GLOMERULONEPHRITIS:What is New

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GLOMERULONEPHRITIS:What is New

  1. 1. GLOMERULONEPHRITIS: What is New Mohamed Hany Hafez Professor of Medicine & Nephrology Cairo University
  2. 2. Basic Structural Patterns of Glomerular Injury
  3. 3. CLASSIFICATION OF GLOMERULAR DISEASES ( H.Rennke,Nephrol fr.Bench to bedside,Boston,Feb 1999 and GN update:Diagnosis &therapy,Postgraduate course, St Louis ,ASN,October 2004) <ul><li>CLINICAL SYNDROMES </li></ul><ul><li>I) NEPHROTIC SYND </li></ul><ul><li>(1, 2, 3) </li></ul><ul><li>II) ACUTE NEPHRITIC Sy </li></ul><ul><li>(4, 5 ) </li></ul><ul><li>III) RAPIDLY PROGRESSIVE GN (6) </li></ul><ul><li>IV)Asymptomatic Proteinuria /hematuria </li></ul><ul><li>(7, 8, 9 ) </li></ul><ul><li>V)CHRONIC </li></ul><ul><li>NEPHRITIC syndrome (10) </li></ul><ul><li>Basic STRUCTURAL PATTERNS OF GLOMERULAR INJURY </li></ul><ul><li>1)Epithelial cell Disease </li></ul><ul><li>2)Focal Segmental Glomeruloscl. </li></ul><ul><li>3)Membranous Nephropathy </li></ul><ul><li>4)Diffuse Proliferative GN (exudative) </li></ul><ul><li>5)Membranoproliferative GN </li></ul><ul><li>6)Crescentic GN </li></ul><ul><li>7)Mesangial Proliferative GN </li></ul><ul><li>8)Focal Proliferative GN (necrotizing) </li></ul><ul><li>9)Basement membrane abnormalities </li></ul><ul><li>10)Focal Global glomerulosclerosis </li></ul>
  4. 4. OVERVIEW <ul><li>More pathological insight &New Classifications </li></ul><ul><li>New terms & Etiologies:C1Q nephropathy,Drug induced(inerferon), Hereditary (eg type III collagen glomerulopathy </li></ul><ul><li>Fibrillary GN update (eg Fibronectin GN) </li></ul><ul><li>VASCULITIS:update </li></ul>Expression of thousands of Genes on GeneChip probe array
  5. 5. MOLECULAR ORGANIZATION
  6. 6. Apical Lateral Basal
  7. 7. ACTIN & SYNAPTOPODIN
  8. 8. Schematic representation of podocyte dysfunction caused by protein overload in chronic nephropathies - A Schieppati and G Remuzzi KI 64:1523, 2003 PODOCYTE DYSFUNCTION
  9. 9. ?Primary role of podocytes in diabetic nephropathy <ul><li>Podocytes shed in urine of albuminuric </li></ul><ul><li>but not non-albuminuric pts with diabetes </li></ul><ul><li>Podocyte numbers reduced in type I DM </li></ul><ul><li>and in Pima Indians with type II diabetes </li></ul>Nakamura et al, NDT 2000;15:1379 Steffes et al, KI 2001 ;59:2104 Meyer et al, Diabetologia 1999;42:1341 <ul><li>Podocyte number is a better early predictor of </li></ul><ul><li>prognosis in diabetic nephropathy than GBM </li></ul><ul><li>thickness or any other morphological feature </li></ul>
  10. 10. ?Primary role of podocytes in diabetic nephropathy <ul><li>Podocytes lost in the urine in diabetes remain </li></ul><ul><li>viable: why do they detach ? </li></ul><ul><li> Vogelmann et al, Am J Physiol 2003; 285: F40-8 </li></ul><ul><li>Podocyte numbers in urine reduced in diabetic </li></ul><ul><li>nephropathy patients by ACE inhibitors </li></ul><ul><li> Gross et al, Diabetologia 2003; 46: 856-868 </li></ul><ul><li>and by pioglitazone </li></ul><ul><li> Vogelmann et al, Am J Physiol 2003; 285: F40-8 </li></ul>Both agents reduce albuminuria, pioglitazone abrogates insulin-resistance
