Tacrolimus is superior to cyclosporin in improving graft survival and preventing acute rejection after kidney transplantation, but increases post-transplant diabetes and other side effects

Kidney transplantation is the treatment of choice for most patients with end-stage renal disease (ESRD). Strategies to increase donor organ availability and to prolong the transplanted kidney's survival have become priorities in kidney transplantation. Standard immunosuppressive therapy consists of initial treatment and maintenance regimes to prevent rejection and short courses of more intensive immunosuppressive therapy to treat episodes of acute rejection. This review compared tacrolimus and cyclosporin used as primary immunosuppression for kidney transplant recipients. Thirty studies (4102 patients) were included. Tacrolimus was shown to be superior to cyclosporin in improving graft survival and preventing acute rejection after kidney transplantation, but increases post-transplant diabetes, neurological and gastrointestinal side effects. There was insufficient information to assess the cost of tacrolimus versus cyclosporin, and there was a general failure to consider global quality of life (QOL) for transplant recipients which may inform our understanding of patient preference and compliance.

Authors' conclusions: 

Tacrolimus is superior to cyclosporin in improving graft survival and preventing acute rejection after kidney transplantation, but increases post-transplant diabetes, neurological and gastrointestinal side effects. Treating 100 recipients with tacrolimus instead of cyclosporin would avoid 12 suffering acute rejection, two losing their graft but cause an extra five to become insulin-requiring diabetics.

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Background: 

Kidney transplantation is the treatment of choice for most patients with end-stage renal disease (ESRD). Standard protocols in use typically involve three drug groups each directed to a site in the T-cell activation or proliferation cascade which are central to the rejection process: calcineurin inhibitors (e.g. cyclosporin, tacrolimus), anti-proliferative agents (e.g. azathioprine, mycophenolate mofetil) and steroids (prednisolone). It remains unclear whether new regimens are more specific or simply more potent immunosuppressants.

Objectives: 

To compare the effects of tacrolimus with cyclosporin as primary therapy for kidney transplant recipients.

Search strategy: 

MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, the Cochrane Renal Group's specialist register and conference proceedings were searched to identify relevant reports of randomised controlled trials (RCTs). Two reviewers assessed studies for eligibility, quality and extracted data independently.

Selection criteria: 

All RCTs where tacrolimus was compared with cyclosporin for the initial treatment of kidney transplant recipients

Data collection and analysis: 

Data were synthesised (random effects model) and results expressed as risk ratio (RR), values <1 favouring tacrolimus, with 95% confidence intervals (CI). Subgroup analysis and meta-regression were used to examine potential effect modification by differences in study design and immunosuppressive co-interventions.

Main results: 

123 reports from 30 studies (4102 patients) were included. At six months graft loss was significantly reduced in tacrolimus-treated recipients (RR 0.56, 95% CI 0.36 to 0.86), and this effect was persistent up to three years. Meta-regression showed that this benefit diminished as higher trough levels of tacrolimus were targeted (P = 0.04), after allowing for differences in cyclosporin formulation (P = 0.97) and cyclosporin target trough level (P = 0.38). At one year, tacrolimus patients suffered less acute rejection (RR 0.69, 95% CI 0.60 to 0.79), and less steroid-resistant rejection (RR 0.49, 95% CI 0.37 to 0.64), but more insulin-requiring diabetes mellitus (RR 1.86, 1.11 to 3.09), tremor, headache, diarrhoea, dyspepsia and vomiting. Cyclosporin-treated recipients experienced significantly more constipation and cosmetic side-effects. We demonstrated no differences in infection or malignancy.

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