carbonate and other drugs that can bind to
the P in the diet, may lead to hypophosphatemia.
After long-standing hyperparathyroidism (primary or
secondary) has resolved, increased avidity of bone for
Ca and P may lead to hypophosphatemia and hypocal-
cemia. This disorder is termed hungry-bone syn-
drome and it is usually transient in nature.
Selected reading
Cho HY, Lee BH, Kang JH, Ha IS, Cheong HI, Choi Y:
A clinical and molecular genetic study of hypophos-
phatemic rickets in children. Pediatr Res 2005;58:
329333.
Hochberg Z: Vitamin-D-dependent rickets type 2.
Horm Res 2002;58:297302.
Holick MF: Resurrection of vitamin D deficiency and
rickets. J Clin Invest 2006;116:20622072.
Kollars J, Zarroug AE, van Heerden J, Lteif A,
Stavlo P, Suarez L, Moir C, Ishitani M, Rodeberg D:
Primary hyperparathyroidism in pediatric patients.
Pediatrics 2005;115:974980.
Langman CB: Disorders of phosphorus, calcium and
vitamin D; in Avner ED, Harmon WE, Niaudet P (eds):
Pediatric Nephrology, ed 5. Philadelphia, Lippincott
Williams & Wilkins, 2004, pp 237254.
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Hypophosphatemia
 Divalent ion metabolism C.B. Langman G. Ariceta B. Hoppe Hyperphosphatemia

/
Hyperphosphatemia Symptoms 0

98 Urine P 1

Reduced Increased

Serum creatinine

Increased Normal

Plasma Ca

Normal Low

PTH

Normal/high Low

Acute renal failure 2 Acromegaly 3 Pseudohypoparathyroidism 4 Hypoparathyroidism 5 Redistribution 6 MAbsorption 7

Chronic renal failure Hyperthyroidism Acute acidosis Enemas
Familial tumoral calcinosis Laxatives
Hyperostosis i.v. infusions
Biphosphonates

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 1 Normal serum P level varies with age, so that
the definition of hyperphosphatemia is age dependent.
Normal P levels according to age are: neonates mean
6.5 mg/dl, range 4.87.4; infants 4.55.8 mg/dl (mean
5.0), mid-childhood 3.55.5 mg/dl (mean 4.4 mg/dl)
and by late adolescence, values are similar to those in
adults: range 2.44.5 mg/dl.
2 Hyperphosphatemia is often asymptomatic.
An acute elevation in serum P level may acutely re-
duce serum Ca levels with resultant symptoms of hy-
pocalcemia including: paresthesias, tetany, seizures,
psychological disturbances, cardiac arrhythmias, hy-
potension and death. During chronic hyperphosphate-
mia, serum Ca is usually normal or elevated and symp-
toms are secondary to increased [P] [Ca] product and
include progressive metastatic tissue calcification or,
less often, acute calciphylaxis syndrome (rapid subcu-
taneous and small vessels calcification leading to pain-
ful necrosis of skin and subcutaneous fat).
3 With a normal dietary intake of P, 1520% of
the filtered P is excreted in the urine. There is a maxi-
mum capacity of P reabsorption (TmpPO4) that varies
with the GFR. During the first 3 years of life, there is
relative renal P retention which constitutes an appro-
priate physiological adaptation to the demands for P
during somatic growth. Interestingly, the adolescent
growth spurt is not associated with P retention by the
kidney.
4 By far the most common cause of hyperphos-
phatemia is acute or chronic renal failure. Hyperphos-
phatemia usually occurs when GFR is less than 30% of
normal, and although there is a low fractional reab-
sorption of P in the remaining functional nephrons,
absolute excretion falls. In acute renal failure, hyper-
phosphatemia is usually observed during the oliguric
phase.
Acute hyperphosphatemia occurs during the rapid
breakdown of cells with release of intracellular P, such
as in tumor-lysis syndrome, rhabdomyolysis, or se-
vere hemolytic anemias. The levels of other intracel-
lular cations such as potassium (K) and magnesium
(Mg) are usually increased during these cytolytic pro-
cesses.
99
Divalent ion metabolism
5 Mild hyperphosphatemia is typical of acro-
Selected reading
megaly (growth hormone excess) and can be also de-
tected in thyrotoxicosis, as both growth hormone and Gelfand IM, Eugster EA, DiMeglio LA: Presentation
thyroxine increase the tubular reabsorption of P. Famil- and clinical progression of pseudohypoparathyroid-
ial tumoral calcinosis is a rare hereditary disorder of ism with multi-hormone resistance and Albright
mineral metabolism characterized by increased proxi- hereditary osteodystrophy: a case series. J Pediatr
mal tubular reabsorption rate of P and increased levels 2006;149:877880.
of 1,25(OH)2D3. Clinically, the disease is characterized Gupta A, Winer K, Econs MJ, Marx SJ, Collins MT:
by subcutaneous calcifications as well as periarticular FGF-23 is elevated by chronic hyperphosphatemia.
calcifications located along the extensor surfaces of J Clin Endocrinol Metab 2004;89:44894492.
major joints, and may be associated with nephrolithia- Langman CB: Disorders of phosphorus, calcium and
sis in some cases. Familial tumoral calcinosis has been vitamin D; in Avner ED, Harmon WE, Niaudet P (eds):
found to result from mutations in several genes in- Pediatric Nephrology, ed 5. Philadelphia, Lippincott
volved in phosphorus metabolism, including GALNT3, Williams & Wilkins, 2004, pp 237254.
SAMD9, KLOTHO, and FGF23. Endosteal hyperostosis Topaz O, Shurman DL, Bergman R, Indelman M,
is another hereditary disease transmitted either in au- Ratajczak P, Mizrachi M, Khamaysi Z, Behar D,
tosomal recessive or autosomal-dominant fashion. Petronius D, Friedman V, Zelikovic I, Raimer S,
This disorder is characterized by asymmetric enlarge- Metzker A, Richard G, Sprecher E: Mutations in
ment of mandibulas and nasal bridge as well as mild GALNT3, encoding a protein involved in O-linked
frontal bone bossing. glycosylation, cause familial tumoral calcinosis.
Nat Genet 2004;36:579581.
6 7 For details on hypo- and pseudohypopara-
thyrodism, see Hypocalcemia.
8 During either acute respiratory or metabolic
acidosis, intracellular P is released into the extracel-
lular fluid. Thus, hyperphosphatemia and subsequent
phosphaturia result.
9 Acute P load with resulting hyperphosphate-
mia may be observed after hypertonic sodium phos-
phate enemas (especially in young children, or in
those with an intestinal ileus) and also after inappro-
priately prescribed intravenous P infusions. Oral so-
dium phosphate laxatives are less likely to cause sus-
tained hyperphosphatemia. Long-term treatment of
osteopenia with biphosphonates may rarely lead to
mild hyperphosphatemia and phosphaturia. Hyper-
phosphatemia and phosphaturia associated with hy-
percalcemia may appear in vitamin D intoxication.
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C.B. Langman G. Ariceta B. Hoppe Hyperphosphatemia
 Divalent ion metabolism I. Eisenstein P. Goodyer I. Zelikovic Hypomagnesemia

/
Hypomagnesemia Symptoms 0

100 FEMg2+ 1

FEMg2+ <2% FEMg2+ >2%

Renal losses
Decreased intake 2 Altered Mg2+ distribution 3 Gastrointestinal losses 4

Acquired 5 Genetic 6

Malnutrition Hungry bone syndrome Malabsorptive syndromes (celiac, IBD) Postobstructive diuresis Gitelman syndrome
Alcoholism Refeeding Diarrhea Recovery from ATN Familial hypomagnesemia,
Low-magnesium food Diabetic ketoacidosis Short bowel syndrome Renal transplantation hypercalciuria and nephrocalcinosis
Parenteral fluids Bowel resection Drugs Isolated hypomagnesemia
Laxative abuse Loop/thiazide diuretics (autosomal-dominant, autosomal-recessive)
Primary intestinal hypomagnesemia Aminoglycosides Autosomal-dominant hypoparathyrodism
Amphotericin B
Cisplatinum

