669: Intermediate Results of Sirolimus (SRL) with Reduced Calcineurin Inhibitors (CNI) in Pediatric Heart Transplant (Htx) Recipients – A Controlled Study
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Cyclosporine and tacrolimus are potent inhibitors of the calcineurin-dependent cytokine synthesis in activated lymphocytes. In renal transplant patients tacrolimus is more powerful in preventing severe and refractory rejections, even when compared with the new cyclosporine microemulsion formulation. Both drugs are equally nephrotoxic, but tacrolimus induces less hypertension and less pronounced hyperlipidaemia. Especially in some categories of patients, a higher incidence of de-novo diabetes mellitus is seen with tacrolimus therapy.
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A de novo calcineurin inhibitor avoidance regimen based on sirolimus has been successfully used worldwide; demonstrating improved renal function from 1 to 5 years. This includes use of an induction antibody followed by sirolimus, mycophenolate mofetil, and steroids. This combination has a somewhat different side effect profile and wider experience has revealed that the use of de novo sirolimus requires careful therapeutic drug level monitoring, especially the first 6 months posttransplant. Experience has also demonstrated that delaying the introduction of sirolimus in patients considered at high risk for early mammalian target of rapamycin associated complications will optimize these results. For such recipients, the initial use of a calcineurin inhibitor drug for 2 to 4 months is preferred, followed by conversion to sirolimus. The late withdrawal of steroids may be possible, but awaits further evaluation in randomized controlled trials.
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BACKGROUND: Transplant recipients in whom cutaneous squamous-cell carcinomas develop are at high risk for multiple subsequent skin cancers. Whether sirolimus is useful in the prevention of secondary skin cancer has not been assessed.METHODS: In this multicenter trial, we randomly assigned transplant recipients who were taking calcineurin inhibitors and had at least one cutaneous squamous-cell carcinoma either to receive sirolimus as a substitute for calcineurin inhibitors (in 64 patients) or to maintain their initial treatment (in 56). The primary end point was survival free of squamous-cell carcinoma at 2 years. Secondary end points included the time until the onset of new squamous-cell carcinomas, occurrence of other skin tumors, graft function, and problems with sirolimus.RESULTS: Survival free of cutaneous squamous-cell carcinoma was significantly longer in the sirolimus group than in the calcineurin-inhibitor group. Overall, new squamous-cell carcinomas developed in 14 patients (22%) in the sirolimus group (6 after withdrawal of sirolimus) and in 22 (39%) in the calcineurin-inhibitor group (median time until onset, 15 vs. 7 months; P=0.02), with a relative risk in the sirolimus group of 0.56 (95% confidence interval, 0.32 to 0.98). There were 60 serious adverse events in the sirolimus group, as compared with 14 such events in the calcineurin-inhibitor group (average, 0.938 vs. 0.250). There were twice as many serious adverse events in patients who had been converted to sirolimus with rapid protocols as in those with progressive protocols. In the sirolimus group, 23% of patients discontinued the drug because of adverse events. Graft function remained stable in the two study groups.CONCLUSIONS: Switching from calcineurin inhibitors to sirolimus had an antitumoral effect among kidney-transplant recipients with previous squamous-cell carcinoma. These observations may have implications concerning immunosuppressive treatment of patients with cutaneous squamous-cell carcinomas. (Funded by Hospices Civils de Lyon and others; TUMORAPA ClinicalTrials.gov number, NCT00133887.). PMID: 22830463
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P649 Aims: Until recently, there has been no practical alternative to the use of calcineurin inhibitors as primary immunosuppressants in lung transplantation. Sirolimus is a novel powerful immunosuppresant without renal toxicity, a common post-transplant problem associated with calcineurin inhibitors therapy. Methods: In 11 patients (3 with cystic fibrosis, 10 with COPD, 1 with CTEPH and 1 with PPH) the indication for lung transplantation was set. After lung transplantation these patients developed chronic kidney failure (creatinine ≥ 2mg/dl) and were switched to a combined immunosuppressive regime with reduced calcineurin inhibitors and sirolimus. The serum levels of the calcineurin inhibitors and of sirolimus should be between 5 ng/ml