Calcineurin inhibitor withdrawal or tapering for kidney transplant recipients

Krishna M Karpe; Girish S Talaulikar; Giles D Walters

doi:10.1002/14651858.CD006750.pub2

. 2017 Jul 21;2017(7):CD006750. doi: 10.1002/14651858.CD006750.pub2

Calcineurin inhibitor withdrawal or tapering for kidney transplant recipients

Krishna M Karpe ^1,^2,^✉, Girish S Talaulikar ^1,², Giles D Walters ^1,²

Editor: Cochrane Kidney and Transplant Group

PMCID: PMC6483545 PMID: 28730648

Abstract

Background

Calcineurin inhibitors (CNI) can reduce acute transplant rejection and immediate graft loss but are associated with significant adverse effects such as hypertension and nephrotoxicity which may contribute to chronic rejection. CNI toxicity has led to numerous studies investigating CNI withdrawal and tapering strategies. Despite this, uncertainty remains about minimisation or withdrawal of CNI.

Objectives

This review aimed to look at the benefits and harms of CNI tapering or withdrawal in terms of graft function and loss, incidence of acute rejection episodes, treatment‐related side effects (hypertension, hyperlipidaemia) and death.

Search methods

We searched the Cochrane Kidney and Transplant Specialised Register to 11 October 2016 through contact with the Information Specialist using search terms relevant to this review. Studies contained in the Specialised Register are identified through search strategies specifically designed for CENTRAL, MEDLINE, and EMBASE; handsearching conference proceedings; and searching the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov.

Selection criteria

All randomised controlled trials (RCTs) where drug regimens containing CNI were compared to alternative drug regimens (CNI withdrawal, tapering or low dose) in the post‐transplant period were included, without age or dosage restriction.

Data collection and analysis

Two authors independently assessed studies for eligibility, risk of bias, and extracted data. Results were expressed as risk ratio (RR) or mean difference (MD) with 95% confidence intervals (CI).

Main results

We included 83 studies that involved 16,156 participants. Most were open‐label studies; less than 30% of studies reported randomisation method and allocation concealment. Studies were analysed as intent‐to‐treat in 60% and all pre‐specified outcomes were reported in 54 studies. The attrition and reporting bias were unclear in the remainder of the studies as factors used to judge bias were reported inconsistently. We also noted that 50% (47 studies) of studies were funded by the pharmaceutical industry.

We classified studies into four groups: CNI withdrawal or avoidance with or without substitution with mammalian target of rapamycin inhibitors (mTOR‐I); and low dose CNI with or without mTOR‐I. The withdrawal groups were further stratified as avoidance and withdrawal subgroups for major outcomes.

CNI withdrawal may lead to rejection (RR 2.54, 95% CI 1.56 to 4.12; moderate certainty evidence), may make little or no difference to death (RR 1.09, 95% CI 0.96 to 1.24; moderate certainty), and probably slightly reduces graft loss (RR 0.85, 95% CI 0.74 to 0.98; low quality evidence). Hypertension was probably reduced in the CNI withdrawal group (RR 0.82, 95% CI 0.71 to 0.95; low certainty), while CNI withdrawal may make little or no difference to malignancy (RR 1.10, 95% CI 0.93 to 1.30; low certainty), and probably makes little or no difference to cytomegalovirus (CMV) (RR 0.87, 95% CI 0.52 to 1.45; low certainty)

CNI avoidance may result in increased acute rejection (RR 2.16, 95% CI 0.85 to 5.49; low certainty) but little or no difference in graft loss (RR 0.96, 95% CI 0.79 to 1.16; low certainty). Late CNI withdrawal increased acute rejection (RR 3.21, 95% CI 1.59 to 6.48; moderate certainty) but probably reduced graft loss (RR 0.84, 95% CI 0.72 to 0.97, low certainty).

Results were similar when CNI avoidance or withdrawal was combined with the introduction of mTOR‐I; acute rejection was probably increased (RR 1.43; 95% CI 1.15 to 1.78; moderate certainty) and there was probably little or no difference in death (RR 0.96; 95% CI 0.69 to 1.36, moderate certainty). mTOR‐I substitution may make little or no difference to graft loss (RR 0.94, 95% CI 0.75 to 1.19; low certainty), probably makes little of no difference to hypertension (RR 0.86, 95% CI 0.64 to 1.15; moderate), and probably reduced the risk of cytomegalovirus (CMV) (RR 0.60, 95% CI 0.44 to 0.82; moderate certainty) and malignancy (RR 0.69, 95% CI 0.47 to 1.00; low certainty). Lymphoceles were increased with mTOR‐I substitution (RR 1.45, 95% CI 0.95 to 2.21; low certainty).

Low dose CNI combined with mTOR‐I probably increased glomerular filtration rate (GFR) (MD 6.24 mL/min, 95% CI 3.28 to 9.119; moderate certainty), reduced graft loss (RR 0.75, 95% CI 0.55 to 1.02; moderate certainty), and made little or no difference to acute rejection (RR 1.13 ; 95% CI 0.91 to 1.40; moderate certainty). Hypertension was decreased (RR 0.98, 95% CI 0.80 to 1.20; low certainty) as was CMV (RR 0.41, 95% CI 0.16 to 1.06; low certainty). Low dose CNI plus mTOR‐I makes probably makes little of no difference to malignancy (RR 1.22, 95% CI 0.42 to 3.53; low certainty) and may make little of no difference to death (RR 1.16, 95% CI 0.71 to 1.90; moderate certainty).

Authors' conclusions

CNI avoidance increased acute rejection and CNI withdrawal increases acute rejection but reduced graft loss at least over the short‐term. Low dose CNI with induction regimens reduced acute rejection and graft loss with no major adverse events, also in the short‐term. The use of mTOR‐I reduced CMV infections but increased the risk of acute rejection. These conclusions must be tempered by the lack of long‐term data in most of the studies, particularly with regards to chronic antibody‐mediated rejection, and the suboptimal methodological quality of the included studies.

Plain language summary

Calcineurin inhibitor withdrawal or tapering for kidney transplant recipients

What is the issue?

Calcineurin inhibitors (CNI, cyclosporin and tacrolimus) are an important part of treatment to suppress the immune system to prevent rejection of transplanted kidneys. However, CNI can cause high blood pressure and kidney scarring which contribute to worsening of risk factors for heart attack, stroke, and loss of the transplanted organ over time.

There are conflicting data on the results of withdrawing these drugs from kidney transplant recipients; some studies suggest improved kidney function but others report a moderate risk of developing rejection. Because of this uncertainty, we assessed the benefits and harms of CNI withdrawal or tapering in kidney transplant recipients to identify which approach was more beneficial.

What did we do?   We included 83 studies that involved more than 16,000 people in our review. Studies which compared standard dose CNI regimens with withdrawal, tapering or low dose CNI in the post‐transplant period were analysed.

What did we find?   Although withdrawing CNI treatment resulted in more rejections in the short term, there was no clear change in transplanted organ failure, death, development of cancer, or infections. Replacing CNI with another group of drugs ‐ the mTOR inhibitors ‐ did not significantly change outcomes, except for fewer cytomegalovirus (CMV) infections. Lower CNI dose was associated with fewer episodes of kidney transplant rejection and loss, but only in the first year to up to five years after the transplant.

Conclusions   We found that the long‐term outcomes for stopping or gradually reducing CNI therapy were not clear, and that mTOR inhibitors can reduce CMV infections with a higher risk of acute rejection. There were insufficient studies with long term follow‐up to clearly determine which treatment is better for people who receive kidney transplants.

Summary of findings

Summary of findings for the main comparison. Calcineurin inhibitor (CNI) withdrawal versus standard dose CNI for kidney transplant recipients.

CNI withdrawal versus standard dose CNI for kidney transplant recipients
Patient or population: kidney transplant recipients  Intervention: CNI withdrawal  Comparison: standard dose CNI
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect  (95% CI)	No. of participants  (studies)	Quality of the evidence  (GRADE)
	Risk with standard dose CNI	Risk with CNI withdrawal
Death  Follow‐up: range 9 months to 20 years	Study population		RR 1.09  (0.96 to 1.24)	2010 (14 )	⊕⊕⊕⊝  MODERATE ^{1 2 3 4}
	225 per 1,000	245 per 1,000  (216 to 279)
Acute rejection  Follow‐up: range 9 months to 15 years	Study population		RR 2.54  (1.56 to 4.12)	1666 (15)	⊕⊕⊕⊝  MODERATE ^{2 4 5 6}
	137 per 1,000	348 per 1,000  (214 to 564)
GFR  Follow‐up: range 1 to 15 years	The mean GFR in the intervention group was 3.56 mL/min more (1.13 less to 8.25 more) than the control group		‐	910 (8)	⊕⊕⊝⊝  LOW ^{7 8}
Graft loss  Follow‐up: range 9 months to 20 years	Study population		RR 0.85  (0.74 to 0.98)	2090 (16)	⊕⊕⊝⊝  LOW ^{1 2 9 10 11 12}
	236 per 1,000	201 per 1,000  (175 to 231)
Adverse events: hypertension  Follow‐up: range 1 to 15 years	Study population		RR 0.82  (0.71 to 0.95)	950 (5 )	⊕⊕⊝⊝  LOW ^{2 10}
	555 per 1,000	455 per 1,000  (394 to 527)
Adverse events: CMV infection  Follow‐up: range 9 months to 15 years	Study population		RR 0.87  (0.52 to 1.45)	608 (7)	⊕⊕⊝⊝  LOW ^{1 2 10}
	98 per 1,000	86 per 1,000  (51 to 143)
Adverse events: malignancy  Follow‐up: range 1 to 15 years	Study population		RR 1.10  (0.93 to 1.30)	1079 (6)	⊕⊕⊝⊝  LOW ^{1 2 4 10}
	257 per 1,000	282 per 1,000  (239 to 334)
*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
GRADE Working Group grades of evidence   High quality: We are very confident that the true effect lies close to that of the estimate of the effect  Moderate quality: 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 quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect  Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

Low dose CNI versus standard dose CNI for kidney transplant recipients
Patient or population: kidney transplant recipients  Intervention: low dose CNI  Comparison: standard dose CNI
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect  (95% CI)	No. of participants  (studies)	Quality of the evidence  (GRADE)	Comments
	Risk with standard dose CNI	Risk with low dose CNI
Death  Follow‐up: range 6 months to 2 years	Study population		RR 0.79  (0.50 to 1.27)	3462 (15)	⊕⊕⊕⊝  MODERATE ^{1 2 3}
	23 per 1,000	19 per 1,000  (12 to 30)
Acute rejection  Follow‐up: range 6 months to 2 years	Study population		RR 0.87  (0.76 to 1.00)	3757 (19)	⊕⊕⊕⊝  MODERATE ^{1 2 4}
	183 per 1,000	159 per 1,000  (139 to 183)
GFR  Follow‐up: range 6 months to 2 years	The mean GFR in the intervention group was 4.1 mL/min more (2.07 more to 6.12 more) than the control group		‐	2623 (13)	⊕⊕⊕⊝  MODERATE ^{5 6 7}
Graft loss  Follow‐up: range 6 months to 2 years	Study population		RR 0.75  (0.55 to 1.02)	3286 (15)	⊕⊕⊕⊝  MODERATE ^{1 2 3 6}	Sensitivity analysis after excluding 1 study which also involved steroid withdrawal; significant reduction in graft loss in the low dose regimen
	58 per 1,000	44 per 1,000  (32 to 60)
Adverse events: hypertension  Follow‐up: range 6 months to 2 years	Study population		RR 0.84  (0.70 to 1.00)	1877 (5)	⊕⊕⊝⊝  LOW ^{2 7 8 9}
	218 per 1,000	184 per 1,000  (153 to 218)
Adverse events: CMV infection  Follow‐up: range 6 months to 2 years	Study population		RR 1.23  (0.94 to 1.62)	1948 (6)	⊕⊕⊕⊝  MODERATE ^{2 8 10}
	101 per 1,000	124 per 1,000  (95 to 163)
Adverse events: malignancy  Follow‐up: range 6 months to 2 years	Study population		RR 0.90  (0.41 to 1.97)	1637 (5)	⊕⊕⊝⊝  LOW ^{2 3 9}
	15 per 1,000	14 per 1,000  (6 to 30)
*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
GRADE Working Group grades of evidence   High quality: We are very confident that the true effect lies close to that of the estimate of the effect  Moderate quality: 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 quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect  Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

