Eicosanoids, Chronic Kidney Disease Progression, and Associated Cardiovascular Risk

PROJECT SUMMARY Over 800 million persons worldwide have chronic kidney disease (CKD) and experience a considerable two-to- three-fold excess risk for cardiovascular disease, starting at even the earliest stages of renal dysfunction. As renal disease severity worsens so do the associated cardiovascular outcomes and, unfortunately, standard risk

reducing therapies become less effective or even harmful. Accumulating data suggest that systemic inflammation is a central mechanistic trigger and driver of renal-related cardiovascular pathobiology, from the earliest through the most advanced stages of renal dysfunction. The upstream initiation of systemic inflammation in humans is

governed primarily by small molecule derivatives of polyunsaturated fatty acid metabolism, termed eicosanoids. These bioactive lipid effectors of both pro- and anti-inflammatory activity include leukotrienes, lipoxins, and prostaglandins. To date, the interaction between eicosanoid pathways, CKD phenotypes, and cardiovascular

outcomes remain poorly understood. This proposal aims to provide a more detailed understanding of how upstream eicosanoid pathways can be variably active, imbalanced, and perturbed in relation to an individual’s propensity for developing not only progressive CKD but, importantly, renal-related adverse cardiovascular

outcomes. Advanced mass spectrometry methods now allow for the rapid and accurate quantification of hundreds of upstream eicosanoid mediators representing multiple enzymatic origins. We will use these methods to test our hypotheses that (i) certain identifiable eicosanoid pathways underlie the development of CKD and

associated cardiovascular risk starting at the earliest stages of disease progression, (ii) perturbed eicosanoid activity also contributes to excess cardiovascular risk in the more advanced stages of CKD, and (iii) certain eicosanoids can be identified as intervenable mechanistic triggers of cardio-renal pathobiology and, if validated,

may later serve as therapeutic targets. We propose a systematic approach to comprehensively investigating the components of upstream inflammatory activity in relation to outcomes across the spectrum of chronic renal disease related cardiovascular risk. This work will pave the way for follow-up studies investigating the efficacy of

anti-inflammatory therapies, including both existing and novel agents, for modulating variation in distinct eicosanoids and, in turn, cardiorenal outcomes.