Kidney tubule dysfunction in APOL1 - PROJECT SUMMARY/ABSTRACT Chronic kidney disease (CKD) is common, costly, and strongly associated with increased mortality. Currently, clinicians are limited in their assessment of CKD since the only markers to measure and monitor kidney health are serum creatinine and albuminuria. These traditional markers, however, do not capture functions critical to life done by the kidney tubules, such as nutrient reabsorption and toxin secretion. During my career development award, I made important discoveries identifying the role that tubular markers play in the progression of CKD, risk of acute kidney injury (AKI), and mortality and how to combine biomarkers in summary scores that could increase their utility. In this grant, I seek to advance the current knowledge of APOL1 by exploring a novel axis of tubular biomarkers in this disease to understand the variability in progression better. African Americans have a 2-to-4-fold higher incidence of kidney failure requiring dialysis compared to their White counterparts. This disparity is partly due to APOL1, a gene found among African Ancestry individuals strongly associated with kidney failure. Even though APOL1 increases the CKD), and is present in the kidney tubules, little is known about the role that the tubules play in the progression of kidney disease. The KDIGO Controversies Conference on APOL1 Kidney Disease, held this year, highlighted the importance of evaluating which biomarkers predict the development and progression of APOL1 kidney disease. In preliminary studies, I have found that individuals with APOL1 risk variants are associated with a higher risk of faster kidney function decline. It is essential to understand the role of tubules in the progression of CKD. To that end, I will first expand the panel of markers to more fully capture the myriad biological functions of kidney tubules. Then, since using many biomarkers is not practical in the clinical setting and there is likely overlap in the underlying pathology reflected by these biomarkers, I will use exploratory factor analysis to combine biomarkers of kidney tubule health in urine and plasma and study their role in longitudinal estimated glomerular filtration rate change. Since AKI) is an important driver of CKD, and some studies suggest that people with APOL1 are more vulnerable to AKI, I will evaluate this syndrome in a well-characterized cohort. I will utilize the SPRINT and REGARDS cohorts for these first two aims, which include numerous participants with APOL1 risk variants. Finally, for the first time, I will evaluate the role of tubular biomarkers in interstitial fibrosis and tubular atrophy, the final common pathway of chronic kidney disease, using the Nephrotic Syndrome Study Network and Cure Glomerulopathy, two related longitudinal cohorts with extremely detailed clinical phenotypes, including biopsy data as well as urine and blood samples. Our results in this proposal will identify a novel paradigm of kidney disease progression in APOL1 and set the stage for a clinical trial to evaluate innovative therapies to mitigate or prevent CKD progression among patients with APOL1 risk variants.
