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

Deirdre Hahn; Elisabeth M Hodson; Lorraine A Hamiwka; Vincent WS Lee; Jeremy R Chapman; Jonathan C Craig; Angela C Webster

doi:10.1002/14651858.CD004290.pub3

. 2019 Dec 16;2019(12):CD004290. doi: 10.1002/14651858.CD004290.pub3

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

Deirdre Hahn ¹, Elisabeth M Hodson ², Lorraine A Hamiwka ³, Vincent WS Lee ^4,⁵, Jeremy R Chapman ⁶, Jonathan C Craig ^2,⁷, Angela C Webster ^5,^8,^✉

Editor: Cochrane Kidney and Transplant Group

PMCID: PMC6953317 PMID: 31840244

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 methods

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.

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.

Plain language summary

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.

Summary of findings

Background

Description of the condition

Kidney transplantation is the treatment of choice for many patients with end‐stage kidney disease (ESKD) providing improved patient survival rates (95% one‐year survival) and satisfactory short‐term graft survival. To maintain long‐term graft survival our challenge is the need to suppress the host immune system. Immunosuppressive therapies used in kidney transplantation inhibit one or more steps in the allo‐immune response that would otherwise result in rejection. Long‐term graft survival beyond five years has shown little improvement since the 1970s. Transplant waiting lists continue to grow with demand exceeding organ availability. Strategies to increase donor organ availability and to prolong kidney allograft survival have become priorities in kidney transplantation (ANZDATA 2017; NHS Blood and Transplant 2019 "Taking Organ Transplantation to 2020 Strategy", USRDS 2018).

Description of the intervention

Standard immunosuppressive therapy consists of initial induction and maintenance regimens to prevent rejection. Most current immunosuppressive regimens in the immediate post‐operative period typically involve three drug groups each directed to a site in the T‐cell activation or proliferation cascade which are central to the rejection process: calcineurin inhibitors (CNI; e.g. cyclosporin, tacrolimus), antimetabolite agents (azathioprine (AZA), mycophenolate mofetil (MMF), mycophenolate sodium (MPS)) and corticosteroids (prednisolone) with 93% recipients in the USA, and 70% in Australia, being discharged from hospital after transplantation on these agents. Following the introduction of CNI (cyclosporin in the early 1980s and tacrolimus the 1990s), one‐year graft survival improved to the current level at of over 90% though long‐term graft survival ranges between 34% and 56% across different population groups in Europe and the USA (KDIGO 2009; Gondos 2013).

Target of rapamycin inhibitors (TOR‐I) (sirolimus, everolimus) are immunosuppressive agents with a mode of action different from other commonly used immunosuppressive agents. Sirolimus is a macrocyclic lactone antibiotic produced from Streptomyces hygroscopicus initially discovered as an antifungal agent. The immunosuppressive properties were deemed an undesirable effect and led to the development of a useful drug. Everolimus is a derivative of sirolimus. Both bind to the same intracellular immunophilin as tacrolimus (FKBP12), but instead of inhibiting calcineurin, the drug‐receptor complex then binds to proteins known as the "mammalian targets of rapamycin" (mTOR). This causes inhibition of a multifunctional serine‐threonine kinase, preventing both DNA and protein synthesis resulting in arrest of the cell cycle (Hernandez 2011, Dumont 2001; Saunders 2001).

Based upon laboratory data, the early expectation was that TOR‐I would provide synergistic immunosuppression when combined with CNI (Schuurman 1997; Stepkowski 1997). The absence of nephrotoxicity in animal models increased expectations of significant clinical benefit (Viklicky 2000). Clinical studies dispelled some of the early optimism as synergistic nephrotoxicity was demonstrated when either sirolimus or everolimus were combined with cyclosporin (Kahan‐301 2000; MacDonald‐302 2001; Vitko‐201 2001). Since then studies have been undertaken to explore strategies that avoid this interaction and clarify other potential benefits such as vascular protection (Ponticelli 2004) and a reduction in malignancy (Stallone 2005), and the impact of harms such as hyperlipidaemia and wound complications. Nevertheless the ANZDATA 2017 report indicates that fewer than 1% of transplant recipients receive everolimus or sirolimus in the initial post transplant regimen and fewer than 4% receive TOR‐I at one year post transplant.

How the intervention might work

The major cause of long‐term graft loss is chronic allograft nephropathy a complex, multifactorial process characterised clinically by a progressive decline in graft function, proteinuria and hypertension, and pathologically characterised by interstitial fibrosis/tubular atrophy. Chronic allograft nephropathy is a consequence of immunological and non‐immunological injury. Immunological factors include human leukocyte antigen (HLA) matching, episodes of acute rejection and suboptimal immunosuppression. Important non‐immunological factors implicated are donor organ characteristics, delayed graft function, recipient‐related factors, hypertension, hyperlipidaemia and viral infections. CNI are linked to nephrotoxicity contributing to long‐term graft failure, hypertension, hyperlipidaemia, and new‐onset diabetes mellitus. The TOR‐I have increased treatment options that produce adequate immunosuppression, allow reduced CNI dose with a reduction in CNI‐associated side effects and reduced incidence of viral infections (Hernandez 2011; Kumar 2017).

Why it is important to do this review

Despite being in use for many years, the place of these agents in kidney transplantation remains uncertain. The aim of this study was to identify and summarise the currently available evidence of the short and long‐term benefits and harms of sirolimus and everolimus when used in primary immunosuppressive regimens for kidney transplant recipients. Since the review, which included 33 studies, was first published in 2006, an additional 37 studies have been identified. Their inclusion in the review should provide a more comprehensive assessment of the place of TOR‐I in immunosuppressive regimens. In this update we have only added studies where participants were commenced on a TOR‐I less than seven days from date of transplant. Studies in which participants commenced TOR‐I after seven days will be considered in a subsequent systematic review.

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.

Methods

Criteria for considering studies for this review

Types of studies

All randomised controlled trials (RCTs) and quasi‐RCTs (RCTs in which allocation to treatment was obtained by alternation, use of alternate medical records, date of birth or other predictable methods) where drug regimens containing sirolimus or everolimus were compared to an alternative drug regimen in the immediate post transplant period (less than seven days post transplant) were included.

Types of participants

Inclusion criteria

All patients of all ages with ESKD, who were the recipient of a first or subsequent deceased donor or living donor kidney transplant, were included. There was no restriction by age of recipients, or dosage of immunosuppressive drugs.

Exclusion criteria

Studies in which participants commenced TOR‐I agents seven days or more post transplant were excluded. Studies in which transplant recipients received another solid organ in addition to a kidney transplant (e.g. kidney and pancreas) were excluded.

Types of interventions

Sirolimus or everolimus, given in combination with any other immunosuppressive agents, at any stage in the intra‐operative or immediate post‐transplant period. All dosage regimens were included. Sirolimus and everolimus were considered together to estimate 'class effect'.

Types of outcome measures

The outcome measures relate to those used by transplant registries to assess patient and graft survival. Outcome events were reported at the end of follow up or at two to three years post transplant depending on data availability.

Primary outcomes

Death (all causes)
All‐cause graft loss (death with functioning allograft or dependence on dialysis)
Graft loss censored for death with functioning allograft
All acute rejection and biopsy‐proven acute rejection
Incidence of cytomegalovirus (CMV) infections (all definitions), with diagnosis by culture, serology, antigen or antibody testing, or as specified by authors.
All adverse wound outcomes and lymphocoele
All malignancies
Number needing to change treatment.

Secondary outcomes

New‐onset diabetes mellitus
Lymphoma/post transplant lymphoproliferative disorder (PTLD)
Number with BK virus infection (all definitions)
Graft function (measured as absolute value or change in serum creatinine (SCr), glomerular filtration rate (GFR), creatinine clearance (CrCl)
Incidence of treatment‐related adverse reactions related to TOR‐I (specifically anaemia, thrombocytopenia, leucopenia, hypercholesterolaemia, hypertriglyceridaemia) and/or to CNI.

Search methods for identification of studies

Electronic searches

Monthly searches of the Cochrane Central Register of Controlled Trials (CENTRAL)
Weekly searches of MEDLINE OVID SP
Handsearching of kidney‐related journals and the proceedings of major kidney conferences
Searching of the current year of EMBASE OVID SP
Weekly current awareness alerts for selected kidney and transplant journals
Searches of the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov.

Studies contained in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE based on the scope of Cochrane Kidney and Transplant. Details of search strategies, as well as a list of handsearched journals, conference proceedings and current awareness alerts, are available on the Cochrane Kidney and Transplant website.

See Appendix 1 for search terms used in strategies for this review.

Searching other resources

Reference lists of review articles, relevant studies and clinical practice guidelines.
Letters seeking information about unpublished or incomplete studies to investigators known to be involved in previous studies.

Data collection and analysis

Selection of studies

The original review was undertaken by four authors (ACW, VWSL, JRC, JCC). The 2019 update was undertaken by three authors (LH, DH, EH) with support from ACW and VWSL. Disagreement about inclusion of studies in the review was resolved by discussion between authors.

Data extraction and management

Data extraction was performed independently by three authors (LH, DH, EH) using a standardised form. Where possible, authors of published work were contacted for clarification of unclear data.

Assessment of risk of bias in included studies

The following items were assessed independently by two authors using the risk of bias assessment tool (Higgins 2011 (seeAppendix 2).

Was there adequate sequence generation (selection bias)?
Was allocation adequately concealed (selection bias)?
Was knowledge of the allocated interventions adequately prevented during the study?
- Participants and personnel (performance bias)
- Outcome assessors (detection bias)
Were incomplete outcome data adequately addressed (attrition bias)?
Are reports of the study free of suggestion of selective outcome reporting (reporting bias)?
Was the study apparently free of other problems that could put it at a risk of bias?

Measures of treatment effect

Studies were grouped and analysed according to the following comparisons.

TOR‐I versus CNI
TOR‐I versus antimetabolite
Variable dosages of TOR‐I and/or CNI
Low versus higher doses of TOR‐I.

For dichotomous outcomes (e.g. death, graft loss, acute rejection) results were expressed as risk ratio (RR) with 95% confidence intervals (CI). Where continuous scales of measurement are used (e.g. SCr, GFR), the mean difference (MD) with 95% CI was used.

Where sufficient RCTs were identified, publication bias was investigated using funnel plots (Egger 1997).

Unit of analysis issues

No cross‐over studies were identified for this review. If we had identified any cross‐over studies, we would only have included data from the first period of treatment in cross‐over studies (Higgins 2011).

Dealing with missing data

Any further information or clarification required from the authors was requested by written or electronic correspondence and relevant information obtained in this manner was included in the review. We aimed to analyse available data in meta‐analyses using intention‐to‐treat (ITT) data. However, where only ITT data were available graphically or were not provided and additional information could not be obtained from the study authors, per‐protocol (PP) data was used in analyses. We imputed standard deviations if necessary based on those from other studies included in meta‐analyses.

Assessment of heterogeneity

We first assessed the heterogeneity by visual inspection of the forest plot. We then quantified statistical heterogeneity using the I² statistic, which describes the percentage of total variation across studies that is due to heterogeneity rather than sampling error (Higgins 2003). A guide to the interpretation of I² values was as follows.

0% to 40%: might not be important
30% to 60%: may represent moderate heterogeneity
50% to 90%: may represent substantial heterogeneity
75% to 100%: considerable heterogeneity.

The importance of the observed value of I² depends on the magnitude and direction of treatment effects and the strength of evidence for heterogeneity (e.g. P‐value from the Chi² test, or a confidence interval for I²) (Higgins 2011).

Assessment of reporting biases

The search strategy applied aimed to reduce publication bias caused by lack of publication of studies with negative results. We investigated for publication bias using funnel plots if there were sufficient studies of each comparison (Higgins 2011).

Data synthesis

Data were summarised using the random‐effects model but the fixed‐effect model was also used to ensure robustness of the model chosen. Where there were multiple publications of the same study, all reports were reviewed to ensure that all details of methods and results were included.

