Membranous nephropathy is a common cause of nephrotic syndrome in adults. It has variable natural history, with about 1/3 of patients achieving spontaneous remission, 1/3 having persistent proteinuria but stable renal function, and 1/3 progressing to end-stage renal disease over 5-10 years. Several factors predict poorer prognosis, including older age, nephrotic syndrome, lower serum albumin and higher proteinuria levels. Studies show immunosuppressive therapy may alter the natural history for patients at high risk of progression, but risks of treatment must be weighed against the likelihood of spontaneous remission.

1. Membranous Nephropathy

17. Untreated Membranous Nephropathy Natural History Schieppati et al , NEJM 1993,329(2):85

28. Conservative vs immunosuppression in IMN Torres et al KI 2002 (61): p 219-227 <3g/dl >3.5 Nephrotic syndrome Normal normal 0.5-2.5 or 50% red fr baseline Partial remission normal Normal <0.5 Complete remission Renal function Serum albumin 24 HUP (g)

29. Conservative vs immunosuppression in IMN Torres et al KI 2002 (61): p 219-227 NS 15.7% 68% 15.7% 0% 10% 75% 15% 0 Stage of MN I II III IV NS 51.8 + 36.5 46.8 + 37.5 Follow-up (months) NS 14 + 18.6 10.8 + 11.8 Interval between bx and renal insufficiency NS 102 + 13 103 + 12 MAP NS 8.9 + 3.6 6.9 + 3.1 Proteinuria NS 11:8 15:5 Sex (M:F) NS 55 + 20 53 + 16 Age Treated(n=19) Nontreated(n=20)

30. Conservative vs immunosuppression in IMN Torres et al KI 2002 (61): p 219-227

31. Conservative vs immunosuppression in IMN Torres et al KI 2002 (61): p 219-227 treated Non-treated

32. Conservative vs immunosuppression in IMN Torres et al KI 2002 (61): p 219-227 Clinical status at end of follow-up 2 (10%) 5 (25%) Death 2 (10%) 13 (65%) Dialysis 4 (21%) 2 (10%) CRF 5 (26%) 0 24HUP>2.5g but N f(x) 2 (10%) 0 Partial remission 5 (26%) 0 Complete remission Treated (n=19) Non-treated (n=20)

33. Conservative vs immunosuppression in IMN Torres et al KI 2002 (61): p 219-227 Probability of renal survival (censoring death) Non-treated treated

38. Idiopathic Membranous Nephropathy Trials on Steroids RCT RCT RCT 77 51 38 placebo Pred 45 mg/m2 Pred 125 mg EOD x 8/52 Pred 100-125 mg EOD x8/52 and taper rx steroid N publications Author 81 158 NEJM 1989 (320):210 Cattran 52 103 QJM 1990 (74):133 Cameron 34 72 NEJM 1979 (301):1301 CSAINS

39. Idiopathic Membranous Nephropathy Trials on Steroids Secondary membranous Impaired GTT Use of cytotoxic within 6/12 Cr Cl < 30 ml/min Secondary membranous Exclusion criteria Inclusion criteria Author 24HUP > 0.3g/day Cr Cl > 0.25 ml/sec Cattran adult >15, <65 NS(alb<30,24HUP >3.5) Cameron Proteinuria > 3.5 g/1.73m 2 on > 2 occasion CSAINS

40. Idiopathic Membranous Nephropathy Trials on Steroids Definition (urine prot in g/24 hrs) Nephrotic syndrome Partial remisson Complete remission Author > 3.0 Reduction of more than 50% initial value <0.3 Cattran >3.5 Alb <30 0.0-3.5 0.0 Cameron > 2.0 0.2 -2.0 < 0.2 CSAINS

41. Steroids CSAINS 1979 0.008 0.008 NS NS 0.052 NS NS

42. Steroids Cattran et al, 1989

43. Steroids Cattran et al, 1989 P=0.4

44. Steroids Cameron et al. QJM 1990 ,74(27) :133-156

45. Steroids alone MRC Trial Cameron et al. QJM 1990 ,74(27) :133-156

47. Steroid Alone Meta analysis Hogan et al, AJKD 1995(25): pg862 Outcome :Rate of complete remission 0.48-13.21 2.25 0.75 0.33 24 Kobayashi 0.99-2.44 1.55 total 0.75 1.75 5.33 RR 0.44-1.27 0.27 0.36 36 Cattran 0.54-5.65 0.15 0.08 36 Cameron 0.67-42.01 0.33 0.06 24 CSAIN 95% CI steroid Non-treated Follow-up (months) Study

