A Randomized 2x2 Factorial Clinical Trial of Renal Transplantation: Steroid-Free Maintenance Immunosuppression with Calcineurin Inhibitor Withdrawal after Six Months Associates with Improved Renal Function and Reduced Chronic Histopathology

PLoS One. 2015 Oct 14;10(10):e0139247. doi: 10.1371/journal.pone.0139247. eCollection 2015.

Abstract

Introduction: The two most significant impediments to renal allograft survival are rejection and the direct nephrotoxicity of the immunosuppressant drugs required to prevent it. Calcineurin inhibitors (CNI), a mainstay of most immunosuppression regimens, are particularly nephrotoxic. Until less toxic antirejection agents become available, the only option is to optimize our use of those at hand.

Aim: To determine whether intensive rabbit anti-thymocyte globulin (rATG) induction followed by CNI withdrawal would individually or combined improve graft function and reduce graft chronic histopathology-surrogates for graft and, therefore, patient survival. As previously reported, a single large rATG dose over 24 hours was well-tolerated and associated with better renal function, fewer infections, and improved patient survival. Here we report testing whether complete CNI discontinuation would improve renal function and decrease graft pathology.

Methods: Between April 20, 2004 and 4-14-2009 we conducted a prospective, randomized, non-blinded renal transplantation trial of two rATG dosing protocols (single dose, 6 mg/kg vs. divided doses, 1.5 mg/kg every other day x 4; target enrollment = 180). Subsequent maintenance immunosuppression consisted of tacrolimus, a CNI, and sirolimus, a mammalian target of rapamycin inhibitor. We report here the outcome of converting patients after six months either to minimized tacrolimus/sirolimus or mycophenolate mofetil/sirolimus. Primary endpoints were graft function and chronic histopathology from protocol kidney biopsies at 12 and 24 months.

Results: CNI withdrawal (on-treatment analysis) associated with better graft function (p <0.001) and lower chronic histopathology composite scores in protocol biopsies at 12 (p = 0.003) and 24 (p = 0.013) months, without affecting patient (p = 0.81) or graft (p = 0.93) survival, or rejection rate (p = 0.17).

Conclusion: CNI (tacrolimus) withdrawal at six months may provide a strategy for decreased nephrotoxicity and improved long-term function in steroid-free low immunological risk renal transplant patients.

Trial registration: ClinicalTrials.gov NCT00556933.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Animals
  • Antilymphocyte Serum / chemistry
  • Biopsy
  • Calcineurin Inhibitors / administration & dosage*
  • Drug Administration Schedule
  • Female
  • Graft Rejection / prevention & control
  • Humans
  • Immunosuppression Therapy / methods*
  • Immunosuppressive Agents / administration & dosage*
  • Kidney / drug effects*
  • Kidney Transplantation*
  • Male
  • Middle Aged
  • Mycophenolic Acid / administration & dosage
  • Mycophenolic Acid / analogs & derivatives
  • Prospective Studies
  • Rabbits
  • Sirolimus / administration & dosage
  • Steroids / administration & dosage*
  • Tacrolimus / administration & dosage
  • Time Factors
  • Young Adult

Substances

  • Antilymphocyte Serum
  • Calcineurin Inhibitors
  • Immunosuppressive Agents
  • Steroids
  • Mycophenolic Acid
  • Sirolimus
  • Tacrolimus

Associated data

  • ClinicalTrials.gov/NCT00556933

Grants and funding

This work was supported by the Ann Goldstein-Cheryl Cooper New Frontiers in Transplant Medicine Fund, a Research Support Fund grant from the Nebraska Medical Center and the University of Nebraska Medical Center, and a research grant from Genzyme Corporation, which partially funded statistical analysis and clinical research nurse time. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.