Pediatric Nephrology Handout Revised May-00 Chris Clardy, M.D.

Nephrotic Syndrome in Children

Definition Nephrosis (i.e. the nephrotic syndrome) is a condition characterized by proteinuria with resultant hypoproteinemia and edema Pathophysiology Edema Proteinuria Hypoproteinemia Decreased Oncotic Pressure Edema & Vascular Hypovolemia Hyperlipidemia Decreased oncotic pressure results in increased hepatic production of VLDL Urinary loss of heparin sulfate and LCAT results in decreased lipoprotein lipase activity with a decreased metabolism of VLDL Urinary loss of HDL and LCAT results in an increased LDL/HDL ratio Hypercoagulability Increased plasma levels of fibrinogen, factor V, and factor VII Decreased plasma levels of antithrombin III Increases in platelet number and aggregation Decreased intra-vascular volume Immunodeficiency Hypogammaglobulinemia secondary to urinary losses Hypocomplementemia secondary to urinary losses Decreased cellular immunity, potentially secondary to urinary losses of Zn and Fe Miscellaneous Artifactual hypocalcemia secondary to hypoalbuminemia True hypocalcemia secondary to urinary losses of vitamin D Copper, zinc, and iron deficiencies secondary to urinary losses of carrier proteins Artifactual hypothyroidism secondary to urinary losses of thyroxine-binding globulin Differential Diagnosis (General) Primary Nephrotic Syndrome Minimal Change Nephrotic Syndrome (MCNS) 76% Focal & Segmental Glomerulosclerosis (FSGS) 9% Membranoproliferative Glomerulonephritis (MPGN) 7% Membranous Glomerulonephritis (MGN) 2% Other glomerulopathies 6% Secondary Nephrotic Syndrome Myriad etiologic agents Artifactual Nephrotic Syndrome Hypoproteinemia unassociated with proteinuria Specific Diseases Minimal Change Nephrotic Syndrome (MCNS) No changes in light microscopy Loss of foot processes in electron microscopy

Pediatric Nephrology Handout Revised May-00 Chris Clardy, M.D. Most common in children Usually responds to immunosuppressive therapy Does not lead to renal failure May cause problems with frequent relapses

Focal and Segmental Glomerulosclerosis (FSGS) Mesangial matrix expansion with loss of normal glomerular structures Second most common in children More frequent in adolescents and African Americans May present with only proteinuria Usually leads to progressive renal failure

Membranoproliferative Glomerulonephritis (MPGN) Mesangial cell proliferation and splitting of GBM Third most common in children A glomerulonephritis which causes nephrosis Associated with a low C3 Will cause renal failure unless treated with steroids

Histopathology by Age

20% MCNS FSGS MPGN 10%

% of New Cases

15%

5%

0% 0 5 Age in Years 10 15

Laboratory Evaluation Initial Urinalysis Total protein and albumin Electrolytes, calcium, BUN, and creatinine Cholesterol (triglycerides) Blood pressure C3 PPD

Pediatric Nephrology Handout Revised May-00 Chris Clardy, M.D.

Evidence of Complicated Nephrotic Syndrome Age6 years Hematuria Hypertension Low serum C3 Normal serum cholesterol Therapy Primary Therapy Prednisone (high dose with slow taper) Cyclophosphamide Cyclosporine Response to Steroid Therapy Response of Minimal Change (J Peds 98:561, 1981)

Fail 8%

Respond 92%

Histopathology of responsive patients (J Peds 98:561, 1981)

MCNS (92%) FSGS (5%) MPGN (1%) Other (2%)

Pediatric Nephrology Handout Revised May-00 Chris Clardy, M.D. Histopathology of non-responsive patients (J Peds 98:561, 1981)

MCNS (29%) FSGS (27%) MPGN (26%) Other (18%)

Adjunctive Therapy Mild diuretic therapy (e.g. HCTZ 1 mg/kg q12) Colloid infusion (e.g. albumin 1 gm/kg accompanied by lasix 1 mg/kg) A.C.E. Inhibitors (e.g. enalapril 0.1 mg/kg q12) Pneumococcal vaccine Evaluation and Therapy of Treatment Failures Renal biopsy to determine glomerular histopathology Treat MCNS with cyclophosphamide, chlorambucil or cyclosporine Treat MPGN and MGN with alternate day steroids for a prolonged course Limit treatment of FSGS to symptomatic therapy

Glomerulonephritis (GN) in Children

Definition GN is an inflammatory glomerular lesion characterized by a) hematuria - >1 RBC/l in fresh urine - >5 RBC/hpf on a spun urine - trace blood or higher by dipstick b) proteinuria - 1+ or higher by dipstick - >150 mg/1.73 M2/day - >4 mg/M2/hour - urine protein/creatinine>0.2 c) azotemia Creatinine Clearance <100 ml/min/1.73 M2 estimated as [Ht(cm) x 0.5] creatinine d) oliguria

Pediatric Nephrology Handout Revised May-00 Chris Clardy, M.D. - <500 ml/1.73 M2/day - (F.E.Na)<1%

Pediatric Nephrology Handout Revised May-00 Chris Clardy, M.D. e) hypertension Pathophysiology Process Glomerular Inflammation Decreased G.F.R. Increased Distal Tubular Na+ and H2O Reabsorption Manifestation Hematuria & Proteinuria Azotemia

Oliguria, Edema, & Hypertension

Differential Diagnosis of GN in Children Low Complement Post Streptococcal GN Membranoproliferative GN Systemic Lupus Erythematosus Normal Complement IgA Nephropathy Henoch-Schnlein Purpura Idiopathic Vasculitis Rapidly Progressive GN Initial Evaluation of GN Goal: To distinguish Post Streptococcal GN from other forms of GN Hx=> Duration of symptoms, infection, rash, arthralgia, family history P.E.=> B.P., edema, purpuric rash Lab=> U/A, SMA-6, CBC, ASO, ANA, & C3 Symptomatic Therapy of GN Na+ restriction Diuretic Rx (e.g. Lasix 1 mg/kg q12) A.C.E. Inhibitor Rx (e.g. Captopril 1 mg/kg q6-8 or Enalapril 0.1 mg/kg/dose q12-24) Vasodilator Rx (e.g. Minoxidil 0.2 mg/kg or Diazoxide 5 mg/kg) (should be accompanied by blocker and diuretic)

Indications for a Biopsy in GN Normal initial C3 Failure of low C3 to normalize after 8 weeks Positive ANA Progressive azotemia

Hematuria & Proteinuria in Office Practice

Hematuria >1 RBC/l in fresh urine >5 RBC/hpf on a spun urine

Pediatric Nephrology Handout Revised May-00 Chris Clardy, M.D.

Trace blood or higher by dipstick Upper versus Lower Gross versus Occult False positive with hemoglobinuria, myoglobinuria, alkaptonuria, porphyria and beet ingestion

Proteinuria 1+ or higher by dipstick (large proteins only) >150 mg/1.73 M2/day >4 mg/M2/hour Urine protein/creatinine>0.2 Epidemiology ~5% of children will have hematuria and/or proteinuria on screening exam ~50% of these will be transient Incidence increases with age Incidence is higher in females than in males Hematuria Alone, Non-Glomerular (Differential Diagnosis) Urinary Tract Infection Idiopathic Hypercalciuria Presents with isolated hematuria Diagnosis by urine calcium/creatinine0.21 Hypercalciuria and hematuria resolve with thiazides May lead to nephrolithiasis or recurrent UTIs Nephrolithiasis Sickle Cell Disease RBCs sickle in high osmotic medulla of kidney 2 papillary necrosis Also seen in trait Coincident with poor concentrating ability Trauma Renal Malformations Common presentation of UPJ obstruction is gross hematuria after minor trauma in adolescent Neoplasia Rare but important Interstitial Nephritis Usually also with proteinuria and pyuria Hematuria Alone, Glomerular (Differential Diagnosis) Benign Hematuria Familial or Recurrent Due to thin or irregular basement membrane Benign condition Glomerulonephritis Usually also with proteinuria IgA, late post-streptococcal or mild SLE may have only hematuria IgA without proteinuria does not warrant biopsy Hematuria Alone (Management) Physical exam (with blood pressure) U/A x 3 (over 1 to 3 months) U/C x 1

