nep_734.fm Page 88 Friday, January 26, 2007 6:47 PM Blackwell Publishing AsiaMelbourne, AustraliaNEPNephrology1320-5358 2006 The Author; Journal compilation 2006 Asian Pacific Society of Nephrology? 200712S18897MiscellaneousCalcineurin Inhibitors in Renal TransplantationThe CARI Guidelines NEPHROLOGY 2007; 12, S88 S97 doi:10.1111/j.1440-1797.2006.00734.x Choice of calcineurin inhibitors in adult renal transplantation: Effects on transplant outcomes Date written: August 2005 Final submission: August 2006 Author: Helen Pilmore SUGGESTIONS FOR CLINICAL CARE (Suggestions are based on Level III and IV evidence) There are excellent results in terms of patient and graft survival in renal transplant recipients treated with both tacrolimus and cyclosporin. Currently, these agents are commonly used as primary immunosuppression in renal transplantation. While these guidelines indicate that tacrolimus is superior to cyclosporin in terms of prevention of acute rejection and death-censored graft loss, the side-effect profile of these agents is important and should be considered in patients when making a decision about primary therapy. Both tacrolimus and cyclosporin are associated with the development of chronic allograft nephropathy (CAN). There are insufficient data from long-term randomized controlled trials (RCT) at present to favour one agent over the other in the prevention of CAN. The outcomes in patients medicated with cyclosporin using C2 monitoring or tacrolimus using trough concentration monitoring appear to be the same (liver transplant data). (Level II evidence) In patients with acute rejection occurring on cyclosporin, conversion to tacrolimus results in a superior response to treatment for rejection and less recurrent rejection than in those remaining on cyclosporin. (Level II evidence) BACKGROUND 2007 The Author Journal compilation 2007 Asian Pacific Society of Nephrology GUIDELINES a. There is a reduced incidence of acute rejection at 12 months after transplantation in patients treated with tacrolimus compared with patients treated with cyclosporin and monitored with trough concentrations. (Level I evidence) b. There is a reduced incidence of death-censored graft loss after transplantation in patients treated with tacrolimus compared with patients treated with cyclosporin and monitored with trough concentrations. (Level I evidence) Kidney transplantation is the treatment for end-stage kidney disease with the best survival outcome. 1 The advent of cyclosporin as primary immunosuppressive therapy was associated with significant improvements in 1 year graft survival 2 and this drug was used as the primary immunosup- Correspondence: Helen Pilmore, Department of Rural Medicine, Auckland City Hospital, Auckland, New Zealand. Email: hpilmore@ adhb.govt.nz pressive agent in renal transplantation from the early 1980s until the late 1990s. Tacrolimus was first used in organ transplantation in 1989 and now is commonly used in place of cyclosporin. 3 Both drugs are felt to be effective agents at preventing acute rejection, but there are no trials showing a difference in graft or patient survival. The side-effect profiles of these two agents overlap, in particular with respect to nephrotoxicity, but differ in clinically important ways (e.g. metabolic and cosmetic side-effects). The objective of this analysis was to determine whether there is any difference in the outcome of kidney transplants when tacrolimus is compared with cyclosporin. RCT comparing cyclosporin with tacrolimus in primary renal transplantation were examined. Additionally, RCT comparing switching calcineurin inhibitors (CNI) with remaining on primary therapy were examined. Outcomes that have been examined include: patient survival graft survival death-censored graft survival acute rejection severity of acute rejection renal function, and CAN. SEARCH STRATEGY Databases searched: Medline (2000 to June Week 2, 2004). MeSH terms and text words for kidney transplantation were combined with MeSH terms and text words for the CNI of interest. The results were then combined with the Cochrane search strategy for RCT and MeSH terms and text words for identifying meta-analyses and systematic reviews. The Cochrane Renal Group Specialized Register of RCT and DARE (Database of Abstracts of Reviews of the Effectiveness of health care) were also searched for relevant trials not indexed in Medline. Date of searches: 29 June 2004.