CNI withdrawal + mTORi versus standard dose CNI for kidney transplant recipients
Patient or population: kidney transplant recipients  Intervention: CNI withdrawal + mTORi  Comparison: standard dose CNI
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect  (95% CI)	No. of participants  (studies)	Quality of the evidence  (GRADE)
	Risk with standard dose CNI	Risk with CNI withdrawal + mTOR
Death  Follow‐up: range 6 months to 5 years	Study population		RR 0.99  (0.69 to 1.40)	5427 (23)	⊕⊕⊕⊝  MODERATE ^{1 2 3 4}
	26 per 1,000	26 per 1,000  (18 to 36)
Acute rejection  Follow‐up: range 6 months to 5 years	Study population		RR 1.43  (1.15 to 1.78)	5903 (30)	⊕⊕⊕⊝  MODERATE ^{1 3 4 5}
	134 per 1,000	191 per 1,000  (154 to 238)
Graft loss  Follow‐up: range 1 to 5 years	Study population		RR 0.94  (0.75 to 1.19)	5446 (25)	⊕⊕⊝⊝  LOW ^{2 4 6}
	53 per 1,000	50 per 1,000  (40 to 64)
Adverse events: hypertension  Follow‐up: range 6 months to 5 years	Study population		RR 0.86  (0.64 to 1.15)	2207 (7)	⊕⊕⊝⊝  LOW ^{7 8}
	218 per 1,000	187 per 1,000  (139 to 250)
Adverse events: CMV Infection  follow‐up: range 6 months to 5 years	Study population		RR 0.60  (0.44 to 0.82)	2503 (13)	⊕⊕⊕⊝  MODERATE ^{9 10}
	150 per 1,000	90 per 1,000  (66 to 123)
Adverse events: malignancy  Follow‐up: range 6 months to 5 years	Study population		RR 0.69  (0.47 to 1.00)	3699 (14)	⊕⊕⊝⊝  LOW ^{2 4 10}
	54 per 1,000	38 per 1,000  (26 to 54)
Adverse events: lymphocele  Follow‐up: range 6 months to 5 years	Study population		RR 1.45  (0.95 to 2.21)	1926 (8)	⊕⊕⊝⊝  LOW ^{6 8 11}
	100 per 1,000	144 per 1,000  (95 to 220)
*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
GRADE Working Group grades of evidence   High quality: We are very confident that the true effect lies close to that of the estimate of the effect  Moderate quality: 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 quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect  Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

Low dose CNI + mTORi versus standard dose CNI for kidney transplant recipients
Patient or population: kidney transplant recipients  Intervention: low dose CNI + mTORi  Comparison: standard dose CNI
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect  (95% CI)	No. of participants  (studies)	Quality of the evidence  (GRADE)
	Risk with standard dose CNI	Risk with low dose CNI + mTORi
Death  Follow‐up: range 6 months to 3 years	Study population		RR 1.16  (0.71 to 1.90)	2750 (11)	⊕⊕⊕⊝  MODERATE ^{1 2 3 4}
	22 per 1,000	26 per 1,000  (16 to 42)
Acute rejection  Follow‐up: range 6 months to 3 years	Study population		RR 1.13  (0.91 to 1.40)	3300 (16)	⊕⊕⊕⊝  MODERATE ^{2 4}
	132 per 1,000	149 per 1,000  (120 to 185)
GFR  Follow‐up: range 6 months to 2 years	The mean GFR in the intervention group was 6.24 mL/min more (3.28 more to 9.19 more) than the control group		‐	1749 (11)	⊕⊕⊕⊝  MODERATE ⁵
Graft loss  Follow‐up: range 6 months to 3 years	Study population		RR 0.67  (0.45 to 1.01)	3304 (16)	⊕⊕⊕⊝  MODERATE ^{2 6}
	38 per 1,000	25 per 1,000  (17 to 38)
Adverse events: hypertension  Follow‐up: range 6 months to 2 years	Study population		RR 0.98  (0.80 to 1.20)	1421 (5)	⊕⊕⊝⊝  LOW ^{7 8}
	203 per 1,000	199 per 1,000  (162 to 243)
Adverse events: CMV infection  Follow‐up: range 1 to 3 years	Study population		RR 0.41  (0.16 to 1.06)	1250 (5)	⊕⊕⊝⊝  LOW ^{5 7 9}
	105 per 1,000	43 per 1,000  (17 to 111)
Adverse events: malignancy  Follow‐up: range 1 to 3 years	Study population		RR 1.22  (0.42 to 3.52)	1074 (5)	⊕⊕⊝⊝  LOW ^{2 4 7}
	11 per 1,000	14 per 1,000  (5 to 40)
*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
GRADE Working Group grades of evidence   High quality: We are very confident that the true effect lies close to that of the estimate of the effect  Moderate quality: 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 quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect  Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

Subgroup analysis: CNI avoidance and late withdrawal versus standard dose CNI for kidney transplant recipients
Patient or population: kidney transplant recipients  Intervention: CNI avoidance and late withdrawal  Comparison: standard dose CNI
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect  (95% CI)	No. of participants  (studies)	Quality of the evidence  (GRADE)
	Risk with standard dose CNI	Risk with CNI avoidance and withdrawal
Acute rejection: avoidance  Follow‐up: range 1 to 12 years	Study population		RR 2.16  (0.85 to 5.49)	238 (3)	⊕⊕⊝⊝  LOW ^{1 2}
	344 per 1,000	744 per 1,000  (293 to 1,000)
Acute rejection: late withdrawal	Study population		RR 3.21  (1.59 to 6.48)	1428 (12)	⊕⊕⊕⊝  MODERATE ³
	102 per 1,000	328 per 1,000  (162 to 661)
GFR: avoidance	The mean GFR for avoidance studies in the intervention group was 2.22 mL/min lower (14.84 less to 10.4 more) than the control group		‐	242 (3)	⊕⊝⊝⊝  VERY LOW ^{1 2 4}
GFR: late withdrawal	The mean GFR for late withdrawal studies in the intervention group was 5.54 mL/min more (1.66 more to 9.43 more) than the control group		‐	668 (5)	⊕⊕⊝⊝  LOW ^{5 6}
Graft loss: avoidance	Study population		RR 0.96  (0.79 to 1.16)	566 (4)	⊕⊕⊝⊝  LOW ^{7 8}
	355 per 1,000	341 per 1,000  (281 to 412)
Graft loss: late withdrawal	Study population		RR 0.84  (0.72 to 0.97)	1831 (13)	⊕⊕⊕⊝  MODERATE ^{3 9 10}
	260 per 1,000	219 per 1,000  (187 to 252)
*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
GRADE Working Group grades of evidence   High quality: We are very confident that the true effect lies close to that of the estimate of the effect  Moderate quality: 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 quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect  Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

DATABASE	Search terms
CENTRAL	1. Kidney Transplantation, MESH term  2. Tacrolimus, MESH  3. (tacrolimus):ti,ab,kw  4. "FK 506" or FK506:ti,ab,kw  5. Cyclosporine, MeSH term  6. (cyclosporin* or ciclosporin):ti,ab,kw  7. (csa or neoral* or cya* or restasis or sandimmun):ti,ab,kw  8. (calcineurin inhibitor):ti,ab,kw  9. (2 OR 3 OR 4 OR 5 OR 6 OR 7 OR 8)  10. (discontinu* or withdraw* or taper* or spar* or avoid* or minim* or remov* or stop* or reduction* or reduc* or free*):ti,ab,kw  11. (9 AND 10)  12. (1 AND 11)
MEDLINE	1. Kidney Transplantation/  2. Tacrolimus/  3. tacrolimus.tw.  4. prograf$.tw.  5. ("FK 506" or FK506).tw.  6. fr‐900506.tw.  7. fujimycin.tw.  8. protopic.tw.  9. Cyclosporine/  10. cyclosporin$.tw.  11. ciclosporin$.tw.  12. csa.tw.  13. neoral.tw.  14. cya$.tw.  15. sandimmun$.tw.  16. restasis.tw.  17. calcineurin inhibitor$.tw.  18. or/2‐17  19. (discontinu$ or withdraw$ or taper$ or spar$ or avoid$ or minim$ or remov$ or stop$ or reduction or reduc$ or free$).tw.  20. and/18‐19  21. and/1,20
EMBASE	1. Kidney Transplantation/  2. Tsukubaenolide/  3. tacrolimus.tw.  4. prograf$.tw.  5. ("FK 506" or FK506).tw.  6. fr‐900506.tw.  7. fujimycin.tw.  8. protopic.tw.  9. Cyclosporin/  10. cyclosporin$.tw.  11. ciclosporin$.tw.  12. (csa or neoral or cya).tw.  13. (sandimmun$ or restaisi).tw.  14. Calcineurin Inhibitor/  15. or/2‐14  16. (discontinu$ or withdraw$ or taper$ or spar$ or avoid$ or minim$ or remov$ or stop$ or reduction or reduc$ or free$).tw.  17. and/15‐16  18. and/1,17

