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Glomerulonephritis

Nephritic or Nephrotic

Nephrotic syndrome describes a group of patients

who have significant proteinuria ( >40 mg/m2/hr),


hypercholesterolemia, hypoalbuminemia, and edema.
They may have azotemia, hypertension, hematuria, and
RBC casts.

Nephritic syndrome describes a group of patients

with hematuria, red cell casts in the urinary sediment,


with or without proteinuria (typically with proteinuria).
They may have hypertension, azotemia, and/or edema.

Nephritic Urine

RBC casts

Diagnosis

History
Physical Examination
Laboratory Studies
Urinalysis casts, red cells, protein
Serum creatinine
C3 Complement
ASO / AntiDNAse B
ANA Titer

Clues to Diagnosis

Age and Sex of patient SLE, HUS


Past history Recurrent hematuria IgA
Family history Alports
Exposures
Raw meat HUS
Unprotected sex Hepatitis C, HIV

Evidence of systemic disease

SLE, Wegeners, HSP

Events in Glomerulonephritis
Clinical manifestations

PATHOPHYSIOLOGY
Glomerular injury

Hematuria, RBC casts,


proteinuria

Inflammation of glomerular
capillary bed
Decreased glomerular
capillary perfusion
Decreased GFR

Increased Na and
H2O reabsorption

Decreased tubular fluid


Increased ECF
Renal Failure

Azotemia,
Inc Uosm, Decr UNa
Decr urinary volume
(Htn, edema, Anemia)

Heart Failure
Encephalopathy

APSGN

Prototypic GN
Streptococcus A specific serotypes
Nephritic presentation, 1-2 weeks after
phayrngitis or 3-6 weeks after a skin infection
Tea-colored urine
Mild to severe hypertension
Less than 5% have nephrotic syndrome
Severe complications include pulmonary edema,
hypertensive encephalopathy, acute renal failure
Treatment is supportive (diuretics, salt
restriction, etc)

Normal Glomerulus

APSGN

Acute Post-Streptococcal Glomerulonephritis


Electron Dense Humps Lumpy-Bumpy Disease

DIAGNOSIS PSGN

Acute glomerulonephritis not chronic disease


Low C3 that returns to normal by 6 weeks
Evidence of streptococcal infection
Elevated ASO titer in pharyngitis
Elevated AHT in pyoderma
Elevated Anti DNase B in either
Elevated streptozyme

Pathogenesis of PSGN

Trapping of immune complexes in capillary wall


Cross reaction between strep antigens and
capillary wall constituents
In situ immune complex formation planting of
strep antigens in wall reacting with circulating
antibodies
Direct complement activation of planted strep
antigens in capillary wall

Treatment of PSGN

Restrict salt - + water


Treat hypertension
volume dependent hypertension
Furosemide

Restrict K if hyperkalemic
Penicillin if + strep culture
Dialysis if usual indication present Rarely
needed

Long Term Outcome

Resolution of gross hematuria and acute


nephritic syndrome in 2 weeks in majority
Urine abnormalities, especially hematuria for a
year
Rare patient left with long term obvious renal
impairment, chronic hypertension
Some question whether subtle long term renal
impairment is common

Post-infectious Glomerulonephritis

Presentation similar to PSGN


C3 usually normal
Associated with a number of viruses, parasites
Seen in chronic shunt infections, SBE, visceral
abscesses
Treatment resolution of infection and
supportive care

IgA Nephritis

Most common cause of nephritis world-wide


More prevalent in males (2:1 to 6:1)
Has been reported in association with other diseases
(liver cirrhosis, CF, Crohns disease, celiac disease)
Recurrent hematuria may be macroscopic
Commonly have hematuria 24-48 hours after the onset
of a URI, typically resolving in a few days
Most have a benign course unless accompanied by
hypertension, nephrotic syndrome, or rapid deterioration
of function
HSP similar histologically, but accompanied by
characteristic rash

IgA

IgA

Treatment of IgA GN

No specific therapy for recurrent macroscopic


hematuria without significant proteinuria
Limited studies have shown some benefits of
fish oil (-3 fatty acid) reduces eicosanoids
Alternate day steroids
Poor prognostic indicators
Hypertension
Heavy proteinuria
FSGS and/or interstitial fibrosis on biopsy

Henoch-Schnlein Purpura
Idiopathic small vessel vasculitis affecting mainly:

skin
bowel
joints
kidney

Time to Rash From Abdominal Pain


or Arthritis
8
7
6
5
4
3
2
1
0

Arthritis
Abd Pain

7
Days

11 13

Nephritis in HSP
Occurs in 20-40% of patients
Rarely presenting complaint
May appear later but rarely after 3 months
Hematuria alone in 20-30%
Hematuria + proteinuria in 50%
Acute nephritis in 10-20%
Acute nephritis + nephrotic syndrome 10-20%

MPGN
Mesangiocapillary

glomerulonephritis and
membranoproliferative glomerulonephritis
20-30% have acute GN at presentation
40% have evidence of a recent strep infection
30-50% may have nephrotic syndrome
50% have low C3 with normal or low C4
Unknown pathogenesis
Histology varies but results in basement membrane
changes that are characteristic
Treatment in children is often alternate day steroids
ESRD may occur in 10-50% of patients

