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【medical-news】术后第一年避免使用钙神经素抑制
"It is well documented that the CNIs are acutely and in the long term nephrotoxic," said lead investigator Thomas Pearson, MD, PhD, the Livingston professor of surgery and chief of renal transplantation at Emory Transplant Center, Emory University School of Medicine in Atlanta, Georgia. "The mechanistic basis of that is the vasoconstriction of the blood flow into the filtering units of the kidney."
In an open-label, prospective, multicenter fashion, patients were first treated with mycophenolate mofetil (MMF) and a CNI, consisting of either tacrolimus or cyclosporine, and then randomized after 30 to 180 days following kidney transplantation to maintaining that same regimen or to switch CNI therapy to sirolimus (SRL). Patients received 1 to 1.5 g of MMF twice daily, with 2 to 10 mg of SRL, "followed by at least 2 mg/day; trough 5-10 ng/ml," according to the investigators.
A total of 35 centers in Canada and the United States participated in the study, with each center implementing its own practice of antibody induction and/or administration of corticosteroids.
The primary outcome was improved renal function as measured by mean percentage change in measured glomerular filtration rate (GFR), with secondary outcomes including biopsy-proven acute rejection (BPAR), graft loss, and death at 12 months of follow-up.
Dr. Pearson noted that the study, which will follow patients for 2 years, did not put patients immediately on sirolimus to reduce adverse events that occur with the drug, such as poor wound healing.
"If you can avoid those side effects in the early posttransplant period, get the wounds healed, and then convert patients to sirolimus-based therapy, you may get the best of both worlds," explained Dr. Pearson. "You get the potent inhibition of the calcineurin inhibitors early posttransplant and the lack of nephrotoxicity with the calcineurin inhibitors in the long term with sirolimus."
A total of 305 single-organ renal allograft recipients initially participated in the study, with 298 randomized to either continue MMF/CNI therapy (n = 150) or to begin a new regimen of MMF/SRL (n = 148). Patients ranged in age from 13 to 75 years with the mean age of 48.7 years. Two thirds of the patients were men. Other baseline characteristics, including GFR, were similar between the treatment groups.
Of the 148 patients who were switched to MMF/SRL therapy, 122 were withdrawn from tacrolimus, and 26 were withdrawn from cyclosporine. Of the 150 patients receiving MMF/CNI therapy, 119 (81%) received tacrolimus, and 31 (19%) received cyclosporine.
There were no statistically significant differences in secondary outcomes such as BPAR, graft loss, or death at 12 months between the 2 study groups. In addition, there was no statistically significant difference in withdrawal due to adverse events: 21MMF/SRL (14%) vs 10 MMF/CNI (7%). No deaths occurred in the MMF/SRL group, and 3 patients died in the MMF/CNI group.
Mouth ulcers and proteinuria were the main adverse events responsible for withdrawal from the study among patients who received MMF/SRL, while diarrhea was mainly responsible for withdrawal among patients who received MMF/CNI.
In measuring the overall percentage change from baseline GFR, investigators found no statistically significant difference between the 2 arms: 27.9 for the MMF/SRL group and 11.0 for the MMF/CNI group (P = .052). In looking at a subset of 91 MMF/CNI patients who received tacrolimus, they did conclude there was a statistically significant difference in the mean GFR percentage change between the MMF/SRL group and the MMF/CNI subset: 27.9 vs. 6.1 (P = .0247).
Sundaram Hariharan, MD, a professor of medicine and chief of nephrology at the Medical College of Wisconsin in Milwaukee, said the data are too premature to advocate CNI withdrawal in renal transplant patients.
"This is a very important trial as we are moving toward calcineurin inhibitor avoidance and withdrawal in renal transplant recipients to preserve renal function," said Dr. Hariharan, who was one of the moderators of the oral session at which the research was presented.
"I would like to see more details about renal function, rather than just seeing the percent change in GFR," he told Medscape Transplantation. "The other question is to know more about the dose of sirolimus that was used. It would be useful to know if they used a very high dose or low dose and translate that practice into patient care."
The study was funded by Roche. Dr. Pearson has received grants from and has sat on advisory boards for Roche. Dr. Hariharan disclosed no relevant financial relationships.
American Transplant Congress 2008: Abstract 129. Presented June 1, 2008.
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作者:admin@医学,生命科学 2010-10-15 05:11
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