缺血性急性肾损伤的风险预测：寻找肾脏“肌钙蛋白”

Ischemic acute kidney injury (AKI) is the leading cause of acute renal failure in hospitalized patients and is independently associates with morbidity and mortality. Early diagnosis has been the ‘Achilles heel’ of AKI due to the silence of renal ischemia and limitations imposed by the use of serum creatinine and urine output to fulfill diagnostic criteria. Advances in basic research have highlighted the pathogenesis of renal ischemia-reperfusion injury and paved the way for successful intervention in animal models. However, therapeutic efforts in patients have yielded disappointing results. The majority reason for the failure in the translation is the scarcity of early biomarkers for AKI, akin to troponins in acute myocardial disease, and hence an inappropriate delay in initiating the intervention. Therefore, there is an urgent need to discovery, characterization and validation of novel biomarkers.. Through proteomics and mechanism studies on ischemic AKI, we have identified several candidate urinary biomarkers for ischemic AKI such as angiotensinogen (AGT), matrix metalloprotease‑7 (MMP‑7), and vascular cell adhesion molecule (VCAM-1). The levels of these urinary proteins were remarkably elevated in the early phase of ischemic renal injury, prior to the rises of serum creatinine, in both ischemia-reperfusion model and patients with AKI. . The present study will be conducted to validate these potential biomarkers through the prospective, multicenter, large sample cohort studies of hospitalized patients. We limited our study population to adult and pediatric patients who receive cardiac surgery or admission for acute decompensated heart failure, in whom the risk of AKI and mortality is extremely great. The primary objective is to evaluate the predictive performance of the novel biomarkers for development of AKI and AKI-associated prognosis 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. Discovery of “renal troponins” may help to break down the barriers in translational research of AKI, facilitate interventional trials, and improve prevention and treatment of this devastating disorder.

缺血性急性肾损伤（AKI）是住院患者致死致残的主要原因。早期诊断一直是AKI防治的“软肋”，在AKI动物模型上有效的干预方法在临床研究中却不尽人意，转化失败的主要原因在于AKI缺少类似急性心肌缺血时肌钙蛋白那样的早期生物标志物，因而丧失了早期干预时机。发现和验证新生物标志物已成当务之急。通过蛋白组学和对缺血性AKI发病机制的研究，我们发现了几种缺血性AKI的尿液候选生物标记物，如AGT、MMP-7和VCAM-1等。在缺血再灌注模型和AKI患者，这些尿液蛋白质浓度在肾损伤早期显著升高。本研究旨在通过前瞻性、多中心、大样本住院患者队列研究，验证上述候选生物标志物。评估新生物标志物预测AKI发病或预后的能力；比较新生物标志物与已知生物标志物或临床模型的预测能力；确定在临床模型中加入生物标志物对风险再分类的影响。肾脏“肌钙蛋白”的发现有助于克服AKI转化研究的障碍，提高缺血性AKI防治水平。

缺血性急性肾损伤（AKI）是住院患者主要致死原因之一。早期诊断是AKI防治的“软肋”，在AKI动物模型上有效的干预在临床研究中却不尽人意，其主要原因在于AKI缺少风险预测的生物标志物，导致干预滞后。通过蛋白组学筛选发现了尿血管紧张素原（uAGT）、尿金属蛋白酶7（uMMP-7）等几种缺血性AKI的潜在生物标记物。本项目旨在通过前瞻性、多中心、大样本住院患者队列研究，验证上述候选生物标志物的应用价值。.取得主要进展：（1）通过前瞻性、多中心、两期队列研究（n=436），首次证实尿液uAGT水平有效预测失代偿性心力衰竭患者AKI的发病风险和一年预后。uAGT预测AKI风险的准确性（AUC=0.84）明显优于已报告的尿NGAL（AC=0.78）和临床模型（AUC=0.77）。uAGT水平并能预测患者一年全因死亡率（OR 4.5;95%CI 2.1-9.5）和再住院率（OR 3.6；95%CI 1.6-5.7）。论文发表于J Am Soc Nephrol. 2015, 26:2032-2041。（2）通过721例心脏手术患者的队列研究，证实术后12小时内uMMP-7水平变化有效预测成人和儿童心脏手术后严重AKI的发病风险。论文发表于J Am Soc Nephrol. 2017, 28:3373-3382。（3）研究了uAGT和其他7种肾损伤生物标志物预测急性心肾综合征患者（n=732）AKI进展风险的能力，证实在AKI诊断时测定的uAGT、uNGAL和uIL-18水平有效预测AKI分级恶化和AKI进展伴死亡的风险。论文发表于Clin J Am Soc Nephrol. 2016;11:1536-1544。（4）通过25家地区中心医院3年住院患者的回顾性队列，首次揭示了我国住院成人和儿童AKI的发病率和危险因素。结果发表于Clin J Am Soc Nephrol. 2015;10:1510-1518 和 Clin J Am Soc Nephrol. 2018;13:1791-1800。（5）鉴于当前儿童AKI的诊断标准没有考虑儿童血清肌酐的高度变异性，我们根据无肾脏病儿童血清肌酐变化参考值建立了儿童AKI的诊断新标准（pROCK）。大样本验证研究证实pROCK改善了儿童AKI的检出率。论文发表于J Am Soc Nephrol. 2018, 29:2432-2442。