Immune Mediated Renal Diseases

Definition

Renal Diseases (damage to Glomeruli, Tubules, Interstitial Tissue)

Glomeruli – Most due to Immunological Mechanism

Tubules, Interstitium – Some Degree

Nephritis

Antibodies with Complement, Polymorph

(↑ Important than Cellular Mechanism in Pathogenesis)

Antibodies Induce Damage (2 ways) React Directly with Glomerular, Tubular Basement Membrane

Antibody forms Immune Comple xes with Circulating Antigen

(Deposited in Kidney)

Immunologic Tests

Diagnose Renal Diseases

Clinical Syndromes

Acute Nephritis

Sudden onset of Haematuria, Proteinuria, Hypertension, Oliguria

Following Streptococcal Infection (of Throat, Skin in Children)

Nephrotic Syndrome

Hypoalbuminaemia, Edema

Resulting from Proteinuria (common presentation of GN)

Persistent Proteinuria

Protein < 300 mg/day Protein > 300 mg/day

Normally Present in Urine Pathologic (Most All Renal Disease)

Recurrent Haematuria (1st

Manifestation of Renal/ Extrarenal Disease)

Micro, Macroscopic

Upper, Lower Urinary Tract

Renal Failure

Acute Chronic

Sudden onset with Severe

Impairment of Renal Function

End-Result of any Disorder

Destroys Renal Architecture

Inflammatory Origin

Poor Correlation (between Clinical Picture, Underlying Morphology)

Diagnosis by Renal Biopsy

Histological Classification of Glomerulonephritis

Glomeruli

Compose d of Mesangial, Endothelial, Epithelial Cells

Glomerulonephritis (by defini ng Types of Cells, Parts or All Parts Damaged)

Classification based on LM, EM, Direct Immunohistology (IF)

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Acute Immune-Complex Nephritis (Serum Sickness)

Occurs when Amount of Circulating Antigen is still in excess of Antibody

Immune Complexes Forme d, Soluble, Trapped in Capillary Membranes

IF

Irregular

Granular (Lumpy-Bumpy) Deposition

Renal Injury (due to Accumulation of Macrophages in Glomeruli, Release of

Inflammatory Mediators)

Transient with Complete Healing

Example

Post-Streptococcal GN

Acute Post-Streptococcal GN

Preceded by Streptococcal Infection of Throat, Skin (90% of Cases)

Acute Nephritis 10-12 days after Throat Infection

3 weeks after Skin Infection

Diagnosis

History of Sore Throat

Throat Culture

↑ Titres of Streptococcal Antibodies

(Anti-Streptolysin, Anti-DNAse B, Anti-Hyaluronidase)

↓ Serum C3 Level

Early Phase Diffuse Proliferation of Endothelial, Mesangial Cells

Polymorph Infiltration of Glomerulus

Presence of Humps (on Epithelial Side)

Deposits of IgG, C3 along Capillary Loop (IF) corresponding to Humps

Immunological Features

Circulating Immune Complexes Present

↓ Serum C3

Prognosis

Worse in Adults

Chronic Immune-Complex Nephritis

Occurs if

Antigen Exposure Persists

Host makes Abnormal Responses

Local Factors

(C3 Receptors, Change in Permeability, Promote Deposition of Complexes)

Complexes made ↓ Soluble

Immune Complex

Criteria in Support of an Immune Complex Mediated Glomerulonephritis

• Immune Complex Present at Site of Tissue Damage

• Immune Complexes Detectable in Circulation

• Antigen of Immune Complex is Identifiable

• Removal of Immune Complexes Produces Clinical Improvement

Role of Complement in Prevention of Immune Complexes

Classical Pathway Alternative Pathway

Prevents formation of Large

Insoluble Immune Complexes

Disruption of Large Insoluble

Complexes

• Smaller Complexes

o Circulate in Blood

o Removed, Degraded by Phagocytes in Liver, Spleen

• Large Complexes

o React with CR1 (Compleme nt Receptor for C3b) on RBC

Transported to Liver for Degradation

Failure – Deposition of Immune Comple xes, Lead to Activation of MAC (C5b-9)

Role of Reticuloendothelial System (RES) Major Mechanism for Clearance of Large, Insoluble Complexes

Troublesome Complexes (I ntermediate Size)

Complexes Deposited on Epithelial Side

(Proliferative, Membranous Nephritis) (Rapid, Slow Rate)

Larger Complexes deposited mainly in Mesangium

Diagnosis of Immune Complex Nephritis

• Direct Immunofluorescence, I mmune Peroxidase of Kidney Biopsies

• Igs, Complement Deposited in Tubular Basement Membrane, Interstitial

Tissue, Blood Vessels, Glomeruli

• Irregular Granular, Lumpy-Dumpy Pattern of Deposition is Characteristic

• Deposition in GBM, Mesangium

Treatment

Antigen Elimination

Removal of Circulating Immune Complex

Manipulation of Inflammation Mediators

Immunosuppressive Drugs

Plasmapheresis

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Membranous Glomerulonephritis

Present with Florid Nephrotic Syndrome (80%)

Proteinuria, Microscopic Haematuria

30 – 50 y/o (Peak Age)