  11. 11. Persistent Trend 1(1999) 2 3 4 5
  12. 12. 2002 ISN & Renal Pathological Society (RPS) consensus conference on the classification of lupus nephritis <ul><li>Class I : Minimal mesangial lupus Glomerulonephritis </li></ul><ul><li>Class II : Mesangial Proliferative LGN </li></ul><ul><li>Class III: Focal LGN (involving <50% of glomeruli) </li></ul><ul><li>Class IV: Diffuse LGN (involving >50% of glomeruli) </li></ul><ul><li>Class V: Membranous LGN </li></ul><ul><li>Class VI:Advanced Sclerotic LGN(>90% sclerotic glomeruli) </li></ul><ul><li>(Charles Jennette,An SLE update, ASN SanDiego,Nov 2003) </li></ul>
  13. 13. 2002 ISN & Renal Pathological Society (RPS) consensus conference on the classification of lupus nephritis <ul><li>NB *for classes III & IV the diagnosis should include one of the following: with active lesions/ with active &chronic lesions/ inactive with scars </li></ul><ul><li>*for classes III & IV the diagnosis should include the percentage of glomeruli with fibrinoid necrosis&/or cellular crescents when present. </li></ul><ul><li>*For class IV the diagnosis should include one of the following:predominantly segmental (IV-S) ,predominantly global (IV-G) </li></ul><ul><li>* Class V may occur in combination with III or IV in which case both will be diagnosed </li></ul>(Charles Jennette,An SLE update,ASN 2003)
  14. 14. Infectious Agents Associated with immune complex GN <ul><li>BACTERIAL </li></ul><ul><li>VIRAL </li></ul><ul><li>PARASITIC </li></ul><ul><li>RICKETTSIAL </li></ul><ul><li>FUNGAL </li></ul>INTERACTION
  15. 15. Shistosomal GLomerulopathy Lesions (BARSOUM, Semin. Nephrol.23(1):34,2003) <ul><li>Class I :Mesangioproliferative(LM), mesangial &subendothelial IgM,C3 </li></ul><ul><li>Class II :Exudative,with monocytes &neutrophils infiltration (+ salmonella) </li></ul><ul><li>Class III : Mesangiocapillary & diffuse proliferative with Cryog in HCV positive,Ig A by IF (in >50%) </li></ul><ul><li>Class IV :FSG(LM),Ig A(in >50%), Amyloid deposits(AA)in 15%. </li></ul><ul><li>MORE RECENTLY 6 Classes (KI,2004) </li></ul>
  16. 16. NYC Consensensus Conference on FSGS The Light Microscopy Patterns (D’Agati V.Seminars in Nephrology 23:117-134,2003 <ul><li>FSGS not otherwise Specified </li></ul><ul><li>Perihilar Variant </li></ul><ul><li>Cellular Variant </li></ul><ul><li>Tip Variant </li></ul><ul><li>Collapsing Variant </li></ul>
  17. 17. “ Pathogenic”Classification of FSGS (Stephen Korbet,ASN,St Louis,2004) <ul><li>Primary alteration of G.Epithelial Cell *Primary FSGS *HIV-associated Nephropathy *Heroin-associated Nephropathy(toxic) *Pamidronate(toxic) *Familial FSGS (inherited) *Sporadic Genetic Mutations (inherited) </li></ul><ul><li>Reduced Nephron mass/Glomerular adaptation : *Obesity related Glomerulopathy (an emerging epidemic) </li></ul><ul><li>2ry to basement membrane defects </li></ul><ul><li>2ry to Focal Proliferative glomerulonephritis </li></ul>
