延迟移植物功能对肾移植后患者吗替麦考酚酸暴露的影响。

How delayed graft function impacts exposure to mycophenolic acid in patients after renal transplantation.

机构信息

Department of Hospital Pharmacy and Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.

出版信息

Ther Drug Monit. 2011 Apr;33(2):155-64. doi: 10.1097/FTD.0b013e31820c0a96.

DOI:10.1097/FTD.0b013e31820c0a96

PMID:21383657

Abstract

INTRODUCTION

Mycophenolic acid (MPA) plasma concentrations are highly variable on standard-dose mycophenolate mofetil therapy. At creatinine clearances below 25 mL/min, MPA clearance increases as a result of a higher nonprotein-bound fraction. Patients with delayed graft function (DGF) after renal transplantation are exposed to low total MPA concentrations, when risk of rejection is highest. This study investigated the influence of DGF on MPA exposure and on clinical outcome.

METHODS

Adult renal transplantation patients treated with mycophenolate mofetil, corticosteroids, and either microemulsified cyclosporine (n = 459) or tacrolimus (n = 371) participated in a randomized controlled trial (the Fixed-Dose Concentration-Controlled [FDCC] Study). Abbreviated MPA areas under the curve (AUCs) were obtained on Day 3, Day 10, Week 4, and Month 3, to calculate MPA AUC₀₋₁₂. Free MPA AUC values were available for a subgroup of patients (n = 269).

RESULTS

The overall incidence of DGF was 187 of 830 (23%) and did not differ between cyclosporine-treated (24%) and tacrolimus- (21%) treated patients. The incidence of biopsy-proven acute rejection at 12 months was significantly higher in patients with DGF (13.8% versus 21.4%). Patients with DGF had significantly lower dose-corrected MPA AUC on Day 3 and Day 10. Free MPA fraction and dose-corrected free MPA AUC were significantly higher in patients with DGF, from Day 3 until Month 3. The total number of patients with at least one opportunistic infection was significantly higher in patients with DGF (33.2%) compared with patients without DGF (25.8%) (P = 0.048). Patients with DGF developing opportunistic infections did not have higher total MPA AUC nor higher free MPA AUC compared with those without opportunistic infections.

CONCLUSION

Patients with DGF have significantly lower dose-corrected MPA AUC in the first month after renal transplantation, presumably as a result of enhanced MPA clearance on account of the elevated MPA free fraction. Because patients with DGF have a higher rate of acute rejection and lower MPA exposure, higher dosing of mycophenolate mofetil in such patients may improve outcome. However, the already increased incidence of opportunistic infections in patients with DGF is a concern.

摘要

简介

在标准剂量吗替麦考酚酯治疗中，麦考酚酸（MPA）的血浆浓度存在高度变异性。在肌酐清除率低于 25 mL/min 时，由于非蛋白结合部分增加，MPA 清除率增加。肾移植后发生延迟移植物功能（DGF）的患者，由于存在排斥反应的最高风险，其总 MPA 浓度较低。本研究旨在调查 DGF 对 MPA 暴露和临床结局的影响。

方法

接受吗替麦考酚酯、皮质类固醇和微乳型环孢素（n = 459）或他克莫司（n = 371）治疗的成人肾移植患者参加了一项随机对照试验（固定剂量浓度控制[FDCC]研究）。在第 3 天、第 10 天、第 4 周和第 3 个月获得了 MPA 的简化 AUC（AUC₀₋₁₂），以计算 MPA AUC₀₋₁₂。一组患者（n = 269）可获得游离 MPA AUC 值。

结果

830 例患者中，DGF 总发生率为 187 例（23%），环孢素治疗组（24%）与他克莫司治疗组（21%）之间无差异。DGF 患者 12 个月时活检证实急性排斥反应的发生率显著较高（13.8%比 21.4%）。DGF 患者在第 3 天和第 10 天的剂量校正 MPA AUC 明显较低。从第 3 天到第 3 个月，DGF 患者的游离 MPA 分数和剂量校正游离 MPA AUC 明显较高。DGF 患者至少发生一次机会性感染的患者比例明显高于无 DGF 患者（33.2%比 25.8%）（P = 0.048）。发生机会性感染的 DGF 患者与未发生机会性感染的患者相比，总 MPA AUC 或游离 MPA AUC 均无明显升高。

结论

肾移植后第一个月，DGF 患者的剂量校正 MPA AUC 明显较低，推测这是由于 MPA 游离部分增加，导致 MPA 清除率增加。由于 DGF 患者发生急性排斥反应的风险较高，MPA 暴露较低，因此增加此类患者的吗替麦考酚酯剂量可能会改善结局。但是，DGF 患者的机会性感染发生率已经增加，这令人担忧。