Pediatric Nephrology Handout Revised May-00 Chris Clardy, M.D. U/A on 1st degree relatives Electrolytes, BUN, and creatinine Urine calcium/creatinine Ratio (nl0.21) ASO, C3, and ANA Ultrasound and/or IVP

Proteinuria Alone (Differential Diagnosis) Transient (2 to exercise, fever, dehydration, etc.) Orthostatic Negative first morning urine 1 Tubulointerstitial Disease Reflux Nephropathy Interstitial Nephritis Glomerular Disease Focal and Segmental Glomerulosclerosis (FSGS) Common form of nephrotic syndrome in children May present with only proteinuria More frequent in adolescents and African Americans Usually leads to progressive renal failure Proteinuria Alone (Management) Physical exam (with blood pressure) U/A x 3 (over 1 to 3 months) 1st morning void Electrolytes, BUN, creatinine, and albumin Ultrasound and or/IVP Renal Biopsy (if 0.5 gm/day/1.73 M2) Hematuria and Proteinuria (Differential Diagnosis) Probable glomerulonephritis Hypocomplementemic (low C3) Post Streptococcal GN (PSAGN) Membranoproliferative GN Systemic Lupus Erythematosus Normocomplementemic (normal C3) IgA Nephropathy Henoch-Schnlein Purpura Idiopathic Vasculitis Rapidly Progressive GN

Hematuria and Proteinuria (Initial Evaluation) Goal: To distinguish PSAGN from other forms of GN History Duration of symptoms, infection, rash, arthralgia, family history Physical Exam BP, edema, purpuric rash Lab U/A, Chemistries, CBC, ASO, ANA, & C3 Indications for Biopsy Biopsy all patients unlikely to have post-streptococcal GN as determined by Normal initial C3

Pediatric Nephrology Handout Revised May-00 Chris Clardy, M.D. Failure of low C3 to normalize after 8 weeks Positive ANA Progressive azotemia

Hypertension in Children
Significance Acute hypertension can lead to heart failure and encephalopathy Prolonged hypertension predisposes to atherosclerotic disease National Heart, Lung and Blood Institute established a Task Force on Blood Pressure Control in Children in 1977 Definitions Normal Blood Pressure Systolic and diastolic blood pressures 90th percentile for height, sex and age High-Normal Blood Pressure Systolic or diastolic blood pressure between the 90th and 95th percentile for height, sex and age High Blood Pressure (Hypertension) Systolic or diastolic blood pressure >95th percentile for height, sex and age on at least three measurements Severe Hypertension Hypertension requiring pharmacologic therapy Measurement Blood pressure should be measured annually on children >3 years old Use appropriate sized cuff Width >2/3 of the length of the upper arm Length > the circumference of the arm Palpation Measures only systolic blood pressure Used only in neonates Doppler Ultrasound Measures both systolic and diastolic blood pressure Auscultation Used to establish standards (based on height, age and sex) 5th Korotkoff sound used for diastolic if possible Population Standards Standards vary by height, age and sex Boys Age 3 6 10 13 16 Height Percentile 5th 25th 104 107 109 112 114 117 121 124 129 132 75th 111 115 121 128 136 95th 113 117 123 130 138

Systolic

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Diastolic

3 6 10 13 16

63 72 77 79 83

64 73 79 81 84

66 75 80 83 86

67 76 82 84 87

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Girls Height Percentile 5th 25th 104 105 108 110 116 117 121 123 125 127 65 71 77 80 83 65 72 77 81 83 75th 108 112 120 126 130 67 73 79 82 85 95th 110 114 122 128 132 68 75 80 84 86

Systolic

3 6 10 13 16 3 6 10 13 16

Diastolic

Epidemiology of Hypertension Incidence usually ~1 to 2% Incidence varies with weight family history Incidence does not vary with age sex race Symptoms of Hypertension Neonates and Infants Failure to Thrive Irritability Feeding problems, especially vomiting Cyanosis Respiratory distress Cardiac failure Seizures Older Children Hypertension in older children is usually symptom-free Severe hypertension may present with headache, seizures or congestive heart failure

Etiology of Hypertension Neonates and Infants Most Common Renal artery thrombosis 2 UAC Coarctation of the aorta Congenital renal disease Renal artery stenosis Less Common Bronchopulmonary dysplasia Patent ductus arteriosus

Pediatric Nephrology Handout Revised May-00 Chris Clardy, M.D. Intraventricular hemorrhage

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Pediatric Nephrology Handout Revised May-00 Chris Clardy, M.D. Older Children Most Common Renal disease Coarctation of the aorta Essential hypertension Less Common Renal Artery Stenosis Hypercalcemia Neurofibromatosis Neurogenic tumors Pheocromocytoma Hyperthyroidism Mineralocorticoid excess 1 hyperaldosteronism 11-hydroxylase deficiency 17-hydroxylase deficiency Syndrome of Apparent mineralocorticoid excess (SAME) Liddles syndrome Status post urologic surgery (transient) 2 limb immobilization 2 sleep apnea

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Evaluation of Hypertension History and physical exam CBC Urinalysis Serum electrolytes, BUN, creatinine, cholesterol Urine culture Echocardiogram Renal ultrasound Treatment of Hypertension Goal is reduction to 95th percentile for height, sex and age Weight loss and salt restriction when appropriate Treat hypertensive crisis with vasodilators Use ACE inhibitors and calcium channel blockers for long term therapy Pharmacologic Therapy Emergent Nifedipine Nitroprusside Labetalol Initial Dose 0.25 mg/kg 0.5 g/kg/min 1 mg/kg/hr (iv) Maximum Dose 0.5 mg/kg 8 g/kg/min 3 mg/kg/hr (iv)

Pediatric Nephrology Handout Revised May-00 Chris Clardy, M.D. Long Term Initial Dose Captopril Neonates Children Enalapril Nifedipine XL Atenolol HCTZ Lasix 0.03 mg/kg/day 1.5 mg/kg/day 0.15 mg/kg/day 0.25 mg/kg/day 1 mg/kg/day 1 mg/kg/day 1 mg/kg/day Maximum Dose 2 mg/kg/day 6 mg/kg/day ? 3 mg/kg/day 8 mg/kg/day 2 mg/kg/day 12 mg/kg/day

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Neonatal Hypertension
Significance Neonatal hypertension can lead to left ventricular hypertrophy retinopathy renovascular changes encephalopathy intraventricular hemorrhage Epidemiology 20 of 10,000 normal newborns are hypertensive ~9% of premature infants who are normotensive at discharge from the hospital will be hypertensive at their first follow-up visit 43% of infants with bronchopulmonary dysplasia will develop hypertension in the first year of life Guidelines Blood pressure will vary according to birth weight until about 8 weeks of age Blood pressure will vary by post natal age In general the systolic blood pressure determination is the most accurate The following chart was put together using extrapolations of published data (Pediatrics 65:1028, 1980, Pediatrics 67:607, 1981, and Pediatric Research 18:321A, 1984)

Pediatric Nephrology Handout Revised May-00 Chris Clardy, M.D.

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Upper Limits of Systolic Blood Pressures

120

110

100

Systolic Blood Pressure

90

80

>2.5 kg

70

1.5-2.5 kg 1.0-1.5 kg

60

<1.0 kg

50 1 10 Post Natal Age (days) 100

Differential Diagnosis Vascular Renal Artery Thrombosis Renal Vein Thrombosis Arterial Calcification Renal Artery Stenosis Coarctation of the Aorta Renal Renal Dysplasia Obstructive Uropathy Infantile Polycystic Kidney Disease Renal Insufficiency Renal Tumor Endocrine Adrenogenital Syndrome Cushing Disease Primary Hyperaldosteronism Thyrotoxicosis

Pediatric Nephrology Handout Revised May-00 Chris Clardy, M.D.