  18. 18. NYC Consensensus Conference on FSGS(cont..) (D’Agati V.Seminars in Nephrology 23:117-134,2003 <ul><li>2ry FSGS (adaptive structural &functional response): </li></ul><ul><li>* Reduced Renal Mass : oligomeganephronia,unilat.reflux agenesis,reflux nephropathy,sequela to cortical necrosis,surgical renal ablation,chronic allograft nephropathy </li></ul><ul><li>* Initially normal renal mass : DM,HTN,obesity,cyanotic congenital Heart D,Sickle cell anemia </li></ul><ul><li>NonSpecific pattern of FSGS caused by renal Scarring: Focal proliferative GN(IgA,SLE,pauciimmune Cresc), Hereditary Nephritis- Diabetic Nephropathy- Hypertensive arterionephrosclerosis –Membranous Glomer. Thrombotic angiopathies </li></ul>
  19. 19. NYC Consensensus Conference on FSGS (D’Agati V.Seminars in Nephrology 23:117-134,2003 <ul><li>Primary(idiopathic)FSGS </li></ul><ul><li>C1q nephropathy </li></ul><ul><li>HIV-associated nephropathy </li></ul><ul><li>Heroin nephropathy </li></ul><ul><li>Familial FSGS (alpha-actinin ,podocin, mitochondrial cytopathies) </li></ul><ul><li>Drug toxicity (Pamidronate,lithium, interfero-alpha) </li></ul>
  20. 20. WHY VARIABLE RESPONSE TO STEROIDS IN GN?
  21. 21. GENOMICS - PROTEOMICS
  22. 22. SDS-PAGE (sodium dodecyl sulphate- Polyacrylamide Gel electrophoresis
  23. 23. 6 proteins of podocytes alered by steroids (3days incubation)
  24. 24. 6 proteins of podocytes alered by steroids (3days incubation)
  25. 25. 3 proteins with known role in protecting cell from injury were upregulated quantitativly by western blotting (ciliary neutrophilic factor,aB crystallin,heat Shock Pr.27)
  26. 26. 3
  27. 27. OVERVIEW <ul><li>More pathological insight &New Classifications </li></ul><ul><li>New terms & Etiologies:C1Q nephropathy, Hereditary (eg type III collagen glomerulopathy Drug induced (inerferon) </li></ul><ul><li>Fibrillary GN update (eg Fibronectin GN) </li></ul><ul><li>VASCULTIS update </li></ul>
  28. 28. C1Q Nephropathy <ul><li>Variant of Minimal/FGS in which “ C1q deposits” in IF & mesangial deposits in EM </li></ul><ul><li>Young black males Present with hematuria,asymptomatic proteinuria, or nephrotic </li></ul><ul><li>Most patients steropid-resistant or dependent </li></ul><ul><li>Reports suggesting benefit of pulse steroids </li></ul><ul><li>Effect of cytotoxic remains to be defined </li></ul><ul><li>Progression to renal failure more likely in patients with heavy proteinuria & high S.creatinine </li></ul>
  29. 29. Electron microscopy gave important data in Hereditary diseases <ul><li>Congenital nephrosis & Fanconi: Swan neck deformity &Dilat.of proximal Tubules </li></ul><ul><li>Alport’s syndrome: Split lamina densa and lamina propria of Glom.basement membrane. </li></ul><ul><li>Medullary cystic disease: cystic dilatation of corticomedullary junction. </li></ul><ul><li>Medullary sponge Kidneys and infantile PKD: dilatation of collecting ducts </li></ul>Hereditary Nephritis
  30. 30. a-Actinin-4 19q13:Familial FSGS AD NEPHRIN : 19q13.1:The congenital Nephrotic Syndrome AR PODOCIN 1q25-q31:Familial & Sporadic SRNS &FSGS AR
  31. 31. HEREDITARY Forms Of Minimal Change Disease & FGS <ul><li>Nephrin (Congenital nephrotic S) </li></ul><ul><li>Podocin(Familial Minimal ch/FSGS) </li></ul><ul><li>Alpha actinin 4 (familial FGS) </li></ul><ul><li>Lysosomal Storage Disease (alpha-galactosidase(Fabry)& Sialidase </li></ul><ul><li>Charcot-Marie-Tooth disease </li></ul><ul><li>B4-Integrin Mutation (epidermolysis bullosa & congenital FSGS) </li></ul><ul><li>Various Collagen IV proteins(inherited Basement membrane defects) </li></ul>