MPGN

MPGN

MPGN

Vasculitis Classification
Large-vessel vasculitis
- Giant-cell arteritis
- Takayasus arteritis
Medium-sized-vessel vasculitis
- Polyarteritis nodosa
- Kawasakis disease
- Primary granulomatous central nervous system vasculitis
Small-vessel vasculitis
- ANCA-associated small-vessel vasculitis
- Microscopic polyangiitis
- Wegeners granulomatosis
- Churg-Strauss syndrome
- Drug-induced ANCA-associated vasculitis

Vasculitis Classification
Small-vessel vasculitis
- Immune-complex small-vessel vasculitis
- Henoch-Schnlein purpura
- Cryoglobulinemic vasculitis
- Lupus vasculitis
- Rheumatoid vasculitis
- Sjgrens syndrome vasculitis
- Hypocomplementemic urticarial vasculitis
- Behets disease
- Goodpastures syndrome
- Serum-sickness vasculitis
- Drug-induced immune-complex vasculitis
- Infection-induced immune-complex vasculitis
- Inflammatory bowel disease vasculitis

Lupus

Clinically variable in presentation and histology


Up to 95% of children will have evidence of renal
involvement (hematuria, proteinuria, casts,
edema, etc)
WHO Classification of lesions based on
histology, activity and chronicity of the lesion
seen on renal biopsy
A renal biopsy is not necessary to diagnose the
disease, but is useful in its management
Treatment varies and outcomes are individual

RPGN
Describes

a clinical course rather than a specific


histologic entity
All causes have crescents around glomerulus
leading to rapid destruction
Causes include:
80-90%

Immune complex disease (PSGN, SLE)


10% Pauci-immune (Wegeners granulomatosis)
Rarely Anti-GBM disease
Treatment

is individualized by cause
Large IV doses of methylprednisolone + cytotoxic
drug usually

Crescentic GN - SLE

Clinical Picture: HUS

Hemolytic anemia with predominantly renal


involvement.
Often preceded by cytotoxin-producing gram
negative organism most commonly E. coli
O157:H7.
Probably three clinical entities: age 1-3, adults,
familial.

Schistocytes

Schistocytes: red blood cell


fragments that result from
membrane damage encountered
during passage through vessels
(probably partly occluded by
platelet thrombi).
Severe burns, uremia, DIC,
preeclampsia, mechanical valves,
TTP/HUS.

Renal Pathology: Glomerulus


Glomerulus in HUS:
Capillary lumina are
narrowed or occluded by
erythrocytes and thrombi.
Swelling of endothelial
cells and thickening of the
capillary walls.
Segmental necrosis.

Renal Pathology: EM
Endothelial cells are swollen
and occasionally detached,
resulting in a translucent
subendothelial space.
Fragmented red cells, an
ultrastructural appearance
characteristic of thrombotic
microangiopathy associated
with the hemolytic-uremic
syndrome.

Hemolytic-Uremic Syndrome:
Acquired

Shigella dysenteriae

E. coli O157:H7

Shiga toxin acquired HUS


9-30% of infected children after
episode of bloody diarrhea by E. coli
O157:H7
Other E. coli serotypes, as well as
Shigella dysenteriae cause HUS
Shiga toxin is encoded in the
genome of Shigella dysenteriae and by
plasmid of E. coli O157:H7

Shiga Toxin

B (binding) subunits A subunit (33 kDa) and five B subunits (7.7 kDa
each)
bind to host cells, A (enzymatic) subunit causes inactivation of 60S
ribosomal subunit.
B subunits specifically bind to glycospingolipid globotriaosyl ceramide
receptor or Gb3.
Once shiga toxin is bound to Gb3, the toxin is internalized and A subunit
is enzymatically active: inhibition of an RNA N-glycosidase.

Renal Expression of Gb3 Receptor

Gb3 western blot in cultured


human PTC and vero
Peroxidase stain of primate
glomerulus with anti Gb3

Hughes et al., KI, Vol 54, Aug 1998

Expression: Kidney - glomerular, tubular and mesangial cells; also expressed to


lesser extend in cerebral epithelium, colon, monocytes and platelets.
Gb3 is mainly expressed in children less than 2 years of age, indicating
developmentally regulated expression (Lingwood et al., Verotoxin-binding in
human renal sections. Nephron, 1994).

Joel Moake, NEJM, Vol 347, Aug 2002

Management of Diarrhea Associated


HUS
Recommendation: Optimal management of D+ HUS requires
meticulous fluid and electrolyte balance and blood pressure control.
Renal dialysis should be administered as required. Anti-motility
drugs and antibiotic treatment adversely affect outcome and should
be avoided.
Recommendation: At present there is no conclusive evidence that
either FFP or therapeutic plasma exchange improves outcome.

When to Biopsy in AGN?

Rapid decline in renal function without etiology


Heavy proteinuria (>40 mg/m2/hr)
Persistent low C3
SLE with any evidence of renal involvement
Family history of renal disease

AGN Summary

Defines clinical syndrome of hematuria,


proteinuria, and RBC casts
Most commonly PSGN in school age children

Evidence of strep infection, low C3

Look for systemic disease


Treatment often supportive but tailored to
specific etiology

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