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Pediatric Nephrology Handout Revised May-00 Chris Clardy, M.D. Drugs Ocular Phenylephrine Corticosteroids Theophylline Deoxycorticosterone Other Increased Intracranial Pressure Fluid Overload Neural Crest Tumor Abdominal Wall Surgery Pneumothorax Hypercalcemia Genitourinary Tract Surgery Bronchopulmonary Dysplasia Evaluation Directed History and Physical Exam Serum Electrolytes, Calcium, BUN, and creatinine CXR Renal Ultrasound DTPA Scan Aortogram Head Ultrasound Treatment Diuretic Hydrochlorothiazide 0.5-2 mg/kg/dose q 8 hours (p.o.) Lasix 0.5 to 2 mg/kg/dose q 12 hours (p.o., i.v.) Vasodilator Hydralazine 0.15-1 mg/kg/dose q 6 hours (i.v.) Diazoxide 2-5 mg/kg/dose (i.v.) Nitroprusside 0.25-8 g/kg/min (i.v.) -Adrenergic Antagonist Propranolol 0.2-2 mg/kg/dose q 6 hours (p.o.) Converting Enzyme Inhibitor Captopril 0.2-1 mg/kg/dose q 6 hours (p.o.)

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Congenital Uropathies
Normal Embryogenesis Kidney formation begins in the 3rd week of life when the intermediate mesoderm is formed (Figure #1A). This subsequently develops into a series of nephrotomes (Figure #1B, left hand side) each of which in turn develops a lumen (Figure #1B, right side). These nephrotomes join together to form a longitudinal duct which develops into two vestigial kidneys, the pronephros and the mesonephros, as well as the permanent kidney, the metanephros.

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Figure #1 The development of the permanent kidney occurs when the metanephros interacts with an offshoot of the cloaca called the ureteric bud (Figure #2).

Figure #2 The ureteric bud undergoes a branching process to form the ureter, the renal pelvis, the calyces, and the collecting tubules (Figure #3).

Figure #3 Meanwhile, the metanephric tissue caps form vesicles (Figure #4A and 4B) which elongate to form glomerulus, the proximal convoluted tubule, the loop of Henle, the and distal convoluted tubule. These structures join to the previously formed collecting system to form the mature nephron.

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Figure #4 The permanent kidney is formed in the pelvis, however as the fetus develops it migrates to its position in the lumbar region (Figure #5).

Figure #5 Finally, the bladder is formed when the cloaca separates into an anorectal and urogenital canal (Figure #6).

Figure #6

Pediatric Nephrology Handout Revised May-00 Chris Clardy, M.D. The timing of the events in renal development are outlined below. Weeks 3 to 4 5 6 8 to 9 10 to 11 14 to 15 20 to 22 32 to 36 Events Formation of the pronephros and mesonephros Formation of the ureteric bud and initiation of the metanephros Formation of the urogenital sinus Renal pelvis and ureter evident, some nephrons completed, bladder formed Renal pelvis completed, calyces initiated Collecting system completed Medulla and cortex demarcated Nephron formation complete

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Mechanical Defects Gross Malformations Renal Agenesis Definition: Absence of the kidney without any evidence of parenchymal maldevelopment Pathophysiology: Failure of development of the kidney as the result of absence of the ureteric bud Bilateral agenesis occurs in 1:6,000 deliveries, unilateral agenesis is more common Clinical Features: Unilateral agenesis usually not detected Bilateral agenesis results in the decreased production of amniotic fluid with consequent oligohydramnios, pulmonary hypoplasia, and a "Potter's facies" Evaluation: Diagnosis is made by either pre- or post-natal ultrasound Therapy & Prognosis: Bilateral agenesis is usually fatal secondary to severe pulmonary disease Unilateral agenesis allows normal renal function although there might be some benefit in a low protein diet Pelvic Kidney Definition: A kidney arising from the iliac artery instead of the aorta Pathophysiology: Failure of the normal ascent of the kidney Clinical Features: Usually detected only as an incidental finding Evaluation: Renal ultrasound and VCUG Therapy & Prognosis: May have increased incidence of infections or obstruction Horseshoe Kidney Definition: Fusion of the lower poles of the kidneys, associated with incomplete ascent with resultant lower lumbar location Pathophysiology:

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Fusion of the kidneys due to close approximation as they ascend through the arterial bifurcation Occurs in 0.25% of the population Clinical Features: Usually detected only as an incidental finding Evaluation: Renal ultrasound and VCUG Therapy & Prognosis: May have increased incidence of infections or obstruction Microscopic Malformations Dysplasia, Aplasia, & Multicystic Kidneys Definition: An abnormal parenchymal differentiation reflected by the presence of abnormal structures including primitive ducts surrounded by collars of connective tissue, metaplastic cartilage, and less specific lesions such as differentiated glomeruli and tubules and cystic dilation of tubular structures A muticystic, dysplastic kidney is a closely related form of severe dysplasia in which the kidney is enlarged and variably distorted with cysts. Pathophysiology: Perturbed development of normal renal architecture as the result of in utero vascular deprivation or ureteral obstruction (e.g. posterior urethral valves, ureteral vesicular obstruction, or ureteral pelvic junction obstruction) resulting in failure of the forming collecting system and glomerulo-tubular apparatus to connect with one another Clinical Features: Unilateral multicystic dysplastic kidney presents as an abdominal mass Bilateral dysplasia presents as chronic high output renal failure with an associated renal tubular acidosis Differential Diagnosis: Dysplastic kidneys are often mislabeled as hypoplastic kidneys, the latter being a very rare variant of renal agenesis Bilateral multicystic dysplastic kidneys may be confused with IPKD ( see below) Evaluation: Diagnosis can be made by post-natal ultrasound Severity of disease may be determined by electrolytes, BUN, and creatinine In the case of a unilateral multicystic, dysplastic kidney, renal dysplasia must be suspected in the contralateral kidney Therapy & Prognosis: Therapy and prognosis of a unilateral multicystic, dysplastic kidney is the same as for unilateral agenesis Low potential for malignant transformation of a unilateral multicystic, dysplastic kidney does not warrant prophylactic nephrectomy Bilateral dysplasia usually results in chronic renal failure requiring eventual dialysis and/or transplantation Molecular Defects Polycystic Kidney Disease Definition: Diffuse cystic changes in both kidneys without other evidence of parenchymal maldevelopment. Cysts are centimeter sized Pathophysiology:

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Infantile polycystic kidney disease (IPKD) is an autosomal recessive disorder characterized by large fluid filled cysts in the kidney. It presents either at birth or in the first few years of life and is associated with congenital hepatic fibrosis Adult polycystic kidney disease (APKD) is an autosomal dominant disorder (with frequent spontaneous occurrences) also characterized by large fluid filled cysts in the kidney. It usually presents in older children and adults and is associated with cysts of the liver, pancreas, lung, and ovary as well as with cerebral aneurysms. Clinical Features: Initial hematuria (especially APKD) followed by hypertension, abdominal masses, and azotemia

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Differential Diagnosis: IPKD may be confused with APKD, obstructive uropathy, bilateral multicystic dysplastic kidneys, tuberous sclerosis, and renal tumors. APKD may be confused with IPKD and tuberous sclerosis Evaluation: Reliable diagnosis of both conditions usually possible with ultrasound Renal biopsy occasionally needed with IPKD Therapy & Prognosis: Unrelenting progression to end stage renal disease is seen in both conditions Medullary Cystic Kidney Disease/ Familial Juvenile Nephronophthisis Definition: Diffuse tubulo-interstitial degeneration either with or without small medullary cysts. Cysts are millimeter sized Pathophysiology: Either an autosomal recessive condition, often associated with retinal degeneration, with onset in younger children or an autosomal dominant condition with onset in older children and adults. Characterized by small cysts formed by dilated distal tubules and collecting ducts. Clinical Features: Inability to concentrate the urine followed by azotemia Differential Diagnosis: May be confused with PKD and medullary sponge kidney. Evaluation: Reliable diagnosis usually possible with ultrasound although renal biopsy occasionally required Therapy & Prognosis: Unrelenting progression to end stage renal disease

Urinary Tract Infections in Children

Definition The broad term urinary tract infection (UTI) is used to describe a myriad of conditions which have only one feature in common, the presence of significant amounts of bacteria in the urine. Classification UTIs may be divided in the following manners those limited to the bladder (cystitis) versus those involving the renal parenchyma (pyelonephritis) symptomatic infections versus asymptomatic bacteriuria detected on screening urine cultures primary, uncomplicated infections versus those with complications such as persistence despite appropriate antibiotic therapy frequent recurrence despite appropriate antibiotic therapy vesicoureteric reflux obstruction Incidence The risk of a newborn girl's falling ill with a symptomatic UTI during childhood is at least 3%; for a boy, about 1%. Approximately 7% of febrile children 6 months old will have UTIs. The incidence of asymptomatic bacteriuria in girls of pre-school and school age is ~1%.