49. Trials in IMN Cytotoxic + steroid Steroid alone Steroid +CBL 91 NEJM1992(327):599 Ponticelli conservative conservative Conservative comparison Active treatment N publications Author Cycloph+ warfarin + dipyridamole 40 Clin Nephrol, 1992(37):229 Murphy cycloph 22 KI 1974, 6: 431 Donadio Steroid +CBL 92 KI 1995(48): 1600 Ponticelli

50. IMN Steroids & cytotoxics versus conservative/no treatment Ponticelli, 1995(48):1600 PR: 24HUP: 0.21- 2.0 g, CR: 24HUP < 0.20 g Renal dysf(x): increase plasma Cr 50% fr baseline Later: renal survival and death End-points 10 years follow-up age<14 and > 65, Cr> 150umol/l,previous steroid or cytotoxic treatment, secondary membranous Exclusion criteria Nephrotic syndrome (24HUP > 3.5 g in 2 specimen, alb < 25g/L) – Inclusion criteria Conservative treatment Control gp N=39 methypred 1g x3/7 at month 0, 2, 4 then oral 0.4 mg/kg/d x27 days chlorambucil 0.2 mg/kg x 6/12 Treatment gp N=42

51. IMN Steroids & cytotoxics versus conservative treatment Ponticelli, 1995(48):1600 Schieppati 10 YRS =0.72 Ponticelli 10 YRS untreated 0.70

52. IMN Steroids & cytotoxics versus conservative treatment Ponticelli, 1995(48):1600 Probability of complete and partial remission Of nephrotic syndrome treated control

53. IMN Steroids & cytotoxics versus conservative/no treatment Ponticelli, 1995(48):1600 Clinical status at end of follow-up 9 2 Dialysis 3 1 death 8 4 Renal dysfunction 6 9 Nephrotic syndrome 11 9 Partial remission 2 17 Complete remission 39 42 Total Conservative treated

54. IMN Steroids & cytotoxics versus steroid alone Ponticelli NEJM1992(327):599-603 PR: 24HUP: 0.21- 2.0 g, CR: 24HUP < 0.20 g Renal dysf(x): increase plasma Cr 50% fr baseline End-points 2-4 years follow-up age<14 and > 65, Cr> 150umol/l,previous steroid or cytotoxic treatment, secondary membranous Exclusion criteria Nephrotic syndrome (24HUP > 3.5 g in 2 specimen, alb < 25g/L) Inclusion criteria Methylpred alone Control gp N=47 Cyclical –ponticelli regime Treatment gp N=45

55. IMN Steroids & cytotoxics versus steroid alone Ponticelli 1992(327):599-603 0.002 0.029 0.011 0.102

56. IMN Steroids & cytotoxics versus steroid alone Ponticelli 1992(327):599-603 Steroid + CBL steroid

57. IMN: Cytotoxics versus conservative/no treatment Murphy, Clin Nephrol, 1992(37):229 24HUP, Cr ,albumin outcome Diuretics and antihypertensives Conservative treatment Cyclophosphamide 1.5 mg/kg/day for 6/12 Dipyridamole100-400 mg daily Warfarin for 2 years Specific treatment N=19 Open randomized study Secondary membranous, proven RVT Prior cytotoxic treatment Exclusion >18 with histological diagnosis of IMN within 3 months of biopsy Proteinuria > 0.5 g/24 hr Inclusion

58. IMN:Cytotoxics versus conservative/no treatment Murphy Clin Nephrol, 1992(37):229 p<0.05

60. IMN:Cytotoxics versus conservative/no treatment Donadio, KI 1974 (6): 431 24HUP, Cr ,albumin outcome Diuretics and antihypertensives Conservative treatment Cyclophosphamide 1.5 -2.5 mg/kg/day for 1 year Specific treatment N=19 Open randomized study Secondary membranous, proven RVT Prior cytotoxic treatment Exclusion >18 with histological diagnosis of IMN within 3 months of biopsy Proteinuria > 2 g/24 hr Inclusion

63. Idiopathic Membranous Nephropathy Trials on chlorambucil vs cyclophosphamide Ponticelli but monthly pulsed iv CYCL Ponticelli regime CBL 0.15 mg/kg 18 Annals int med 1994, 72(4):277 Reichert Similar but CBL substituted with cyclophos 2.5 mg/kg Ponticelli regime but chlorambucil 0.2 mg/kg 87 JASN 1998, 9(3):444 Ponticelli CBL substituted with cyclophos 1.5-2.0 mg/kg Ponticelli regime. CBL 0.15 mg/kg 32 QJM 1998 91(5):359 Branten Steroid & cyclophospha Steroid & chlorambucil N Publication Author

