Identifying acute tubular necrosis in cirrhosis patients with renal dysfunction

描述（申请人提供）：肾功能不全是肝硬化住院患者的常见并发症。虽然在许多情况下，肾功能障碍在入院的第一天内是可逆的，但在相当大比例的患者中可能发生迅速进展的肾功能障碍。在这些病例中，主要的区别是1型肝肾综合征（HRS）和急性肾小管坏死（ATN）。对这两种疾病进行准确的鉴别诊断具有重要的治疗和预后意义。1型HRS是一种发生在晚期肝病背景下的功能性肾功能衰竭，中位生存期仅为2周。它的最终治疗是肝移植，然而，血管收缩剂加白蛋白已被证明是有效的临时措施，直到移植进行。1型HRS的诊断是一种排除性诊断，在排除其他肾衰原因，特别是急性肾小管坏死（ATN）之前不能确诊。ATN的治疗只能通过血液透析来支持，因为血管收缩剂和白蛋白不会改善肾功能，而且可能会使肾功能恶化。区分1型HRS和ATN可能很困难，通常需要几天时间，因为传统上使用的区分尿液参数可能在晚期肝病中改变。因此，诊断的严重延误损害了尽早开始治疗和尽早开始移植过程的能力，这可能导致发病率和死亡率的增加。对实验动物和人类的研究已经确定了能够检测肾小管损伤（ATN的必要条件）的尿液生物标志物，具有高度的敏感性和特异性。其中两种有前景的生物标志物是白细胞介素-18 （IL-18）和中性粒细胞明胶酶相关脂钙蛋白（NGAL），它们在心脏手术和危重患者中识别ATN的诊断准确率为90%。然而，它们尚未在肝脏疾病的情况下进行测试。在这项前瞻性多中心队列研究中，我们计划招募来自5个主要学术中心的80-100例肝硬化肾功能不全患者，确定尿IL-18和NGAL在肝硬化肾功能不全住院患者中正确识别ATN的疗效，从而促进1型HRS的诊断。公共卫生相关性：肝硬化住院患者的肾功能衰竭是常见的，并与严重的预后相关。目前，在这种情况下，很少有工具来区分两种主要形式的肾功能衰竭，即急性肾小管坏死和1型肝肾综合征。尿液生物标志物，如IL-18和NGAL，在其他临床情况下对识别急性肾小管坏死很有价值，将在肾功能衰竭和肝硬化患者中进行前瞻性队列研究。

DESCRIPTION (provided by applicant): Renal dysfunction is a common complication in hospitalized patients with cirrhosis. While in many cases renal dysfunction is reversible within the first days of admission, rapidly progressive renal dysfunction may occur in a sizable proportion of patients. In these cases, the main differential is between type 1 hepatorenal syndrome (HRS) and acute tubular necrosis (ATN). Making an accurate differential diagnosis between these two entities has important therapeutic and prognostic implications. Type 1 HRS is a form of functional renal failure that occurs in the setting of advanced liver disease, and has a median survival of only 2 weeks. Its definitive therapy is liver transplantation, however, vasoconstrictors plus albumin have been demonstrated to be efficacious as a temporizing measure until transplantation is performed. The diagnosis of Type 1 HRS is one of exclusion, and cannot be made until other causes of renal failure, particularly acute tubular necrosis (ATN) are ruled out. The treatment for ATN is solely supportive via hemodialysis, as vasoconstrictors and albumin will not improve renal function, and may potentially worsen it. Differentiating between Type 1 HRS and ATN may be difficult and often takes several days, as traditionally-used distinguishing urinary parameters may be altered in advanced liver disease. Hence, crucial delays in diagnosis impair the ability to institute treatment earlier and initiate the transplantation process sooner, which may lead to increased morbidity and mortality. Research in both experimental animals and humans has identified urine biomarkers that are capable of detecting renal tubular injury (a sine qua non for ATN) with a high degree of sensitivity and specificity. Two of these promising biomarkers are interleukin-18 (IL-18) and neutrophil gelatinase associated lipocalin (NGAL) that have been shown to have an diagnostic accuracy of >90% in identifying ATN in the setting of cardiac surgery, and in critically ill patients. However, they have not yet been tested in the setting of liver disease. In this prospective multi-center cohort study, we plan to enroll 80-100 patients, from 5 major academic centers, with cirrhosis and renal dysfunction and determine the efficacy of urinary IL-18 and NGAL in correctly identifying ATN in hospitalized patients with cirrhosis and renal dysfunction, thereby facilitating the diagnosis of Type 1 HRS. PUBLIC HEALTH RELEVANCE: Renal failure in patients with hospitalized patients with cirrhosis is common and associated with a grave prognosis. Currently, there are few tools to distinguish between two major forms of renal failure in this setting, namely acute tubular necrosis and Type 1 Hepatorenal Syndrome. Urinary biomarkers, such as IL-18 and NGAL, which are valuable for identifying acute tubular necrosis in other clinical settings, will be tested in patients with renal failure and cirrhosis in this prospective cohort study.