Shared Mechanisms and Markers of Renal Injury and Neurocognitive Impairment in People with HIV

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PROJECT SUMMARY People with HIV (PWH) experience an unusually high burden of chronic, aging-related diseases, which have major impact on functional status and quality of life. Chronic kidney disease (CKD) and neurocognitive impairment (NCI) are two prototype disorders of aging that are frequently encountered in this population and may be linked by a common underlying mechanism. While vascular and metabolic factors, in addition to altered mitochondrial metabolism, chronic inflammation and oxidative stress, are implicated in CKD and NCI, the possibility of shared mechanisms that drive development of multiple such disorders in the same individual has not been sufficiently explored. Altered iron metabolism is a fundamental hallmark of aging that links several important aspects of the aging process - inflammation, reduced mitochondrial function, and oxidative stress - and our team has identified levels of a critically important iron-binding protein (ferritin) subunit as an independent predictor of neurocognitive function in a longitudinal study of NCI in PWH on suppressive therapy. Preliminary data link this protein also to CKD in the same individuals. The newly identified receptor in brain for this protein is also expressed in kidney and doubles as a marker of chronic kidney injury (Kim-1), possibly playing a role in CKD. We therefore propose that an HIV-related shift in the ratio of ferritin subunits may explain several aging phenomena in PWH, due to the critical role of one of the subunits in antioxidant responses, immune-cell function, and mitochondrial energy metabolism. In 324 participants from an observational HIV cohort with a wealth of outcome data and biospecimens, we will measure ferritin subunit levels in serum and urinary Kim-1. Specifically, we plan the following: AIM 1: Evaluate associations between ferritin subunit levels, sensitive markers of oxidative stress, and existing plasma metabolite levels in virologically suppressed PWH; AIM 2: Assess associations between urinary Kim-1 and ferritin subunit levels, and evaluate Kim-1 as a noninvasive marker of NCI; AIM 3: Determine associations of ferritin subunits with prevalent and incident CKD, NCI, and frailty outcomes, which are ascertained in this cohort of middle-aged and older PWH, adjusting for important confounders. Results from this proof-of-concept study could significantly improve our understanding of accentuated aging in PWH, highlighting new markers and targets for intervention.