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  1. 1. Membranoproliferative Glomerulonephritis SUMANEE PRAKOBSUK
  2. 2. Scopes Classification Pathophysiology Pathology Clinical features Treatment
  3. 3. Overview Also termed mesangiocapillary glomerulonephritis. MPGN accounts for approximately 7 to 10% of all cases of biopsy-confirmed glomerulonephritis. Brenner&Rector’s: The Kidney 9th Edition
  4. 4. Classification Idiopathic Secondary Type I Infection Hepatitis C and B Type II Visceral abscess Infectious endocarditis Type III Shunt nephritis Mycoplasma infection Rheumatologic disease SLE Scleroderna Sjogren syndrome Mixed essential cryoglobulinemia with or without hepatitis C infection Malignancy Carcinoma,Lymphoma,LeukemiaBrenner&Rectoer’s 9th Edition Complement deficiency Hereditary C2,C4 deficiency
  5. 5. Classification Traditionally been classified into three subtypes  MPGN types I  MPGN types II  MPGN types III The primary basis for this classification is histologic, the appearance of the capillary wall by electron microscopy and the location of electron-dense deposits. Brenner&Rector’s: The Kidney 9th Edition
  6. 6. Type I : Subendothelial depositsType II : Densedeposits in Laminadensa of GBMType III : Subendothelial&Subepithelial deposits
  7. 7. Membranoproliferative Glomerulonephritis Type I Epidemiology  The majority of patients with MPGN are children between the ages of 8 and 16 years.  The proportions of males and females with the disorder are nearly equal. Brenner&Rector’s: The Kidney 9th Edition
  8. 8. IMMUNE-COMPLEX-MEDIATED MPGN Pathogenesis MPGN typeI Results from the deposition of immune complexs in the glomeruli owing to persistent antigenemia. Type I MGPN often is secondary to recognizable causes. Brenner&Rector’s: The Kidney 9th Edition
  9. 9. Secondary MPGN Brenner&Rector’s: The Kidney 9th Edition
  10. 10. Pathogenesis of MPGN type I
  11. 11. Pathology of MPGN Type I LM  Mesagial proliferation  Endocapillary proliferation  Diffuse global capillary wall thickening “Lobular glomerulonephritis” Brenner&Rector’s: The Kidney 9th Edition
  12. 12. Pathology of MPGN Type I LM  Mesangial interposition  Doubing or replication of GBM Brenner&Rector’s: The Kidney 9th Edition
  13. 13. Pathology of MPGN Type IIF Granular staining for complement, especially C3, and usually immunoglobulins (IgG or IGM) GBM,Mesangial Few at TBM Brenner&Rector’s: The Kidney 9th Edition
  14. 14. Pathology of MPGN Type IEM The ultrastructural hallmark of type I Subendothelial Electron- dense -deposits Mesangial interposition Brenner&Rector’s: The Kidney 9th Edition
  15. 15. Clinical Features of MPGN typeI Nephrotic syndrome 40-70% Acute nephritic syndrome 25 % Asymptomatic proteinuria and hematuria 25 % HT (not severe) Renal insufficiency 50% Pediatr Nephrol.2010;25:1409-18.
  16. 16. MembranoproliferativeMembranoproliferative Glomerulonephritis Type III Type III MPGN occurs in a very small number of children and young adults. Clinical features of disease quite similar to those of type I MPGN. Regardless of the pathologic distinctions of MPGN type III ,few distinguishing clinical characteristics are noted in these patients. EM: subendothelial and subepithelial EDD Brenner&Rector’s: The Kidney 9th Edition
  17. 17. Membranoproliferative Glomerulonephritis Type II Dense Deposit Disease Epidemiology  About 25% of MPGN in children but is much less common in adults.  The large majority of patients are children 8 - 16 years.  2-3person/million.  Female:male = 3:2 J Am Soc Nephrol 16: 1392–1404, 2005 Brenner&Rector’s: The Kidney 9th Edition
  18. 18. Pathogenesis of MPGN type II (DDD) DDD is characterized by deposits of dense material within the basement membranes of glomeruli, Bowman’s capsule, and tubules. A porcine model of MPGN  Massive deposition of C3 and the terminal C5b9 complement complex (the membrane attack complex).  No immune complex deposits were detected in renal tissue. Dysregulation of alternative pathway. J Am Soc Nephrol 16: 1392–1404, 2005 Brenner&Rector’s: The Kidney 9th Edition
  19. 19. Peter F. Zipfel*‡ and Christine Skerka*NATuRe RevIeWs Immunology vOLuMe 9 | OCTObeR 2009
  20. 20. Factor H Factor H
  21. 21. Pathogenesis of MPGN type II (DDD) Three distinct mechanisms result in uncontrolled activation of C3 convertase. 1 .The development of an autoantibody, the C3 nephritic factor (C3NeF). - Protects C3 convertase form factor H. 2. The absence of circulating factor H . 3. The presence of a circulating inhibitor of factorH. Brenner&Rector’s: The Kidney 9th Edition
  22. 22. Dysregulation of the alternative pathway
  23. 23.  To investigate causes for AP dysregulation 32 patients with DDD (renal Bx C3+ and intramembranous electron-dense deposits by EM) C3Nef detection assays Factor H antoantibodies(FHAA) Factor B autoantibodies (FBAA) Factor H Mutation screening.
