Systematic Review of Calcineurin Inhibitors for Renal Transplant

Project Summary Title and Description

Systematic Review of Calcineurin Inhibitors for Renal Transplant
The calcineurin inhibitors (CNIs) tacrolimus and cyclosporine A (CsA) are effective immunosuppressive agents for renal transplantation, but they must be managed carefully to avoid toxicity. Routine therapeutic monitoring guides dosing, but uncertainty surrounds different monitoring methods and timepoints. Additionally, the effectiveness of strategies to reduce CNI exposure with lower therapeutic levels and other immunosuppressants is unclear. This systematic review evaluates the evidence for three Key Questions. Key Question 1 compares immunoassay analysis with liquid chromatographic or mass spectrometric analytical techniques for therapeutic monitoring of CNIs. Key Question 2 examines CsA monitoring timepoints. Key Question 3 evaluates alternatives to full-dose CNI regimens.
Authors of Report
Methodology description
We searched four bibliographic databases and gray literature sources, covering literature published from 1994 through May 2015. English-language studies of adult renal transplants were included. All donor types and retransplants were eligible, but multi-organ recipients were excluded. We meta-analyzed data when appropriate, assessed studies for risk of bias, and evaluated the strength of evidence.
AHRQ report available at: Retrospective manual data entry. Related publication PubMedID: 26990455. Uploaded document is complete AHRQ final report, including all data, appendices, and references.
Funding Source
Agency for Healthcare Research and Quality (AHRQ)

Key Questions

1. In adult renal transplants, how do liquid chromatographic and mass spectrometric analytical techniques compare with immunoassay analysis for therapeutic monitoring of full dosing regimens of the calcineurin inhibitors (CNIs) cyclosporine and tacrolimus? AND In adult renal transplants, how do liquid chromatographic and mass spectrometric analytical techniques compare with immunoassay analysis for therapeutic monitoring of lower CNI doses used in minimization, conversion, or withdrawal strategies?
2. In adult renal transplants, how does 2-hour post-administration cyclosporine monitoring (C2) compare with trough monitoring (C0) for health outcomes?
3. In adult renal transplants, how do immunosuppressive regimens designed to reduce or eliminate exposure to CNI toxicity compare with each other and with full-dose CNI regimens for health outcomes? AND How does the type of induction agent (including when no induction is used) and the use of concurrent immunosuppressive agents affect outcomes of regimens that reduce or eliminate CNI exposure?

Associated Extraction Forms

Associated Studies (each link opens a new tab)