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 1 Magnesium ion (Mg2+), which is the second
most common intracellular action, has an essential
role in many biological processes. The kidney is the
main organ responsible for Mg2+ homeostasis. Of total
plasma Mg2+, 80% is filtered through the renal glom-
eruli and more than 95% of the filtered Mg2+ is reab-
sorbed by the renal tubule, mainly in the thick ascend-
ing limb of the loop of Henle. Normal serum Mg2+ lev-
els range from 0.62 to 1 mmol/l (1.52.4 mg/dl).
2 Hypomagnesemia is often asymptomatic.
The signs and symptoms may be nonspecific and in-
clude nausea, vomiting and muscle weakness. In more
severe cases, symptoms are mostly of neuromuscular
origin and include tremor, tetany, seizures, irritability
and confusion. In addition, cardiac manifestation such
as tachycardia, premature contractions and prolonged
QT interval leading to fatal torsades de pointes may
exist. Of note, hypomagnesemia may lead to hypocal-
cemia and hypokalemia.
3 Determination of urinary Mg2+ excretion is an
important part of the evaluation of the patient with hy-
pomagnesemia. To differentiate GI losses or reduced
intake from renal losses, fractional excretion of Mg2+
(FEMg) should be determined. FEMg is calculated using
the following formula: (UMg Scr)/ ([0.8 SMg] Ucr) ing to renal magnesium losses. In Gitelman syndrome,
100 when UMg/Ucr and SMg/Scr are urine and serum
Mg2+ and urine and serum creatinine concentrations,
respectively. The factor 0.8 is used because only ap-
proximately 80% of plasma Mg2+ is filtered through the
renal glomeruli. The additional 20% are protein (mainly
albumin)-bound and therefore are not filterable. Nor-
mally, FEMg is under 2%.
4 Poor oral intake is a rare cause of hypomag-
nesemia in children. It may be seen along with other
electrolyte deficiencies.
5 In hungry bone syndrome, seen mostly after
parathyroidectomy, there is rapid bone formation
leading to rapid intake of phosphorus, calcium and
magnesium and hence to low plasma levels of these
ions. The same clinical picture may be seen in the
refeeding phase of malnourished children. In diabetic
ketoacidosis, insulin therapy leads to magnesium in-
101 take into the cells.
6 The small intestine is the major site of mag-
nesium absorption. Any pathological process leading
to a disease in this part of the GI tract may cause mag-
nesium deficiency. Diarrhea has high magnesium con-
Divalent ion metabolism
tent (up to 200 mg/l) and thus may lead to hypomagne-
semia. In steatorrhea, hypomagnesemia can ensue
due to the formation of magnesium lipid-salts. Primary
intestinal hypomagnesemia with secondary hypocal-
cemia is a rare autosomal-recessive disorder. Patho-
physiology is related to impaired intestinal absorption
of magnesium accompanied by renal magnesium
wasting as a result of a reabsorption defect in the dis-
tal convoluted tubule. The disease is caused by muta-
tions in the gene encoding TRPM6, a member of the
transient receptor potential family of cation channels
which is expressed in the small intestine and the distal
convoluting tubule. Primary intestinal hypomagnese-
mia with secondary hypocalcemia manifests clinically
as refractory seizures in infancy with very low serum
calcium and magnesium levels.
7 Conditions leading to renal magnesium wast-
ing include postobstructive diuresis and the recovery
phase of ATN. In children who received renal trans-
plantion, hypomagnesemia is usually the result of
therapy with calcineurin inhibitors [cyclosporine A, ta-
crolimus (FK-506)]. Other drugs causing hypomagne-
semia are listed in the algorithm.
8 There are several hereditary disorders lead-
van den Heuvel LP, van Cutsem E, Hoenderop JG,
a variant of Bartter syndrome, patients present during
late childhood or adolescence with muscle weakness
and tetany. Typical laboratory findings include, in addi-
tion to hypomagnesemia, hypokalemia, metabolic al-
kalosis and hypocalciuria. Although the most common
genetic defect leading to GS is a mutation in the gene
encoding the NaCl cotransporter in the distal convo-
luted tubule, a defect in the Cl- channel ClCKb may
also lead to Gitelman syndrome. Familial hypomagne-
semia, hypercalciuria and nephrocalcinosis, previous-
ly called Michellis-Castrillo syndrome, is an autosomal-
recessive disorder causing severe renal magnesium
and calcium wasting leading to hypomagnesemia and
nephrocalcinosis with normal serum calcium levels.
The typical patient presents in early childhood with
seizures, tetany, recurrent urinary tract infections, kid-
ney stones, polyuria and polydipsia. Renal failure de-
velops later in most patients. Extrarenal manifesta-
tions may include ocular involvement. The disease
is due to a mutation in the gene encoding paracellin-1,
a member of the claudin family of tight junction pro-
teins located in the thick ascending limb of the loop of
Henle. Isolated hypomagnesemia (autosomal-domi-
nant) is an extremely rare disorder of renal magne-
sium wasting. Patients with the autosomal-dominant
I. Eisenstein P. Goodyer I. Zelikovic
variant are usually asymptomatic. An additional typi-
cal laboratory finding is hypocalciuria. The genetic
defect is in the -subunit of the Na-K-ATPase trans-
porter located in the basolateral membrane of the dis-
tal convoluting tubule. Autosomal-dominant hyper-
parathyroidism is caused by an activating mutation of
the calcium-sensing receptor in the parathyroid gland.
The mutation in this receptor, which also senses mag-
nesium levels, leads to renal magnesium and calcium
wasting. PTH levels are inappropriately low for the de-
gree of hypocalcemia. Very recently, a defect in the
gene encoding epidermal growth factor has been im-
plicated in hereditary renal magnesium wasting.
Selected reading
Cole DE, Quamme GA: Inherited disorders of renal
magnesium handling. J Am Soc Nephrol 2000;11:
19371947.
Greenbaum LA: Electrolyte and acid-base disorders;
in Behrman RE, Kliegman RM, Jenson HB (eds):
Nelson Textbook of Pediatrics, ed 17. Philadelphia,
Saunders, 2004.
Groenestege WM, Thebault S, van der Wijst J,
van den Berg D, Janssen R, Tejpar S,
Knoers NV, Bindels RJ: Impaired basolateral sorting
of pro-EGF causes isolated recessive renal hypo-
magnesemia. J Clin Invest 2007;117:22602267.
Kang JH, Choi HJ, Cho HY, Lee JH, Ha IS, Cheong HI,
Choi Y: Familial hypomagnesemia with hypercalci-
uria and nephrocalcinosis associated with CLDN16
mutations. Pediatr Nephrol 2005;20:14901493.
Riveira-Munoz E, Chang Q, Bindels RJ, Devuyst O:
Gitelmans syndrome: towards genotype-pheno-
type correlations? Pediatr Nephrol 2007;22:326332.
Rodrguez Soriano J: Tubular disorders of electro-
lyte regulation; in Avner ED, Harmon WE, Niaudet P
(eds): Pediatric Nephrology, ed 5. Philadelphia,
Lippincott Williams & Wilkins, 2004, pp 729757.
Schlingmann KP, Konrad M, Seyberth HW: Genetics
of hereditary disorders of magnesium homeostasis.
Pediatr Nephrol 2004;19:1325.
Zelikovic I: Molecular pathophysiology of tubular
transport disorders. Pediatr Nephrol 2001;16:
919935.
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Hypomagnesemia
 Divalent ion metabolism F.B. Stapleton J. Smith Hypercalciuria

Hypercalciuria
102 Urolithiasis, hematuria, dysuria

Urine calcium/creatinine ratio

24-hour collection or spot /

>0.2 mg/mg (0.56 mmol/mmol <0.2 mg/mg (0.56 mmol/mmol) Ultrasound

in children older than 2 years in children older than 2 years
Abnormal Normal

Normal Urolithiasis
History and physical examination 0 Nephrocalcinosis
Family history 1
Dietary history 2
Medication history 3
Defer evaluation if patient has urinary tract infection 4
Blood tests
Electrolytes, bicarbonate, pH, calcium, phosphorus,
magnesium, PTH and vitamin D metabolites
Repeat urinary testing including 24-hour collection for
calcium, sodium, citrate, creatinine:
onsider testing uric acid and oxalate levels 5

Idiopathic hypercalciuria Possible causes of secondary hypercalciuria (table)

Hypercalcemia
Hypophosphatemia
Urine calcium/creatinine Urine citrate Metabolic acidosis
Hypomagnesemia
Renal tubular acidosis
Dent disease
Bartter syndrome
>0.2 mg/mg <0.2 mg/mg <400 mg/mg creatinine
Hypercalciuria Normal (Consider distal RTA) High fluid intake 6
Reduced Na+ intake

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 1 Whenever possible, the diagnosis of hyper-
calciuria should be made on the basis of a 24-hour uri-
nary excretion. In young children, timed urinary collec-
tions may be impractical or impossible. Urinary cal-
cium excretion in younger children is estimated by use
of the ratio of urinary calcium to creatinine on a fasting
spot urine. Normal calcium excretion during childhood
has been defined as <4 mg/kg per day while eating a
routine diet. Normal values for fasting spot or 24-hour
urine calcium/creatinine ratio for children are: 06
months is <0.8 mg/mg, 712 months is <0.6 mg/mg,
and >2 years is <0.2 mg/mg. Use of random urinary
collections may be misleading. The urine calcium to
creatinine ratio may increase by 40% or as high as 0.28
following a meal. A first morning fasting collection
along with a postprandial sample can provide consid-
erable information. If only a single random sample is
available, it would be desirable to collect a sample
24 h following a meal in which milk is given. In such a
sample, if the ratio of urinary calcium to creatinine is
<0.2, further evaluation for hypercalciuria is not neces-
sary.
2 Hypercalciuria is most often considered in
the evaluation of urolithiasis, hematuria, or less com-
monly dysuria. The purpose is to identify idiopathic or
secondary causes of hypercalciuria.
3 As many as 80% of patients with idiopathic
hypercalciuria have a family member with urolithiasis.
In familial idiopathic hypercalciuria, an autosomal-
dominant pattern of inheritance has been postulated.
When males in multiple generations have hypercalci-
uria, urinary stones, and proteinuria (with or without
renal failure), one should suspect X-linked hypercalciu-
ric nephrolithiasis (Dent disease) (table).
4 A careful dietary history should be obtained
in all children with hypercalciuria to ascertain if dietary
factors might account for the finding. High intake of
dietary sodium and/or protein may increase the uri-
nary excretion of calcium.
103
5 Some of the medications that have been
associated with hypercalciuria include furosemide,
corticosteroids, vitamin D and methylxanthines.
6 Diagnostic studies for hypercalciuria should
be deferred if the patient has a urinary tract infection,
as pyelonephritis increases urinary calcium excretion.
7 Once an abnormal value is discovered, it
should be re-confirmed and examined in relationship
to urinary sodium excretion. If the urinary collections
suggest a high dietary sodium intake, a collection fol-
lowing 24 weeks of sodium restriction (23 g sodium
per day) is indicated. Additional urinary studies should
be performed including creatinine level, to establish
the adequacy of the collection and normalization of
values, and citrate level to evaluate for renal tubular
acidosis. Urinary uric acid and oxalate levels should be
tested if indicated. Both, hyperuricosuria and hyperox-
aluria may coexist with hypercalciuria. Normal urinary
values for school-age children: calcium <4 mg/kg/day;
citrate >400 mg/g creatinine; uric acid <0.56 mg/dl
GFR; oxalate <50 mg/1.73 m2/day; cystine <60 mg/
1.73 m2/day.
8 When idiopathic hypercalciuria is confirmed,
the next step is to assess whether dietary manipula-
tions can normalize calcium excretion. High fluid in-
take is mandatory. A reduced sodium, high potassium,
and low oxalate diet is recommended for children with
hypercalciuria. Sodium restriction is indicated be-
cause of the well-known calciuric effect of high dietary
sodium intake. Increased potassium intake may re-
duce urine calcium excretion. For children unrespon-
sive to dietary sodium restriction and potassium sup-
plementation, hydrochlorothiazide (12 mg/kg/day)
and/or citrate therapy may be helpful. Dietary calcium
restriction is not recommended for children with hy-
percalciuria especially in the light of reports of osteo-
penia in affected children, as well as increased urinary
oxalate excretion with low-calcium diets.
Selected reading
Frick KK, Bushinsky DA: Molecular mechanisms of
primary hypercalciuria. J Am Soc Nephrol 2003;14:
10821095.
Gillespie RS, Stapleton FB: Nephrolithiasis in
children. Pediatr Rev 2004;25:131138.
Southwest Pediatric Nephrology Study Group:
Idiopathic hypercalciuria: association with isolated
hematuria and risk urolithiasis in children.
Kidney Int 1990;37:807811.
Stapleton FB, Kroovand RL: Stones in childhood;
in Coe FL, Favus MJ, Pan CYC, et al (eds): Kidney
Stones: Medical and Surgical Management.
Philadelphia, Lippincott-Raven, 1996, pp 10651080.
Stapleton FB, Noe HN, Jerkins GR, et al: Hyper-
calciuria in children with urolithiasis. Am J Dis Child
1982;136:675678.
Stapleton FB. McKay CP, Noe HN: Urolithiasis in
children: the role of hypercalciuria. Pediatr Ann
1987;16:980992.
Thomas SE, Stapleton FB: Leave no stone unturned:
understanding the genetic basis of calcium-contain-
ing stones in children. Adv Pediatr 2000;47:199221.
Table. Selected causes of hypercalciuria and urolithiasis
Increased intestinal calcium absorption
Vitamin D excess
Renal tubular dysfunction
Renal tubular phosphate leak
Impaired renal tubular calcium absorption
Hypercalciuric hypocalcemia
Hypomagnesemia-hypercalciuria syndrome
Type 1 (distal) renal tubular acidosis
Dent disease
Bartter syndrome
Endocrine disturbances
Hypothyroidism
Adrenocorticoid excess
Hyperparathyroidism
Bone metabolism disorder
Immobilization
Rickets
Malignancies
Juvenile rheumatoid arthritis
Other
Familial idiopathic hypercalciuria
Drugs (certain diuretics, corticosteroids)
Urinary tract infection
Williams syndrome
Increased renal prostaglandin E2 production
Hypercalcemia

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Divalent ion metabolism F.B. Stapleton J. Smith Hypercalciuria
 Divalent ion metabolism F.B. Stapleton J. Smith Nephrolithiasis/urolithiasis

