Low-dose tacrolimus, trough-monitored mycophenolate mofetil, and planned steroid withdrawal for cadaveric kidney transplantation: A single center experience
Unité de Transplantation, Hôpital Notre-Dame du Centre Hospitalier de l'Université de Montréal, 1560 Severbrooke Est, Montréal, Québec, Canada H2L HM1.Transplantation Proceedings (Impact Factor: 0.98). 09/2002; 34(5):1694-5. DOI: 10.1016/S0041-1345(02)02986-X
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ABSTRACT: Two previous meta-analyses of randomized, controlled trials of steroid withdrawal after renal transplantation have shown significant increases in acute rejection (both analyses) and graft failure rates (the last analysis). A new examination of this topic including only randomized, controlled trials based on currently used, new, potent therapy with calcineurin inhibitors and mycophenolate mofetil (MMF), avoiding early trials with azathioprine, is justified. Steroid withdrawal in patients on triple therapy including a calcineurin inhibitor and MMF was assessed through meta-analysis of randomized, controlled trials in which intention-to-treat rates of acute rejection and renal allograft failure were established after steroid withdrawal or continuation. Six trials were included, four in patients receiving cyclosporine and two in patients receiving tacrolimus. The risk ratio (RR) for acute rejection was 2.28 (95% confidence interval [CI], 1.65-3.16; P < 0.00001) and the pooled risk difference (RD) was 0.08 (95% CI, 0.05-0.11; P < 0.001), indicating that the proportion of patients with acute rejection after prednisone withdrawal was significantly higher compared with controls. The RR for graft failure was 0.73 (95% CI, 0.42-1.28; P = 0.27) and the RD was -0.01 (95% CI, -0.03-0.01; P = 0.28), indicating that the proportion of patients with graft failure after withdrawal was not significantly different from that observed in controls. Total cholesterol was significantly lower after steroid withdrawal (weighted mean difference, -0.53 microM (95% CI, -0.70 to -0.36; P < 0.0001). Renal allograft recipients on triple therapy with a calcineurin inhibitor, MMF, and steroids are at low but significant risk of acute rejection after steroid withdrawal but do not suffer an increased risk of early graft failure. It is necessary to extend controlled follow-up to confirm graft function stabilization.
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ABSTRACT: The introduction of triple-therapy regimens that include a calcineurin inhibitor (CNI), steroids, and azathioprine greatly reduced the risk of acute rejection in renal transplantation. However, the long-term use of both CNIs and steroids is associated with serious toxicities that ultimately can impact patient/graft survival. Mycophenolate mofetil (MMF), a highly effective immunosuppressant with no known nephrotoxicity, has been shown to provide benefits in preserving long-term renal allograft function relative to azathioprine. For these reasons, MMF has become an integral component of toxicity-sparing maintenance regimens that seek to minimize patient exposure to CNIs and steroids. This paper provides an overview of current strategies for reducing the toxicities associated with these agents, which include both withdrawal and avoidance regimens with or without induction therapy. Data are accumulating that toxicity-sparing regimens involving MMF are safe and decrease the risk of side effects that accompany the use of CNIs and steroids. Future studies will determine how to best implement these regimens in the renal transplant population.
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ABSTRACT: Steroid-sparing strategies have been attempted during the last two decades in order to avoid morbidity in kidney transplant recipients. Previous systematic reviews of steroid withdrawal after kidney transplantation have shown significant increases in acute rejection and an increase in graft failure rates. Steroid avoidance in kidney transplantation is increasingly attempted and the possible benefits or harms have never been a subject of a systematic review. To assess the safety and efficacy of steroid withdrawal or avoidance in patients receiving a kidney transplant. We searched CENTRAL, MEDLINE and EMBASE, references lists and abstracts from international transplantation society scientific meetings. Randomised controlled studies (RCTs) of steroid avoidance or withdrawal were included providing that one treatment arm consisted in steroid avoidance or withdrawal and intention-to-treat rates of acute rejection and graft failure were clearly established after steroid avoidance or use or withdrawal or continuation. Observational studies were tabulated. Two authors independently assessed trial quality and extracted data. Statistical analyses were performed using the random effects model and results expressed as risk ratio (RR) or mean difference (MD) with 95% confidence intervals (CI). We included 30 RCTs (5949 participants). Steroid-sparing strategies showed no effect on mortality or graft loss including death. Patients on any steroid-sparing strategy showed a higher risk of graft loss excluding death than those with conventional steroid use (RR 1.23, 95% CI 1.00 to 1.52), especially in those not receiving MMF/Myf or everolimus (RR 1.70, 95% CI 1.00 to 2.90). Acute rejection was more frequent with a steroid-sparing strategy (RR 1.27, 95% CI 1.14 to 1.40) and more frequent after steroid withdrawal or avoidance when compared with standard steroid treatment when cyclosporin (CsA) was used. Steroid-sparing and withdrawal strategies showed benefits in reducing antihypertensive drug need, serum cholesterol, antihyperlipidaemic drug need, new-onset diabetes after transplantation (NODAT) requiring any treatment and cataracts. Steroid avoidance did not alter serum cholesterol, but was associated with less frequent NODAT requiring any treatment. Cardiovascular events were reduced with steroid avoidance. Reduced antihypertensive drug need and serum cholesterol were similar with CsA or tacrolimus (TAC). Reduced antihyperlipidaemic drug need was only evident with TAC, whereas the reduction in NODAT requiring any treatment was only evident with CsA. Infection was lower in steroid-sparing patients using CsA (RR 0.88, 95% CI 0.78 to 1.00). NODAT requiring any treatment was less frequent with steroid avoidance than with steroid withdrawal. This review confirms that steroid avoidance and steroid withdrawal strategies in kidney transplantation are not associated with increased mortality or graft loss despite an increase in acute rejection. These immunosuppression strategies may allow safe steroid avoidance or elimination a few days after kidney transplantation if antibody induction treatment is prescribed or after three to six months if such induction is not used.
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