Immune Mediated Renal Diseases

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Immune Mediated Renal Diseases Powered By Docstoc
					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 Complexes 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                End-Result of any Disorder
  Impairment of Renal Function            Destroys Renal Architecture
  Inflammatory Origin
Poor Correlation (between Clinical Picture, Underlying Morphology)
Diagnosis by Renal Biopsy

Histological Classification of Glomerulonephritis
Glomeruli
Composed of Mesangial, Endothelial, Epithelial Cells
Glomerulonephritis (by defining Types of Cells, Parts or All Parts Damaged)
Classification based on LM, EM, Direct Immunohistology (IF)
Acute Immune-Complex Nephritis (Serum Sickness)                             Immune Complex
Occurs when Amount of Circulating Antigen is still in excess of Antibody
Immune Complexes Formed, 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                                                             Criteria in Support of an Immune Complex Mediated Glomerulonephritis
10-12 days after Throat Infection                                                Immune Complex Present at Site of Tissue Damage
3 weeks after Skin Infection                                                     Immune Complexes Detectable in Circulation
Diagnosis                                                                        Antigen of Immune Complex is Identifiable
History of Sore Throat                                                           Removal of Immune Complexes Produces Clinical Improvement
Throat Culture                                                              Role of Complement in Prevention of Immune Complexes
↑ Titres of Streptococcal Antibodies                                                    Classical Pathway                      Alternative Pathway
(Anti-Streptolysin, Anti-DNAse B, Anti-Hyaluronidase)                         Prevents formation of Large              Disruption of Large Insoluble
↓ Serum C3 Level                                                              Insoluble Immune Complexes               Complexes
Early Phase                                                                      Smaller Complexes
Diffuse Proliferation of Endothelial, Mesangial Cells                                    o    Circulate in Blood
Polymorph Infiltration of Glomerulus                                                     o    Removed, Degraded by Phagocytes in Liver, Spleen
Presence of Humps (on Epithelial Side)                                           Large Complexes
Deposits of IgG, C3 along Capillary Loop (IF) corresponding to Humps                     o    React with CR1 (Complement Receptor for C3b) on RBC
Immunological Features                                                                        Transported to Liver for Degradation
Circulating Immune Complexes Present                                        Failure – Deposition of Immune Complexes, Lead to Activation of MAC (C5b-9)
↓ Serum C3
Prognosis
Worse in Adults




                                                                            Role of Reticuloendothelial System (RES)
                                                                            Major Mechanism for Clearance of Large, Insoluble Complexes
                                                                            Troublesome Complexes (Intermediate Size)
                                                                            Complexes Deposited on Epithelial Side
                                                                            (Proliferative, Membranous Nephritis) (Rapid, Slow Rate)
                                                                            Larger Complexes deposited mainly in Mesangium