Nephrolithiasis/urolithiasis
104 Symptoms/signs of urinary stone /

History 0, physical examination, urinalysis 1, urine culture

Imaging 2

Stone passed and Stone identified in No stone identified but High fluid intake 5
recovered urinary tract history suggestive of stone Reduced sodium intake 5

+ + + + +
Urologic or Complete metabolic evaluation 3
surgical consultation Serum creatinine, calcium, bicarbonate, Hypercalciuria Hyperoxaluria Uric acid Cystinuria Struvite
uric acid, potassium, phosphorus, lithiasis
magnesium, PTH and vitamin D metabolites,
if indicated
24-hour urine volume, calcium, creatinine,
oxalate, uric acid, sodium, citrate, High K+ and Bicarbonate/citrate Prevent/treat
Options include
or random urine calcium/creatinine, low oxalate diet (urine pH 7.07.5) infection
observation, ESWL,
oxalate and uric acid Citrate when Allopurinol
surgical removal
indicated Avoid excessive
Consider thiazides purines

Stone analysis 4
Avoid oxalate-rich foods Bicarbonate/citrate
Supplemental citrate, (urine pH 7.07.5)
Mg2+ and orthophosphate MPG
Consider thiazides
Consider pyridoxine
Calcium oxalate Cystine Struvite Uric acid Avoid vitamin C supplements
Calcium phosphate

Complete metabolic Urine cystine Urine culture Urine and serum uric Evaluation positive for
evaluation 3 acid and creatinine stone disease

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 1 Symptoms and signs of urolithiasis/nephrolithiasis may
include abdominal, flank, or pelvic pain, gross or microscopic hema-
turia and, occasionally, UTI.
2 The age of the patient can provide clues to a specific meta-
bolic cause. A dietary history should include questions regarding
intake of fluid, vitamins, minerals and drugs (furosemide, and sulfa-
methoxazole). Particular attention should be paid to growth and de-
velopment, blood pressure, and bone development. Any family his-
tory of urolithiasis, hematuria, or renal failure is important to elicit.
Genetic conditions leading to nephrolithiasis include diseases such
as hereditary hyperoxaluria, cystinuria, Dent disease, hypoxanthine-
guanine phophoribosyl transferase deficiency, hereditary renal
hypouricemia and xanthinuria.
3 The urinary sediment should be examined for crystalluria.
Triphosphates suggest an infectious etiology. Uric acid and cystine
crystals may focus the work-up. Others require more extensive initial
evaluation.
4 Imaging studies for urolithiasis include sonogram of the
kidneys and the urinary tract, plain abdominal radiography, intrave-
nous pyelography and, occasionally, nonenhanced helical CT.
5 Metabolic evaluation is ideally performed while the patient
is at home, consuming his or her regular diet, and free of infection.
Although 24-hour urinary collections form the criterion for most uri-
nary measurements (table 1), obtaining such collections from small
children can be difficult or impossible. Standards based on single
specimens have been developed (table 2).
Hypercalciuria (see algorithm).
Primary hyperoxaluria types 1 and 2 are rare autosomal-recessive
disorders caused by defects in specific hepatic enzymes that result in
overproduction of oxalate. In type 1 hyperoxaluria, the defective en-
zyme is peroxysomal alanine- glyoxylate aminotransferase and in
type 2, glyoxylate reductase/hydroxyl pyruvate reductase. In most
patients, symptoms of urolithiasis occur in childhood. Definitive di-
agnosis requires a liver biopsy for appropriate enzyme studies. Sec-
ondary hyperoxaluria occurs with excessive intake of oxalate precur-
sors (ethylene glycol, ascorbic acid), increased absorption of oxalate
(extensive bowel resection, inflammatory bowel disease) or pyridox-
ine deficiency.
Uric acid calculi account for 34% of urinary calculi in the pediatric
population. Uric acid lithiasis may be associated with hereditary or
acquired conditions leading to hyperuricosuria (see Hypouricemia
and Hyperuricemia). These hereditary disorders include inborn er-
105 rors of metabolism associated with overproduction of uric acid such
as Lesch-Nyhan syndrome and type 1 glycogen storage disease, and
hereditary disorders of tubular transport of uric acid, such as familial
renal hypouricemia. High purine intake, uricosuric drugs, hemolysis
Cystine stones account for up to 5% of calculi in the pediatric popula-
tion. Cystinuria is a group of inherited tubular transport disorders Selected reading
characterized by excessive urinary excretion of cystine and the diba- Danpure CJ: Genetic disorders and urolithiasis. Urol Clins N Am
sic amino acids arginine, lysine, and ornithine (see Cystinuria). Chil- 2000;27:287299.
dren may suffer from recurrent urinary calculi in childhood and into Gillespie RS, Stapleton FB: Nephrolithiasis in children. Pediatr Rev
adulthood. 2004;25:131138.
Hulton SA: Evaluation of urinary tract calculi in children. Arch Dis
6 If a stone analysis reveals cystine, struvite, or uric acid cal- Childh 2001;84:320323.
culus, the metabolic work-up may be more focused. Calcium phos- Polinsky MS, Kaiser BA, Baluarte HJ, Grsukin AB: Renal stones and
phate or calcium oxalate stones necessitate a broader metabolic hypercalciuria. Adv Pediatr 1993;40:353384.
evaluation. Santos-Victoriano M, Brouhard BH, Cunningham RJ: Renal stone
disease in children. Clin Pediatr 1998;37:583600.
7 Adequate fluid intake is a key to treatment regardless of the Stapleton FB, Kroovand RL: Stones in childhood; in Coe FL,
cause of stones. Patients should increase fluid intake even more dur- Favus MJ, Pan CYC, et al (eds): Kidney Stones: Medical and
ing hot weather or strenuous exercise. Water is preferable over other Surgical Management. Philadelphia, Lippincott-Raven, 1996,
beverages. Decreasing urinary sodium concentration by reducing pp 10651080.
sodium intake is another measure to prevent stone precipitation of Thomas SE, Stapleton FB: Leave no stone unturned: understanding
any cause. the genetic basis of calcium-containing stones in children.
Hypercalciuria: A high potassium and low oxalate diet is recommend- Adv Pediatr 2000;47:199221.
ed for children with hypercalciuria. Citrate supplementation helps
prevent stones in patients who have renal tubular acidosis or hypo-
citraturia. For children unresponsive to dietary sodium restriction
and potassium supplementation, hydrochlorothiazide may be helpful
(see Hypercalciuria).
Hyperoxaluria: Limiting or avoiding high-oxalate foods such as spin-
ach, rhubarb, nuts, tea wheat bran, and strawberries is recommend-
ed. Supplemental citrate, magnesium, and phosphorus may help
decrease urinary oxalate crystallization. Calcium intake should not
be restricted because this can increase intestinal calcium absorption.
Oral citrate has been suggested as adjunctive therapy. Thiazides may
be considered. Approximately 1040% of patients respond to pyri-
doxine supplementation, but vitamin C should be avoided.
Uric acid lithiasis: Treatment of uric acid stones includes urinary alka-
linization. Supplementation with citrate or bicarbonate is indicated.
The resulting elevation in urinary pH increases the solubility of uric
acid. Allopurinol decreases uric acid synthesis by inhibiting xanthine
oxidase and is useful in disorders associated with excess uric acid Table 2. Normal urinary values in children based on random urine
production. Dietary purine restriction is of limited value; however,
Age Norman values,
counseling patients to avoid unusual amounts of purine intake is ap-
mg/mg
propriate.
Cystinuria: Treatment of cystinuria includes urinary alkalinization us- Calcium/creatinine 06 months <0.8
612 months <0.6
ing citrate or bicarbonate. D-penicillamine, and -MPG may help in
28 years <0.2
refractory cases.
Oxalate/creatinine 06 months <0.3
6 months to 4 years <0.15
>4 years to adult <0.1
Table 1. Normal urinary values for school aged children based on 24-hour urine
Cystine/creatinine all ages <0.02
collection Citrate/creatinine all ages <0.51
Calcium <4 mg/kg/day
Uric acid/GFR calculated as: 63 years <0.56 mg uric acid/dl
Uric acid <0.56 mg/dl GFR
Urine uric acid* serum creatinine* glomerular filtrate
Oxalate <50 mg/1.73 m2/day

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Urine creatinine*
and myeloproliferative disorders may also result in hyperuricosuria Cystine <60 mg/1.73 m2/day
and uric acid stones. Volume 20 ml/kg/day
* All values in same units: mg/dl or mmol/l

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Divalent ion metabolism F.B. Stapleton J. Smith Nephrolithiasis/urolithiasis
 Renal failure J.-P. Guignard R.N. Fine Oliguria/anuria

/
Oliguria/anuria
106

Oliguria Anuria

Assess volume status 0 Renal ultrasound

Hypovolemia Euvolemia Hypervolemia No renal pelvic dilatation Renal pelvic dilatation

Rehydration 1 Furosemide 4
15 mg/kg

Diuresis No diuresis No diuresis Diuresis

Fluid challenge 2
furosemide

Prerenal failure No diuresis Oliguric intrinsic Non-oliguric intrinsic Anuric intrinsic Postrenal failure
acute renal failure acute renal failure acute renal failure

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Maintenance Treat fluid and electrolyte abnormalities 5 Relief of obstruction 6
fluid therapy 3 Discontinue nephrotoxic drugs Treat fluid and

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Extracorporeal therapy electrolyte abnormalities

