The kidney is the most commonly transplanted organ in the US, with more than 17,000 transplants performed each year. Following kidney transplant, patients are routinely placed on a regimen of immunosuppressant medications to prevent organ rejection, which often includes calcineurin inhibitors (CNIs) as the backbone medication of this regimen. However, questions remain about the best use of these drugs to strike the balance between preventing rejection and avoiding drug-related complications.
Researchers from the Perelman School of Medicine at the University of Pennsylvania, in partnership with ECRI Institute under the ECRI Institute-Penn Medicine Evidence-based Practice Centre contract, investigated four immuno-suppression strategies and found that many patients might benefit from a lower-than-standard dose of CNIs.
One of the main hurdles in using immuno-suppressant medications is finding the right balance between too little drug, which results in organ rejection, and too much drug, which can increase risk of infections, renal failure, cardiovascular disease and diabetes. As part of the larger AHRQ report, the team conducted an analysis of 105 studies from 1994 through 2015 to compare laboratory techniques for monitoring CNI drug levels, to examine the best times to collect CNI drug levels, and to evaluate alternatives to using standard dose CNIs as part of the immuno-suppressant regimen in kidney transplant recipients.
“A big question in the field is whether there is a benefit to prescribing an alternative CNI dose, or even an entirely different immuno-suppressant regimen for kidney recipients,” said Dr Deirdre Sawinski, an assistant professor in the division of renal electrolyte and hypertension. “CNI dosing protocols have changed over time but the impact on clinical outcomes is unknown.”
The AHRQ report and study focused on determining whether the standard CNI recommendations provide the best results for patients and their kidneys. Researchers evaluated four CNI strategies to determine which had the best long-term clinical impact.
These strategies included: minimisation: using a lower-than-standard CNI dosage
Conversion: switching to a different class of immuno-suppressants after starting a standard dosage CNI; withdrawal: tapering off of a CNI regimen without adding a new immuno-suppressant; and avoidance: the use of a immuno-suppressant regimen that does not include CNIs from the start of therapy
“To answer this specific dosage question, we evaluated 88 randomised controlled trials that examined one or more of the four CNI strategies,” said Dr Craig A Umscheid, an assistant professor of general internal medicine and epidemiology and director of the Centre for Evidence-based Practice. “Findings suggest that CNI minimisation results in better clinical outcomes than standard dose CNI regimens. Evidence for the conversion and withdrawal strategies suggested trade-offs between improved renal function and higher risk of rejection, and the evidence for the avoidance strategy was insufficient to make conclusions.”
Researchers agree that there is more to be explored when it comes to CNI immuno-suppression regimens and finding the best therapies for maintaining renal function over a longer period of time. The study notes that a majority of the research analysed only evaluated low-risk patients and did not examine high-risk kidney recipients, such as those with second transplants, other organ transplants, or HIV. The available studies also tended to evaluate the older CNI cyclosporine, rather than the newer CNI tacrolimus, which is now more commonly used. In addition, there were limited data on patient outcomes after long-term use of CNI regimens, which is a critical evidence gap given that patients are living longer following transplants, and adverse events associated with CNIs can often take years to manifest.
Despite their clinical efficacy, concerns about calcineurin inhibitor (CNI) toxicity make alternative regimens that reduce CNI exposure attractive for renal transplant recipients. In this systematic review and meta-analysis, we assessed four CNI immunosuppression strategies (minimization, conversion, withdrawal, and avoidance) designed to reduce CNI exposure and assessed the impact of each on patient and allograft survival, acute rejection and renal function. We evaluated 92 comparisons from 88 randomized controlled trials and found moderate- to high-strength evidence suggesting that minimization strategies result in better clinical outcomes compared with standard-dose regimens; moderate-strength evidence indicating that conversion to a mammalian target of rapamycin inhibitor or belatacept was associated with improved renal function but increased rejection risk; and moderate- to high-strength evidence suggesting planned CNI withdrawal could result in improved renal function despite an association with increased rejection risk. The evidence base for avoidance studies was insufficient to draw meaningful conclusions. The applicability of the review is limited by the large number of studies examining cyclosporine-based strategies and low-risk populations. Additional research is needed with tacrolimus-based regimens and higher risk populations. Moreover, research is necessary to clarify the effect of induction and adjunctive agents in alternative immunosuppression strategies and should include more comprehensive and consistent reporting of patient-centered outcomes.