Subgroup analysis and investigation of heterogeneity

Subgroup analysis was used to explore possible sources of heterogeneity by assessing the P‐value for subgroup differences provided in RevMan analyses. Subgroups, defined a priori, were publication type (abstract or full publication), study methodological quality (sequence generation and allocation concealment), CNI used (whether tacrolimus or cyclosporin), whether or no induction with antibody was included in the immunosuppressive co‐interventions, the TOR‐I used (whether sirolimus or everolimus) and the antimetabolite used (whether mycophenolate or azathioprine).

Sensitivity analysis

Sensitivity analyses tested decisions where inclusion of a study may have altered the results of the meta‐analysis or when it may have led to heterogeneity.

'Summary of findings' tables

We presented the main results of the review in 'Summary of findings' tables. These tables present key information concerning the quality of the evidence, the magnitude of the effects of the interventions examined, and the sum of the available data for the main outcomes (Schunemann 2011a). The 'Summary of findings' tables also include an overall grading of the evidence related to each of the main outcomes using the GRADE (Grades of Recommendation, Assessment, Development and Evaluation) approach (GRADE 2008; GRADE 2011). The GRADE approach defines the quality of a body of evidence as the extent to which one can be confident that an estimate of effect or association is close to the true quantity of specific interest. The quality of a body of evidence involves consideration of within‐trial risk of bias (methodological quality), directness of evidence, heterogeneity, precision of effect estimates and risk of publication bias (Schunemann 2011b). We presented the following outcomes in the 'Summary of findings' tables.

Primary outcomes

Death
Graft loss (censored for death)
Biopsy‐proven acute rejection
CMV infection
All adverse wound outcomes
All malignancies
Number needing to change treatment (for adverse effects, unsatisfactory response, other medical event. Does not include poor compliance, withdrawal of consent, death, graft loss, protocol violation, loss to follow up, non‐medical events)

Secondary outcomes

New‐onset diabetes mellitus
Number with BK infection
Glomerular filtration rate
Number with hypercholesterolaemia
Number with hypertriglyceridaemia
Number with leucopenia
Number with thrombocytopenia

Results

Description of studies

Results of the search

The initial review published in 2006 included 33 studies (142 reports). Further searches up to 30 September 2019 identified 37 new included studies (294 reports), 27 excluded studies (61 reports), and five ongoing studies (EVER TWIST 2013; Ferreira 2019; NCT02077556; NCT03468478; Traitanon 2019). Prior to publication of this review, two of these ongoing studies (Ferreira 2019; Traitanon 2019) were published and shall be included in a future update of this review (Figure 1).

Included studies

See Characteristics of included studies.

The 70 completed studies included 17,462 randomised participants; eight studies (Gelens 2006; Kahan‐301 2000; Kandaswamy 2005; Kovarik‐251 2001; ORION 2011; Tedesco‐Silva 2010; Vitko‐201 2001; Vitko‐TERRA 2004) included three interventions so that 78 comparisons were included in the review. Twenty‐two studies compared TOR‐I (sirolimus or everolimus) with a CNI (tacrolimus or cyclosporin). Thirty‐three studies compared TOR‐I with an antimetabolite (MMF, MPS or AZA). Nine studies compared variable doses of TOR‐I with variable doses of a CNI. Thirteen studies compared low doses with higher doses of TOR‐I. One study compared everolimus with sirolimus (Rostaing 2001). Duration of follow‐up ranged from six months to three years.

TOR‐I versus calcineurin inhibitor

The 22 studies of TOR‐I compared with a CNI included 4011 participants (CALFREE 2006; Cattaneo 2005; Durlik 2008; Durrbach 2008; EVEROLD 2014; Fernandes‐Charpiot 2014; FIBRASIC 2009; Flechner 2013; Flechner‐318 2002; Gelens 2006; Glotz 2010; Groth‐207 1999; Kreis‐210 2000; Lebranchu‐132 2004; Martinez‐Mier 2006; Morelon 2010; ORION 2011; Pescovitz 2007; Riad 2007; Schaefer 2006; Stegall 2003; SYMPHONY 2007).

One study (EVEROLD 2014) did not report the participant numbers in each group so 1523 participants were included in the TOR‐I group and 2184 in the CNI group. All participants also received an antimetabolite.

TOR‐I versus antimetabolite

The 33 studies of TOR‐I compared with an antimetabolite included 10,599 participants (Anil Kumar 2005; Anil Kumar 2008; ATHENA 2016; AVESTA 2017; Bertoni 2011; Burke 2002; Ciancio 2016; Esmeraldo 2015; Favi 2009; Favi 2012; Gallon 2006; Gelens 2006; Gonwa‐PSG 2003; Kahan‐301 2000; Kandaswamy 2005; Kovarik‐251 2001; Machado 2001; ORION 2011; Paoletti 2012; Qazi 2017; RECORD 2017; Sampaio 2008; Shetty 2015; Souza 2017; Spagnoletti 2017; Stallone 2004; Takahashi 2013a; Tedesco‐Silva 2010; Tedesco‐Silva 2015; TRANSFORM 2018; van Gurp 2010; Vitko‐201 2001; Vitko‐TERRA 2004).

Two studies (AVESTA 2017; Spagnoletti 2017) did not report the participant numbers in each group so 6123 participants were included in the TOR‐I group and 4318 in the antimetabolite group. All study participants also received a CNI (tacrolimus or cyclosporin). Participants in the antimetabolite group received MMF or MPS except in two studies where azathioprine was administered (Kahan‐301 2000; Machado 2001).

Variable doses of TOR‐I and CNI

The nine studies comparing variable doses of TOR‐I and CNI included 1509 participants with 744 in the higher dose TOR‐I with reduced dose CNI group and 765 in the lower dose TOR‐I with standard dose CNI group (Bertoni 2011; Cohen 2002; EVEREST 2009; Grinyo 2004; Kahan‐203 1999; Kandaswamy 2005; MacDonald‐302 2001; Russ 2003; Velosa‐212 2001).

Lower versus higher doses of TOR‐I

The thirteen studies of lower versus higher doses of TOR‐I included 3898 participants with 1951 in the lower dose TOR‐I group and 1947 participants in the higher dose TOR‐I group (Hamdy 2005; Kahan‐157 2001; Kahan‐301 2000; Kovarik‐2306 2004; Kovarik‐251 2001; Kramer‐2307 2003; MacDonald‐302 2001; Pascual 2010; Tedesco‐Silva 2003; Tedesco‐Silva 2010; van Hooff 2003; Vitko‐201 2001; Vitko‐TERRA 2004).

Sirolimus versus everolimus

One study (28 participants) compared sirolimus (16 participants) with everolimus (12 participants) (Rostaing 2001).

Excluded studies

See Characteristics of excluded studies.

For the 2019 update, 27 studies (61 reports) were excluded. Seventeen studies were excluded because TOR‐I was commenced seven days or more post transplant. TOR‐I were commenced after day 14 in one study; the remaining 16 studies commenced TOR‐I four weeks or more after study commencement. Six studies were excluded because they: 1) compared early with delayed administration of TOR‐I (two studies); 2) studied steroid withdrawal (one study); 3) compared liquid with tablet formulation of sirolimus (one study); 4) studied the effect of increasing the dose of TOR‐I at one year (one study); or 5) compared increased dose of TOR‐I at three months as TAC ceased (one study). Three studies were excluded because it was unclear whether they were RCTS and one study was terminated because of inability to recruit participants.

Risk of bias in included studies

Risk of bias attributes are summarised for all studies in Figure 2 and Figure 3. Risk of bias attributes are reported for each of the five groups of comparisons below

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Allocation

TOR‐1 versus calcineurin inhibitor

Of 22 studies, 14 were at low risk for sequence generation and allocation concealment. The remaining seven were at high risk of bias for both sequence generation and random allocation concealment.

TOR‐I versus antimetabolite

Of 33 studies, 14 were at low risk of bias for sequence generation and 18 were at unclear risk. Twelve comparisons were at low risk of bias for allocation concealment and 20 studies were at unclear risk. Two comparisons were at high risk of sequence generation and allocation concealment (Favi 2009; Kandaswamy 2005).

Variable dosage of TOR‐I and calcineurin inhibitor

Of nine studies, two comparisons were at low risk of bias for sequence generation and allocation concealment (EVEREST 2009; Grinyo 2004), one was at high risk of bias (Kandaswamy 2005) while six studies were at unclear risk.

Lower versus higher doses of TOR‐1

Of 13 studies, five were at low risk of bias and the remaining eight studies were assessed as unclear for sequence generation and allocation concealment.

Sirolimus versus everolimus

Rostaing 2001 was judged to be at unclear risk of bias for both sequence generation and allocation concealment.

Blinding

TOR‐1 versus calcineurin inhibitor

Twenty studies were at high risk of bias for performance bias and one study was assessed as unclear (Flechner 2013).

All studies were assessed as at low risk for detection bias as the primary outcomes (GFR and/or biopsy‐proven acute rejection) were laboratory based and unlikely to be influenced by detection bias.

TOR‐I versus antimetabolite

Three studies were at low risk of performance bias (Kahan‐301 2000; Kovarik‐251 2001; Vitko‐201 2001), 29 comparisons were at high risk and one comparison was at unclear risk (RECORD 2017).

In most comparisons, the primary outcomes were laboratory based so were considered unlikely to be influenced by detection bias. Thirty‐two studies were at low risk and one study was at unclear risk of detection bias (Durlik 2008).

Variable dosage of TOR‐I and calcineurin inhibitor

All nine studies were at high risk of performance bias.

In most comparisons, the primary outcomes were laboratory based so were considered unlikely to be influenced by detection bias. Eight studies were at low risk while one study (Cohen 2002) was at unclear risk of detection bias.

Lower versus higher doses of TOR‐I

Four comparisons were assessed at low risk of performance bias (Kahan‐301 2000; Kovarik‐251 2001; MacDonald‐302 2001; Vitko‐201 2001), nine studies were at high risk of bias and two was assessed as at unclear risk (Kahan‐157 2001; Tedesco‐Silva 2010).

All studies were assessed at low risk of detection bias as the primary outcomes were laboratory based and unlikely to be influenced by detection bias.

Sirolimus versus everolimus

Rostaing 2001 was judged to be at unclear risk of bias for both performance and detection bias.

Incomplete outcome data

TOR‐1 versus calcineurin inhibitor

Seventeen studies were considered at low risk of attrition bias, with four at unclear risk (Cattaneo 2005; Durlik 2008; FIBRASIC 2009; Riad 2007) and one at high risk of bias (Flechner 2013).

TOR‐I versus antimetabolite

Twenty‐six comparisons were considered to be at low risk of attrition bias while two were at high risk (Gallon 2006: RECORD 2017) and five were at unclear risk (AVESTA 2017; Esmeraldo 2015; Shetty 2015; Souza 2017; Spagnoletti 2017).

Variable dosage of TOR‐I and CNI

Eight studies were considered to be at low risk of attrition bias while one study (Russ 2003) was at high risk.

Lower versus higher doses of TOR‐I

Twelve studies were considered to be at low risk of attrition bias while one study was at high risk (Pascual 2010).

Sirolimus versus everolimus

Rostaing 2001 was judged to be at unclear risk of bias for attrition bias.

Selective reporting

TOR‐1 versus calcineurin inhibitor

Fourteen studies were considered at low risk of bias for selective reporting, with three assessed as at high risk of bias (Cattaneo 2005; Gelens 2006; Morelon 2010) and the remaining five assessed as at unclear risk (Durlik 2008; EVEROLD 2014; Fernandes‐Charpiot 2014; FIBRASIC 2009; Riad 2007).

TOR‐I versus antimetabolite

Twenty‐one studies were considered to be at low risk of attrition bias while seven were at high risk (Bertoni 2011; Favi 2009; Gallon 2006; Gelens 2006; Gonwa‐PSG 2003; Paoletti 2012; Stallone 2004) and five studies were at unclear risk (AVESTA 2017; Esmeraldo 2015; Shetty 2015; Souza 2017; Spagnoletti 2017).

Variable dosage of TOR‐I and calcineurin inhibitor

Nine studies were considered to be at low risk of reporting bias.

Lower versus higher doses of TOR‐I

All 13 studies were considered to be at low risk of reporting bias

Sirolimus versus everolimus

Rostaing 2001 was judged to be at unclear risk of bias for selection bias.