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; minimization (minimization 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 standardized 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. subscales) 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	14	2010	Odds Ratio (M‐H, Random, 95% CI)	1.19 [0.93, 1.54]
1.1 Avoidance	4	566	Odds Ratio (M‐H, Random, 95% CI)	1.31 [0.85, 2.01]
1.2 Late withdrawal	10	1444	Odds Ratio (M‐H, Random, 95% CI)	1.14 [0.83, 1.56]
2 Acute rejection	15	1666	Risk Ratio (M‐H, Random, 95% CI)	2.54 [1.56, 4.12]
2.1 Unspecified	7	1066	Risk Ratio (M‐H, Random, 95% CI)	1.72 [1.08, 2.75]
2.2 Biopsy‐proven	8	600	Risk Ratio (M‐H, Random, 95% CI)	4.48 [2.10, 9.55]
3 GFR	8	910	Mean Difference (IV, Random, 95% CI)	3.56 [‐1.13, 8.25]
3.1 One year	5	653	Mean Difference (IV, Random, 95% CI)	‐0.22 [‐5.38, 4.94]
3.2 Two years	1	108	Mean Difference (IV, Random, 95% CI)	7.90 [1.43, 14.37]
3.3 Over 5 years	2	149	Mean Difference (IV, Random, 95% CI)	11.09 [4.81, 17.37]
4 Graft loss	16	2090	Risk Ratio (M‐H, Random, 95% CI)	0.85 [0.74, 0.98]
5 Serum creatinine	4	189	Mean Difference (IV, Random, 95% CI)	19.17 [5.89, 32.44]
5.1 Six months	1	24	Mean Difference (IV, Random, 95% CI)	31.78 [10.58, 52.98]
5.2 One year	3	165	Mean Difference (IV, Random, 95% CI)	11.04 [‐5.99, 28.06]
6 Adverse events	13		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
6.1 Hypertension	5	950	Risk Ratio (M‐H, Random, 95% CI)	0.82 [0.71, 0.95]
6.2 Hyperlipidaemia	3	562	Risk Ratio (M‐H, Random, 95% CI)	0.88 [0.63, 1.21]
6.3 CMV infection	7	608	Risk Ratio (M‐H, Random, 95% CI)	0.87 [0.52, 1.45]
6.4 Diabetes	6	810	Risk Ratio (M‐H, Random, 95% CI)	0.94 [0.62, 1.42]
6.5 Malignancy	6	1079	Risk Ratio (M‐H, Random, 95% CI)	1.10 [0.93, 1.30]
6.6 Infection	6	724	Risk Ratio (M‐H, Random, 95% CI)	0.96 [0.61, 1.51]
7 Subgroup analysis: acute rejection	15	1666	Risk Ratio (M‐H, Random, 95% CI)	2.54 [1.56, 4.12]
7.1 Avoidance	3	238	Risk Ratio (M‐H, Random, 95% CI)	2.16 [0.85, 5.49]
7.2 Late withdrawal	12	1428	Risk Ratio (M‐H, Random, 95% CI)	3.21 [1.59, 6.48]
8 Subgroup analysis: GFR	8	910	Mean Difference (IV, Random, 95% CI)	3.56 [‐1.13, 8.25]
8.1 Avoidance	3	242	Mean Difference (IV, Random, 95% CI)	‐2.22 [‐14.84, 10.40]
8.2 Late withdrawal	5	668	Mean Difference (IV, Random, 95% CI)	5.54 [1.66, 9.43]
9 Subgroup analysis: graft loss	16	2414	Risk Ratio (M‐H, Random, 95% CI)	0.88 [0.78, 0.99]
9.1 Avoidance	4	566	Risk Ratio (M‐H, Random, 95% CI)	0.96 [0.79, 1.16]
9.2 Late withdrawal	13	1848	Risk Ratio (M‐H, Random, 95% CI)	0.84 [0.73, 0.97]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Acute rejection	15	1666	Risk Ratio (M‐H, Random, 95% CI)	2.54 [1.56, 4.12]
1.1 MMF/MPA	10	1110	Risk Ratio (M‐H, Random, 95% CI)	3.51 [1.79, 6.88]
1.2 AZA	5	556	Risk Ratio (M‐H, Random, 95% CI)	1.81 [0.78, 4.19]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Death	15	3462	Risk Ratio (M‐H, Random, 95% CI)	0.79 [0.50, 1.27]
1.1 Early intervention	13	3272	Risk Ratio (M‐H, Random, 95% CI)	0.78 [0.48, 1.27]
1.2 Late intervention	2	190	Risk Ratio (M‐H, Random, 95% CI)	1.02 [0.15, 6.94]
2 Acute rejection	19	3757	Risk Ratio (M‐H, Random, 95% CI)	0.87 [0.76, 1.00]
2.1 Unspecified	8	2028	Risk Ratio (M‐H, Random, 95% CI)	0.88 [0.74, 1.03]
2.2 Biopsy‐proven	11	1729	Risk Ratio (M‐H, Random, 95% CI)	0.86 [0.64, 1.16]
3 GFR	13	2623	Mean Difference (IV, Random, 95% CI)	4.10 [2.07, 6.12]
3.1 Six months	5	812	Mean Difference (IV, Random, 95% CI)	1.96 [‐1.35, 5.28]
3.2 One year	7	1710	Mean Difference (IV, Random, 95% CI)	4.30 [1.78, 6.82]
3.3 Two years	1	101	Mean Difference (IV, Random, 95% CI)	11.10 [4.14, 18.06]
4 Graft loss	15	3286	Risk Ratio (M‐H, Random, 95% CI)	0.75 [0.55, 1.02]
5 Serum creatinine	6	742	Mean Difference (IV, Random, 95% CI)	‐4.28 [‐14.65, 6.10]
5.1 Six months	4	530	Mean Difference (IV, Random, 95% CI)	‐1.46 [‐11.25, 8.33]
5.2 One year	2	212	Mean Difference (IV, Random, 95% CI)	‐23.18 [‐46.12, ‐0.23]
6 Change in GFR at 12 months	1		Mean Difference (IV, Random, 95% CI)	Totals not selected
7 Adverse events	14		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
7.1 Hypertension	5	1877	Risk Ratio (M‐H, Random, 95% CI)	0.84 [0.70, 1.00]
7.2 Hyperlipidaemia	3	1443	Risk Ratio (M‐H, Random, 95% CI)	1.04 [0.90, 1.19]
7.3 CMV infection	6	1948	Risk Ratio (M‐H, Random, 95% CI)	1.23 [0.94, 1.62]
7.4 Diabetes	5	1292	Risk Ratio (M‐H, Random, 95% CI)	0.82 [0.50, 1.34]
7.5 Malignancy	5	1637	Risk Ratio (M‐H, Random, 95% CI)	0.90 [0.41, 1.97]
7.6 Infection	9	1437	Risk Ratio (M‐H, Random, 95% CI)	0.95 [0.84, 1.07]
8 Subgroup analysis: acute rejection	18	2968	Risk Ratio (M‐H, Random, 95% CI)	0.85 [0.70, 1.02]
8.1 Immediate intervention	12	2209	Risk Ratio (M‐H, Random, 95% CI)	0.82 [0.67, 1.00]
8.2 Late intervention	6	759	Risk Ratio (M‐H, Random, 95% CI)	1.05 [0.61, 1.81]
9 Subgroup analysis: GFR	12	2443	Mean Difference (IV, Random, 95% CI)	4.21 [1.90, 6.51]
9.1 Immediate intervention	9	2200	Mean Difference (IV, Random, 95% CI)	3.09 [0.95, 5.23]
9.2 Late intervention	3	243	Mean Difference (IV, Random, 95% CI)	8.81 [3.79, 13.83]
10 Subgroup analysis: graft loss	14	3106	Risk Ratio (M‐H, Random, 95% CI)	0.75 [0.55, 1.03]
10.1 Immediate intervention	11	2800	Risk Ratio (M‐H, Random, 95% CI)	0.75 [0.55, 1.03]
10.2 Late intervention	3	306	Risk Ratio (M‐H, Random, 95% CI)	0.95 [0.12, 7.56]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Death	23	5427	Risk Ratio (M‐H, Random, 95% CI)	0.96 [0.68, 1.36]
1.1 Avoidance	9	1689	Risk Ratio (M‐H, Random, 95% CI)	0.89 [0.54, 1.47]
1.2 Withdrawal	14	3738	Risk Ratio (M‐H, Random, 95% CI)	1.02 [0.59, 1.76]
2 Acute rejection	30	5903	Risk Ratio (M‐H, Random, 95% CI)	1.43 [1.15, 1.78]
2.1 Unspecified	4	937	Risk Ratio (M‐H, Random, 95% CI)	1.34 [1.12, 1.60]
2.2 Biopsy‐proven	26	4966	Risk Ratio (M‐H, Random, 95% CI)	1.43 [1.10, 1.85]
3 GFR	23	4427	Mean Difference (IV, Random, 95% CI)	5.29 [2.08, 8.51]
3.1 Six months	2	187	Mean Difference (IV, Random, 95% CI)	5.22 [‐0.02, 10.46]
3.2 One year	16	3144	Mean Difference (IV, Random, 95% CI)	5.02 [0.59, 9.45]
3.3 Two years	4	796	Mean Difference (IV, Random, 95% CI)	6.08 [‐0.85, 13.01]
3.4 Five years	1	300	Mean Difference (IV, Random, 95% CI)	6.30 [2.43, 10.17]
4 Graft loss	25	5446	Risk Ratio (M‐H, Random, 95% CI)	0.94 [0.75, 1.19]
5 Serum creatinine at 1 year	12	1702	Mean Difference (IV, Random, 95% CI)	‐17.10 [‐26.95, ‐7.25]
6 Change in GFR	2		Mean Difference (IV, Random, 95% CI)	Subtotals only
6.1 One year	1	246	Mean Difference (IV, Random, 95% CI)	6.10 [0.01, 12.19]
6.2 Two years	2	521	Mean Difference (IV, Random, 95% CI)	0.28 [‐15.00, 15.56]
7 Adverse events	24		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
7.1 Hypertension	7	2207	Risk Ratio (M‐H, Random, 95% CI)	0.86 [0.64, 1.15]
7.2 Hyperlipidaemia	13	3494	Risk Ratio (M‐H, Random, 95% CI)	1.76 [1.40, 2.20]
7.3 CMV infection	13	2503	Risk Ratio (M‐H, Random, 95% CI)	0.60 [0.44, 0.82]
7.4 Diabetes	11	2833	Risk Ratio (M‐H, Random, 95% CI)	1.27 [0.97, 1.66]
7.5 Malignancy	14	3699	Risk Ratio (M‐H, Random, 95% CI)	0.69 [0.47, 1.00]
7.6 Infection	9	1624	Risk Ratio (M‐H, Random, 95% CI)	0.99 [0.92, 1.07]
7.7 Lymphocele	8	1926	Risk Ratio (M‐H, Random, 95% CI)	1.45 [0.95, 2.21]
8 Subgroup analysis: acute rejection	28	5480	Risk Ratio (M‐H, Random, 95% CI)	1.56 [1.27, 1.91]
8.1 Avoidance	11	1844	Risk Ratio (M‐H, Random, 95% CI)	1.27 [0.98, 1.65]
8.2 Late withdrawal	17	3636	Risk Ratio (M‐H, Random, 95% CI)	1.90 [1.44, 2.51]
9 Subgroup analysis: GFR	23	4427	Mean Difference (IV, Random, 95% CI)	5.29 [2.08, 8.51]
9.1 Avoidance	9	1748	Mean Difference (IV, Random, 95% CI)	6.45 [1.33, 11.58]
9.2 Late withdrawal	14	2679	Mean Difference (IV, Random, 95% CI)	4.55 [0.26, 8.85]
10 Subgroup analysis: graft loss	25	5446	Risk Ratio (M‐H, Random, 95% CI)	0.94 [0.75, 1.19]
10.1 Avoidance	8	1420	Risk Ratio (M‐H, Random, 95% CI)	1.03 [0.72, 1.48]
10.2 Late withdrawal	17	4026	Risk Ratio (M‐H, Random, 95% CI)	0.92 [0.65, 1.30]

