Cytotoxic agents in idiopathic membranous nephropathy Claudio Ponticelli
Cytotoxic drugs in IMN • cyclophosphamide and chlorambucil the most frequently used drugs • the doses , the durations of treatment (2 months to > 2 years), the lengths of follow- up, the criteria for inclusion (normal or impaired renal function, nephrotic or asymptomatic proteinuria etc) were considerably different
Uncontrolled studies in IMN patients with normal renal function • A number of studies reported good results with the use of cytotoxic drugs generally given together with steroids (Suki 1981, Bruns 1991, Kibriya 1994, Faedda 1995, Rihova 2006, Polenakovic 2006) while other investigators reported no benefit (Row 1975, Pierides 1977, Honkanen 1994)
CONTROLLED TRIALS WITH IMMUNOSUPPRESSIVE DRUGS IN MEMBRANOUS NEPHROPATHY Pts THERAPY F-U mo RESULTS DONADIO 19 CYCLOPHOSP No effect 12 1974 12 months LAGRUE 41 More remission CHLORAMB 12 months 24 AZA 12 months 1975 with Ch 13/16 TILLER 54 CYCLOPHOSP + WARF + 36 Better prot u DIPYR 36 months 1981 better alb s 40 24 MURPHY CYCLOPHOSP 6 months Better prot u WARF + DIPYR 2 years 1992
ITALIAN TRIALS WITH MP AND CYTOTOXIC DRUGS • INCLUSION • ADULT PATIENTS (>16 years) • PROTEINURIA >3.5 g per day • MEMBRANOUS NEPHROPATHY (renal biopsy) • EXCLUSION • SECONDARY MEMBRANOUS NEPHROPATHY • SERUM CREATININE >1.7 mg/dl • PREVIOUS CYTOTOXIC OR STEROID THERAPY
Cycle A (month 1, 3, 5) Methylprednisolone 1 g i.v. for 3 days then Oral prednisone 0.5 mg/Kg/day for 27 days Cycle B (month 2, 4, 6) Chlorambucil 0.2 mg/Kg/day for 30 days
10-YEAR SURVIVAL RATE INCLUDING DEATH AND RENAL FAILURE IN PATIENTS GIVEN MP + Ch AND IN UNTREATED PATIENTS % 92% 100 90 80 P=0.0038 70 60 50 60% 40 30 20 0 12 24 36 48 60 72 84 96 108 120 months Ponticelli et al: Kidney Int 48,1600,1995
CLINICAL STATUS AT 10 YEARS Ponticelli C et al Kidney Int 48,1600, 1995 Untreated pts Treated pts (%) (%) Complete remission 7 47 P=0.020 Partial remission 36 19 Nephrotic syndrome 16 Renal insufficiency 18 9 Dialysis 25 6 P=0.043 Death 14 3
Methylprednisolone plus chlorambucil as compared with methylprednisolone alone for the treatment of idiopathic membranous nephropathy Ponticelli C, Zucchelli P, Passerini P et al N Engl J Med 327,599,1992
REMISSION OF NEPHROTIC SYNDROME IN PATIENTS WITH IMN MP+Ch MP P Pts (remission) Pts (remission) Year 1 45 (58%) 47 (26%) 0.002 Year 2 44 (54%) 47 (32%) 0.029 Year 3 41 (66%) 43 (40%) 0.011 Year 4 32 (62%) 31 (42%) 0.102
PERCENT VARIATION OF THE RECIPROCAL OF PLASMA CREATININE % 5 0 MP+Ch -5 -10 MP alone -15 -20 0 12 24 36 48 months Ponticelli et al, N Eng J Med, 1992
Methylprednisolone and chlorambucil vs methylprednisolone and cyclophosphamide Ponticelli C, Altieri P, Scolari F et al J Am Soc Nephrol 9,444,1998
TIME TO FIRST COMPLETE OR PARTIAL REMISSION % 100 80 Mp+Ch 36/44 (82%) 60 40 Mp+Cy 40/43 (93%) 20 0 0 6 12 18 24 30 36 42 48 54 60 66 72 months
TIME TO FIRST RELAPSE FROM COMPLETE OR PARTIAL REMISSION % 100 80 60 Mp+Ch 40 20 Mp+Cy 0 0 6 12 18 24 30 36 42 48 54 60 months
