ABSTRACT Our strategies for preventing, detecting, and monitoring kidney disease in people living with HIV (PLWH) have lagged far behind the incredible advances in HIV treatment and management over the past decades. Despite their proven limitations for diagnosing chronic kidney disease (CKD), the serum creatinine and the urine protein concentration remain the mainstays of kidney health monitoring for PLWH. While clinical kidney diagnostic testing has stagnated, PLWH face an increasing myriad of insults to the kidneys, including metabolic and vascular risk factors, chronic inflammation, direct viral toxicity, and potentially nephrotoxic medications. Consequently, CKD has accelerated as a cause of morbidity and mortality in PLWH. Over the past decade, our pioneering work in PLWH has shown that biomarkers of tubule health yield significantly more diagnostic and prognostic information than could be obtained by conventional kidney health assessments. This competitive renewal application will build upon this prior work to fulfill our mission of fundamentally changing how kidney disease is detected, diagnosed and monitored. This proposal strategically addresses the most challenging aspects of CKD diagnosis and treatment, and will provide the evidence needed to advance kidney biomarker-based diagnostic algorithms into clinical practice. Successful completion and clinical translation of our Aims will allow clinicians to achieve the following major goals. 1) Among PLWH with acute elevations of the serum creatinine, we will be able to distinguish whether or not the individual has true kidney injury and to identify the patterns of injury that forecast the likelihood of kidney function recovering or worsening during subsequent follow-up (Aim 1). 2) For each modifiable kidney disease risk factor in PLWH, we will be able to monitor the impact of improvements and deteriorations in risk factor control on the kidney, using a tailored set of surrogate biomarkers (Aim 2a). 3) We will use a time- updated algorithm that will integrate dynamic changes in risk factors and kidney biomarkers to prognosticate longitudinal changes in risk for rapidly progressive kidney disease, for each individual PLWH (Aim 2b). 4) For the many PLWH with myriad exposures that threaten or lower risk for progressive kidney disease, we will utilize a novel biomarker-based monitoring algorithm to identify and prioritize each risk factor based on its Bayesian probability of causing the observed pattern and severity of kidney damage. Despite these ambitious goals, this proposal is both feasible and efficient as we will use biospecimens and clinical data that have been or will be collected among PLWH in the Multicenter AIDS Cohort Study (MACS), the Women’s Interagency HIV Study (WIHS), the MACS-WIHS Combined Cohort Study (MWCCS), and the Predictors of Acute Renal Injury Study (PARIS) cohorts. The study investigators are a multi-disciplinary team of experts who bring enormous enthusiasm, experience and commitment to the proposal and will guarantee its success.

PROJECT NARRATIVE Kidney disease is increasingly common in people living with HIV infection, but routine clinical tests are insensitive and cannot determine the specific causes. The findings from these projects will help clinicians to monitor kidney health and detect and treat earlier stages of kidney disease, which would allow unique opportunities for individualized prevention and treatment strategies in this high-risk population.