Division of Nephrology, Department of Medicine, Chulalongkorn University, Bangkok, Thailand.
Excellent Center of Organ Transplantation (ECOT), King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand.
PLoS One. 2018 Dec 21;13(12):e0209708. doi: 10.1371/journal.pone.0209708. eCollection 2018.
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 < 0.0001) and a hazard ratio (HR) of 2.54 (95% CI 1.45 to 9.33; p < 0.001). We conclude that uNGAL is a sensitive biomarker of TAC induced subtle renal injury and TAC-induced chronic renal allograft fibrosis. We propose that uNGAL measurements, in addition to trough levels of TAC, should be used to predict TAC-induced chronic renal allograft fibrosis in the recipients of KT.
尽管进行了他克莫司（TAC）药物水平监测，但 TAC 诱导的慢性肾移植纤维化仍然是一个重要问题。本研究在一项两阶段研究（概念验证和队列研究）中探讨了尿中性粒细胞明胶酶相关脂质运载蛋白（uNGAL）作为慢性肾移植纤维化生物标志物的潜力。在研究的概念验证阶段，与基线相比，剂量调整后 3 天增加 TAC 剂量与升高的 uNGAL（+ΔuNGAL）和尿白细胞介素 18（IL-18）相关，但 TAC 的治疗谷浓度正常。在队列研究中，与基线相比，招募后 uNGAL 升高（+ΔuNGAL）的患者与移植后 12 个月（移植后）肾脏病理学协议活检中更严重的肾移植纤维化相关。在移植后 3、6、9 和 12 个月期间，uNGAL 浓度≥125.2ng/ml 与更高的纤维化评分相关，接受者操作特征曲线下面积为 0.80（95%置信区间 0.72 至 0.88，p<0.0001），风险比（HR）为 2.54（95%置信区间 1.45 至 9.33；p<0.001）。我们得出结论，uNGAL 是 TAC 诱导的轻微肾损伤和 TAC 诱导的慢性肾移植纤维化的敏感生物标志物。我们建议，除了 TAC 的谷浓度外，还应使用 uNGAL 测量值来预测肾移植受者中 TAC 诱导的慢性肾移植纤维化。
