Calcineurin inhibitor withdrawal or tapering for kidney transplant recipients
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
This review aims to look at the benefits and harms of calcineurin inhibitor tapering or withdrawal in terms of graft function and loss, incidence of acute rejection episodes, treatment‐related side effects (hypertension, hyperlipidaemia) and mortality.
Background
Standard immunosuppressive protocols to prevent acute graft rejection in the setting of kidney transplantation involve three major groups of drugs ‐ calcineurin inhibitors, antimetabolites and steroids. Calcineurin inhibitors have been an important part of primary immunosuppression with adjunctive agents like mycophenolate mofetil or azathioprine and steroids in kidney transplant recipients (Hariharan 2000).
Calcineurin inhibitors act by inhibiting the calcium‐dependent enzyme serine phosphatase calcineurin. This process prevents the dephosphorylation of NFAT (nuclear factors of activated T lymphocytes), which is essential for translocation of itself into the nucleus leading to reduced activation of cytokine genes for IL‐2 production. Cyclosporin and tacrolimus are the two calcineurin inhibitors used in transplantation (Melk 2003). Both drugs have dramatically reduced the incidence of acute transplant rejection and decreased early graft loss (Ahsan 2001). However calcineurin inhibitors have been associated with significant adverse effects such as nephrotoxicity (Bennett 1996) causing decreased GFR, hypertension, hyperlipidaemia and a significant contribution to chronic allograft nephropathy. These effects could lead to subsequent graft loss and contribute directly or indirectly to patient morbidity and mortality by affecting the cardiovascular risk factors (Kasiske 1996).
The significant toxicity profile of calcineurin inhibitors have encouraged numerous trials on calcineurin inhibitor withdrawal strategies and tapering of these agents. However some randomised controlled trials (RCTs) have highlighted an increase in acute rejection following withdrawal (Abramowicz 2005) while others have shown no effect on graft survival and a short term improvement in creatinine values (Gonwa 2002).
Despite the number of clinical trials conducted on calcineurin inhibitors, there is still confusion regarding the tapering or withdrawal of these drugs. These strategies must be balanced with the significant benefits conferred by calcineurin inhibitors in preventing early graft rejection. In the absence of a clear clinical consensus, this systematic review aims to assess the benefits and harms of calcineurin inhibitor withdrawal or tapering in kidney transplant recipients.
Objectives
This review aims to look at the benefits and harms of calcineurin inhibitor tapering or withdrawal in terms of graft function and loss, incidence of acute rejection episodes, treatment‐related side effects (hypertension, hyperlipidaemia) and mortality.
Methods
Criteria for considering studies for this review
Types of studies
All RCTs and quasi‐RCTs (RCTs in which allocation to treatment was obtained by alternation, use of alternate medical records, date of birth or other predictable methods) looking at calcineurin inhibitor withdrawal or tapering in kidney transplant recipients will be included. The first period of randomised cross‐over studies shall also be included.
Types of participants
Inclusion criteria
Patients with end‐stage kidney failure (ESKF), irrespective of age or gender, who received a first or subsequent cadaveric or living donor kidney transplant and received calcineurin inhibitors (cyclosporin or tacrolimus) as the primary immunosuppression.
Exclusion criteria
Recipients who have received another solid organ in addition to a kidney transplant (e.g. pancreas) will be excluded.
Types of interventions
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Transplant recipients who received calcineurin inhibitors (cyclosporin or tacrolimus) as the primary immunosuppression which was subsequently tapered or withdrawn completely will be included.
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All RCTs where tapering/withdrawal is compared with controls will be included irrespective of the duration of treatment prior to the intervention. In cases of significant heterogeneity, subgroup analysis will be performed.
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All definitions of tapering mentioned in the trials will be included irrespective of the duration of tapering, sensitivity analysis would be used to differentiate between the tapering groups.
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RCTs which define low dose either by exposure to cyclosporin and tacrolimus calculated using 12‐hour post‐dose nadir (trough) blood levels or studies which employed fixed doses (mg/kg) will be included.
