At 2 years, SRL conversion among patients with baseline GFR more than 40 mL/min was associated with excellent patient and graft survival, no difference in BCAR, increased urinary protein excretion, and a lower incidence of malignancy compared with CNI continuation. Superior renal function was observed among patients who remained on SRL through 12 to 24 months, particularly in the subgroup of patients with baseline GFR more than 40 mL/min and UPr/Cr less than or equal to 0.11.

Daclizumab reduces the frequency of acute rejection in kidney-transplant recipients.

Sirolimus (SRL) is a mammalian target of rapamycin inhibitor that, in contrast to cyclosporine (CsA), has been shown to inhibit rather than promote cancers in experimental models. At 3 mo ؎ 2 wk after renal transplantation, 430 of 525 enrolled patients were randomly assigned to remain on SRL-CsA-steroids (ST) or to have CsA withdrawn and SRL troughs increased two-fold (SRL-ST). Median times to first skin and nonskin malignancies were compared between treatments using a survival analysis. Mean annualized rates of skin malignancy were calculated, and the relative risk was determined using a Poisson model. Malignancy-free survival rates for nonskin malignancies were compared using Kaplan-Meier estimates and the log-rank test. At 5 yr, the median time to a first skin carcinoma was delayed (491 versus 1126 d; log-rank test, P ‫؍‬ 0.007), and the risk for an event was significantly lower with SRL-ST therapy (relative risk SRL-ST to SRL-CsA-ST 0.346; 95% confidence interval 0.227 to 0.526; P < 0.001, intention-to-treat analysis). The relative risks for both basal and squamous cell carcinomas were significantly reduced. Kaplan-Meier estimates of nonskin cancer were 9.6 versus 4.0% (SRL-CsA-ST versus SRL-ST; P ‫؍‬ 0.032, intention-to-treat analysis). Nonskin cancers included those of the lung, larynx, oropharynx, kidney, gastrointestinal tract, prostate, breast, thyroid, and cervix as well as glioma, liposarcoma, astrocytoma, leukemia, lymphoma, and Kaposi's sarcoma. Patients who received SRL-based, calcineurin inhibitor-free therapy after CsA withdrawal at month 3 had a reduced incidence of both skin and nonskin malignancies at 5 yr after renal transplantation compared with those who received SRL therapy combined with CsA. Longer follow-up and additional trials are needed to confirm these promising results.

Abstract. Graft function at 6 or 12 mo is positively correlated with renal transplant survival. The 36-mo results of a study that tested whether withdrawing cyclosporine (CsA) from a sirolimus (SRL)-CsA-steroid (ST) regimen would affect renal graft survival are reported. Eligible patients (n ϭ 430) who were receiving SRL-CsA-ST were randomly assigned at 3 mo to remain on SRL-CsA-ST or to have CsA withdrawn (SRL-ST group). At 36 mo, the calculated GFR was significantly better with SRL-ST (47.3 versus 59.4 ml/min; P Ͻ 0.001) as was the slope of the GFR (Ϫ3.6 versus 0.8 ml/min; P Ͻ 0.001). This was accompanied by growing trend for improved graft survival in the SRL-ST group (85.1% versus 91.2%, P ϭ 0.052 at 36 mo; 81.4% versus 91.2%, P ϭ 0.015 in a cumulative data analysis up to 54 mo), despite numerically more biopsy-proven acute rejections after randomization (5.6% versus 10.2%; P ϭ 0.107). Lipid parameters were similar between groups, whereas both systolic and diastolic BP were significantly lower in the SRL-ST group. Investigator-reported hypertension, abnormal kidney function, edema, hyperuricemia, hyperkalemia, gingival hyperplasia, and Herpes zoster occurred significantly more often in SRL-CsA-ST patients. Abnormal liver function test results, hypokalemia, thrombocytopenia, and abnormal healing were reported significantly more often with SRL-ST. The discontinuation rate was significantly higher for SRLCsA-ST (48% versus 38%; P ϭ 0.041). In conclusion, withdrawing CsA from a SRL-CsA-ST regimen at 3 mo after transplantation resulted in long-term benefits for renal transplant recipients.Multiple risk factors, including donor origin and age, acute rejection, human leukocyte antigen (HLA) mismatches, ethnic origin, and diabetes, influence long-term graft survival in renal transplantation. The calcineurin inhibitors (CNI) cyclosporine (CsA) and tacrolimus are immunosuppressive agents that have been associated with a reduced incidence of acute rejection and improved graft survival during the first year (1). CNI, however, increase BP, decrease GFR, and contribute to chronic allograft nephropathy. Studies have shown that renal function (2, 3) and BP control (4) are important predictors of graft survival. Therefore, an intervention to improve renal function and BP control by eliminating CNI-related toxicity may result in an improvement in graft survival.

Tacrolimus is more effective than cyclosporine in preventing acute rejection in both African-American and Caucasian patients. However, tacrolimus was associated with an increased risk of posttransplant diabetes mellitus, particularly in African-Americans, which was reversible in some patients.