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 1 Oliguria is defined as the excretion of less
than 400 ml/m2 body surface area of urine. Anuria is
the complete cessation of urine output. Oligouria/an-
uria may be one of the first signs of impaired renal
function. The purpose of this algorithm is to give the
clinical approach to the oligo-anuric child. The differ-
ential diagnosis of the conditions leading to oligo-an-
uria are described in the algorithms on Neonatal
acute renal failure and Acute renal failure (child/ado-
lescent).
2 In the child with oliguria, assessment of
volume status is vital in order to proceed with the
work-up.
3 4 When dehydration is present: the fluid
deficit should be corrected initially by administration
of 2040 ml/kg of isotonic fluid over 2 h. The use of
isotonic saline is a safe method of rehydration. If diure-
sis does not ensue, consider the administration of a
colloid such as plasma or albumin at a rate of 20 ml/kg
over 2 h. If the above measures do not initiate diuresis,
furosemide at a dose of 25 mg/kg may be attempted.
5 Once normal urine output has been achieved,
maintenance fluid therapy should begin either intrave-
nously or orally: for the first 10 kg bodyweight, 100 ml/
kg. For the next 10 kg body weight, 50 ml/kg. For each
kg above 20 kg, 20 ml/kg.
107
Renal failure
6 In some cases of oliguric acute renal failure,
high-dose furosemide (up to 5 mg/kg) may initiate di-
uresis. Patients with nonoliguric renal failure have a
generally better prognosis and the management of
these patients in terms of drug and nutrition adminis-
tration is easier. If the child remains oligoanuric, fluid
intake should be restricted to 400 ml/m2 + ongoing
losses (urine, vomiting, gastric drainage, etc.) of hypo-
tonic fluids.
7 In cases of intrinsic renal failure, apart from
treating the specific condition, fluids, electrolytes and
acid-base abnormalities should be addressed. If pos-
sible, nephrotoxic drugs should be discontinued.
These include agents such as NSAIDs, ACE inhibitors,
angiotensin II AT1 receptors blockers, amphotericin B,
aminoglycoside antibiotics and vancomycin. If the
conservative measures mentioned above fail to re-
store renal function or if complications of severely re-
duced GFR occur (hyperkalemia, metabolic acidosis,
pulmonary edema, pericarditis, hypertension) RRT
must be started. The choice of RRT to be used (perito-
neal dialysis, hemodialysis or hemofiltration) depends
on a variety of factors.
8 Whenever urinary tract obstruction is diag-
nosed, the obstruction should be promptly relieved.
Of note, polyuria (postobstructive diuresis) and elec-
trolyte abnormalities are common after the relief of
obstruction.
J.-P. Guignard R.N. Fine
Selected reading
Andreoli SP: Clinical evaluation and management
of acute renal failure; in Avner ED, Harmon WE,
Niaudet P (eds): Pediatric Nephrology, ed 5.
Philadelphia, Lippincott/Williams & Wilkins, 2004,
pp 12331252.
Bailey D, Phan V, Litalien C, Ducruet T, Merouani A,
Lacroix J, Gauvin F: Risk factors of acute renal failure
in critically ill children: A prospective descriptive
epidemiological study. Pediatr Crit Care Med 2007;8:
2935.
Hui-Stickle S, Brewer ED, Goldstein SL: Pediatric
ARF epidemiology at a tertiary care center from
1999 to 2001. Am J Kidney Dis 2005;45:96101.
Krause I, Cleper R, Eisenstein B, Davidovits M:
Acute renal failure, associated with non-steroidal
anti-inflammatory drugs in healthy children.
Pediatr Nephrol 2005;20:12951298.
Mannix R, Tan ML, Wright R, Baskin M: Acute
pediatric rhabdomyolysis: causes and rates of renal
failure. Pediatrics 2006;118:21192125.
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Oliguria/anuria
 Renal failure J.-P. Guignard R.N. Fine Neonatal acute renal failure

/
Neonatal acute renal failure
108 Assess volume status 1 Gestational/postnatal history 0
Clinical manifestations
Blood chemistry
Urinalysis and urine indices
Renal US
Hypovolemia Euvolemia Hypervolemia

Rehydration 2
Replacement of blood loss Consider furosemide 4
Restoration of cardiac output

Diuresis No diuresis

Prerenal failure Intrinsic renal failure Postrenal failure

CBC Fluid challenge CBC

Chest X-ray furosemide CPK
Echocardiogram Plasma and urine myoglobin
Blood and urine culture
Renal US + Doppler
No diuresis

Dehydration 3 Congenital nephropathies 5 Congenital obstructive uropathies 6

Inadequate fluid intake, vomiting, diarrhea, Bilateral renal agenesis or dysgenesis, Bilateral uretero-pelvic junction obstruction,
phototherapy, high environmental temperature infantile polycystic kidney disease bilateral vesico-ureteric junction obstruction,
Blood loss Acute tubular necrosis ureterocele, obstruction in a single kidney,
Perinatal hemorrhage, clamping of the aorta during cardiac surgery, Cortical necrosis posterior urethral valves
hypovolemia secondary to fluid shifts, feto-fetal transfusion Nephrotoxic agents Obstruction by fungal bezoar
Perinatal asphyxia Hemoglobinuria Closure of abdominal wall defects
Severe respiratory distress Vascular disorders Imperforated prepuce
Heart failure Renal vein thrombosis, renal artery thrombosis
Congestive/noncongestive Acute pyelonephritis

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Maintenance fluid therapy, Treat fluid and electrolyte abnormalities Relief of obstruction
Packed RBC infusion Discontinue nephrotoxic agents

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Repair of heart anomaly Intravenous antibiotics

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 1 Acute renal failure is observed in 824% of
neonates admitted to neonatal intensive care units.
Although acute renal failure in a neonate is a serious
and life-threatening condition, prognosis in neonates
with nonoliguric acute renal failure is excellent. In con-
trast, mortality rates in neonates with oliguric acute
renal failure are high, ranging from 25 to 80%.
2 Detailed history (pre- and postnatal) and
physical examination are mandatory in the work-up of
the neonate with acute renal failure. Pre- and postnatal
history should include information regarding: abnor-
mal perinatal sonogram findings (oligohydroamnios,
hydronephrosis, kidneys size, kidneys location, ap-
pearance of the parenchyma and appearance of the
urinary bladder), maternal or neonatal drug use (ACE
inhibitors, angiotensin II AT1 receptor antagonists,
NSAIDs, aminoglycosides, amphotericin B, etc.), previ-
ous intrauterine fetal demise or stillbirth or congenital
kidney malformations in family relatives.
Physical examination should include: vital signs
(tachypnea/dyspnea, hypotension/hypertension,
tachycardia/irregular pulse), cardiac murmur or gallop,
palpation of femoral pulses, signs of dehydration/hy-
pervolemia, abnormal neurologic findings or abdomi-
nal masses. The initial evaluation of the neonate with
acute renal failure includes the following tests: serum
levels of creatinine, BUN, electrolytes (potassium, so-
dium, magnesium, calcium, phosphorus), albumin and
bicarbonate. Urine sample for sediment examination,
electrolytes and creatinine levels, osmolality and cul-
ture. The urine sodium level and osmolality are very
helpful in the differential diagnosis of acute renal fail-
ure (table). In addition to the laboratory tests men-
tioned above, a renal sonogram is mandatory in every
neonate with acute renal failure. Additional tests
should be reserved for the subsequent evaluation de-
pending on the suspected condition (as outlined in the
algorithm).
3 Assessment of the volume status of the
neonate with acute renal failure according to the
physical examination and laboratory work-up
mentioned above is vital in order to proceed with
the work-up.
109 4 When dehydration is present: the fluid deficit
should be corrected initially by administration of
2040 ml/kg of isotonic fluid over 2 h. The use of an
isotonic saline is a safe method of rehydration. If
diuresis does not ensue, administer plasma at a rate of
20 ml/kg over 2 h. Furosemide, 25 mg/kg, may be
Renal failure
attempted. In hypotensive neonates, dopamine may
Selected reading
be used at a dose of 24 g/kg/min. Higher doses
(<10 g /kg min) may produce renal vasoconstriction Andreoli SP: Acute renal failure in the newborn.
by an -adrenergic agonist effect. Semin Perinatol 2004;28:112123.
Cuzzolin L, Fanos V, Pinna B, di Marzio M, Perin M,
5 Any condition that causes hypovolemia, hy- Tramontozzi P, Tonetto P, Cataldi L: Postnatal renal
potension or hypoxemia may decrease renal perfusion function in preterm newborns: a role of diseases,
and lead to prerenal failure. If severe and of long dura- drugs and therapeutic interventions. Pediatr
tion, prerenal failure may lead eventually to intrinsic Nephrol 2006;21:931938.
renal damage. Gouyon JB, Guignard JP: Management of acute
renal failure in newborns. Pediatr Nephrol 2000;14:
6 In some cases of oliguric acute renal failure, 10371044.
high-dose furosemide (up to 5 mg/kg) may initiate di- Guignard JP, Drukker A: Why do newborn infants
uresis. have a high plasma creatinine? Pediatrics 1999;
103:e49.
7 The main conditions leading to intrinsic renal Toth-Heyn P, Drukker A, Guignard JP: The stressed
failure in the neonatal period are congenital renal neonatal kidney: from pathophysiology to clinical
anomalies and acute tubular necrosis. The most com- management of neonatal vasomotor nephropathy.
mon congenital kidney malformation leading to renal Pediatr Nephrol 2000;14:227239.
failure is bilateral renal agenesis/dysgenesis. This ab-
normality is commonly associated with Potter syn-
drome (oligohydroamnios, pulmonary hypoplasia and
distinctive facies). The manifestations of PKD (either
autosomal-dominant or autosomal-recessive) can
range from intrauterine fetal demise or neonatal ESRD,
to slowly deteriorating kidney function leading to
ESRD later in life. For further details see Cystic kid-
neys. Renal ischemia (usually due to birth asphyxia,
septic shock, massive bleeding or heart failure) can
lead to either medullary, papillary or most commonly
cortical necrosis. Although prognosis is generally
poor, the extent of necrosis, duration of oliguria, and
severity of associated conditions determine the ulti-
mate prognosis. The most common drugs causing re-
nal impairment in the newborn period are aminoglyco-
sides and NSAIDs.
8 The most common obstructive congenital
malformations leading to neonatal acute renal failure
are bilateral UPJ obstruction, bilateral uretero-vesicle
junction obstruction and posterior urethral valves.
For details, see Fetal hydronephrosis.
Table. Diagnostic urinary indices
Prerenal Intrinsic
Urinalysis normal >5 RBC/HPF
Uosm, mosm/kg H2O >400 <400
UNa, mmol/l <30 >60
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FeNa, % <2 >3
U/Posm 61.3 ^1.0
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J.-P. Guignard R.N. Fine Neonatal acute renal failure
 Renal failure R.N. Fine J.-P. Guignard Acute renal failure (child/adolescent)

/
Acute renal failure (child/adolescent)
110 Assess volume status 1 History 0
Clinical manifestations
Blood chemistry
Urinalysis and urine indices
Renal US
Hypovolemia Euvolemia Hypervolemia

Prerenal failure Intrinsic renal failure Postrenal failure

CBC, Serum: CBC, CPK, LDH, albumin, C3, C4, ANA, ANCA, Metabolic stones profile
Liver function tests anti-GBM ab, hepatitis serology, myoglobin Abdominal US/CT
Chest X-ray Urine: eosinophils, myoglobin
ECG Renal US + Doppler
Echocardiogram Kidney biopsy

Dehydration 2 Renovascular 3 Posterior urethral valves 4

Inadequate fluid intake Renal artery stenosis Nephro-/urolithiasis
GI losses (vomiting, diarrhea) RVT Blood clot
Third-spacing (sepsis, burns, pericarditis, NS) Vascular Fungal ball
Salt-wasting (renal/adrenal disease) Vasculitis Tumors
Blood loss HUS Retroperitoneal process
Reduced cardiac output Glomerular Fibrosis
Congestive heart failure Glomerulonephritides Hematoma
Cardiac tamponade RPGN
Cardiogenic shock Tubulointerstitial
Sepsis TIN
HRS Acute tubular necrosis (nephrotoxic drugs, rhabdomyolysis,

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radio-contrast nephropathy, uric acid nephropthy, etc.)