                                                                            Diagnosis of Immune Complex Nephritis
Chronic Immune-Complex Nephritis                                                Direct Immunofluorescence, Immune Peroxidase of Kidney Biopsies
Occurs if                                                                       Igs, Complement Deposited in Tubular Basement Membrane, Interstitial
Antigen Exposure Persists                                                        Tissue, Blood Vessels, Glomeruli
Host makes Abnormal Responses                                                   Irregular Granular, Lumpy-Dumpy Pattern of Deposition is Characteristic
Local Factors                                                                   Deposition in GBM, Mesangium
(C3 Receptors, Change in Permeability, Promote Deposition of Complexes)     Treatment
Complexes made ↓ Soluble                                                    Antigen Elimination
                                                                            Removal of Circulating Immune Complex
                                                                            Manipulation of Inflammation Mediators
                                                                            Immunosuppressive Drugs
                                                                            Plasmapheresis
Membranous Glomerulonephritis                                                 IgA Nephropathy (Idiopathic = Berger Disease)
Present with Florid Nephrotic Syndrome (80%)                                  Mesangial Deposition of IgA
Proteinuria, Microscopic Haematuria                                           Male ↑ (Any Age)
30 – 50 y/o (Peak Age)                                                        Discovered as Asymptomatic Microscopic Haematuria
Characteristic                                                                Children – Recurrent Episodes of Haematuria after Respiratory, GIT Infections
Thickening of GBM without Proliferation of Cells                              Clinical
Types                                                                         ↑ Serum Creatinine (in 1/3)
               Idiopathic                          Secondary                  Tubular Injury
  Causal Antigen Never Found            Drugs                                 Obstruction by Red Cell Cast
Complexes Accumulated only on Epithelial Side of GBM                          Progress
(Serum Complement Normal)                                                     End Stage Renal Failure (1/3 of Patients)
                                                                              Poor Prognosis
Membranoproliferative Glomerulonephritis                                      Hypertension
(Persistent Hypocomplementaemia GN)                                           Older Age at Onset
Identified on Basis of Persistently ↓ C3                                      Male
(However, ↓ C3 is not a constant finding) (Clinical Picture not specific)     Persistent Proteinuria
2 Types of MPGN (detected by Electron, Immunofluorescent Microscopy)          Persistent Azotemia
                 Type I                                   Type II             Renal Biopsy – Cellular Crescents, Endocapillary Proliferation, Extension of
                                                                              Immune deposits to Peripheral GLomerular Capillary Walls
  Deposits in Subendothelial Space,      Deposits in Intramembranous
  Mesangium                              (GBM, Mesangium)                     Treatment
                                         Ribbon-like Appearance               Hypertension control
                                                                              Fish Oil (Dietary)
  ↓ C4, C3, CIq                          ↓ C3
                                                                              Immunosuppressive Drugs
                                         Presence of C3 Nephritic Factor
                                         (Ab against C3 Convertase)
                                                                              Henoch-Schoniein Nephritis
                                         (Not a marker of MPGN)
                                                                              Henoch-Schonlein Purpura (HSP)
                                         Strong correlation between Type II
                                                                              Generalized Vasculitis
                                         with Partial Lipodystrophy
                                                                              Involves - Skin (Purpura), Joints, Kidneys, GIT
                                         Treatment
                                                                              Diagnosis
                                         Transplantation (Successful)
                                                                              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)

                                                                              Nephropathies associated with ANCA
                                                                              (ANCA – Anti-Neutrophil Cytoplasmic Antibody)
Anti-GBM Antibody-Mediated Nephritis (Goodpasture Syndrome)                   Renal Involvement (common in Vasculitis)
Rare                                                                                 PAN (Polyarteritis Nodosa)              Wegener Granulomatosus
Etiology – Unknown                                                              Arteries outside Glomerulus             Arteries within the Glomerulus
Type II HSR                                                                     affected                                affected
Include
                                                                              Lesions
Pulmonary Haemorrhage
                                                                              Focal, Segmental Distribution with Fibrinoid Necrosis, Crescent Formation
Rapid Progressive Glomerulonephritis (with Oliguric Renal Failure)
                                                                              Presence of ANCA
(within Weeks → Moths)
                                                                              Strong correlation between Presence of ANCA, Glomerular Involvement in
Clinical
                                                                              Vasculitis (but precise mechanism not understood)
Haematuria, Proteinuria (Gross, Microscopic)
                                                                              Treatment
↓ 24h Creatinine Clearance
                                                                                             Early Phase                       Rapid Progressive GN
↑ Blood Urea
                                                                                Glucocorticoids                         Pulse Methylprednisolone
↑ Serum Creatinine
                                                                                                                        Prednisolone, Cyclophosphamide
Hallmark
     Autoantibodies to Type IV Collagen                                      Plasmapheresis (value not proven)
      (Present in Capillary BM of Kidney, Lung)                                                                            ANCA Test Positivity (%)
                                                                                       Renal Vasculitis
      (Antiglomerular Basement Membrane Antibodies)                                                                    P-ANCA                  C-ANCA
      (Detected in Immunoassays) (Early in Course)                              PAN                                     10-20                   10-20
     Linear Deposition of Immunoglobulin G, C3                                 Microscopic Polyangitis                 50-80                   10-20
Treatment                                                                       Wegener Granulomatosis                  10-20                   80-90
Pulse Methylprednisolone                                                        Necrotizing, Crescentic GN              50-80                   10-20
Cyclophosphamide
Plasma Exchange
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
  Hypocomplementaemia
  ↑ Titre of Anti-DNA Antibodies
Diagnosis
     Serum Complement - ↓ Level Indicate Flares
     Antibodies Detection
     Renal Biopsy
Other Connective Tissue Diseases
Scleroderma (Diffuse Form)
Sjogren Syndrome
Rheumatoid Arthritis