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Glomerular Diseases Prof C V Raghuveer. 21st ,23rd and 27th March 2013 II MBBS Regular Batch Classification • 1. Primary Glomerulonephritis : Glomeruli are primarily involved. • 2. Secondary glomerular diseases: Glomeruli affected secondarily in some systemic diseases. • 3.Hereditary Syndromes: Alports, Fabrys, Nail patella,s Syndromes Primary Glomerulonephritis (1ᴼGN) • • • • • • • • • • • 1 Acute GN. A) Post-streptococcal. B) Non-streptococcal. 2. RPGN. 3. Minimal Change Disease. 4. MGN. 5. MPGN. 6. Focal Proliferative GN. 7. FSGS. 8. IgA Nephropathy. 9. Chronic GN. Secondary/Systemic Glomerular Diseases. • • • • • • • • 1. Lupus Nephritis. 2. Diabetic Nephropathy. 3. Amyloidosis. 4. PAN. 5. Wegeners Granulomatosis. 6. Goodpastures Syndrome. 7. H S Purpura. 8. Systemic Infections e.g, SBE, HBV,HCV,HIV,F.Malaria,Filariasis. • 9. Idiopathic mixed cryoglobulinemia. Hereditary Nephritis • 1. Alports Syndrome. • 2. Fabry,s Disease. • 3. Nail-patella Syndrome. Clinical Manifestations of GN • Clinical manifestation is variable. • Four features in general are seen in different combinations. • 1. Acute Nephritic Syndrome. • 2. Nephrotic Syndrome. • 3. Asymptomatic proteinuria. • 4. Asymptomatic hematuria • 5. A R F. • 6. C R F. Acute Nephritic Syndrome • 1. Hematuria : Smoky urine. • Microscopy RBC+ and casts + • 2. Oliguria. • 3. Hypertension : Mild. • 4. Proteinuria : Mild <3 g/24hrs. Non-selective. • 5. Oedema : Mild- due to Na & H₂O retention. Causes of acute nephritic syndrome I. Primary GN. 1.Acute GN • Acute Post streptococcal GN • Acute non-streptococcal GN. 2.RPGN. 3.MPGN. 4.Focal GN. 5. IgA nephropathy. II Systemic Disease 2ᴼ G N. 1. SLE. 2. PAN 3. W G 4. HS P 5. Cryoglobulinemia. Nephrotic Syndrome • 1. Massive proteinuria. > 3g/24 hrs. • 2. Hypoalbuminemia : 1-3 g/dL (N;3-5g/dL), Reversal of A /G Ratio. • 3.Oedema : generalised (Anasarca) • 4. Hyperlipidemia. • 5. Lipiduria. • 6. Hypercoagulability. Causes of Nephrotic Syndrome. • I.1ᴼ G N. MCD, MGN, MPGN, FSGS, Focal GN, IgA nephropathy. • II. Systemic Diseases. DM, Amyloidiosis, SLE. • III. Systemic infections. HBV,HCV,HIV,SBE,F.malaria,Filaria. • IV. Hypersensitivity. Bee sting. • V. Malignancy. Myeloma. • VI. Pregnancy. Toxemia. • VII. Circulatory disturbances. RVT. • VIII. Hereditary. Alports, Fabrys, Nail patella. Pathogenesis of Glomerular Injury • 1. Immunologic Injury: Most 1ᴼ & some 2ᴼ GN have immunologic pathogenesis. Evidence: deposits of immunoglobulins and complement seen by IF. Mostly antibody mediated “immune complex” some cell mediated, some non-immune, some even by secondary mechanisms. Immunologic Mechanism. • A. Antibody mediated glomerular injury: 1.Immune Complex Disease. Immune complex contains IgG/IgM/IgA and Cᴈ Deposited as irregular/granular deposits by IF. Three areas of deposition: Subendothelial. Subepithelial. Mesangial. How are these immune complexes formed ? • i) Local immune complex deposits: In situ formation due to planted antigens on glomeruli. • Antigens could be : • Brush border antigens-Heyman nephritis -rat model, MGN in humans • Cationic proteins- lectins, DNA, bacterial products ( e.g, a protein of group A streptococci in acute GN ) viral and parasitic products. How are the immune complexes formed ? • ii) Circulating immune complex deposits: • Antigens may be Endogenous- e.g, DNA in SLE. • Exogenous- e.g,HBV, • T.pallidum, • P.falciparum, • Tumors. • Antigen+Antibody complexes formed in circulation, trapped in glomeruli and cause injury after complement activation. Examples for Immune complex glomerular diseases. • • • • • • • Acute diffuse proliferative GN. MGN. MPGN. Ig