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 1 Acute renal failure is defined as a rapid de-
cline in GFR and the inability to maintain normal fluids,
electrolytes and metabolic balance. It is observed in
23% of children admitted to tertiary care centers. The
outcome of the child with acute renal failure depends
on the underlying etiology. The mortality rates in chil-
dren with acute renal failure secondary to multiorgan
failure are very high (up to 90%) in contrast to those
with acute renal failure due to postinfectious glomeru-
lonephritis who have an excellent long-term prognosis.
Depending on the etiology, acute renal failure may cul-
minate in chronic renal failure.
2 Detailed history (pre- and postnatal) and
physical examination are mandatory in the workup of
the child with acute renal failure. History should in-
clude information regarding: kidney, endocrine or
heart disease, decreased fluid intake, voiding abnor-
malities (hematuria, dysuria, reduced urine output,
etc.), edema, shortness of breath, fever, rash, arthritis/
arthralgia, recent intercurrent infection, hemoptysis,
drug use (ACE inhibitors, NSAID , aminoglycosides,
amphotericin B, etc.), previous history of stones or kid-
ney malformations in family relatives.
Physical examination should include: vital signs
(tachypnea/dyspnea, hypotension/hypertension,
tachycardia/irregular pulse), cardiac murmur or gallop,
signs of dehydration/hypervolemia, rash, purpura, ar-
thritis, abdominal masses or loin pain.
The initial evaluation of the child with acute renal fail-
ure include the following tests: serum levels of creati-
nine, BUN, electrolytes (potassium, sodium, magne-
sium), calcium, phosphorus, albumin and bicarbonate.
Urine sample for sediment examination, electrolytes
and creatinine levels, osmolarity and culture. The
urine sodium level and osmolarity are very helpful in
the differential diagnosis of acute renal failure (table).
In addition to the laboratory tests mentioned above, a
renal sonogram is mandatory in every child with acute
renal failure. Additional tests should be reserved for
the subsequent evaluation depending on the suspect-
ed condition (as outlined in the algorithm).
3 Assessment of the volume status of the child
with acute renal failure according to the physical ex-
amination and laboratory workup mentioned above is
111 vital in order to proceed with the work-up.
4 Prerenal failure is defined as an acute deterio-
ration in kidney function due to renal hypoperfusion.
Any condition that causes hypovolemia may lead to
prerenal failure. If severe and of long duration, the pre-
Renal failure
renal condition may eventually lead to intrinsic renal
damage. Of note, some of the conditions that lead to
prerenal failure are characterized by total body fluid
overload (congestive heart failure, hepatorenal syn-
drome), but a decreased effective circulatory volume
which leads to the renal failure. HRS is defined as an
acute renal failure in a child with severe liver disease in
the absence of any other identifiable causes of renal
disease. Although not fully understood, HRS is be-
lieved to be the result of severe renal vasoconstriction.
HRS is characterized by a normal urinary sediment
(like most other prerenal conditions), very low urinary
sodium concentration, resistance to fluids and diuret-
ics administration and a generally poor prognosis.
5 Intrinsic renal failure can result from a dam-
age to any of the structures that compose the kidney
(vascular bed, glomeruli, interstitium and tubule). Vas-
cular conditions leading to acute renal failure include
renal artery stenosis, RVT, vasculitis and hemolytic-
uremic syndrome. For details, see appropriate algo-
rithms. Any type of glomerulonephritis, if severe
enough, can lead to acute renal failure. These condi-
tions lead to nephritic syndrome, which is character-
ized by gross hematuria with urinary casts, proteinuria,
hypertension and variable degrees of decreased renal
function. Severe injury may lead to RPGN. For details,
see algorithms on Hematuria, RPGN and Acute ne-
phritic syndrome. ATN results from severe damage to
the tubular cell either due to prolonged prerenal failure
or as a result of direct injury to the tubular cell from
various endogenous or exogenous toxins (drugs, ra-
diocontrasts, ethylene glycol, myoglobin, hemoglobin,
uric acid). Major drugs that lead to ATN include amino-
glycoside antibiotics, amphotericin B, acyclovir, ifos-
famide and cisplatin. Hemolysis and, more commonly,
rhabdomyolysis can lead to ATN. Since hemoglobin is
a relatively large molecule and because, it is mostly
bound to plasma proteins (haptoglobin, etc.), hemoly-
sis rarely causes acute renal failure. Myoglobin, on the
other hand, is filtered in the glomeruli and its presence
in the urine may lead to tubular injury. Treatment of
hemoglobinuria and myoglobinuria includes hyperhy-
dration, diuretic therapy (mannitol or loop diuretics)
and alkalinization of the urine. Radiocontrast agents
may lead to acute renal failure due to intense renal va-
soconstriction, tubular obstruction or direct tubular
damage. Pre-existing renal impairment, volume deple-
tion, and drugs like NSAID and ACE inhibitors are the
main risk factors for radiocontrast-induced acute renal
failure. The incidence of radiocontrast nephropathy
can be decreased by hydration and by the use of new-
R.N. Fine J.-P. Guignard
er iso-osmolar, nonionic agents. The prophylactic ad-
ministration of N-acetylcysteine, may be helpful as
well. Uric acid nephropathy is most commonly due to
tumor lysis syndrome seen after the treatment of tu-
mors such as leukemia and lymphoma. In addition to
the hyperuricemia, hyperkalemia and hyperphospha-
temia are frequently observed. Treatment includes
hyperhydration, diuretic therapy (mannitol or loop di-
uretics), alkalinization of the urine and the use of uric
acid-lowering agents.
6 Obstructive stone may lead to acute renal
failure if the obstruction is in both kidneys or ureters or
if in a single kidney. For the workup and management
of the child with uro/nephrolithiasis, see appropriate
algorithms. Any tumor or other space-occupying pro-
cess in the retroperitoneal space may compress both
ureters leading to acute renal failure.
Selected reading
Andreoli SP: Clinical evaluation and management
of acute renal failure; in Avner ED, Harmon WE,
Niaudet P (eds): Pediatric Nephrology, ed 5.
Philadelphia, Lippincott Williams & Wilkins, 2004,
pp 12331252.
Bailey D, Phan V, Litalien C, Ducruet T, Merouani A,
Lacroix J, Gauvin F: Risk factors of acute renal failure
in critically ill children: a prospective descriptive
epidemiological study. Pediatr Crit Care Med 2007;
8:2935.
Hui-Stickle S, Brewer ED, Goldstein SL: Pediatric
acute renal failure epidemiology at a tertiary care
center from 1999 to 2001. Am J Kidney Dis 2005;45:
96101.
Krause I, Cleper R, Eisenstein B, Davidovits M:
Acute renal failure, associated with non-steroidal
anti-inflammatory drugs in healthy children.
Pediatr Nephrol 2005;20:12951298.
Mannix R, Tan ML, Wright R, Baskin M: Acute
pediatric rhabdomyolysis: causes and rates of renal
failure. Pediatrics 2006;118:21192125.
Table. Diagnostic urinary indices
Prerenal Intrinsic
Urinalysis normal >5 RBC/HPF
Uosm, mosm/kg H2O >400 <400
UNa, mmol/l <30 >60
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FeNa, % <2 >3
U/Posm 61.3 ^1.0
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Acute renal failure (child/adolescent)
 Renal failure R.N. Fine J.-P. Guignard Chronic renal failure

/
Chronic renal failure
112 Etiology 0

Congenital malformations Metabolic/genetic disorders Acquired disorders Miscellaneous

Hypoplasia/dysplasia Hyperoxaluria FSGS Tumors
Reflux nephropathy Cystinosis Chronic glomerulonephritidies Drugs
Obstructive uropathy PKD HUS Unknown
Posterior urethral valves Alport syndrome
Nephronophthisis
Congenital nephrotic syndrome

Prevent decline in GFR

Reduce proteinuria 1
Control blood pressure
Metabolic control
Optimize nutrition

Treat ESRD 2

Cardiovascular 3 Growth 4 Anemia 5 Renal bone disease 6 Infections 7 Development 8

Control hypertension Adequate nutrition
Prevent fluid overload Vitamin supplements
Treat hyperlipidemia Correct acidosis and
Treat carnitine deficiency sodium depletion
Prevent renal bone disease
rhGH treatment
Iron/folic acid supplements
Treat carnitine deficiency
rHuEpo treatment
Identify bone disorder Treat blood-borne Physiotherapy
Control P, Ca2+, PTH levels infections Treat learning disabilities
Correct acidosis and Immunizations Treat speech/hearing
sodium repletion impairments
Sociofamilial support

Renal replacement therapy 9

Dialysis

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Renal transplantation :

