Tacrolimus with mycophenolate mofetil (MMF) or sirolimus vs. cyclosporine with MMF in cardiac transplant patients: 1-year report.

The most advantageous combination of immunosuppressive agents for cardiac transplant recipients has not yet been established. Between November 2001 and June 2003, 343 de novo cardiac transplant recipients were randomized to receive steroids and either tacrolimus (TAC) + sirolimus (SRL), TAC + mycophenolate mofetil (MMF) or cyclosporine (CYA) + MMF. Antilymphocyte induction therapy was allowed for up to 5 days. The primary endpoint of >/=3A rejection or hemodynamic compromise rejection requiring treatment showed no significant difference at 6 months (TAC/MMF 22.4%, TAC/SRL 24.3%, CYA/MMF 31.6%, p = 0.271) and 1 year (p = 0.056), but it was significantly lower in the TAC/MMF group when compared only to the CYA/MMF group at 1 year (23.4% vs. 36.8%; p = 0.029). Differences in the incidence of any treated rejection were significant (TAC/SRL = 35%, TAC/MMF = 42%, CYA/MMF = 59%; p < 0.001), as were median levels of serum creatinine (TAC/SRL = 1.5 mg/dL, TAC/MMF = 1.3 mg/dL, CYA/MMF = 1.5 mg/dL; p = 0.032) and triglycerides (TAC/SRL = 162 mg/dL, TAC/MMF = 126 mg/dL, CYA/MMF = 154 mg/dL; p = 0.028). The TAC/SRL group encountered fewer viral infections but more fungal infections and impaired wound healing. These secondary endpoints suggest that the TAC/MMF combination appears to offer more advantages than TAC/SRL or CYA/MMF in cardiac transplant patients, including fewer >/=3A rejections or hemodynamic compromise rejections and an improved side-effect profile.

Randomized trial of tacrolimus plus mycophenolate mofetil or azathioprine versus cyclosporine oral solution (modified) plus mycophenolate mofetil after cadaveric kidney transplantation: results at 2 years.

BACKGROUND: A previous report described the 1-year results of a prospective, randomized trial designed to investigate the optimal combination of immunosuppressants in kidney transplantation. Recipients of first cadaveric kidney allografts were treated with tacrolimus+mycophenolate mofetil (MMF), cyclosporine oral solution (modified) (CsA)+MMF, or tacrolimus+azathioprine (AZA). Results at 1 year revealed that optimal efficacy and safety were achieved with a regimen containing tacrolimus+MMF. The present report describes results at 2 years. METHODS: Two hundred twenty-three recipients of first cadaveric kidney allografts were randomized to receive tacrolimus+MMF, CsA+MMF, or tacrolimus+AZA. All regimens contained corticosteroids, and antibody induction was used only in patients who experienced delayed graft function. Patients were followed up for 2 years. RESULTS: The results at 2 years corroborate and extend the findings of the previous report. Patients randomized to either treatment arm containing tacrolimus experienced improved kidney function. New-onset insulin dependence remained in four, three, and four patients in the tacrolimus+MMF, CsA+MMF, and tacrolimus+AZA treatment arms, respectively. Furthermore, patients with delayed graft function/acute tubular necrosis who were treated with tacrolimus+MMF experienced a 23% increase in allograft survival compared with patients receiving CsA+MMF (P=0.06). Patients randomized to tacrolimus+MMF received significantly lower doses of MMF compared with those administered CsA+MMF. CONCLUSIONS: All three immunosuppressive regi-mens provided excellent safety and efficacy. How-ever, the best results overall were achieved with tacrolimus+MMF. The combination may provide particular benefit to kidney allograft recipients who develop delayed graft function/acute tubular necrosis. Renal function at 2 years was better in the tacrolimus treatment groups compared with the CsA group.

Randomized trial of tacrolimus (Prograf) in combination with azathioprine or mycophenolate mofetil versus cyclosporine (Neoral) with mycophenolate mofetil after cadaveric kidney transplantation.