Other potential sources of bias

TOR‐1 versus CNI

Sixteen studies were industry funded studies and assessed as high risk of bias and the remaining six studies were assessed as unclear (Cattaneo 2005; Durlik 2008; FIBRASIC 2009; Martinez‐Mier 2006; Riad 2007; Schaefer 2006).

TOR‐I versus antimetabolite

Three studies were at low risk (Bertoni 2011; Favi 2009; Paoletti 2012) and 22 studies reporting on industry funded studies were considered to be at high risk of bias. Eight studies did not report funding sources and were considered to be at unclear risk of bias (Anil Kumar 2008; Esmeraldo 2015; Favi 2012; Machado 2001; Shetty 2015; Souza 2017; Spagnoletti 2017; Stallone 2004).

Variable dosage of TOR‐I and CNI

Eight studies reporting on industry funded studies were considered to be at high risk while one study (Cohen 2002) was at unclear risk as it did not report funding sources.

Lower versus higher doses of TOR‐I

Nine studies reported industry funding and were assessed at high risk of bias.

Sirolimus versus everolimus

Rostaing 2001 was judged to be at unclear risk of bias as it did not report funding sources.

Effects of interventions

See: Table 1; Table 2; Table 3; Table 4; Table 5; Table 6; Table 7; Table 8

Summary of findings for the main comparison. Target of rapamycin inhibitors (TOR‐I) versus calcineurin inhibitors (CNI): main outcomes for primary immunosuppression in kidney transplant recipients.

TOR‐I versus CNI: outcomes up to 2 years (main outcomes) for primary immunosuppression in kidney transplant recipients
Patient or population: primary immunosuppression in kidney transplant recipients  Setting: kidney transplant services Intervention: TOR‐I  Comparison: CNI
Outcomes (up to 2 years for primary outcomes)	*Anticipated absolute effects^ (95% CI)**		Relative effect  (95% CI)	No. of participants  (studies)	Certainty of the evidence  (GRADE)
Outcomes (up to 2 years for primary outcomes)	Risk with CNI	Risk with TOR‐I	Relative effect  (95% CI)	No. of participants  (studies)	Certainty of the evidence  (GRADE)
Death (all causes)	25 per 1,000	33 per 1,000  (22 to 50)	RR 1.31  (0.87 to 1.98)	3618 (19)	⊕⊕⊕⊝  MODERATE ¹
Graft loss censored for death	51 per 1,000	68 per 1,000  (49 to 93)	RR 1.32  (0.96 to 1.81)	3277 (14)	⊕⊕⊕⊝  MODERATE ¹
Biopsy‐proven acute rejection	196 per 1,000	333 per 1,000  (258 to 429)	RR 1.70  (1.32 to 2.19)	3309 (15)	⊕⊕⊕⊝  MODERATE¹
CMV infection	157 per 1,000	68 per 1,000  (46 to 99)	RR 0.43  (0.29 to 0.63)	2026 (13)	⊕⊕⊕⊕  HIGH
Adverse wound outcomes: all complications	77 per 1,000	198 per 1,000  (150 to 260)	RR 2.56  (1.94 to 3.36)	1679 (12)	⊕⊕⊕⊝  MODERATE ¹
All malignancies	24 per 1,000	20 per 1,000  (12 to 35)	RR 0.86  (0.50 to 1.48)	2584 (10)	⊕⊕⊕⊝  MODERATE ¹
Number needing to change treatment	132 per 1,000	320 per 1,000  (249 to 412)	RR 2.42  (1.88 to 3.11)	3148 (14)	⊕⊕⊕⊝  MODERATE ¹
*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).    CI: Confidence interval; RR: Risk ratio; CMV: cytomegalovirus
GRADE Working Group grades of evidence  High certainty: We are very confident that the true effect lies close to that of the estimate of the effect  Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different  Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect  Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

TOR‐I versus CNI: outcomes up to two years (secondary outcomes) for primary immunosuppression in kidney transplant recipients
Patient or population: primary immunosuppression in kidney transplant recipients  Setting: kidney transplant services Intervention: TOR‐I  Comparison: CNI: outcomes up to two years (secondary outcomes)
Outcomes (up to 2 years for secondary outcomes)	*Anticipated absolute effects^ (95% CI)**		Relative effect  (95% CI)	No. of participants  (studies)	Certainty of the evidence  (GRADE)
Outcomes (up to 2 years for secondary outcomes)	Risk with CNI	Risk with TOR‐I	Relative effect  (95% CI)	No. of participants  (studies)	Certainty of the evidence  (GRADE)
New‐onset diabetes mellitus	60 per 1,000	56 per 1,000  (42 to 76)	RR 0.93  (0.69 to 1.26)	2791 (13)	⊕⊕⊕⊝  MODERATE ¹
Lymphoma/PTLD	2 per 1,000	6 per 1,000  (2 to 19)	RR 2.47  (0.78 to 7.86)	2537 (8)	⊕⊕⊕⊝  MODERATE ¹
Tremor	204 per 1,000	51 per 1,000  (31 to 83)	RR 0.25  (0.15 to 0.41)	799 (6)	⊕⊕⊕⊕  HIGH
GFR (mL/min)	The mean GFR was 2.2 mL/min higher with TOR‐I (1.29 lower to 5.68 higher) than CNI		‐‐	2983 (15)	⊕⊕⊝⊝  LOW ^{2 3}
Cholesterol (mmol/L)	The mean cholesterol level was 0.77 mmol/L higher with TOR‐I (0.45 higher to 1.09 higher) than CNI		‐‐	579 (7)	⊕⊕⊝⊝  LOW ^{1 2}
Triglycerides (mmol/L)	The mean triglyceride level 0.57 mmol/L higher with TOR‐I (0.28 higher to 0.86 higher) than CNI		‐‐	843 (8)	⊕⊕⊝⊝  LOW ^{1 2}
Thrombocytopenia	38 per 1,000	200 per 1,000  (109 to 367)	RR 5.26  (2.87 to 9.63)	593 (4)	⊕⊕⊝⊝  LOW ^{1 2}
*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).    CI: Confidence interval; RR: Risk ratio; PTLD: post‐transplant lymphoproliferative disease; GRF: glomerular filtration rate
GRADE Working Group grades of evidence  High certainty: We are very confident that the true effect lies close to that of the estimate of the effect  Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different  Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect  Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

TOR‐I versus antimetabolites: outcomes up to 2 years (primary outcomes) for primary immunosuppression in kidney transplant recipients
Patient or population: primary immunosuppression in kidney transplant recipients  Setting: kidney transplant services  Intervention: TOR‐I  Comparison: antimetabolites
Outcomes (up to 2 years for primary outcomes)	*Anticipated absolute effects^ (95% CI)**		Relative effect  (95% CI)	No. of participants  (studies)	Certainty of the evidence  (GRADE)
Outcomes (up to 2 years for primary outcomes)	Risk with antimetabolites	Risk with TOR‐I	Relative effect  (95% CI)	No. of participants  (studies)	Certainty of the evidence  (GRADE)
Death (all causes)	29 per 1,000	31 per 1,000  (24 to 38)	RR 1.06 (0.84 to 1.33)	10,482 (31)	⊕⊕⊕⊝  MODERATE ¹
Graft loss (censored)	35 per 1,000	38 per 1,000  (29 to 51)	RR 1.09  (0.82 to 1.45)	8966 (26)	⊕⊕⊕⊝  MODERATE ¹
Biopsy‐proven acute rejection	141 per 1,000	134 per 1,000  (113 to 158)	RR 0.95  (0.81 to 1.12)	10,101 (24)	⊕⊕⊕⊝  MODERATE ²
CMV infection	136 per 1,000	59 per 1,000  (46 to 78)	RR 0.44  (0.34 to 0.58)	10,049 (26)	⊕⊕⊕⊝  MODERATE ²
Adverse wound outcomes: all complications	155 per 1,000	241 per 1,000  (199 to 297)	RR 1.56  (1.28 to 1.90)	6913 (17)	⊕⊕⊕⊝  MODERATE ²
All malignancies	34 per 1,000	28 per 1,000  (22 to 36)	RR 0.83  (0.64 to 1.07)	8799 (17)	⊕⊕⊕⊝  MODERATE ¹
Number needing to change treatment	174 per 1,000	248 per 1,000  (203 to 302)	(RR 1.56, 1.28 to 1.90)	9747 (25)	⊕⊕⊕⊝  MODERATE ²
*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).    CI: Confidence interval; RR: Risk ratio; CMV: cytomegalovirus
GRADE Working Group grades of evidence  High certainty: We are very confident that the true effect lies close to that of the estimate of the effect  Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different  Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect  Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

TOR‐I compared to antimetabolites: outcomes to 2 years (secondary outcomes) for primary immunosuppression in kidney transplant recipients
Patient or population: primary immunosuppression in kidney transplant recipients  Setting: kidney transplant units  Intervention: TOR‐I  Comparison: antimetabolites
Outcomes (up to 2 years for secondary outcomes)	*Anticipated absolute effects^ (95% CI)**		Relative effect  (95% CI)	No. of participants  (studies)	Certainty of the evidence  (GRADE)
Outcomes (up to 2 years for secondary outcomes)	Risk with antimetabolites	Risk with TOR‐I	Relative effect  (95% CI)	No. of participants  (studies)	Certainty of the evidence  (GRADE)
New‐onset diabetes mellitus	85 per 1,000	103 per 1,000  (86 to 124)	RR 1.28, (1.07 to 1.54)	8728 (23)	⊕⊕⊕⊝  MODERATE ¹
BK virus infection	84 per 1,000	52 per 1,000  (42 to 64)	RR 0.62  (0.50 to 0.76)	5152 (12)	⊕⊕⊕⊕  HIGH
GFR (mL/min)	The mean GFR was 2.89 mL/min lower with TOR‐I (4.91 lower to 0.88 lower) than with antimetabolites		‐‐	7099 (25)	⊕⊕⊕⊝  MODERATE ²
Hypercholesterolaemia	102 per 1,000	187 per 1,000  (151 to 229)	RR 1.83  (1.48 to 2.25)	5725 (12)	⊕⊕⊝⊝  LOW ^{1 2}
Hypertriglyceridaemia	143 per 1,000	212 per 1,000  (180 to 249)	RR 1.48  (1.26 to 1.74)	4698 (9)	⊕⊕⊕⊝  MODERATE¹
Leucopenia	123 per 1,000	50 per 1,000  (38 to 65)	RR 0.43  (0.33 to 0.56)	8396 (15)	⊕⊕⊝⊝  LOW ^{1 2}
Thrombocytopenia	33 per 1,000	65 per 1,000  (46 to 92)	RR 1.96  (1.38 to 2.79)	5028 (8)	⊕⊕⊝⊝  LOW ^{1 3}
*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).    CI: Confidence interval; RR: Risk ratio; GFR: glomerular filtration rate
GRADE Working Group grades of evidence  High certainty: We are very confident that the true effect lies close to that of the estimate of the effect  Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different  Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect  Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