Methods	Study design: parallel RCT Study duration: 5 years from 1997 to 2002 Duration of follow‐up: 5 years
Participants	Setting: multicentre (21 centres) Countries: Europe and South America Post kidney transplant recipients on triple therapy for at least 3 months with no rejection 3 months Number(randomised/analysed): treatment group (85/74); control group (85/77) Age, range (years): treatment group (45, 18 to 69); control group (48, 22 to 69) Sex (M/F): treatment group (51/34); control group (50/35) Exclusion criteria: WCC < 2.5 x 10⁹/L; Hb < 5 g/dL; severe diarrhoea or severe gastrointestinal disorders that interfere with oral absorption; malignancy or a history of malignancy; PRA > 50% at time of transplant
Interventions	Treatment group Gradual withdrawal of CsA over a 3 month period in the treatment group CsA was weaned off over 12 weeks, one 3rd each time MMF was administered 1 g twice daily and steroids were administered based according to the individual centre practice Control group Continued on triple drug therapy of CsA, MMF and steroids CsA was administered to achieve a trough of 100 to 200 ng/ml MMF was administered at 1 g twice daily and steroids according to practice of the individual centre Baseline immunosuppression At randomisation all patents were on triple immunosuppression of MMF, CsA and corticosteroids for at least 3 months
Outcomes	SCr CrCl Patient survival Graft survival AR episodes Malignancies
Notes	Funding source: Hoffman La‐Roche Contact with study authors for additional information: no Other: AR included both BPAR and clinical suspicion of rejection without biopsy
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Randomisation performed centrally using the minimisation method, with frequency matching for variables
Allocation concealment (selection bias)	Low risk	Central randomisation performed
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Open‐label study
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Insufficient information to permit judgement
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Follow‐up completed and reported as per ITT
Selective reporting (reporting bias)	Low risk	All relevant outcome data reported
Other bias	High risk	Pharmaceutical industry funded: Hoffman La‐Roche

Methods	Study design: parallel RCT Study duration: not reported Duration of follow‐up: 6 months
Participants	Setting: single centre Country: Spain Kidney transplant recipients randomised immediately post‐transplant Number: treatment group 1 (25); treatment group 2 (25) Age: not reported Sex (M/F): not reported Exclusion criteria: not reported
Interventions	Treatment group 1 CsA: 8 mg/kg/d; CsA level trough 300 to 600 ng/mL PRED: 0.25 mg/kg/d ALG: 10 mg/kg alternate days (6 doses) Treatment group 2 CsA: 15 mg/kg/d; CsA level trough 300 to 800 ng/mL PRED: 0.5 mg/kg/d
Outcomes	Patient survival Graft survival AR
Notes	Funding source: not reported Abstract‐only publications
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Study was described as randomised, method of randomisation was not reported
Allocation concealment (selection bias)	Unclear risk	Not reported
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Open‐label study
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Not reported
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	Outcome reporting complete; 3/6 of our outcomes of interest reported
Selective reporting (reporting bias)	Unclear risk	Insufficient information to permit judgement
Other bias	Unclear risk	Abstract‐only publications

Methods	Study design: 3 arm, parallel RCT Study duration: recruitment March 2002 to March 2003 Duration of follow‐up: 6 months
Participants	Setting: multicentre (17 centres) Country: Spain Primary and secondary cadaveric transplant recipients randomised within 24 hours post‐transplant Number: treatment group 1 (38); treatment group 2 (40); treatment group 3 (39) Mean age ± SD (years): treatment group 1 (56.4 ± 9.5); treatment group 2 (55.7 ± 9.5); treatment group 3 (57.7 ± 12.3) Sex (M/F): treatment group 1 (23/15); treatment group 2 (26/14); treatment group 3 (24/15) Multiorgan transplantation, previously transplanted with another organ; previous graft loss due to AR in 1st post‐transplant year
Interventions	Treatment group 1 Low dose early CsA CsA: 3 mg/kg administered twice daily to maintain C2 levels of 800 ng/mL (days 2 to 14), 1700 ng/mL (day 15 to month 2), 1500 ng/mL (during month 2), 1300 ng/mL (during month 3), 1100 ng/mL (month 4 to 6) Treatment group 2 Normal dose early CsA CsA: 5 mg/kg administered twice daily to maintain C2 levels of 1200 ng/mL (days 2 to 14), 1700 ng/mL (day 15 to month 2), 1500 ng/mL (during month 2), 1300 ng/mL (during month 3), 1100 ng/mL (month 4 to 6) Treatment group 3 Normal dose delayed CsA, CsA and MMF were delayed until day 7 to 10 CsA: 5 mg/kg administered twice daily to maintain C2 levels of 1200 ng/mL (days 7 to 14), 1700 ng/mL (day 15 to month 2), 1500 ng/mL (during month 2), 1300 ng/mL (during month 3), 1100 ng/mL (month 4 to 6) All groups MMF: initiated on day 0 at 1 g twice/d Oral PRED was started from days 1 to 3 at a maximum of 20 mg/d after pulse methyl‐PRED at maximum of 500 mg. Oral steroids were dose reduced over time and received at least 5 mg/d for the rest of the study period
Outcomes	Graft loss Death GFR AR Infection
Notes	Funding source: 1st author was an employee of Novartis, funding source not clarified Contact with study authors for additional information: no BPAR and clinical assessed AR reported separately
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Study was described as randomised, method of randomisation was not reported
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	High risk	Not reported; AR was clinical and BPAR
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	Modified ITT analysis
Selective reporting (reporting bias)	Low risk	Prespecified outcomes reported
Other bias	High risk	First author employee of Novartis; funding source not clarified

Methods	Study design: parallel RCT Study duration: November 2005 to March 2009 Duration of follow‐up: 5 years
Participants	Setting: multicentre (11 centres) Country: Germany Maintenance kidney transplant recipients (> 6 months post‐transplant) on CNI therapy (TAC or CsA) Number: treatment group 1 (46); control group (47) Mean age ± SD (years): treatment group (51.0 ± 10.3); control group (49.8 ± 11.1) Sex (M/F): treatment group (29/1); control group (35/12) Exclusion criteria: received a multiorgan transplant (including kidney‐pancreas); more than one previous kidney transplant or any previous non‐kidney transplant; rejection of Banff grade ≥ II, recurrent AR, or steroid‐resistant rejection in the preceding 6 months; proteinuria > 1 g/d, platelets < 100,000 cells/ mm³; leukocytes < 4000/mm³; Hb < 8 g/dL; evidence of severe liver disease
Interventions	Treatment group EVL was initiated at a dose of 1.5 mg/d, and the dose of CNI was reduced by 50% on the same day (day 0) One week later (day 7), the dose of EVL was increased to 3.0 mg/d, and CNI therapy was discontinued. From day 7, the dose of EVL was adjusted to target a trough level of 6 to 10 ng/mL Control group Treatment regimen continued unchanged CsA trough levels: 80 to 150 ng/mL TAC trough levels: 5 to 10 ng/mL Both groups Received EC‐MPS and steroids if administered at study entry
Outcomes	eGFR (Nankivell) at 12 months eGFR (Cockcroft‐Gault and abbreviated four‐variable MDRD formulae) SCr slope (1/SCr versus time) from baseline BPAR Graft loss Death Treatment failure defined as composite endpoint of BPAR, graft loss, death, loss to follow‐up, discontinuation due to lack of efficacy or toxicity, or conversion to another regimen
Notes	Funding source: 3 authors full‐time employees of Novartis
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Randomised using a validated, automated, central system
Allocation concealment (selection bias)	Low risk	Investigators notified of the treatment group by fax from central system
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Open‐label study
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	study not feasible to blinded assessment
Incomplete outcome data (attrition bias)   All outcomes	Low risk	ITT analysis
Selective reporting (reporting bias)	Low risk	All prespecified outcomes reported
Other bias	High risk	Pharma funded (Funding source: Novartis), study terminated early, 5 year outcome awaited

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Death	11	2750	Risk Ratio (M‐H, Random, 95% CI)	1.16 [0.71, 1.90]
1.1 Low dose CNI + immediate mTOR	9	2182	Risk Ratio (M‐H, Random, 95% CI)	1.07 [0.62, 1.87]
1.2 low dose CNI + late mTOR	2	568	Risk Ratio (M‐H, Random, 95% CI)	1.55 [0.52, 4.59]
2 Acute rejection	16	3300	Risk Ratio (M‐H, Random, 95% CI)	1.13 [0.91, 1.40]
2.1 Unspecified	3	496	Risk Ratio (M‐H, Random, 95% CI)	1.37 [0.90, 2.09]
2.2 Biopsy‐proven	13	2804	Risk Ratio (M‐H, Random, 95% CI)	1.07 [0.83, 1.37]
3 GFR	11	1749	Mean Difference (IV, Random, 95% CI)	6.24 [3.28, 9.19]
3.1 Six months	4	244	Mean Difference (IV, Random, 95% CI)	5.79 [‐3.57, 15.15]
3.2 One year	6	1293	Mean Difference (IV, Random, 95% CI)	6.63 [4.11, 9.14]
3.3 Two years	1	212	Mean Difference (IV, Random, 95% CI)	0.58 [‐3.00, 6.16]
4 Graft loss	16	3304	Risk Ratio (M‐H, Random, 95% CI)	0.67 [0.45, 1.01]
5 Serum creatinine at 1 year	6	1320	Mean Difference (IV, Random, 95% CI)	‐14.14 [‐22.55, ‐5.72]
6 Change in GFR at 2 years	1		Mean Difference (IV, Random, 95% CI)	Totals not selected
7 Adverse events	13		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
7.1 Hypertension	5	1421	Risk Ratio (M‐H, Random, 95% CI)	0.98 [0.80, 1.20]
7.2 Hyperlipidaemia	8	1793	Risk Ratio (M‐H, Random, 95% CI)	1.07 [0.89, 1.28]
7.3 CMV infection	5	1250	Risk Ratio (M‐H, Random, 95% CI)	0.41 [0.16, 1.06]
7.4 Diabetes	5	686	Risk Ratio (M‐H, Random, 95% CI)	1.36 [0.81, 2.27]
7.5 Malignancy	5	1074	Risk Ratio (M‐H, Random, 95% CI)	1.22 [0.42, 3.52]
7.6 Infection	5	1271	Risk Ratio (M‐H, Random, 95% CI)	0.95 [0.83, 1.08]
8 Subgroup analysis: graft loss	16	3304	Risk Ratio (M‐H, Random, 95% CI)	0.67 [0.45, 1.01]
8.1 Immediate mTOR	14	2736	Risk Ratio (M‐H, Random, 95% CI)	0.75 [0.48, 1.18]
8.2 Late mTOR	2	568	Risk Ratio (M‐H, Random, 95% CI)	0.40 [0.15, 1.04]
9 Subgroup analysis: GFR	11	1749	Mean Difference (IV, Random, 95% CI)	6.24 [3.28, 9.19]
9.1 Immediate mTOR	10	1537	Mean Difference (IV, Random, 95% CI)	6.91 [3.86, 9.96]
9.2 Late mTOR	1	212	Mean Difference (IV, Random, 95% CI)	0.58 [‐3.00, 6.16]
10 Subgroup analysis: acute rejection	16	3300	Risk Ratio (M‐H, Random, 95% CI)	1.13 [0.91, 1.40]
10.1 Immediate mTOR	14	2736	Risk Ratio (M‐H, Random, 95% CI)	1.09 [0.86, 1.39]
10.2 Late mTOR	2	564	Risk Ratio (M‐H, Random, 95% CI)	1.38 [0.82, 2.31]