Characteristic Thickening of GBM without Proliferation of Cells

Types

Idiopathic Secondary

Causal Antigen Never Found Drugs

Complexes Accumulated only on Epithelial Side of GBM

(Serum Comple ment Normal)

Membranoproliferative Glomerulonephritis (Persistent Hypocomplementaemia GN)

Identified on Basis of Persistently ↓ C3

(However, ↓ C3 is not a constant finding) (Clinical Picture not specific)

2 Types of MPGN (detected by Electron, Immunofluorescent Microscopy)

Type I Type II

Deposits in Subendothelial Space,

Mesangium

Deposits in Intramembranous

(GBM, Mesangium)

Ribbon-like Appearance

↓ C4, C3, CIq ↓ C3

Presence of C3 Nephritic Factor

(Ab against C3 Convertase)

(Not a marker of MPGN)

Strong correlation between Type II

with Partial Lipodystrophy

Treatment

Transplantation (Successful)

Anti-GBM Antibody -Mediated Nephritis (Goodpasture Syndrome)

Rare

Etiology – Unknown

Type II HSR

Include

Pulmonary Haemorrhage

Rapid Progressive Glomerulonephritis (with Oliguric Renal Failure)

(within Weeks → Moths)

Clinical Haematuria, Proteinuria (Gross, Microscopic)

↓ 24h Creatinine Clearance

↑ Blood Urea

↑ Serum Creatinine

Hallmark

• Autoantibodies to Type IV Collagen

(Present in Capillary BM of Kidney, Lung)

(Antiglomerular Basement Membrane Antibodies)

(Detected in Immunoassays) (Early in Course)

• Linear Deposition of Immunoglobulin G, C3

Treatment

Pulse Methylprednisolone

Cyclophospha mide

Plasma Exchange

IgA Nephropathy (Idiopathic = Berger Disease)

Mesangial Deposition of IgA

Male ↑ (Any Age)

Discovered as Asymptomatic Microscopic Haematuria

Children – Recurrent Episodes of Haematuria after Respiratory, GIT Infections

Clinical

↑ Serum Creatinine (in 1/3)

Tubular Injury

Obstruction by Red Cell Cast

Progress

End Stage Renal Failure (1/3 of Patients)

Poor Prognosi s

Hypertension

Older Age at Onset

Male

Persistent Proteinuria

Persistent Azotemia

Renal Biopsy – Cellular Crescents, Endocapillary Proliferation, Extension of

Immune deposits to Peripheral GLomerular Capillary Walls

Treatment

Hypertension control

Fish Oil (Dietary)

Immunosuppressive Drugs

Henoch-Schoniein Nephritis

Henoch-Schonlein Pur pura (HSP)

Generalized Vasculitis

Involves - Skin (Purpura), Joints, Kidneys, GIT

Diagnosis

Skin Biopsy (Leukocytoclastic Vasculitis with Granular Deposition of IgA)

(along Dermal Vessels)

Renal Biopsy

Remit Spontaneously (most patients)

Microscopic Haematruia (in all cases) (90% with Proteinuria)

Immune Deposits – Mesangial, Contain IgA

Patients

• Rarely Progress to Renal Failure

(if Present with Microscopic Haematuria without Proteinuria)

• ↑ Risk of Renal Failure

(if Complicated Nephrotic Syndrome)

↑ Glomeruli Exhibiting Crescents - ↑ Risk of Renal Failure

Treatment Pulse Intravenous Methylprednisolone

Renal Transplantation (for patients with Renal Failure)

Nephropathie s associated with ANCA

(ANCA – Anti-Neutrophil Cytoplasmic Antibody)

Renal Involvement (common in Vasculitis)

PAN (Polyarteritis Nodosa) Wegener Granulomatosus

Arteries outside Glomerulus

affected

Arteries within the Glomerulus

affected

Lesions

Focal, Segmental Distribution with Fibrinoid Necrosis, Crescent Formation

Presence of ANCA

Strong correlation between Presence of ANCA, Glomerular Involvement in

Vasculitis (but precise mechanism not understood)

Treatment

Early Phase Rapid Progressive GN

Glucocorticoids Pulse Methylprednisolone

Prednisolone, Cyclophosphamide

Plasmapheresis (value not proven)

Renal Vasculitis ANCA Test Positivity (%)

P-ANCA C-ANCA

PAN 10-20 10-20

Microscopic Polyangitis 50-80 10-20

Wegener Granulomatosis 10-20 80-90

Necrotizing, Cresce ntic GN 50-80 10-20

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Renal Involvement (Systemic Connective Tissue Disease)

Lupus Nephritis

Renal Involement (affects most of SLE patients)

Nephritis (Major cause of Morbidity, Mortality)

DNA, anti-DNA Antibodies (Glomerular Deposits in Subepithelial)

(Central Role in Pathogenesis of Proliferative LN)

Proliferative LN Rapid Progressive LN

Symptomatic Haematruia Cellular Crescents

Proteinuria

Hypertension

Azotaemia

Hypocompleme ntaemia

↑ Titre of Anti-DNA Antibodies

Diagnosis

• Serum Complement - ↓ Level Indicate Flares

• Antibodies Detection

• Renal Biopsy

Other Conne ctive Tissue Diseases

Scleroderma (Diffuse Form)

Sjogren Syndrome

Rheumatoid Arthritis

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