ABSTRACT In the last 2 decades, the all-age death rate from chronic kidney disease (CKD) has nearly doubled, and its all- age prevalence increased by 30% to 700 million people world-wide. Most of these deaths are related to cardiovascular diseases, including thrombotic cardiovascular events. Cardiovascular risk increases as the severity of CKD increases (i.e., declining glomerular filtration rate [GFR]). Potential mechanisms underlying this high cardiovascular risk include increased inflammation and platelet activation. Coinciding with this increased cardiovascular risk is heightened inflammation, one of the hallmarks of the CKD state. The simplest model to account for thrombosis and inflammation in the CKD patient is one in which platelets drive inflammation and thrombosis. Platelet microparticles are small vesicles released during platelet activation and play a significant role in driving inflammation. We have observed platelet P2Y12 receptor-dependent inflammation in patients with CKD that was modifiable with a P2Y12 antagonist. Specifically, we found that ticagrelor, a potent platelet P2Y12 antagonist, decreased inflammation in CKD patients. Because our pilot clinical study did not demonstrate mechanisms for how platelets modulate leukocyte phenotype in CKD patients, we now propose a mechanistic study to investigate if P2Y12 antagonism alters release of platelet microparticles that could potentially explain its anti-inflammatory response in non-dialysis CKD patients. We will recruit 50 non-dialysis CKD patients with GFR <45 (±P2Y12 antagonist) and 25 matched controls with normal kidney function (total N=75) to compare release of platelet microparticles. We hypothesize that P2Y12 receptor antagonism will alter release of platelet microparticles in CKD patients. We will also use bulk RNA sequencing of leukocytes and proteomics of platelet microparticles to determine if P2Y12 antagonism alters protein expression of platelet microparticles or leukocyte gene expression in CKD patients to resemble that of controls with normal kidney function. We hypothesize that P2Y12 receptor antagonism with ticagrelor will inhibit platelets and alter protein expression of platelet microparticles, resulting in favorable reprogramming of leukocyte gene expression. Finally, preclinical studies in mouse models will examine the direct effects of platelets deficient in releasing platelet microparticles (± CKD) on normal leukocyte function. If P2Y12 antagonism reduces the inflammatory burden of CKD by altering release of platelet microparticles that results in reprogramming of leukocytes, it will lay the groundwork for studying the anti-inflammatory effect of P2Y12 antagonism on CV events in this high- risk patient population. Likewise, platelet microparticle proteome and leukocyte transcriptome data will inform future mechanistic studies to understand CKD pathophysiology. Defining these mechanisms would establish new therapeutic targets with the potential to reduce bot...