Methods	Study design: 3‐arm, parallel RCT Study duration: February 2005 to October 2011 Duration of follow‐up: 24 months
Participants	Setting: multicentre Countries: 25 (Europe, Canada, Australia) Maintenance kidney transplant recipients; 1st of 2nd transplant at least 6 months previously from living or cadaveric donor; kidney impairment (GFR 30 to 70 mL/min) Number: treatment group 1 (127); treatment group 2 (144); control group (123) Mean age ± SD (years): treatment group 1 (49.4 ± 11.8); treatment group 2 (49.7 ± 13.0); control group (48.2 ± 12.2) Sex (M/F): treatment group 1 (86/41): treatment group 2 (91/53); control group 82/45) Exclusion criteria: multiorgan transplant; treated AR within the previous 3 months, presence of de novo or recurrent glomerular nephritis or BK polyomavirus nephropathy, and protein:creatinine ratio ≥ 150 mg/mmol
Interventions	Treatment group 1 CNI elimination EVL: 2 mg two times/d from day 1 with dose adjustments from week 1 onward to target an EVL trough levels of 8 to 12 ng/mL CNI: dose was reduced by 20% on day 1 and was discontinued when EVL trough level was ≥ 8 ng/mL Treatment group 2 CNI withdrawal EVL: 2 mg twice/d from day 1 with dose adjustments from week 1 onward to target an EVL trough levels of 3 to 8 ng/mL CNI: dose was reduced by 20% on day 1 and reduced to 70% to 90% below baseline values when EVL trough levels ≥ 3 ng/mL Control group CNI therapy remained unchanged All groups Baseline doses of MPA, AZA, and corticosteroids, where administered, were continued unaltered
Outcomes	GFR at 24 months Patient survival Graft survival BPAR Hypertension Hyperlipidaemia Diabetes
Notes	Funding source: Novartis Pharma AG
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Randomisation, stratified by centre, was performed using a validated, automated system
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	Unclear risk	Insufficient information to permit judgement
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Outcome data at 24 weeks was reported as ITT
Selective reporting (reporting bias)	Low risk	Data at 24 weeks was reported as ITT
Other bias	High risk	Funded by Novartis Pharma AG

Methods	Study design: parallel RCT (2:1) Study duration: recruitment July 2002 to July 2006 Duration of follow‐up: 2 years
Participants	Setting: single centre Country: Egypt Live donor recipients (84% unrelated), randomised immediate post‐transplant Number: treatment group (76); control group (37) Mean age ± SD (years): treatment group (45 ± 15.3); control group (44 ± 15.0) Sex (M/F): treatment group (47/29); control group (27/10) Exclusion criteria: not reported
Interventions	Treatment group SRL + MMF + PRED after 3 months of CsA (C2 levels 600 mg/mL) SRL: level 5 to 10 ng/mL after 3 months Control group CsA + MMF + PRED CSA C2 level: 1600 ng/mL (6 months), thereafter 1200 ng/mL
Outcomes	Patient survival at 2 years Graft survival at 2 years BPAR Early and late graft function Hypertension
Notes	Funding source: performed exclusively by The Cairo Kidney Center team without technical or financial support by any other institution, firm, or organisation Rejection episodes: BPAR
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Process of generating random numbers not clear
Allocation concealment (selection bias)	High risk	Sequentially randomised
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Open‐label study
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Insufficient information to permit judgement
Incomplete outcome data (attrition bias)   All outcomes	Low risk	ITT performed and outcome reported
Selective reporting (reporting bias)	Low risk	All outcomes reported completely
Other bias	Low risk	Appears free of other biases

Methods	Single centre RCT Study duration: not reported Duration of follow‐up: 6 months
Participants	Setting: single centre Country: Italy Kidney transplant recipients Number: 52 Mean age ± SD (years): not reported Sex (M/F): not reported Exclusion criteria: not reported
Interventions	Treatment group Basiliximab induction CsA: standard dose MMF Steroids Control group Basiliximab induction CsA: reduced dose (to obtain predefined levels) EVL: trough levels 3 to 8 ng/mL Steroids
Outcomes	DGF Graft survival Patient survival BPAR Triglycerides Need for hospitalisation
Notes	Funding source: not reported Abstract‐only publication
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Study was described as randomised, method of randomisation was not reported
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	Unclear risk	Insufficient information to permit judgement
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	Insufficient information to permit judgement
Selective reporting (reporting bias)	Unclear risk	Insufficient information to permit judgement
Other bias	Unclear risk	Insufficient information to permit judgement

Methods	Study design: 3‐arm, parallel RCT (1:1:1) Study duration: recruitment 12 January 2001 to 24 October 2002 Duration of follow‐up: 1 year
Participants	Setting: international, multicentre (32 centres) Countries: Australia, Europe and North America Patients of low‐to‐moderate immunologic risk who had received their 1st kidney transplant Number: treatment group 1 (179); treatment group 2 (184); control group (173) Mean age, range (years): treatment group 1 (47.2, 19 to 78); treatment group 2 (47.6, 20 to 77); control group (48.7, 21 to 73) Sex (males): treatment group 1 (60%); treatment group 2 (65%); control group (65%) Exclusion criteria: HLA‐identical living‐related donor recipients; patients anticipated to require ALG preparations for DGF
Interventions	Treatment group 1 Daclizumab induction MMF: maintenance dose of at least 1.5 g/d Steroids CsA withdrawal trough levels: 50 to 100 ng/mL (months 1 to 3), at month 4, CsA decreased by 33% every month, until it was completely withdrawn at month 6 Treatment group 2 Daclizumab induction MMF Steroids Low‐dose CsA trough levels: 50 to 100 ng/mL for 12 months Control group MMF Steroids Standard‐dose CsA: target trough level 150 to 300 ng/mL from baseline through to month 4 and 100 to 200 ng/mL thereafter
Outcomes	Kidney function at 3 and 12 months (GFR) Patient survival Graft survival Calculated CrCl at 12 months SCr at 12 months BPAR at 6 and 12 months
Notes	Unless medically contraindicated, all rejection episodes were BPAR Funding source: "Thanks to Elizabeth Calleja of Roche USA for her critique and Iain Bartlett for his editorial assistance... Funding for this study was provided by F. Hoffmann‐La Roche Ltd., Basel, Switzerland"
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	The randomisation code for the CAESAR study (M67005) was generated in the Oracle Clinical randomisation module, Each site was supplied with a list of unique patient numbers
Allocation concealment (selection bias)	Low risk	Treatment assignment, corresponding to patient number, was provided on a sheet sealed inside a randomisation envelope
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Open‐label study
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Insufficient information to permit judgement
Incomplete outcome data (attrition bias)   All outcomes	Low risk	ITT analysis and had minimal missing data
Selective reporting (reporting bias)	Low risk	The report include all possible outcomes
Other bias	High risk	Funded by Roche, Switzerland

Methods	Study design: parallel RCT; patients were stratified according to epithelial‐mesenchymal transition profile based on month 3 protocol biopsies and then randomised 1:1:1:1 (i) EMT+ patients assigned to CNI‐free therapy (ii) EMT+ patients assigned to CNI (ii) EMT− patients assigned to CNI‐free therapy and (iv) EMT− patients assigned to CNI Study duration: recruitment September 2009 to June 2012 Duration of follow‐up: 12 months
Participants	Setting: multicentre (23 centres) Country: France Primary or secondary kidney transplant recipients (deceased or living donor) were randomised at 3 months post‐transplant after a biopsy Number: treatment group (96); control group (98) Mean age ± SD (years): treatment group (48.2 ± 12.3); control group (50.4 ± 11.0) Sex (M/F): treatment group (62/34); control group (66/32) Exclusion criteria: BPAR prior to randomisation; donor specific antibody positive, eGFR < 30 mL/min; proteinuria > 0.8 g/24 h; severe uncontrolled hypercholesterolaemia or hypertriglyceridaemia; elevated liver enzymes
Interventions	Treatment group EVL: starting dose of 1.5 mg twice/d (target concentration 6 to 10 ng/mL) CsA: dose was reduced by 50% then discontinued when the EVL concentration was in the target range EC‐MPS: dose was reduced immediately to 360 mg twice/d Control group CsA: dose was tapered over time EC‐MPS: continued unchanged (1440 mg/d) Both groups Basiliximab induction (20 mg on day 0 and day 4) CsA: during the 1st 3 months post‐transplant, all patients received CsA at an initial dose of 8 mg/kg/d, adjusted to target pre‐specified trough or C2 levels EC‐MPS: 1440 mg/d Oral steroids: continued to month 12 post‐transplant in both treatment arms, dosed according to local practice
Outcomes	Progression of Interstitial fibrosis and tubular atrophy increase ≥1 between months 3 and 12 post‐transplant Treatment failure: defined as BPAR, graft loss, death or lost to follow‐up) Graft survival Patient survival Proteinuria Adverse events
Notes	Analysed also as CNI‐free and CNI group Funding source: Novartis Pharma SAS, Rueil‐Malmaison, France
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Study was described as randomised, method of randomisation was not reported
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	High risk	Primary outcome comparison of pathology pre and post randomisation not blinded
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Minimal lost to follow‐up at 2 year period
Selective reporting (reporting bias)	High risk	All prespecified outcomes not reported
Other bias	High risk	Funded by Novartis Pharma

Methods	Study design: parallel RCT (1:1) Study period: September 2005 to March 2007 Duration of follow‐up:6 months
Participants	Setting: multicentre (32 centres) Countries: Canada, France, Italy, Poland, Spain, UK, and USA Patients aged 18 to 70 years of low immunologic risk who had received their 1st kidney transplant allograft randomised within 24 h after transplantation Number: treatment group (151); control group (141) Mean age ± SD (years): treatment group (47.7 ± 12.6); control group (45.3 ± 12.9) Sex (males): treatment group (72.2%); control group (65.2%) Exclusion criteria: recipients of human leukocyte antigen (HLA)‐identical living‐related kidney; multiorgan transplant; donation after cardiac death; females of child‐bearing potential; donor age > 65 years; cold ischaemia time > 30 h; PRA > 20%;positive test for HBV or HCV of donor or recipient
Interventions	Treatment group Low‐dose TAC trough levels: 5 to 9 ng/mL (1st 3 months), 3 to 6 ng/mL for the next 3 months Basiliximab induction EC‐MPS: 1440 mg/d Corticosteroids Control group Standard‐dose TAC trough levels: 10 to 15 ng/mL (1st 3 months), 8 to 12 ng/mL for the next 3 months Basiliximab induction EC‐MPS: 1440 mg/d Corticosteroids
Outcomes	Kidney function at 6 months Incidence of BPAR Graft loss Death NODAT
Notes	Funding source: funded by Novartis Pharma AG, Basel, Switzerland
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	The randomisation list was generated by using a validated automated system
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	Unclear risk	Insufficient information to permit judgement
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	Results stated to be ITT but are different from the randomised number
Selective reporting (reporting bias)	Low risk	All prespecified outcomes reported
Other bias	High risk	Funded by Novartis Pharma AG, Basel, Switzerland

Methods	Study design: parallel RCT randomised 2:1; stratified according to baseline GFR Study duration: recruitment 5 February 2002 to 1 March 2004 Duration of follow‐up: 24 months
Participants	Setting: multicentre (111 centres) Countries: Asia, Australia, Europe, the Middle East, Canada, Mexico, United States, South Africa, Argentina, Brazil, Chile Patients aged ≥ 13 years and recipients of living or deceased donor with functioning graft; received a CNI (CsA or TAC) after transplantation along with corticosteroids, and AZA (50 mg/d) or MMF (500 mg/d) for at least 12 weeks before randomisation kidney transplant 6 to 120 months before randomisation Number: treatment group (555); control group (275) Mean age ± SE (years): treatment group (43.7 ± 0.6); control group (42.6 ± 0.82) Sex (males): treatment group (69.4%); control group (70.5%) Exclusion criteria: treated for BPAR or clinically diagnosed AR within 12 weeks of enrolment
Interventions	Treatment group CNI ceased and SRL introduced (trough 8 to 20 ng/mL) Control group CNI group: continued CsA or TAC (CsA trough 50 to 250 ng/mL; TAC trough 4 to 10 ng/mL) Both groups AZA MMF
Outcomes	GFR at 12 months BPAR Graft survival at 12 and 24 months Patient survival at 12 and 24 months
Notes	Stratified into GFR 20 to 40 mL/min and > 40 mL/min pre randomisation Study included both TAC and CsA Funding source: This study was supported by Wyeth Research, Collegeville, PA
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computerized randomisation/enrolment system used
Allocation concealment (selection bias)	Low risk	Automatic transtelephonic randomisation was used to assign study treatment groups.
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Open‐label study
Blinding of outcome assessment (detection bias)   All outcomes	High risk	Not performed
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	High dropout, however ITT
Selective reporting (reporting bias)	Low risk	Report included all expected outcomes
Other bias	High risk	Funded by Wyeth Research

