Prednisone withdrawal in kidney transplant recipients on cyclosporine and mycophenolate mofetil--a prospective randomized study. Steroid Withdrawal Study Group.
BACKGROUND
Prospective randomized trials have shown a reduced rate of acute rejection (AR) in mycophenolate mofetil-treated kidney transplant recipients. We hypothesized that this increased protection from AR could allow successful prednisone (P) withdrawal in cyclosporine/mycophenolate mofetil/P-treated recipients.


METHODS
A multicenter, prospective, randomized, double-blind trial of P withdrawal at 3 months post-transplant was initiated. Entry criteria were: primary transplant, adult, no AR by 90 days, mycophenolate mofetil dose > or =2 g/day, cyclosporine dose = 5-15 mg/kg/ day, P dose = 10-15 mg/day. Study participants were randomized to have P tapered over 8 weeks (beginning at 3 months posttransplant) to 0 vs. 10 mg/day. Prestudy power analysis determined 500 recipients should be randomized for 80% statistical power to test equivalence of the primary endpoint, AR, or treatment failure at 1 year posttransplant. By design, the study was to be stopped if interim data precluded reaching equivalence. An established data safety monitoring board monitored the study.


RESULTS
After 266 patients were enrolled, the patient enrollment was stopped (after safety monitoring board review) because of excess rejection in the P withdrawal group. The Kaplan-Meier estimate of the cumulative incidence of rejection or treatment failure within 1 year posttransplant (+/-95% confidence interval) for the maintenance group was 9.8% (4.4%; treatment failure, 14.9%); for the withdrawal group, 30.8% (21.0%; 39.3%). Treatment differences in the distribution of time to event were highly significant (P = 0.0007). Of note, risk was higher in blacks (39.6%) versus nonblacks (16.0%) (P<0.001). At 1 year post-transplant, there was no difference between groups in patient or graft survival. For the patients with functioning grafts at 6 months posttransplant, withdrawal patients had lower cholesterol (P = 0.0005), had higher creatinine (P = 0.03), and were less likely to use antihypertensives (P = 0.001). These differences persist to 1 yr posttransplant.


CONCLUSIONS
We conclude that for recipients on cyclosporine/mycophenolate mofetil/P with no AR at 90 days, the chance of developing subsequent AR is small; if P is tapered and withdrawn, the risk increases (but the majority remain free of acute and chronic rejection). After withdrawal, the risk of AR is different for blacks versus nonblacks. Withdrawal patients had a lower cholesterol level and less need for antihypertensives.
Ahsan
N
N
Milton S. Hershey Medical Center, Hershey, USA.
Hricik
D
D
Matas
A
A
Rose
S
S
Tomlanovich
S
S
Wilkinson
A
A
Ewell
M
M
McIntosh
M
M
Stablein
D
D
Hodge
E
E
D000293:Adolescent; D000328:Adult; D000368:Aged; D016572:Cyclosporine / Q000627:therapeutic use*; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D005938:Glucocorticoids / Q000008:administration & dosage* / Q000627:therapeutic use; D006084:Graft Rejection / Q000453:epidemiology / Q000209:etiology / Q000517:prevention & control; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D015994:Incidence; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000627:therapeutic use; D011182:Postoperative Care; D011241:Prednisone / Q000008:administration & dosage* / Q000627:therapeutic use; D011446:Prospective Studies; D019233:Retreatment; D012307:Risk Factors
D005938:Glucocorticoids; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D009173:Mycophenolic Acid; D011241:Prednisone