Kidney Tubular Damage and Dysfunction Identify a Novel Axis of Chronic Kidney Disease
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PROJECT SUMMARY For over 50 years, clinicians have relied upon serum creatinine and albuminuria as the sole biomarkers to measure and monitor kidney health. These measures primarily mark the glomerular filtration rate (GFR) and glomerular damage, yet the kidney tubules are responsible for a myriad of functions critical to life, including toxin secretion, nutrient reabsorption, acid/base control, and immune defense. Currently, clinicians cannot evaluate tubule health except in rare instances when kidney biopsies are obtained. In our parent grant, R01DK098234, an ancillary study in the landmark Systolic Blood Pressure Intervention Trial (SPRINT), we found that non-invasive biomarkers that characterize health of the kidney tubules predict CKD progression and cardiovascular disease events, independent of creatinine, albuminuria, and other risk factors. We also made an important additional discovery that could challenge current paradigms, and will be a major focus of this renewal application. SPRINT found that while intensive blood pressure lowering reduced cardiovascular events and mortality, it also worsened serum creatinine. Yet, we found that participants in the intensive blood pressure lowering arm appeared to have reduced tubule injury. These findings indicate that rising serum creatinine levels in this setting typically reflect hemodynamic accommodation rather than intrinsic kidney injury; yet the concern for kidney damage in clinical care prevents many individuals from receiving life-extending, optimal hypertension treatment. Building on our successes in unlocking the prognostic potential of the kidney tubules in the parent grant, this renewal has the objective of building a Kidney Tubule Health Panel (KTHP) that can be applied to individual patients for eventual translation to clinical care. Our three major goals are: a) prediction of progressive CKD; b) prediction of cardiovascular disease; and c) differentiation of intrinsic tubule damage from benign hemodynamic accommodation within individuals who develop rising creatinine levels. To accomplish these prediction goals, we must explore several additional critical functions of the kidney tubules, including toxin secretion and ammonia production; and, we must explore more sensitive measures of kidney tubule injury, including biomarkers measured in blood as well as urine. We will evaluate, compare, and combine these new measures with existing measures from the parent award to identify a parsimonious set of measures that maximally achieves each of the afore-mentioned prediction goals, utilizing latent variable approaches to develop distinct and physiologically relevant axes of kidney tubule health that will comprise the KTHP. The KTHP will then be measured, evaluated and validated in the community-based Nord-TrØndelag Health (HUNT) Study and the Norwegian Kidney Biopsy Registry. This comprehensive work will allow us to advance the KTHP as a novel and useful clinical tool to improve prediction in CKD and to maximize adherence to life-saving therapies, moving beyond kidney measures that are exclusively glomerular focused.
