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.
