Role of Kidney Proximal Tubular Secretion in Critical Illness

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PROJECT ABSTRACT Coronavirus disease 2019 (COVID-19) is a global pandemic caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). SARS-CoV-2 has been identified within multiple cell types of the kidneys, including tubular epithelial cells, endothelial cells, and podocytes, suggesting pathologic effects. Early clinical data suggest a greater incidence and severity of acute kidney injury (AKI) in persons who have COVID-19; however, existing studies lack comparisons with similarly ill persons who do not have COVID-19, preventing reliable assessment of the causal impact of SARS-CoV-2 on kidney injury and function. Most underlying causes of AKI involve injury to tubular epithelial cells and their microenvironment. Yet, the prevailing clinical assessment of kidney function in AKI is based on incremental changes in serum creatinine concentrations under the assumption that glomerular filtration and tubular functions are tightly coupled within an individual. To challenge this assumption, our parent NIDDK funded grant, “Role of Kidney Proximal Tubular Secretion in Critical Illness” (R01DK124063, PI Kestenbaum) is recruiting a prospective cohort of critically ill adults without COVID-19, quantifying tubular secretory clearance using a novel assay that we have developed, and determining the impact of this intrinsic kidney function on prognosis and kidney drug dosing. In this supplement, we propose to expand the unique tools of the parent grant to delineate the impact of SARS- CoV-2 on the kidney tubules. To accomplish this goal, we will comprehensively characterize kidney tubular functions in the Covid-19 Host Response and Outcomes (CHROME) study, an ongoing prospective study of critically ill persons with COVID-19 that includes a comparison group of similarly ill persons without COVID-19. To our existing measurements of tubular secretory clearance, we will add markers of tubular synthesis, distal tubular viability, and tubular injury. We will test whether COVID-19 is associated with changes in these tubular processes over the course of hospitalization and with persistent kidney dysfunction at 30-day follow-up.