  32. 32. X-linked Alport Syndrome COL4A5 INHERITED BASEMENT MEMBRANE DEFECTS (present with proteinuria,Familial FSGS,or Renal Failure) Autosomal Recessive Hereditary Nephritis COL4 A3 COL4A4 Thin Basement Membrane Disease COL4A4
  33. 33. Type III Collagen Glomerulopathy <ul><li>New type of Hereditary nephropathy distinct from nail-patella syndrome </li></ul><ul><li>Autosomal recessive inheritance </li></ul><ul><li>Marked mesangial & subendothelial fibrillar type III collagen accumulation (collagenofibrotic glomerulopathy) </li></ul><ul><li>Systemic massive peculiar collagen fiber accumulation in kidney(ESRD), spleen,liver,myocardium & thyroid in case reports </li></ul>
  34. 34. HCV-associated GN <ul><li>Cryoglobulinemia </li></ul><ul><li>(Type II and III) </li></ul><ul><li>Membranoproliferative GN </li></ul><ul><li>type 1 </li></ul><ul><li>Membranous GN </li></ul><ul><li>others </li></ul><ul><li>-Diffuse proliferative GN </li></ul><ul><li>-Focal segmental GS </li></ul>
  35. 35. Pathophysiology of HCV glomerulopathy associated with cryoglobulins <ul><li>1)Deposition of AgAb complexes in small & medium sized arteries </li></ul><ul><li>2) HCV RNA may serve as the inciting agent, since found in cryoprecipitate </li></ul><ul><li>3)Ag released from damaged hepatocytes or by activated Kupffer contribute to Ab formation </li></ul><ul><li>4)Decrease clearance of Cryos due to hepatic dysfunction promote Cryos accumulation in circulation,then tissue depositionProof:HCV associated cryo majority have liver disease(CAH 35%,Cirrhosis 28%,CPH 17%) Dammaco,Blood84:3336,1994 </li></ul>
  36. 36. HCV associated MPGN <ul><li>Cryogloglobulinemia 76% </li></ul><ul><li>Low CH50 90% </li></ul><ul><li>Low C3 48% </li></ul><ul><li>Low C4 69% </li></ul><ul><li>Rheumatoid factor 72% </li></ul><ul><li>Nephrotic Syndrome 71% </li></ul><ul><li>Elevated ALT 68% </li></ul><ul><li>From study on 34 patients Johnson,Kid Int 46:1700,1994 </li></ul>
  37. 37. HCV associated membranous <ul><li>Less Common </li></ul><ul><li>Cryoglobulinemia absent </li></ul><ul><li>Mormal complement levels </li></ul><ul><li>Liver disease mild </li></ul><ul><li>Periera,Harvard CME,1999 </li></ul>
  38. 38. 6 cases
  39. 39. INTERFERON <ul><li>Alfa Interferon </li></ul><ul><li>(formerly was leucocyte IFN,Beta was fibroblastat,Gamma was immune) </li></ul><ul><li>Mechanism of action : </li></ul><ul><li>directly antiviral to HCV </li></ul>
  40. 40. Can Interferon induce GN? <ul><li>Interferon alfa may induce or exacerbate GN in some patients with chronic HCV infection </li></ul><ul><li>The clinical & pathological features of this phenomenon was evaluated in a series of 23 patients with chronic HCV infection </li></ul><ul><li>The appearance &/or worsening of proteinuria soon after the administration of Interferon alfa was evaluated </li></ul>
  41. 41. Can Interferon Induce GN? <ul><li>Proteinuria (mean 2.1 g/day) began approximately 12 days after ttt started </li></ul><ul><li>11 patients underwent renal biopsy : </li></ul><ul><li>9 patients mesangioproliferative GN </li></ul><ul><li>1 patient membranoproliferative GN </li></ul><ul><li>1 patient glomerulosclerosis </li></ul>