Variable TOR‐I and CNI: primary outcomes for primary immunosuppression in kidney transplant recipients
Patient or population: primary immunosuppression in kidney transplant recipients  Setting: kidney transplant centres  Intervention: lower dose TOR‐I and standard CNI  Comparison: higher dose TOR‐I and reduced CNI
Outcomes (up to 2 years for primary outcomes)	*Anticipated absolute effects^ (95% CI)**		Relative effect  (95% CI)	No. of participants  (studies)	Certainty of the evidence  (GRADE)
Outcomes (up to 2 years for primary outcomes)	Risk with higher dose TOR‐I	Risk with low dose TOR‐I	Relative effect  (95% CI)	No. of participants  (studies)	Certainty of the evidence  (GRADE)
Death (all causes)	39 per 1,000	41 per 1,000  (25 to 69)	RR 1.07  (0.64 to 1.78)	1501 (9)	⊕⊕⊕⊝  MODERATE ¹
Graft loss (censored)	36 per 1,000	39 per 1,000  (19 to 79)	RR 1.09  (0.54 to 2.20)	1385 (8)	⊕⊕⊕⊝  MODERATE ¹
Biopsy‐proven acute rejection	155 per 1,000	135 per 1,000  (104 to 175)	RR 0.87  (0.67 to 1.13)	1381 (8)	⊕⊕⊕⊝  MODERATE ¹
CMV infection	40 per 1,000	57 per 1,000  (32 to 105)	RR 1.42  (0.78 to 2.60)	865 (5)	⊕⊕⊕⊝  MODERATE ²
Adverse wound outcomes: all complications	135 per 1,000	128 per 1,000  (72 to 231)	RR 0.95  (0.53 to 1.71)	291 (3)	⊕⊕⊝⊝  LOW ³
All malignancies	15 per 1,000	16 per 1,000  (5 to 46)	RR 1.04  (0.36 to 3.04)	1163 (7)	⊕⊕⊝⊝  LOW ¹
Number needing to change treatment	186 per 1,000	219 per 1,000  (108 to 450)	RR 1.18  (0.58 to 2.42)	734 (5)	⊕⊕⊝⊝  LOW ⁴
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).    CI: Confidence interval; RR: Risk ratio; CMV: cytomegalovirus
GRADE Working Group grades of evidence  High certainty: We are very confident that the true effect lies close to that of the estimate of the effect  Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different  Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect  Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

Variable TOR‐I and CNI: secondary outcomes for primary immunosuppression in kidney transplant recipients
Patient or population: primary immunosuppression in kidney transplant recipients  Setting: kidney transplant centres  Intervention: lower dose TOR‐I and standard CNI  Comparison: higher dose TOR‐I and reduced CNI
Outcomes (up to 2 years for secondary outcomes)	*Anticipated absolute effects^ (95% CI)**		Relative effect  (95% CI)	No. of participants  (studies)	Certainty of the evidence  (GRADE)
Outcomes (up to 2 years for secondary outcomes)	Risk with higher dose TOR‐I	Risk with lower dose TOR‐I	Relative effect  (95% CI)	No. of participants  (studies)	Certainty of the evidence  (GRADE)
New‐onset diabetes mellitus: TAC	57 per 1,000	102 per 1,000  (56 to 183)	RR 1.79  (0.99 to 3.23)	580 (5)	⊕⊕⊝⊝  LOW ^{1 2}
New‐onset diabetes mellitus: CSA	63 per 1,000	36 per 1,000  (17 to 75)	RR 0.57  (0.27 to 1.20)	606 (3)	⊕⊕⊝⊝  LOW ^{1 2}
GFR (mL/min)	The mean GFR was 5.96 mL/min lower with low dose TOR‐I (9.54 lower to 2.38 lower) compared to higher dose TOR‐I		‐‐	1305 (7)	⊕⊕⊝⊝  LOW^{1 3}
Hypercholesterolaemia	251 per 1,000	241 per 1,000  (188 to 307)	RR 0.96  (0.75 to 1.22)	734 (4)	⊕⊕⊕⊝  MODERATE ²
Hypertriglyceridaemia	521 per 1,000	443 per 1,000  (380 to 526)	RR 0.85  (0.73 to 1.01)	734 (4)	⊕⊕⊕⊝  MODERATE ²
Anaemia	339 per 1,000	315 per 1,000  (271 to 366)	RR 0.93  (0.80 to 1.08)	1074 (6)	⊕⊕⊕⊝  MODERATE ²
Leucopenia	107 per 1,000	106 per 1,000  (75 to 150)	RR 0.99  (0.70 to 1.40)	1012 (5)	⊕⊕⊕⊝  MODERATE²
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).    CI: Confidence interval; RR: Risk ratio; TAC: tacrolimus; CSA: cyclosporin; GFR: glomerular filtration rate
GRADE Working Group grades of evidence  High certainty: We are very confident that the true effect lies close to that of the estimate of the effect  Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different  Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect  Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

Low versus higher dose TOR‐I: primary outcomes for primary immunosuppression in kidney transplant recipients
Patient or population: primary immunosuppression in kidney transplant recipients  Setting: kidney transplant centres  Intervention: lower dose TOR‐I  Comparison: higher dose TOR‐I
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect  (95% CI)	No. of participants  (studies)	Certainty of the evidence  (GRADE)
Outcomes	Risk with higher dose TOR‐I	Risk with lower dose TOR‐I	Relative effect  (95% CI)	No. of participants  (studies)	Certainty of the evidence  (GRADE)
Death (all causes)	35 per 1,000	31 per 1,000  (22 to 44)	RR 0.89  (0.63 to 1.25)	3894 (13)	⊕⊕⊕⊝  MODERATE ¹
Total graft loss (with death)	85 per 1,000	72 per 1,000  (57 to 90)	RR 0.84  (0.67 to 1.06)	3476 (11)	⊕⊕⊕⊝  MODERATE ¹
Biopsy‐proven acute rejection	179 per 1,000	226 per 1,000  (197 to 257)	RR 1.26  (1.10 to 1.43)	3731 (11)	⊕⊕⊕⊝  MODERATE ¹
CMV infection	49 per 1,000	43 per 1,000  (31 to 60)	RR 0.87  (0.63 to 1.21)	3099 (9)	⊕⊕⊕⊝  MODERATE ²
All malignancy	29 per 1,000	24 per 1,000  (15 to 38)	RR 0.84  (0.54 to 1.32)	3175 (10)	⊕⊕⊕⊝  MODERATE ¹
Number needing to change treatment	325 per 1,000	296 per 1,000  (254 to 341)	RR 0.91  (0.78 to 1.05)	3652 (10)	⊕⊕⊝⊝  LOW ^{1 2}
*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).    CI: Confidence interval; RR: Risk ratio; CMV: cytomegalovirus
GRADE Working Group grades of evidence  High certainty: We are very confident that the true effect lies close to that of the estimate of the effect  Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different  Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect  Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

Low versus higher dose TOR‐ I: secondary outcomes for primary immunosuppression in kidney transplant recipients
Patient or population: primary immunosuppression in kidney transplant recipients  Setting: kidney transplant centres  Intervention: low dose TOR‐I  Comparison: higher dose TOR‐ I
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect  (95% CI)	No. of participants  (studies)	Certainty of the evidence  (GRADE)
Outcomes	Risk with higher dose TOR‐ I	Risk with low dose TOR‐I	Relative effect  (95% CI)	No. of participants  (studies)	Certainty of the evidence  (GRADE)
Diabetes	119 per 1,000	82 per 1,000  (61 to 111)	RR 0.69  (0.51 to 0.93)	2125 (6)	⊕⊕⊕⊝  MODERATE ¹
Lymphoma/PTLD	9 per 1,000	6 per 1,000  (2 to 15)	RR 0.66  (0.25 to 1.73)	2792 (7)	⊕⊕⊕⊝  MODERATE ¹
Acne/rash	152 per 1,000	131 per 1,000  (95 to 185)	RR 0.86  (0.62 to 1.21)	2958 (6)	⊕⊕⊝⊝  LOW ^{1 2}
GRF (mL/min)	The mean GFR was 2.88 mL/min higher with low dose TOR‐I (0.71 lower to 6.48 higher) compared to higher dose TOR‐I		‐‐	1863 (7)	⊕⊕⊝⊝  LOW ^{1 3}
Hypercholesterolaemia	266 per 1,000	232 per 1,000  (208 to 261)	RR 0.87  (0.78 to 0.98)	3250 (9)	⊕⊕⊕⊝  MODERATE ¹
Anaemia	294 per 1,000	238 per 1,000  (212 to 267)	RR 0.81  (0.72 to 0.91)	3179 (10)	⊕⊕⊝⊝  LOW ^{1 3}
Thrombocytopenia	145 per 1,000	84 per 1,000  (64 to 109)	RR 0.58  (0.44 to 0.75)	2242 (9)	⊕⊕⊝⊝  LOW ^{1 3}
*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).    CI: Confidence interval; RR: Risk ratio; PTLD: post‐transplant lymphoproliferative disease; GFR: glomerular filtration rate
GRADE Working Group grades of evidence  High certainty: We are very confident that the true effect lies close to that of the estimate of the effect  Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different  Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect  Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

Variable	TOR‐I versus CNI^			TOR‐I versus antimetabolite*
Variable	Studies	RR (95% CI)	P‐value for  subgroup differences	Studies	RR (95% CI)	P‐value  for subgroup differences
Publication type
Abstract	3	RR 2.03 (95% CI 1.13 to 3.65)	0.35	5	RR 0.68 (95% CI 0.29 to 1.61)	0.49
Journal	16	RR 1.53 (95% CI 1.23 to 1.90)	0.35	27	RR 0.93 (95% CI 0.80 to 1.08)	0.49
Risk of bias
Low risk	7	RR 1.64 (95% CI 1.31 to 2.06)	0.65	12	RR 0.85 (95% CI 0.50 ‐ 1.46)	0.21
High or unclear risk	12	RR 1.61 (95% CI 1.28 to 2.03)	0.65	21	RR 1.04 (95% CI 0.87 to 1.26)	0.21
CNI co‐intervention
Tacrolimus	7^^	RR 2.09 (95% CI 1.56 to 2.78)	0.06	18**	RR 0.93 (95% CI 0.76 to 1.14)	0.25
Cyclosporin	13	RR 1.48 (95% CI 1.20 to 1.83)	0.06	9	RR 0.85 (95% CI 0.64 ‐ 1.14)	0.25
TOR‐I
Everolimus	1	Not analysed^^^	‐‐	16	RR 1.04 (95% CI 0.85 to 1.28)	0.17
Sirolimus	18	Not analysed^^^	‐‐	16	RR 0.85 (95% CI 0.70 ‐ 1.04)	0.17
Antimetabolite comparator
Azathioprine	1	Not analysed^^^	‐‐	2	RR 0.71 (95% CI 0.39 ‐ 1.28)	0.30
Mycophenolate	18	Not analysed^^^	‐‐	30	RR 0.98 (95% CI 0.86 to 1.12)	0.30
Antibody induction
No induction	4	RR 1.24 (95% CI 0.91 to 1.68)	0.13	10***	RR 0.93 (95% CI 0.77 ‐ 1.12)	0.88
Antibody induction	13^^^^	RR 1.81 (95% CI 1.29 to 2.53)	0.13	21	RR 0.90 (95% CI 0.70 to 1.16)	0.88

Variable	Variable doses of TOR‐I and CNI*			Lower versus higher doses of TOR‐I**
Variable	Studies	RR (95% CI)	P‐value  for subgroup differences	Studies	RR (95% CI)	P‐value  for subgroup differences
Publication type
Abstract	2	RR 0.85 (95% CI 0.50 ‐ 1.46)	0.7	0	No studies	Not applicable
Journal	7	RR 0.83 (95% CI 0.63 ‐ 1.08)	0.7	13	(RR 1.24, 95% CI 1.10 to 1.41)	Not applicable
Risk of bias
Low risk	2	RR 0.85 (95% CI 0.50 ‐ 1.46)	0.81	5	(RR 1.33, 95% CI 1.15 to 1.55)	0.10
High or unclear risk	7	RR 0.79 (95% CI 0.59 ‐ 1.06)	0.81	8	(RR 1.06, 95% CI 0.84 to 1.33)	0.10
CNI co‐intervention
Tacrolimus	5	RR 0.77 (95% CI 0.51 ‐ 1.16)	0.67	3	(RR 1.62, 95% CI 1.19 to 2.19)	0.06
Cyclosporin	4	RR 0.85 (95% CI 0.64 ‐ 1.14)	0.67	9	(RR 1.17, 95% CI 1.02 to 1.35)	0.06
Antibody induction
No induction	6	RR 0.72 (95% CI 0.53 ‐ 0.98)	0.97	10	(RR 1.25, 95% CI 1.09 to 1.45)	0.81
Antibody induction	3	RR 1.01 (95% CI 0.69 ‐ 1.46)	0.97	3	(RR 1.20, 95% CI 0.90 to 1.62)	0.81
TOR‐I
Everolimus	2	(RR 0.93, 95% CI 0.65 to 1.32)	0.4	7	(RR 1.11, 95% CI 0.93 to 1.33)	0.09
Sirolimus	7	(RR 0.75, 95% CI 0.55 to 1.03)	0.4	6	(RR 1.39, 95% CI 1.16 to 1.66)	0.09