Results of 3 RCT in MN NEJM 1992; KI 1995; JASN 1998 Treated pts 174 Mean FU 54months First event response 82.6% Complete remission 72 (41.3%) Partial remission 72 (41.3%) Last follow-up response 74.7% Complete remission 59 (33.9%) Partial remission 71 (40.8%)
Renal survival in 174 patients with IMN and NS treated with steroid/cytotoxic drugs Renal survival censored by death 100 ��� 90 ��� Renal survival 80 70 0 1 2 3 4 5 6 7 8 9 10 �����
Side effects leading to interruption of treatment in pts given cytotoxic drugs Infections 5 Gastric intolerance 4 Leukopenia -BM inhibition 3 Peptic ulcer 2 Transient ischemic attack 1 Liver dysfunction 1 Total 16/174 (9.2%)
RISK OF CANCER Patients treated with MP and chlorambucil (results of 3 controlled studies) 3/662 pts/year = 4.5/1000 pts/year General population (Bolt WJ 2000) Males = 5.0/1000 pts/year Females = 3.5/1000 pts/year
IS IT WORTH TO TREAT PATIENTS WITH IMN AND RENAL INSUFFICIENCY ?
Steroids and chlorambucil Author Renal CR-PR Side effects function improved stable worsened Mathieson 7/8 1 7 Severe Araque 4/4 4 no Warwick 7/21 5 9 6 Severe Brunkhorst 10/17 7 10 Mild Torres 11/19 6 2 7 Severe TOTAL 57% 26% 17% 49%
Steroids and cyclophoshamide du Buf-Vereijken et al AJKD 6,1012,2005 Author Renal CR+PR function improved stable worsened Bruns 7/11 4 7 Jindal 3/9 3 3 9 Alexopoulos 1/17 12 4 7 Buf-Vereijken 35/65 20 10 47 TOTAL 45% 38% 17% 68%
A RCT comparing steroids and iv. pulses of cyclophosphamide vs steroids alone Falk R et al Ann Int Med 113,48,1992 • 26 pts with MN and s. creatinine > 2 mg/dl or GFR < 50% were randomized to MPP + oral prednisone + iv cyclophosphamide for 6 months or to prednisone 2 mg/Kg/48 h for 8 weeks • No difference in the baseline parameters • After 2 years of follow-up no difference in the risk of ESRD (4/13 in both groups), in mean proteinuria and in reciprocal of serum creatinine
Controlled trial with MP-chlorambucil vs MPP and i.v. cyclophosphamide pulses (Reichert et al Ann Int Med 121, 328, 1994) Pl. creatinine µ µ mol/L µ µ Final (6-36 mo) Initial P=0.003 MP + Ch 260 ± ± 112 186 ± ± 74 ± ± ± ± 9 pts P < 0.001 P=0.002 MP + Cy 218 ± ± 85 297 ± ± 143 ± ± ± ± 9 pts
CONCLUSIONS (1) • Cytotoxic agents (usually associated with prednisone) may be of benefit both in MN patients with normal renal function and in those with declining renal function • Prolonged treatments may be loaded by side effects , including bone marrow inhibition, infection, gonadal toxicity, bladder toxicity, neoplasia • The iatrogenic morbidity is more frequent and severe in patients with renal insufficiency
CONCLUSIONS (2) • Alternating steroids and an alkylating agent may allow to use cytotoxic drugs for a short period of time (3 months) with good probability of obtaining remission and protecting renal function in the long- term • Some 9% of patients may experience severe side effects usually reversible after the withdrawal of treatment . Such a risk is higher in elderly patients and in those with renal insufficiency
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