Membranous Nephropathy

Epidemiology Uncommon in children. 2-12% (< 5%) of pediatric patients undergoing biopsy for nephrotic syndrome. Adults Most common cause of nephrotic syndrome in adults 30% all biopsies for nephrotic syndrome Older population 50% of all biopsies for nephrotic syndrome

Epidemiology Because of its frequency ,2 nd /3 rd common cause of ESRD within 1 o GN group USRDS 1991-95: 0.5% ESRD was due to idiopathic Membranous GN Has been reported in < 1 year old and > 90 years old. Uncommon in < 30 years old Peak age 30-40 and 50-60 Men:women- 2-3:1

Membranous Nephropathy Clinical Manifestations Presentation: Nephrotic : 60-70% Asymptomatic proteinuria : 30-40% Associated findings: Hypertension : 10-20% Renal insufficiency : 10% Microhematuria : 50% Renal vein thrombosis : 5-30%

Aetiology Systemic disease SLE Diabetes mellitus Infections Hep B /C Drugs Gold Penicillamine NSAID’s Malignancies Solid Organ tumors Transplant Uncommon Autoimmune disease eg: Rheumatoids arthritis Infections: syphilis, filariasis, malaria, leprosy, schistosomiasis. Sarcoidosis Sickle cell disease Drugs: mercury, captopril, hydrocarbons

Pathogenesis Heymann nephritis in rats: Podocytes is the target of injury. Research has focused on : 1. Responsible antigen 2. Subsequent immune response 3. The role of complement 4. Delineation of the injury process

Pathogenesis Antigen target Antigenic target has been localized to the membrane of glomerular epithelial cell, specifically a 515 kD glycoprotein called MEGALIN MEGALIN: A polyspecific receptor related to LDL receptor family

Pathogenesis Immune response CD4+ T cell dependent and humoral response results in glomerular immunoglobulin deposition and complement activation. The CD4+ help for antibody response is a function of Th2 cells which produce IL-4, 5, 6, 10 and 13. A role of cell mediated injury is supported by observation: - depletion of CD8+ cell reduces injury - monoclonal anti CD4 and CD8 modifies the disease

Pathogenesis Immune response Complement involvement: Complement C5b-9 :Membrane attack complex (MAC) present within the immune deposits Depletion of complement by cobra venom serum prevent subsequent proteinuria confirm role of complement . Podocytes ? Retrieves MAC from the immune deposits by endocytosis, transport them across the cells and exocytosed to the urinary space--- Therefore detectable in the urine

Pathogenesis Subsequent injury process Podocytes response to injury is not proliferative but hypertrophy and increased matrix production and finally glomeruloslerosis and interstitial fibrosis

Pathology Light microscopy-H&E GBM becomes thickened thru the accumulation of additional matrix material along the outer surface of GBM Later immune deposits becomes surrounded by GBM material

Pathology Light microscopy-silver stain Spikes formation

Pathology Immnunoflurescence Subepithelial immune complex of Ig G and complement along the outer surface of capillary wall.

Pathology Electron Microscopy Electron dense deposit on the subepithelial surface of GBM

Membranous Nephropathy Management controversy Debate regarding its management continues since early 1970’s….. Marked variability in its natural history ?accurately predicts which patients is going to progress to ESRD ? Ability to identify it early enough ,so the kidney retain the ability to improve with treatment but late enough to avoid therapy in patient that remits spontaneously Do we have effective treatment??

Idiopathic Membranous Nephropathy Natural History 1/3 patients achieved spontaneous complete remission within 3 to 5 years. 25% who enter remission suffer subsequent relapse. 1/3 have partial remission (24HUP< 2g) with persistent proteinuria but no loss of GFR 1/3 progress to ESRD over 5 to 10 years period Patients that achieved remission/ maintain normal GFR for > 3 years , prognosis is excellent.

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

Idiopathic Membranous Nephropathy Natural history 50% with persistent nephrotic range proteinuria has a progressive course 15% of all patients are dead/on dialysis in 5 years. 35% of all patients are dead/on dialysis in 10 years >40% of all patients are dead/on dialysis in 15 years Mean time to doubling in serum Cr is 30 months

Membranous Nephropathy Management controversy Generally good prognosis but 25% end stage at 8 years Some authors recommend conservative approach given high rates of spontaneous remission and long term good prognosis Some use immunosuppressive drugs to all patients with NS since several RCT demonstrated superior outcome with this regime

Membranous Nephropathy Management controversy The aggressive approach has been criticized as many patients who would evolved into spontaneous remission are exposed to the risk of immunosuppression The conservative approach,would leave considerable amount of patients with progressive renal failure Balance: select patients at high risk of progression for immunosupressive therapy.

Membranous Nephropathy Can we predicts those patients who will progress to end stage renal disease?