BACKGROUND: Our clinical trial was designed to investigate the optimal combination of immunosuppressants for renal transplantation. METHODS: A randomized three-arm, parallel group, open label, prospective study was performed at 15 North American centers to compare three immunosuppressive regimens: tacrolimus + azathioprine (AZA) versus cyclosporine (Neoral) + mycophenolate mofetil (MMF) versus tacrolimus + MMF. All patients were first cadaveric kidney transplants receiving the same maintenance corticosteroid regimen. Only patients with delayed graft function (32%) received antilymphocyte induction. A total of 223 patients were randomized, transplanted, and followed for 1 year. RESULTS: There were no significant differences in baseline demography between the three treatment groups. At 1 year the results are as follows: acute rejection 17% (95% confidence interval 9%, 26%) in tacrolimus + AZA; 20% (confidence interval 11%, 29%) in cyclosporine + MMF; and 15% (confidence interval 7%, 24%) in tacrolimus + MMF. The incidence of steroid resistant rejection requiring antilymphocyte therapy was 12% in the tacrolimus + AZA group, 11% in the cyclosporine + MMF group, and 4% in the tacrolimus + MMF group. There were no significant differences in overall patient or graft survival. Tacrolimus-treated patients had a lower incidence of hyperlipidemia through 6 months posttransplant. The incidence of posttransplant diabetes mellitus requiring insulin was 14% in the tacrolimus + AZA group, 7% in the cyclosporine + MMF and 7% in the tacrolimus + MMF groups. CONCLUSIONS: All regimens yielded similar acute rejection rates and graft survival, but the tacrolimus + MMF regimen was associated with the lowest rate of steroid resistant rejection requiring antilymphocyte therapy.

Prospective risk stratification in renal transplant candidates for cardiac death.

In previous studies to predict future cardiac death of patients undergoing evaluation for renal transplantation, noninvasive or invasive testing of all, or nearly all, patients has been used. In an attempt to decrease the cost of cardiac risk assessment, we prospectively used a two-tiered cardiac risk assessment algorithm on 189 consecutive patients referred for renal transplant evaluation. First, patients were stratified by clinical characteristics of age > or = 50 years, history of angina, insulin-dependent diabetes, congestive heart failure, or abnormal electrocardiogram (excluding left ventricular hypertrophy). Patients having none of these risk factors (n = 94) were considered at low risk for cardiac events and underwent no further cardiac evaluation. Patients with one or more of the cardiac risk factors (n = 95) were considered to be in a high-risk group and were required to undergo further evaluation with thallium myocardial scintigraphy. Follow-up of patients was for 46 +/- 16 months. Cardiac mortality was significantly higher in the clinical high-risk group compared with the clinical low-risk group (17% v 1%, respectively; P < 0.001). Further cardiac risk stratification was evident by thallium myocardial scintigraphy. Patients with reversible thallium defects had significantly higher cardiac mortality rates than patients with no thallium defects (23% v 5%, respectively; P < 0.05). Fixed thallium defects also had predictive value for cardiac mortality (29%,; P < 0.05), but deaths in this fixed defect group tended to occur later in the follow-up period. The initial clinical stratification obviated the need for further noninvasive or invasive testing in nearly half of the renal transplant candidates.(ABSTRACT TRUNCATED AT 250 WORDS)

Outcome of renal transplantation at Oregon Health Sciences University: 1982 to 1990.

1. Graft survival increased over the 4 periods between 1982 and 1990 (82-84, 85-86, 87-88, 89-90). The largest increase was in the 89-90 period. 2. Immunosuppression was the key to improved outcome. Cadaveric graft recipients given OKT3 induction plus triple therapy with cyclosporine, azathioprine, and prednisone had significantly better graft survival compared with all other drug combinations. Other factors were improved patient selection, donor management, and outpatient care. 3. Mean serum creatinine levels did not change after cyclosporine was introduced for immunosuppression. The mean serum creatinine level was approximately 1.7 mg/dl at 3 months, 6 months, and 12 months post-transplantation in all 4 periods. 4. Living-related donor outcome was significantly better than cadaveric donor outcome. Half-life for 2-haplotype-matched kidneys was 37 years compared with 12 years for 1-haplotype matches and 6.5 years for cadaveric kidneys. 5. Immediate function and a rejection-free first month were both associated with significantly improved graft survival. 6. Neither peak PRA nor graft number (1st vs regraft) correlated with graft survival. Highly sensitized (PRA greater than 50%) patients and regrafted patients fared as well as less sensitized (PRA less than or equal to 50%) and first graft recipients. This outcome was attributed to a sensitive crossmatch. Because of the crossmatch, highly sensitized patients received much better HLA matches. 7. The incidence of early rejection and delayed function declined significantly between the earliest and latest periods. Improved immunosuppression, donor management, and renal preservation were cited as contributing factors.