Specific comparisons will be made between:
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Low dose cyclosporin versus normal dose cyclosporin
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Low dose tacrolimus versus normal dose tacrolimus
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Normal dose cyclosporin versus cyclosporin withdrawal
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Normal dose tacrolimus versus tacrolimus withdrawal
In case of significant heterogeneity between various interventions, subgroup analysis will be carried out in:
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Cyclosporin withdrawal group between those converted to target of rapamycin (mTOR) inhibitors or where no conversion was made.
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Azathioprine and mycophenolate mofetil groups.
Types of outcome measures
Data on the following outcomes will be collected where possible;
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Graft loss (censored and not censored for death)
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All‐cause mortality
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Acute rejection episodes: Both clinical and biopsy proven rejections would be included and then be classified if adequate studies.
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Graft kidney function at six months and one, two and five years measured by serum creatinine, calculated GFR or creatinine clearance
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Treatment‐related side effects (e.g. hyperlipidaemia, hypertension)
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Rates of malignancy
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Incidence of infections
Search methods for identification of studies
1). The Cochrane Renal Groups specialised register and the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library (most recent) will be searched using the following terms:‐
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. (cas* 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)
CENTRAL and the Renal Groups specialised register contain the handsearched results of conference proceedings from general and speciality meetings. This is an ongoing activity across the Cochrane Collaboration and is both retrospective and prospective (Master List 2007). Therefore we will not specifically search conference proceedings. Please refer to The Cochrane Renal Review Group's Module in The Cochrane Library for the most up‐to‐date list of conference proceedings.
2). MEDLINE (1966 to most recent) using the optimally sensitive strategy developed for the Cochrane Collaboration for the identification of RCTs (Dickersin 1994) with a specific search strategy developed with input from the Cochrane Renal Groups Trial Search Co‐ordinator.
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$).tw.
20. and/18‐19
21. and/1,20
22. randomized controlled trial.pt.
23. controlled clinical trial.pt.
24. randomized controlled trials/
25. random allocation/
26. double blind method/
27. single blind method/
28. or/22‐27
29. animals/ not (animals/ and humans/)
30. 28 not 29
31. clinical trial.pt.
32. exp clinical trials/
33. (clinic$ adj25 trial$).ti,ab.
34. cross‐over studies/
35. (crossover or cross‐over or cross over).tw.
36. ((singl$ or doubl$ or trebl$ or tripl$) adj25 (blind$ or mask$)).ti,ab.
37. placebos/
38. placebo$.ti,ab.
39. random$.ti,ab.
40. research design/
41. or/31‐40
42. 41 not 29
43. 30 or 42
44. and/21,43
3). EMBASE (1980 to most recent) using a search strategy adapted from that developed for the Cochrane Collaboration for the identification of RCTs (Lefebvre 1996) together with a specific search strategy developed with input from the Cochrane Renal Groups Trial Search Co‐ordinator.
1. Kidney Transplantation/
2. Tsukubaenolide/
3. tacrolimus.tw.
4. prograf$.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$).tw.
17. and/15‐16
18. and/1,17
19. exp clinical trial/
20. evidence based medicine/
21. outcomes research/
22. crossover procedure/
23. double blind procedure/
24. single blind procedure/
25. prospective study/
26. major clinical study/
27. exp comparative study/
28. placebo/
29. "evaluation and follow up"/
30. follow up/
31. randomization/
32. or/19‐31
33. controlled study/ not case control study/
34. or/32‐33
35. (clinic$ adj5 trial$).ti,ab.
36. ((singl$ or doubl$ or trebl$ or tripl$) adj (blind$ or mask$)).ti,ab.
37. random$.ti,ab.
38. placebo$.ti,ab.
39. or/35‐38
40. 34 or 39
41. limit 40 to human
42. and/18,41
4). Reference lists of nephrology textbooks, review articles and relevant trials.