Outcomes	2006 review (8 studies)	2019 update (22 studies)
Death	No difference	No difference
All graft loss	No difference	No difference
Graft loss censored for death	No difference	No difference
All acute rejection	No difference	Increased with TOR‐I
Biopsy‐proven acute rejection	No difference	Increased with TOR‐I
CMV infection	No difference	Reduced with TOR‐I
Wound complications	Increased with TOR‐I	Increased with TOR‐I
Malignancies	No difference	No difference
Need to change treatment	Increased with TOR‐I	Increased with TOR‐I
New‐onset diabetes mellitus	No difference	No difference
Lymphoma/PTLD	No difference	No difference
BK virus infection	No difference (1 study)	No difference
Tremor	Reduced with TOR‐I	Reduced with TOR‐I
Acne/rash	Increased with TOR‐I	Increased with TOR‐I
GFR	Increased with TOR‐I	No difference
SCr	Reduced with TOR‐I	Reduced with TOR‐I
Hypercholesterolaemia	No difference	Increased with TOR‐I
Hypertriglyceridaemia	No difference	Increased with TOR‐I
Bone marrow suppression	Increased with TOR‐I	Increased with TOR‐I

Electronic databases	Search terms
CENTRAL	MeSH descriptor: [Kidney Transplantation] this term only MeSH descriptor: [Sirolimus] explode all trees sirolimus:ti,ab,kw in Trials rapamycin:ti,ab,kw in Trials rapamune:ti,ab,kw in Trials everolimus:ti,ab,kw in Trials "SDZ RAD":ti,ab,kw in Trials (RAD or RAD100):ti,ab,kw in Trials certican:ti,ab,kw in Trials "TOR‐I":ti,ab,kw in Trials deforolimus:ti,ab,kw in Trials temsirolimus:ti,ab,kw in Trials mtor and inhibitor:ti,ab,kw in Trials {OR #2‐#23} in Trials {AND #1, #14 in Trials
MEDLINE	kidney transplantation/ exp Sirolimus/ sirolimus.tw. rapamycin.tw. rapamune.tw. ay 22‐989.tw. everolimus.tw. SDZ RAD.tw. (RAD or RAD100).tw. certican.tw. "TOR‐1".tw. or/2‐11 and/1,12
EMBASE	exp "mammalian target of rapamycin inhibitor"/ sirolimus.tw. rapamycin.tw. rapamune.tw. everolimus.tw. ay 22989.tw. SDZ RAD.tw. (RAD or RAD100).tw. certican.tw. deforolimus.tw. temsirolimus.tw. (mtor and inhibitor$).tw. or/1‐12

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Death (all causes)	19	3618	Risk Ratio (M‐H, Random, 95% CI)	1.31 [0.87, 1.98]
2 Total graft loss including death	19	3619	Risk Ratio (M‐H, Random, 95% CI)	1.41 [1.11, 1.80]
2.1 Tacrolimus	7	1386	Risk Ratio (M‐H, Random, 95% CI)	1.78 [1.25, 2.56]
2.2 Cyclosporin	13	2233	Risk Ratio (M‐H, Random, 95% CI)	1.16 [0.83, 1.61]
3 Graft loss censored for death	14	3277	Risk Ratio (M‐H, Random, 95% CI)	1.32 [0.96, 1.81]
3.1 Tacrolimus	5	1238	Risk Ratio (M‐H, Random, 95% CI)	1.95 [1.17, 3.25]
3.2 Cyclosporin	10	2039	Risk Ratio (M‐H, Random, 95% CI)	1.02 [0.68, 1.54]
4 All acute rejection	19	3016	Risk Ratio (M‐H, Random, 95% CI)	1.59 [1.31, 1.92]
5 Biopsy‐proven acute rejection	15	2708	Risk Ratio (M‐H, Random, 95% CI)	1.60 [1.25, 2.04]
6 CMV infection	13	2026	Risk Ratio (M‐H, Random, 95% CI)	0.43 [0.29, 0.63]
7 Adverse wound outcomes	13		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
7.1 All complications	12	1679	Risk Ratio (M‐H, Random, 95% CI)	2.56 [1.94, 3.36]
7.2 Lymphocoele	8	2538	Risk Ratio (M‐H, Random, 95% CI)	2.29 [1.73, 3.02]
8 All malignancies	10	2584	Risk Ratio (M‐H, Random, 95% CI)	0.86 [0.50, 1.48]
9 Number needing to change treatment	14	3148	Risk Ratio (M‐H, Random, 95% CI)	2.42 [1.88, 3.11]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 New‐onset diabetes mellitus	13	2791	Risk Ratio (M‐H, Random, 95% CI)	0.93 [0.69, 1.26]
1.1 Tacrolimus	6	1274	Risk Ratio (M‐H, Random, 95% CI)	0.80 [0.55, 1.16]
1.2 Cyclosporin	8	1517	Risk Ratio (M‐H, Random, 95% CI)	1.22 [0.74, 1.99]
2 Lymphoma/PTLD	8	2537	Risk Ratio (M‐H, Random, 95% CI)	2.47 [0.78, 7.86]
3 Number with BK virus infection	3	386	Risk Ratio (M‐H, Random, 95% CI)	0.46 [0.16, 1.29]
4 Adverse cosmetic outcomes	7		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
4.1 Tremor	6	799	Risk Ratio (M‐H, Random, 95% CI)	0.25 [0.15, 0.41]
4.2 Gingival hyperplasia ‐ cyclosporin	3	222	Risk Ratio (M‐H, Random, 95% CI)	0.11 [0.02, 0.57]
4.3 Hirsutism ‐ cyclosporin	1	78	Risk Ratio (M‐H, Random, 95% CI)	0.24 [0.03, 2.03]
4.4 Acne/rash	4	622	Risk Ratio (M‐H, Random, 95% CI)	3.51 [1.75, 7.02]
5 Glomerular filtration rate	15	2983	Mean Difference (IV, Random, 95% CI)	2.20 [‐1.29, 5.68]
6 Serum creatinine	10	672	Mean Difference (IV, Random, 95% CI)	‐10.64 [‐19.19, ‐2.10]
7 Number with elevated lipid levels	5		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
7.1 Hypercholesterolaemia	4	1877	Risk Ratio (M‐H, Random, 95% CI)	1.74 [1.17, 2.59]
7.2 Hypertriglyceridaemia	5	1922	Risk Ratio (M‐H, Random, 95% CI)	1.72 [1.20, 2.46]
8 Lipid outcomes	8		Mean Difference (IV, Random, 95% CI)	Subtotals only
8.1 Cholesterol	7	579	Mean Difference (IV, Random, 95% CI)	0.77 [0.45, 1.09]
8.2 Triglycerides	8	843	Mean Difference (IV, Random, 95% CI)	0.57 [0.28, 0.86]
9 Number with abnormal haematological values	6		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
9.1 Anaemia	6	2216	Risk Ratio (M‐H, Random, 95% CI)	1.47 [1.28, 1.70]
9.2 Leucopenia	5	1922	Risk Ratio (M‐H, Random, 95% CI)	1.52 [0.95, 2.44]
9.3 Thrombocytopenia	4	593	Risk Ratio (M‐H, Random, 95% CI)	5.26 [2.87, 9.63]
10 Haematological outcomes	6		Mean Difference (IV, Random, 95% CI)	Subtotals only
10.1 Haemoglobin [g/dL]	5	481	Mean Difference (IV, Random, 95% CI)	‐0.64 [‐1.17, ‐0.11]
10.2 White cell count [per mm³]	5	433	Mean Difference (IV, Random, 95% CI)	‐0.81 [‐1.21, ‐0.41]
10.3 Platelet count [per mm²]	3	247	Mean Difference (IV, Random, 95% CI)	0.03 [‐1.79, 1.85]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Death	2	206	Risk Ratio (M‐H, Random, 95% CI)	1.36 [0.60, 3.08]
2 Total graft loss	2	206	Risk Ratio (M‐H, Random, 95% CI)	0.86 [0.44, 1.68]
3 Graft loss censored for death	2	206	Risk Ratio (M‐H, Random, 95% CI)	0.68 [0.25, 1.81]
4 Malignancies	2	206	Risk Ratio (M‐H, Random, 95% CI)	0.48 [0.20, 1.13]
5 Glomerular filtration rate	2	163	Mean Difference (IV, Random, 95% CI)	13.51 [6.94, 20.08]

Outcomes	2006 review (11 studies)	2019 update (33 studies)
Death	No difference	No difference
All graft loss	No difference	No difference
Graft loss censored for death	No difference	No difference
All acute rejection	Reduced with TOR‐I	No difference
Biopsy‐proven acute rejection	Reduced with TOR‐I	No difference
CMV infection	Reduced with TOR‐I	Reduced with TOR‐I
Wound complications	Increased with TOR‐I	Increased with TOR‐I
Malignancies	No difference	No difference
Need to change treatment	No difference	Increased with TOR‐I
New‐onset diabetes mellitus	No difference	Increased with TOR‐I
Lymphoma/PTLD	No difference	No difference
BK virus infection	Not reported	Lower with TOR‐I
Tremor	No difference (1 study)	No difference
Acne/rash	Increased with TOR‐I (1 study)	Increased with TOR‐I
GFR	Reduced with TOR‐I	Reduced with TOR‐I
SCr	Increased with TOR‐I	Increased with TOR‐I
Hypercholesterolaemia	Increased with TOR‐I	Increased with TOR‐I
Hypertriglyceridaemia	Increased with TOR‐I	Increased with TOR‐I
Leucopenia	Reduced with TOR‐I	Reduced with TOR‐I
Thrombocytopenia	Increased with TOR‐I	Increased with TOR‐I

Outcome	2006 review (8 studies)	2019 update (9 studies)
Death	No difference	No difference
All graft loss	No difference	No difference
Graft loss censored for death	No difference	No difference
All acute rejection	Reduced in low TOR‐I	No difference
Biopsy‐proven acute rejection	Reduced in low TOR‐I	No difference
CMV infection	No difference	No difference
Wound complications	No difference	No difference
Malignancies	No difference	No difference
Need to change treatment	No difference	No difference
New‐onset diabetes mellitus	No difference	No difference
Lymphoma/PTLD	No difference	No difference
BK virus infection	Not reported	No difference
Tremor	No difference (1 study)	No difference
Acne/rash	Not reported	No difference
GFR	Increased in low TOR‐I	Increased in low TOR‐I
SCr	No difference	No difference
Hypercholesterolaemia	No difference	No difference
Hypertriglyceridaemia	No difference	No difference
Leucopenia	No difference	No difference
Thrombocytopenia	No difference	No difference

Outcome	2006 review (8 studies)	2019 update (13 studies)
Death	No difference	No difference
All graft loss	No difference	No difference
Graft loss censored for death	No difference	No difference
All acute rejection	Reduced in high TOR‐I	Reduced in high TOR‐I
Biopsy‐proven acute rejection	Reduced in high TOR‐I	Reduced in high TOR‐I
CMV infection	No difference	No difference
Wound complications	No difference	No difference
Malignancies	No difference	No difference
Need to change treatment	No difference	No difference
New‐onset diabetes mellitus	Increased in high TOR‐I	Increased in high TOR‐I
Lymphoma/PTLD	No difference	No difference
BK virus infection	Not reported	Not reported
Tremor	Not reported	No difference
Acne/rash	No difference	No difference
GFR	Reduced in high TOR‐I	Reduced in high TOR‐I
SCr	No difference	No difference
Hypercholesterolaemia	No difference	Increased in high TOR‐I
Hypertriglyceridaemia	No difference	No difference
Leucopenia	Increased in high TOR‐I	Increased in high TOR‐I
Thrombocytopenia	Increased in high TOR‐I	Increased in high TOR‐I

Date	Event	Description
11 November 2019	New citation required and conclusions have changed	New studies added ‐ some changes to direction of results
11 November 2019	New search has been performed	37 new studies added

