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GLOMERULONEPHRITIS
Vivette D’AgatiJai Radhakrishnan
Approach to Glomerular Diseases: Clinical Presentation
NephritisRenal failureHypertensionHematuria
A t
Nephrotic SyndromeHeavy ProteinuriaLow serum AlbuminEdema
Asymptomatic Urinary Abnormalities
• Acute• Chronic• Rapidly
Progressive
High serum lipids
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Urine Analysis
Urinary RBC’s, sometimes deformedRBC Casts
Large amounts Albuminuria ( >3g/Day )
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Approach to Glomerulonephritis
1 M h l i1. Morphologic2. Immunologic3. Etiologic4. Clinical
Vulnerability of Glomerulus to IC Injury
1 20 2 % f di1. 20-25% of cardiac output2. High glomerular capillary pressure3. Fenestrated endothelium4. Concentration (sieving effect)
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Mechanisms of Immunologic Injury to the Glomerulus
1 Gl l d i i f i l i1. Glomerular deposition of circulating Ag-Ab complexes
2. Binding of Circulating Ab to fixed glomerular Ag (i.e. anti-GBM Ab)
3 In situ immune complex formation3. In situ immune complex formation
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Glomerular Proliferation
1. Endocapillary
2 Extracapillary2. Extracapillary(crescentic)
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Patterns of Glomerular Disease: Proliferation or Sclerosis
1. Focal Vs Diffuse
2 Segmental Vs Global2. Segmental Vs Global
Approach to Glomerular Disease: Etiology
History Primary GlomerularHistory Physical ExamLaboratory, Radiological tests
Primary Glomerular Disease• e.g. minimal change
diseaseSecondary (Systemic) es sDisease• e.g. Lupus
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• 7 year old child • Several days of sore throat + low grade fever; he
is given acetaminophen, and recovers uneventfully. 2 k l t d l d k l l d i• 2 wks later develops dark, coca-cola colored urine and notes urinating less.
• Exam: pedal edema and elevated blood pressure.• Labs:
– Urine: rbc’s, rbc casts, 2+ prot.– Creatinine 2.4 mg/dl
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Acute Nephritic Syndrome
Decreased GFRDecreased GFROliguriaEdemaHypertensionActive urine sediment
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Etiology: Post-streptococcal GNFollowing infection with certain “nephritogenic”Following infection with certain nephritogenic streptococcal strains (pharyngitic, dermal, etc)Children more common than adultsTime lag from infection to onset of GNNephritic picture commonLow complement and C3Positive serologic tests for recent strep infectionPositive serologic tests for recent strep infectionPrognosis: excellent in children; good in adults
Serum Complement Levels in Glomerulonephritis
Low Levelsacute post infectious GN• acute post-infectious GN
• lupus nephritis• idiopathic MPGN• cryoglobulinemic GN
Normal Levels • IgA nephropathyg p p y• ANCA-RPGN / Wegener’s / Microscopic PAN• Anti-GBM disease• Minimal change, FSGS, Membranous, Diabetes, • Amyloid, etc….
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• A 16 year old high school junior notices dark brown urine after playing basketball.
• Labs:– Creatinine 1.1 mg/dl– Urinary sediment has rbc’s and rbc
casts.– Creatinine clearance 128 cc/min– 660 mg proteinuria/day– Serologic tests are normal or
negative
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Demographics of IgA Nephropathy
Ages 4 – 80 (mean 25) yearsAges 4 80 (mean 25) years(65% of patients in 2nd/3rd decade)
M/F = 2/1Rare in blacks
Incidence (% primary glomerulopathies)5 10% N America5-10% N. America
U.K.Scandinavia
20-30% EuropeAustralia
25-45% Asia
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Pathogenesis
1. Defective hepatic clearanceLiver cirrhosis• Liver cirrhosis
2. Increased IgA production• Association with elevated serum IgA• Onset may follow URI or Gastroenteritis
3. Defect of antigen exclusion at the mucosal surfacemucosal surface • URI• Gastroenteritis• Celiac disease
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Structure of Human Secretory IgA (sigA)
Henoch-Schönlein Purpura
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Henoch-Schönlein PurpuraVasculitis with IgA-dominant immune depositsaffecting small vessels, i.e. capillaries, venules, or arterioles Typically involves skin gut &or arterioles. Typically involves skin, gut & glomeruli, and is associated with arthralgias or arthritis.
Henoch-Schönlein PurpuraSchönlein-Henoch Purpura
Purpura
Abdominal pain
Arthralgias
(Nephritis)
Johann Lukas Schönlein Edward Henoch
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Etiology: IgA NephropathyMost common idiopathic GN worldwideDefined by IgA deposition in mesangiumClinical PresentationClinical Presentation • Young – gross hematuria• Adults – Proteinuria + hematuria
Not “benign” hematuria ( Berger’s Disease ) • 20-30 % progress ESRD over 20 years
Treatment OptionsACE i hibit /AR bl k• ACE inhibitor/AR blockers
• Steroids• Fish Oil• Mycophenolate
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• A 29 year old saleswoman develops arthritis of multiple joints, feverE am L mphadenopath and a malar• Exam: Lymphadenopathy, and a malar rash.