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UTIs are more common in males in children 6 months old and more common in females in all other age groups. The incidence of UTIs in uncircumcised males is ~10 times that in circumcised males. About 50% of children with symptomatic UTIs and about 80% of those with asymptomatic bacteriuria will develop one or several recurrent infections.

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Significance Some 5% to 7% of children with symptomatic, febrile UTIs during the first year of life will acquire a renal scar. This incidence is increased by such factors as obstruction gross vesicoureteric reflux intrarenal reflux increased bacterial virulence therapeutic delay Diagnosis Clinical Presentation: Neonates and infants in the first year of life tend to present with signs of a systemic illness, i.e., fever, lethargy or irritability, decreased perfusion, etc. In addition, they may have vomiting, abdominal tenderness and distention, foul smelling urine or hematuria. Older children tend to present with frequency, urgency, burning and diurnal enuresis. N.B. dysuria in females may result from vulvovaginitis unassociated with a UTI. All children suspected of having a UTI should be examined for increased blood pressure, fever, abdominal masses and costovertebral angle tenderness. Laboratory Presentation: A urinalysis with pyuria (10 to 20 WBC/hpf on an unspun urine) is adjunctive to the diagnosis of UTI. 50% of patients with pyuria do not have a UTI and 50% of patients with a UTI do not have pyuria. An urinalysis with bacteriuria (1 organism/hpf on an unspun urine) is adjunctive to the diagnosis of UTI. The presence of nitrites and leukocyte esterase by dipstick are 90% specific for a UTI. The only absolute diagnostic criteria for UTI is the presence of significant amounts of bacteria in the urine. This is defined as either any growth in a urine obtained by bladder aspiration or urinary catheterization or 100,000 colonies/ml in a "clean catch" urine. N.B. Urine must be plated out within 30 minutes if at room temperature or within 24 hours if refrigerated. As most antibiotics are concentrated and excreted unchanged in the urine, any pre-treatment is likely to result in a potentially false negative urine culture. The most common pathogens are Enterobacteriaceae (EMB plate) E. coli Klebsiella Proteus Enterobacter "White" Staph (Blood agar plate) S. epidermidis S. saprophyticus Cystitis vs. Pyelonephritis: Most reliable sign of pyelonephritis is a high fever. CVA tenderness is often not present, especially at 5 years of age. Abdominal pain and vomiting suggest pyelonephritis. Laboratory tests (e.g. urinary LDH or antibody coated bacteria) are not usually helpful but an elevated ESR or a low urine specific gravity may indicate pyelonephritis. Therapy Pyelonephritis in children 6 months old should be treated with iv ampicillin and gentamicin (or a 3rd generation cephalosporin) pending culture results. IV therapy should be continued until the child has had negative urine cultures for 48 hours. Thereafter and in older children, treatment should be oral (see below) for a total antibiotic course of 10 days.

Pediatric Nephrology Handout Revised May-00 Chris Clardy, M.D. Asymptomatic bacteriuria and cystitis can be treated for 10 days with oral Dose (mg/kg/day) 6 30 25-50 3 # Doses/Day 2 3 4

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Antibiotic TrimethoprimSulfamethoxazole Amoxicillin Nitrofurantoin

Recurrent UTIs can be prophylaxed with Dose (mg/kg/day) 2 10 1

Antibiotic Trimethoprim Sulfamethoxazole Nitrofurantoin

Follow-Up Follow-up urine cultures should be obtained 2 to 3 days after the discontinuation of therapy, again at 2 to 3 weeks and 3 more times during the next year. Radiographic visualization of the kidney (IVP or Renal US) and the vesicoureteric dynamics (VCUG or Nuclear Reflux-o-gram) should be obtained after any UTI in a male 2 symptomatic UTIs in a female 5 years persistent UTIs in older females The goal of radiologic evaluation is to detect factors predisposing to infection and kidney damage, principally congenital or acquired obstructions of the urinary flow, calculi, vesicoureteric reflux and intrarenal reflux. N.B. ~10% of children with UTIs will have reflux. detect and outline narrowing of renal parenchyma and calyceal dilation, which may be an early sign of progressive renal scarring. determine the rate of growth of the kidney, which may be a valuable aid in assessing the effect of treatment. Radiologic evaluation is not emergent but should be obtained without delay Renal scan for function (DTPA) or for detection of a scar (DMSA) are not useful. Referral to a urologist for gross vesicoureteric reflux with dilation of the collecting system (grade IV or V). reflux associated with frequent recurrence of UTIs which can not be adequately treated with prophylactic antibiotics. any reflux in a child 9 years old.

Systemic Lupus Erythematosus

Definition An autoimmune disease characterized by at least 4 of the 11 following manifestations 1) malar rash 2) discoid rash 3) photosensitivity 4) oral ulcers 5) arthritis 6) serositis (pleuritis/pericarditis) 7) renal disorder (proteinuria>500 mg/day or cellular casts) 8) neurologic disorder (seizures or psychosis) 9) hematologic disorder (hemolytic anemia, leukopenia, lymphocytopenia, or thrombocytopenia)

Pediatric Nephrology Handout Revised May-00 Chris Clardy, M.D. 10) 11)

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immunologic disorder (positive LE cell test, anti-DNA antibody, anti-Sm antibody, or false positive serologic test for syphilis) positive anti-nuclear antibody test

Epidemiology 90% female peak incidence in the third decade of life 1 in 500 adult females afflicted 35% to 90% have renal involvement depending on how it is defined Classification W.H.O. Classification: Normal Glomeruli (Class I) Mesangiopathic Glomerulonephritis (Class II)- E.M. deposits in the mesangium either without (IIa) or with (IIb) mesangial cellularity Focal and Segmental Proliferative Lupus Glomerulonephritis (Class III)- diffuse mesangial hypercellularity with focal and segmental accentuation, with mesangial and sub-endothelial deposits in <50% of the glomeruli Diffuse Proliferative Lupus Glomerulonephritis (Class IV)- same as II but in >50% of glomeruli Membranous Lupus Glomerulonephritis (Class V)- membranous lesion secondary to sub-epithelial deposits either alone (Va), with mesangial hypercellularity (Vb), with segmental hypercellularity (Vc), or with diffuse hypercellularity (Vd) Glomerular Sclerosis (Class VI) Cliniopathologic Correlations in Lupus Glomerulonephritis Class II Class III Class IV Class V No Clinical 40% 30% 25% 5% Findings of Renal Involvement Renal Involvement 7% 16% 65% 12%

Pediatric Nephrology Handout Revised May-00 Chris Clardy, M.D. Treatment/Outcome Most patients developing ESRD will have had W.H.O. Class IV or Vd (DPGN/MPGN)

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Effect of Treatment on High Risk SLE

100

IV Cytoxan, ~0.8% ESRD/year 80

60
Survival %

40

Prednisone Rx, ~12% ESRD/year 20

0 0 20 40 60 80 100 120 140 160

Month

IgA Nephropathy in Children

Definition: IgA Nephropathy (IgAN) is a clinical/pathological entity defined by - hematuria, usually episodic, proteinuria - mesangial IgA deposits - after SLE, HSP, and liver disease have been ruled out

Pediatric Nephrology Handout Revised May-00 Chris Clardy, M.D. Pathology: Light Microscopy

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Minimal Change Focal, Segmental Glomerulosclerosis Diffuse Proliferation

Immunofluorescence Microscopy Electron Microscopy

Mesangial IgA, IgG and/or C3 Mesangial Electron Dense Deposits

Epidemiology: - Statistics vary with study and population - Potentially the most common form of glomerulonephritis - 2:1 male predominance - Increased incidence in Caucasian and Asian populations - Peak incidence in the 1st and 2nd decade of life - Increased incidence in family members Clinical Presentation: - High coincidence with upper respiratory infections - High coincidence with loin pain - Clarkson et al. (Clin Nephrol 8:459, 1977) found Macroscopic Hematuria Proteinuria Microscopic Hematuria Nephrotic Syndrome Acute Nephritis Hypertension Chronic Renal Failure Acute Renal Failure as the initial presentation in 50 patients with IgAN.