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 1 Chronic renal failure is defined as an irreversible reduction
in GFR. When the chronic renal failure is severe enough to mandate
the initiation of dialysis, it is termed ESRD. The prevalence of chronic
renal failure in children is approximately 18 per million children. The
purpose of this algorithm is to discuss the major treatment strategies
and complications of chronic renal failure in children. For details on
the various disorders leading to chronic renal failure and ESRD, see
appropriate algorithms.
2 The most common causes of chronic renal failure in chil-
dren are congenital malformations (including aplastic/hypolastic/
dysplastic kidneys, reflux nephropathy and obstructive uropathies),
which account for 3540% of the cases. FSGS and other chronic glo-
merulopathies account for approximately 20% and metabolic/genetic
diseases for an additional 10% of cases.
3 In the child with chronic renal failure who has not reached
ESRD the goal is to halt the deterioration in renal function. Antipro-
teinuric agents such as ACE inhibitors and angiotensin II receptor
blockers have been shown to reduce the proteinuria in chronic renal
failure and thereby slow the progression of renal disease. In a child
treated with these agents, it is important to monitor serum creatinine
and potassium levels. Hypertension in children with chronic renal
failure is caused by various factors including sodium and water re-
tention, activation of the renin-angiotensin-aldosterone system and
sympathetic overactivity. Hypertension is a major pathogenic factor
in the progression of chronic renal failure. For treatment of hyperten-
sion, see Pediatric Hypertension. Metabolic control and adequate
nutrition are very important measures in the care of the child with
chronic renal failure (see below).
4 ESRD has major adverse effects on the child afflicted with
this condition. A multidisciplinary approach is mandatory in the
management of these children in order to treat the variety of physical
and developmental complications of ESRD and to maintain normal
lifestyle in these children.
5 The main cardiovascular complication in children with
ESRD is left ventricular failure secondary to hypertension. Other car-
diovascular complications include nonhypertrophic cardiomyopathy
secondary to carnitine deficiency, hyperlipidemia, and, rarely, car-
diac arrhythmias. There is accumulating evidence that morbidity
from cardiovascular complications in children with ESRD is higher
than previously recognized and may have serious, long-term effects
on the health of these children.
113 6 Growth retardation is very common in children with chronic
renal failure and ESRD. Growth failure in these children is caused by
metabolic acidosis, sodium depletion, inadequate nutrition, bone
disease and abnormalities in the growth hormone axis. Dietary con-
sultation and follow-up is mandatory in every child with ESRD and
Renal failure
should include careful monitoring of weight and height, anthropo-
metric measurements and monitoring of the daily intake of calories,
protein, electrolytes, minerals, vitamins and trace elements recom-
mended for the child with ESRD. Recombinant human growth hor-
mone (rhGH) therapy should be considered when indicated.
7 In children with chronic renal failure, hemoglobin levels de-
crease when the GFR is below 35 ml/min/1.73 m2 body surface area.
The most important cause for anemia in these children is inadequate
erythropoiesis secondary to low erythropoietin levels normally pro-
duced by the kidneys. Other causes of anemia in ESRD include poor
iron intake, blood loss in children treated with hemodialysis, carni-
tine deficiency and hyperparathyroidism. The follow-up of anemia in
children with ESRD includes blood testing for CBC, iron, ferritin and
transferrin levels checked at regular intervals. The recommended
hemoglobin levels in children with ESRD are 1112 g/dl. Treatment
strategies of the anemia include iron, folic acid and, when indicated,
carnitine supplements. Recombinant erytheropoietin administration
has become the mainstay of the management of anemia in these
children. Transfusion of RBCs is occasionally required. It should be
emphasized, however, that multiple transfusions of RBCs increase
the risk of renal graft rejection following transplantation.
8 For details on Renal Bone Disease, see appropriate
algorithm.
9 Children with ESRD are prone to develop infections. Rea-
sons for this tendency include immune system dysregulation, in-
dwelling catheters and treatment with immunomodulatory drugs.
Meticulous handling of catheter and dialysis equipment as well as
high index of suspicion for signs of infection should be exercised.
Follow-up of children with ESRD should include serological blood
tests performed periodically to check the immunological status of
these children and to exclude viral infections such as HIV, hepatitis B
and C, varicella zoster, CMV and EBV. In addition, immunization ac-
cording to the specific recommendations for children with chronic
renal failure should be pursued.
10 ESRD in children and its complications can lead to severe
developmental handicaps, hearing and language disturbances as
well as psychological and emotional disorders. Academic achieve-
ments in children with ESRD are often less than optimal.
They also have more neurologic deficits, microcephaly, seizures and
hypotonicity than their normal peers. Untreated uremia, hearing im-
pairments (secondary to adverse reactions of drugs), prolonged hos-
pitalization periods and, in the past, aluminum toxicity are important
causative factors in these impairments. To prevent or minimize these
impairments, aggressive control of uremia, adequate nutrition and
avoidance of ESRD-related complications as well as a team work of
the pediatric nephrologist, family physician, social worker, physio-
therapist and a psychologist is needed.
R.N. Fine J.-P. Guignard Chronic renal failure
11 When ESRD (GFR <510 ml/min/1.73 m2) has been reached,
RRT is indicated. The choice of the mode of RRT (hemodialysis or
peritoneal dialysis) depends on a variety of disease-, patient- and
family-related factors. Hemodialysis is performed in the hospital 36
times per week depending on the childs age and condition. Perito-
neal dialysis is usually performed at home using an automated ma-
chine (automated peritoneal dialysis).
12 The ultimate goal of therapy in the child with ESRD is renal
transplantation. The options of donations for transplantation include
living-related, living-nonrelated and deceased donors. Renal trans-
plantation in children has become a well-established therapy. The
graft survival rates have improved dramatically with current 5-year
graft survival rates of 83% and 73% for living-related and deceased
donors, respectively.
Selected reading
Bakr A, Amr M, Sarhan A, Hammad A, Ragab M, El-Refaey A,
El-Mougy A: Psychiatric disorders in children with chronic renal
failure. Pediatr Nephrol 2007;22:128131.
Filler G: Renal transplantation: literature review 2004-2005.
Pediatr Transplant 2006;10: 418428.
Fine RN, Whyte DA, Boydstun II: Conservative management of
chronic renal insufficiency; in Avner ED, Harmon WE, Niaudet P
(eds): Pediatric Nephrology, ed 5. Philadelphia, Lippincott
Williams & Wilkins, 2004, pp 12911312.
Mahan JD, Warady BA, the Consensus Committee: Assessment
and treatment of short stature in pediatric patients with chronic
kidney disease: a consensus statement. Pediatr Nephrol 2006;21:
917930.
Mitsnefes MM, Kimball TR, Kartal J, Witt SA, Glascock BJ, Khoury
PR, Daniels SR: Progression of left ventricular hypertrophy in
children with early chronic kidney disease: 2-year follow-up study.
J Pediatr 2006;149:671675.
Schroder CH, European Pediatric Peritoneal Dialysis Working
Group: The management of anemia in pediatric peritoneal
dialysis patients: guidelines by an ad hoc European committee.
Pediatr Nephrol 2003;18:805809.
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 Renal failure R.N. Fine J.-P. Guignard Renal osteodystrophy

/
Renal osteodystrophy
114 Clinical manifestations 0
Blood chemistry
Bone films
Bone biopsy

Bone pain, calcifications Bone pain, pathologic fractures Bone deformities, bone pain
PhosphorusMCa2+mN, PTHM Ca2+Malkaline phosphatasemPTHm Phosphorusmalkaline phosphataseM
Subperiosteal erosions Metaphyseal widening

Osteitis fibrosa 1 Adynamic bone disease 3 Rickets/osteomalacia 5

(2nd hyper-PTH)

Dietary phosphate restriction 2 Reduce PTH suppression 4 Phosphate and calcium supplements 6
Phosphate binders Active vitamin D analogues
Active vitamin D analogues
Calcium-sensing-receptor agonist

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 1 ROD is the term used for a variety of bone
disorders secondary to renal failure. The metabolic
abnormalities leading to ROD have a tremendous ef-
fect on a childs growth because if left untreated, ROD
can lead to severe growth retardation, pathologic frac-
tures and developmental delay. As such, it is impor-
tant to identify the exact nature of the bone disease
and to treat it accordingly. Of note, although there are
3 different types of ROD (see below), overlap between
the different disorders is common.
2 Evaluation of the child with ROD includes ob-
taining history regarding bone pain, pathologic frac-
tures, restriction of motion and limping. In case of
limping, slipped capital femoral epiphyses should be
suspected. Physical examination includes height mea-
surement, signs of rickets (bowing, frontal bossing,
etc.), bone or muscle tenderness, or signs of periar-
ticular calcifications. Laboratory evaluation includes
serum levels of creatinine, BUN, calcium, inorganic
phosphorus, alkaline phosphatase, bicarbonate and
PTH. Bone film is an essential part of the work-up of
the child with ROD. The radiologic findings depend on
the specific disorder (see below). If the above work-up
does not lead to the identification of the specific bone
disorder, bone biopsy is needed (see below). Bone bi-
opsy is also needed in the case of unexplained hyper-
calcemia or suspected aluminum bone disease.
3 The most common form of ROD in children is
2nd hyperparathyroidism also known as osteitis fibro-
sa or high-turnover bone disease. The pathophysiol-
ogy of this disorder is the result of phosphorus reten-
tion and impaired synthesis of calcitriol, the active
form of vitamin D. Clinical manifestations can range
from asymptomatic disease to bone and muscle pain,
height stunting, skeletal deformities and SCFE. The
biochemical abnormalities include hyperphosphate-
mia, low-to-normal calcium levels and elevated PTH
levels in a child with GFR of <2530% of the normal
values for age. The radiologic findings include subperi-
osteal erosions due to increased bone resorption.
Bone biopsy demonstrates increased number and vol-
ume of osteoclasts and osteoblasts, high bone forma-
tion rate and, in severe cases, fibrosis.
115 4 Treatment strategy in 2nd hyperparathyroid-
ism is aimed towards the suppression of the excessive
levels of PTH. Of note, recommended serum PTH lev-
els in children with ESRD are between 150 and 300 pg/
ml. If hyperphosphatemia is present, restriction of di-
etary phosphate and therapy with phosphate binders
Renal failure
are initiated. Once serum phosphate level is controlled,
Selected reading
treatment with an active vitamin D analog is initiated.
The recently introduced therapy with calcium-sensing- Kuizon BD, Salusky IB: Renal osteodystrophy; in
receptor agonists promises to be an effective treat- Avner ED, Harmon WE, Niaudet P (eds): Pediatric
ment of 2nd hyperparathyroidism. Nephrology, ed 5. Philadelphia, Lippincott Williams
& Wilkins, 2004, pp 13471374.
5 Adynamic bone disease is characterized by Martin KJ, Olgaard K, Coburn JW, Coen GM,
reduced activity of bone formation and, hence, is a Fukagawa M, Langman C, Malluche HH,
low-turnover bone disease. The pathophysiology of McCarthy JT, Massry SG, Mehls O, Salusky IB,
this disorder is not completely understood, but PTH Silver JM, Smogorzewski MT, Slatopolsky EM,
suppression, overtreatment with vitamin D analogs or McCann L, Bone Turnover Work Group: Diagnosis,
aluminum toxicity (prevalent in the past) plays a major assessment, and treatment of bone turnover
role. Children with this type of bone disease suffer abnormalities in renal osteodystrophy. Am J Kidney
from higher rates of pathological fractures. Typical Dis 2004;43:558565.
laboratory findings include low PTH and alkaline phos- Salusky IB, Kuizon BG, Juppner H: Special aspects of
phatase levels accompanied by hypercalcemia. Bone renal osteodystrophy in children. Semin Nephrol
film cannot help in differentiating between this entity 2004;24:6977.
and other types of ROD. Histological findings are the Waller SC, Ridout D, Cantor T, Rees L: Parathyroid
opposite of those seen in 2nd hyperparathyroidism hormone and growth in children with chronic renal
and include low osteoblast number and volume, low failure. Kidney Int 2005;67:23382345.
bone formation rate and absence of fibrosis as well as Hruska KA, Teitelbaum SL: Renal osteodystrophy.
reduced uptake of tetracycline. N Engl J Med 1995;333:166174.
6 The treatment of adynamic bone disease
consists of reduction or cessation of the administra-
tion of agents suppressing PTH activity (vitamin D an-
alogs and phosphate binders).
7 The third type of ROD is ostemalacia/rickets.
Similar to adynamic bone disease, ostemalacia/rickets
is also a low-turnover bone disease. It is characterized
by several features of adynamic bone disease but the
hallmark of this disorder is defective bone mineraliza-
tion. If the defective bone mineralization occurs before
growth has ceased, it is called rickets. If, on the other
hand, the defective mineralization occurs at mature,
trabecular bone, the condition is termed osteomalacia.
In the past, the most common cause of ostemalacia/
rickets in children with ESRD was aluminum toxicity.
Nowadays, however, phosphate and/or vitamin D defi-
ciency are the most common causes of this condition in
children with chronic renal failure. Laboratory findings
are similar to those seen in adynamic bone disease. Hy-
pophosphatemia is an additional finding in ostemala-
cia/rickets. Bone film may show widening of epiphyseal
growth plate and other signs typical of rickets. Bone
histology has many similarities to adynamic bone dis-
ease except for high osteid volume in ostemalacia/rick-
ets and low-to-normal in adynamic bone disease.
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8 In ostemalacia/rickets, phosphate and
calcium supplements may be needed.
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R.N. Fine J.-P. Guignard Renal osteodystrophy
 Index of Signs and Symptoms
A Abdominal wall defects 108 Bone deformities 114 Cystic kidney diseases 44
116 Acromegaly 42, 98 Bone pain 114 Cystic nephroma 42, 48
Acute acidosis 98 Bowel resection 100 Cystinosis 36, 60, 62, 112
Acute glomerulonephritis 44, 90 Brain trauma 52 Cystinuria 62, 104
Acute hemolysis 82 Brain tumor 52 Cytomegalovirus 10
Acute lymphoblastic leukemia 42 Bromide poisoning 78
Acute pyelonephritis 108 Bronchopulmonary dysplasia 50 Defective renal secretion 82
Acute renal failure 68, 82, 98,106, 108 Burns 72, 74, 76, 80, 82, 88
D Dehydration 108, 110
Acute tubular necrosis 42, 44, 108, 110 Delayed bladder emptying 30
Acute tubulointerstitial nephritis 42 C Calcifications 114 Dent disease 60, 62,102
Acute urate nephropathy 42 Calcipenic rickets 92 Denys-Drash syndrome 10
Addison disease 84 Cardiac tamponade 110 Diabetes insipidus 74, 88
Adrenal insufficiency 94 Cardiogenic shock 110 Diabetes mellitus 42, 60, 66, 84, 88
Adrenocortical failure 82 Central diabetes insipidus 64 Diabetic ketoacidosis 100
Adrenogenital syndrome 64 Cerebral salt wasting 72 Diarrhea 72, 74, 100, 108, 110
Adynamic bone disease 114 Chronic active hepatitis 60 Dicarboxylic aminoacidosis 54
Alcoholism 96 Chronic glomerulonephritidies 112 Dietary calcium deficiency 70
Aldosterone 86 Chronic kidney disease 70 Dietary chloride deficiency 76
Aldosteronism 86 Chronic metabolic acidosis 70 Diffuse mesangial sclerosis 10
Alport syndrome 4, 16, 112 Chronic renal failure 44, 82, 88, 98 DiGeorge syndrome 92
Amiloride administration 60 Chronic tubulointerstitial damage 60 Distal renal tubular acidosis 84
Anal reflex 30 Churg-Strauss syndrome 4, 14, 18 Diuresis 106
Analgesic abuse 60 Cirrhosis 72 Diuretics 72, 76, 80, 88, 96
Anasarca 88 Classic cystinuria 54 Down syndrome 68
Anemia 112 Clear cell sarcoma 42, 48 Duplex kidney 42, 48
Aneurysms, coronary artery, hepatic artery, CNS bleeding 52 Dysplasia/hypoplasia 36, 44
renal artery 18 Coarctation of aorta 50, 52
Angioedema 90 Colonic adenoma 86 Ehlers-Danlos syndrome 60
Angiomyolipoma 42, 48 Column of Bertin 42, 48
E Elevated intracranial pressure 50
Antenatal ultrasonography 26 Complement dysregulation 20 Endocarditis 6
Anuria 106 Congenital adrenal hyperplasia 50, 52, 60, 82, 84 End-stage renal disease 112
Aortal stenoses 18 Congenital chloride diarrhea 80 Enemas 98
Apparent mineralocorticoid excess 76, 80 Congenital hemihypertrophy 42 Enterostomy losses 80
Ascites 88 Congenital nephropathies 108 Euvolemia 76, 106, 108, 110
Autosomal-dominant hypoparathyrodism 100 Congenital nephrotic syndrome 112 Excessive sweating 76, 80, 88
Congenital obstructive uropathies 108 Extracorporeal membrane oxygenation 50
Bacteriuria 22 Congenital rubella syndrome 50 Extracorporeal shock wave lithotripsy 104
B Barium poisoning 80 Congenital syphilis 10 Extrarenal losses 74
Bartter syndrome 64, 76, 80, 86, 102 Congestive heart failure 68, 90, 110 Extreme prematurity 58
Beckwith-Weidemann syndrome 42 Constipation 30
Benign familial hematuria 4 Continuous incontinence/drip 30 Fabrys disease 42
Bladder lesion 32 Contraction alkalosis 86
F Familial dysautonomia 52
Bladder rupture 34 Cortical necrosis 44, 108 Familial glucosuria 62
Blood anion gap 84 Corticosterone methyl oxidase deficiency 60, 82 Familial hyperkalemic periodic paralysis 82

