Alteration of urinary neutrophil gelatinase–associated lipocalin as a predictor of tacrolimus-induced chronic renal allograft fibrosis in tacrolimus dose adjustments following kidney transplantation

Despite tacrolimus (TAC) drug-level monitoring, TAC-induced chronic renal allograft fibrosis remains an important problem. This study investigated the potential of urinary neutrophil gelatinase–associated lipocalin (uNGAL) as a chronic renal allograft fibrosis biomarker in a two-phase study (proof of concept and cohort). In the proof of concept stage of the study, increased TAC-doses at 3 days after dose adjustment compared with the baseline were associated with elevated uNGAL (+ΔuNGAL) and urinary interleukin 18 (IL-18), but normal serum creatinine (SCr), despite the therapeutic trough levels of TAC. In the cohort study, the patients with elevated uNGAL post-recruitment in comparison with the baseline (+ΔuNGAL) was associated with the more severe renal allograft fibrosis from renal pathology of the protocol biopsy at 12 months post kidney transplantation (post-KT). A cut-off value of uNGAL ≥ 125.2 ng/mL during a 3, 6, 9 and 12 months post-KT was associated with a higher fibrosis score, with an area under the receiver operating characteristics curve of 0.80 (95% confidence interval [CI] 0.72 to 0.88, p p尽管已开展他克莫司（tacrolimus, TAC）的血药浓度监测，但他克莫司诱导的慢性肾移植纤维化仍是临床亟待解决的重要问题。本研究通过两阶段研究（概念验证阶段与队列研究），探讨了尿中性粒细胞明胶酶相关脂质运载蛋白（urinary neutrophil gelatinase–associated lipocalin, uNGAL）作为慢性肾移植纤维化生物标志物的潜力。在本研究的概念验证阶段，相较于基线水平，剂量调整后3天内升高的他克莫司给药剂量，与尿中性粒细胞明胶酶相关脂质运载蛋白（+ΔuNGAL）及尿白细胞介素18（urinary interleukin 18, IL-18）水平升高相关，但此时血清肌酐（serum creatinine, SCr）仍处于正常范围，且他克莫司的治疗谷浓度符合治疗标准。在队列研究中，肾移植术后（post kidney transplantation, post-KT）12个月时，通过方案规定活检获取的肾脏病理结果显示，入组后尿中性粒细胞明胶酶相关脂质运载蛋白水平较基线升高（+ΔuNGAL）的患者，其肾移植纤维化程度更为严重。肾移植术后3、6、9及12个月时，尿中性粒细胞明胶酶相关脂质运载蛋白≥125.2 ng/mL的截断值，与更高的纤维化评分相关，其受试者工作特征曲线下面积为0.80（95%置信区间[CI] 0.72至0.88，p p）