34% 30% 6% 10% 8% 6% 6%

Prognosis: - 10 year renal survival of 75 to 90% - Outcome worse in persistent as opposed to episodic disease older patients cases with hypertension, marked proteinuria, or renal impairment sclerotic or proliferative disease cases with basement membrane deposits - Significant recurrence after renal transplant Pathophysiology: There is no cohesive explanation for the pathophysiology of IgAN. Two lines of evidence are presently being followed. Associated Immunologic Abnormalities: The histology of IgAN is consistent with an immune complex disease. Elevated levels of IgA per se, polymeric IgA, IgA1, and IgA containing immune complexes have been found in the serum of some patients with IgAN. However these findings are highly variable and of unclear significance. Genetic Linkage: Multiple members of the same family may have IgAN suggesting a genetic linkage. In French and Japanese studies IgAN has been linked to HLA B35 and DR4. This linkage has not

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30

been associated with extended haplotyes of the short arm of the 6th chromosome. American studies have shown an increased incidence of null alleles for one of the C4 genes in IgAN. All of these HLA linkages are associated with a worse outcome. In addition to these HLA linkages, patients with IgAN have an increased incidence of the fast allele of C3 (19th chromosome) and have a distinct RFLP for the switch region for IgA (14th chromosome). Therapy: - There is no acknowledged therapy for IgAN - Attempts at therapy have included corticosteroids fish oil cytotoxic agents anti-coagulants plasmapheresis tonsillectomy phenytoin none of which has been an unqualified success. IgAN vis--vis Henoch-Schnlein Purpura (HSP): HSP is an acute vasculitis which affects the mucosa of the gut, the skin, the synovial lining of the joints, and the glomerulus of the kidney causing abdominal pain, a petechial rash, arthralgias, and glomerulonephritis. IgAN and HSP have many similarities. Clinical Presentation: - 10% to 30% of patients with HSP will have subsequent bouts of gross hematuria with URIs - 30% of patients with IgAN will have abdominal pain, rash and/or arthralgia - patients with HSP and IgAN who have similar renal findings (eg. proteinuria, hypertension, renal insufficiency) will have a similar incidence of chronic renal failure Histopathology: The glomerulonephritis in HSP is characterized by mesangial proliferation, mesangial IgA, and occasional sclerosis and crescent formation. The only difference between the histopathology of IgAN and HSP is that the cellular infiltrate in IgAN consists of mesangial cells whereas that in HSP consists of monocytes and T-lymphocytes. Serology: Several studies have shown an increased serum level of IgA and IgA containing immune complexes in some patients with HSP Genetics: HSP and IgAN are often seen in the same families. Patients with HSP have an increased frequency of C4 null alleles compared to a normal population.

Fluid & Electrolytes

General Taken as a whole, the maintenance of fluid and electrolyte homeostasis is astoundingly complex. However, almost all fluid and electrolyte problems can be broken down into relatively autonomous subproblems involving Water (H2O) Sodium (Na+) Acid (H+)

Pediatric Nephrology Handout Revised May-00 Chris Clardy, M.D. Potassium (K+)

31

As a general rule, the body will prioritize the normalization of fluid and electrolytes in the same order as that given above. Therefore, it is easiest to approach problems using the same order.

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Water (H2O) H2O homeostasis depends on both a normal intake and an appropriate output. The former is usually defined as consisting of Insensible Urine Stool "Extra" 500 ml/M2/day 650 ml/M2/day 50 ml/M2/day 800 ml/M2/day 2,000 ml/M2/day

and the latter is controlled by the renal tubule under the influence of anti-diuretic hormone, aldosterone, atrial naturetic factor and other mediators. Over hydration can result in hypertension, congestive heart failure or pulmonary edema whereas dehydration may cause hyperosmia or circulatory collapse. Causes of Over Hydration Oliguria e.g. SIADH, ATN Excess Intake Causes of Dehydration Polyuria e.g. DKA, DI Vomiting & Diarrhea High Insensible Loss e.g. Burn Injury Exsanguination Altered Vascular Tone e.g. Septic Shock

Sodium (Na+) Na+ homeostasis depends on a normal intake of approximately 50 mEq/M2/day and a normal output which is usually via the renal tubule. Hypo- and hypernatremia are deleterious because of their alteration of the serum osmolality. As there is a blood/brain barrier for Na+, rapid changes in serum [Na+] can lead to catastrophic swelling or contraction of the brain. Causes of Hyponatremia Loss of Na+ Alone Causes of Hypernatremia Excess of Na+ Alone

e.g. Inappropriate formula dilution

Excess H2O Alone e.g. Polydipsia, SIADH Losses of H2O & Na+ (Na+>H2O) e.g. Diuretic abuse, 3rd space losses Treatment of Hypo-/Hypernatremia The Baby as a Bucket Theory

e.g. Hyperaldosteronism, Iatrogenic

Loss of H2O Alone e.g. DI Losses of H2O & Na+ (H2O>Na+) e.g. Diarrhea

Volume of distribution of sodium is 0.67 L/kg Therefore sodium space can be conceptualized as a bucket whose volume is 2/3 of the bodys weight

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Pediatric Nephrology Handout Revised May-00 Chris Clardy, M.D. Hyponatremia Example:

34

+ 3 Kg child with [Na ]=123 mEq/L

Goal:

+ To increase [Na ] by 12 mEq/L

Concept: How much extra Na+ is needed to increase the [Na+] of a 2 L bucket of H2O by 12 mEq/L?

Answer: Give (2 L x 12 mEq/L) or 24 mEq of Na+ Hypernatremia Example:

+ 3 Kg child with [Na ]=157 mEq/L

Goal:

+ To decrease [Na ] by 12 mEq/L

Concept: How much extra H2O is needed to decrease the [Na+] of a 2 L bucket of from 157 to 145 mEq/L?

Answer: New [Na+] = {Total Body Na+} / {Present Body H2O + Supplemental H2O} 145 mEq/L = {2 L x 157 mEq/L}/ {2 L + Supplemental H 2O} Give supplemental H2O of 165 ml

Acid (H+) Acid (H+) and alkali (HCO3-) are balanced with each other to maintain the body's pH. An imbalance can result in either acidosis or alkalosis, which in turn alters the efficiency of biochemical processes in the body. Of note, too rapid a correction of acidosis may lead to a paradoxical increase in intra-cellular acidosis with deleterious consequences (Figure #1).

Pediatric Nephrology Handout Revised May-00 Chris Clardy, M.D.

35

Cell

Extra-Cellular Space
H+ & HCO3H2CO3

Blood
HCO3-

CO2 & H2O

CO2 & H2O

CO2

Figure #1 Types of acidosis can be classified by their anion gap ([Na+] - [HCO3-] - [Cl-], Figure #1) which is normally 8-16 mEq/L. An elevated anion gap indicates the presence of an unmeasured anion such as lactate.

160 140 120

mEq/L
OTHER

ORGANIC

ORGANIC ORGANIC

100 80 NA 60 40 20 0 HCO3 CATION ANION NORMAL CL

CL

CL

HCO3 ACIDOSIS NORMAL ANION GAP

HCO3 ACIDOSIS HIGH ANION GAP

Figure #2 Causes of Acidosis (Normal Anion Gap)

Pediatric Nephrology Handout Revised May-00 Chris Clardy, M.D. GI Loss of HCO3e.g. Diarrhea, Pancreatic fistula Renal Loss of HCO3e.g. Proximal RTA Defective H + Excretion

36

e.g. Distal RTA

(High Anion Gap) Excess H+ Production

e.g. DKA, Lactic acidosis Exogenous H + e.g. Salicylate ingestion

The kidney's response to sodium chloride deficiency can cause a secondary alkalosis as shown in figure #2. Types of alkalosis can therefore be classified by their response to sodium chloride.