• Labs:– Urinalysis 3+ protein, 18-20 rbc’s– Creatinine 1.2 mg/dl
24 h t i 1 8– 24 hr. protein 1.8 – Complement 18% (normal 50-150%)– ANA positive, Anti-DNA antibody positive
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Lupus Nephritis Class IV
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Lupus Nephritis WHO Classification
CLASSESCLASSESI Minimal mesangialII Mesangial ProliferativeIII Focal Proliferative (<50% glom)IV Diffuse Proliferative (> 50% glom)IV Diffuse Proliferative (> 50% glom)V MembranousVI Chronic sclerosing
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Lupus Nephritis Class II
Class II: Mesangial electron dense deposits
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Class III: Focal segmental lupus nephritis
Class V: Membranous lupus nephritis with spikes
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Treatment Approach to SLE Nephritis
Class I: Minimal mesangial LN(normal LM, +deposits)g ( p )• TREAT EXTRARENAL LUPUS
Class II: Mesangial proliferative LN• TREAT EXTRARENAL LUPUS
Class III: Focal LN (<50% of all glomeruli)• STEROIDS, CYTOTOXICS
Class IV: Diffuse LN (>50% of all glomeruli)STEROIDS, CYTOTOXICSSTEROIDS, CYTOTOXICS
Class V: Membranous LN• STEROIDS, CYTOTOXICS (IN HIGH RISK PTS)
Class VI: Advanced sclerotic LN (90% sclerosed, no activity)
• PREPARE FOR RENAL REPLACEMENT
Kidney Int. 2004 Feb;65(2):521-30.
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Probability of Developing End-Stage Renal Disease with Different Treatment Regimens
IV CYC
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Probabilityof
End-StageRenal
Disease
IV CYCOral CYC + AZAOral CYC
AZA
Prednisone80
100220200180160140120100806040200
CYC = cyclophosphamide; AZA = azathioprine.Steinberg AD, Steinberg SC. Arthritis Rheum. 1991;34:945-950.
Months
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Corticosteroids: Side Effects
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Cyclophosphamide: Side effects
EVENT CYCLOPHOSPHAMIDE COMBINATIONEVENT CYCLOPHOSPHAMIDE COMBINATION
MAJOR INFECTIONS 50% 50%
HERPES ZOSTER 29% 25%HYPERLIPIDEMIA 25% 42%AVASCULAR 29% 30%AVASCULAR NECROSIS 29% 30%
OSTEOPOROSIS 22% 16%PREMATURE MENOPAUSE 56% 55%
Gourley MF.. Ann Int Med 135: 248-247, 2001
Strategies for Alternate Therapies
Sequential cytotoxic therapySequential cytotoxic therapy• Cyclophosphamide followed by
Mycophenolate/Imuran• Mycophenolate
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• A 58 year old insurance salesman develops sinusitis, weight loss, malaise and a dry cough over three weeks.
• His sinus films show opacification of the left• His sinus films show opacification of the left maxillary sinus, and he is found to have a cavitary lesion on his chest X-ray.
• Labs:– Urinalysis: rbc’s, wbc’s, and rbc casts– Creatinine 2.7 mg/dl– Serum complement is normal– Anti-GBM antibodies are absent– ANCA is positive
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Pulmonary-Renal Vasculitic Syndrome
P i i ( ll ANCA i t d)Pauci-immune (usually ANCA associated)• Wegener’s granulomatosis• Microscopic PolyangiitisImmune Complex Deposits (granular)
• SLE• Cryoglobulinemic vasculitisAnti-Glomerular Basement Membrane Antibody Deposits (linear)
• Goodpasture’s Syndrome
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Circulating anti-GBMantibodies with linear
Circulating ANCA withpaucity of glomerular IF
Glomerular immunecomplex localization with
ANTIBODY MEDIATED GLOMERULONEPHRITIS
antibodies with linearglomerular IF staining
paucity of glomerular IFimmunoglobulin staining
complex localization withgranular IF staining
>80% ANCA+
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Rapidly Progressive Glomerulonephritis
Rapidly progressive renal failure (weeks)Rapidly progressive renal failure (weeks) RPGN = Crescentic GNPathogenesis• Anti-GBM disease• Immune complex GN
Pauci immune GN• Pauci-immune GNTreatment and Course depend on etiology and stage
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Anti-Neutrophil Cytoplasmic Antibodies (ANCA)
Anti proteinase-3 (PR3) Anti- myeloperoxidase (MPO)
ANCA is to RPGN as Anti-DNA is to SLE
