Idiopathic Membranous Glomerulopathy: Diagnosis and Treatment Geeta Gyamlani, MD

Clinical case 35 yr old male pt s/b pcp At that time, he was noted to have elevated total cholesterol of 353 mg/dl and triglycerides of 417 mg/dl and was started on simvastatin 40 mg/d Next 2 mo, he started developing swelling + tenderness in his calves. Diagnosed with DVT was started on oral anticoagulant therapy.

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

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

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

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

Swaminathan et al Clin J Am Soc Nephrol 2006

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%

Debiec et al. NEJM 346 (26): 2053 June 27, 2002 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

Results of Western Blotting of Glomerular Proteins with Serum from Patients with Idiopathic Membranous Nephropathy Western Blotting Reactivity to 185-kD Protein Beck et al: NEJM 361:11, 2009

Anti Phospholipase A2 receptor Ab ( PLA2 R)

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

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

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

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

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

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

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

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

Idiopathic Membranous Nephropathy Probability of Surviving Without Developing End-Stage Renal Disease According to Baseline Proteinuria Donadio et al: KI, 1988

Survival from Renal Failure in Patients with Complete, 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)

  Univariate Multivariate Hazard ratio (95% CI) P value At onset  CrCl mL/min 0.97 (0.96–0.99) <0.001  Proteinuria g/d 1.07 (1.02–1.13) 0.008 1.08 (1.02–1.15) 0.009 Follow-up  MAP Remission  NR 1  PR 0.17 (0.09–0.33) NR<PR<CR 0.08 (0.03–0.19)b  CR –b – Troyanov et al. Kidney Int. (2004)

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

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 > 8 g/d <6/12 Pei et al, KI 42,960-966,1992

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

Goal of therapy is to reduce proteinuria and prevent progression to renal failure

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

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 Rx arm n=39 Conservative arm N=42 p Renal Survival 92% 60% P<0.0005 CR/PR 88% 47% P<0.0001 Time spent without NS 58% total f/u period 22% of total 1/sr cr 0.84 0.51 P<0.05

A 10-year follow-up - Renal Survival Ponticelli C et al: KI 48:1600, 1995

Characteristics of Patients at Start of Treatment with MP plus Chlorambucil or MP plus Cyclophosphamide Ponticelli et al: JASN 9:444, 1998

Cumulative Probability of Obtaining (P) or (C) Remission Ponticelli et al: JASN 9:444, 1998

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

Cytoxan in this era Jha, V. et al. J Am Soc Nephrol 2007;18:1899-1904 Characteristic Group 1 Group 2 P No. of cases 46 47 Age (yr) 37.2 ± 12.4 38.0 ± 13.6 0.77 range 16 to 66 18 to 64 Gender ratio 27:19 30:17 0.67 Disease duration (mo) 11.7 ± 6.2 10.8 ± 7.9 0.48 Serum creatinine (mg/dl) 1.17 ± 0.22 1.21 ± 0.31 MDRD GFR (ml/min) 84 ± 22 89 ± 26 0.32 Serum albumin (g/dl) 2.42 ± 0.81 2.34 ± 0.58 0.58 Serum cholesterol (mg/dl) 306.4 ± 88.2 336.7 ± 99.6 0.12 Proteinuria (g/d) 5.91 ± 2.2 6.11 ± 2.5 0.68 Jha, V. et al. J Am Soc Nephrol 2007;18:1899-1904

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

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

What about Cyclosporine ?

Cyclosporine in progressive membranous nephropathy

Cyclosporine How to Use? Initial dose of 3-4mg/kgX6months ( bid dosing). If no response d/c, use something else. If CR occurs stop 3-4 months after CR. If PR ct for 1-2 yrs at full dose. What to target? CR, PR, maintaining stable GFR +/- 20% of pretreatment levels and a non toxic cyclosporine level i.e C0 level of 125-175 or a C2 level of 400-600.

Tacrolimus Monotherapy Randomized Controlled Trial T = tacrolimus; C = control Praga et al: Kid Int, 2007

Tacrolimus Monotherapy Randomized Controlled Trial 56% 36% 13% 9% T = tacrolimus; C = control; numbers within columns indicate the total number of pt in CR or PR in both groups Praga et al: Kid Int, 2007

Mean time to PR and CR in tac group was 6. 1 vs 11 Mean time to PR and CR in tac group was 6.1 vs 11.3 in the control group. 9/19 patients (47%)who achieved CR or PR by month 18 relapsed after tac withdrawal. Time to NS relapse was 4.2 months. Sec endpt of 50% increase in cr: 4% tac vs 26% control. Limitation: short f/u

Tacrolimus +steroids vs CTX + steroids N=73, RCT, 39 Tac 0.1mg/kg/day X6months (T0 levels 5-10) foll by reduced dose X3 months to keep levels 2-5 + prednisone. 34 pts received CTX 100mg/day X 4 months+ prednisone 1yr f/u Wang et al, The American Journal of the Medical Sciences Issue: Volume 339(3), March 2010, pp 233-238

