Dimensions of Kidney Tubule Health and Atherosclerotic Cardiovascular Disease and Heart Failure in Middle-Aged and Older Adults

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ABSTRACT Two clinical measures are currently used to stage chronic kidney disease (CKD), the estimated glomerular filtration rate (eGFR) and urine albumin-to-creatinine ratio (ACR). The elevated morbidity and mortality risk that is experienced by persons with CKD is overwhelmingly a result of progressive atherosclerotic cardiovascular disease (ASCVD) and heart failure (HF) rather than kidney failure. Unfortunately, eGFR and ACR inadequately depict the kidney’s complexity because they represent glomerular function and injury respectively; yet the kidney is predominantly comprised of tubules, and the kidney tubules are responsible for myriad homeostatic functions that likely have more direct influence on the cardiovascular system than does damage to the glomerulus. Moreover, pathology studies have convincingly demonstrated that tubule damage is more prognostic for loss of kidney function than glomerular scarring. Novel urine measures that quantify the health of the kidney tubules have recently allowed us to define four additional dimensions of kidney health that independently influence risk for progressive CKD: proximal tubule injury, proximal tubule function, tubule fibrosis and repair, and tubule synthetic function. Our team has selected eight distinct urine measures that capture each of these four dimensions and comprise the Kidney Tubule Health Panel (KTHP). In specific, high-risk populations, the KTHP dimensions are strongly associated with risk for ASCVD, HF and mortality; but no studies have evaluated the contributions of kidney tubule health to the development of ASCVD and HF in the general population. Our global hypothesis is that kidney tubule damage and dysfunction are related to the onset and progression of ASCVD and HF. Within two well-established, general population cohorts, CARDIA and MESA, this proposal will address the following research questions that are critical to understanding the development of each dimension of kidney tubule disease and their role in promoting ASCVD and HF: 1) Does kidney tubule disease develop earlier and progress faster with advancing age than ACR and eGFR? 2) Is kidney tubule disease more severe in Black and Hispanic persons compared with White persons? 3) Which atherosclerotic risk factors have the strongest associations with each dimension of kidney tubule disease? 4) How strongly associated is kidney tubule disease with several subclinical CVD measures? 5) How strongly associated are kidney tubule disease markers with ASCVD and HF, and do they improve prediction of these endpoints? If these Aims are successful, these easily measured, non-invasive indices of kidney tubule health may have value for population screening, to provide insights into race/ethnic differences in kidney and cardiovascular disease, and to identifying pathways for novel therapeutics that target kidney tubules, such as the SGLT2 inhibitors and the non-steroidal aldosterone antagonists, that reduce risk for both kidney and cardiovascular adverse outcomes.