nep_734.fm Page 89 Friday, January 26, 2007 6:47 PM Calcineurin Inhibitors in Renal Transplantation S89 WHAT IS THE EVIDENCE? Tacrolimus compared with cyclosporin in renal transplantation: trough monitoring There are 30 RCT comparing cyclosporin with tacrolimus in the setting of renal transplantation and three metaanalyses. 4 6 The more recent meta-analysis by Webster et al. includes trials examined in the first and second metaanalyses and is the primary study used in the formulation of this section of the guidelines. There are no published studies comparing transplant outcomes in renal transplant recipients using tacrolimus and cyclosporin, using 2 h post-dose concentration monitoring. However, there is one RCT in liver transplantation and this has been examined. 7 For further information on CNI drug monitoring, refer to the CARI guideline on therapeutic drug monitoring. The meta-analysis by Webster et al. 6,8 examines 123 reports of 30 trials including 4102 patients. The trials included in this analysis were all RCT comparing tacrolimus with cyclosporin (both Sandimmun and Neoral formulations). There was, however, varied additional baseline immunosuppression and varied reporting on patient demographics. Studies were analysed at different time points after transplantation. This was dependent on the study design and on the published study results. The time points examined were 3, 6 and 12 months and 2, 3, 4 and 5 years after transplantation. There was no difference in patient survival between tacrolimus and cyclosporin. Tacrolimus was associated with a reduction in total graft loss and death-censored graft loss at 6 months and 3 years after transplantation (Fig. 1). There was no significant benefit in graft survival at the other time points studied. Tacrolimus was also associated with a reduction in the incidence of both clinical- and biopsy-proven acute rejection at 6 and 12 months after transplantation. In addition, the use of tacrolimus resulted in a reduction in steroidresistant acute rejection at 6 and 12 months compared with cyclosporin (Fig. 2). There was no significant difference in renal function when comparing trials of patients on tacrolimus and cyclosporin at any time point other than at 6 months after transplantation when the use of tacrolimus was associated with a slightly lower serum creatinine than cyclosporin (Fig. 3). There was no significant difference in the incidence of CAN at 6 months and 3 years, while at 1, 4 and 5 years, there appeared to be less CAN in patients on tacrolimus than in patients on cyclosporin (Fig. 4). However, these results are based on the long-term follow up of a 12 month open-label study 9,10 where there were more patients with biopsy-proven CAN in the cyclosporintreated group than in the tacrolimus-treated group. This study was powered to detect a difference in the incidence of acute rejection and was neither designed nor powered to study CAN. The trials used varying formulations of cyclosporin and varying antiproliferative regimens. In addition, some trials used induction therapy. Different formulations of cyclosporin were used: 6 trials compared tacrolimus with Sandimmun 19 trials compared tacrolimus with Neoral 5 trials did not note the formulation of cyclosporin used. Different anti-proliferative agents were used: 16 trials used azathioprine with tacrolimus or cyclosporin 8 trials used mycophenolate mofetil 3 trials varied the anti-proliferative agent 1 trial used sirolimus 1 trial used mirzoribine 1 trial did not use an anti-proliferative agent. Twelve trials used induction agents. A meta-regression was performed in order to determine whether the use of Sandimmun versus Neoral confounded the outcome for acute rejection or graft loss. This showed no confounding effect between these two formulations of cyclosporin. Similarly, there was no confounding effect caused by the varied use of azathioprine versus mycophenolate mofetil on acute rejection or graft loss. Tacrolimus compared with cyclosporin in transplantation: C2 monitoring One RCT 7 examined the efficacy and safety of cyclosporin using C2 (2 h post-dose concentration) monitoring compared with tacrolimus in de novo liver transplant recipients. This study recruited 500 patients. There was no difference in the incidence of biopsy-proven acute rejection or in the severity of acute rejection between the two groups. The incidence of the composite endpoint of graft loss, death or biopsy-proven acute rejection was 34% for both groups. Calcineurin inhibitor switch trials There are no RCT examining switching from tacrolimus to cyclosporin. There are, however, a number of reports of four RCT where patients were switched from cyclosporin to tacrolimus or remained on primary therapy in the setting of renal transplantation. One trial was excluded from this section of the guidelines as it examined the effect of the conversion on gingival hypertrophy only. Each trial was powered to examine different outcomes. Briggs et al. 11 randomized 119 patients with biopsyproven acute rejection to remaining on cyclosporin/mycophenolate-based therapy or switching to tacrolimus. There was no difference in patient or graft survival. Despite there being a similar histological severity of acute rejection in the initial biopsy, the initial episode responded to treatment in significantly more patients in the tacrolimus group (93.4%) than in the cyclosporin group (63.8%; P = 0.001). In addition, the incidence of recurrent rejection was significantly lower in the tacrolimus group (8.8%) than in the cyclosporin group (34.1%; P = 0.002). There was no difference in the renal function of the two groups at the end of the study.
