Glomerulonephritis

Scott Wenderfer
Pediatric Renal Fellow
November 11, 2004
 Presentation
Acute
Rapidly Progressive
Chronic

Overlap w/ nephrotic syndrome

 Presentation
• Hematuria
with Proteinuria
with Dysmorphic rbcs
with Rbc casts
• Oliguria
• Volume overload
• Hypertension
Liquid Renal Biopsy
Urine Sediment Analysis
G4 cell
 Other H&P findings
• Neurological changes
• Pharyngitis
• URI / sinusitis
• Hemoptysis
• Rash
• Murmur
• Arthritis
• Edema
 Complement Abnormalities
Ab-Ag complexes

Classical pathway C3 convertase

(C4bC2a)
Membrane
(C4 + C2)
attack complex

Recruitment of
C3 C3b PMNs
C3a Opsonization,
phagocytosis

Alternative pathway C3 convertase

Anaphylaxis,
Microbial surfaces Chemotaxis
(polysaccharides)
 Differential Diagnosis
Hypocomplementemia Normal complement

• PIGN • HUS
• MPGN • IgAN
• SLE • HSP
• Cryoglobulinemia • Alport’s / TBMD
• Bacterial Endocarditis
• Shunt nephritis
 Post Infectious GN
• Most common ACUTE cause
• Most common cause in US
• Sporadic vs epidemic
• Winter/spring - pharyngitis infections
• Summer fall – cutaneous infections
• Organisms:
• Bacteria (GAS, S. viridans, pneumococcus, S. aureus, S. epi,
atypical mycobacterium, meningococcus, Brucella,
Leptospirosis, Propionibacterium)
• Viruses (VZV, EBV, CMV, rubeola)
• Parasites (Toxo, Trich, Riskettsia)
• ASO titers are NOT helpful
 -hemolytic Streptococci
• Most common organism in PIGN
• 20% children are asymptomatic carriers
• Nephritic factor
• Host susceptibility factors (HLA-DR)
• Treatment of prodromal illness doesn’t
prevent nephritis
• ASO titers are NOT helpful
 Post Infectious GN
Pathogenesis
• Strep antigens trigger antibodies that cross-react to glomeruli
• Circulating immune complexes get filtered by glomerulus & get
stuck
• Immune complexes activate complement
• Diffuse & generalized damage to glomeruli
• ↓ GFR due to inflammation, damage to BM
• ↓ RBF in proportion to GFR, so filtration fraction normal
• Tubular function is preserved
• Plasma renin and aldosterone are normal
Presentation
• 7-14 days after pharyngitis
• 14-21 days after impetigo (upto 6 wks)
• Abrupt onset
 Manifestations of PIGN
• Edema 85%
• HTN 60-80%
• Gross hematuria 25-33%
• CNS (i.e. Sz) 10%
• Nephrotic syndrome rare
• ARF not uncommon
• C3 decreased
• C4 typically normal
 Management of PIGN
• Antibiotics do NOT prevent GN
• Sodium & Fluid restriction
• Antihypertensives, diuretics for HTN
• Dialysis if necessary
• Prognosis usually excellent
 0.5% mortality due to pulmonary edema or pneumonia
 <1% progress to CKD stage 5
• Follow-up
 Gross hematuria resolves within 2 weeks
 Complement low for 6-8 weeks
 Proteinuria remains upto 6 months
 Hematuria remains upto 2 years
Renal Biopsy
 Histopathology

Diffuse = all glomeruli

Generalized = all segments of glomeruli
IgG Immunofluorescence

Starry Sky Pattern

Electron microscopy - Normal
Basement
membrane

Foot
processes
 Electron microscopy of PIGN

• Subepithelial immune deposits (humps)

 Mesangial, subendothelial, intramembranous deposits less common
• Effacement of foot processes
 Differential Diagnosis
Hypocomplementemia

• PIGN
• MPGN
• SLE
• Cryoglobulinemia
• Bacterial Endocarditis
• Shunt nephritis
 Membranoproliferative GN
• Epidemiology
 Usually >5yo, Caucasian, ♀> ♂
• Presentation
 Persistent hypocomplementemia
 Nephrotic range proteinuria typical
 20-30% with HTN, ARF
• Pathology
 Type I tram track
 Type II dense deposit disease
 Type III mixed
 Membranoproliferative GN
Type C3 C4 Pathway
MPGN I low very low classical
MPGN II very low normal alternative
MPGN III low low/normal either