  42. 42. ( interferon can induce GN!) <ul><li>9 patients in whom immunofluorescence was performed had IgG,IgA & compl. in the glomeruli with only trace HCV core antigen deposition in three </li></ul><ul><li>Proteinuria cleared in almost all patients one month after the discontinuation of therapy </li></ul><ul><li>( Yokoyama et al, Am J Kid.Dis.,1999) </li></ul>
  43. 43. OVERVIEW <ul><li>More pathological insight &New Classifications </li></ul><ul><li>New terms & Etiologies:C1Q nephropathy,Drug induced(inerferon), Hereditary (eg type III collagen glomerulopathy) </li></ul><ul><li>Fibrillary GN update (eg Fibronectin GN) </li></ul><ul><li>VASCULITIS:update </li></ul>
  44. 44. Prevalence of Dysproteinemias 1 % 0.4 % Fibrillary-ITC 0.1 % 0.4 % 0.2 % MIDD 0.3 % 0.3 % 0.9 % Amyloid (AL) 357051 4689 556 Number USRDS 1999 Vanderbilt 1986-99(Fogo) RushPresbyterian 1989-99(Korbet) Lesion
  45. 45. FIBRILLARY GLOMERULOPATHIES Diseases Defined by organized deposits comprised of extracellular, non-branching, elongated microtubules or microfibrils without periodicity and range from 8 to 60 nm in diameter (Stephen Korbet, ASN ,Philad.,Nov.2002) Differential Diagnosis is important because these rare diseases have different therapeutic &Prognostic implications GREAT MIMICKER IN CLINICAL NEPHROLOGY
  46. 46. FIBRILS SIZE(nm)
  47. 47. ِِ Microtubule By High power Randomly oriented Fibrils 8-10 nm (beta fibrilosis)
  48. 48. CONGO RED AMYLOID POSITIVE FIBRILLARY GLOMERULOPATHIES
  49. 49. AMYLOIDOSIS <ul><li>INCIDENCE 5-12 patients per million /year </li></ul><ul><li>In USA , Mayo Clinic Series ( Kyle ,Adv in Nephrol,1998) Renal Involvement is the most common manifestation(80-90%) in 1ry & 2ryAmyloidosis , It is rare in familial . </li></ul><ul><li>15 different types of amyloid identified &named according to the precursor protein. </li></ul><ul><li>focus onThe Common AL Amyloidosis </li></ul>2 ,,,,,,,, Asc Senile 3.5 Trans thyretin AF Familial 8 Light chain AL localized 3.5 Prot. A AA 2ry 83 Light Chain AL 1ry % Subunit protein Am. type Class
  50. 50. DIAGNOSIS of 1ry amyloidosis <ul><li>Depends on histologic demonstration OF AMYLOID in tissue </li></ul><ul><li>Renal biopsy is diagnostic in >95% of patients with clinical evidence of renal disease. </li></ul><ul><li>SC Fat aspirate and bone marrow give positive diagnosis in 90% . </li></ul>
  51. 51. DIAGNOSIS of amyloidosis <ul><li>Proteinuria,high CRP,Polyclonal hypergammaglobulinemia,Elevated SAA (serum amyloid A protein) </li></ul><ul><li>Radiolabelled SAP scanning </li></ul><ul><li>Immunohistochemistry staining with specific monoclonal anti-amyloid A antibodies. </li></ul>
  52. 52. TREATMENT STRATEGIES <ul><li>Colchicine is thought to interfere with fibril formation and is good in FMF ,it could be continued for long periods . </li></ul><ul><li>A recent randomized trial compared colchicine therapy alone(o.6mg BID),with colchicine plus melphalan (total dose is 600mg to avoid myledysplasia or Leukemia) &prednisone showed increased survival from 6.7 to 12.2 months in later group supporting use of chemotherapy in AL-amyloidosis not associated with multiple myeloma </li></ul><ul><li>However,The overall survival for patients whose 1ry manifestation was renal disease is 16 months </li></ul><ul><li>40% reduction of proteinuria &improvement in renal function in nephrotics with normal serum creatinine(with prednisone&melphalan),but 15% response in nephrotics with renal insuff. </li></ul>
