Calcineurin inhibitor withdrawal or tapering for kidney transplant recipients

• Published in: Cochrane database of systematic reviews 2017-07, Vol.7 (7), p.CD006750
• Main Authors: Karpe, Krishna M, Talaulikar, Girish S, Walters, Giles D
• Format: Article
• Language: English
• Subjects: Acute Disease; Calcineurin Inhibitors - administration & dosage; Calcineurin Inhibitors - adverse effects; Cytomegalovirus Infections - epidemiology; Cytomegalovirus Infections - prevention & control; Drug Substitution; Graft Rejection - epidemiology; Graft Rejection - etiology; Graft Rejection - prevention & control; Graft Survival; Humans; Hypertension - epidemiology; Immunosuppression Therapy - methods; Immunosuppressive Agents - therapeutic use; Intention to Treat Analysis; Kidney; Kidney disease; Kidney Transplantation - mortality; Neoplasms - epidemiology; Randomized Controlled Trials as Topic; Time Factors; TOR Serine-Threonine Kinases - antagonists & inhibitors; TRANSPLANTATION: KIDNEY; Withholding Treatment
• ISSN: 1469-493X
• DOI: 10.1002/14651858.CD006750.pub2

Calcineurin inhibitors (CNI) can reduce acute transplant rejection and immediate graft loss but are associated with significant adverse effects such as hypertension and nephrotoxicity which may contribute to chronic rejection. CNI toxicity has led to numerous studies investigating CNI withdrawal and tapering strategies. Despite this, uncertainty remains about minimisation or withdrawal of CNI. This review aimed to look at the benefits and harms of CNI tapering or withdrawal in terms of graft function and loss, incidence of acute rejection episodes, treatment-related side effects (hypertension, hyperlipidaemia) and death. We searched the Cochrane Kidney and Transplant Specialised Register to 11 October 2016 through contact with the Information Specialist using search terms relevant to this review. Studies contained in the Specialised Register are identified through search strategies specifically designed for CENTRAL, MEDLINE, and EMBASE; handsearching conference proceedings; and searching the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov. All randomised controlled trials (RCTs) where drug regimens containing CNI were compared to alternative drug regimens (CNI withdrawal, tapering or low dose) in the post-transplant period were included, without age or dosage restriction. Two authors independently assessed studies for eligibility, risk of bias, and extracted data. Results were expressed as risk ratio (RR) or mean difference (MD) with 95% confidence intervals (CI). We included 83 studies that involved 16,156 participants. Most were open-label studies; less than 30% of studies reported randomisation method and allocation concealment. Studies were analysed as intent-to-treat in 60% and all pre-specified outcomes were reported in 54 studies. The attrition and reporting bias were unclear in the remainder of the studies as factors used to judge bias were reported inconsistently. We also noted that 50% (47 studies) of studies were funded by the pharmaceutical industry.We classified studies into four groups: CNI withdrawal or avoidance with or without substitution with mammalian target of rapamycin inhibitors (mTOR-I); and low dose CNI with or without mTOR-I. The withdrawal groups were further stratified as avoidance and withdrawal subgroups for major outcomes.CNI withdrawal may lead to rejection (RR 2.54, 95% CI 1.56 to 4.12; moderate certainty evidence), may make little or no difference to death (RR 1.09, 95% CI 0.96 to 1.24;