Methods	Study design: parallel RCT; 2:1 randomisation Study duration: November 2010 to May 2015 Duration of follow‐up: 24 months
Participants	Setting: multicentre Country: USA Non‐sensitised primary recipients of living donor kidney transplants; ≥ 18 years; enrolled before transplantation and eligible for randomisation 6 months after transplantation Number: treatment group (14); control group (7) Mean age ± SD (years): treatment group (44.1 ± 11.65); control group (47.4 ± 11.12) Sex (M/F): treatment group (6/8); control group (4/3) Exclusion criteria: AR in the 1st 6 months; de novo DSA at 6 months, BK polyoma viraemia; MMF dose of < 1500 mg daily; AR (including Banff borderline) on a 6‐month protocol biopsy read by the Central Pathology
Interventions	Treatment group TAC: reduced by one 3rd at initiation of taper, reduced by another one 3rd after 1 month, and discontinued no longer than 4 months after randomisation MMF: ≥1500 mg/d PRED Control group TAC trough levels: 5 to 8 ng/mL MMF PRED Initial treatment for 6 months (both groups) Induction therapy with ATG MMF: 1000 mg twice/d PRED TAC: doses were adjusted to maintain trough levels of 8 to 12 ng/mL for the 1st 3 months and 5 to 8 ng/mL thereafter
Outcomes	Percentage of subjects in each arm with incremental changes in IF/TA scores, comparing a 24‐month protocol biopsy with the preimplantation biopsy Incidence of AR eGFR at 6, 12, 18, and 24 months Graft survival at 6, 12, 18, and 24 months Patient survival at 6, 12, 18, and 24 months Percentage of subjects with de novo post‐transplant DSA at 6, 12, 18, and 24 months
Notes	Enrolment was targeted to 300 subjects, with 210 subjects randomised 2:1 to TAC withdrawal: TAC maintenance; both groups received MMF and PRED. Only 47 subjects were enrolled, and 21 subjects were randomised before the study was terminated by safety board Funding source: The work was supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under Award Number U01‐AI063594 (to P.S.H.)
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Study was described as randomised, method of randomisation was not reported
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	Unclear risk	Nature of the study does not let for physician blinding
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Prespecified outcomes reported in randomised patients
Selective reporting (reporting bias)	High risk	Study was prematurely stopped and TAC was introduced in more than half of the patients
Other bias	High risk	Only 21 of the planned 210 patients were randomised

Methods	Study design: parallel, 4‐arm RCT, randomised 2:2:2:1 Study duration: recruitment completed 9 January 2003 Duration of follow‐up: 1 year
Participants	Setting: multicentre (43 centres) Countries: five continents (USA, Europe, Australia, Asia and South America) Aged > 18 years, immediate post‐transplant; primary cadaveric or HLA‐mismatched living donor (related or unrelated). Number: treatment group 1 (72); treatment group 2 (74); treatment group 3 (76); control group (39) Mean age ± SD (years): treatment group 1 (47.4 ± 11.20); treatment group 2 (44.1 ± 12.73); treatment group 3 (43.4 ± 13.35); control group (45.5 ± 10.42) Sex (M/F): treatment group 1 (49/23); treatment group 2 (49/25); treatment group 3 (43/33); control group (20/19) Exclusion criteria: allograft cold ischaemia time >30 h, PRA > 50%, or an ABO‐incompatible or T‐cell crossmatch positive transplant; baseline pulse rate < 50 BPM; significant thrombocytopenia(< 75,000/mm³); leukopenia (< 2500/mm³); absolute neutrophil count < 1500/mm³, Hb < 6 g/dL; severe liver disease; patients in whom antibody induction therapy was planned or those who were treated with other immunosuppressive agents within the preceding 4 weeks
Interventions	Treatment group 1 FTY720: 5 mg Reduced dose CsA: 2 to 3 mg/kg Treatment group 2 FTY720: 2.5 mg Reduced dose CsA: 2 to 3 mg/kg Treatment group 3 FTY720: 2.5 mg Full‐dose CsA: 8 to 10 mg/kg Control group Full‐dose CsA: 8 to 10 mg/kg MMF C2 levels difference 50 to 70% between reduced and full dose group.
Outcomes	BPAR GFR at 1 year death Graft loss
Notes	Funding source: "This study was funded by Novartis Pharma AG"
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Study was described as randomised, method of randomisation was not reported
Allocation concealment (selection bias)	Unclear risk	Insufficient information to permit judgement
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Partial blinding
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Not performed
Incomplete outcome data (attrition bias)   All outcomes	Low risk	No missing outcome data
Selective reporting (reporting bias)	Low risk	All prespecified outcomes reported
Other bias	High risk	Funded by Novartis Pharma AG

PERMALINK

Calcineurin inhibitor withdrawal or tapering for kidney transplant recipients

Krishna M Karpe

Girish S Talaulikar

Giles D Walters

Abstract

Background

Objectives

Search methods

Selection criteria

Data collection and analysis

Main results

Authors' conclusions

Plain language summary

Summary of findings

Summary of findings for the main comparison. Calcineurin inhibitor (CNI) withdrawal versus standard dose CNI for kidney transplant recipients.

Summary of findings 2. Low dose calcineurin inhibitors (CNI) versus to standard dose CNI for kidney transplant recipients.

Summary of findings 3. Calcineurin inhibitor (CNI) withdrawal + mammalian target of rapamycin inhibitor (mTORi) versus standard dose CNI for kidney transplant recipients.

Summary of findings 4. Low dose CNI calcineurin inhibitor (CNI) + mammalian target of rapamycin inhibitor (mTORi) versus standard dose CNI for kidney transplant recipients.

Summary of findings 5. Calcineurin inhibitor (CNI) avoidance and late CNI withdrawal versus standard dose CNI.

Summary of findings 6. Calcineurin inhibitor (CNI) avoidance and late withdrawal with mammalian target of rapamycin inhibitor (mTORi) versus standard dose CNI.

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

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

Dealing with missing data

Assessment of heterogeneity

Data synthesis

Subgroup analysis and investigation of heterogeneity

Sensitivity analysis

'Summary of findings' tables

Results

Description of studies

Results of the search

1.

Included studies

CNI withdrawal or avoidance versus standard dose CNI regimens

Standard versus low dose CNI

Standard dose CNI versus CNI withdrawal or avoidance with mTOR‐I substitution

Standard dose CNI versus low dose CNI and mTOR‐I

Low versus normal dose CNI with or without mTOR‐I (mixed studies)

Excluded studies

Risk of bias in included studies

2.

Allocation

Random sequence generation

Allocation concealment

Blinding

Incomplete outcome data

Selective reporting

Other potential sources of bias

Effects of interventions

CNI withdrawal (avoidance or late withdrawal) versus standard dose CNI

1.1. Analysis.

1.2. Analysis.

1.3. Analysis.

1.4. Analysis.

1.6. Analysis.

Subgroup analyses

CNI avoidance versus standard dose CNI

1.7. Analysis.

1.8. Analysis.

Methods	Study design: parallel RCT, randomised in 1st phase, non‐randomised 2nd phase Study duration: recruitment 6 January 2001 to 16 August 2003 Duration of follow‐up: 1 year
Participants	Setting: single centre Country: Brazil Recipients of one‐haplotype living‐related allografts Number: group 1 (92); group 2 (38); group 3 (21) Mean age ± SD (years): group 1 (37.4 ± 11.6); group 2 (33.0 ± 10.0); group 3 (38.2 ± 11.0) Sex (M/F): group 1 (21/17); group 2 (22/11); group (12/9) Exclusion criteria: evidence of systemic infection; history of clinically significant cardiac abnormalities; malignancy with 10 years
Interventions	Group 1 TAC: 0.1 mg/kg twice/d within 24 hours of graft insertion Trough levels: 10 to 20 ng/mL (1st month), 8 to 15 ng/mL (2nd month), 5 to 8 ng/mL thereafter AZA PRED Group 2 Daclizumab induction: 3 doses MMF PRED Enrolment was interrupted in 2002 and a 3rd group of patients were enrolled in a non‐randomised fashion Group 3 Daclizumab induction MMF SRL: 6 mg loading and 2 mg daily PRED
Outcomes	1st occurrence of a BPAR Graft loss Death Incidence, time and histological grade of 1st BPAR Incidence of all treated rejections, antibody‐treated rejections and repeated rejections Patient survival Graft and functioning (death censored) Graft survival Graft function measured by SCr and calculated CrCl Malignancies Infections
Notes	Rejections: BPAR Funding source: none declared
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	High risk	Study was described as randomised, method of randomisation was not reported; a 3rd group of non‐randomised patients included after interim analysis
Allocation concealment (selection bias)	High risk	Process not clarified, also a 3rd group of non‐randomised patients included after interim analysis
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Open‐label study
Blinding of outcome assessment (detection bias)   All outcomes	High risk	Not performed
Incomplete outcome data (attrition bias)   All outcomes	Low risk	There is no missing outcome data
Selective reporting (reporting bias)	Low risk	All prespecified outcomes reported
Other bias	High risk	A 3rd group of non‐randomised patients included after the interim analysis

Methods	Study design: parallel pilot RCT Study duration: recruitment December 2000 to January 2002 Duration of follow‐up: 12 months
Participants	Setting: multicentre (7 centres) Country: Spain Low‐risk adult kidney cadaveric allograft; 2nd transplantations were allowed only if the 1st graft was maintained for at least 6 months or if the graft was lost owing to technical surgical causes Number: treatment group (44); control group (43) Mean age ± SD (years): treatment group (45.2 ± 13.5); control group (47.4 ± 11.2) Sex (% M/F): treatment group (70.5/29.5); control group (69.8/30.2) Exclusion criteria: HIV infection; PRA > 50%; donors younger than 9 or older than 65 years old; cold ischaemic time > 36 h or non‐heart beating donors; HCV or HBV with impairment in liver function tests; history of malignancy in the previous 10 years
Interventions	Treatment group SRL trough levels: 8 to 16 ng/mL TAC trough levels: 3 to 8 ng/mL with elimination from month 3 onwards Control group SRL trough levels: 4 to 8 ng/mL TAC trough levels: 8 to 12 ng/mL (3 months), 5 to 10 ng/mL thereafter
Outcomes	GFR at 12 months BPAR at 12 months BP
Notes	Funding source: "This study was supported by Wyeth"
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer generated randomisation
Allocation concealment (selection bias)	High risk	Envelopes for randomisation prepared by Wyeth
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Open‐label study
Blinding of outcome assessment (detection bias)   All outcomes	High risk	Not performed
Incomplete outcome data (attrition bias)   All outcomes	High risk	High drop‐out rate resulting in protocol change
Selective reporting (reporting bias)	Low risk	Prespecified outcomes reported
Other bias	High risk	Funded by Wyeth; high drop‐out resulting in protocol amendment mid trial

