Reports

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

Canadian Society of Transplantation Annual Meeting

Banff, Alberta / March 15-18, 2007

Regardless of the organ being transplanted, the primary goal of post-transplantation management is to balance effective immunosuppression and avoidance of rejection on the one hand and minimize toxicity, especially long-term toxicity to the kidney, on the other. One strategy that might accomplish these dual goals is to use low-dose immunosuppression. As discussed here this week during the scientific sessions, results presented from the SYMPHONY study demonstrated efficacy with low-dose immunosuppressive regimens using either one of the two available calcineurin inhibitors.

The SYMPHONY trial randomized 1645 renal transplant recipients to one of four immunosuppressive regimens. The first group received normal-dose cyclosporine, mycophenolate mofetil (MMF) and steroids; the second, following induction with daclizumab, received low-dose cyclosporine (trough levels between 50 and 100 ng/mL), MMF and steroids; the third, again following daclizumab induction, received low-dose tacrolimus (trough levels between 3 and 7 ng/mL), MMF and steroids; and the fourth group received low-dose sirolimus (4 to 8 mg/mL), MMF and steroids, again following induction with daclizumab.

As related by Dr. Bjorn Nashan, Director, Multi-Organ Transplant Program, and Professor of Surgery, Medicine, Urology, Microbiology and Immunology, Dalhousie University, Halifax, Nova Scotia, “Patients enrolled were the standard-risk group of patients chosen for studies. The primary end point was calculated glomerular filtration rate [GFR] at 12 months.” Secondary end points included biopsy-proven acute rejection (BPAR) and patient and graft survival, also at 12 months.

“At 12 months in particular, the low-dose tacrolimus group did extremely well in comparison to low- and normal-dose cyclosporine and low-dose sirolimus,” Dr. Nashan reported. Specifically, the mean calculated GFR was 65.4 mL/min/1.73 m² for the low-dose tacrolimus group compared with 59.4 mL/min/1.73 m² for the low-dose cyclosporine group, 57.1 mL/min/1.73 m² for the normal-dose cyclosporine group and 56.7 mL/min/1.73 m² for the low-dose sirolimus group. Differences between the low-dose tacrolimus group and both cyclosporine arms as well as the sirolimus arm were all significant.

“Another striking feature was the incidence of BPAR,” Dr. Nashan noted. In the low-dose tacrolimus group, the acute rejection rate was very low at 12%, whereas it was “unacceptably high” at 37% in the low-dose sirolimus group—“something that we did not expect and which clearly indicates that sirolimus without a calcineurin inhibitor at the beginning does not work,” Dr. Nashan commented. BPAR rates in the low-dose and normal-dose cyclosporine groups were approximately 25% in each group and were again significantly higher than those seen in the low-dose tacrolimus arm.

Rates of graft and patient survival at 12 months ranged from 89 to 94% overall and were not significantly different between the four groups. The rate of infection overall was not different between the different groups, but the incidence of cytomegalovirus was numerically higher in the normal-dose cyclosporine group. The incidence of lymphoceles as well as poor wound healing was also highest in the low-dose sirolimus group, while the incidence of diarrhea was highest in the low-dose tacrolimus group, as was the rate of post-transplant diabetes mellitus. There were no differences in malignancy rates between the four groups at the end of the year.

Dr. Nashan concluded, “The SYMPHONY study showed that low-dose tacrolimus plus MMF maximized the function and survival of the transplanted kidney and protects the patient by providing the optimal balance between efficacy and toxicity.”

Effects on Renal Function

Although not a prospective trial, a comparison of the effects of C2-monitored cyclosporine and C0-tacrolimus on renal function and cardiovascular disease (CVD) risk factors again suggest that the two calcineurin inhibitors have variable effects on both end points. As presented by Dr. Ramesh Prasad, Assistant Professor of Medicine, University of Toronto, Ontario, approximately 200 adult transplant recipients who received cyclosporine and approximately 175 who received tacrolimus were included in the comparative analysis. The outcomes of interest were the slope of GRF between one and six months following transplantation, mean arterial blood pressure at six months, fasting lipids between six and 12 months, glucose metabolism and new-onset diabetes.

Between one and six months’ post-transplant, renal function declined by 1.82 mL/min/1.73 m² per month in the cyclosporine group compared with 0.44 mL/min/1.73 m² per month in the tacrolimus group. “Mean arterial pressures were identical at months 1 and 6 in both groups but patients who received cyclosporine were on a significantly greater number of antihypertensive agents,” Dr. Prasad noted. More cyclosporine patients also required statin therapy than those who received tacrolimus, he added. The incidence of new-onset diabetes was similar in both groups and acute rejection rates at approximately 10% were identical in both arms as well.

“In the Toronto experience, it appears that cyclosporine is associated with more rapid decline in renal function and lower GFR at six months, but further studies are needed to assess outcomes such as cardiac events,” Dr. Prasad concluded.

Assessing a New Formulation

Results from a meta-analysis of 16 randomized controlled trials comparing tacrolimus to cyclosporine in liver transplant recipients suggest that on balance, tacrolimus is associated with better outcomes and fewer long-term toxicities than either the old or the new formulations of cyclosporine, new-onset diabetes being the one exception.

As presented by Dr. Douglas Quan, Assistant Professor of Surgery, University of Western Ontario, London, the aim of the group’s systematic review of the 16 randomized controlled trials was to determine the effect of each treatment on the primary end point of patient and graft survival at the end of one year. A few of the earlier studies compared tacrolimus with the older oil-based formulation of cyclosporine but the majority compared tacrolimus to the new formulation. The number of patients included in the analysis totalled 1899 in the tacrolimus group and 1914 in the cyclosporine group.

At one year, the mortality rate was 13.4% in the tacrolimus group vs. 15.8% in the cyclosporine group, suggesting that two deaths out of 100 transplant recipients could be prevented by using tacrolimus. Rates of graft loss at one year were 17% in tacrolimus patients vs. 21.9% in cyclosporine recipients, which would translate into the prevention of five graft losses out of 100 recipients with tacrolimus use. Acute rejection rates were 38.6% for tacrolimus vs. 47% for cyclosporine, with nine fewer acute rejection events being prevented with the use of tacrolimus.

Although not frequently seen, rates of steroid-resistant rejection were also lower at 9.2% among tacrolimus patients vs. 16.6% for cyclosporine recipients. There were, however, no differences in the rates of either lymphoproliferative disorders or the need for dialysis between the two groups, both of which were low. The only end point that favoured cyclosporine was in the risk of new-onset diabetes, which at 20.4% for the tacrolimus group vs. 15.9% for cyclosporine recipients, suggested that the use of cyclosporine would prevent the development of diabetes in four patients vs. tacrolimus.

“Results from the later trials were not different from the earlier ones, so the new formulation of cyclosporine did not have much of an impact on outcomes,” Dr. Quan reported. In an interview, he added that the optimal result of transplantation has always been to try and induce tolerance such that immunosuppression would not be necessary. Unfortunately, that goal has remained elusive despite major research efforts to achieve tolerance. Given the choice of agents to date, the real challenge in managing immunosuppression is to “walk a tightrope” between optimal immunosuppression and minimization of long-term adverse events, something that Dr. Quan noted that “we have to do with each and every patient.”