Background: Urinary tissue inhibitor of metalloproteinase-2 (TIMP2) and insulin-like growth factor binding protein-7 (IGFBP7) predict severe acute kidney injury (AKI) in critical illness. Earlier but subtle elevation of either biomarker from nephrotoxicity may predict drug-induced AKI. Methods: A prospective study involving serial urine collection in patients treated with vancomycin, aminoglycosides, amphotericin, foscarnet, or calcineurin inhibitors was performed. Urinary TIMP2 and IGFBP7, both absolute levels and those normalized with urine creatinine, were examined in days leading to AKI onset by KDIGO criteria in cases or at final day of nephrotoxic therapy in non-AKI controls, who were matched for age, baseline kidney function, and nephrotoxic exposure. Results: Urinary biomarker analyses were performed in 21 AKI patients and 28 non-AKI matched-controls; both groups had comparable baseline kidney function and duration of nephrotoxic drug therapy. Significantly higher absolute, normalized, and composite levels of TIMP2 and IGFBP7 were observed in AKI cases versus controls as early as 2-3 days before AKI onset (all P<0.05); >70% of patients with corresponding levels above 75th percentile developed AKI. Normalized TIMP2 at 2-3 days pre-AKI predicted AKI with the highest average AUROC of 0.81, followed by that of composite [TIMP2]x[IGFBP7] (0.78) after cross-validation. [TIMP2]x[IGFBP7] >0.01 (ng/mL)2/1000 predicted AKI with a sensitivity of 79% and specificity of 60%. Conclusion: Elevated urinary TIMP2 or IGFBP7 predicts drug-induced AKI with a lead-time of 2-3 days; an opportune time for interventions to reduce nephrotoxicity.

中文翻译：

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金属蛋白酶 2 和胰岛素样生长因子结合蛋白 7 的泌尿组织抑制剂升高可预测药物引起的急性肾损伤

背景：尿液组织金属蛋白酶抑制剂 2 (TIMP2) 和胰岛素样生长因子结合蛋白 7 (IGFBP7) 可预测重症患者的严重急性肾损伤 (AKI)。肾毒性引起的任一生物标志物较早但微妙的升高可能预测药物诱发的 AKI。方法：对接受万古霉素、氨基糖苷类、两性霉素、膦甲酸或神经钙蛋白抑制剂治疗的患者进行连续尿液收集的前瞻性研究。尿 TIMP2 和 IGFBP7，绝对水平和用尿肌酐标准化的水平，在导致 AKI 发作的天数中根据 KDIGO 标准在病例中或在肾毒性治疗的最后一天在非 AKI 对照中进行检查，这些对照与年龄、基线肾功能相匹配和肾毒性暴露。结果：在 21 名 AKI 患者和 28 名非 AKI 匹配对照中进行了尿液生物标志物分析；两组的基线肾功能和肾毒性药物治疗的持续时间相当。早在 AKI 发作前 2-3 天，AKI 病例中观察到 TIMP2 和 IGFBP7 的绝对、标准化和复合水平显着高于对照组（所有 P < 0.05）；相应水平高于第 75 个百分位数的患者中 >70% 发生了 AKI。AKI 前 2-3 天标准化 TIMP2 预测 AKI 的平均 AUROC 最高为 0.81，其次是交叉验证后复合 [TIMP2]x[IGFBP7] (0.78)。[TIMP2]x[IGFBP7] >0.01 (ng/mL)2/1000 预测 AKI，灵敏度为 79%，特异性为 60%。结论：尿液 TIMP2 或 IGFBP7 升高可预测药物性 AKI，提前期为 2-3 天；