Methods	Study design: parallel, 3‐arm RCT Study duration: recruitment 1983 and 1986 Duration of follow‐up: 24 months
Participants	Setting: multicentre (7 centres) Country: Australia Adults receiving 1st cadaveric kidney transplant recipients randomised Immediately post‐transplant Number: group 1 (158); group 2 (166); group 3 (165) Mean age ± SD (years): group 1 (43.6 ± 14); group 2 (43.1 ± 14); group 3 (43.0 ± 13) Sex (males): group 1 (55.7%); group 2 (59%); group 3 (56.4%) Exclusion criteria: insulin‐dependent diabetes; abnormal liver function tests; malignancy; malabsorption; active infection; contraindication to AZA
Interventions	Group 1 AZA: 2 mg/kg/d PRED: IV methyl‐PRED (100 mg pre‐op and 500 mg day 1); oral PRED from day 2 with daily tapering to maintenance dose of 10 to 15 mg/d ATG: induction optional Group 2 Methyl‐PRED induction only: 100 mg pre‐op and 500 mg day 1; no maintenance PRED Long‐term CsA: IV CsA (5 mg/kg pre‐op and 4 mg/kg day 1); 12.5 mg/kg oral CsA from day 2 tapering to 7.5 mg/kg by 3 months post‐transplant Group 3 Methyl‐PRED induction only: 100 mg pre‐op and 500 mg day 1 Short‐term CsA: IV CsA (5 mg/kg pre‐op and 4 mg/kg day 1); 12.5 mg/kg (day 2) tapering to 7.5 mg/kg by 3 months post‐transplant; at 3 months if no evidence of rejection CsA was replaced with AZA and PRED AZA: 2 mg/kg/d PRED: 20 mg/d
Outcomes	Death‐censored graft survival Patient survival Graft loss Kidney function using MDRD
Notes	Funding sources Sandoz to 10 years follow‐up Australian NHMRC research scholarship (MG; AC) Australian National Heart Foundation Postdoctoral Fellowship (VP)
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	The randomisation sequence was centrally generated by computer and stratified by centre
Allocation concealment (selection bias)	Low risk	Patient assignment was delivered to each of the centres opaque, sealed envelopes
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Open‐label study
Blinding of outcome assessment (detection bias)   All outcomes	High risk	Not performed
Incomplete outcome data (attrition bias)   All outcomes	Low risk	No missing outcome data, ITT analysis
Selective reporting (reporting bias)	Low risk	All expected outcomes reported
Other bias	High risk	Funded by Sandoz to 10 years

Methods	Study design: parallel, 3‐arm study (1:1:1) Study duration: recruitment October 2007 to 2010 Duration of follow‐up: 48 months (planned for 60 months)
Participants	Setting: multicentre (20 centres) Country: Germany Adults randomised 3 months post‐transplant Number: group 1 (159); group 2 (163); group 3 (163) Mean age ± SD (years): not reported Sex (M/F): not reported Exclusion criteria: SCr > 3.0 mg/dL; graft loss during the trial period; alterations in immunosuppressive regimen because of AR events (Banff II), platelets < 75,000/mm³; leucocytes < 2500/mm³; Hb < 6 g/dL; proteinuria > 1 g/d; clinically significant infection that required continuous treatment or occurrence of severe side effects caused by the immunosuppressive drugs
Interventions	Group 1 Standard CsA trough levels: 100 to 180 ng/mL EC‐MPS Group 2 CSA withdrawal EVL trough levels: 5 to 10 ng/mL EC‐MPS Group 3 Low‐CsA trough levels: 50 to 75 ng/mL EVL trough levels: 3 to 8 ng/mL Both groups (to 3 months) Basiliximab induction CsA EC‐MPS steroids
Outcomes	Death Graft loss Composite failure: BPAR, death, graft loss, loss to follow‐up Premature discontinuation due to adverse effects Kidney function (eGFR)
Notes	Abstract‐only publications for main study Funding source: not reported
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Study was described as randomised, method of randomisation was not reported
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	Unclear risk	Insufficient information to permit judgement
Incomplete outcome data (attrition bias)   All outcomes	Low risk	ITT analysis
Selective reporting (reporting bias)	Low risk	Prespecified outcomes reported
Other bias	Unclear risk	Insufficient information to permit judgement

Methods	Study design: parallel, 4‐arm study (1:1:1:1) Study duration: recruitment January 1986 to May 1987 Duration of follow‐up: 1 year
Participants	Setting: single centre Country: Finland Adults with 1st cadaveric transplant; patients were on triple therapy with CsA, AZA and PRED during the 1st 10 weeks post‐transplantation Number: group 1 (32); group 2 (32); group 3 (32); group 4 (32) Mean age ± SD (years): group 1 (47 ± 11); group 2 (49 ± 13); group 3 (45 ± 12); group 4 (43 ± 13) Sex (M/F): group 1 (20/12); group 2 (15/17); group 3 (17/15); group 4 (17/15) Exclusion criteria: "exclusions from the study were for medical reasons. mainly on the grounds that triple therapy was not considered suitable for these patients"
Interventions	Group 1 Continued with triple therapy (CsA, AZA, PRED) CsA: maintained at pre‐conversion levels AZA: 1 mg/d PRED: tapered to 4 to 12 mg/d for the 1st year Group 2 CsA: maintained at pre‐conversion levels AZA: temporarily increased to 2 mg/kg/d then adjusted to WCC PRED: gradually withdrawn over 2 weeks Group 3 CsA: discontinued abruptly AZA: 2 mg/kg/d PRED: initially increased to 0.5 mg/kg/d then tapered to 4 to 12 mg/d Group 4 CsA: maintained at pre‐conversion levels AZA: discontinued abruptly PRED: initially increased to 0.5 mg/kg/d then tapered to 4 to 12 mg/d All groups (1st 10 weeks) CsA: single pre‐op dose (5 mg/kg) then 10 mg/kg/d adjusted for trough levels (200 to 600 ng/mL to 3 months then 150 to 400 ng/mL after 6 months) AZA: 2 mg/kg/d tapered to 1 mg/kg/d by day 14 PRED: 1 mg/kg/d tapered to 0.25 mg/kg/d by day 10
Outcomes	BPAR Graft survival Patient survival
Notes	Funding source: not reported
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Study was described as randomised, method of randomisation was not reported
Allocation concealment (selection bias)	Low risk	Sealed envelopes used
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Open‐label study
Blinding of outcome assessment (detection bias)   All outcomes	High risk	Not performed
Incomplete outcome data (attrition bias)   All outcomes	Low risk	No obvious missing data
Selective reporting (reporting bias)	Low risk	Prespecified outcomes reported
Other bias	Unclear risk	Insufficient information to permit judgement

Methods	Study design: parallel, 3‐arm RCT (1:1:1) Study duration: recruitment commenced 2005 Duration of follow‐up: 24 months
Participants	Setting: single centre Country: Netherlands Patients aged 18 to 70 years receiving a 1st or 2nd kidney transplant from a deceased or living donor were randomised 6 months post‐transplant if biopsy did not reveal rejection Number: treatment group 1 (36); treatment group 2 (38); control group (39) Mean age ± SD (years): treatment group 1 (52 ± 12.5); treatment group 2 (49 ± 13.2); control group (55 ± 10.1) Sex (males): treatment group 1 (61%); treatment group 2 (60%); control group (51%) Exclusion criteria: HLA‐identical sibling donor; a 3rd or 4th transplant; current or historical PRA > 50%, female patients unwilling to use adequate contraception during the study; cholesterol > 8.5 mmol/L despite statin use
Interventions	Treatment group 1 MPS: target AUC₁₂ 35 mg.h/L or a trough level > 2 mg/L PRED: 10 mg/d Treatment group 2 EVL: target AUC₁₂ 150 mg.h/L PRED: 10 mg/d Control group CsA: Target AUC₁₂ 3250 µg.h/L PRED: 10 mg/d All groups (1st 6 months) Basiliximab induction PRED MPS CSA
Outcomes	Interstitial graft fibrosis Hyalinosis AR (not defined) Graft survival Patient survival SCr Infections GFR
Notes	Funding source: Novartis Pharma
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	The randomisation list was generated with “Random Allocation Software” Version 1.0 2004 tripod.com
Allocation concealment (selection bias)	Low risk	A sealed opaque envelope was used, containing a sheet with the number of the treatment arm. All patients received an envelope after recruitment
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Open‐label study
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Not performed
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	Study prematurely terminated after increased rejection in one arm
Selective reporting (reporting bias)	High risk	Study prematurely terminated after increased rejection in one arm
Other bias	High risk	Funded by Novartis Pharma. Early termination of the study

Methods	Study design: parallel, pilot RCT Study duration: recruitment not reported Duration of follow‐up: planned follow‐up 3 years (only 1 year data reported)
Participants	Setting: single centre Country: USA Adults randomised between 2 and 16 months post‐transplant Number: treatment group (20); control group (20) Mean age ± SD (years): treatment group (55.2 ± 9.5); control group (53.6 ± 9.2) Sex (males): treatment group (85%); control group (75%) Exclusion criteria: PRA > 10%; eGFR < 40 mL/min; pre‐randomisation antibody‐mediated or Banff IA AR
Interventions	Treatment group CNI: reduced by 25% to 50% on day of randomisation, continued for 7 to 14 days and then stopped MMF/EC‐MPS: up to 1000/720 mg every 12 hours Control group CNI CsA trough levels: 100 to 200 ng/mL TAC trough levels: 5 to 10 ng/mL Both groups Alemtuzumab induction TAC or CsA MMF/EC‐MPS: 500/360 mg every 12 hours at enrolment Low‐dose steroids
Outcomes	AR Patient survival Graft survival Graft kidney function: GFR, SCr Peripheral Treg levels
Notes	All but one rejection episode was biopsy proven Funding source: "This work was supported by a grant from ILEX, Inc., San Antonio, TX, USA. JP is supported by a grant from the Institute Carlos III‐Spanish Health Department (BA06/90020)"
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Study was described as randomised, method of randomisation was not reported
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	Unclear risk	Insufficient information to permit judgement
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	3 year data not available
Selective reporting (reporting bias)	Low risk	Prespecified outcomes reported
Other bias	High risk	Funded by ILEX Inc, San Antonio (makers of Alemtuzumab).

