Key messages
• After kidney transplantation (a surgical procedure where a kidney is transferred from one person - the donor - to another person - the recipient), it may take a few days for the kidney to start working, especially if the kidney donor was older or the kidney was without blood flow for a long time.
• The best treatment for people at high risk of this delayed recovery is still unclear. Current options include delaying the use of a medication to prevent rejection, called a calcineurin inhibitor, or starting it at a lower dose.
What is the treatment for kidney failure?
Kidney transplantation (a surgical procedure where a kidney is transferred from one person - the donor - to another person - the recipient) is the preferred treatment for most people with kidney failure because it improves quality of life and eliminates the need for dialysis (a procedure where a machine is used to remove waste products and excess salts and fluid from the blood when the kidneys stop working properly). After transplantation, it may take a few days for the transplanted kidney to start working. This condition is called delayed graft function. This delay is more likely when the donor kidney comes from someone older (usually older than 50 years of age) or who died from a heart condition, or when the kidney has been stored for a long time without blood flow. The best treatment for people at high risk of this delayed recovery is not yet known. Some approaches include delaying the start of calcineurin inhibitors (an immunosuppressive medicine that dampens down the body's immune system and prevents it from attacking the transplanted kidney) or using them at a lower dose.
What did we want to find out?
We wanted to know if delaying the initiation or starting calcineurin inhibitors at a lower dose can reduce the risk of delayed recovery of the kidney.
What did we do?
We searched for all studies that compared the benefits and harms of randomly allocating the delayed start of calcineurin inhibitors or using them at a lower dose in people who have received a kidney transplant and are at risk of delayed kidney function immediately after receiving the transplanted kidney.
We compared and summarised the studies' results and rated our confidence in the information based on factors such as study methods and sizes.
What did we find?
We reviewed 12 studies, with 2230 randomised participants, which compared delayed versus early initiation or reduced versus standard initial dose of calcineurin inhibitors for kidney transplant recipients at high risk of delayed recovery of the kidney.
All studies were performed in Europe. Around 60% of the participants were males, reflecting the expected proportion in the population on kidney replacement therapy in Europe. There may be little to no difference in delayed recovery of the kidney or acute rejection risk between any of the evaluated strategies. There may also be little or no differences found in kidney function, risk of death, or infection between the groups.
What are the limitations of the evidence?
We have little confidence in the evidence because studies used different types of additional treatments, and most studies were published more than 10 years ago.
How up to date is this evidence?
The review is current to 11 December 2024.
There may be little or no difference in DGF or acute rejection when delaying the start of CNI or when starting it at a lower dose in kidney transplant recipients at high risk of DGF. The available data are of low certainty.
Kidney transplantation is the preferred therapy for many patients with kidney failure. Delayed graft function (DGF) is more common in donors after cardiac death (DCD), especially those with older age, longer cold ischemia time, or higher creatinine levels. Currently, there is no agreement on the optimal immunosuppressive approach for patients at increased risk of DGF. Strategies include delaying the introduction of calcineurin inhibitors (CNI) or using an initial low dose of CNI.
To evaluate the benefits and harms of delayed initiation of CNI or reduced CNI dose as initial immunosuppression therapy for kidney transplant recipients at high risk of DGF.
The Cochrane Kidney and Transplant Register of Studies was searched up to 11 December 2024 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Registry Platform (ICTRP) Search Portal, and ClinicalTrials.gov.
All randomised controlled trials (RCTs) and quasi-RCTs evaluating delayed versus early initiation of CNI or reduced versus standard initial dose of CNI in kidney transplant recipients at high risk of DGF.
Three authors independently assessed study eligibility, and two assessed the risk of bias, certainty of evidence, extracted the data, and performed the analysis. Results were reported as risk ratios (RR) with 95% confidence intervals (CI) for dichotomous outcomes and as mean difference (MD) with 95% CI for continuous outcomes. Statistical analysis was performed using the random-effects model. Risk of bias was assessed with the Cochrane risk of bias assessment tool 1.0, and the certainty of the evidence according to the Grades of Recommendation, Assessment, Development and Evaluation (GRADE) methods, which are presented in the summary of findings tables.
We included 12 studies (2230 randomised participants). All studies were performed in Europe. Around 60% of the participants were males, reflecting the expected proportion in the population on kidney replacement therapy in Europe. Most studies had insufficient information to judge adequate random sequence generation and, or allocation concealment. All studies were unblinded, and judged as high risk of bias for DGF if the definition was based on need for dialysis, and for acute rejection if the diagnosis did not require a biopsy. Overall, the level of certainty was low, and reasons to downgrade were mainly due to risk of bias and imprecision.
Delayed versus early initiation of CNI
There may be little or no difference in DGF between the groups (6 studies, 905 recipients: RR 0.92, 95% CI 0.76 to 1.12; low certainty evidence) or in acute rejection (8 studies, 1295 recipients: RR 1.02, 95% CI 0.75 to 1.40; low certainty evidence).
Delaying the initiation of CNI probably makes little or no difference to eGFR (6 studies, 851 recipients: MD -0.81 mL/min, 95% CI -3.33 to 1.72; moderate certainty evidence).
Delaying the initiation of CNI may make little or no difference to graft loss censored for death (8 studies, 1295 recipients: RR 1.58, 95% CI 0.68 to 3.65; very low certainty evidence) or to all-cause death (8 studies, 907 recipients: RR 1.08, 95% CI 0.54 to 2.14; very low certainty evidence) although the evidence is very uncertain.
There is probably little or no difference in all infections between the groups (6 studies, 1226 recipients: RR 1.10, 95% CI 0.97 to 1.25; moderate certainty evidence).
Low versus standard initial dose of CNI
There may be little or no difference to DGF between the groups (5 studies, 983 recipients: RR 1.16, 95% CI 0.90 to 1.50; low certainty evidence) or in acute rejection (5 studies, 947 recipients: RR 0.83, 95% CI 0.52 to 1.30; low certainty evidence).
Starting CNI at a lower dose may make little or no difference to eGFR (5 studies, 935 recipients: MD 4.06 mL/min, 95% CI -1.36 to 9.48, low certainty evidence).
Starting CNI at a lower dose may make little or no difference to graft loss censored for death, although the evidence is very uncertain (5 studies, 983 recipients: RR 1.05, 95% CI 0.64 to 1.71; very low certainty evidence), or to all-cause death (4 studies, 521 recipients: RR 1.01, 95% CI 0.41 to 2.47; low certainty evidence).
There is probably little or no difference in all infections between the groups (4 studies, 828 recipients: RR 0.87, 95% CI 0.71 to 1.07; moderate certainty evidence).