尿生物标志物预测急性肾损伤进展和慢性化研究

Acute kidney injury (AKI) is the leading cause threatening hospitalized patients’ life and associates with worse clinical outcomes. AKI also independently associated with increased risk of developing future chronic kidney disease (CKD) and end stage renal disease (ESRD). Early identification of patients who are at high risk for progressing to further stage and/or developing future CKD is helpful for close monitoring and timely intervention, which in turn will improve patients clinical outcomes and save medical cost. Biomarkers, such as NGAL, KIM-1 and IL-18, were used to predicting AKI progression (to higher severity stage) but only showed moderate performance (AUC 0.7~0.75). Lack of high performance biomarker or biomarkers combination hinders early prediction of AKI progressing to further stage or developing future CKD, thus delays timely management and prevention...Through base science and preliminary clinical study on AKI, we have identified two candidate biomarkers (urinary angiotensinogen，uAGT and urinary matrix metalloprotease 7, uMMP-7) for predicting AKI progression. Our preliminary data showed that uAGT levels significantly elevated in AKI stage 1 (KDIGO 2012) patients who subsequently progressed to stage 2 and/or stage 3 compared with those did not progressed. In AKI patients who developed CKD after 3 months, uMMP-7 remained continuously in higher levels compared with those did not developed CKD...The present study will set up three prospective, multicenter, large sample cohorts to investigate the performance of new biomarkers (uAGT and uMMP-7) in predicting AKI progression (progressing to higher stage or developing future CKD). The participants in three cohorts were patients with acute decompensated heart failure, admitted to mixed ICU or acute tubular necrosis (ATN), who enrolled at the day of first diagnosed AKI stage 1. Patients with advance CKD (eGFR<30ml/min/1.73m2) or receiving maintenance dialysis were excluded. The primary objective is to evaluate the predictive performance of the novel biomarkers for AKI progressing to higher stage and developing future CKD either individually or in combination; to compare their performance with that of previously reported biomarkers or clinic predictive model; and to determine the effect on risk reclassification by addition of the new biomarkers to the clinic model currently used in clinical practice.

进展(严重度分期升级)和慢性化（发生慢性肾脏病）是急性肾损伤（AKI）发生后两个最主要的临床后果，是影响病人死亡和长期预后的最主要因素。如何早期预测AKI进展和慢性化是减少病人死亡或进入终末期肾脏病的关键问题。在临床传统指标基础上验证和寻找新的生物标志物预测AKI进展和慢性化将有助于临床医生及时甄别高危病人，提前采取措施保护肾脏，避免肾损伤的持续和进展，改善临床预后。本项目旨在通过建立三个AKI高危住院病人队列，采用前瞻性、多中心、大样本队列研究方法，评估我们之前基础研究发现的新生物标志物（AGT,MMP-7）对人类AKI后进展和慢性化的预测能力；比较新生物标志物和已报道的生物标志物对AKI进展和慢性化的预测价值。最后，建立基于生物标志物和临床危险因素的AKI进展和慢性化风险预测模型，为生物标志物在临床实践中的应用提供新信息，为防治AKI、改善AKI预后的临床转化研究提供新策略。

进展(严重度分期升级)和慢性化（发生慢性肾脏病）是急性肾损伤（AKI）发生后两个最主要的临床后果，是影响病人死亡和长期预后的最主要因素。本项目计划在临床传统指标基础上验证和寻找新的生物标志物预测AKI进展和慢性化风险，帮助临床医生及时甄别高危病人，提前采取措施保护肾脏，改善AKI临床预后。上述计划包括建立三个AKI高危住院病人队列，采用前瞻性、多中心、大样本队列研究方法，评估我们之前基础研究发现的新生物标志物对人类AKI后进展和慢性化的预测能力。项目执行期间，取得的研究成果：（1）顺利完成了AKI高危住院病人队列生物样本库和临床数据库建立工作，奠定研究了基础，建立了AKI生物标志物的统一检测平台。（2）通过成人和儿童心脏大手术的双子队列研究，发现预测心脏大手术后AKI发生和发展的新生物标志物，证实术后6小时内的尿基质金属蛋白酶 （uMMP-7）水平能有效预测术后AKI的发生和进展。论文发表于J Am Soc Nephrol. 2017 , 28:3373-3382。（3）针对预测心脏大手术后AKI进展风险这一临床挑战问题，评价了新生物标志物—uMMP-7和其他已报道的经典生物标志物对心脏大手术后AKI进展（严重度分期升级）的预测效力和准确性。在校正临床危险因素后，尿MMP-7水平是心脏大手术后AKI进展的独立预测因素，预测效能AUC为0.80，联合尿 IL-18可进一步提高至0.84。而且，尿MMP-7加入临床模型后显著提高临床模型对心脏大手术后的危险分层。研究结果为早期筛查心脏大手术后AKI进展的高危人群提供了新手段，发表于Dis Markers.;2019: 9217571。（4）完成了AKI慢性化的临床表征和危险因素分析，建立了初步的临床风险预测模型。项目发现的AKI进展生物标志物和建立的AKI慢性化风险预测模型将有助于临床医生筛查高危病人，为早期发现和处理AKI进展和慢性化高危病人提供新手段，为临床诊疗AKI相关并发症提供有潜在应用价值的新技术。