RENALASE IN ACUTE KIDNEY INJURY: UTILITY AS A BIOMARKER, AND THERAPEUTIC AGENT

Yale University, New Haven CT

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Abstract

DESCRIPTION (provided by applicant): The challenge area (03-DK-102) is the development and validation of novel, noninvasive methods to detect and monitor disorders of relevance to NIDDK at early stages of disease before major organ damage and dysfunction has occurred. Novel diagnostic methodologies relevant to disorders that are currently difficult to detect early in the course of disease and/or that require invasive procedures (such as tissue or organ biopsies) are of highest priority. The specific challenge topic is the development of early, sensitive, non-invasive methods to diagnose acute kidney injury. We propose to examine utility of renalase, a novel molecule discovered in our laboratory, as an early and sensitive biomarker for acute kidney injury. Acute kidney injury (AKI) is a clinical condition commonly associated with sepsis, surgery, and certain drugs, and which affects up to 20% of hospitalized patients. Epidemiologic data indicate those who develop AKI are more likely to die than those who don't, and the risk is proportional to the severity of the renal injury and of the concomitant reduction in renal function. The development of effective treatment protocols for AKI has been hampered by the fact the diagnosis relies heavily of serum creatinine measurements, and is, therefore, often made 48-72 hours following the original insult. There is a clear and pressing need to identify patients with AKI early, and the best approach is believed to involve the identification biomarkers and their validation in human clinical trials. Renalase is an amine oxidase that metabolizes catecholamines such as dopamine, epinephrine and norepinephrine. It is synthesized by the renal proximal tubule, secreted in blood and continuously excreted in urine in the basal state. Renalase levels can be measured either by Western blot or ELISA. Preliminary data suggest that renalase is a novel biomarker for AKI. Moderately severe ischemic insults (global ischemia for 45 min), caused a dramatic and long-lasting decrease in urinary renalase excretion. These data are very exciting and suggest that urinary renalase may be an early biomarker for ischemic AKI. The main goal of this proposal is test the hypothesis that urinary renalase can serve as an early and sensitive biomarker for AKI in rodents, and that renalase administration is a useful therapeutic option to treat AKI in rodents. If the proposed studies are successful, future studies (not part of this proposal) will aim to validate renalase as a biomarker of AKI in humans using the TRIBE-AKI database and or similar available databases, and to test the therapeutic utility of recombinant renalase in AKI in humans. PUBLIC HEALTH RELEVANCE: Acute kidney injury (AKI), a clinical condition commonly associated with sepsis, surgery, and certain drugs, affects up to 20% of hospitalized patients and is associated with increased mortality. The development of effective treatment protocols for AKI has been hampered by the fact the diagnosis relies heavily of serum creatinine measurements, and is, therefore, often made 48-72 hours following the original insult. There is a clear and pressing need to identify patients with AKI early, and the best approach is believed to involve the identification biomarkers and their validation in human clinical trials.