Gaynor Jeffrey J, Ciancio Gaetano, Guerra Giselle, Sageshima Junichiro, Roth David, Goldstein Michael J, Chen Linda, Kupin Warren, Mattiazzi Adela, Tueros Lissett, Flores Sandra, Hanson Lois, Ruiz Phillip, Vianna Rodrigo, Burke George W
Miami Transplant Institute, Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, USA.
Miami Transplant Institute, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, USA.
Transpl Int. 2016 Feb;29(2):216-26. doi: 10.1111/tri.12699. Epub 2015 Nov 3.
The premise that lower TAC trough levels are associated with subsequently higher first BPAR risk during the first 12 mo post-transplant was recently questioned. Using our prospectively followed cohort of 528 adult, primary kidney transplant recipients (pooled across four randomized trials) who received reduced TAC dosing plus an IMPDH inhibitor, TAC trough levels measured at seven time points, 7, 14 days, 1, 2, 3, 6 and 9 months post-transplant, were utilized along with Cox's model to determine the multivariable significance of TAC level(t) (a continuous time-dependent covariate equaling the most recently measured TAC level prior to time t) on the hazard rate of developing first BPAR during the first 12 months post-transplant. The percentage developing BPAR during the first 12 months post-transplant was 10.2% (54/528). In univariable analysis, lower TAC level(t) was associated with a significantly higher BPAR rate (P = 0.00006), and its significance was maintained even after controlling for 2 significant baseline predictors (African-American/Hispanic Recipient and Developed DGF) in Cox's model (multivariable P = 0.0003). Use of a cutpoint, TAC level(t) <4.0 vs. ≥4.0 ng/ml, yielded an even greater association with BPAR rate (univariable and multivariable P < 0.000001), with an estimated hazard ratio of 6.33. These results suggest that TAC levels <4.0 ng/ml should be avoided during the first 12 months post-transplant when TAC is used in combination with fixed-dose mycophenolate with or without corticosteroids and induction therapy.
移植后最初12个月内较低的他克莫司（TAC）谷浓度与随后较高的首次活检证实的急性排斥反应（BPAR）风险相关这一前提最近受到质疑。利用我们前瞻性随访的528例接受TAC剂量减少加肌苷-5'-单磷酸脱氢酶（IMPDH）抑制剂的成年原发性肾移植受者队列（汇集了四项随机试验），移植后7天、14天、1个月、2个月、3个月、6个月和9个月这七个时间点测量的TAC谷浓度，与Cox模型一起用于确定TAC水平（t）（一个连续的时间依赖性协变量，等于时间t之前最近测量的TAC水平）对移植后最初12个月内发生首次BPAR的风险率的多变量显著性。移植后最初12个月内发生BPAR的百分比为10.2%（54/528）。在单变量分析中，较低的TAC水平（t）与显著较高的BPAR发生率相关（P = 0.00006），即使在Cox模型中控制了两个显著的基线预测因素（非裔美国人/西班牙裔受者和发生了延迟性移植物功能不全）后，其显著性仍然存在（多变量P = 0.0003）。使用切点TAC水平（t）<4.0 ng/ml与≥4.0 ng/ml，与BPAR发生率的关联更大（单变量和多变量P < 0.000001），估计风险比为6.33。这些结果表明，当TAC与固定剂量霉酚酸酯联合使用，无论是否使用皮质类固醇和诱导治疗时，移植后最初12个月内应避免TAC水平<4.0 ng/ml。
