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GLOMERULONEPHRITIDES

Vivette D’AgatiJai Radhakrishnan

Approach to Glomerular Diseases: Clinical Presentation

NephritisRenal failureHypertensionHematuria

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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 Glomerular Diseases: Pathology

Proliferation or SclerosisDistribution

Glomerular Proliferation

1. Endocapillary

2 Extracapillary2. Extracapillary(crescentic)

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Patterns of Glomerular Disease

1. Focal Vs Diffuse

2 Segmental Vs Global2. Segmental Vs Global

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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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

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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….

• 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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Classification

P iPrimary• IgA Nephropathy• Henoch-Schonlein Purpura

Secondary• Liver Cirrhosis• Liver Cirrhosis• Inflammatory Bowel Disease

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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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 Membranous

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Lupus Nephritis Class II

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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

Immunomodulation• IVIg• IVIg• Anti CD40-ligan

Immunoablation

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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