DISTAL TUBULE

Na ALDOSTERONE MEDIATED PUMP K,H

Figure #3 Causes of Alkalosis (Chloride Responsive) GI Chloride Loss e.g. vomiting Renal Chloride Loss e.g. Diuretic abuse (Chloride Resistant) Hyperaldosteronism K+ Deficiency Excess Alkali Ingestion Potassium (K+)

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37

Potassium (K+) levels are balanced by intake, renal and gastrointestinal loss and by redistribution between the intra- and extra-cellular space. Hypokalemia may cause cardiac conduction defects, however these are usually not fatal unless a patient is being treated with digoxin. Hyperkalemia, on the other hand, may lead to ventricular fibrillation. Causes of Hypokalemia (No Body K+) Alkalosis -Adrenergic drugs ( Body K+) Poor Intake e.g. Anorexia nervosa Cellular Incorporation e.g. Refeeding GI Loss e.g. Vomiting, Diarrhea Renal Loss e.g. Diuretic abuse, Hyperaldosteronism Causes of Hyperkalemia Pseudohyperkalemia Excess Intake Redistribution e.g. Acidosis, Cell breakdown Excretion e.g. Renal failure Hypoaldosteronism

Renal Tubular Acidosis

Definition Renal Tubular Acidosis (RTA) is a disorder of urinary acidification resulting in a hyperchloremic (i.e. normal anion gap) metabolic acidosis. Pathophysiology As a byproduct of normal metabolism the average child produces 1 to 3 mEq H+/kg/day in the form of non-carbonic acids. Although respiratory variation of the PCO2 may transiently buffer these acids, the only means of removing them from the body is via the kidney. The kidney has two basic mechanisms for handling acid homeostasis: Proximal tubular reabsorption of glomerularly filtered HCO3 Distal tubular excretion of H +

Types of RTA Distal RTA (Type I) An inability to adequately excrete H+ into the urine against a concentration gradient. Normal distal tubules can produce a 1,000x concentration gradient of H+ (i.e. a pH of 4.4 in the urine versus 7.4 in the blood). Distal RTA is associated with renal dysplasia, medullary cystic disease and hypercalcinuria.

Proximal RTA (Type II) An inadequate reabsorption of glomerularly filtered HCO3-. Normal proximal tubules reabsorb 85% of filtered HCO3-. If this was decreased to 75% in a patient with a GFR of 125 ml/min and a serum HCO3- of 20 mEq/L an additional 180 mEq of HCO3- would be lost in the urine each day!

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Proximal RTA is associated with other tubulopathies (e.g. renal phosphate wasting) and with the aminoacidopathies.

Combined Distal and Proximal RTA (Type III) Acidosis 2 to Hypoaldosteronism (Type IV)

Potassium in RTA Depending on the type and location the of tubular defect in RTA, a patient may be hypo-, normo- or hyperkalemic. In hypokalemic RTA the kidney's Na+/K+ exchange pump wastes potassium in order to retrieve sodium. This is seen in all proximal RTA and in some distal RTA (see figure below).

Proximal Tubule

Failure toreabsorb NaHCO3

Na+

Failure to swap H+ Na+ for H+

Distal Tubule
Na+ K+ Swap of Na+for K+

Hyperkalemia is seen mainly in type IV RTA where the aldosterone mediated ability to transport potassium from the blood into the urine is impaired. Diagnosis Suspected in failure to thrive and nephrolithiasis. Diagnosis of RTA made if patient has normal anion gap metabolic acidosis without any other cause of bicarbonate loss (e.g. diarrhea). Diagnosis may be confirmed by urine anion gap ([Na+] + [K+] - [Cl-]). If urine anion gap is positive (i.e. >0) then this is consistent with RTA. Distinction between distal and proximal RTA is made by whether urine pH is able to go below 5.5 which excludes distal RTA. Diagnosis of hypoaldosteronism is made if serum aldosterone level is low. Evaluation should also include a urine calcium, a urine amino acid screen and a renal ultrasound to screen for associated anomalies.

Treatment The treatment of RTA is always to normalize the serum HCO -. 3 - is normalized by replacing the aldosterone. In hypoaldosteronism the HCO3 In all other forms of RTA the treatment is with supplemental alkali in the form of either citrate or bicarbonate.

Acute Renal Failure

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Etiology Prerenal Factors eg. Renal Factors Arterial eg.

hypovolemia cardiac insufficiency

thromboembolism arteritis hemolytic-uremic syndrome Glomerular eg. glomerulonephritis Venous eg. renal venous thrombosis Tubular eg. ischemic acute tubular necrosis nephrotoxic acute tubular necrosis crystal nephropathy Interstitial eg. acute interstitial nephritis pyelonephritis Postrenal Factors eg. congenital or acquired obstruction Complications of Renal Failure Hyperkalemia Arrhythmia Cardiac Arrest Death Fluid Overload Hypertension & Congestive Heart Failure Inadequate Cardiac Function Death Initial Evaluation Blood Laboratories SMA-6 Blood Gas Ca++, PO4--, & Mg++ Urate Total Protein & Albumin CBC Acidosis Impaired Cellular Function Death

Uremia Impaired Cardiac, Cerebral, & Thrombotic Function Death

Pediatric Nephrology Handout Revised May-00 Chris Clardy, M.D. Auto-Immune Serology Urine Laboratories U/A Culture Osmolality, Creatinine, & Na+ Other Chest X-Ray Renal Ultrasound E.K.G. Initial Management of Acute Renal Failure N.B. This protocol should only be used as a guideline

40

1) Obtain a history with specific emphasis on previous health, recent ingestions, fever, arthralgia, bloody diarrhea, and change in urine amount and/or quality. 2) Do a physical exam with specific emphasis on the blood pressure, estimation of vascular volume, presence of rash or petechiae, and presence of abdominal masses. 3) Establish an iv and obtain blood laboratories, place EKG leads, insert a foley catheter and obtain urine laboratories. 4) Treat EKG evidence of severe hyperkalemia ( T wave amplitude with qrs length) with 10% Calcium Chloride 0.25 ml/kg (maximum 10 ml) Dextrose 1 gm/kg and Insulin 0.2 unit/kg Sodium Bicarbonate 1-2 mEq/kg Kayexalate 1 gm/kg 5) Treat malignant hypertension with Minoxidil 0.2 mg/kg p.o. Hyperstat 5 mg/kg slow iv push over 20 minutes 6) Treat metabolic acidosis resulting in a pH7.20 with sodium bicarbonate 7) In the oliguric patient, unless fluid overload exists, give a fluid challenge with 10 ml/kg of normal saline. Repeat this if there is no increase in urine output after 30 minutes. 8) Call for pediatric nephrology help. 9) While waiting for pediatric nephrology, use the urine and serum concentrations of creatinine and Na+ to calculate the fractional excretion of Na+ (FENA) in your oliguric patients. FENA= ([urine Na+] x [serum creatinine] x 100%) ([urine creatinine] x [serum Na+])

This can be used to distinguish pre-renal oliguria (FENA1%) from renal oliguria (FENA>1%). N.B. this test may be falsely elevated for 48 after a patient is given a loop diuretic. Subsequent Management of Acute Renal Failure Many cases of acute renal failure can be managed using only the protocol outlined above. Two conditions require more specialized management Uremia requires removal of nitrogenous wastes from the blood. This is accomplished by dialyzing the blood versus a balanced saline solution across a semi-permeable membrane.

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Dialysis
High B.U.N., Creatinine, other N2 products Blood Semi-permeable Membrane Diffusion of N2 waste Across a Concentration Gradient Dialysis Solution

Fluid Overload require removal of excess H2O from the blood. This is accomplished by ultrafiltering the blood through a semipermeable membrane using either an osmotic or a pressure gradient.

Ultrafiltration
High Hydrostatic or Osmotic Pressure Blood
Methods: Peritoneal Dialysis: Definition- dialysis across the peritoneal membrane with ultrafiltration using a dextrose osmotic gradient Access- a single lumen peritoneal catheter

Diffusion of H2O Across a Pressure Gradient Semi-permeable Membrane Dialysis Solution

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Peritoneal Membrane Dialysate Solution Sodium Potassium Chloride Magnesium Calcium Lactate Dextrose Osmolality pH Volume 130-135 mEq/L 0-3 mEq/L 96-102 mEq/L 1.2-1.8 mg/dl 6.0-8.0 mg/dl 35-40 mEq/L 1.36/2.27/3.86 gm/dl 346/396/485 mOsm/kg 5.0-5.5 15-30 ml/kg

Arteriole in Peritoneal Membrane

Advantagesunlikely to cause rapid fluid and electrolyte shifts does not require systemic anticoagulation Disadvantagesineffective in low perfusion states risk of infection and/or N.E.C. impairs diaphragmatic motion Hemodialysis: Definition- dialysis of extra-corporeal blood across an artificial membrane with ultrafiltration using a machine generated pressure gradient Access- a double lumen venous catheter

Pediatric Nephrology Handout Revised May-00 Chris Clardy, M.D.