  24. 24. Results C3Nef detection assays:  25 patiests (78%) Factor H antoantibodies(FHAA)  1 patients (3%) Factor B autoantibodies (FBAA)  3 patiests (9%) Factor H Mutation screening.  26 patiests(81%) carried at least one copy of the FH His402 polymorphism.
  25. 25. Pathology :MPGN II( DDD)LM 5 distinct patterns: (1) Membranoproliferative pattern (2) Mesangioproliferative pattern (3) Crescentic pattern (4) Acute proliferative and exudative pattern (5) Unclassified dense deposit disease. Sibley RK, Kim Y. Dense intramembranous deposit disease: new pathologic features. Kidney Int. 1984;25:660-670.
  26. 26. Pathology :MPGN II( DDD) •Intense capillary wall linear to bandlike staining for C3 •Little or no staining for Ig
  27. 27. Pathology :MPGN II( DDD)A bandlike intramembranous dense deposit
  28. 28. Clinical Features :MPGN type II (DDD) ¾ of patients have all of the components of nephrotic syndrome on presentation. ¼ of patients have acute nephritic syndrome. HT is typically mild, but may be severe in some cases. Renal dysfunction occurs in at least half of cases and is more common in adults han in children. Brenner&Rector’s: The Kidney 9th Edition
  29. 29. Clinical Features :MPGN type II (DDD) May have deposits in the retina There is no correlation between the severity of kidney and ocular involvement. J Am Soc Nephrol 16: 1392–1404, 2005
  30. 30. Clinical Features :MPGN type II (DDD) DDD may be associated with the syndrome of acquired partial lipodystrophy. About 80% of patients with this syndrome have low C3 levels and C3NeF. About 20% of patientsdevelop MPGN
  31. 31. Prognosis:MPGN II (DDD) The prognosis for type II is worse than that for type I, worse in adults than in children. Clinical remissions are rare,occurring in fewer than 5% of children. Patients generally reach ESRD in 8 to 12 years from the onset of disease. Brenner&Rector’s: The Kidney 9th Edition
  32. 32. Proposal for A new classification of MPGNProposal of a New classification Immune complex mediated MPGN. Complement mediated MPGN. Sanjeev Sethi, Fernando C. Semin Nephrol 31:341-348 © 2011
  33. 33. Semin Nephrol 31:341-348 © 2011
  34. 34. Treatment Based on the heterogeneity of cause and pattern of histologic injury of MPGN. All patients with MPGN must be thoroughly evaluated for underlying diseases before classifying as idiopathic MPGN, and before any specific treatment decisions can be made. When there is a secondary MPGN, treatment should be directed against that cause
  35. 35. Treatment Idiopathic MPGN is now an uncommon condition. The few RCTs of treatment of idiopathic MPGN in children and adults have given inconsistent and largely inconclusive results . Many of the reported trials have weak experimental design or are underpowered, and the evidence base underlying the recommendations for treatment of “idiopathic” MPGN is very weak.
  36. 36. Treatment Immunosuppressive agent  Prednisolone Cytotoxic agent  Cyclophosphamide  Mycophenolate Antiplatelet Non-specific Tx
  37. 37.  Double-blinded RCT. Compare altermate day prednisolone VS placebo Between February 1970 and October 1980 Pediatr Nephrol(1992)6:123-130
  38. 38. Treatment of mesangiocapillary glomerulonephritis with alternate-day prednisone Inclusion criteriaInclusion criteria 1. Biopsy-prove MCGN 2. GFR by crcl ≥ 70 ml/min per 1.73 m 2 3. Heavy proteinuria ≥ 40 mg/h per m 2 4. No evidence of SLE, HSP, nephritis accompanying bacteremia (such as IE), or malaria, 5. No treatment with corticosteroids during the year prior to entry into the trial or with immunosuppressive agents at any time. Pediatr Nephrol(1992)6:123-130
  39. 39. Treatment of mesangiocapillary glomerulonephritis with alternate-day prednisone • Prednisolone 40 mg/m2 alternate daysTreatment • Maximum dose 60 mg • 5 years • Treatment failure: increase from baseline in serum creatinine of 30% or more, or more than 0.4 mg/dl.Outcome • Renal failure : cr ≥ 4 mg/dl • Stable: no change or increase in S.Cr <0.4 mg/dl Pediatr Nephrol(1992)6:123-130
  40. 40. 61% P=0.07 12%Mean Tx 41 months Alternate- day prednisone therapyTreatment failure improves the prognosis of Treatment 40% patients with MCGN, when used at doses control 54% of 40 mg/m2.
