Review
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World J Transplant. Jun 24, 2014; 4(2): 57-80
Published online Jun 24, 2014. doi: 10.5500/wjt.v4.i2.57
Calcineurin inhibitor sparing strategies in renal transplantation, part one: Late sparing strategies
Andrew Scott Mathis, Gwen Egloff, Hoytin Lee Ghin
Andrew Scott Mathis, Hoytin Lee Ghin, Pharmacy Department, Monmouth Medical Center, Long Branch, NJ 07740, United States
Gwen Egloff, School of Pharmacy, University of Connecticut, Storrs, CT 06268, United States
Author contributions: All authors have made substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data, drafting the article or revising it critically for important intellectual content, and final approval of the version to be published.
Correspondence to: Andrew Scott Mathis, RPh, BS, PharmD, Pharmacy Department, Monmouth Medical Center, 300 Second Avenue, Long Branch, NJ 07740, United States. smathis@barnabashealth.org
Telephone: +1-732-9236753 Fax: +1-732-9236757
Received: February 8, 2014
Revised: March 24, 2014
Accepted: May 14, 2014
Published online: June 24, 2014
Processing time: 161 Days and 21.4 Hours
Abstract

Kidney transplantation improves quality of life and reduces the risk of mortality. A majority of the success of kidney transplantation is attributable to the calcineurin inhibitors (CNIs), cyclosporine and tacrolimus, and their ability to reduce acute rejection rates. However, long-term graft survival rates have not improved over time, and although controversial, evidence does suggest a role of chronic CNI toxicity in this failure to improve outcomes. Consequently, there is interest in reducing or removing CNIs from immunosuppressive regimens in an attempt to improve outcomes. Several strategies exist to spare calcineurin inhibitors, including use of agents such as mycophenolate mofetil (MMF), mycophenolate sodium (MPS), sirolimus, everolimus or belatacept to facilitate late calcineurin inhibitor withdrawal, beyond 6 mo post-transplant; or using these agents to plan early withdrawal within 6 mo; or to avoid the CNIs all together using CNI-free regimens. Although numerous reviews have been written on this topic, practice varies significantly between centers. This review organizes the data based on patient characteristics (i.e., the baseline immunosuppressive regimen) as a means to aid the practicing clinician in caring for their patients, by matching up their situation with the relevant literature. The current review, the first in a series of two, examines the potential of immunosuppressive agents to facilitate late CNI withdrawal beyond 6 mo post-transplant, and has demonstrated that the strongest evidence resides with MMF/MPS. MMF or MPS can be successfully introduced/maintained to facilitate late CNI withdrawal and improve renal function in the setting of graft deterioration, albeit with an increased risk of acute rejection and infection. Additional benefits may include improved blood pressure, lipid profile and serum glucose. Sirolimus has less data directly comparing CNI withdrawal to an active CNI-containing regimen, but modest improvement in short-term renal function is possible, with an increased risk of proteinuria, especially in the setting of baseline renal dysfunction and/or proteinuria. Renal outcomes may be improved when sirolimus is used in combination with MMF. Although data with everolimus is less robust, results appear similar to those observed with sirolimus.

Keywords: Kidney transplantation; Calcineurin inhibitor; Withdrawal; Sparing; Cyclosporine; Tacrolimus; Renal function; Graft survival

Core tip: Mycophenolic acid derivatives have been used successfully to facilitate late calcineurin inhibitor withdrawal to improve short-term renal function in kidney transplantation. The benefit carries an increased risk of acute cellular rejection. Sirolimus and everolimus are also options, but have comparatively less evidence and carry and increased risk of proteinuria, which is dependent on baseline renal function.