Distal Venous Access Proximal Venous Access

43

Heparin

Discard

Filter
Dialysis Solution

Advantagesallows efficient dialysis and ultrafiltration effective even in low perfusion states Disadvantagesrequires significant extra-corporeal volume requires systemic anti-coagulation may cause rapid fluid and electrolyte shifts complex procedure requiring specialized personnel Continuous Arterio-Venous Hemofiltration: Definition- isolated ultrafiltration of extra-corporeal blood across an artificial membrane using a biologically generated pressure gradient Access- a single lumen arterial catheter and a second single lumen venous catheter

Pediatric Nephrology Handout Revised May-00 Chris Clardy, M.D.

Heparin

44

Arterial Access

Filter

Venous Access

Discard

Advantagesallows continuous fluid removal in an unstable patient Disadvantagesrequires significant extra-corporeal volume requires systemic anti-coagulation does not allow efficient dialysis risk of rapid exsanguination via arterial catheter

Chronic Renal Failure in Children

Incidence: 1.5 to 3.0 children per million population will develop End Stage Renal Disease (ESRD)

Pediatric Nephrology Handout Revised May-00 Chris Clardy, M.D.

Glomerulosclerosis (6%)

45

Obstructive Uropathy (7%)

Cystinosis (8%)

Glomerulonephritis (31%)

Medullary Cystic Disease (8%)

Congenital Dysplasia (19%) Reflux Nephropathy (21%)

Pathophysiology/Treatment: Impaired H 2O and Na+ Excretion: May result in fluid retention (eg. glomerulosclerosis) with resultant edema, hypertension, and congestive heart failure or in the inability to conserve free H2O (eg. congenital dysplasia) resulting in chronic dehydration. Appropriate management consists of prescribing a fluid intake equal to the urine output plus the insensible fluid loss (~600 ml/M2/day). In fluid retention diuretics and, potentially, dialysis may be needed. Impaired H + Excretion: The normal kidney clears 1 to 2 mEq/kg/day of H+ from the body. In renal failure a metabolic acidosis will develop initially requiring alkali therapy with 10% sodium citrate and, eventually, dialysis.

Excessive Renin Production: Dysfunctional renal vasculature may result in hypoperfused segments of the kidney producing large amounts of renin with resultant hypertension. This can usually be treated using -blocking drugs (eg. propranolol) and A.C.E. inhibitors (eg. captopril) however it may require a nephrectomy. Impaired Phosphorus Excretion and Vitamin D Production: In a complex series of reactions, children with renal failure will develop hyperphosphatemia, hypocalcemia, hypovitamin D-emia, hyperparathyroidism, and rickets. This can be controlled by limiting phosphorus intake to 12.5 to 20 mg/kg/day, by using an oral phosphorus binder (eg. CaCO3),

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by assuring that the oral calcium intake is 20 to 80 mg of elemental calcium/kg/day in the form of diet and calcium supplements (N.B. 100 mg of CaCO3 contains 40 mg of elemental calcium, 100 mg of calcium lactate contains 12 mg, and 100 mg of calcium gluconate contains 9 mg), and by starting vitamin D supplementation (eg. rocaltrol). Impaired Production of Erythropoietin: The normal kidney regulates the red cell mass by the production of erythropoietin. This function may be impaired in renal failure resulting in a profound, normocytic anemia. This may be corrected by supplementing the patient with exogenous erythropietin. Impaired Clearance of Nitrogenous Wastes: A decreased glomerular filtration rate will result in reduced clearance of the metabolic breakdown products of amino acid metabolism. This is manifested by an elevation in the BUN and creatinine as well as by "uremic symptoms" such as lethargy and fatigue. Uremia in and of itself can cause sudden death as a result of its effect on nerve conduction. The degree of uremia may be controlled by limiting protein intake to 1 to 2 gm/kg/day, by providing adequate calories from carbohydrate and fat to prevent protein catabolism (ie. 200 non-protein calories per gram of N2, where 6.5 grams of protein equals 1 gram of N2).

Diuretics
I Water Physiology of the Kidney

Glomerulus

PCT CORTEX
Na Cl H2O [Na]T=[Na]I

DCT

K,H [Na]T<[Na]I Na

Na Cl

COLL. DUCT

MEDULLA LOOP OF HENLE

H2O H2O

ADH

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In the proximal convoluted tubule (PCT) active ionic transport, coupled with passive diffusion of H2O, results in reabsorption of ~70% of the glomerular filtrate. This results in an equal [Na+ ] in the tubule and interstitium. In the ascending loop of Henle and distal convoluted tubule active ionic transport occurs uncoupled from H2O transport resulting in hypotonic tubular fluid and a hypertonic interstitium, i.e. in a lower [Na+] in the tubule versus the interstitium. In the collecting duct H2O passively diffuses from the hypotonic tubule into the hypertonic interstitium under the control of ADH. II Types of Diuretics a) Osmotic Diuretics Examples: Mannitol, Urea, Glycerin and Isosorbide

Glomerulus

Na Cl H2O H2O H2O Mannitol H2O H2O [Na]T<[Na]I

Mechanism of Action: Osmotic diuretics are freely filterable at the glomerulus undergo limited reabsorption by the renal tubule are relatively biologically inert Therefore, their osmotic force retains H2O in the proximal convoluted tubule resulting in a diuresis. The retained H2O makes the [Na+ ] in the tubule lower then that in the interstitium. This concentration gradient decreases proximal tubular Na+ reabsorption resulting in a small natriuresis with a net H2O loss. Other Phenomena: Osmotic diuretics result in dehydration of the eye and brain. Diuresis is mitigated by subsequent H2O reabsorption in the distal nephron. Mannitol increases medullary blood flow, thereby decreasing the medullary urea gradient and enhancing the diuretic effect. Osmotic diuretics may cause hyperosmolality Osmotic diuretics may cause fluid overload (e.g. 1 gm/kg of mannitol in a 75 kg person requires an infusion of 300 to 1,500 ml)

Pediatric Nephrology Handout Revised May-00 Chris Clardy, M.D. b) Carbonic Anhydrase Inhibitors Examples: Acetazolamide, Dichlorphenamide, Methazolamide

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Glomerulus

PCT
HCO3 Na H2O
Carbonic Anhydrase

Mechanism of Action: One mechanism of proximal tubular Na+ reabsorption is passive accompaniment with HCO3 , the reabsorption of which depends on tubular carbonic anhydrase. Therefore, inhibition of carbonic anhydrase results in diuresis natriuresis alkaline urine normal anion gap metabolic acidosis Other Phenomena: Carbonic anhydrase inhibitors also dehydrate the eye and decrease CSF production. Diuretic efficacy is mitigated by subsequent distal HCO3- reabsorption. Effectiveness of carbonic anhydrase inhibitors is increased by metabolic alkalosis and decreased by metabolic acidosis. + Na salvage in the distal nephron results in hypokalemia. Inhibition of red blood cell carbonic anhydrase limits CO2 transport and results in hypercapnia.

Pediatric Nephrology Handout Revised May-00 Chris Clardy, M.D. c) High-Ceiling (Loop) Diuretics Examples: Furosemide, Bumetanide, Ethacrynic Acid

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DCT

K,H [Na]T![Na]I Na

Na Cl H2O

Blocked by Loop Diuretics

LOOP OF HENLE

Mechanism of Action: The loop diuretics are a diverse group of drugs which block reabsorption of Na+ and Cl- in the thick ascending loop of Henle. This causes a less hypotonic urine to enter the collecting duct with a lower gradient for ADH dependent H2O reabsorption. This results in a diuresis and natriuresis. The loop diuretics also interfere with the generation of a hypertonic medullary interstitium which reduces ADH dependent H2O reabsorption and augments their efficacy. Other Phenomena: Loop diuretics, particularly ethacrynic acid, perturb endolymph electrolyte composition causing transient or permanent deafness. Na+ salvage in the distal nephron results in hypokalemia. Loop diuretics decrease systemic vascular resistance thereby augmenting their dehydrating effect. Loop diuretics do not differ in their maximal effect. Loop diuretics will displace protein bound drugs (e.g. warfarin). Nephrotic syndrome decreases loop diuretic efficacy as urinary protein binds and inactivates the diuretics. Loop diuretics decrease urate excretion and may worsen hyperuricemia. Loop diuretics may worsen hyperglycemia. Loop diuretics increase both Mg++ and Ca++ excretion. Loop diuretics may cause idiopathic interstitial nephritis. Hypochloremia may decrease loop diuretic efficacy.