  41. 41. Prednisolone for Idiopathic MPGN There has been no systematic evaluation of glucocorticoid therapy for idiopathic MPGN in adults. Retrospective studies showed no clear benefit from glucocorticoid therapy, but treatment was not as prolonged in adults as it was in children. Kidney International,Vol55(1999)pps41-s46
  42. 42. Cytotoxic Agent Cyclophosphamide Mycophenolate
  43. 43.  RCT Compare  Combination Cyclophosphamide 1.5-2.0 mg/dl Coumadin keep PT 2-2.5 times Dipyridamole start 25 mg qid  full dose 100 mg qid  No specific therapy
  44. 44. CycloInclusion MPGN type I &II ( no crescent) Proteinuria > 2 g/day Ccr < 80 mI/mm. Ruled out Secondary causes of MPGNExclusion Active infectin Previous tuberculosis, Hx PU Uncontrolled HTOutcome Change of crcl from baseline at 18 months
  45. 45. BaselineMPGN Type I Control(N =25) Treatmemt (N=22)Age 33 (6-70) 38 (12-77)Crcl (ml/min/1.73 m2) 64 (18-135) 65 (16-113)Cr (mg/dl) 1.8 (0.7-7.0) 1.7 (0.7-5.9)Proteinuria ( g/day) 5.2 (0.85-16.4) 3.6(0.4-8.3)MPGN Type II Control(N =7) Treatmemt (N=5)Age 19(7-58) 17.5 (6-26)Crcl (ml/min/1.73 m2) 87 (51-131) 63 (37-115)Cr (mg/dl) 0.9 (0.3-1.2) 1.2 (0.7-2.1)Proteinuria ( g/day) 4.3 (0.1-11.7) 6.8 (1.7-12.8)
  46. 46. Change in Crcl /18 monthsMPGN Type I MPGN Type II P=0.4 P=0.5 -1 0 -14 -8
  47. 47. Proteinuria ,g/dayNo significant benefit could be observed over a period of 18 months.
  48. 48.  Retrospective analysis Treatment group  MMF started 500 mg/daymaximum 2 gm /day  Oral Prednisolone 60 mg/day , tapering to 20mg within 2 months and withdrawn by 1 year. Control group  Did not receive immunosuppressive therapy
  49. 49. Change in proteinuria over timein control and MMF treated patients P=0.03 control MMF
  50. 50. Change in creatinine clearance over time in control and MMF treated patients. MMF P=0.06 control
  51. 51. Antiplatelete Rationale  Demonstrations of platelet activation and deposition of platele antigen are invole in initiating or contributing to glomerular injury . Glomerular prostaglandin and thromboxane systesis in rat nephrotoxic serum nephritis.J Clin Invest 1983;72:1439-48
  52. 52.  Randomized,double blind placebo-controlled trial . Renal biopsy prove MPGN TypeI 1975-1981 Only 2 were receiveing therapy with prednisolone,with discontinued at the time of entry None had been treated with cytotoxic drugs. Excluded  SLE,essential mixed cryoglobulinemia,PIGN,dialysis James V.Donadio,JR.Nejm1984;vol310(22)
  53. 53.  Treatment  Dipyridamole 75 mg  Aspirin 325 mg  12 months Outcome  Treatment failure: decline of 25% Iotalamate clearance from pre treatment. James V.Donadio,JR.Nejm1984;vol310(22)
  54. 54. Pretreatment Clinical manifestations Treatment Placebo N=21 N=19
  55. 55. Treatment failures(loss of renal function) P<0.05 James V.Donadio,JR.Nejm1984;vol310(22)
  56. 56. Change in Iothalamate clearance -1.3 ml/min -19.6 ml/min P<0.02 No differences between the groups Proteinuria,Amount of RBC cast, C3,C4,CH50 James V.Donadio,JR.Nejm1984;vol310(22)
  57. 57. Platelet SurvivalJames V.Donadio,JR.Nejm1984;vol310(22)