Methods	Study design: parallel RCT, randomised 10 to 24 days post‐transplant Study duration: recruitment February 2005 to April 2007 Duration of follow‐up: 12 months
Participants	Setting: multicentre (6 centres) Country: Germany Patients aged 8 and 65 years, scheduled to receive a single organ kidney transplant from a living or a deceased donor Number: treatment group (69); control group (71) Mean age ± SD (years): treatment group (47.0 ± 10.8); control group (47.1 ± 11.1) Sex (males): treatment group (65.2%); control group (70.4%) Exclusion criteria: current or historic PRA > 30%; positive cross‐match; gastrointestinal disorder that might interfere with the ability to absorb oral medication; history of cancer, except successfully treated; receipt of a new investigational drug within the previous 3 months and a BMI > 32 kg/m²; WCC ≥ 4000 mm³; platelet count ≥100,000 mm³; fasting triglycerides ≤ 4.6 mmol/L; fasting cholesterol ≤ 7.8 mmol/L
Interventions	Treatment group SRL: 01 mg/kg (loading dose) then 2 to 4 mg/d; target trough level 8 to 12 ng/mL CsA: reduced to 50% then eliminated by day 3 MMF: initially decreased to 1.5 g/d Control group CsA trough levels: 150 to 200 ng/mL, then 100 to 150 ng/mL (month 4) MMF: 2 g/d Both groups ATG induction (modified after 1st 25 patients) PRED: according to local protocol CsA tough levels: 200 to 250 ng/mL (for 1st 2 to 3 weeks)
Outcomes	BPAR Graft survival Patient survival Treatment failure Change in graft function Infections
Notes	Funding source: "This study was supported by Wyeth Pharma (Munster, Germany) and Fresenius Biotech (Munich, Germany"
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	A permuted block randomisation scheme was used to assign trial participants to one of the treatment groups
Allocation concealment (selection bias)	Low risk	Allocation concealment was secured by a centralized distribution of sequentially numbered, opaque, sealed envelopes, and a confirmatory randomisation fax to the clinical research organization
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Open‐label study
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Insufficient information to permit judgement
Incomplete outcome data (attrition bias)   All outcomes	Low risk	All possible outcomes reported as ITT
Selective reporting (reporting bias)	Low risk	Pre specified outcomes reported
Other bias	High risk	Funded by Wyeth and Fresenius

Methods	Study design: parallel, 4‐arm RCT (1:1:1:1) Study duration: recruitment November 2002 to November 2004 Duration of follow‐up: 12 months
Participants	Setting: multicentre (83 centres) Country: 15 countries (Australia, Austria, Belgium, Brazil, Canada, Czech Republic, Germany, Greece, Israel, Mexico, Poland, Spain, Sweden, Turkey, UK) Recipients of deceased or living donor kidneys were enrolled immediately post‐transplant; 1st or 2nd transplant; aged 18 to 75 years Number: group 1 (390); group 2 (399); group 3 (401); group 4 (399) Mean age ± SD (years): group 1 (45.9 ± 13.8); group 2 (47.2 ± 13.5); group 3 (45.4 ± 14.7); group 4 (44.9 ± 14.5) Sex (males): group 1 (62.3%); group 2 (66.4%); group 3 (65.8%); group 4 (66.7%) Exclusion criteria: need for treatment with AZA, methotrexate or CPA, polyclonal or monoclonal antilymphocyte antibodies, basiliximab, or any investigational drug; current or historic PRA > 20%; positive cross‐match; a cold ischaemia time > 30 hours for the allograft; receipt of an allograft from a deceased donor without a heartbeat; a gastrointestinal disorder that might interfere with the ability to absorb oral medication; a history of cancer; active peptic ulcer; evidence of active liver disease; severe anaemia, leukopenia, or thrombocytopenia; the receipt of a new investigational drug within the previous 3 months; and previous treatment with daclizumab or basiliximab
Interventions	Group 1 Standard dose CsA trough levels: 150 to 300 ng/mL (to month 3), thereafter 100 to 200 ng/mL Group 2 Low dose CsA trough levels: 50 to 100 ng/mL throughout the study Daclizumab: 2 mg/kg within 24 h prior to transplant; 1 mg/kg every 2 weeks (up to 2 months) Group 3 Low dose TAC trough levels: 3 to 7 ng/mL throughout the study Daclizumab: 2 mg/kg within 24 h prior to transplant; 1 mg/kg every 2 weeks (up to 2 months) Group 4 Low dose SRL trough levels: 4 to 8 ng/mL throughout the study Daclizumab: 2 mg/kg within 24 h prior to transplant; 1 mg/kg every 2 weeks (up to 2 months) All groups MMF: 2 g/d PRED: as per local protocol
Outcomes	Graft loss Death eGFR AR Malignancy Opportunistic infections
Notes	Funding source: "Funding for the study was provided by Hoffmann–La Roche, which had advisory input into the study design, collected the data, monitored the conduct of the study, performed the statistical analyses, and coordinated the writing of the manuscript with all authors"
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Study was described as randomised and stratified, "A minimization algorithm was used to optimize the balance of characteristics of patients in study groups, overall and across the strata."
Allocation concealment (selection bias)	Low risk	Central randomisation, voice interactive allocation
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Open‐label study
Blinding of outcome assessment (detection bias)   All outcomes	High risk	Not performed
Incomplete outcome data (attrition bias)   All outcomes	Low risk	No missing outcome data
Selective reporting (reporting bias)	Low risk	Outcomes that are of interest reported
Other bias	High risk	Funded by Hoffmann‐La Roche

Study	Reason for exclusion
Abouna 1991	Wrong intervention: abrupt CNI withdrawal compared to slow withdrawal, no standard dose CNI comparison group
Alexander 2006	Wrong intervention: determined if steroids can be eliminated with early discontinuation of CsA and later discontinuation of MMF
Alpay 2013	Wrong outcomes: study outcomes were effects of switch from CNI to EVL on serum/urinary markers of fibrosis (TGF‐beta), inflammation, glomerular and tubular injury. the follow‐up data was at 3 months of conversion
Artz 2002	Wrong intervention: conversion from CsA to TAC
Asberg 2013	Wrong intervention: CNI withdrawal versus mycophenolate withdrawal
Baboolal 2003	Wrong intervention: CsA elimination versus withdrawal, no standard dose
Baboolal 2004	Wrong intervention: CsA elimination versus withdrawal, no standard dose
Baxter 1982	Other: abstract more than 30 years old; no full text publication
Brady 1990	Wrong intervention: low dose CNI pre‐operatively
Burkhalter 2012	Wrong intervention: low dose CNI versus CNI withdrawal, no standard dose comparison
CAMPASIA Study 2005	Wrong intervention: Intervention also included steroid withdrawal
Cattaneo 2005	Wrong intervention: low dose SRL versus low dose CsA; part of a study to evaluate campath and MMF
Chapman 1985	Wrong intervention: CsA withdrawal compared to avoidance, no continuation arm
CIS Trial 2014	Wrong intervention: randomised to either trough CsA monitoring or by residual NFAT‐regulated gene expression
CONCERTO Study 2005	Wrong intervention: evaluated C2 monitoring in the context of a quadruple immunosuppressive regimen and planned to assess the efficacy and safety of two C2 targets for patients 3 to 6 months post‐transplantation. However, because differences between the groups post‐month 2 were not discernible; the secondary endpoints were highlighted as combined outcome
David‐Neto 2001	Wrong intervention: compared low versus high dose CsA in presence and absence of antibody induction
de Sandes Freitas 2011	Wrong intervention: steroid withdrawal versus CNI withdrawal
de Sevaux 1998	Wrong intervention: CNI + AZA converted to CNI + PRED
EVEREST Study 2009	Wrong intervention: both arms included low dose CsA, no standard dose arm
Flechner 2004	Wrong intervention: compared 2 doses of MMF
Fleming 2016	Wrong intervention: compared mTOR‐I based CNI withdrawal with CNI minimisation, no standard dose CNI for comparison
Forwell 1986	Wrong intervention: compared normal CsA dose with historical controls on azathioprine
Fries 1988	Wrong intervention: CsA with AZA regimen was compared with CsA, antilymphocyte antibody and steroids
Fries 1988a	Wrong intervention: CsA with AZA regimen was compared with CsA, antilymphocyte antibody and steroids
Fruchaud 1996	Wrong intervention: CNI based immunosuppression with and without antilymphocyte antibody compared
Gaber 2003	Wrong intervention: compared CNI sparing with withdrawal
Gelens 2006	Wrong intervention: TAC and SRL versus TAC and SRL versus SRL and MMF intervention
Ghafari 2007	Wrong intervention: compared standard versus high dose which was tapered to standard dose at 3 months, not relevant to this review
Gotti 2003	Wrong population: CNI versus steroid tapering based on biopsy
Griffin 1993	Wrong intervention: Timing of CNI
Grino 1991	Wrong intervention: compared 2 induction regimens (OKT3 and ALG)
Hamdy 2005	Wrong intervention: did not compare low dose/withdrawal to standard dose regimen
Hariran 2015	Other: conversion of TAC based regimen to SRL in DGF; 6/15 randomised patients shifted back to TAC
Henny 1986	Wrong intervention: Study compared very high dose of CsA in the arm with high dose had CsA withdrawal
Hernandez 2007	Wrong intervention: low dose CNI with MMF and normal dose with AZA
Hiesse 1991	Wrong Intervention: multivariate analysis of various doses
Hilbrands 1993	Wrong intervention: CNI versus steroid withdrawal
Hourmant 1987	Wrong intervention: delayed introduction of CNI with monoclonal antibodies
Hricik 1990	Wrong intervention: low dose CNI versus withdrawal, no standard dose comparison
Infante 2008	Wrong intervention: compared withdrawal with low dose CNI, no standard comparison group
Jain 2001	Wrong intervention: no standard CsA group comparison, both arms were low dose
Jindal 2002	Wrong intervention: compared CNI elimination and withdrawal, no standard dose comparison
John 1999	Wrong outcome: compared high and low dose CsA with single outcome (lipid profile)
Kamar 2012	Wrong intervention: compared different doses of MMF
Kandaswamy 2005	Wrong intervention: multiple comparisons not relevant to this review; compared CsA + MMF with high and low dose TAC with variable SRL
Keitel 1999	Wrong intervention: compared early versus late CNI withdrawal, no standard dose comparison
Kovarik 2001	Wrong intervention: early versus delayed CsA
Kovarik 2003	Wrong intervention: compared early versus delayed introduction of CNI
Kovarik‐2306 2004	Wrong intervention: did not include standard dose
Liu 2002a	Wrong intervention: compared CNI reduction versus withdrawal with mTOR‐I, no standard dose comparison
Liu 2007b	Wrong intervention: compared CNI reduction versus withdrawal with mTOR‐I, no standard dose comparison
Maiorano 2006	Wrong intervention: compared CsA reduction with CsA withdrawal and SRL, no standard dose comparison
McGrath 2001	Wrong intervention: CsA withdrawal and substitution with another CNI (TAC) versus mycophenolate
McMaster 1983	Wrong intervention: CsA use alone in one arm
Meier 2006	Wrong intervention: compared two different CNIs (TAC and CsA)
Messa 2009	Wrong outcome: evaluated Treg changes between the SRL and TAC group, not relevant outcomes noted for this review
Metcalfe 2002	Wrong intervention: compared MMF and AZA
Miserlis 2008	Wrong intervention: variable co‐intervention (MMF and EVL)
Mourad 2004a	Wrong intervention: Simulect versus ATG
Mourad 2005	Wrong intervention: early versus late introduction of CNI
Mourer 2012	Wrong intervention: mycophenolate withdrawal versus CNI withdrawal
Noris 2007	Wrong intervention: compared low dose SRL with low dose CNI does not satisfy inclusion criteria of this review
Novoa 2011	Wrong intervention: standard dose CNI not part of comparison
OPTIMA‐TX Study 2008	Wrong outcomes: reported CsA versus TAC, not relevant to this review
Pankewycz 2011	Wrong intervention: primary intervention to study low dose ATG irrespective of maintenance immunosuppression and included low dose SRL and low dose TAC, no standard dose TAC for comparison
Ponticelli 1988	Wrong intervention: double therapy compared to 3 drug CNI regimen
Rahamimov 2008	Other: incomplete study, stopped prematurely
Ritz 1998	Wrong intervention: CsA was withdrawn with ATG support and reintroduced within a week immediate transplant for ATN
Saunders 2003	Wrong intervention: CNI dose reduction in both arms
SOCRATES Study 2014	Wrong intervention: CNI withdrawal versus steroid withdrawal
Westhoff 1995	Other: study discontinued before conclusion
Wu 2007d	Wrong population: randomisation only if GFR < 40 mL/min