Pediatric Nephrology Handout Revised May-00 Chris Clardy, M.D. d) Thiazide Diuretics Examples: Chlorothiazide, Hydrochlorothiazide, Metolazone (thiazide-like)

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DCT

K,H [Na]T![Na]I Na

Na Cl H2O

Blocked by Thiazides

Mechanism of Action: The thiazides block a specific site in the early distal tubule which would normally reabsorb Na+ and Cl-. Like the loop diuretics, this causes a less hypotonic urine to enter the collecting duct with a lower gradient for ADH dependent H2O reabsorption. This results in a diuresis and natriuresis. Unlike the loop diuretics, the thiazides do not interfere with the generation of a hypertonic medullary interstitium. This, and the fact that the majority of the generation of hypotonic tubular fluid occurs before the distal tubule, makes these diuretic less effective than the loop diuretics. Other Phenomena: Some thiazides have carbonic anhydrase inhibitor activity, but this does not cause significant diuresis. Na+ salvage in the distal nephron results in hypokalemia. Thiazide diuretics do not differ in their maximal effect. Thiazides decrease urate excretion and may worsen hyperuricemia. Thiazides may worsen hyperglycemia. Thiazides increase Mg++ excretion but decrease Ca++ excretion. Thiazides may cause idiopathic interstitial nephritis. e) Potassium-Sparing Diuretics Examples: Spironolactone (aldosterone antagonist), Triamterene (aldosterone independent)

DCT

K,H

Na

Mechanism of Action: The K+-sparing diuretics block either the aldosterone dependent or independent pumps in the late distal tubule and early collecting duct. This results in a mild diuresis. In normal conditions there is little change

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in the K+ output, however these drugs are very effective in mitigating an ongoing kaluresis. These drugs should never be used in combination with K+ supplements.

Pediatric Nephrology Handout Revised May-00 Chris Clardy, M.D. III Clinical Uses of Diuretics a) Diuretic Braking Phenomena

52

With continued bolus doses of diuretics the intra-dose urinary Na+ retention increases, thereby causing diuretic tachyphylaxis. This effect is not related to aldosterone, angiotensin, adrenergic stimulation but instead appears to be secondary to autonomous increases in tubular cell function. This effect is decreased by maintaining a low Na+ intake. b) Diuretic Resistance The following may cause edema to be resistant to diuretics Edema not caused by fluid overload (e.g. edema 2 to venous or lymphatic obstruction) Excessive Na+ or H2O intake Inadequate drug reaching tubular lumen (e.g. non-compliance, inadequate dose, proteinuria) Decreased renal response (e.g. low GFR, diuretic braking phenomena, prostaglandin inhibitors) c) Methods to Increase Diuretic Effect Combination of diuretic classes (e.g. loop and thiazide diuretic) Continuous infusion as opposed to bolus dosing: Continuous infusion of loop diuretics increases the net diuresis. This occurs because the tubular lumen is continuously bathed with the diuretic, producing a continuous as opposed to an intermittent blockade of the Na/Cl ATPase in the ascending loop of Henle. N.B.: A continuous infusion of loop diuretics does not provide the ability to rapidly adjust the diuretic effect of the drug. The relatively long half lives of the loop diuretics mean that new steady state drug concentrations will only be achieved after several hours. The comparison of dobutamine versus lasix pharmacokinetics shown below demonstrates this point.

100%

Lasix versus Dobutamine Pharmacokinetics

Dobutamine 90% @ 7 minutes Lasix 90% @ 6.5 hours

% of Steady State

0% 0 2 4 Hours 6 8 10

Enuresis In Childhood
Normal Bladder Physiology

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The detrusor muscle of the bladder wall is composed of 3 smooth muscle layers which extend along the urethra. This urethral musculature forms the internal or involuntary sphincter. The striated muscles of the urogenital diaphragm surround the urethra and form the external or voluntary sphincter. The majority of the smooth muscle of the bladder is innervated by parasympathetic nerves arising from the sacral portion of the spinal cord. The smooth muscle in the trigone of the bladder (the infero-posterior portion defined by the ureters and the urethra, see Figure #10) is innervated by sympathetic nerves arising from the sacral portion of the spinal cord.

Figure #10 The bladder fills to its normal capacity without any changes in intraluminal pressure. When a certain volume is reached, the spinal arc "detrusor reflex" occurs. A signal is sent from the bladder to the spinal cord. In response to this "stretch" signal, the spinal cord initiates the following sequential actions. 1. Relaxation of the voluntary sphincter with the consequent dropping of the bladder in the pelvis 2. Contraction of the trigonal muscles allowing closure at the uretero-vesicular junction and initial opening of the internal sphincter via the loss of the acute urethral-vescicular angle (see Figure #11) 3. Contraction of the remainder of the detrusor muscles causing both a rise in the intraluminal pressure as well as a longitudinal pulling of the urethra with consequent further opening of the internal sphincter

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Figure #11

The detrusor reflex can be initiated or inhibited by brain stem and cortical centers. Development of Bladder Control At birth the detrusor reflex is intact, the ability to control this reflex develops in the first 5 years. At 1 1/2 years a child can start to defer urination. At 2 years a child will "exclaim" while voiding. At 2 1/2 years 80% to 90% of children will make known their need to urinate. At 3 years a child can be toilet trained, usually urinating 8 to 14 times per day. Night control is achieved 6 to 12 months later. At 5 years a child voids only 7 to 8 times per day. Achieving dryness is a natural function which will occur independent of training. Definitions Enuresis is the inappropriate voiding of urine in a child who has reached an age at which bladder control is expected. In primary enuresis, a child never achieves dryness. Secondary enuresis is a relapse to wetting after dryness is achieved. Nocturnal enuresis is wetting while asleep whereas diurnal enuresis is wetting while awake. Epidemiology At 5 years, 10% of children wet their beds at least once a month. At 10 years this has decreased to 7% and by 15 years to only 1%. The majority of enuresis is nocturnal as opposed to diurnal. The incidence of nocturnal enuresis is increased in certain countries (e.g.. USA and Australia) as compared to others (e.g.. Sweden). Nocturnal enuresis is more common in first borns. Nocturnal enuresis is more common in lower socio-economic classes. Nocturnal enuresis is more common in children who have had a social or psychological handicap in the first 4 years of life. Up to age 11 years, nocturnal enuresis is twice as common in boys. 80% of nocturnal enuresis is primary. Etiology

Pediatric Nephrology Handout Revised May-00 Chris Clardy, M.D.

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Nocturnal enuresis is, to some degree, genetically inherited (e.g.. monozygotic twins have twice the concordance of dizygotic twins). Therefore, 74% of boys and 58% of girls with nocturnal enuresis have a parent who was enuretic. Children with nocturnal enuresis have an early detrusor reflex during filling of the bladder and are less likely to be able to suppress this reflex. There is no proven association between nocturnal enuresis and depth of sleep. Organic causes such as bacterial infection, polyuria secondary to renal disease, and abnormalities of the bladder neck and spinal cord may cause secondary enuresis.

Management Initial evaluation should consist of a careful history and physical exam. In addition, children should be screened with serum electrolytes, BUN, creatinine, urinalysis and, potentially, a VCUG and renal ultrasound. Diurnal enuresis especially if unassociated with nocturnal enuresis, usually requires psychiatric referral. The spontaneous remission rate of nocturnal enuresis is 14% per year from 5 to 9 years and 16% per year from 10 to 19 years. 10% of children with nocturnal enuresis will remit after a single visit to a doctor, regardless of treatment offered. Treatment regimens include Behavioral modification (Rewards alone versus a reward economy) Wetness alarms Fluid restriction Interval training Medications (e.g.. tofranil 25 to 100 mg qhs or DDAVP 10 to 40 g qhs)