Cytotoxic agents in idiopathic membranous nephropathy Claudio - - PowerPoint PPT Presentation

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

• ther investigators reported no benefit

(Row 1975, Pierides 1977, Honkanen 1994)

CONTROLLED TRIALS WITH IMMUNOSUPPRESSIVE DRUGS IN MEMBRANOUS NEPHROPATHY

DONADIO 1974 LAGRUE 1975 TILLER 1981 MURPHY 1992

CYCLOPHOSP 12 months CHLORAMB 12 months AZA 12 months CYCLOPHOSP + WARF + DIPYR 36 months CYCLOPHOSP 6 months WARF + DIPYR 2 years

No effect More remission with Ch 13/16 Better prot u better alb s Better prot u 12 24 36 24

THERAPY Pts F-U mo RESULTS

19 41 54 40

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

20 30 40 50 60 70 80 90 100 12 24 36 48 60 72 84 96 108 120

60% 92%

P=0.0038

months %

10-YEAR SURVIVAL RATE INCLUDING DEATH AND RENAL FAILURE IN PATIENTS GIVEN MP + Ch AND IN UNTREATED PATIENTS

Ponticelli et al: Kidney Int 48,1600,1995

CLINICAL STATUS AT 10 YEARS

Ponticelli C et al Kidney Int 48,1600, 1995

Complete remission Partial remission Nephrotic syndrome Renal insufficiency Dialysis Death 47 19 16 9 6 3 7 36 18 25 14

Treated pts (%) Untreated pts (%)

P=0.020 P=0.043

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 Year 1 Year 2 Year 3 Year 4 45 (58%) 44 (54%) 41 (66%) 32 (62%) 47 (26%) 47 (32%) 43 (40%) 31 (42%) 0.002 0.029 0.011 0.102 MP+Ch Pts (remission) MP Pts (remission)

P

Ponticelli et al, N Eng J Med, 1992

• 20
• 15
• 10
• 5

5 12 24 36 48

months

MP+Ch MP alone

PERCENT VARIATION OF THE RECIPROCAL OF PLASMA CREATININE

%

Methylprednisolone and chlorambucil vs methylprednisolone and cyclophosphamide

Ponticelli C, Altieri P, Scolari F et al J Am Soc Nephrol 9,444,1998

20 40 60 80 100 6 12 18 24 30 36 42 48 54 60 66 72

months %

Mp+Ch 36/44 (82%) Mp+Cy 40/43 (93%)

TIME TO FIRST COMPLETE OR PARTIAL REMISSION

20 40 60 80 100 6 12 18 24 30 36 42 48 54 60

months %

Mp+Ch Mp+Cy

TIME TO FIRST RELAPSE FROM COMPLETE OR PARTIAL REMISSION

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%)

70 80 90 100 1 2 3 4 5 6 7 8 9 10

Renal survival in 174 patients with IMN and NS treated with steroid/cytotoxic drugs

• Renal survival censored by death

Renal survival

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%)

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

RISK OF CANCER

IS IT WORTH TO TREAT PATIENTS WITH IMN AND RENAL INSUFFICIENCY ?

Steroids and chlorambucil

49% 17% 26% 57% TOTAL Severe 7 2 6 11/19

Torres

Mild 10 7 10/17

Brunkhorst

Severe 6 9 5 7/21

Warwick

no 4 4/4

Araque

Severe 7 1 7/8

Mathieson worsened stable improved

Side effects CR-PR Renal function Author

Steroids and cyclophoshamide

du Buf-Vereijken et al AJKD 6,1012,2005 68% 17% 38% 45% TOTAL 47 10 20 35/65 Buf-Vereijken 7 4 12 1/17 Alexopoulos 9 3 3 3/9 Jindal 7 4 7/11 Bruns

worsened stable improved

CR+PR Renal function Author

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

• r 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)

MP + Ch 260±

± ± ±112 186± ± ± ±74 P=0.003

9 pts

P < 0.001

MP + Cy 9 pts

218± ± ± ±85 297± ± ± ±143 P=0.002

Initial Final (6-36 mo)

• Pl. creatinine µ

µ µ µmol/L

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