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/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.

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. 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

14. 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

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,

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 : ; doi: /ndt/

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:

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

29. 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)

30. 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)

31. 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

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

35. Cattran et al, KI 51, ,1997

37. Goal of therapy is to reduce proteinuria and prevent progression 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:

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
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

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

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

42. Cumulative Probability of Obtaining (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
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:

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:

47. What about Cyclosporine ?

50. Cyclosporine in progressive membranous nephropathy

53. 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 or a C2 level of

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

55. 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

56. 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

57. 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 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

58. 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
Tac
CTX

59. 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:

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

61. 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).

62. 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

63. 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

68. Ruggenenti, JASN 14, ,2003

72. 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

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

74. 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.

75. Clinical response not parallel with circulating CD19 cells

76. 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 , 2006

77. 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)

78. 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.

79. 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)

81. 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

82. 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.

84. Thankyou