A Nephropathy. RPGN- some cases. Focal GN. Systemic diseases- SLE, malaria, syphilis,HS purpura etc. Antibody mediated glomerular injury (contd.) • 2. Anti-GBM disease: • Here GBM components act as antigens • E.g, type 4 collagen. • Antibodies are formed against this and they • get deposited as interrupted linear deposits on IF along GBM-Goodpastures syndrome. • Some cases of RPGN. Antibody mediated injury (contd.) • 3. Alternate pathway disease: • Here alternate pathway of complement activation occurs – Cᴈ and properdin get • deposited in glomerulus without immunoglo. • There is a circulating CᴈNeF – an IgG auto antibody to Cᴈ-convertase, leading to persistent alternate pathway activation. • E.g, Type 2 MPGN, RPGN, Acute diffuse GN, IgA nephropathy, SLE. B. Cell Mediated Injury. • Delayed type hypersensitivity. • E.g, pauci immune type 3 RPGN. • Activated T cells ( CD⁴/ CD⁸/NK Cells), release cytokines which injure glomerulus. C. Secondary mechanisms causing glomerular injury. • • • • • • 1. Neutrophils. 2. Mononuclear phagocytes. 3. Complement itself. MAC (C⁵ᵇC⁶⁷⁸⁹) causes injury. 4. Platelets. 5. Mesangial cells. II. Non-immunological mechanisms. • • • • • • 1. Metabolic- DM. 2. Hemodynamic- HT, FSGS. 3. Deposition disease- Amyloidosis. 4. Infections- HBV,HCV,HIV. 5. Drugs- NSAIDs 6. Inherited- Alports, Nail-patellar syndrome. Normal Structure of Glomerulus Normal Glomerulus. E M -Normal Filtration Membrane Normal Glomerulus & Filtration membrane. Immunological Pathogenesis Planted Antigens Acute Diffuse Proliferative GN • 1. Post streptococcal. Following Infection by nephritogenic streptococci. 12, 4, 1 & Group A β-hemolytic streptococci. • Immune complex disease. • Clinically Nephritic Syndrome. • 2. Non-streptococcal. • Following infection by other bacteria, viruses, parasites. Clinical Features and Lab findings • Children• Sudden onset. • Past H/O sore throat/skin infection. • Acute Nephritic Syndrome • • • • • Urine- smoky. RBCs and RBC casts + Mild non selective proteinuria. S G high. Pathogenesis of Acute GN • Glomerular lesions are due to immune complex deposition. • Evidences: • Strep.inf 1-2 wks before. • Latent period to build antibodies. • Elevated ASO, DNase,ASkinase. • Hypocomplimentemia. • Antigenic component- endostreptosin can be identified. Morphology. • Gross: Both kidneys enlarged. • Cortex- petechial spots.(Flea bitten) Normal Glomerulus Acute G N Light microscopy. E M Sub-epithelial hump granular I F Prognosis • Excellent 95 % recover on their own. • 5 % may get complications: • RPGN, Chronic GN, Uremia, CRF. R P G N (Crescentic G N ) • Presents with acute reduction in Renal Function – ARF. • Characterised by crescents due to parietal epithelial cell proliferation • Caused by fibrin deposition in Bowmans space. • Common in adults • Slight male predominance. Aetipathogenesis • • • • Based on aetiopathogenesis 3 types of RPGN . 1.RPGN-seen in systemic disease( anti-GBM type) 2.Post-infectious RPGN( Immune complex type) 3.Pauci- immune RPGN. • 3 serologic markers are seen in above. • 1) anti-GBM antibody. • 2)serum C3. • 3) ANCA Type-1 RPGN- Anti-GBM disease. • Systemic diseases which produce RPGN due to anti-GBM pathogenesis : • Goodpastures syndrome- classic example • SLE vasculitis. • Wegeners granulomatosis. • H S purpura. • Idiopathic mixed cryoglobulinemia. Goodpastures Syndrome • • • • • • • Produces RPGN , presents with ARF. Common in males 3rd decade. Damage to GBM by anti-GBM antibodies which cross-react with alveolar BM. RPGN + Pulmonary hemorrhages occur Linear deposits of IgG+ Complement along GBM Goodpastures :antigen appears to be collagen-4 RPGN R P G N- IF : Type -1 on the