  53. 53. Light chain Related Renal Lesions (every compartment of Kidney can be damaged from monoclonal light chain deposition) <ul><li>1)GLOMERULOPATHIES Light Chain Deposition Disease(LCDD) AL-amyloidosis Cryoglobulinemia Fibrillary GN Immunotactoid GN </li></ul><ul><li>2)TUBULOINTERSTITIAL LESIONS Cast nephropathy(“myeloma kidney) Fanconi Syndrome Proximal tubule injury (acute tubular necrosis) Tubulointerstitial nephritis(rare) </li></ul>
  54. 54. Light Chain Related Renal Lesions(Cont..) <ul><li>3)VASCULAR LESIONS </li></ul><ul><li>4)ASYMPTOMATIC : Bence Jones Proteinuria: -----60----------------100 c (William Macintyre Then Henry Bence Jones in 1847) which represent Ig light chains Causes: MM 65%-Al Amyloidosis 20% LCDD (raarely HCD)-Waldenstrom macroglobulinemia-monoclonal gammopathy of undetermined significance- Lymphoprolif D-rifampicin therapy Q: normal free light chain in urine2.5ug/ml 20-50ug/ml monoc of undetermined 0.02-12 mg/ml in MM & Waldenstrom </li></ul><ul><li>5)HYPERVISCOSITY SYNDROME (more with Waldenstrom in which monoclonal lymphocytoid plasma cells secrete IgM (macroglobulin) 60-70y,Neurol,Visual,bleeding Diath,RF ttt:Chlorambucil &plasmapheresis) </li></ul><ul><li>6)NEOPLASTIC CELL iNFILTRATION(rare ) </li></ul>(Sanders PW,1998
  55. 55. Non Amyloid Monoclonal Immunoglobulin Deposition Disease (MIDD) <ul><li>B-cell proliferative disorder resulting in disease from deposition of monoclonal Ig in major organs : Renal 100% Cardiac 45-80% Liver 25-80% Neurol.15-20% </li></ul><ul><li>Renal disease is often the earliest manifestation. - Proteinuria more than 90% (nephrotic 30-50%) -Renal insufficiency > 60% -urine/serum monoclonal protein 80% </li></ul>
  56. 56. Monoclonal Immunoglobulin Deposition Disease (MIDD) Diagnosis is Made by Immunofluorescence , interesting that it is in the tubules (Kappa light chains mainly,possibly Heavy Chain deposition or Both Light & Heavy)
  57. 57. Non Amyloid Monoclonal Immunoglobulin Deposition Disease (MIDD) <ul><li>(In 20-35% no Ig detected by immunoelectrophoresis of serum or urine,but BM study demonstrate excess production of abnormal Immunoglobulin) -Kappa light chain 70% (Lambda in 20%,Both Light and Heavy chain deposits in < 10% ,recently,few pts with heavy chain deposition disease ). </li></ul><ul><li>Lymphoplasmacytic disorders as myloma present in 40-70% of cases </li></ul><ul><li>Age 55y(30-80y) </li></ul>
  58. 58. FIBRILLARY –IMMUNOTACTOID GLOMERULOPATHY BY DEFINITION THE FIBRILLARY DEPOSITS DO NOT STAIN WITH CONGO RED OR THIOFLAVIN T (thus distinguishing them from amyloid fibrils), AND ARE OBSERVED IN ABSENCE OF CIRCULATING CRYOGLOBULINS OR PARAPROTEINS (Brady HR,1998)
