Membranous Nephropathy: The Role of Glucocorticoids or, Plus a - PowerPoint PPT Presentation

Membranous Nephropathy: The Role of Glucocorticoids or, Plus ça change, plus c'est la même chose Ronald J. Falk, MD UNC Kidney Center Chapel Hill NC USA

Racial Distribution of Membranous Racial Distribution of Membranous Glomerulopathy in the GDCN Registry Glomerulopathy in the GDCN Registry (as of 12/2006) (as of 12/2006) Race N (%) † Race N (%) White 926 (63%) White 926 (63%) Black 518 (35%) Black 518 (35%) Other 31 (2%) Other 31 (2%) 1475 1475 † Estimates are among those with known race. Approximately 19% of all patients with membranous on biopsy (n=1826) had unknown race

Patient Course Biopsy Prednisone started Repeat biopsy Prednisone Flare Protein Excretion (g’day) 4 – 3 – ARB 2 – ACEi Remission 1 - 4 Years 18 Mos 4 Mos 8 Years Time line

Hogan SL et al. Am J Kidney Dis 1995; 25(6):862-875

Cattran DC et al. N Engl J Med 1989; 320(4):210-215

Decline in Renal Function in Patients Treated With Prednisone for Idiopathic Membranous Nephropathy and in Controls Cattran DC et al. N Engl J Med 1989; 320(4):210-215

Cameron JS et al. Q J Med 1999; 274:133-156

Treatment of Membranous Nephropathy with Corticosteroids F-Up Study Treatment Results/Comments (months) Coggins CH et al Prednisolone 125 23 • Prednisone associated with Collaborative study mg on alternate day more remission of NS for 8-12 weeks NEJM 1979 • Rapid decline of renal function in steroids N=72, TR 32, PLA 38 Cattran DC et al Prednisolone 45 48 No difference in rates of: mg/m 2 on alternate Toronto Study Group • Progression of RI day for 6 months NEJM 1989 • Remission of NS N=158, TR 81, PLA 77 Ponticelli C et al Prednisolone + 48 • Prednisolone + chlorambucil chlorambucil (TR1) for 6 months induced earlier Italian Study Group on alternating 1 remission of nephrotic NEJM 1992 month course vs syndrome than prednisolone N=92, TR1 45, TR2 47 prednisolone alone alone, but difference may (TR2) for 6 months diminish with time Cameron JS et al Prednisolone 125 36 • No difference in renal mg on alternate day function or proteinuria at 36 MCR study for 8 weeks months QJM 1999 • Modest early benefit (3-6) on N=103, TR 52, PLA 51 proteinuria

Complete and Partial Remission in Patients with Idiopathic Membranous Nephropathy Treated with Methylprednisolone + Chlorambucil (group 1) or Methylprednisolone Alone (group 2) Remission Relative Risk of 95% Confidence Time/Type Group 1 Group 2 P Value Remission Interval Group 1 vs. 2 Year 1 Complete 9/45 (20) 5/47 (11) 1.88 0.67-5.26 Partial 17/45 (38) 7/47 (15) Both 26/45 (58) 12/47 (26) 0.002 2.26 1.23-4.17 Year 2 Complete 11/44 (25) 4/47 (8) 2.94 0.99-8.64 Partial 13/44 (29) 11/47 (23) Both 24/44 (54) 15/47 (32) 0.029 1.71 0.97-3.02 Year 3 Complete 14/41 (34) 4/43 (9) 3.67 1.29-10.42 Partial 13/41 (32) 13/43 (30) Both 27.41 (66) 17.43 (40) 0.011 1.67 1.00-2.80 Year 4 Complete 8/32 (25) 7/31 (23) 1.11 0.44-2.81 Partial 12/32 (38) 6/31 (19) Both 20/32 (62) 13/31 (42) 0.102 1.49 0.83-2.70 Ponticelli C et al. N Engl J Med 1992; 327:599-603

Cyclosporine in Patients with Steroid- Resistant Membranous Nephropathy • Randomized trial in 51 biopsy-proven idiopathic MGN patients • 26 wks of cyclosporine treatment plus low-dose prednisone to placebo + prednisone followed for an average of 78 wks • 75% of treatment group vs. 22% of control group had partial or complete remission of proteinuria by 26 wks • Relapse in 43% of cyclosporine remission group and 40% of placebo group 52 wks • Fraction of population in remission remained almost unchanged until the end of the study (cyclosporine 39%, placebo 13%) Cattran DC et al. Kidney Int 2001; 59:1484-1490

CsA Therapy of MGN Monotherapy or Combined with Steroids • Treatment groups – Prednisone + CsA 21 patients – CsA alone 20 patients • Treatment regimen – Prednisone 0.6 mg/kg BW with tapering – CsA 2-3 mg/kg BW • Target whole blood 12-hour trough levels 100-200 ng/ml • Duration of treatment – 12 months Alexopoulos E et al. Nephrol Dial Transplant 2006; 21(11):3127-3132

Membranous Nephropathy: Cyclosporin Alexopoulos E et al. Nephrol Dial Transplant 2006; 21(11):3127-3132

Relapses and CsA Dose/Levels I) CsA CsA Dose Dose Non- - I) Non Relapsers p Relapsers p relapsers relapsers (mg/kg) (mg/kg) Pred+CsA 15% <0.05 Pred+CsA 15% <0.05 CsA 47% CsA 47% II) CsA CsA Levels (C Levels (C 0 ) 72±48 194±80 <0.03 II) 0 ) 72±48 194±80 <0.03 (ng/ml) (ng/ml) Alexopoulos Alexopoulos et al, et al, Nephrol Nephrol Dial Transplant 21(11):3167,2006 Dial Transplant 21(11):3167,2006

ACTH in Patients with Membranous Nephropathy • 30 nephrotic patients with idiopathic MN randomized to ACTH or no specific treatment (control) for 9 months • ACTH 1.0 mg once/week alternating with 0.75 mg twice/week for the first 8 months, then 0.5 mg once/week during month 9 • Complete or partial remission in 15/15 ACTH group vs. 1/15 patients in controls (p<0.0001) • Results were similar after further 12-month followup Berg A-L et al. Kidney Int 1999; 56:1534-1543

Methylprednisolone + Cytotoxic Agent vs. Synthetic Adrenocorticotropic Hormone in Idiopathic Membranous Nephropathy • Patients randomized to IV prednisolone alternating with cytotoxic drug qo month x 6 months (group A), or to IM synthetic adrenocorticotropic hormone qo week x 1 yr • Complete or partial remission in 15/16 patients in group A and 14/16 patients in group B; 4 complete and 8 partial remissions in group A and 8 complete and 6 partial remissions in group B after 24 months • Most nephrotic patients responded to either treatment; proteinuria significantly ↓ ↓ ↓ ↓ without significant differences between therapies Ponticelli C, et al. Am J Kidney Dis 2006; 47(2):233-240

Conclusions • Glucocorticoids may play a role in the therapy of membranous nephropathy, but not sure of the dose, the route of administration, or the duration of its use