Idiopathic Membranous Glomerulopathy: Diagnosis and Treatment

1. Idiopathic Membranous Glomerulopathy: Diagnosis and Treatment Geeta Gyamlani, MD

2. Clinical case • 35 yr old male pt s/b pcp • At that time,he was noted to have elevated total cholesterol of 353 mg/dland triglycerides of 417 mg/dl and was started on simvastatin40 mg/d • Next 2 mo, he started developingswelling + tenderness in hiscalves. Diagnosed with DVT was started onoral anticoagulant therapy.

3. UA showed 3+ proteinuria, 24 hr urine showed 9 gms of protein. • Referred to Nephrology clinic • No DM, HTN, Macroscopic hematuria, • Serologic w/u for complements, monoclonal proteins, ANCA, Hep B, HepC, HIV and ANA negative • BP 137/87, wt 90kg BMI 29kg/m2 • No LN, No JVD, 2+ LE edema

4. Lab data • Hb 15 g/dl, WBC 4.7, plt 236, Cr 1, alb 2.5, cholesterol 260, trig 224. • Proteinuria 8.6 g/24 hrs • CxR normal • Renal US normal, renal veins were patent bilaterally

6. Features of secondary membranous • Proliferative changes( measangial/endocapillary) • Full house pattern on IF • Glomerular deposits containing Ig other than IgG4 • EDD in subendothelial , mesangium and along TBM+ vessel wall. • Endothelial tubuloreticular inclusions

7. The second most common causes of primary NS in Caucasian adults ( upto 33% of adult cases of NS). • ~ 40% of patients eventually develop ESRD. • Because of its frequency, it remains the 2nd or 3rd cause of a primary glomerulopathy leading to ESRD. • Patients with MN who remain nephrotic are at an increased risk for thromboembolic and CV events. Epidemiology

8. Swaminathan et al Clin J Am Soc Nephrol 2006

9. Clinical manifestations • M>F 2:1 • Peak incidence 4-5th decade of life • 60-70% have NS, 30-40% have SNP. • Microscopic hematuria may be seen in 30% patients • Majority of patients are normotensive and hypertension + in 10-20%. • At presentation significant renal insufficiency <20%

12. Fluorescence-activated cell-sorter analysis (Panels A and B) and immunoblotting (Panel C) show a lack of expression of neutral endopeptidase in the mother’s granulocytes. Debiec et al. NEJM 346 (26): 2053   June 27, 2002

14. Results of Western Blotting of GlomerularProteins with Serum from Patients withIdiopathic Membranous Nephropathy Western Blotting Reactivity to 185-kD Protein Beck et al: NEJM 361:11, 2009

16. Anti Phospholipase A2 receptor Ab ( PLA2 R)

17. Relationship between clinical disease (proteinuria) and immunological activity (circulating anti-PLA2R) Beck et al,Kidney International (2010) 77, 765–770

18. Probability of renal survival from a pooled analysis of all 32 studies Cattran et al,Kidney International (2001) 59, 1983–1994

20. Natural History • 30% Undergo spontaneous remission • 30% Variable proteinuria with stable renal fx • 30% Progress to renal failure • 10% Die of non renal causes Donadio et al , KI , 33,1988, 708-715

21. Can prognostic factors assist in therapeutic decision. • Age • Gender • Pathology • GFR • Proteinuria • Biomarkers- Urinary NAG, B2 microglobulin and IgG

22. Gender, proteinuria, age at onset and decline of renal fx.

23. Troyanov et al, Kidney International (2006) 69, 1641–1648

26. Probability of CR/PR according to UNAG 86% 27% Probability of renal survival acc to UNAG 0% 47% Bazzi, C. et al. Nephrol. Dial. Transplant. 2002 17:1890-1896; doi:10.1093/ndt/17.11.1890

27. B2 microglobulin/ IgG as predictors of renal survival. Sn=88%, sp 91% Sn and sp 88% Branten, A. J.W. et al. J Am Soc Nephrol 2005;16:169-174

28. Idiopathic Membranous NephropathyProbability of Surviving Without Developing End-StageRenal Disease According to Baseline Proteinuria Donadio et al: KI, 1988

29. Survival from Renal Failure in Patients withComplete, Partial, and No Remission 90% 45% 5 pt out of 348 had a creatinine clearance <15 mL/min at initial assessment and were excluded from this analysis Troyanov et al. Kidney Int. (2004)

30. Troyanov et al. Kidney Int. (2004)

31. Number of Partial and Complete SR and Time to Achieve Partialand Complete SR According to Baseline Proteinuria Polanco et al: J Am Soc Nephrol, 2010

32. Risk of Progression Categories Low risk Laboratory Time Normal Function Proteinuria < 4 g/d 6/12 Medium risk Normal function Persistent proteinuria > 4<8 g/d 6/12 High risk Abnormal function and/or Persistent proteinuria > 8 g/d <6/12 Pei et al, KI 42,960-966,1992

35. Cattran et al, KI 51,901-907,1997

37. Goal of therapy is to reduceproteinuria and preventprogression to renal failure

38. Probability of SR in patients treated with ACEIs/ARBs and in patients who did not receive this treatment Polanco, N. et al. J Am Soc Nephrol 2010;21:697-704

39. A 10-year follow-up - Ponticelli Protocol Study Design: RCT, Pts with MN and NS, 42 pts received CB + steroids, 39 received symptomatic Rx. Outcome: Renal survival, slopes of reciprocal of creatinine, Remisssion of proteinuria RESULTS

40. A 10-year follow-up - Renal Survival P<0.005 Ponticelli C et al: KI 48:1600, 1995

41. Characteristics of Patients at Start of Treatmentwith MP plus Chlorambucil or MP plus Cyclophosphamide Ponticelli et al: JASN 9:444, 1998

42. Cumulative Probability ofObtaining (P) or (C) Remission Ponticelli et al: JASN 9:444, 1998

43. Efficacy of chlorambucil based regimen vs steroid alone Ponticelli, C et al, N Engl J Med 1992; 327:599

44. Cytoxan in this era Jha, V. et al. J Am Soc Nephrol 2007;18:1899-1904

45. Probability of Reaching a Remission Dialysis free survival 90% Ctx-73% 65% Supp-34% Jha et al: JASN 18:1899, 2007 ---Group 1 placebo,--- Group 2- Cytoxan therapy

46. Proteinuria (A) and (MDRD) estimated GFR (eGFR; B) during the follow up-period Jha, V. et al. J Am Soc Nephrol 2007;18:1899-1904

47. What about Cyclosporine ?

50. Cyclosporine in progressive membranous nephropathy