Biomarkers of Kidney Injury to Predict AKI Onset and Progression in HIV Infection

点击翻译按钮获取中文摘要

 DESCRIPTION (provided by applicant): Acute kidney injury (AKI) is extremely common among HIV-infected individuals, affecting 1 in 6 patients. AKI substantially increases the risk for cardiovascular disease, end-stage renal disease and mortality among HIV-infected persons. To address the disproportionate risk of AKI and its adverse consequences in the HIV- infected population, strategies are needed to identify patients at highest risk of AKI and its consequences. These methods need to be tailored for HIV-infected persons as their risk factors for AKI and progressive kidney disease are distinct from the general population. Interventions for AKI have failed, however, in part due to the reliance for AKI diagnosis on serum creatinine which rises only after substantial kidney damage has already occurred. Despite the promise of novel urine biomarkers for early AKI diagnosis, at present, their clinical application is considerably hampered by the techniques currently used to measure them which are slow, have constrained detectable ranges, and measure biomarkers in isolation. The Johns Hopkins HIV Clinical Cohort (JHHCC) represents a unique opportunity to examine the associations of novel kidney injury biomarkers with AKI and related adverse health outcomes in the HIV- infected population. The JHHCC has a well-characterized population of HIV-infected patients and a highly integrated system that enables the collection of ambulatory and inpatient data as well as biospecimens which are imperative in the study of AKI. In this proposal, we will leverage the extensive resources within the JHHCC to achieve the following Aims: 1) to determine the association of ambulatory kidney damage with incident hospitalized clinical AKI and progressive kidney disease after AKI; 2) to investigate the prevalence of subclinical and clinical AKI among hospitalized HIV-infected individuals and their associations with progressive kidney disease after hospitalization; and 3) to develop and validate a predictive model which integrates a multiplex panel of complementary, informative urine biomarkers and clinical variables that will distinguish risk for incident AKI and subsequent progressive kidney disease. We will measure urine biomarkers of kidney endothelial and tubulointerstitial injury, inflammation and fibrosis at ambulatory visits and serially during hospitalizations in Aims 1 and 2. We will then utilize the observed associations in Aims 1 and 2 to guide the development of a clinically adaptable multiplex panel of urine biomarkers. This panel will be combined with clinical variables to develop a model that distinguishes the risk of AKI and subsequent kidney disease progression among HIV-infected persons. This study will greatly enhance our understanding of subclinical and clinical AKI and their contribution to adverse health outcomes among HIV-infected persons. Our study will yield a predictive model which incorporates the multiplex HIV-AKI Risk Panel which could then be tested as a screening tool in clinical trials comparing early management of AKI or intensive management after AKI with the current standards of care as well as a surrogate endpoint for early phase therapeutic candidates for AKI.