  58. 58.  Follow up 7 years ESRD - 47 % in Placebo (33 months) - 14 % in Treatment (62 months)GFR and was better maintained, and progression toESRD occurred less often and over a longer period,inthe group treated with platelet-inhibitor drugs thanin the group given placebo James V.Donadio,JR.Nejm1984;vol310(22)
  59. 59. PlasmapheresisCase report , improve renal function MPGN type II Rucurrent MPGN typeII post trasplant
  60. 60. Immunosuppressive drugsLevel of Author Design N Rx Duration Results/CommentsEvidence [Rx : C]1 Tarshish RCT 80 [47/33] Pred 40 mg/m2 130 mo Children only, predomly MPGN I, stable renal fn AD vs pcb Pred 61% [Rx] vs 12% [C] No difference found,1 Cattran RCT 59 CY + coumadin 18 mo [27/32] + dipyridamole mixed MPGN I > II CY vs No Rx 19853 Strife UCT 17 Pred 2 mk AD 2y MPGN III only, nephrotic range [16/1] did worse, 3/16 dvled RF3 Davis CT 27 Pred+IS [NS] - No effect [19/8]3 Orlowski UCT 50 P/AZA/CP/chlorambucil 79 mo 10 y F/U, ↓ Uprot c triple drug in combi Rx3 Ford UCT 19 PO/IV pred 2 mk + 8-10 wk, Children; 6.5 y F/U, early Rx, ACEI then x2-3 shorter course, y tapered ↓ glom prolif dose3 Faedda UCT 19 IV/PO CY+P 10 mo 15/19 remission, 7 y F/U 1994 [different combinations] Adeera Levin., Mx of MPGN; Evidence based recommendations; KI 1999; 55: S41-S46
  61. 61. AntiplateletLevel Author Design Rx Durati Results/Commentsof evi N [Rx : C] on1 Donadio 1984 RCT Dipyridamole 75mg/d + ASA 325 12 mo -Tx : significantly delay rate of GFR ↓ Prospective mg/d vs Pcb [Sig difference at 7 y] 40 [21/19] -No change in Uprot, hematuria, Complement -Mild bleeding complication required discontinuation 15%1 Zimmer man RCT Warfarin [INR 1.5-2] + dipyridamole [75-100 12 mo [2 y Prot restriction & HTN control standardized. Crossover mg qid] vs Pcb study] Sig reduction in proturia 18 [8/10] NS diff in renal fn Significantly ↓ Uprot1 Zauner 1994 RCT ASA 500 mg/d + dipyridamole 75 36 mo [1 g Tx vs 8 g control] [Sig] 18 [9/9] mg/d PR : Tx 7/10 vs Control [I 15 + III [both : prot restriction 2/8 3] & HTN control] -Comment : short F/U SCr 1.8, Uprot 7 g/d Adeera Levin., Mx of MPGN; Evidence based recommendations; KI 1999; 55: S41-S46
  62. 62. Evidence based recommendations : KI 1999 Idiopathic MPGN 24 h Uprot & CCr <3 g >3 g Normal renal function Abn renal function Normal renal function Abn renal fn Grade C; Grade A; Grade B; Child : trial of steroid x 3 Child : trial of Adult : trial of ASA mo [AD; IV or PO 1 mk] steroids 40 mg/m2 325 mg/d & Or AD x 6-12 mo Dipyridamole 75-100 Adult : no Rx, observe mg tid x 6-12 mo F/U q 3 mo; BP, Lipid monitoring -No change : continued F/U, ↓ frequency - Increase cr or proteinuria  Rx Adeera Levin., Mx of MPGN; Evidence based recommendations; KI 1999; 55: S41-S46
  63. 63. Pediatr Nephrol (2010) 25:1409–1418
  64. 64. Recurrence in KT 67-100% in MPGN II , graft loss 34-66% 20-33% in MPGN I Related to severity of previous disease > type of MPGN.
  65. 65.  The Mayo Clinic Transplant database. On examination of the records of 1321 patients following kidney transplant over an 11-year period 29 patients of MPGN Excluded MPGN type II, secondary MPGN Follow up Protocal Bx 0,4,12,24,60 months Kidney International (2010) 77, 721–728
  66. 66. 52 months of follow uprMPGN 12 /29 patients (41.4%) Recurrence occurred during first 14 months( Median 3.3 months) Kidney International (2010) 77, 721–728