right, crescent on the left Anti-GBM Disease Type-2 RPGN. Immune Complex Disease • A few post-streptococcal acute GN in adults • develop RPGN, as a complication. • Show granular IF of IgG and C3 along capillary walls. Type-3 RPGN- Pauci immune RPGN. • A few cases of Wegeners granulomatosis,PAN • develop RPGN . • They are ANCA +, implying defect in humoral immunity • Serum complement is normal, no immune deposits seen in glomeruli. • Anti-GBM antibody is negative. Morphology of RPGN • • • • • • • • Gross : Kidneys are large pale. C/S pale cortex and congested medulla. LM: Glomeruli –Hypercellular, Crescent formation+ Fibrin deposition along the crescents. Tubules-hyaline droplets, casts, RBCs, fibrin. Interstitium- oedema, fibrosis, LC and PC. Vessels- no changes. IF in RPGN. • Linear pattern in Type-1 RPGN. • Granular pattern in Type-2 • No pattern in Type-3.. Clinical features of RPGN • Acute GN with ARF. • Type-1 present with ARF and pulmonary bleed • Prognosis is uniformly bad. Minimal Change Disease. (Lipoid Nephrosis) • Presents as Nephrotic Syndrome. • L M :No apparent change in glomeruli. • Accounts for 80 % cases of N S in children < 16yrs. • More in boys. Aetiopathogenesis of MCD • 1. Idiopathic in majority cases. • 2. Some associated with HD, HIV, NSAID , Rifampicin, interferon etc.. • Evidences for Possible immune mechanism : • Presence of circulating immune complexes in • some cases. • Response to corticosteroids. • Increased suppressor T-cell activity- IL 8 released causes foot process flattening and loss of charge. Clinical features of MCD • • • • N S in children- selective massive proteinuria. No hypertension. Past H/O- URI/ atopic allergy/ immunisation + In adults with NS- non selective proteinuria. Morphology of MCD • • • • • L M : no apparent changes in glomeruli. Tubules- fine lipid droplets. E M- fusion of foot processes. IF- no deposits. Disease responds to corticosteroids EM- Morphology Normal & MCD Prognosis of MCD • Mostly patients are children < 16yrs. • Respond to corticosteroids. • Remissions may be there, but overall prognosis is excellent. Quiz -1 • An 8 yrs old boy brought to Paediatrics OPD with H/O having passed high colored small quantity of urine past 2 days. • The boy is tired. Past H/O itching skin lesions which started oozing about a month back. • Urine examined microscopically and pt. admitted after noting his BP & some blood chemistry tests. • Unfortunately the pt. took 6 weeks to recover necessitating kidney biopsy. • Eventually there was good recovered. Quiz -1 What is your diagnpsis? What is the IF pattern in this condition ? Quiz -2 • A 10 yrs old boy admitted for persistent hypertension of 1 week duration after having had “some kidney problem” according to the mother. His urine showed RBC casts and protein. His serum creatinine was mounting. • He had to be admitted and evaluated. Quiz -2.What is your diagnosis ? What is the EM appearance ? QUIZ-3 • A 10 YRS OLD GIRL PRESENTED WITH GENERALISED OEDEMA OF 2 WEEKS DURATION. SHE WAS VACCINATED ABOUT 4 WEEKS BACK. • SHE WAS ADMITTED AND GIVEN STEROIDS TO WHICH SHE RESPONDED WELL. • RENAL BIOPSY HAD TO BE DONE. Quiz-3.What is your diagnosis ? MGN • Widespread thickening of capillary wall. • Most common cause of Nephrotic Syndrome in adults. • 85 % cases-MGN is truly idiopathic. • 15 % cases-secondary to underlying cause • E.g, SLE, Malignant tumors, HBV, HCV, Syphilis • Malaria, drugs. Aetiopathogenesis of MGN • Idiopathic MGN is due to in situ immune complex • No neutrophilic infiltrate. • Damage to GBM is by MAC (C⁵ᵇC⁶⁷⁸⁹) • Secondary MGN due to circulating immune • complexes due to endogenous(e.g,DNA in SLE) • antigens or