Potential source of bias	Assessment criteria
Random sequence generation Selection bias (biased allocation to interventions) due to inadequate generation of a randomised sequence	Low risk of bias: Random number table; computer random number generator; coin tossing; shuffling cards or envelopes; throwing dice; drawing of lots; minimisation (minimisation may be implemented without a random element, and this is considered to be equivalent to being random).
	High risk of bias: Sequence generated by odd or even date of birth; date (or day) of admission; sequence generated by hospital or clinic record number; allocation by judgement of the clinician; by preference of the participant; based on the results of a laboratory test or a series of tests; by availability of the intervention.
	Unclear: Insufficient information about the sequence generation process to permit judgement.
Allocation concealment Selection bias (biased allocation to interventions) due to inadequate concealment of allocations prior to assignment	Low risk of bias: Randomisation method described that would not allow investigator/participant to know or influence intervention group before eligible participant entered in the study (e.g. central allocation, including telephone, web‐based, and pharmacy‐controlled, randomisation; sequentially numbered drug containers of identical appearance; sequentially numbered, opaque, sealed envelopes).
	High risk of bias: Using an open random allocation schedule (e.g. a list of random numbers); assignment envelopes were used without appropriate safeguards (e.g. if envelopes were unsealed or non‐opaque or not sequentially numbered); alternation or rotation; date of birth; case record number; any other explicitly unconcealed procedure.
	Unclear: Randomisation stated but no information on method used is available.
Blinding of participants and personnel Performance bias due to knowledge of the allocated interventions by participants and personnel during the study	Low risk of bias: No blinding or incomplete blinding, but the review authors judge that the outcome is not likely to be influenced by lack of blinding; blinding of participants and key study personnel ensured, and unlikely that the blinding could have been broken.
	High risk of bias: No blinding or incomplete blinding, and the outcome is likely to be influenced by lack of blinding; blinding of key study participants and personnel attempted, but likely that the blinding could have been broken, and the outcome is likely to be influenced by lack of blinding.
	Unclear: Insufficient information to permit judgement
Blinding of outcome assessment Detection bias due to knowledge of the allocated interventions by outcome assessors.	Low risk of bias: No blinding of outcome assessment, but the review authors judge that the outcome measurement is not likely to be influenced by lack of blinding; blinding of outcome assessment ensured, and unlikely that the blinding could have been broken.
	High risk of bias: No blinding of outcome assessment, and the outcome measurement is likely to be influenced by lack of blinding; blinding of outcome assessment, but likely that the blinding could have been broken, and the outcome measurement is likely to be influenced by lack of blinding.
	Unclear: Insufficient information to permit judgement
Incomplete outcome data Attrition bias due to amount, nature or handling of incomplete outcome data.	Low risk of bias: No missing outcome data; reasons for missing outcome data unlikely to be related to true outcome (for survival data, censoring unlikely to be introducing bias); missing outcome data balanced in numbers across intervention groups, with similar reasons for missing data across groups; for dichotomous outcome data, the proportion of missing outcomes compared with observed event risk not enough to have a clinically relevant impact on the intervention effect estimate; for continuous outcome data, plausible effect size (difference in means or standardised difference in means) among missing outcomes not enough to have a clinically relevant impact on observed effect size; missing data have been imputed using appropriate methods.
	High risk of bias: Reason for missing outcome data likely to be related to true outcome, with either imbalance in numbers or reasons for missing data across intervention groups; for dichotomous outcome data, the proportion of missing outcomes compared with observed event risk enough to induce clinically relevant bias in intervention effect estimate; for continuous outcome data, plausible effect size (difference in means or standardized difference in means) among missing outcomes enough to induce clinically relevant bias in observed effect size; ‘as‐treated’ analysis done with substantial departure of the intervention received from that assigned at randomisation; potentially inappropriate application of simple imputation.
	Unclear: Insufficient information to permit judgement
Selective reporting Reporting bias due to selective outcome reporting	Low risk of bias: The study protocol is available and all of the study’s pre‐specified (primary and secondary) outcomes that are of interest in the review have been reported in the pre‐specified way; the study protocol is not available but it is clear that the published reports include all expected outcomes, including those that were pre‐specified (convincing text of this nature may be uncommon).
	High risk of bias: Not all of the study’s pre‐specified primary outcomes have been reported; one or more primary outcomes is reported using measurements, analysis methods or subsets of the data (e.g. sub‐scales) that were not pre‐specified; one or more reported primary outcomes were not pre‐specified (unless clear justification for their reporting is provided, such as an unexpected adverse effect); one or more outcomes of interest in the review are reported incompletely so that they cannot be entered in a meta‐analysis; the study report fails to include results for a key outcome that would be expected to have been reported for such a study.
	Unclear: Insufficient information to permit judgement
Other bias Bias due to problems not covered elsewhere in the table	Low risk of bias: The study appears to be free of other sources of bias.
	High risk of bias: Had a potential source of bias related to the specific study design used; stopped early due to some data‐dependent process (including a formal‐stopping rule); had extreme baseline imbalance; has been claimed to have been fraudulent; had some other problem.
	Unclear: Insufficient information to assess whether an important risk of bias exists; insufficient rationale or evidence that an identified problem will introduce bias.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Death	31	10482	Risk Ratio (M‐H, Random, 95% CI)	1.06 [0.84, 1.33]
2 Total graft loss	27	7626	Risk Ratio (M‐H, Random, 95% CI)	1.14 [0.93, 1.40]
3 Graft loss censored for death	26	8966	Risk Ratio (M‐H, Random, 95% CI)	1.09 [0.82, 1.45]
4 All acute rejection	31	10075	Risk Ratio (M‐H, Random, 95% CI)	0.90 [0.79, 1.02]
5 Biopsy‐proven acute rejection	24	10101	Risk Ratio (M‐H, Random, 95% CI)	0.95 [0.81, 1.12]
5.1 TOR‐I/reduced CNI versus AM/standard CNI	7	4170	Risk Ratio (M‐H, Random, 95% CI)	1.10 [0.87, 1.40]
5.2 TOR‐I/standard CNI versus AM/standard CNI	17	5931	Risk Ratio (M‐H, Random, 95% CI)	0.90 [0.74, 1.09]
6 CMV infection	25	10049	Risk Ratio (M‐H, Random, 95% CI)	0.44 [0.34, 0.58]
7 Adverse wound outcomes	20		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
7.1 All complications	17	6913	Risk Ratio (M‐H, Random, 95% CI)	1.56 [1.28, 1.91]
7.2 Lymphocoele	16	8415	Risk Ratio (M‐H, Random, 95% CI)	1.55 [1.32, 1.81]
8 All malignancies	17	8799	Risk Ratio (M‐H, Random, 95% CI)	0.83 [0.64, 1.07]
9 Number needing to change treatment	25	9747	Risk Ratio (M‐H, Random, 95% CI)	1.56 [1.28, 1.90]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 New‐onset diabetes mellitus	23	8728	Risk Ratio (M‐H, Random, 95% CI)	1.28 [1.07, 1.54]
2 Lymphoma/PTLD	14	5415	Risk Ratio (M‐H, Random, 95% CI)	1.52 [0.62, 3.72]
3 BK virus infection	12	5152	Risk Ratio (M‐H, Random, 95% CI)	0.62 [0.50, 0.76]
4 Tremor and adverse cosmetic outcomes	8		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
4.1 Tremor	5	3803	Risk Ratio (M‐H, Random, 95% CI)	0.87 [0.66, 1.15]
4.2 Gingival hyperplasia	2	903	Risk Ratio (M‐H, Random, 95% CI)	0.30 [0.15, 0.60]
4.3 Hirsutism	2	1542	Risk Ratio (M‐H, Random, 95% CI)	1.25 [0.30, 5.28]
4.4 Acne/Rash	5	2022	Risk Ratio (M‐H, Random, 95% CI)	1.74 [1.08, 2.81]
5 Glomerular filtration rate	25	8099	Mean Difference (IV, Random, 95% CI)	‐2.89 [‐4.91, ‐0.88]
5.1 TOR‐I/reduced CNI versus AM/standard CNI	8	3954	Mean Difference (IV, Random, 95% CI)	1.58 [‐1.12, 4.28]
5.2 TOR‐I/standard CNI versus AM/standard CNI	17	4145	Mean Difference (IV, Random, 95% CI)	‐5.45 [‐7.55, ‐3.35]
6 Serum creatinine	16	4453	Mean Difference (IV, Random, 95% CI)	10.22 [1.72, 18.72]
7 Elevated lipid levels	13		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
7.1 Hypercholesterolaemia	12	5725	Risk Ratio (M‐H, Random, 95% CI)	1.83 [1.48, 2.25]
7.2 Hypertriglyceridaemia	9	4698	Risk Ratio (M‐H, Random, 95% CI)	1.48 [1.26, 1.74]
8 Lipid outcomes	14		Mean Difference (IV, Random, 95% CI)	Subtotals only
8.1 Cholesterol	14	5176	Mean Difference (IV, Random, 95% CI)	0.57 [0.43, 0.71]
8.2 Triglycerides	13	5099	Mean Difference (IV, Random, 95% CI)	0.40 [0.29, 0.51]
9 Abnormal haematological values	18		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
9.1 Anaemia	15	8595	Risk Ratio (M‐H, Random, 95% CI)	1.06 [0.92, 1.23]
9.2 Leucopenia	15	8396	Risk Ratio (M‐H, Random, 95% CI)	0.43 [0.33, 0.56]
9.3 Thrombocytopenia	8	5028	Risk Ratio (M‐H, Random, 95% CI)	1.96 [1.38, 2.79]
10 Haematological outcomes	9		Mean Difference (IV, Random, 95% CI)	Subtotals only
10.1 Haemoglobin [g/dL]	6	1035	Mean Difference (IV, Random, 95% CI)	‐0.38 [‐0.63, ‐0.12]
10.2 White cell count [per mm³]	7	3635	Mean Difference (IV, Random, 95% CI)	0.47 [‐0.03, 0.96]
10.3 Platelet count [per mm²]	6	3569	Mean Difference (IV, Random, 95% CI)	‐0.01 [‐1.43, 1.41]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Death	5	791	Risk Ratio (M‐H, Random, 95% CI)	1.00 [0.72, 1.39]
2 Total graft loss	5	791	Risk Ratio (M‐H, Random, 95% CI)	1.08 [0.73, 1.60]
3 Graft loss censored for death	5	791	Risk Ratio (M‐H, Random, 95% CI)	1.01 [0.51, 2.00]
4 Malignancies	3	617	Risk Ratio (M‐H, Random, 95% CI)	0.70 [0.47, 1.05]
5 GFR	5	534	Mean Difference (IV, Random, 95% CI)	‐7.21 [‐19.50, 5.08]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Death (all causes)	9	1501	Risk Ratio (M‐H, Random, 95% CI)	1.07 [0.64, 1.78]
2 Total graft loss	8	1385	Risk Ratio (M‐H, Random, 95% CI)	1.09 [0.68, 1.75]
3 Graft loss censored for death	8	1385	Risk Ratio (M‐H, Random, 95% CI)	1.09 [0.54, 2.20]
4 All acute rejection	9	1509	Risk Ratio (M‐H, Random, 95% CI)	0.84 [0.67, 1.07]
5 Biopsy‐proven acute rejection	8	1381	Risk Ratio (M‐H, Random, 95% CI)	0.87 [0.67, 1.13]
6 CMV infection	5	865	Risk Ratio (M‐H, Random, 95% CI)	1.42 [0.78, 2.60]
7 Adverse wound outcomes	5		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
7.1 All complications	3	291	Risk Ratio (M‐H, Random, 95% CI)	0.95 [0.53, 1.71]
7.2 Lymphocoele	3	702	Risk Ratio (M‐H, Random, 95% CI)	0.86 [0.45, 1.63]
8 All malignancies	7	1163	Risk Ratio (M‐H, Random, 95% CI)	1.04 [0.36, 3.04]
9 Number needing to change treatment	5	734	Risk Ratio (M‐H, Random, 95% CI)	1.18 [0.58, 2.42]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Death	13	3894	Risk Ratio (M‐H, Random, 95% CI)	0.89 [0.63, 1.25]
2 Total graft loss	11	3476	Risk Ratio (M‐H, Random, 95% CI)	0.84 [0.67, 1.06]
3 Graft loss censored for death	12	3863	Risk Ratio (M‐H, Random, 95% CI)	0.92 [0.71, 1.19]
4 All acute rejection	13	3898	Risk Ratio (M‐H, Random, 95% CI)	1.25 [1.10, 1.42]
5 Biopsy‐proven acute rejection	11	3731	Risk Ratio (M‐H, Random, 95% CI)	1.26 [1.10, 1.43]
6 CMV infection	9	3099	Risk Ratio (M‐H, Random, 95% CI)	0.87 [0.63, 1.21]
7 All malignancy	10	3175	Risk Ratio (M‐H, Random, 95% CI)	0.84 [0.54, 1.32]
8 Adverse wound outcomes	11		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
8.1 All wound complications	7	2792	Risk Ratio (M‐H, Random, 95% CI)	0.92 [0.66, 1.29]
8.2 Lymphocoele	10	3302	Risk Ratio (M‐H, Random, 95% CI)	0.81 [0.63, 1.04]
9 Number needing to change treatment	10	3652	Risk Ratio (M‐H, Random, 95% CI)	0.91 [0.78, 1.05]