Idiopathic Membranous Nephropathy Poor Prognostic Factors Reichert et al, AJKD 1998(31),1:1-11 Clinical features: Age Sex race HLA Hypertension Serum albumin Serum cholesterol Serum creatinine at presentation

Idiopathic Membranous Nephropathy Poor Prognostic Factors(cont) Reichert et al, AJKD 1998(31),1:1-11 Urine protein Nephrotic syndrome 24HUP > 8g for > 6 months. C5b-9 excretion Biopsy appearances Focal sclerosis Tubulointerstitial disease Electron microscopy (stages III and IV)

Predicting CRI in IMN Pei et al, KI 1992(42):960 Level of persistent proteinuria over time improve PPV of predicting renal insufficiency 92 79 30 62 25 X=8, Y=12 88 88 66 66 47 X=8, Y =6 77 87 49 42 55 X=8, Y at biopsy 86 83 50 55 42 X=6, Y=12 78 90 75 54 65 X=6, Y= 6 64 84 66 38 80 X=6, at biopsy 75 84 58 44 61 X=4, Y=12 62 92 85 44 92 X=4 , Y=6 37 89 87 32 127 X=4 at biopsy spec NPV sens PPV n PP (> x g/day, >y month)

Membranous Nephropathy Do we lose ability to effectively treat by waiting??

Conservative vs immunosuppression in IMN Torres et al KI 2002 (61): p 219-227 Retrospective study Biopsy proven MN who developed progressive renal insufficiency (1975-2000) Secondary membranous excluded. Renal insufficiency: SCr > 1.5 mg/dl + Cr Cl ,60 ml/min in at least3 consecutive determination Renal insufficiency was progressive in all patients. Other causes of renal failure ruled out before attributing to glomerular disease

Conservative vs immunosuppression in IMN Torres et al KI 2002 (61): p 219-227 Therapeutic approaches: First period 1975-1989: conservative Mx for all. Second period 1990-2000: immunosuppressive to new patients with renal insufficiency of recent onset. Prednisolone 1mg/kg/d x1/12 0.5 mg/kg/d x 1/12 0.5 mg/kg/eod x 4/12 chlorambucil 0.15 mg/kg x 14 weeks.

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)

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)

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

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

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)

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

Conservative vs immunosuppression in IMN Torres et al KI 2002 (61): p 219-227 No patients received immunosuppression until serum Cr 1.5 mg/dl or Cr Cl < 60 ml/min (mean 2.3 + 0.94) Time to reach this point was 14 months after biopsy Only 30% went to develop CRF compared to 75% if treated conservatively Suggest that we can safely wait and observe the patient before beginning treatment and still alter the natural history

Risk of Progression Categories Low risk normal renal function Proteinuria < 4g/day for 6/12 Medium risk normal renal function proteinuria > 4g/d < 8g/d for 6/12 High risk abnormal renal function or/and persistent proteinuria >8g/d for >6/12

Treatment Strategies Specific immunosuppression Non-specific –reduction of proteinuria Dietary protein restriction BP control ACE inhibitor/AARB Treatment of secondary effect Control of oedema - diuretics Hyperlipidaemia-statin Treatment prophylaxis Anticoagulation: against deep/renal vein thrombosis PCP prophylaxis Osteoporosis prophylaxis: high dose corticosteroid therapy

Idiopathic Membranous Nephropathy Specific Immunosuppression Steroid alone Steroid & cytotoxic Cyclosporine.

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

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

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

Steroids CSAINS 1979 0.008 0.008 NS NS 0.052 NS NS

Steroids Cattran et al, 1989 P=0.4

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

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

Steroids alone MRC Trial Cameron et al. QJM 1990 ,74(27) :133-156 At 36 months, there were no significant difference between control and treatment group in: Plasma Cr Cr CL 24 hr urine protein excretion Conclusion: no significant benefit of high dose short term steroid treatment in the medium term

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

Idiopathic Membranous Nephropathy Steroid alone :summary Therapy with corticosteroid alone does not: increase the odds of complete remission Influence renal survival.

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

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

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

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

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

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

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

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

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

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

IMN:Cytotoxics versus conservative/no treatment Murphy Clin Nephrol, 1992(37):229 No effect on renal f(x) Reduction in proteinuria Significant increase in remission of NS Short follow-up Remission of nephrotic syndrome <0.05 P value 9 4 total 2 1 Complete Remis. 7 3 Partial Remis. treatment N=13 conservative N=13

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

IMN:Cytotoxics versus conservative/no treatment Donadio, KI 1974 (6): 4 Downward trend in proteinuria No significant difference in the 2 groups 4/9 of treated gp had partial remission 2/9 of non-treated gp had partial remission Treatment gp Proteinuria

IMN:Cytotoxics versus conservative/no treatment Donadio, KI 1974 (6): 4 No changes in GFR Inulin Cl : increased by 8 ml/min/1.73 m2 in treated gp : increased by 2 ml/min/1.73 m2 in non-treated gp : p=0.2 Cr Clearance

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

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

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

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

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)

Steroids & cytotoxics :meta-analysis Imperial et al, JASN 1995,5:1553-1558 5 controlled studies(4 randomized) Treatment: Chloramucil & prednisolone(6 months) or cyclophosphamide(6-12 months) Outcome: complete resolution of nephrotic syndrome 4x more likely with cytotoxic therapy

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

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

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

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

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

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

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

Membranous Nephropathy

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