Urinary Biomarkers Indicative of Apoptosis and Acute Kidney Injury in the Critically Ill

Background
Apoptosis is a key mechanism involved in ischemic acute kidney injury (AKI), but its role in septic AKI is controversial. Biomarkers indicative of apoptosis could potentially detect developing AKI prior to its clinical diagnosis.
Methods
As a part of the multicenter, observational FINNAKI study, we performed a pilot study among critically ill patients who developed AKI (n = 30) matched to critically ill patients without AKI (n = 30). We explored the urine and plasma levels of cytokeratin-18 neoepitope M30 (CK-18 M30), cell-free DNA, and heat shock protein 70 (HSP70) at intensive care unit (ICU) admission and 24h thereafter, before the clinical diagnosis of AKI defined by the Kidney Disease: Improving Global Outcomes -creatinine and urine output criteria. Furthermore, we performed a validation study in 197 consecutive patients in the FINNAKI cohort and analyzed the urine sample at ICU admission for CK-18 M30 levels.
Results
In the pilot study, the urine or plasma levels of measured biomarkers at ICU admission, at 24h, or their maximum value did not differ significantly between AKI and non-AKI patients. Among 20 AKI patients without severe sepsis, the urine CK-18 M30 levels were significantly higher at 24h (median 116.0, IQR [32.3–233.0] U/L) than among those 20 patients who did not develop AKI (46.0 [0.0–54.0] U/L), P = 0.020. Neither urine cell-free DNA nor HSP70 levels significantly differed between AKI and non-AKI patients regardless of the presence of severe sepsis. In the validation study, urine CK-18 M30 level at ICU admission was not significantly higher among patients developing AKI compared to non-AKI patients regardless of the presence of severe sepsis or CKD.
Conclusions
Our findings do not support that apoptosis detected with CK-18 M30 level would be useful in assessing the development of AKI in the critically ill. Urine HSP or cell-free DNA levels did not differ between AKI and non-AKI patients.

【背景】细胞凋亡（Apoptosis）是缺血性急性肾损伤（AKI）的关键发病机制，但其在脓毒症相关性AKI中的作用仍存在争议。可反映细胞凋亡的生物标志物，或能在AKI临床确诊前识别出即将发生的AKI。

【方法】作为多中心观察性FINNAKI研究的一部分，本研究开展了一项预试验：纳入30例发生AKI的重症患者，并匹配30例未发生AKI的重症患者作为对照。我们分别于重症监护病房（ICU）入院时及入院后24小时，在AKI临床确诊前（AKI临床诊断依据改善全球肾脏病预后组织（Kidney Disease: Improving Global Outcomes）的肌酐与尿量标准），检测了受试者尿液及血浆中的细胞角蛋白18新表位M30（CK-18 M30）、无细胞DNA（cell-free DNA）及热休克蛋白70（HSP70）水平。此外，我们在FINNAKI队列的197例连续入组患者中开展了验证研究，于ICU入院时检测其尿液样本的CK-18 M30水平。

【结果】在预试验中，AKI患者与非AKI患者在ICU入院时、入院后24小时的检测生物标志物水平，或其最大值均无显著差异。在20例无重度脓毒症的AKI患者中，入院后24小时的尿液CK-18 M30水平[中位数116.0，四分位间距（IQR）32.3~233.0 U/L]显著高于20例未发生AKI的患者[46.0，0.0~54.0 U/L]，P=0.020。无论是否合并重度脓毒症，AKI患者与非AKI患者的尿液无细胞DNA及HSP70水平均无显著差异。在验证研究中，无论是否合并重度脓毒症或慢性肾脏病（CKD），发生AKI的患者在ICU入院时的尿液CK-18 M30水平均未显著高于非AKI患者。

【结论】本研究结果不支持通过CK-18 M30水平检测细胞凋亡，可用于评估重症患者AKI的发生风险。AKI患者与非AKI患者的尿液HSP或无细胞DNA水平无显著差异。