Discriminating Causes of Creatinine Change in Acute Heart Failure

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This is a resubmission of a Career Development Award (CDA) application by Dr. Nicholas Wettersten, mentored by Dr. Joachim Ix at the VA San Diego Health System (VASDHS). Through this proposal Dr. Wettersten intends to establish himself as an independent investigator studying acute heart failure (AHF), cardiorenal syndrome, and biomarkers. Candidate: Dr. Wettersten’s training objectives are designed to parallel his research project and provide skills required to lead an independent VA Merit Award upon completion of his CDA. These include: learning biostatistics for interpretation and analysis of multiple biomarkers concurrently, develop skills for designing and implementing clinical trials, and develop skills for scientific writing and independent lab management. Dr. Wettersten will achieve these objectives through coursework, workshops, and mentorship. His mentorship committee includes Dr. Joachim Ix (primary mentor), an expert in heart-kidney disease interaction, and co- mentors Dr. Kirk Hammond, an expert in clinical trials and translational research at the VASDHS, Dr. Patrick Murray, an expert in acute kidney injury and biomarkers at University College Dublin, and Dr. Florin Vaida, an expert biostatistician at UCSD. Research: AHF accounts for almost 1 million hospitalizations annually with significant morbidity and mortality. Approximately 350,000 Veterans suffer from heart failure with an annual mortality of almost 15%. Periods of AHF are an especially vulnerable period of heightened morbidity and mortality. Up to one-third of AHF patients will experience a rise in serum creatinine (sCr) with diuretics. This rise in sCr could be from true kidney injury or a benign reversible hemodynamic effect. Currently, clinicians have no means to distinguish these scenarios. Recently, a panel of urine kidney biomarkers of injury and dysfunction has been shown to discriminate the rise in sCr with intensive blood pressure lowering as hemodynamic vs. injury. This same process may occur in AHF, but this panel has not been tested in AHF. This proposal will leverage the Acute Kidney Injury N-gal Evaluation of Symptomatic Heart Failure Study (AKINESIS), a well-characterized study of 927 patients presenting with AHF and with repeat urine specimens available during treatment, as well as conduct an observational pilot study from admission into the post-discharge period of AHF patients admitted to the VASD hospital, to address the following specific aims: 1) To determine if admission values of urinary kidney tubule function and injury biomarkers associate with risk of adverse outcomes among AHF patients beyond admission sCr, 2) to determine whether changes in urinary kidney tubule function and injury biomarkers during hospitalization for AHF are more strongly associated with mortality and HF readmission than changes in sCr, and 3) to assess trajectories of urine kidney tubule function and injury biomarkers with changes in patient volume status during hospitalization and the first 30 days after discharge among AHF patients prospectively enrolled at the SDVA hospital. These findings will advance the understanding of renal function in AHF and will lead directly to randomized intervention studies to determine if modifying AHF treatment based on kidney biomarkers may improve re-hospitalizations and other outcomes in AHF patients.