to 7ng/ml. We documented the values of the kidney function parameters (creatinine, BUN), lung function parameters (VC, FEV1, MEF50, TLC), number of thrombocytes, cholesterol values, triglycerid values on the day of the switch to a combined immunosuppressive regime with calcineurin inhibitors and sirolimus and three month after this switch. Results: All patients had stable lung function parameters during the observed period. There was no significant improvement of all investigated parameters in the whole patient group. According to the time between manifestation of chronic kidney failure and the switch to a combined immunosuppressive regime with calcineurin inhibitors and sirolimus we divided the patients in two groups: group A (n=5) with an early (192 ± 121.12 days) and group B (n=6) with a later (1520 ± 1151.13 days) switch. In group A there was a trend to improvement of renal function (creatinine from 2.85±0.92m/dl to 2.18±0.42mg/dl, p=0.11; BUN from 45.94±19.26mg/dl to 42.06±12.46mg/dl, p=0.69) which however was not significantly (perhaps due to the small number of patients). The number of thrombocytes changed from 251±93.57G/l to 218.25±116.59G/l, p=0.19, cholesterol values from 200.00±1.41mg/dl to 256.5±58.6mg/dl, p=0.4, the triglycerides from 201.5 ±127.99mg/dl to 338.00±52.33mg/dl, p=0.23. In group B there was no improvement of chronic renal insufficiency. Two patients died in fact of chronic kidney failure; one patient is in a dialyses program with the option of a kidney transplantation. Conclusions: This investigation suggests that the early addition of sirolimus and the reduction of the calcineurin inhibitors could be a valuable alternative immunosuppressant in patients with chronic kidney failure.
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This review of immunosuppression in renal transplantation has allowed us to highlight the deleterious effect of calcineurin inhibitor nephrotoxicity and to emphasise the importance of sirolimus. Now, a whole new set of possibilities has opened up in immunosuppression: sirolimus-based immunosuppression without calcineurin inhibitors; sirolimus in combination with calcineurin inhibitors in reduced doses; early calcineurin inhibitor withdrawal from a regimen that combines sirolimus, calcineurin inhibitors and steroids; and calcineurin inhibitor conversion to sirolimus when the first signs of graft nephrotoxicity appear. These new strategies in immunosuppression in renal transplantation are associated with good results in graft and patient survival in year 1, and with better renal function. Therefore, we can hope for better long-term results in transplantation, with a significant increase in the graft half-life and in the patient survival.
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Background. Registry analyses suggest that tacrolimus (TAC)/mycophenolate (MPA) immunosuppression is associated with superior kidney graft survival versus TAC/sirolimus (SRL). Large single-center experience can assist in clarifying these findings, by examining outcomes related to specific utilization practice. Methods. We retrospectively examined the outcomes of 518 consecutive first renal transplants at a single center treated with TAC/SRL (n=307) or TAC/MPA (n=211) with prednisone. Graft and patient survival, acute rejection, and 1-year glomerular filtration rate (GFR) were analyzed by era of transplant (2000–2002 vs. 2003–2006). Changes in TAC/SRL utilization between eras included elimination of the SRL loading dose and a reduction in TAC target trough concentrations. Results. Three-year graft survival with TAC/SRL was lower when first used (2000–2002) because of a higher incidence of patient death, primarily due to cardiovascular causes. Survival improved from 85.3% to 95.9% between 2000 to 2002 and 2003 to 2006 (P=0.001), with comparable graft and patient survival between TAC/SRL and TAC/MPA cohorts, confirmed following multivariable analysis controlling for donor and recipient factors. Rates of BK virus and acute rejection were comparable, but a higher incidence of hyperlipidemia, anemia, posttransplant diabetes, and a lower 1-year GFR (57.6 vs. 63.1 mL/min, P=0.008) was noted in the TAC/SRL cohort. Conclusions. These data, as the largest long-term single-center report comparing TAC/SRL with TAC/MPA in kidney transplantation, demonstrate worse patient survival initially with TAC/SRL, with improved outcomes in a later era that were temporally associated with reduced TAC exposure. Differences in cardiovascular risk factors and 1-year GFR highlight the need for further investigation of the optimal utilization of SRL in kidney transplantation.
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