Target of rapamycin inhibitors (TOR-I; sirolimus and everolimus) for primary immunosuppression in kidney transplant recipients

What is the issue?

Kidney transplantation is the treatment of choice for many patients with end-stage kidney disease. However, some kidney transplants do not work for long periods so it is important to find ways to improve long-term transplant function by choosing the best therapies to maintain kidney function and keep transplant recipients healthy with minimal side effects.

What did we do?

We reviewed 70 studies, with 17,462 randomised participants, which compared TOR-1 (everolimus or sirolimus) with other agents for initial immunosuppressive therapy for kidney transplant recipients.

What did we find?

We found that everolimus or sirolimus combined with cyclosporin or tacrolimus prevented kidney transplant failure and rejection as effectively as mycophenolate (an antimetabolite) with cyclosporin or tacrolimus in studies with follow-up from six months to three years. The risk for viral infections (CMV and BK) was lower with TOR-I. However, wound complications were more common with TOR-I and more people had to stop TOR-I and change to other immunosuppressive medications.

Conclusions

Although the results indicate that TOR-I were effective in preventing transplant failure and rejection in the short term, studies do not follow-up participants beyond six months to three years. Therefore, we do not need further studies but we do need much longer periods of follow-up of participants in existing studies to determine how useful these medications are for maintaining kidney transplant function in the longer term.

Authors' conclusions: 

In studies with follow-up to three years, TOR-I with an antimetabolite increases the risk of graft loss and acute rejection compared with CNI and an antimetabolite. TOR-I with CNI potentially offers an alternative to an antimetabolite with CNI as rates of graft loss and acute rejection are similar between interventions and TOR-I regimens are associated with a reduced risk of CMV infections. Wound complications and the need to change immunosuppressive medications are higher with TOR-I regimens. While further new studies are not required, longer-term follow-up data from participants in existing methodologically robust RCTs are needed to determine how useful immunosuppressive regimens, which include TOR-I, are in maintaining kidney transplant function and survival beyond three years.

Read the full abstract...
Background: 

Kidney transplantation is the therapy of choice for many patients with end-stage kidney disease (ESKD) with an improvement in survival rates and satisfactory short term graft survival. However, there has been little improvement in long-term survival. The place of target of rapamycin inhibitors (TOR-I) (sirolimus, everolimus), which have different modes of action from other commonly used immunosuppressive agents, in kidney transplantation remains uncertain. This is an update of a review first published in 2006.

Objectives: 

To evaluate the short and long-term benefits and harms of TOR-I (sirolimus and everolimus) when used in primary immunosuppressive regimens for kidney transplant recipients.

Search strategy: 

We searched the Cochrane Kidney and Transplant Register of Studies up to 20 September 2019 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register were identified through searches of CENTRAL, MEDLINE and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov.

Selection criteria: 

All randomised controlled trials (RCTs) and quasi-RCTs in which drug regimens, containing TOR-I commenced within seven days of transplant, were compared to alternative drug regimens, were included without age restriction, dosage or language of report.

Data collection and analysis: 

Three authors independently assessed study eligibility, risk of bias, and extracted data. Results were reported as risk ratios (RR) with 95% confidence intervals (CI) for dichotomous outcomes and mean difference (MD) with 95% CI for continuous outcomes. Statistical analyses were performed using the random-effects model. The certainty of the evidence was assessed using GRADE

Main results: 

Seventy studies (17,462 randomised participants) were included; eight studies included two comparisons to provide 78 comparisons. Outcomes were reported at six months to three years post transplant.

Risk of bias was judged to be low for sequence generation in 25 studies, for allocation concealment in 23 studies, performance bias in four studies, detection bias in 65 studies, attrition bias in 45 studies, selective reporting bias in 48 studies, and for other potential bias in three studies. Risk of bias was judged to be at high risk of bias for sequence generation in two studies, allocation concealment in two studies, performance bias in 61 studies, detection bias in one study, attrition bias in four studies, for selective reporting bias in 11 studies and for other potential risk of bias in 46 studies.

Compared with CNI and antimetabolite, TOR-I with antimetabolite probably makes little or no difference to death (RR 1.31, 95% CI 0.87 to 1.98; 19 studies) or malignancies (RR 0.86, 95% CI 0.50 to 1.48; 10 studies); probably increases graft loss censored for death (RR 1.32, 95% CI 0.96 to 1.81; 15 studies), biopsy-proven acute rejection (RR 1.60, 95% CI 1.25 to 2.04; 15 studies), need to change treatment (RR 2.42, 95% CI 1.88 to 3.11; 14 studies) and wound complications (RR 2.56, 95% CI 1.94 to 3.36; 12 studies) (moderate certainty evidence); but reduces CMV infection (RR 0.43, 95% CI 0.29 to 0.63; 13 studies) (high certainty evidence).

Compared with antimetabolites and CNI, TOR-I with CNI probably makes little or no difference to death (RR 1.06, 95% CI 0.84 to 1.33; 31 studies), graft loss censored for death (RR 1.09, 95% CI 0.82 to 1.45; 26 studies), biopsy-proven acute rejection (RR 0.95, 95% CI 0.81 to 1.12; 24 studies); and malignancies (RR 0.83, 95% CI 0.64 to 1.07; 17 studies); probably increases the need to change treatment (RR 1.56, 95% CI 1.28 to 1.90; 25 studies), and wound complications (RR 1.56, 95% CI 1.28 to 1.91; 17 studies); but probably reduces CMV infection (RR 0.44, 95% CI 0.34 to 0.58; 25 studies) (moderate certainty evidence).

Lower dose TOR-I and standard dose CNI compared with higher dose TOR-I and reduced dose CNI probably makes little or no difference to death (RR 1.07, 95% CI 0.64 to 1.78; 9 studies), graft loss censored for death (RR 1.09, 95% CI 0.54 to 2.20; 8 studies), biopsy-proven acute rejection (RR 0.87, 95% CI 0.67 to 1.13; 8 studies), and CMV infection (RR 1.42, 95% CI 0.78 to 2.60; 5 studies) (moderate certainty evidence); and may make little or no difference to wound complications (RR 0.95, 95% CI 0.53 to 1.71; 3 studies), malignancies (RR 1.04, 95% CI 0.36 to 3.04; 7 studies), and the need to change treatments (RR 1.18, 95% CI 0.58 to 2.42; 5 studies) (low certainty evidence).

Lower dose of TOR-I compared with higher doses probably makes little or no difference to death (RR 0.84, 95% CI 0.67 to 1.06; 13 studies), graft loss censored for death (RR 0.92, 95% CI 0.71 to 1.19; 12 studies), biopsy-proven acute rejection (RR 1.26, 95% CI 1.10 to 1.43; 11 studies), CMV infection (RR 0.87, 95% CI 0.63 to 1.21; 9 studies), wound complications (RR 0.92, 95% CI 0.66 to 1.29; 7 studies), and malignancy (RR 0.84, 95% CI 0.54 to 1.32; 10 studies) (moderate certainty evidence); and may make little or no difference to the need to change treatments (RR 0.91, 95% CI 0.78 to 1.05; 10 studies) (low certainty evidence).

It is uncertain whether sirolimus and everolimus differ in their effects on kidney function and lipid levels because the certainty of the evidence is very low based on a single small study with only three months of follow-up.

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