Primary MPGN
Secondary MPGN
• Infection (HCV, malaria)
• Malignancy (Non-hodgkins lymphoma, CLL)
• Vasculitis (SLE, PAN, HSP)
Pathology of MPGN
 Pathology of type I MPGN

Type I Type II
 Type I Membranoproliferative GN

PAS stain

Electron microscopy
 Type II Membranoproliferative

Trichrome stain Electron microscopy

 Naturnal Hx of MPGN
• Sparce data
• 50% renal survival to 10yrs
Progression to CKD stage 5 slower in children
• Poor prognostic factors:
type II
nephrotic syndrome
 Differential Diagnosis
Hypocomplementemia

• PIGN
• MPGN
• Lupus nephritis
• Cryoglobulinemia
• Bacterial Endocarditis
• Shunt nephritis
 Lupus nephritis
• 66% of all ptns with SLE
• RF: Hispanic, African, Asian background
♀ predominance less significant in children
• WHO classification
 Type I no pathology
Type II mesangial abnormalities
Type III focal proliferative GN
Type IV diffuse proliferative GN (most common)
Type V membranous GN
Lupus nephritis

Jo H.M. Berden & Karel J.M. Assmann

 Type III : focal
proliferative
Type II : mesangial

Type V : membranous

Type IV : diffuse
proliferative
Lupus Nephritis
 Lupus nephritis
• Hematuria and proteinuria
• HTN common
• Active urine sediment: rbc casts
• Decreased C3 and C4
• anti-double stranded DNA antibody specific for
active nephritis
• Prognosis varies greatly based on initial
pathology, usually guarded
 Type IV greatest risk of progressing to CKD stage 5
• Treatment with steroids, cytoxan
 Differential Diagnosis
Hypocomplementemia
• PIGN
• MPGN
• Lupus nephritis
• Cryoglobulinemia
• Bacterial Endocarditis
 Upto 25% of cases in autopsy studies
 Symptoms of GN are preceded by other symptoms of SBE
 C3 and C4 both are low from systemic immune complex disease
• Shunt nephritis
 Upto 4% of ventriculoatrial shunt infections
 Indolent course, w/ lethargy, weight loss, fever, purpura
 Differential Diagnosis
Normal complement

• HUS
• IgAN
• HSP
• Alport’s / TBMD
 Hemolytic Uremic Syndrome
• 2 cases/100,000 annually
• Peak incidence <5yo (6/100,000)
• More common June-September
• Classification
D+ diarrhea associated
Strep pneumo
Atypical HUS ADAM-TS13, C1q def
 Presentation of D+ HUS
• Prodromal acute gastroenteritis
 Shiga toxin producing E.coli O157:H7
 Transmission from beef, veggies, direct person-to-person, and
contaminated water all reported
 Incubation period 3-4 days
 Bloody diarrhea 2-3 days after cramping begins
 50% with emesis, afebrile or low grade fever only
• Hemolytic anemia
• Thrombocytopenia
• ARF
 Begins 2-14 days after diarrhea
• CNS disease
 Overlap with ITP in 33% HUS cases
 Somnolence, confusion, seizures, coma
Microangiopathic Hemolytic Anemia
 Atypical HUS
1. ADAMTS13 is a metalloproteinase
 Target is VWF multimers
 Deficiency causes HMW multimers to
deposit in vessels
 vWF multimer deposits shear rbc & plts
 vWF multimers form nidus of inflammation
 Can correct with FFP to replace enzyme
2. Factor H mutation
 Treatment HUS
• Antibiotics do NOT prevent HUS
Some studies suggest Abx increase risk of HUS
• Supportive Therapy
50% ptns with ARF require dialysis
• Plasma exchange helpful in atypical HUS
ITP, ADAMTS13
 Prognosis D+ HUS
Ptns with E.coli O157:H7 infections
• 40-60% develop hemorrhagic colitis
• 2-7% of ptns with hemorrhagic colitis develop HUS

