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.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Exploratory/Developmental Grants (R21)
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Special Emphasis Panel (ZRG1-RUS-F (51))
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Kimmel, Paul
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Yale University
Internal Medicine/Medicine
Schools of Medicine
New Haven
United States
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Belcher, Justin M; Sanyal, Arun J; Peixoto, Aldo J et al. (2014) Kidney biomarkers and differential diagnosis of patients with cirrhosis and acute kidney injury. Hepatology 60:622-32
Belcher, Justin M; Garcia-Tsao, Guadalupe; Sanyal, Arun J et al. (2014) Urinary biomarkers and progression of AKI in patients with cirrhosis. Clin J Am Soc Nephrol 9:1857-67
Belcher, Justin M; Garcia-Tsao, Guadalupe; Sanyal, Arun J et al. (2013) Association of AKI with mortality and complications in hospitalized patients with cirrhosis. Hepatology 57:753-62