Long-term effects on renal function of dose-reduced calcineurin inhibitor and sirolimus in cardiac transplant patients
Cardiovascular Institute, University of Pittsburgh Medical Center, Pittsburgh, PA, USA. Clinical Transplantation
(Impact Factor: 1.52).
02/2011; 26(1):42-9. DOI: 10.1111/j.1399-0012.2011.01407.x
Khandhar SJ, Shah HV, Shullo MA, Zomak R, Navoney M, McNamara DM, Kormos RL, Toyoda Y, Teuteberg JJ. Long-term effects on renal function of dose-reduced calcineurin inhibitor and sirolimus in cardiac transplant patients. Clin Transplant 2012: 26: 42–49. © 2011 John Wiley & Sons A/S.
Abstract: Calcineurin inhibitor (CNI)-associated renal insufficiency is common after cardiac transplantation (CTX); however, the addition of sirolimus allows for CNI dose reduction and this strategy may limit CNI renal toxicity. This study examines the long-term effects of such a strategy.
Methods: Patients from a single center who had CTX from 1990 to 2007 and who were converted to sirolimus and a dose-reduced CNI were compared to group-matched controls maintained on CNI and an antiproliferative agent.
Results: One hundred and fifty-five patients (79 sirolimus and 76 controls) were included and had similar baseline characteristics. Sirolimus was started a mean of 1429 d post-CTX and maintained for a mean of 823 d. Reason for conversion to sirolimus was renal insufficiency (34%), vasculopathy (29%), recurrent rejection (19%), and other (18%). The eGFR was not different between groups at baseline (44.7 mL/min/1.73 m2 vs. 46.0, p = 0.64) or at any point during follow-up: 90 d, 180 d, 1 yr, 2 yr, and 3 yr.
Conclusion: Patients converted to a regimen of sirolimus and a dosed-reduced CNI have stable renal function over the following three yr, but do not have an improvement in renal outcomes compared to patients maintained on full dose CNI.
Available from: Juan F Delgado
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ABSTRACT: In the last decade, mTOR inhibitors (mTOR-is) have become the cornerstone of the calcineurin inhibitor (CNI)-reduced/free regimens aimed to the preservation of post-transplant renal function. We compared utility and safety of the total replacement of calcineurin inhibitors with a mTOR-i with a strategy based on calcineurin inhibitor minimization and concomitant use of m-TOR-i.
In a retrospective multi-center cohort of 394 maintenance cardiac recipients with renal failure (GFR<60mL/min/1.73m(2)), we compared 235 patients in whom CNI was replaced with a mTOR-i (sirolimus or everolimus) with 159 patients in whom mTOR-is were used to minimize CNIs. A propensity score analysis was carried out to balance between group differences.
Overall, after a median time of 2years from mTOR-i initiation, between group differences for the evolution of renal function were not observed. In a multivariate adjusted model, improvement of renal function was limited to patients with mTOR-i usage within 5years after transplantation, particularly with the conversion strategy, and in those patients who could maintain mTOR-i therapy. Significant differences between strategies were not found for mortality, infection and mTOR-i withdrawal due to drug-related adverse events. However, conversion group tended to have a higher acute rejection incidence than the minimization group (p=0.07).
In terms of renal benefits, our results support an earlier use of mTOR-is, irrespective of the strategy. The selection of either a conversion or a CNI minimization protocol should be based on the clinical characteristics of the patients, particularly their rejection risk.
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ABSTRACT: The effects of sirolimus (SIR), as a substitution for calcineurin inhibitor (CNI) immunoprophylaxis, on renal function in very-long-term cardiac transplant recipients have been a matter of controversy.
To assess the impacts of SIR as a substitution for CNI on renal function up to 24 months in long-term cardiac recipients as well as the renal histological changes in patients with suspected CNI-induced nephrotoxicity.
A total of 23 cardiac transplant recipients aged 57.7 ± 11.2 years, 91 months post-cardiac transplantation were recruited; 15 patients were randomized to CNI-free immune suppression with SIR, and 8 patients were allocated to continue their CNI regimens. Serum creatinine and calculated serum creatinine clearance were measured at prespecified time points up to 24 months. Renal structure and function were assessed by renal biopsies, renal ultrasound, and magnetic resonance imaging at baseline.
There were no significant changes in creatinine clearance during the course of the study in patients treated with SIR. However, SIR-treated patients exhibited a significant decrease in 24-hours and nighttime systolic and diastolic blood pressures. Typical findings of significant hypertensive renal disease were detected in 9 of the 11 (82%) patients. Features of chronic CNI toxicity were detected in 6 (55%) patients.
There is a very high rate of hypertensive renal disease concomitantly with some degree of CNI toxicity in long-term cardiac transplant recipients with renal dysfunction. This very high rate of hypertension-related disease may limit the impact of SIR on improving renal function long term following cardiac transplantation.
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ABSTRACT: Renal dysfunction after heart transplantation is a frequently observed complication, in some cases resulting in significant limitation of quality of life and reduced survival. Since the pathophysiology of renal failure (RF) is multifactorial, the current etiologic paradigm for chronic kidney disease after heart transplantation relies on the concept of calcineurin inhibitor (CNI)-related nephrotoxicity acting on a predisposed recipient. Until recently, the management of RF has been restricted to the minimization of CNI dosage and general avoidance of classic nephrotoxic risk factors, with somewhat limited success. The recent introduction of proliferation signal inhibitors (PSIs) (sirolimus and everolimus), a new class of immunosuppressive drugs lacking intrinsic nephrotoxicity, has provided a completely new alternative in this clinical setting. As clinical experience with these new drugs increases, new renal-sparing strategies are becoming available. PSIs can be used in combination with reduced doses of CNIs and even in complete CNI-free protocols. Different strategies have been devised, including de novo use to avoid acute renal toxicity in high-risk patients immediately after transplantation, or more delayed introduction in those patients developing chronic RF after prolonged CNI exposure. In this review, the main information on the clinical relevance and pathophysiology of RF after heart transplantation, as well as the currently available experience with renal-sparing immunosuppressive regimens, particularly focused on the use of PSIs, is reviewed and summarized, including the key practical points for their appropriate clinical usage.
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