脓毒症患者的游离 DNA：长期轨迹与 28 天死亡率和脓毒症相关急性肾损伤的关系。

INTRODUCTION: Outcome-prediction in patients with sepsis is challenging and currently relies on the serial measurement of many parameters. Standard diagnostic tools, such as serum creatinine (SCr), lack sensitivity and specificity for acute kidney injury (AKI). Circulating cell-free DNA (cfDNA), which can be obtained from liquid biopsies, can potentially contribute to the quantification of tissue damage and the prediction of sepsis mortality and sepsis-associated AKI (SA-AKI). METHODS: We investigated the clinical significance of cfDNA levels as a predictor of 28-day mortality, the occurrence of SA-AKI and the initiation of renal replacement therapy (RRT) in patients with sepsis. Furthermore, we investigated the long-term course of cfDNA levels in sepsis survivors at 6 and 12 months after sepsis onset. Specifically, we measured mitochondrial DNA (mitochondrially encoded NADH-ubiquinone oxidoreductase chain 1, , and mitochondrially encoded cytochrome C oxidase subunit III, ) and nuclear DNA (nuclear ribosomal protein S18, ) in 81 healthy controls and all available samples of 150 intensive care unit patients with sepsis obtained at 3 ± 1 days, 7 ± 1 days, 6 ± 2 months and 12 ± 2 months after sepsis onset. RESULTS: Our analysis revealed that, at day 3, patients with sepsis had elevated levels of cfDNA (, and , all p<0.001) which decreased after the acute phase of sepsis. 28-day non-survivors of sepsis (16%) had higher levels of cfDNA (all p<0.05) compared with 28-day survivors (84%). Patients with SA-AKI had higher levels of cfDNA compared to patients without AKI (all p<0.05). Cell-free DNA was also significantly increased in patients requiring RRT (all p<0.05). All parameters improved the AUC for SCr in predicting RRT (AUC=0.88) as well as APACHE II in predicting mortality (AUC=0.86). CONCLUSION: In summary, cfDNA could potentially improve risk prediction models for mortality, SA-AKI and RRT in patients with sepsis. The predictive value of cfDNA, even with a single measurement at the onset of sepsis, could offer a significant advantage over conventional diagnostic methods that require repeated measurements or a baseline value for risk assessment. Considering that our data show that cfDNA levels decrease after the first insult, future studies could investigate cfDNA as a "memoryless" marker and thus bring further innovation to the complex field of SA-AKI diagnostics.

简介：脓毒症患者的预后预测具有挑战性，目前依赖于对许多参数的连续测量。血清肌酐（SCr）等标准诊断工具对急性肾损伤（AKI）缺乏敏感性和特异性。循环无细胞 DNA（cfDNA）可从液体活检中获得，可能有助于组织损伤的定量和脓毒症死亡率以及脓毒症相关 AKI（SA-AKI）的预测。

方法：我们研究了 cfDNA 水平作为预测脓毒症患者 28 天死亡率、发生 SA-AKI 和开始肾脏替代治疗（RRT）的指标的临床意义。此外，我们研究了脓毒症幸存者在脓毒症发作后 6 个月和 12 个月时 cfDNA 水平的长期变化。具体来说，我们测量了 81 名健康对照者和 150 名 ICU 脓毒症患者的所有可用样本中的线粒体 DNA（编码 NADH-泛醌氧化还原酶链 1 的线粒体编码、编码细胞色素 C 氧化酶亚基 III 的线粒体编码）和核 DNA（核核糖体蛋白 S18，），采集时间为脓毒症发作后 3±1 天、7±1 天、6±2 个月和 12±2 个月。

结果：我们的分析表明，在第 3 天，脓毒症患者的 cfDNA 水平升高（所有 p<0.001），在脓毒症的急性期后下降。脓毒症 28 天非幸存者（16%）的 cfDNA 水平高于 28 天幸存者（84%）（所有 p<0.05）。与无 AKI 的患者相比，发生 SA-AKI 的患者的 cfDNA 水平更高（所有 p<0.05）。需要 RRT 的患者的 cfDNA 也显著增加（所有 p<0.05）。所有参数均提高了 SCr 预测 RRT 的 AUC（AUC=0.88）以及 APACHE II 预测死亡率的 AUC（AUC=0.86）。

结论：总之，cfDNA 可能有助于改善脓毒症患者的死亡率、SA-AKI 和 RRT 的风险预测模型。cfDNA 的预测价值，即使在脓毒症发作时进行单次测量，也可能优于需要重复测量或基线值进行风险评估的传统诊断方法。考虑到我们的数据表明 cfDNA 水平在第一次损伤后下降，未来的研究可以将 cfDNA 作为一种“无记忆”标志物进行研究，从而为 SA-AKI 诊断这一复杂领域带来进一步的创新。