Clinical evaluation of the QMS® Tacrolimus immunoassay.2014
Multi-center analytical evaluation of a novel automated tacrolimus immunoassay.2014
Cloned enzyme donor immunoassay tacrolimus assay compared with high-performance liquid chromatography-tandem mass spectrometry and microparticle enzyme immunoassay in liver and renal transplant recipients.2007
Clinical outcomes of renal transplantation using liquid chromatographic monitoring of tacrolimus.2006
Comparison of an ELISA and an LC/MS/MS method for measuring tacrolimus concentrations and making dosage decisions in transplant recipients.2002
High-performance liquid chromatography-tandem mass spectrometry as a reference for analysis of tacrolimus to assess two immunoassays in patients with liver and renal transplants.1997
Reduced exposure to calcineurin inhibitors in renal transplantation.2007
Conversion of long-term kidney transplant recipients from calcineurin inhibitor therapy to everolimus: a randomized, multicenter, 24-month study.2011
A randomized, controlled trial of everolimus-based dual immunosuppression versus standard of care in de novo kidney transplant recipients.2014
Cyclosporine sparing with mycophenolate mofetil, daclizumab and corticosteroids in renal allograft recipients: the CAESAR Study.2007
Randomized trial of Alemtuzumab for prevention of graft rejection and preservation of renal function after kidney transplantation.2005
Fixed- or controlled-dose mycophenolate mofetil with standard- or reduced-dose calcineurin inhibitors: the Opticept trial.2009
Cardiovascular risk profile in kidney transplant recipients treated with two immunosuppressive regimens: tacrolimus and mycophenolate mofetil versus everolimus and low-dose cyclosporine.2009
Randomized controlled study comparing reduced calcineurin inhibitors exposure versus standard cyclosporine-based immunosuppression.2007
Conversion of ciclosporin A to tacrolimus in kidney transplant recipients with chronic allograft nephropathy.2006
A single-centre, open-label, prospective study of an initially short-term intensified dosing regimen of enteric-coated mycophenolate sodium with reduced cyclosporine A exposure in Chinese live-donor kidney transplant recipients.2014
Enteric-coated mycophenolate sodium in combination with full dose or reduced dose cyclosporine, basiliximab and corticosteroids in Australian de novo kidney transplant patients.2013
A 50% reduction in cyclosporine exposure in stable renal transplant recipients: renal function benefits.2010
Impact of daclizumab, low-dose cyclosporine, mycophenolate mofetil and steroids on renal function after kidney transplantation.2010
Reduced-exposure cyclosporine is safe and efficacious in de novo renal transplant recipients treated with enteric-coated mycophenolic acid and basiliximab.2007
Renal function with cyclosporine C2 monitoring, enteric-coated mycophenolate sodium and basiliximab: a 12-month randomized trial in renal transplant recipients.-- Not Found --
Low-dose versus high-dose cyclosporine induction protocols in renal transplantation.2007
Impact of cyclosporine reduction with MMF: a randomized trial in chronic allograft dysfunction. The 'reference' study.2006
Long-Term Impact of Cyclosporin Reduction with MMF Treatment in Chronic Allograft Dysfunction: REFERENECE Study 3-Year Follow Up.2010
A randomized controlled trial of immunosuppression conversion for the treatment of chronic allograft nephropathy.2004
A prospective, randomized clinical trial of cyclosporine reduction in stable patients greater than 12 months after renal transplantation.2003
A controlled trial comparing two doses of cyclosporine in conjunction with mycophenolate mofetil and corticosteroids.2001
Renal Function and NODM in De Novo Renal Transplant Recipients Treated with Standard and Reduced Levels of Tacrolimus in Combination with EC-MPS.2012
A multicenter, randomized trial of increased mycophenolic acid dose using enteric-coated mycophenolate sodium with reduced tacrolimus exposure in maintenance kidney transplant recipients.2012
Optimizing tacrolimus therapy in the maintenance of renal allografts: 12-month results.2008
The efficacy and safety of cyclosporine reduction in de novo renal allograft patients receiving sirolimus and corticosteroids: results from an open-label comparative study.2014
Randomized trial of everolimus-facilitated calcineurin inhibitor minimization over 24 months in renal transplantation.2013
Efficacy and safety of concentration-controlled everolimus with reduced-dose cyclosporine in Japanese de novo renal transplant patients: 12-month results.2013
Safety and efficacy of the early introduction of everolimus with reduced-exposure cyclosporine a in de novo kidney recipients.2015
Effect of everolimus on left ventricular hypertrophy of de novo kidney transplant recipients: a 1 year, randomized, controlled trial.2012
Good outcomes with cyclosporine very low exposure with everolimus high exposure in renal transplant patients.-- Not Found --
