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Low-Dose Tacrolimus Superior to Other Immunosuppressives After Renal Transplant
By Katherine Kahn, DVM
Medscape Medical News
August 2, 2006 (Boston) — When compared with standard and low-dose immunosuppression regimens in renal transplant patients, low-dose tacrolimus results in higher glomerular filtration rate (GFR) and lower incidence of acute rejection at 12-month follow-up, a new study reveals. Henrik Ekberg, MD, PhD, from the transplant surgery department at the Lund University Hospital in Malmö, Sweden, presented the findings here at the World Transplant Congress.
The 12-month study, entitled SYMPHONY, was a prospective, randomized open-label study designed to "examine all the current alternatives of low-toxicity regimens," Dr. Ekberg told Medscape.
"A lot of physicians are already using the combination of tacrolimus and MMF, but this shows that if they start with daclizumab induction, they can probably reduce the doses of tacrolimus," Dr. Ekberg said. "A number of centers involved in the study have now changed their routines and started to use this combination."
Bruce Kaplan, MD, the codirector of the University of Illinois at Chicago Multiorgan Transplant Center, commented to Medscape about the study. "It's one of the best-designed studies in kidney transplant medicine in quite some time," Dr. Kaplan told Medscape. "It asks a real-world clinical question where we really didn't have a good answer. These 4 combinations have never been put to test in a large-scale, randomized, prospective trial." Dr. Kaplan was not associated with the study.
Four Treatment Regimens
The study enrolled 1645 patients from 83 centers in 15 countries. More than 93% of the patients were white, with a mean age of 46 years at the time of transplantation. About 18% of the patients received kidneys from expanded criteria donors.
Patients randomly received 1 of 4 treatment regimens: normal-dose cyclosporine (150-300 ng/mL for 3 months, 100-200 ng/mL thereafter), low-dose cyclosporine (50-100 ng/mL), low-dose tacrolimus (3-7 ng/mL), or low-dose sirolimus (4-8 ng/mL). The normal-dose cyclosporine group also received mycophenolate mofetil (MMF) and corticosteroids. All patients in the low-dose groups received daclizumab induction, MMF, and corticosteroids.
The primary end point at 12 months was GFR, with secondary 12-month end points of acute rejection rate, graft survival, patient survival, and overall safety.
The authors reported that patients receiving the tacrolimus regimen had the highest GFRs at 12 months (P < .0001), significantly lower rates of biopsy-proven rejection (P < .0001), and the highest graft survival rate (P = .014) among the regimens.
SYMPHONY: GFR, Rejection and Graft Survival Rates by Immunosuppression Regimen
End Point
| Tacrolimus
| Normal-Dose Cyclosporine
| Low-Dose Cyclosporine
| Sirolimus
| Mean GFR (mL/min)
| 65.4
| 57.1
| 59.4
| 56.7
| Biopsy-proven rejection, %
| 12
| 26
| 24
| 37
| Graft survival, %
| 94
| 89
| 93
| 89
|
This study did not show statistically significant differences for patient survival, which was 97% to 98% in all groups.
Dr. Kaplan told Medscape that the GFR results for sirolimus vs normal-dose cyclosporine were surprising. "I would expect the low-dose sirolimus arm to have the best GFR, but in fact, they had the same GFR as the normal-dose cyclosporine arm. All other head-to-head comparisons have shown better renal function for sirolimus. So that is a little hard to reconcile."
Dr. Ekberg and coinvestigators found that patients in each group had about a 60% infection rate; however, patients in the normal-dose cyclosporine group had a 14% rate of cytomegalovirus (CMV) infection, which was significantly higher than that in the other groups. The sirolimus group had the lowest rate of CMV infection at 6%.
The sirolimus group had a significantly higher rate of lymphoceles, affecting 14% of patients vs about 4% to 6% for the other groups. In addition, the sirolimus group had poor wound healing at 2 weeks in 16% of patients vs 9.5% to 11.3% of patients in the other groups.
Although not statistically significant, more malignancies were seen in patients taking sirolimus (3.5%) than in the other groups (1.7%-2.0%). "This was surprising," Dr. Ekberg told Medscape, "because sirolimus is said to result in fewer malignancies."
The most prevalent adverse effects for the tacrolimus group were diarrhea (25% vs 13%-19% in the other groups) and diabetes mellitus (11.5% vs 5.7%-8.6% in the others groups).
Dr. Ekberg concluded that results of the SYMPHONY study show that low-dose tacrolimus and MMF maximized the function and survival of the transplanted kidney. "This combination protects the patient by providing the optimal balance between efficacy and toxicity available today," Dr. Ekberg said.
Dr. Kaplan agreed that the data strongly suggest that the low-dose tacrolimus group had the best outcomes, but the findings may not translate to other situations where different regimens, such as induction with thymoglobulin or steroid withdrawal, are used, she said.
"Essentially this is nothing new because most clinicians in the United States are using this low-dose tacrolimus regimen right now," Dr. Kaplan said. "For those using sirolimus, this study may give them pause to reconsider." However, he emphasized that most clinicians claiming good success with sirolimus use thymoglobulin, not daclizumab, for induction and use higher doses of sirolimus than researchers used in this study.
In addition, Dr. Kaplan cautioned that the study's data are relevant only to 12 months. "Some people are extrapolating the results to longer term and I think that's dangerous. We should stick with the data," he said.
The study was funded by a grant from Roche. The authors report no other relevant financial relationships.
World Transplant Congress 2006: Abstract 49. Presented July 24, 2006.
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发表于 2006-8-28 09:46:28
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