  59. 59. FIBRILLARY-IMMUNOTACTOID GLOMERULOPATHY:NOT DETECTED BY CLINICAL DATA <ul><li>* EM (F<=30nm,random </li></ul><ul><li>IT>30nm,focal organizat) </li></ul><ul><li>* Don’t stain with congo red (DD amyloid),and observed in absence of cryoglobulins or paraproteins </li></ul><ul><li>* 1% of renal biopsies </li></ul><ul><li>* Assoc :Monoclonal Gammopathy,CLL, lymphomas,GIT cancer </li></ul><ul><li>Mixed connective tissue </li></ul>FIBRILLARY GN
  60. 60. Progression to ESRD <ul><li>40-50% develop ESRD within 2-6 years </li></ul><ul><li>Prognosis suggested to be better in immunotactoid than fibrillary </li></ul><ul><li>Fogo A, Qureshi N,Horn RG Morphologic &Clinical features of fibrillary vs Immunotactoid GN,AJKD,22:367,1993 </li></ul>
  61. 61. NO PROVEN EFFECTIVE TTT <ul><li>16 patients ttt with prednisone &/or cyclophosphamide:14 No response </li></ul><ul><li>Crescentic GN:Pulse MP then Cyclophosphamide and steroids </li></ul><ul><li>Membranous cases benefit from cyclosporin </li></ul><ul><li>Successful ttt of underlying disease as CLL leads to improved renal function &reduced proteinuria </li></ul><ul><li>Chronic colchicine therapy not effective </li></ul>
  62. 62. Immunotactoid-Fibrillary FIBRILLARY Fibronectin deposition IMMUNOTACTOID (Ig content+Tactoid Spindle shape body in EM)
  63. 63. Should patients with fibrillary-immunotactoid be subclassified? <ul><li>NO :-Clinical presentation is similar whether fibrils are less or more than 30 nm -Incidence of malignancy similar -Pathogenesis is unknown “IT WOULD BE FOLLY TO SUBCLASSIFY” (Brady,Kidney Int,1998) </li></ul><ul><li>YES -Prognosis different(Immunotactoid have better )(Fogo et al,AJKD,93) </li></ul><ul><li> -Third variant described:Fibronectin deposition,not immunoglobulin deposit usually hereditary due to ? Deficient uteroglobin gene (Appel G,2001) </li></ul>
  64. 64. FIBRONECTIN GlOMERULOPATHY (Agnes Fogo,ASN,St Louis,2004) <ul><li>Considered hereditary ,with gene disorder </li></ul><ul><li>at locus 1q32 associated with uteroglobin deficiency (This protein normally binds fibronectin) </li></ul><ul><li>Presents in early adolescence </li></ul><ul><li>Congo red negative fibrils 12 nm </li></ul><ul><li>Always limited to kidney </li></ul><ul><li>(2 case reports of alveolar Hge and BM deposition) </li></ul><ul><li>Proteinuria(30%nephrotic),hematuria(50%),stable or slowly decreasing renal function </li></ul><ul><li>Glomeruli show membranoproliferative like features by LM, </li></ul><ul><li>with granular fibronectin deposits by EM </li></ul><ul><li>Can recurr in transplantation </li></ul>
  65. 65. OVERVIEW <ul><li>More pathological insight &New Classifications </li></ul><ul><li>New terms & Etiologies:C1Q nephropathy,Drug induced(inerferon), Hereditary (eg type III collagen glomerulopathy) </li></ul><ul><li>Fibrillary GN update (eg Fibronectin GN) </li></ul><ul><li>VASCULITIS:update </li></ul>
  66. 66. The Serologic Analysis of Patients with Glomerulonephritis C3 nephritic factor serologic analysis anti-neutrophil cytoplasmic autoantibodies (ANCA) anti-glomerular basement membrane (GBM) autoantibodies immune complex disease markers no extra- renal disease Systemic necrotizing vasculitis Respiratory necrotizing granulomas Asthma and eosinophilia no lung hemorrhage Lung hemorrhage anti- nuclear antibodies anti- pathogen antibodies IgA- fibronectin aggregates Cryo- globulins ANCA- associated crescentic GN Microscopic poly- arteritis Wegener’s granulo- matosis Churg- Strauss syndrome anti-GBM GN Goodpasture's syndrome Lupus GN Postinfectious or peri- infectious GN IgA nephro- pathy Cryoglobu- linemic GN Membrano- proliferative GN ANCA GN anti-GBM GN immune complex GN glomerulonephritis (GN) + + +