nep_734.fm Page 90 Friday, January 26, 2007 6:47 PM S90 The CARI Guidelines Artz et al. 12 randomized 124 stable renal transplant patients more than 1 year from transplantation to remaining on standard therapy (cyclosporin/steroids ± mycophenolate mofetil/azathioprine) or switching to tacrolimus. This study aimed to examine the effects on renal function and cardiovascular risk profile; follow up was for 6 months. There were no episodes of acute rejection. There was no change in renal function as measured by the serum creatinine in the cyclosporin group; however, there was a reduction in serum creatinine in the tacrolimus group (baseline = 137 µmol/l; 6 months = 131 µmol/l; P < 0.05). Stoves et al. 13 randomized 42 renal transplant recipients with a deterioration in renal function and biopsy-proven CAN to one of three groups: mycophenolate mofetil/reduced-dose cyclosporin; tacrolimus; standard cyclosporin therapy. This study compared the reciprocal of creatinine versus time slope before and after the intervention and showed that mycophenolate mofetil/reduced-dose cyclosporin was superior to the other groups in patients with a baseline glomerular filtration rate (GFR) of >20 ml/min per 1.73 m 2. WHAT DO THE OTHER GUIDELINES SAY? Kidney Disease Outcomes Quality Initiative: No recommendation. UK Renal Association: No recommendation. Canadian Society of Nephrology: No recommendation. European Best Practice Guidelines: No recommendation. International Guidelines: No recommendation. IMPLEMENTATION AND AUDIT No recommendation. SUGGESTIONS FOR FUTURE RESEARCH 1 Perform an RCT comparing outcomes after renal transplantation in patients on tacrolimus with those treated with cyclosporin measured at 2 h post-dose concentrations. 2 Perform trials examining long-term outcomes in renal transplantation focusing on late graft loss, GFR and development of CAN. CONFLICT OF INTEREST Helen Pilmore has no relevant financial affiliations that would cause a conflict of interest according to the conflict of interest statement set down by CARI. REFERENCES 1. Wolfe RA, Ashby VB, Milford EL et al. Comparison of mortality in all patients on dialysis, patients on dialysis awaiting transplantation, and recipients of a first cadaveric transplant. N. Engl. J. Med. 1999; 341: 1725 30. 2. A randomized clinical trial of cyclosporin in cadaveric renal transplantation. N. Engl. J. Med. 1983; 309: 809 15. 3. Vincenti F. A decade of progress in kidney transplantation. Transplantation 2004; 77 (9 Suppl.): S52 S61. 4. Knoll GA, Bell RC. Tacrolimus versus cyclosporin for immunosuppression in renal transplantation: Meta-analysis of randomised trials. BMJ 1999; 318: 1104 7. 5. Heisel O, Heisel R, Balshaw R et al. New onset diabetes mellitus in patients receiving calcineurin inhibitors: A systematic review and meta-analysis. Am. J. Transplant. 2004; 4: 583 95. 6. Webster A, Woodroffe RC, Taylor RS et al. Tacrolimus versus cyclosporin as primary immunosuppression for kidney transplant recipients. Cochrane Database Syst. Rev. 2005; (4): Art no. CD003961. 7. Levy G, Villamil F, Samuel D et al. Results of list, a multicenter, randomized study comparing cyclosporin microemulsion with C2 monitoring and tacrolimus with C0 monitoring in de novo liver transplantation. Transplantation 2004; 77: 1632 8. 8. Webster AC, Woodroffe RC, Taylor RS et al. Tacrolimus versus ciclosporin as primary immunosuppression for kidney transplant recipients: Meta-analysis and meta-regression of randomised trial data. BMJ 2005; 331: 810. 9. Mayer AD, Dmitrewski J, Squifflet JP et al. Multicenter randomized trial comparing tacrolimus (FK506) and cyclosporin in the prevention of renal allograft rejection: A report of the European Tacrolimus Multicenter Renal Study Group. Transplantation 1997; 64: 436 43. 10. Mayer D. Tacrolimus vs cyclosporin in renal transplantation: Fiveyear follow-up of the European multicentre study [abstract]. Annual Meeting of the American Society of Transplant Surgeons and the American Society of Transplantation. Am. J. Transplant. 2002; 2 (Suppl. 3): 238. 11. Briggs D, Dudley C, Pattison J et al. Effects of immediate switch from cyclosporin microemulsion to tacrolimus at first acute rejection in renal allograft recipients. Transplantation 2003; 75: 2058 63. 12. Artz MA, Boots JM, Ligteberg G et al. Improved cardiovascular risk profile and renal function in renal transplant patients after randomized conversion from cyclosporin to tacrolimus. J. Am. Soc. Nephrol. 2003; 14: 1880 99. 13. Stoves J, Newstead CG, Baczkowski AJ et al. A randomized controlled trial of immunosuppression conversion for the treatment of chronic allograft nephropathy. Nephrol. Dial. Transplant. 2004; 19: 2113 20. 14. Webster A, Woodroffe RC, Taylor RS, Chapman JR, Craig JC. Tacrolimus versus cyclosporin as primary immunosuppression for kidney transplant recipients. Cochrane Database Syst. Rev. 2006; (2). 10.1002/14651858. CD003961.pub. This version first published online: 19 October 2005 in Issue 4, 2005. Copyright Cochrane Library reproduced with permission.