64. Idiopathic Membranous Nephropathy Trials on chlorambucil vs cyclophosphamide Cr>150 umol/l,Age <18 Secondary membranous DM , RVT IMN . NS with deteriorating renal f(x) Reichert N=18 IMN with nephrotic syndrome Ponticelli Cr>150 umol/l,Age <18 Secondary membranous DM , RVT IMN . NS with deteriorating renal f(x) Branten N=32 Exclusion Inclusion criteria Author

65. Steroids/cyclophosphamide vs steroid/chlorambucil Branten, QJM 1998 91(5):359 Greater efficacy with cyclophosphamide with better tolerability 26 (5-68) 38 (8-71) F/up (median ,range) <0.01 6/17 11/15 Adverse event <0.01 -121 - 6.3 Change in S Cr (umol/l) <0.05 1/17 4/15 Proportion of pt dev ESRD 15/17 164 + 86 to 274 + 126 cyclophosph <0.05 5/15 Remission of proteinuria 148 + 50 to 219 + 73 Serum Cr 6/12 preceeding rx P value chlorambucil

66. Steroids/cyclophosphamide vs steroid/chlorambucil Reichert et al. QJM 1994 121(5): 328 Pulsed iv cyclophosphamide is ineffective in treating IMN <0.05 -3.1 -2.6 Urine prot: Cr index (g/10 mmol) at 6/12 <0.05 +322 -38.0 Change Serum Cr at 12/12(umol/l0 <0.05 +79.0 -74.0 Change Serum Cr at 6/12(umol/l) 4/9 1/9 Patient reaching ESRD NS -2.9 -2.8 Urine prot: Cr index (g/10 mmol) at 12/12 P value Cyclophosph Chlorambucil

67. Steroids/cyclophosphamide vs steroid/chlorambucil Ponticelli JASN 1998, 9(3):444 Both treatment are effective in inducing remission and preserving renal function, ? Cyclophosphamide more effective and better tolerated 2 did not complete 0 zoster 6 did not complete 4 zoster Side effect NS 10/40 (25%) 11/36 (30.5%) Relapse between 6-30 months 0.116 40 (93%) 36 (82%) Remission (comp/part) P value Cyclophosphamide (n= 43) Chlorambucil (n=44)

69. IMN: Trials on Cyclosporin RCT 64 KI 1995, 47(4):1130 Cattran Prednisolone 0.15mg/kg/D & placebo Prednisolone 0.15mg/kg/D & cyclosporine (3.5mg/kg/day) CSA level of 125-225 RCT 51 KI 2001, 59(4):1484 Cattran Control gp Study gp n publications Author

70. Cyclosporin Cattran 1995, KI Membranous n=64 Low protein diet <0.9g/kg/day Prog of renal failure Decrease in Cr Cl 8ml/min/year And persistent nephrosis Stable renal f(x) Placebo N=8 Cyclosporin N=9 for 12/12

71. Cyclosporin Cattran KI 1995, 47(4):1130 Slope of Cr Clearance (ml/min/month) 49 8 9 N - - -0.5 Non-randomized NS -2.1 -2.2 Placebo <0.02 -0.7 -2.4 Cyclosporin P value Part 2 Part 1

72. Cyclosporin Cattran KI 1995, 47(4):1130 cyclosporin placebo

73. Cyclosporin Cattran KI 1995, 47(4):1130 P=0.02 P=0.03

74. Cyclosporin Cattran et al, KI 2001,59(4):1484-90. Randomized double blind placebo controlled Study Complete remission (<0.3 g/day) Partial remission (50% reduction from baseline, and < 3.5 g/day with stable renal function) Stable f(x): Cr Cl within 15% of baseline) Outcome CSA at 3.5 mg/kg/day. Blood level 125 – 225 umol/l Pred 0.15 mg/kg/day Treatment Female unwilling to take effective birth control Comorbid condition with expected survival < 2 years Secondary membranous, DM malignancy Exclusion criteria Age 18-70, failure to achieve remission after 8 weeks of pred I mg/kg.proteinuria > 3.5g/day, Cr Cl> 42ml/min and BP< 135/85 Inclusion criteria

75. Cyclosporin Cattran et al, KI 2001,59(4):1484-90 . P=0.001 P=0.004 P=0.007