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.

Public Health Relevance

Acute Kidney Injury (AKI) occurs commonly in HIV-infected individuals and has a huge impact on morbidity and mortality in these patients. In this proposal, we examine the association of novel urinary biomarkers with the risk of AKI and subsequent kidney disease progression and develop a predictive model that includes a panel of urinary biomarkers that discerns AKI risk and predicts subsequent long-term kidney function. This tool could ultimately be used to identify patients at greatest risk of AKI and its complications and lower their risk of AKI and related complications.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK103574-02
Application #
9099842
Study Section
AIDS Clinical Studies and Epidemiology Study Section (ACE)
Program Officer
Kimmel, Paul
Project Start
2015-07-01
Project End
2020-06-30
Budget Start
2016-07-01
Budget End
2017-06-30
Support Year
2
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21205
Chen, Teresa K; Appel, Lawrence J; Grams, Morgan E et al. (2017) APOL1 Risk Variants and Cardiovascular Disease: Results From the AASK (African American Study of Kidney Disease and Hypertension). Arterioscler Thromb Vasc Biol 37:1765-1769
Corona-Villalobos, Celia P; Shlipak, Michael G; Tin, Adrienne et al. (2017) Predictors of Acute Renal Injury Study (PARIS) among HIV-positive individuals: design and methods. BMC Nephrol 18:289
Chen, Teresa K; Tin, Adrienne; Peralta, Carmen A et al. (2017) APOL1 Risk Variants, Incident Proteinuria, and Subsequent eGFR Decline in Blacks with Hypertension-Attributed CKD. Clin J Am Soc Nephrol 12:1771-1777
Chen, Teresa K; Estrella, Michelle M (2016) APOL1 risk variants and death among African American hemodialysis patients: survival of the fittest? Kidney Int 90:249-252
Chen, Teresa K; Estrella, Michelle M; Parekh, Rulan S (2016) The evolving science of apolipoprotein-L1 and kidney disease. Curr Opin Nephrol Hypertens 25:217-25