nep_734.fm Page 91 Friday, January 26, 2007 6:47 PM Calcineurin Inhibitors in Renal Transplantation S91 APPENDICES Table 1 Characteristics of included studies Study ID (author, year) Artz et al., 2003 12 124 Randomized controlled clinical trial Briggs et al., 119 Randomized 2003 11 controlled clinical trial Stoves et al., 42 Randomized 2004 13 controlled clinical trial n Table 2 Quality of randomized trials Study ID (author, year) Study design Setting Participants 4 renal transplant centres 15 centres in 7 European countries Method of allocation concealment Intervention (experimental group) 124 stable renal recipients Conversion to tacrolimus 119 renal graft recipients with first biopsy-proven acute rejection episode while receiving cyclosporin 3 hospitals 42 cyclosporin-treated renal transplant recipients Blinding Participants Investigators Outcome assessors Conversion to tacrolimus Conversion to tacrolimus Intervention (control group) Intention-to-treat analysis Follow up (months) Cyclosporin 6 Cyclosporin 3 Cyclosporin 6 Loss to follow up (%) Artz et al., 2003 12 Not specified No No No Yes 0.8 Briggs et al., 2003 11 Not specified No No Yes Yes 0.0 Stoves et al., 2004 13 Computer-generated, sealed envelopes No No Yes No 0.0 Table 3 Results for continuous outcomes Study ID (author, year) Outcomes Intervention group (mean (SD)) Control group (mean (SD)) Difference in means (95% CI) Artz et al., 2003 12 Serum creatinine at 6 months 139 (29) 146 (53) 7.00 ( 22.18, 8.18) CI, confidence interval; SD, standard deviation. Table 4 Results for dichotomous outcomes Study ID (author, year) Outcomes Intervention group (number of patients with events/number of patients exposed) Control group (number of patients with events/number of patients not exposed) Relative risk (95% CI) Risk difference (95% CI) Artz et al., Mortality 1/64 2/61 0.48 (0.04, 5.12) 0.02 ( 0.07, 0.04) 2003 12 Acute rejection 0/64 0/60 Not estimable 0.00 ( 0.03, 0.03) Briggs et al., Mortality 2/61 0/58 4.76 (0.23, 97.05) 0.03 ( 0.02, 0.09) 2003 11 Withdrawal 10/61 29/58 0.33 (0.18, 0.61) 0.34 ( 0.49, 0.18) Return to dialysis 4/61 4/58 0.95 (0.25, 3.63) 0.00 ( 0.09, 0.09) Recurrent acute rejection 5/57 15/44 0.26 (0.10, 0.65) 0.25 ( 0.41, 0.10) Stoves et al., Return to dialysis 1/13 1/13 1.00 (0.07, 14.34) 0.00 ( 0.20, 0.20) 2004 13 Acute rejection 0/13 0/13 Not estimable 0.00 ( 0.14, 0.14) CI, confidence interval.
nep_734.fm Page 92 Friday, January 26, 2007 6:47 PM S92 The CARI Guidelines Fig. 1 Comparison of tacrolimus versus cyclosporin for primary therapy: death-censored graft loss. 14
nep_734.fm Page 93 Friday, January 26, 2007 6:47 PM Calcineurin Inhibitors in Renal Transplantation S93 Fig. 1 Continued
nep_734.fm Page 94 Friday, January 26, 2007 6:47 PM S94 The CARI Guidelines Fig. 2 Comparison of tacrolimus versus cyclosporin for primary therapy: steroid-resistant acute rejection. 14
nep_734.fm Page 95 Friday, January 26, 2007 6:47 PM Calcineurin Inhibitors in Renal Transplantation S95 Fig. 3 Comparison of tacrolimus versus cyclosporin for primary therapy: renal function. 14
nep_734.fm Page 96 Friday, January 26, 2007 6:47 PM S96 The CARI Guidelines Fig. 3 Continued
nep_734.fm Page 97 Friday, January 26, 2007 6:47 PM Calcineurin Inhibitors in Renal Transplantation S97 Fig. 4 Comparison of tacrolimus versus cyclosporin for primary therapy: chronic allograft nephropathy. 14