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Blood clot 110 Cushing syndrome 44 Familial hypocalciuric hypercalcemia 94
Blood lactate 84 Cutaneous polyarteritis 18 Familial hypokalemic periodic paralysis 80

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Blood loss 108, 110 Cystic fibrosis 72, 76, 80, 86 Fanconi syndrome 54, 56, 58, 64, 70, 80, 96

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 Fanconi-Bickel glycogenosis 60, 62 High-dose hydrochlorothiazide therapy 94 Intracranial hypertension 76
Fanconi-Bickel syndrome 58 Histidinuria 54 Intrinsic renal failure 108, 110
Fat deposition 44 HIV nephropathy 20 Ischemia 44
Fetal lobulation 42, 48 Hodgkin/non-Hodgkin lymphoma 42 Isolated cystinuria 54
Fever 74 Horseshoe kidney 48 Isolated glycinuria 54
Fibrosis 110 Human immunodeficiency syndrome 10 Isolated hereditary renal glycosuria 58
Focal segmental glomerulosclerosis 10, 12, 90, 112 Hungry bone syndrome 96, 100 Isolated hypomagnesemia 100
Fractures 114 Hydronephrosis 4 Isolated lysinuria 54
Fungal ball 110 Hydrops fetalis 90
Fungal bezoar 108 1--Hydroxylase deficiency 70 Jansen chondrodysplasia 96
Hypercalcemia 50, 52, 64, 102
J Jansen osseous dysplasia 94
G Galactosemia 60, 62 Hypercalciuria 44, 104 Jansen syndrome 70
Gastric drainage 76, 80 Hyperdibasic AA type I 54 Juvenile nephronophthisis 46
Gastrocystoplasty 86 Hyperkalemia 60
Gastrointestinal bleeding 82 Hyperkalemic distal renal tubular acidosis 84 K Kawasaki syndrome 18
Genetic cobalamin C defect 20 Hyperosmolality 82 Ketonuria 72
Giggle/stress incontinence 30 Hyperostosis 98
Gitelman syndrome 64, 76, 80, 86, 100
Glomerulocystic kidney disease 42
Hyperoxaluria 36, 44, 104, 112
Hyperparathyroidism 62, 96
L Laceration 34
Laxative abuse 100
Glomerulonephritides 52, 110 Hypertension 76 Laxatives 98
Glomerulonephritis 32, 42, 44 Hyperthyroidism 50, 52, 94, 98 Lazy bladder 30
Glucocorticoid deficiency 72 Hypertrophy 42 Lesch-Nyhan syndrome 68
Glucocorticoid-remediable aldosteronism 52, 76, 80 Hypervolemia 106, 108, 110 Leukemia 68, 84
Glucocorticoids 52, 96 Hypoadrenalism 88 Leukocyte esterase 22
Glucose infusion 96 Hypoaldosteronism 88 Licorice ingestion 76, 80, 86
Glucose-6-phosphatase deficiency 68 Hypocalcemia 64 Liddle syndrome 52, 76, 80, 86
Glucose-galactose malabsorption 58 Hypocomplementemic urticarial vasculitis 18 Liver disease 70, 88
Glucosuria 62 Hypokalemia 60 Liver failure 84
Glue sniffing 60, 62 Hypomagnesemia 92, 102 Loaded colon 30
Glycogen storage disease type 1 42, 60, 68 Hyponatremic hypertensive syndrome 88 Loin pain hematuria syndrome 4
Goodpasture syndrome 4, 14 Hypoparathyroidism 68, 86, 92, 98 Loop 86
Gordon syndrome 50, 52, 60, 82, 84 Hypophosphatasia 94 Lowe syndrome 60, 62
Guillain-Barr syndrome 52 Hypophosphatemia 102 Lower limb reflexes 30
Hypophosphatemic rickets 62, 70, 96 Low-magnesium food 100
H Hartnup disease 54
Heart failure 72, 108
Hypoplasia/dysplasia 40, 112
Hyporeninemic hypoaldosteronism 60, 82, 84
Lung hemorrhage 14
Lupus nephritis 4, 6
Heavy metal poisoning 52, 60, 62 Hypothyroidism 72, 94 Lymphangiectasis 48
Hematoma 48, 110 Hypovolemia 76, 106, 108, 110 Lymphoma 68
Hematuria 4 Lysinuric protein intolerance 54
Hemoglobinuria 42, 108 I Idiopathic crescentic glomerulonephritis 90
Hemolytic-uremic syndrome 4, 20, 52, 90,
110, 112
Idiopathic Fanconi syndrome 62
Idiopathic hypercalciuria 102
M Malabsorption 88
Malabsorptive syndromes 100
Hemophilia 42 Idiopathic nephrotic syndrome 90 Malnutrition 88, 90, 100
Henoch-Schnlein purpura 6, 18 Idiopathic renal hypouricemia 66, 72 Marfan syndrome 60
Hepatic failure 90 IgA nephropathy 4 Marked volume depletion 60
Hepatitis B glomerulonephritis 12 Imperforated prepuce 108 Maternal drug abuse 50
117 Hepatitis C glomerulonephritis 12 Inadequate fluid intake 108, 110 Medullary sponge kidney 44, 46
Hepatorenal syndrome 16, 110 Infantile idiopathic hypercalcemia 94 Melena 88
Hereditary fructose intolerance 60, 62 Insensible losses 74, 88 Membranoproliferative glomerulonephritis 6, 14,
Hereditary malformation syndrome 46 Insulin deficiency 82 16, 90

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Hereditary tyrosinemia 42 Insulin 80 Membranous glomerulonephritis 12
Hereditary/metabolic conditions 68 Interstitial nephritis 44, 60 Membranous glomerulopathy 90

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Index of Signs and Symptoms
 Index of Signs and Symptoms

Meningitis 20 Osteitis fibrosa 114 Primary hyperparathyroidism 94

118 Mesoblastic nephroma 42, 48, 50 Osteomalacia 70, 114 Protein-losing enteropathy 90
Metabolic acidosis 78, 82, 88, 96, 102 Outdated tetracyclines 60, 62 Proteinuria, transient, persistent 8
Metabolic alkalosis 72, 80, 88 Overactive bladder 30 Proximal renal tubular acidosis 62
Metabolic disorders 66 Overload proteinuria 8 Proximal tublar defect 66
Metabolic storage diseases 44 Proximal tubulopathy 88
Metaphyseal widening 114 P Pancreatitis 72, 88 Prune belly syndrome 42, 48
Methioninuria 54 Pararenal mass 42 Pseudohypoaldosteronism 60, 64, 82
Microcystic kidneys 10 Parathyroid hormone 70 Pseudohypoparathyroidism 92
Microscopic polyangiitis 14, 18 Parenteral fluids 100 Pseudorickets 70
Mid-aortic coarctation 50 Passage of stone 56 Pseudotumor, cerebri 52
Mineralocorticoid excess 52, 74 Pelvic kidney 48 Pseudotumor, sarcoid 42
Minimal-change disease 12 Perinatal asphyxia 108 Psoriasis 68
Minimal-change nephrotic syndrome 90 Perinatal hemorrhage 108 Pyelonephritis 32, 42, 44, 52
Mitochondriopathies 60, 62 Perirenal hematoma 42 Pyloric stenosis, psychogenic 76
Moderate/severe urinary tract dilatation 24 Perirenal urinoma 42 Pyuria 22
Modified Chapel Hill Classification 18 Peritonitis 88
Moyamoya disease 52 Persistent asymptomatic hematuria 4 R Radiocontrast nephropathy 42
Multicystic dysplasia 40 Persistent glomerulonephritis 4 Rapidly progressive glomerulonephritis 4, 6, 110
Multicystic dysplastic kidney 42 Persistent stone 56 Reduced cardiac output 110
Multiple stones 56 Pheochromcytoma 52 Reflux nephropathy 36, 112
Muscle hyperactivity 84 Phosphate depletion 94 Reflux/obstructive nephropathy 52
Myelofibrosis 42 Phosphoribosyl pyrophosphate synthetase Renal agenesis 38
Myoglobinuria 42 overactivity 68 Renal amyloidosis 42
Myxedema 90 Plasma aldosterone 82 Renal angioplasty 42
Plasma renin activity 76, 80, 84 Renal artery stenosis 50, 52, 86, 110
N Nail-patella syndrome 16
Nasogastric suction 86
Pleural effusion 88
Pneumonia 20
Renal artery thrombosis 108
Renal bleeding 34
Necrotizing glomerulonephritis 14 Polyangiitis 12 Renal bone disease 112
Neonatal hyperechoic kidney with normal GFR 44 Polyarteritis nodosa 4, 6, 18 Renal candidiasis 44
Nephroblastomatosis 42 Polycystic kidney disease 4, 42, 46, 48, 50, 108, 112 Renal cell carcinoma 48
Nephrocalcinosis 102 Polycythemia 68 Renal contusion 34
Nephrogenic diabetes insipidus 64, 68 Posterior urethral valves 42 Renal disease 88
Nephronophthisis 44, 64, 112 Posthypercapnia 86 Renal dysplasia 74
Nephrotic syndrome 10, 44, 72 Postinfectious glomerulonephritis 4, 6 Renal failure 72
Nephrotoxic agents 108 Post-kidney transplant 96 Renal free water loss 64
Neuroblastoma 4, 42, 50, Postobstructive diuresis 80, 100 Renal hypertrophy 48
Nutcracker syndrome 4, 32 Postobstructive uropathy 88 Renal losses 74
Postrenal failure 106, 108, 110 Renal malakoplakia 42, 48
O Obesity 68
Obstructive nephropathy 36
Post-streptococcal glomerulonephritis 12, 14
Potassium wasting 62
Renal osteodystrophy 92
Renal pelvic diameter 26
Obstructive stones 56 Prebiliary obstruction 76 Renal salt wasting 64
Obstructive uropathy 26, 50, 60, 82, 112 Prerenal failure 106, 108, 110 Renal transplantation 100, 112
Oligomeganephronia 40 Primary biliary cirrhosis 60 Renal trauma 52