exogenous antigens (HBV, Tumor antigen, T.pallidum,drugs) Morphology of MGN • L M: • Glomeruli –diffuse capillary wall thickening. • Spike & Dome appearance-best seen by silver stains or PAS. • No cellular proliferations. Morphology of MGN • E M -Immune deposits occur in subepithelial region • In between deposits BM material protrudes• SPIKE AND DOME APPEARANCE. • IF- granular deposits of IgG and C3. • In secondary MGN particular antigen like HBV • can be demonstrated. Morphology of MGN- LM Morphology of MGN Clinical Features of MGN • • • • • • • Insidious onset of N S. Proteinuria of non-selective type. Microscopic hematuria & HT may be seen. Changes in MGN are irreversible in majority. 50 % cases go for Impaired renal function--Azotemia---ESRD in 2-20 years. Renal vein thrombosis occurs in many cases. MPGN • Another imp cause of NS in young adults & children. • Characterised by increased cellularity,irregular • thickening of capillary wall & lobulation. Aetiopathogenesis of MPGN • • • • Aetiology is largely unknown, but past H/O streptococcal infection, in many cases. Based on EM,IF & pathogenesis 3 types: Type-1: Comprises > 70 % cases. Classic form. Immune complex disease. • Immune deposits in subendothelial space • Seen in association with SLE, Sjogrens, • SBE,HIV,HBV, HCV, NHL, leukemias. Aetiopathogenesis of MPGN • Type -2 /Dense Deposit Disease ( 30 % cases) is due to activation of alternate pathway of complement activation. • Capillary wall is thickened due to immune deposits in the lamina densa of GBM. • It is an autoimmune disease with IgG auto antibody Aetiopathogenesis of MPGN • Type-3 : is rare and shows features of Type-1 MPGN and MGN in association with systemic diseases or drugs. Morphology of MPGN • LM: • Glomeruli enlarged due to proliferation of mesangial cells and increased matrix, with lobular accentuation. • GBM markedly thickened. • Silver stain- “double contour”/Split/ Tram track BM. • Tubules : vacuolation & hyaline droplets. Morphology of MPGN • EM: • Type- 1 : Electron dense deposits of C3 and IgG in subendothelial location. • Type-2 : Deposits in lamina densa of GBM & in mesangium. • IF : C3 and properdin in granular patern. • Immunoglobulins absent. • Type-3 : Deposits within GBM, sub endothelial • and sub epithelial locations. • IF : IgG, IgM, C3. Morphology of MPGN Type – 1 Morphology of Type -1 MPGN MPGN-EM Morphology Type-2 MPGN. Dense Deposit Disease Clinical Features of MPGN • • • • • • • • Common between 15 & 20 yrs 50 % pts present with Nephrotic Syndrome. 30 % with asymptomatic proteinuria. 20 % with Nephritic Syndrome. Proteinuria is non-selective. Hematuria and Hypertension common. Hypocomplementemia common. Prognosis not good. Majority go to CRF. FSGS • • • • • Sclerosis and hyalinosis- focal & segmental. Involvement of some glomeruli & portions of glomeruli. 3 types: 1. Idiopathic: Children, NS, non-selective proteinuria, steroid resisitant, progress to CRF. • IF: C3 and IgM in the sclerosed part. FSGS • 2. With superimposed primary GN : FSGS with superimposed MCD or IgA nephropathy.Good response to C’steroids. CRF late. • 3. Secondary type- FSGS secondary to diseases like HIV, analgesic nephropathy. FSGS Morphology • LM: Focal and segmental sclerosis. • Homogenous PAS + material. • Mesangial hypercellularity. FSGS Morphology H & E, Trichrome Stains IgA Nephropathy • • • • • • Aggregates of IgA in mesangium. C3 and properdin + Alternate pathway of complement activation + Association with GIT and respiratory infection. LM: Looks like FSGS, MPGN and even RPGN. IF: Deposits of IgA, C3 and properdin in mesangium. IgA Nephropathy IF : Mesangial IgA, properdin & C3 Ig A Nephropathy