Ptns with HUS

• 90% have complete recovery
• 5% die in acute phase
• 5% develop stage 2-5 CKD
 anuria
 Severe GI prodrome
 Age < 2yo
 Differential Diagnosis
Normal complement

• HUS
• IgAN
• HSP
• Alport’s / TBMD
 IgA Nephropathy
• Most common cause of chronic GN
• Most common cause of GN worldwide
<10% of GN in US, 40% of GN in Japan
• Most common during 2nd-3rd decade of life
• Male:female ratio 2:1 to 6:1
• 20-50% progress to CKD stage 5
Older age
Heavy proteinuria
Acroscopic hematuria
Pathology of IgAN
 Presentation of IgAN
H&E
• Macroscopic
hematuria in 80%
• Synpharyngitic
disease
Presents within 1-2
days of sore throat
• Same pathology as
HSP

IgA IF
Henoch Schönlein Purupura
 Henoch Schönlein Purupura
• GI tract
Cramping, vomiting, diarrhea
• Skin rash
Lower extremities, buttocks
• Joint involvement
• HSP nephritis
Incidence 20-50%
In 80%, occurs within 4 weeks of rash & GI upset
In 15%, occurs upto 1-3 months after rash & GI
upset
 HSP Nephritis
Presentation
• 90% transient microscopic hematuria
• 5% recurrent hematuria (IgAN?)
• 3% hematuria with proteinuria
• <2% ARF
 RF: nephrotic syndrome > nephrotic range proteinuria >
proteinuria > no proteinuria
Prognosis
• <1% progress to CKD stage 5
 Differential Diagnosis
Normal complement

• HUS
• IgAN
• HSP
• Alport’s / TBMD
 Alport’s Syndrome
• Familial Thin Basement Membrane Disease
• Classically X-linked dominant
 Autosomal recessive mutations seen too (chromosome 2)
• Criteria for diagnosis
 Familial hematuria
◦ 15% by 1yo, 70% by 6yo
 Characteristic ocular lesions
 Bilateral high frequency sensorineural hearing loss
◦ Absent at birth, by 15yo in 85% of ♂ and 20% of ♀
◦ Progressive, involves conversational hearing range
◦ Requires hearing aids
 Thickenning & splitting of glomerular BM
Pathogenesis of Alport’s
• Abnormality of type
IV collagen
• Disordered
basement
membrane
• Splitting of lamina
densa of GBM
 Management of Alport’s
• Progression to CKD stage 5 by 30-40yo
Causes 0.5-2% of end stage kidney disease in US
Unusual in females
Females progress at slower rate
 Rapidly Progressive GN
• Infectious (PIGN, endocarditis, hep B)
• Vasculitis (lupus, HSP, Wegener’s, RA)
• Goodpasture’s
• malignancy
• Drugs (hydralazine, penicillamine)
 Crescentic GN

Type Serology Primary Secondary

I Anti-GBM+ ANCA- Anti-GBM disease Goodpasture’s
II Anti-GBM- ANCA- idiopathic SLE, IgAN, MPGN
III Anti-GBM- ANCA+ Microscopic polyangiitis, Drug-induced
Wegener’s
IV Anti-GBM+ ANCA+ Anti-GBM disease Goodpasture’s
 Vasculitides

C-ANCA P-ANCA
Anti-proteinase 3 antibodies Anti-myeloperoxidase antibodies

75% sensitive for Wegener’s 66% sensitive for

Microscopic polyangiitis
 Anti-GBM Disease

Silver stain IgG immunofluorescence

 Glomerulonephritis
Take Home messages
• Check BP, creatinine in all patients with hematuria
• Proteinuria + Hematuria = GN  consult
• Nephrotic syndrome + hematuria is not minimal change dz
• Complements low after 8 weeks  consult
• Hematuria concurrent with pharyngitis  consult
• No antibiotics for nonfebrile bloody diarrhea
• Antibiotics for culture proven Strep pharyngitis / impetigo
 To prevent rheumatic fever, not glomerulonephritis
• Nephrologists don’t bite (except Dr. Portman)
Happy Veteran’s Day