PERMALINK

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

Deirdre Hahn

Elisabeth M Hodson

Lorraine A Hamiwka

Vincent WS Lee

Jeremy R Chapman

Jonathan C Craig

Angela C Webster

Abstract

Background

Objectives

Search methods

Selection criteria

Data collection and analysis

Main results

Authors' conclusions

Plain language summary

Summary of findings

Background

Description of the condition

Description of the intervention

How the intervention might work

Why it is important to do this review

Objectives

Methods

Criteria for considering studies for this review

Types of studies

Types of participants

Inclusion criteria

Exclusion criteria

Types of interventions

Types of outcome measures

Primary outcomes

Secondary outcomes

Search methods for identification of studies

Electronic searches

Searching other resources

Data collection and analysis

Selection of studies

Data extraction and management

Assessment of risk of bias in included studies

Measures of treatment effect

Unit of analysis issues

Dealing with missing data

Assessment of heterogeneity

Assessment of reporting biases

Data synthesis

Subgroup analysis and investigation of heterogeneity

Sensitivity analysis

'Summary of findings' tables

Primary outcomes

Secondary outcomes

Results

Description of studies

Results of the search

1.

Included studies

TOR‐I versus calcineurin inhibitor

TOR‐I versus antimetabolite

Variable doses of TOR‐I and CNI

Lower versus higher doses of TOR‐I

Sirolimus versus everolimus

Excluded studies

Risk of bias in included studies

2.

3.

Allocation

TOR‐1 versus calcineurin inhibitor

TOR‐I versus antimetabolite

Variable dosage of TOR‐I and calcineurin inhibitor

Lower versus higher doses of TOR‐1

Sirolimus versus everolimus

Blinding

TOR‐1 versus calcineurin inhibitor

TOR‐I versus antimetabolite

Variable dosage of TOR‐I and calcineurin inhibitor

Lower versus higher doses of TOR‐I

Sirolimus versus everolimus

Incomplete outcome data

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 New‐onset diabetes mellitus	6	2125	Risk Ratio (M‐H, Random, 95% CI)	0.69 [0.51, 0.93]
2 Lymphoma/PTLD	7	2792	Risk Ratio (M‐H, Random, 95% CI)	0.66 [0.25, 1.73]
3 Adverse cosmetic outcomes	7		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
3.1 Tremor	1	387	Risk Ratio (M‐H, Random, 95% CI)	0.90 [0.63, 1.29]
3.2 Gingival hyperplasia	2	622	Risk Ratio (M‐H, Random, 95% CI)	1.45 [0.48, 4.42]
3.3 Hirsutism	2	1102	Risk Ratio (M‐H, Random, 95% CI)	0.50 [0.30, 0.85]
3.4 Acne/rash	6	2408	Risk Ratio (M‐H, Random, 95% CI)	0.86 [0.62, 1.21]
4 Glomerular filtration rate	7	1863	Mean Difference (IV, Random, 95% CI)	2.88 [‐0.71, 6.48]
5 Serum creatinine	7	1951	Mean Difference (IV, Random, 95% CI)	‐2.21 [‐13.68, 9.26]
6 Elevated lipid levels	9		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
6.1 Hypercholesterolaemia	9	3250	Risk Ratio (M‐H, Random, 95% CI)	0.87 [0.78, 0.98]
6.2 Hypertriglyceridaemia	5	1064	Risk Ratio (M‐H, Random, 95% CI)	0.71 [0.47, 1.07]
7 Lipid outcomes	5		Mean Difference (IV, Random, 95% CI)	Subtotals only
7.1 Cholesterol	5	1041	Mean Difference (IV, Random, 95% CI)	‐0.13 [‐0.35, 0.08]
7.2 Triglycerides	4	1041	Mean Difference (IV, Random, 95% CI)	‐0.37 [‐0.72, ‐0.03]
8 Abnormal haematological values	12		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
8.1 Anaemia	10	3179	Risk Ratio (M‐H, Random, 95% CI)	0.81 [0.72, 0.91]
8.2 Leucopenia	12	3831	Risk Ratio (M‐H, Random, 95% CI)	0.72 [0.57, 0.92]
8.3 Thrombocytopenia	9	2242	Risk Ratio (M‐H, Random, 95% CI)	0.58 [0.44, 0.75]
9 Haematological outcomes	1		Mean Difference (IV, Random, 95% CI)	Totals not selected
9.1 Haemoglobin [g/dL]	1		Mean Difference (IV, Random, 95% CI)	0.0 [0.0, 0.0]
9.2 White cell count [per mm³]	1		Mean Difference (IV, Random, 95% CI)	0.0 [0.0, 0.0]
9.3 Platelet count [per mm²]	1		Mean Difference (IV, Random, 95% CI)	0.0 [0.0, 0.0]

Outcome or subgroup title	No. of studies	Statistical method	Effect size
1 Serum creatinine	1	Mean Difference (IV, Random, 95% CI)	Totals not selected
2 Estimated glomerular filtration rate	1	Mean Difference (IV, Random, 95% CI)	Totals not selected
3 Lipid outcomes	1	Mean Difference (IV, Random, 95% CI)	Totals not selected
3.1 Cholesterol	1	Mean Difference (IV, Random, 95% CI)	0.0 [0.0, 0.0]
3.2 Triglycerides	1	Mean Difference (IV, Random, 95% CI)	0.0 [0.0, 0.0]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 All acute rejection (publication type)	19	3016	Risk Ratio (M‐H, Random, 95% CI)	1.59 [1.31, 1.92]
1.1 Abstract	3	228	Risk Ratio (M‐H, Random, 95% CI)	2.03 [1.13, 3.65]
1.2 Journal	16	2788	Risk Ratio (M‐H, Random, 95% CI)	1.56 [1.26, 1.92]
2 All acute rejection (risk of bias for sequence generation and allocation concealment)	19	3016	Risk Ratio (M‐H, Random, 95% CI)	1.59 [1.31, 1.92]
2.1 Low risk of bias	7	1841	Risk Ratio (M‐H, Random, 95% CI)	1.45 [0.98, 2.15]
2.2 High or unclear risk of bias	12	1175	Risk Ratio (M‐H, Random, 95% CI)	1.70 [1.35, 2.14]
3 All acute rejection (CNI comparator)	19		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
3.1 Tacrolimus	7	1384	Risk Ratio (M‐H, Random, 95% CI)	2.19 [1.71, 2.81]
3.2 Cyclosporin	13	2233	Risk Ratio (M‐H, Random, 95% CI)	1.48 [1.20, 1.83]
4 All acute rejection (antibody induction)	17	2795	Risk Ratio (M‐H, Random, 95% CI)	1.60 [1.29, 1.99]
4.1 No induction	4	307	Risk Ratio (M‐H, Random, 95% CI)	1.24 [0.91, 1.68]
4.2 Antibody induction	13	2488	Risk Ratio (M‐H, Random, 95% CI)	1.83 [1.35, 2.50]
5 Graft loss censored for death (CNI comparator)	14	3277	Risk Ratio (M‐H, Random, 95% CI)	1.32 [0.96, 1.81]
5.1 Tacrolimus	5	1238	Risk Ratio (M‐H, Random, 95% CI)	1.95 [1.17, 3.25]
5.2 Cyclosporin	10	2039	Risk Ratio (M‐H, Random, 95% CI)	1.02 [0.68, 1.54]
6 Acute rejection (antimetabolite co‐intervention)	6	670	Risk Ratio (M‐H, Random, 95% CI)	1.09 [0.81, 1.48]
6.1 Azathioprine	1	83	Risk Ratio (M‐H, Random, 95% CI)	1.09 [0.64, 1.85]
6.2 Mycophenolate	5	587	Risk Ratio (M‐H, Random, 95% CI)	1.10 [0.75, 1.59]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Acute rejection (publication type)	32	10687	Risk Ratio (M‐H, Random, 95% CI)	0.92 [0.80, 1.07]
1.1 Abstract	5	273	Risk Ratio (M‐H, Random, 95% CI)	0.68 [0.29, 1.61]
1.2 Journal	27	10414	Risk Ratio (M‐H, Random, 95% CI)	0.93 [0.80, 1.08]
2 Acute rejection (risk of bias for sequence generation and allocation concealment	32	10535	Risk Ratio (M‐H, Random, 95% CI)	0.95 [0.83, 1.09]
2.1 Low risk of bias	12	7313	Risk Ratio (M‐H, Random, 95% CI)	0.88 [0.73, 1.06]
2.2 High risk or unclear risk of bias	20	3222	Risk Ratio (M‐H, Random, 95% CI)	1.04 [0.87, 1.26]
3 Acute rejection (CNI co‐intervention)	27	7437	Risk Ratio (M‐H, Random, 95% CI)	0.89 [0.78, 1.02]
3.1 Tacrolimus	18	4341	Risk Ratio (M‐H, Random, 95% CI)	0.93 [0.76, 1.14]
3.2 Cyclosporin	9	3096	Risk Ratio (M‐H, Random, 95% CI)	0.81 [0.70, 0.93]
4 Acute rejection (TOR‐I)	32	10538	Risk Ratio (M‐H, Random, 95% CI)	0.94 [0.82, 1.08]
4.1 Everolimus	16	6126	Risk Ratio (M‐H, Random, 95% CI)	1.04 [0.85, 1.26]
4.2 Sirolimus	16	4412	Risk Ratio (M‐H, Random, 95% CI)	0.85 [0.70, 1.04]
5 Acute rejection (antibody induction)	31	10476	Risk Ratio (M‐H, Random, 95% CI)	0.92 [0.79, 1.07]
5.1 No induction	10	5293	Risk Ratio (M‐H, Random, 95% CI)	0.93 [0.77, 1.12]
5.2 Antibody induction	21	5183	Risk Ratio (M‐H, Random, 95% CI)	0.90 [0.70, 1.16]
6 Acute rejection (antimetabolite comparator)	32	10538	Risk Ratio (M‐H, Random, 95% CI)	0.94 [0.82, 1.08]
6.1 Azathioprine	2	789	Risk Ratio (M‐H, Random, 95% CI)	0.71 [0.39, 1.28]
6.2 Mycophenolate	30	9749	Risk Ratio (M‐H, Random, 95% CI)	0.98 [0.86, 1.12]

