Calcineurin Inhibitor-Sparing Regimens In Solid Organ Transplantation: Focus On Improving Renal Function And Nephrotoxicity

Main Category: Transplants / Organ Donations
Also Included In: Urology / Nephrology
Article Date: 24 Feb 2008 - 0:00 PDT

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BERKELEY, CA (UroToday.com) - Clinical solid organ transplantation is a great success story, and when permanent failure of the kidney, liver, heart, or lung occurs, replacement by transplant is the preferred treatment option. Today with 1-year graft survivals approaching 90% the number of waiting recipients far outstrips organ supply, which has limited further expansion. The improvement in survivals, both for patients and grafts has been an incremental process resulting from advances in surgical and preservation techniques, immunosuppression, better understanding of the rejection process, and advances in diagnosing and treating post transplant infections, among others. One of the major recent advances has been a significant reduction in acute rejection episodes that has coincided with the near universal use of the calcineurin inhibitor drugs, cyclosporine and tacrolimus. However, these reductions have not translated into parallel increases in 5 and 10-year survivals, especially for kidney transplants. Also troubling, is a rising rate of permanent renal failure among non-renal transplant recipients. The toll on the allograft or native kidney appears related to the continuous use of the calcineurin inhibitor drugs, which are nephrotoxic and contribute to chronic renal scarring and loss of function. This phenomenon was also observed 13 months after the first partial face transplant.

During the past few years reducing the use of calcineurin inhibitor drugs has become an intense focus of transplant research. Immunosuppressive protocols have been developed that incorporate either a minimization of the dose of these drugs, complete avoidance of calcineurin inhibitors, or the withdrawal of these agents after 3-6 months of initial use.

An attractive replacement for calcineurin inhibitors has been the mammalian target of rapamycin inhibitor drugs, sirolimus and everolimus, which exhibit little direct nephrotoxicity. Several studies have demonstrated that transplantation with limited use of calcineurin inhibitor drugs results in improved post transplant renal function. Additional follow-up is still needed to confirm that these findings eventuate in better long-term graft survival. No one approach appears to be advantageous for all recipients of solid organs, and using the TOR inhibitors instead of calcineurin inhibitors are accompanied by differing toxicities such as hyperlipidemia, bone marrow suppression, and delayed wound healing. Future trials are needed to help refine precisely which recipients can be safely transplanted without calcineurin inhibitors, and if they are used, when is the best time to withdraw them before permanent renal injury has occurred.

Written by

Stuart M. Flechner MD, Jon Kobashigawa MD, Goran Klintmalm MD, PhD, as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.

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