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

Membranous Nephropathy: The Role of Glucocorticoids

• r,

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) 1475 1475 31 (2%) 31 (2%) Other Other 518 (35%) 518 (35%) Black Black 926 (63%) 926 (63%) White White N (%) N (%)† Race Race

† Estimates are among those with known race. Approximately 19% of all patients with membranous on biopsy (n=1826) had unknown race

Patient Course

Protein Excretion (g’day)

4 – 3 – 2 – 1 - Time line

Biopsy Prednisone started Remission 8 Years Flare Repeat biopsy Prednisone ARB ACEi 18 Mos 4 Years 4 Mos

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

• Prednisolone + chlorambucil

for 6 months induced earlier remission of nephrotic syndrome than prednisolone alone, but difference may diminish with time 48 Prednisolone + chlorambucil (TR1)

• n alternating 1

month course vs prednisolone alone (TR2) for 6 months Ponticelli C et al Italian Study Group NEJM 1992 N=92, TR1 45, TR2 47 No difference in rates of:

• Progression of RI
• Remission of NS

48 Prednisolone 45 mg/m2 on alternate day for 6 months Cattran DC et al Toronto Study Group NEJM 1989 N=158, TR 81, PLA 77

• No difference in renal

function or proteinuria at 36 months

• Modest early benefit (3-6) on

proteinuria 36 Prednisolone 125 mg on alternate day for 8 weeks Cameron JS et al MCR study QJM 1999 N=103, TR 52, PLA 51

• Prednisone associated with

more remission of NS

• Rapid decline of renal

function in steroids 23 Prednisolone 125 mg on alternate day for 8-12 weeks Coggins CH et al Collaborative study NEJM 1979 N=72, TR 32, PLA 38

Results/Comments F-Up (months) Treatment Study

Complete and Partial Remission in Patients with Idiopathic Membranous Nephropathy Treated with Methylprednisolone + Chlorambucil (group 1) or Methylprednisolone Alone (group 2)

Remission Time/Type Group 1 Group 2 P Value Relative Risk of Remission Group 1 vs. 2 95% Confidence Interval Year 1 Complete Partial Both 9/45 (20) 17/45 (38) 26/45 (58) 5/47 (11) 7/47 (15) 12/47 (26) 0.002 1.88 2.26 0.67-5.26 1.23-4.17 Year 2 Complete Partial Both 11/44 (25) 13/44 (29) 24/44 (54) 4/47 (8) 11/47 (23) 15/47 (32) 0.029 2.94 1.71 0.99-8.64 0.97-3.02 Year 3 Complete Partial Both 14/41 (34) 13/41 (32) 27.41 (66) 4/43 (9) 13/43 (30) 17.43 (40) 0.011 3.67 1.67 1.29-10.42 1.00-2.80 Year 4 Complete Partial Both 8/32 (25) 12/32 (38) 20/32 (62) 7/31 (23) 6/31 (19) 13/31 (42) 0.102 1.11 1.49 0.44-2.81 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

<0.03 <0.03 194±80 194±80 72±48 72±48 II) II) CsA CsA Levels (C Levels (C0

0)

) (ng/ml) (ng/ml) 47% 47% CsA CsA <0.05 <0.05 15% 15% Pred+CsA Pred+CsA p p Non Non-

• relapsers

relapsers Relapsers Relapsers I) I) CsA CsA Dose Dose (mg/kg) (mg/kg)

Alexopoulos Alexopoulos et al, et al, Nephrol Nephrol Dial Transplant 21(11):3167,2006 Dial Transplant 21(11):3167,2006

Relapses and CsA Dose/Levels

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