Everolimus with very low-exposure cyclosporine a in de novo kidney transplantation: a multicenter, randomized, controlled trial.2009
Everolimus and reduced-exposure cyclosporine in de novo renal-transplant recipients: a three-year phase II, randomized, multicenter, open-label study.2004
A comparative, randomized trial of concentration-controlled sirolimus combined with reduced-dose tacrolimus or standard-dose tacrolimus in renal allograft recipients.-- Not Found --
Everolimus plus early tacrolimus minimization: a phase III, randomized, open-label, multicentre trial in renal transplantation.2012
Multicenter, randomized study of the use of everolimus with tacrolimus after renal transplantation demonstrates its effectiveness.2008
Observations regarding the use of sirolimus and tacrolimus in high-risk cadaveric renal transplantation.2004
Deferred pre-emptive switch from calcineurin inhibitor to sirolimus leads to improvement in GFR and expansion of T regulatory cell population: a randomized, controlled trial.
Conversion from cyclosporine to everolimus at 4.5 months posttransplant: 3-year results from the randomized ZEUS study.2012
A randomized controlled trial of late conversion from CNI-based to sirolimus-based immunosuppression following renal transplantation.
Renal, efficacy and safety outcomes following late conversion of kidney transplant patients from calcineurin inhibitor therapy to everolimus: the randomized APOLLO study.2015
Mycophenolate mofetil-based immunosuppression with sirolimus in renal transplantation: a randomized, controlled Spare-the-Nephron trial.2011
Conversion from calcineurin inhibitors to sirolimus maintenance therapy in renal allograft recipients: 24-month efficacy and safety results from the CONVERT trial.2009
Impact of calcineurin-inhibitor conversion to mTOR inhibitor on renal allograft function in a prednisone-free regimen.2013
Planned randomized conversion from tacrolimus to sirolimus-based immunosuppressive regimen in de novo kidney transplant recipients.2013
Results of a prospective randomized trial of sirolimus conversion in kidney transplant recipients on early corticosteroid withdrawal.2011
Fibrosis progression according to epithelial-mesenchymal transition profile: a randomized trial of everolimus versus CsA.
Improved renal function after early conversion from a calcineurin inhibitor to everolimus: a randomized trial in kidney transplantation.2012
Sirolimus versus calcineurin inhibitor-based immunosuppressive therapy in kidney transplantation: a 4-year follow-up.2012
Renal function, efficacy, and safety of sirolimus and mycophenolate mofetil after short-term calcineurin inhibitor-based quadruple therapy in de novo renal transplant patients: one-year analysis of a randomized multicenter trial.2010
Efficacy on renal function of early conversion from cyclosporine to sirolimus 3 months after renal transplantation: concept study.2009
Prospective comparison of the use of sirolimus and cyclosporine in recipients of a kidney from an expanded criteria donor.2008
The Cairo kidney center protocol for rapamycin-based sequential immunosuppression in kidney transplant recipients: 2-year outcomes.2007
Conversion from cyclosporine to azathioprine at three months reduces the incidence of chronic allograft nephropathy.2003
Long-term outcome of a prospective randomized trial of conversion from cyclosporine to azathioprine treatment one year after renal transplantation.1998
The effect of immunosuppressive drugs on quality of life after renal transplantation.1995
Mycophenolate mofetil substitution for cyclosporine a in renal transplant recipients with chronic progressive allograft dysfunction: the "creeping creatinine" study.2005
Switching from calcineurin inhibitor-based regimens to a belatacept-based regimen in renal transplant recipients: a randomized phase II study.2011
Calcineurin inhibitor withdrawal after renal transplantation with alemtuzumab: clinical outcomes and effect on T-regulatory cells.2008
Assessment of the risk of chronic allograft dysfunction after renal transplantation in a randomized cyclosporine withdrawal trial.2006
Early withdrawal of cyclosporine A improves 1-year kidney graft structure and function in sirolimus-treated patients.2003
Open randomized trial comparing early withdrawal of either cyclosporine or mycophenolate mofetil in stable renal transplant recipients initially treated with a triple drug regimen.2002
Randomized trial comparing late concentration-controlled calcineurin inhibitor or mycophenolate mofetil withdrawal.2012
Withdrawal of cyclosporine or tacrolimus after addition of mycophenolate mofetil in patients with chronic allograft nephropathy.2004
Long-term outcomes after cyclosporine or mycophenolate withdrawal in kidney transplantation - results from an aborted trial.-- Not Found --
Cyclosporine withdrawal from a mycophenolate mofetil-containing immunosuppressive regimen in stable kidney transplant recipients: a randomized, controlled study.2002