5). Letters seeking information about unpublished or incomplete trials to investigators known to be involved in previous trials.
Data collection and analysis
Included and excluded studies
The review will be undertaken by three authors (KK, GW, GT). The search strategy described will be used to obtain titles and abstracts of studies that may be relevant to the review. The titles and abstracts will be screened independently by KK and GW, who will discard studies that are not applicable, however studies and reviews that might include relevant data or information on trials will be retained initially. KK and GW will independently assess retrieved abstracts and, if necessary the full text, of these studies to determine which studies satisfy the inclusion criteria. Data extraction will be carried out independently by the same authors using standard data extraction forms. Studies reported in non‐English language journals will be translated before assessment. Where more than one publication of one trial exists, reports will be grouped together and the most recent or most complete dataset will be used. Any discrepancy between published versions will be highlighted. Any further information required from the original author will be requested by written correspondence and any relevant information obtained in this manner will be included in the review. Disagreements will be resolved in consultation with GT.
Study quality
The quality of studies to be included will be assessed independently by KK and GW without blinding to authorship or journal using the checklist developed for the Cochrane Renal Group. Discrepancies will be resolved by discussion with GT. The quality items to be assessed are allocation concealment, blinding (participants, investigators, outcome assessors and data analysis), intention‐to‐treat analysis and completeness of follow‐up.
Quality checklist
Allocation concealment
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Adequate (A): Randomisation method described that would not allow investigator/participant to know or influence intervention group before eligible participant entered in the study
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Unclear (B): Randomisation stated but no information on method used is available
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Inadequate (C): Method of randomisation used such as alternate medical record numbers or unsealed envelopes; any information in the study that indicated that investigators or participants could influence intervention group
Blinding
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Blinding of investigators: Yes/No/not stated
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Blinding of participants: Yes/No/not stated
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Blinding of outcome assessor: Yes/No/not stated
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Blinding of data analysis: Yes/No/not stated
The above are considered not blinded if the treatment group can be identified in > 20% of participants because of the side effects of treatment.
Intention‐to‐treat
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Yes: Specifically reported by authors that intention‐to‐treat analysis was undertaken and this was confirmed on study assessment.
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Yes: Not stated but confirmed on study assessment
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No: Not reported and lack of intention‐to‐treat analysis confirmed on study assessment. (Patients who were randomised were not included in the analysis because they did not receive the study intervention, they withdrew from the study or were not included because of protocol violation)
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No: Stated but not confirmed upon study assessment
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Not stated
Completeness of follow‐up
Per cent of participants excluded or lost to follow‐up.
Statistical assessment
For dichotomous outcomes ( e.g. incidence of acute rejections,graft loss and death) results will be expressed as risk ratio (RR) with 95% confidence intervals (CI). Data will be pooled using the random‐effects model but the fixed‐effect model will also be analysed to ensure robustness of the model chosen and susceptibility to outliers. Where continuous scales of measurement are used to assess the effects of treatment ( e.g. blood pressure, serum creatinine ,lipid profile etc), the mean difference (MD) will be used, or the standardised mean difference (SMD) if different scales have been used. Heterogeneity will be analysed using a Cochran Q test on N‐1 degrees of freedom, with an alpha of 0.05 used for statistical significance and with the I² test (Higgins 2003). In case of significant heterogeneity, subgroup analysis will be considered. Sensitivity analysis would be used to differentiate between the tapering groups.
Subgroup analysis will be used to explore possible sources of heterogeneity (e.g. participants, interventions and study quality). Heterogeneity among participants could be related to age and renal pathology. Heterogeneity in treatments could be related to prior agent(s) used, the agent (cyclosporin/tacrolimus) and duration of therapy prior to withdrawal or tapering. Adverse effects will be tabulated and assessed with descriptive techniques, as they are likely to be different for the various agents used. Where possible, the risk difference with 95% CI will be calculated for each adverse effect, either compared to no treatment or to another agent.
