Podcast: Calcineurin inhibitor withdrawal or tapering for kidney transplant recipients

When a patient receives a kidney transplant, there is a possibility that their body will reject this new organ and a variety of treatments are used to try to prevent this. However, these treatments can cause their own unwanted side effects. In a new Cochrane Review in July 2017, Krishna Karpe and colleagues from Canberra Hospital in Australia looked at the evidence for alleviating this for the group of drugs known as Calcineurin inhibitors. Here’s Krishna to tell us what they found.

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John: Hello, I'm John Hilton, editor of the Cochrane Editorial unit.  When a patient receives a kidney transplant, there is a possibility that their body will reject this new organ and a variety of treatments are used to try to prevent this. However, these treatments can cause their own unwanted side effects. In a new Cochrane Review in July 2017, Krishna Karpe and colleagues from Canberra Hospital in Australia looked at the evidence for alleviating this for the group of drugs known as Calcineurin inhibitors. Here’s Krishna to tell us what they found.

Krishna: Calcineurin inhibitors (or CNIs) are used in renal transplant recipients to reduce acute rejection and prevent immediate loss of the transplanted kidney, but they have adverse effects such as raised blood pressure and an increased risk of infection and cancers. Long term CNIs could also cause scarring in the kidney, which may contribute to chronic damage of the transplanted kidney. This CNI toxicity has led to a large number of studies of CNI withdrawal and the effects of using a lower CNI dose. Some studies have also investigated adding an additional agent, such as a mammalian target of rapamycin inhibitor, or mTOR-I. However, there is still considerable uncertainty and we hope that our Cochrane Review will help move things forward.
We investigated the benefits and harms of CNI tapering or withdrawal in terms of loss of the transplanted kidney or “graft”, acute rejection episodes, side effects, and death. We looked for all randomised trials where standard CNI drug regimens were compared to CNI withdrawal, avoidance or low dose and found 83 eligible studies. These involved more than 16,000 renal transplant recipients, and we classified them into four groups: CNI withdrawal with or without substitution with mTOR-I; and low dose CNI with or without mTOR-I. The withdrawal groups were further sub-divided into CNI avoidance and late withdrawal when we analysed the major outcomes.
CNI avoidance resulted in increased acute graft rejection but made no difference to graft loss. Withdrawal of CNI resulted in more acute rejections with no change in death, cytomegalovirus (CMV) infection or cancers, but reductions in hypertension and graft loss. CNI withdrawal when combined with mTOR-I increased acute rejection and probably reduced the risk of cytomegalovirus infection and cancer. Low dose CNI regimens reduced graft loss with no major adverse events in the short term. Low dose CNI when combined with mTOR-I probably reduced graft loss but made no difference to acute rejection, death or malignancy.
In summary, CNI withdrawal increased acute graft rejection but reduced graft loss at least over the short term. Low dose CNI with induction regimens reduced acute rejection and graft loss with no major adverse events, also in the short-term. The use of mTOR-I with withdrawal or low dose CNI reduced CMV infections but increased the risk of acute rejection. However, our conclusions are limited by the overall quality of evidence, which we judged to be low to moderate and the lack of long-term data in most of these studies.

John: If you would like to read the fine detail on Krishna’s conclusions, including full listings of all 83 included studies, go online to Cochrane Library dot com and search 'CNI and kidney transplant'.

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