Withdrawal of cyclosporine or prednisone six months after kidney transplantation in patients on triple drug therapy: a randomized, prospective, multicenter study.2002
Improved renal function in sirolimus-treated renal transplant patients after early cyclosporine elimination.2002
Sirolimus allows early cyclosporine withdrawal in renal transplantation resulting in improved renal function and lower blood pressure.2001
The ORION study: comparison of two sirolimus-based regimens versus tacrolimus and mycophenolate mofetil in renal allograft recipients.2011
Steroid or tacrolimus withdrawal in renal transplant recipients using sirolimus.2011
A phase III study of belatacept-based immunosuppression regimens versus cyclosporine in renal transplant recipients (BENEFIT study).
A phase III study of belatacept versus cyclosporine in kidney transplants from extended criteria donors (BENEFIT-EXT study).2010
Kidney transplantation without calcineurin inhibitor drugs: a prospective, randomized trial of sirolimus versus cyclosporine.2002
A Prospective Randomised Paired Trial of Sirolimus versus Tacrolimus as Primary Immunosuppression following Non-Heart Beating Donor Kidney Transplantation.2014
Thymoglobulin induction and sirolimus versus tacrolimus in kidney transplant recipients receiving mycophenolate mofetil and steroids.2010
Short-term results under three different immunosuppressive regimens at one center.2006
Sirolimus (rapamycin)-based therapy in human renal transplantation: similar efficacy and different toxicity compared with cyclosporine. Sirolimus European Renal Transplant Study Group.1999
Alemtuzumab preconditioning allows steroid-calcineurin inhibitor-free regimen in live-donor kidney transplant.2011
Conversion from cyclosporine to sirolimus in chronic renal allograft dysfunction: a 4-year prospective study.2011
Protective effects of sirolimus by attenuating connective tissue growth factor expression in human chronic allograft nephropathy.2007
Conversion to low-dose tacrolimus or rapamycin 3 months after kidney transplantation: a prospective, protocol biopsy-guided study.2011
Renal function outcomes in kidney transplant recipients after conversion to everolimus-based immunosuppression regimen with CNI reduction or elimination.2009
Rapamycin for treatment of chronic allograft nephropathy in renal transplant patients.2005
High incidence of rejection episodes and poor tolerance of sirolimus in a protocol with early steroid withdrawal and calcineurin inhibitor-free maintenance therapy in renal transplantation: experiences of a randomized prospective single-center study.2012
Early withdrawal of calcineurin inhibitor from a sirolimus-based immunosuppression stabilizes fibrosis and the transforming growth factor-β signalling pathway in kidney transplant.2015
Comparison of sirolimus with low-dose tacrolimus versus sirolimus-based calcineurin inhibitor-free regimen in live donor renal transplantation.2005
Comparison of sirolimus-based calcineurin inhibitor-sparing and calcineurin inhibitor-free regimens in cadaveric renal transplantation.2004
Predictive factors of acute rejection after early cyclosporine withdrawal in renal transplant recipients who receive mycophenolate mofetil: results from a prospective, randomized trial.2005
Everolimus-based, calcineurin-inhibitor-free regimen in recipients of de-novo kidney transplants: an open-label, randomised, controlled trial.2011
Application of low-dose calcineurin inhibitors in living-related donor renal transplantation2011
Measurement of whole blood tacrolimus level by high performance liquid chromatography tandem mass spectrometry in renal transplant recipients - a single center perspective2005
Conversion of C-0 to C-2 monitoring of cyclosporine in stable kidney transplant patients.2003
Early cyclosporine C0 and C2 monitoring in de novo kidney transplant patients: a prospective randomized single-center pilot study.2006
Long-term comparative results of C0 and C2 monitoring of CyA in renal transplanted patients.2005
Outcome of microemulsion cyclosporine C2 concentration monitoring in kidney transplantation.2005
Comparison between C0 and C2 monitoring in de novo renal transplant recipients: retrospective analysis of a single-center experience.2004
Analysis of NFAT-regulated gene expression in vivo: a novel perspective for optimal individualized doses of calcineurin inhibitors.2004
Analytical performance of the CEDIA cyclosporine PLUS whole blood immunoassay.2004
Evaluation of four automated methods for determination of whole blood cyclosporine concentrations.1999
Cyclosporin whole blood immunoassays (AxSYM, CEDIA, and Emit): a critical overview of performance characteristics and comparison with HPLC.1998
A method of relating whole blood cyclosporin A results by HPLC to Abbott TDx monoclonal and polyclonal immunoassays.1995

Downloadable Data Content

  • XLSX Project Data