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transplantation, 430 of 525 enrolled patients were randomly assigned to remain on SRL-CsA-steroids (ST) or to have CsA withdrawn and SRL troughs increased two-fold (SRL-ST).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patients (n ϭ 430) who were receiving SRL-CsA-ST were randomly assigned at 3 mo to remain on SRL-CsA-ST or to have CsA withdrawn (SRL-ST group).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.

Summary We report the 48‐month results of a trial testing whether withdrawal of cyclosporine (CsA) from a sirolimus (SRL)‐CsA‐steroid (ST) regimen would impact renal allograft survival. Eligible patients receiving SRL‐CsA‐ST from transplantation were randomly assigned at 3 months to remain on triple therapy (SRL‐CsA‐ST, n = 215) or to have CsA withdrawn and SRL trough concentrations increased (SRL‐ST, n = 215). SRL‐ST therapy resulted in significantly better graft survival, either when including death with a functioning graft as an event (84.2% vs. 91.5%, P = 0.024) or when censoring it (90.6% vs. 96.1%, P = 0.026). Calculated glomerular filtration rate (43.8 vs. 58.3 ml/min, P < 0.001) and mean arterial blood pressure (101.3 vs. 97.1 mmHg, P = 0.047) were also improved with SRL‐ST. Differences in the incidences of biopsy‐proven acute rejection after randomization (6.5% vs. 10.2%, SRL‐CsA‐ST versus SRL‐ST, respectively) and mortality (7.9% vs. 4.7%) were not significant. SRL‐CsA‐ST‐treated patients had significantly higher incidences of adverse events generally associated with CsA, whereas those in the SRL‐ST group experienced greater frequencies of events commonly related to higher trough levels of SRL. In conclusion, early withdrawal of CsA from a SRL‐CsA‐ST regimen rapidly improves renal function and ultimately results in better graft survival.

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The effect of age on the peripheral nervous system was investigated by clinical examination and neurophysiological studies in 59 subjects aged 60-103 years and 23 young subjects. A full laboratory screen for factors which, though clinically silent, may constitute risk factors (RFs) for peripheral neuropathy was also performed in the elderly subjects. Our findings show that the presence of RFs affects exceptionally the electrophysiological parameters in a statistically significant way. The age-dependent changes in nerve conduction parameters were well predicted by non-linear models. The simultaneous electromyographical study demonstrates the re-innervation capacity of the motor system.