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Oliguria 106 Primary hyperaldosteronism 52, 76, 80, 86 Renal tubular acidosis 78, 80, 84, 102
Oncogenic osteomalacia 96 Primary intestinal hypomagnesemia 100 Renal tumors 52

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Osmotic diuresis 72, 74, 88 Primary polydipsia 72 Renal vein thrombosis 42, 44, 50, 82, 108, 110

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 Renin-secreting tumor 80, 86 T Takayasu arteritis 18, 52 V Vascular congestion 44
Renovascular disease 80 Tamm-Horsfall protein 42, 44 Vascular disorders 108
Respiratory alkalosis 96 Tertiary hyperparathyroidism 94 Vascular pathology 88
Retroperitoneal hematoma 34 Thalassemia 42 Vasculitides 52
Retroperitoneal process 110 Thiazides 86 Vasculitis 18, 36, 90, 110
Rhabdomyolysis 82 Thick-walled bladder 24 Vesicoureteral reflux 24, 26, 28, 42
Rhabdomyosarcoma 4 Thin basement membrane disease 16, 32 Vitamin A intoxication 94
Rheumatoid arthritis 60 Thromboembolism 50 Vitamin D 52
Rickets 114 Thrombotic thrombocytopenic purpura 20 Vitamin D depletion 70
Rubella 10 Tissue hypoperfusion and hypoxia 84 Vitamin D intoxication 50, 70, 94, 98
Total parenteral nutrition 50, 78, 96 Vitamin D-deficient rickets 92
S Salicylates 84
Salt-losing CAH 82
Transient neonatal hypercalcemia 94
Transluminal angioplasty 18
Vitamin D-related rickets 96
Vitamin D-resistant rickets 70, 92
Salt-losing nephropathy 72, 88 Tuberous sclerosis 42 Vomiting 72, 76, 80, 86, 108, 110
Salt-wasting (renal/adrenal disease) 110 Tubular disorders 8
Sarcoidosis 68, 94 Tubulointerstitial nephritis 4, 36, 110 W Water deprivation test 74
Sepsis 110 Tumor hypercalcemia 94 Wegeners granulomatosis 4, 12, 14, 18
Serum aldosterone 88 Tumor lysis syndrome 68 Williams syndrome 94
Severe loin pain 28 Tyrosinemia 60, 62 Wilms tumor 4, 42, 48, 50
Severe respiratory distress 108 Wilson disease 36, 60, 62
Short bowel syndrome 100 Umbilical artery catheter 52
Sickle cell disease 36, 42, 60, 82
U Urate nephropathy 44 Xanthinuria 44, 66
Sjogren disease 42 Ureteropelvic avulsion 34
X Xanthogranulomatous malakoplakia 48
Sjogren syndrome 60 Ureteropelvic junction obstruction 42 X-linked hypophosphatemic rickets 70
Skin nodules 18 Ureterosigmoidostomy 78, 80
Solid tumors 84 Uric acid excretion 66
Splenic compression 42 Uric acid lithiasis 104
Starvation 68 Urinary stone 104
Strenuous exercise 4 Urinary tract abnormalities 38
Struvite 104 Urinary tract obstruction 64
Subperiosteal erosions 114 Urine anion gap 60, 78, 84
Sweat test 86 Urine chloride 86
Sweating 74 Urinoma 48
Syndrome of inappropriate antidiuretic hormone Urolithiasis 102
secretion 66 Uromodulim disorders 68
Systemic lupus erythematosus 10, 12, 14, 16, 36,
60, 83, 90
Systemic manifestations 90

119

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Index of Signs and Symptoms
 Abbreviations
AA Aminoaciduria DMSA Dimercaptosuccinic acid LDH Lactate dehyrogenase
120 ABPM Ambulatory blood pressure monitoring DRTA Distal RTA LE Leukocyte esterase
ACE Angiotensin-converting enzyme DTPA Diethylene triamine pentaacetic acid LMW Low molecular weight
ACTH Adrenocorticotropin LPI Lysinuric protein intolerance
ADPKD Autosomal-dominant polycystic kidney ECF Extracellular fluid
disease ECMO Extracorporeal membrane oxygenation MA Metabolic acidosis
AGBMAb Anti-glomerular basement antoantibody EHEC Enterohemorrhagic Escherichia coli MAG3 Mercaptoacetyltriglycine
AGN Acute glomerulonephritis ESR Erythrocyte sedimentation rate MCD Minimal-change disease
AIDS Acquired immunodeficiency syndrome ESRD End-stage renal disease MCDK Multicystic dysplastic kidney
AIN Acute tubulointerstitial nephritis ESWL Extracorporeal shock wave lithotripsy MCKD Medullary cystic kidney disease
ALT Alanine transferase MCP Membrane co-factor protein
AME Apparent mineralocorticoid excess FENa Fractional excretion of urinary sodium MEN Multiple endocrine neoplasia
ANA Antinuclear antibody FH Complement factor H MGN Membranous glomerulonephritis
ANCA Antineutrophil cytoplasmic autoantibody FHH Familial hypocalciuric hypercalcemia MMF Mycophenolate mofetil
ANS Acute nephritic syndrome FI Complement factor I MPA Microscopic polyangiitis
ARPKD Autosomal-recessive polycystic kidney FJHN Familial juvenile hyperuricemic MPG Mercaptopropionylglycine
disease nephropathy MPGN Membranoproliferative glomerulonephritis
ASLO Antistreptolysin O FSGS Focal segmental glomerulosclerosis MRI Magnetic resonance imaging
AST Aspartate aminotransferase MSK Medullary sponge kidney
ATN Acute tubular necrosis G6P Glucose-6-phosphatase
AV Arteriovenous GBM Glomerular basement membrane NDI Nephrogenic diabetes insipidus
AZA Azathioprine GCKD Glomerulocystic kidney disease NPH-MCKD Nephronophtisis-medullary cystic kidney
GFR Glomerular filtration rate disease
BMT Bone marrow transplantation GLUT2 Glucose transporter 2 NS Nephrotic syndrome
BP Blood pressure GN Glomerulonephritis NSAID Nonsteroidal anti-inflammatory drugs
BPD Bronchopulmonary dysplasia
BUN Blood urea nitrogen HCMA Hyperchloremic metabolic acidosis PAN Polyarteritis nodosa
HGPRT Hypoxanthine guanine phosphoribosyl- P-ANCA Perinuclear ANCA
CAH Congenital adrenal hyperplasia transferase PE Plasma exchange
C-ANCA Cytoplasmic ANCA HHRH Hereditary hypophosphatemia with PHA Pseudohypoaldosteronism
CBC Complete blood cell count renal hypercalciuria PHE Physical examination
CCD Cortical collecting duct HIV Human immunodeficiency virus PHP Pseudohypoparathyroidism
CDI Central diabetes insipidus HIVN HIV nephropathy PKD Polycystic kidney disease
CHF Congestive heart failure HPF High power field PP Pregnancy puerperium
CKD Chronic kidney disease HRS Hepatorenal syndrome PRA Plasma renin activity
CMO Corticosterone methyl oxidase HSP Henoch-Schnlein purpura PRPS Phosphoribosyl pyrophosphate synthetase
CMV Cytomegalovirus HUS Hemolytic-uremic syndrome PRTA Proximal RTA
COPD Chronic obstructive pulmonary disease HUV Hypocomplementemic urticarial vasculitis PSGN Post-streptococcal glomerulonephritis
CPA Cutaneous polyarteritis Hx History PTH Parathyroid hormone
CPK Creatine phosphokinase PUV Posterior urethal valve
CT Computerized tomography IBD Irritable bowel disease
CUG Cystourethrogram IC Immune complexes RBCs Red blood cells
CYP Cyclophosphamide ICGN Idiopathic crescentic glomerulonephritis ROD Renal osteodystrophy
IF Immunofluorescence RPD Renal pelvic diameter

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DDAVP Desmopressin IgAN IgA nephropathy RPGN Rapidly progressive glomerulonephritis
DI Diabetes insipidus ISHG Isolated hereditary renal glycosuria RR Renal replacement

Univ. of California San Diego

DMS Diffuse mesangial sclerosis IVIG Intravenous immunoglobulins RRT Renal replacement therapy
IVP Intravenous pyelogram RTA Renal tubular acidosis
RVT Renal vein thrombosis

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 SBE Subacute bacterial endocarditis
SCFE Slipped capital femoral epiphysis
S-Hcys Serum homocysteine
SIADH Syndrome of inappropriate antidiuretic
hormone secretion
SLE Systemic lupus erythematosus
SMX Sulfamethoxazole
Stx Shiga toxin

T4 Tyroxine
TAP Transluminal angioplasty
TBI Total body irradiation
TFA Thomsen-Friedenreich cryptantigen
TIN Tubulointerstitial nephritis
TINU Tubulointerstitial nephritis with uveitis
TMP Trimethoprim
TPN Total parenteral nutrition
TSH Thyroid-stimulating hormone
TTKG Transtubular potassium gradient
TTP Thrombotic thrombocytopenic purpura

U-mma Urinary methylmalonic acid

UPJ Ureteropelvic junction
US Ultrasound
UTI Urinary tract infection
UVJ Ureterovesical junction

VCUG Voiding cystourethrogram

VUR Vesicoureteral reflux
vWF von Willebrand factor

WBC White blood cell

WHO World Health Organization

XLH X-linked hypophosphatemic rickets

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Univ. of California San Diego
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Abbreviations