Tacrolimus +steroids vs CTX + steroids Remission Rate was 85% in Tac arm vs 65% in CTX arm, p<0.05 at 6 months but no change at 12 months More pts with Tac had developed glucose tolerance( 30%) Relapse rates similar 6/33 pts in the tac gp and 5/22 in CTX gp. 6 Pts had a repeat renal bx in tac gp. No pts had typical signs of CNI. P<0.01 Wang et al, The American Journal of the Medical Sciences Issue: Volume 339(3), March 2010, pp 233-238 Tac CTX

1 yr prospective RCT, MGN+ NS N=36 received MMF 2gm/day X 12 mths, 17 conservative Rx Outcome: proteinuria, PR, CR 1 yr f/u Am J Kidney Dis 52:699-705

MMF as monotherapy Remission 41% 37% Dussol et al AJKD 2008

Mycophenolate Mofetil + steroids or Cyclophosphamide + steroids Study design: 32 cases and 32 historic controls with MN and renal insufficiency ( Cr >1.5). Intervention: MMF 1gm bid or CTX 1.5mg/kg/day X 1yr + steroids. Outcome: GFR, proteinuria, side effects. Median F/U 23 mths(11-46 months).

Cumulative Incidence of Partial Remission of Proteinuria in Patients Treated with Mycophenolate Mofetil or Cyclophosphamide 72% 66% Branten et al: Am J Kidney Dis 50:248, 2007

Cumulative Incidence of Relapses in Patients Treated with Mycophenolate Mofetil or Cyclophosphamide 55% 38% 13% Branten et al: Am J Kidney Dis 50:248, 2007

Ruggenenti, JASN 14, 1851-57 ,2003

Rituximab Open-label pilot trial n= 15 severely nephrotic patients , 7 failed other IS agents. Rituximab was given at 0, 2 weeks and, 6 months. At 12 mths 2/14 were in CR and 6/14 achieved PR. Prospective identification of responsive pts not possible in their study. Fervenza et al ,Kidney International (2008) 73, 117–125

Rituximab treatment of idiopathic membranous nephropathy Fervenza et al ,Kidney International (2008) 73, 117–125

13 patients with normal renal fx, MGN and dependence to CnI were included. Intervention: 4 weekly doses of ritux Outcome: CR, PR 30 months after CNI withdrawal.

Clinical response not parallel with circulating CD19 cells

A Randomized Pilot Trial Comparing Methylprednisolone Plus a Cytotoxic Agent Versus Synthetic Adrenocorticotropic Hormone in Idiopathic Membranous Nephropathy Ponticelli et al,American Journal of Kidney Diseases - 47, 2006

Prophylactic anticoagulation in MG No RCT Venous thromboembolic events occur in 40% of patients with membranous nephropathy and nephrotic syndrome with a serum albumin concentration of <2.5 g/dl vs 2.7% in those with a serum albumin concentration of >2.5 g/dl(Bellomo et al, Nephron 63 : 249 –254, 1993) . Severe nephrotic syndrome (serum albumin <2.0 to 2.5 g/dl) with other risk factors for thrombosis (e.g., congestive heart failure; prolonged immobilization; morbid obesity; abdominal, orthopedic, or gynecologic surgery) or a family history of "thrombophilia" (who might have a genetic predisposition to thrombosis)

MGN and Transplant Recurrent 10-45% 10-14 months post Tx Graft loss at 10yrs about 12.5% Cyclosporine, MPA, steroids other immunosuppressives do not work. Small series showing rituximab may work.( Sprangers ,CJASN,May 2010 ) De-Novo 2-6% 18-24 months post tx Cause Rejection -exposure of previously unseen glomerular antigens- secondary antibody response. Glomerular injury icreases capillary wall permeability facilitating the deposition of IC Circulating Ab directed against HLA Ag expressed on the graft. Graft loss at 10 yrs about 40-50% Cyclosporine and steroids do not work. Pulse steroids do not work.Treatment is an enigma.

Current Therapies for Idiopathic Membranous Nephropathy Efficacy Safety Chlorambucil + corticosteroids Efficacy in RCT vs placebo Bone marrow suppression, seizures, malignancy, infertility Cyclophosphamide + corticosteroids Small studies suggest efficacy Leukopenia, infertility, hemorrhagic cystitis, malignancy Calcineurin inhibitors placebo; frequent relapses once stopped Hypertension, hyperlipidemia, glucose intolerance, nephrotoxicity (blood levels need to be measured)

Take Home Message Establish whether primary or secondary If pt has normal renal fx, ct monitoring X6 mths + ct conservative therapy. Establish progression score If medium risk/ high risk then treat

Take Home Message The primary regimens used to treat idiopathic MN include Cyclophosphamide or chlorambucil or CNI with glucocorticoids. MMF + glucocorticoids, may be as effective in inducing remission of proteinuria but is associated with a high rate of relapse. No data on the long term effect of MMF on renal survival Synthetic ACTH has been associated with complete or partial remission in a large percentage of patients in one study. No data on long-term outcomes. Rituximab. Data mostly from case series. No data on long term outcomes.

Thankyou