Methods	Design: open‐label parallel RCT Duration: October 2001 to June 2004 Follow up: 12 months
Participants	Setting: single centre transplant unit Country: USA Kidney transplant recipients aged ≥ 18 years, HIV negative, PRA < 10% Number (group 1/group 2): 150 (75/75) Mean age ± SD (years): group 1 (55.0 ± 12.0); group 2 (49.0 ± 13.7) Sex (M/F): group 1 (51/49); group 2 (54/46) Exclusions: not reported
Interventions	Co‐interventions Basiliximab, MP TAC: 0.2 mg/kg/d from day 1 for level 10 to 18 ng/mL, then maintenance Treatment group 1 SRL: 2 mg/d from day 4 for trough level 6 to 10 ng/mL Treatment group 2 MMF: 2 g/d from day 1
Outcomes	Death (all causes) Graft loss censored for death Graft loss or death with a functioning graft Acute rejection CrCl SCr CAN Haematological adverse effects Surgical adverse effects Cosmetic/life style adverse effects
Notes	Comparison: TOR‐I versus antimetabolite
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Randomisation sequence was determined using the First Generator Plan (www.randomization.com)
Allocation concealment (selection bias)	Low risk	Randomisation sequence was determined using the First Generator Plan (www.randomization.com)
Blinding of participants and personnel (performance bias)   All outcomes	High risk	No blinding of participants/personnel reported
Blinding of outcome assessment (detection bias)   All outcomes	Low risk	Primary endpoint was acute rejection diagnosed on biopsy by pathologist without knowledge of the patient’s clinical diagnosis
Incomplete outcome data (attrition bias)   All outcomes	Low risk	All participants accounted for. Complete follow‐up to 6 months
Selective reporting (reporting bias)	Low risk	Expected primary outcomes reported
Other bias	High risk	This clinical study was supported by an unrestricted financial grant from Fujisawa Healthcare and clinical revenue of Division of Transplantation, Drexel University College of Medicine

Methods	Design: parallel RCT Duration: June 2000 to October 2004 Follow up: 4 years or more
Participants	Setting: single centre; Drexel University College of Medicine and Hahnemann University Hospital Country: USA First kidney transplant; recipients > 20 years, LD or DD donors Number (group 1/group 2/group 3/ group 4): 200 (50/50/50/50) Mean age ± SD (years): group 1 (51 ± 14); group 2 (56 ± 13); group 3 (48 ± 14); group 4 (59 ± 12) Sex (M/F): group 1 (35/15); group 2 (37/13); group 3 (34/16); group 4 (34/16) Exclusions: < 20 years; unable to sign an informed consent form; were HIV or HBV positive
Interventions	Treatment group 1 (MMF/CSA) CSA: as above MMF: 2 g/d for trough levels 1 to 3 µg/mL of MPA Treatment group 2 (SRL/CSA) CSA: as above SRL: 2mg/d from day 4 for levels 5 to 10 ng/mL. Treatment group 3 (MMF/TAC) TAC: as above MMF: 2 g/d for trough levels 1 to 3 µg/mL of MPA Treatment group 4 (SRL/TAC) TAC: as above SRL: 2 mg/d from day 4 for levels 5 to 10 ng/mL Co‐interventions Basiliximab MP (2 doses) and no further steroids CSA: 3 mg/kg/d for C2 blood levels of 1000 to 1200 ng/mL at 1 month and 700 ng/mL by 1 year TAC: 0.02 mg/kg for trough levels 15 to 18 ng/mL by day 4 till 1 month, then 10 ng/mL by 1 year
Outcomes	Death Acute rejection Graft loss CMV infection DGF
Notes	NOTE: for the analysis, groups 2 and 4 (SRL/CNI) were compared with 1 and 3 (MMF/CNI) Significantly younger recipients in TAC/MMF group and significantly older recipients in the TAC/SRL group. Significantly older donors in the CSA/SRL group and significantly younger in the TAC/MMF group. Significantly more diabetes in recipients of the CSA/SRL and TAC/SRL groups. Significantly less cold ischaemia time in CSA/MMF group and significantly longer cold ischaemia time in the TAC/SRL group. Significantly fewer males in the CSA/SRL donor group and significantly more males in the TAC/SRL donor group
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Randomisation sequence was determined using the First Generator Plan (http://www.randomization.com)
Allocation concealment (selection bias)	Low risk	Patients allocated using the First Generator Plan (http://www.randomization.com)
Blinding of participants and personnel (performance bias)   All outcomes	High risk	No blinding of participants/personnel reported
Blinding of outcome assessment (detection bias)   All outcomes	Low risk	Outcomes of death, graft loss, biopsy‐confirmed acute rejection were unlikely to be influenced by lack of blinding
Incomplete outcome data (attrition bias)   All outcomes	Low risk	All surviving patients completed 4 years of follow up; analysed in groups to which randomised
Selective reporting (reporting bias)	Low risk	Expected outcomes reported for all four treatment groups
Other bias	Unclear risk	Funding source not reported

Methods	Design: open‐label RCT Duration: December 2012 to March 2016 Follow up: 12 months
Participants	Setting: multicentre Country: Germany (15 sites); France (12 sites) Kidney transplant recipients (first or second LD or DD) Number (group 1/group 2/group 3): 612 (208/199/205) Mean age ± SD (years): group 1 (54.3 ± 13.5); group 2 (55.1 ± 12.6); group 3 (55.3 ± 12.1) Gender (M/F): group 1 (138/70); group 2 (133/66): group 3 (140/65) Exclusions: ABO‐incompatible transplant; pre‐existing donor‐specific antibodies; cold ischaemia time ≥ 30 hours; multi‐organ transplant; PRA > 20%; malignancy in previous 5 years (except skin, kidney, thyroid); pregnant/nursing mother or refusal to take contraception; thrombocytopenia; leucopenia; uncontrolled hypercholesterolaemia; hypertriglyceridaemia
Interventions	Treatment group 1 (EVL/TAC) EVL: C0 target: 3 to 8 ng/mL (M1 to M12) TAC: 4 to 8 ng/mL (M1 to M3); 3 to 5 ng/mL (M3 to M5) Treatment group 2 (EVL/CSA) EVL: C0 target: 3 to 8 ng/mL (M1 to M12) CSA: 75 to 125 ng/mL (M1 to M3); 50 to 100 ng/mL (M3 to M12) Treatment group 3 (MPA/TAC) TAC: 4 to 8 ng/mL (M1 to M3); 3 to 5 ng/mL (M3 to M5) MPA: 1.44 g/d mycophenolate sodium or 2 g/d of MMF Co‐interventions Corticosteroids/basiliximab in each group
Outcomes	Death (all causes) Graft loss BPAR Infections: CMV, BK Adverse events
Notes	Comparisons: TOR‐I versus antimetabolite
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: "validated system to ensure an unbiased treatment assignment in a 1:1:1 ratio"
Allocation concealment (selection bias)	Unclear risk	Quote: "validated system to ensure an unbiased treatment assignment in a 1:1:1 ratio"
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Open‐label study
Blinding of outcome assessment (detection bias)   All outcomes	Low risk	Primary outcome is GFR and unlikely to be influenced by blinding
Incomplete outcome data (attrition bias)   All outcomes	Low risk	655 randomised; 43 did not receive medication. ITT population 612/safety population 612
Selective reporting (reporting bias)	Low risk	Expected outcomes were reported
Other bias	High risk	The study was funded by Novartis Pharma GmbH, Nürnberg, Germany

Methods	Design: open‐label RCT Duration: not reported Follow up: 13 months
Participants	Setting: single centre Country: Iran 60 kidney transplant recipients of LD or DD organs aged 18 to 65 years Age and gender: not reported Exclusions: not reported
Interventions	Treatment group 1 (EVL/rCSA) EVL: 0.75 mg twice/day 3 to 8 ng/mL CSA: 3 to 5 mg/kg 100 to 200 ng/mL (M1); 75 to 100 ng/mL (M2 to M3); 50 to 100 ng/mL (M4); 25 to 50 ng/mL (M6 to M12) Treatment group 2 (MPA/sCNI) MMF: 1 g twice/d (CSA patients) MMF: 500 mg twice/d (TAC patients) TAC: 0.1 mg/kg, 7 to 10 ng/mL to M3 CSA: 7.5 mg/kg, 150 to 300 ng/mL to M3 Co‐interventions Corticosteroids in each group
Outcomes	BPAR CMV and BK virus GFR
Notes	Abstract only available Patient numbers in each group not reported so data cannot be entered in meta‐analyses
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Eligible patients randomised 1:1 prior to transplantation
Allocation concealment (selection bias)	Unclear risk	Eligible patients randomised 1:1 prior to transplantation
Blinding of participants and personnel (performance bias)   All outcomes	High risk	No information provided to suggest study was blinded
Blinding of outcome assessment (detection bias)   All outcomes	Low risk	Primary outcome was GFR so unlikely to be influenced by lack of blinding
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	Insufficient data to permit judgement ‐ abstract only
Selective reporting (reporting bias)	Unclear risk	Insufficient data to permit judgement ‐ abstract only
Other bias	Unclear risk	Insufficient data to permit judgement ‐ abstract only

Methods	Design: parallel group RCT Duration: not reported Follow up: 12 months
Participants	Setting: single centre study Country: Italy Kidney transplant recipients Number (group 1/group 2): 106 (50/56) Mean age ± SD (years): group 1 (49.7 ± 12.1); group 2 (45.7 ± 12.8) Sex (MF): not reported Exclusions: donor and recipient age > 65 years; PRA > 50%; retransplants; combined transplants; FSGS as primary disease, BMI > 25
Interventions	Treatment group 1 (sCSA/MMF) MPA (EC‐MPS): 1440 mg/d CSA: starting at 6 mg/kg/d for C2 levels 500 to 700 ng/mL Treatment group 2 (rCSA/EVL) EVL: 8 to 12 ng/mL initially then 3 to 8 ng/mL CSA: starting at 4 mg/kg/d for C2 levels 250 to 300 ng/mL Co‐interventions Basiliximab Corticosteroids
Outcomes	Death (all causes) Graft loss with death censored CrCl Biochemical adverse effects Cosmetic/lifestyle adverse effects
Notes	Comparison: TORI‐I versus antimetabolite
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Insufficient information to permit judgement
Allocation concealment (selection bias)	Unclear risk	Insufficient information to permit judgement
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Open‐label study
Blinding of outcome assessment (detection bias)   All outcomes	Low risk	Primary outcomes (graft loss, BPAR) unlikely to be influenced by lack of blinding
Incomplete outcome data (attrition bias)   All outcomes	Low risk	All patients accounted for
Selective reporting (reporting bias)	High risk	No report on wound complications
Other bias	Low risk	Quote: "no financial support"

Methods	Design: parallel RCT Duration: May 2000 to December 2001 Follow up: 36 months
Participants	Setting: single centre study Country: USA Kidney transplant recipients aged 14 to 78 years; DD and non‐HLA identical LD Number (group 1/group 2/group 3): 150 (50/50/50) Mean age ± SD (years): group 1 (50 ± 13); group 2 (47 ± 16); group 3 (44 ± 16) Sex (M/F): group 1 (35/15); group 2 (32/18); group 3 (32/18) Exclusions: not reported
Interventions	Treatment group 1 (SRL/TAC) SRL: 4 mg/d for level 8 ng/mL TAC: 0.2 g/kg/d for levels 10ng/mL; 6 to 8 ng/mL by 3 to 6 months; 6 ng/mL by 12 months Treatment group 2 (MMF/TAC) MMF: 2 g/d TAC: 0.2 g/kg/d for level 10ng/mL, 8 ng/mL by 12 months Treatment group 3 (SRL/CS) SRL: 4 mg/d for level 8 ng/mL CSA: 10 mg/kg/d for levels 200 to 250 ng/mL, 150 to 200 ng/mL at 12 months Baseline immunosuppression Daclizumab Prednisolone
Outcomes	Death (all causes) Cause‐specific death Graft loss censored for death Graft loss or death with a functioning graft Acute rejection Steroid‐resistant rejection CrCl SCr Infection CMV infection Biochemical adverse effects Surgical adverse effects Cosmetic/life style adverse effects
Notes	Comparison: TOR‐I versus antimetabolite; groups 1 and 3 combined and compared with group 2
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Block randomisation scheme; equally divided into three groups
Allocation concealment (selection bias)	Unclear risk	Insufficient information to permit judgement
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Open‐label study
Blinding of outcome assessment (detection bias)   All outcomes	Low risk	Primary outcomes were laboratory based and unlikely to be influenced by lack of blinding
Incomplete outcome data (attrition bias)   All outcomes	Low risk	All patients accounted for
Selective reporting (reporting bias)	Low risk	Expected outcomes reported
Other bias	High risk	National Institutes of Health (grant R01DK25243‐25), Miami Veterans Affairs Medical Center research support, Astellas Pharma US, Roche Laboratories, and Wyeth