  67. 67. URINARY MCP-1 <ul><li>Urinary monocyte chemoattractant protein-1 is a new marker of active renal vasculitis </li></ul><ul><li>Rising titer of ANCA </li></ul><ul><li>CRP </li></ul><ul><li>Serial biopsy </li></ul>
  68. 68. Negative result of Etanaracept <ul><li>25 mg Etanaracept (soluble anti-TNF factor) </li></ul><ul><li>180 WG patients (WGET trial) </li></ul><ul><li>No significant difference from placebo </li></ul><ul><li>Not effective for maintenance of remission </li></ul><ul><li>NEJM ,2005 </li></ul>
  69. 69. 3 NEW ANTIBODIES <ul><li>INFLIXIMAB (Active STUDY) </li></ul><ul><li>ATG (directed to T lymphocytes) </li></ul><ul><li>For refractory WG ,2.5 mg/kg/d for 10 days (15 patients) </li></ul><ul><li>RITUXIMAB (B cell depletion) </li></ul><ul><li>For ANCA associated Vasculitis, </li></ul><ul><li>375 mg/m2 every week for 4 weeks, 11 pts, relapse in 5/11 (5-12 months) </li></ul>
  70. 70. ACTIVE <ul><li>PROSPECTIVE STUDY OF TNF-a BLOCKADE with INFLIXIMAB </li></ul><ul><li>IN ANCA –ASSOCIATED SYSTEMIC VASCULITIS </li></ul><ul><li>Booth et al, JASN,15:717-721,2004 </li></ul>
  71. 71. ACTIVE :summary of results <ul><li>32 patients with WG/MP </li></ul><ul><li>16 active disease (study 1), </li></ul><ul><li>16 persistent disease (study 2) </li></ul><ul><li>TREATED with INFLIXIMAB 5mg/kg at 0,2,6,10 W </li></ul><ul><li>88% remission (both groups) </li></ul><ul><li>20% relapse (mainly study 2) </li></ul><ul><li>25% Infection </li></ul><ul><li>Steroid Sparing </li></ul>
  72. 72. EARLY SYSTEMIC VASCULITIS <ul><li>ANCA + </li></ul><ul><li>Serum Creatinine 1.5 mg/dl </li></ul><ul><li>1year Cyclophos. + Ster= 47% relapse </li></ul><ul><li>1year Mesotrexate +ster= 70% relapse </li></ul>
  73. 73. MAINTENANCE IN ANCA +ve <ul><li>Azathioprine (still gold standard mainten) </li></ul><ul><li>MMF 2gm/d relapse rate 43% from stopping time 1-25 months, </li></ul><ul><li>Does not seem to be superior than AZA </li></ul><ul><li>So,Switch from cyclophosp to AZA in patients who become ANCA -ve </li></ul>
  74. 74. Double positive patients <ul><li>ANCA + and ANTI GBM + </li></ul><ul><li>More severe glomerular affection </li></ul><ul><li>81% P-ANCA, 41% lung He </li></ul><ul><li>Mean serum creatinine 6.4 </li></ul><ul><li>Outcome similar to anti-GBM </li></ul><ul><li>Ttt: Pred + cyclophosphamide+Plasma Exchange </li></ul><ul><li>1 y renal survival:creatinine <5 is 73% </li></ul>
  75. 75. CONCLUSION <ul><li>More pathological insight &New Classifications </li></ul><ul><li>New terms & Etiologies:C1Q nephropathy,Drug induced(inerferon), Hereditary (eg type III collagen glomerulopathy) </li></ul><ul><li>Fibrillary GN update (eg Fibronectin GN) </li></ul><ul><li>VASCULITIS:Update </li></ul>
  76. 76. THANK YOU

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