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Effect of Platelet Inhibition with Ticagrelor to Reduce Inflammation and Surrogate Cardiovascular Markers in Patients with Chronic Kidney Disease

Award Number: R01HL187306
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/10/2026
PERIOD OF PERFORMANCE END DATE: 07/31/2031

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Effect of Platelet Inhibition with Ticagrelor to Reduce Inflammation and Surrogate Cardiovascular Markers in Patients with Chronic Kidney Disease - PROJECT SUMMARY/ABSTRACT Cardiovascular (CV) events are the leading causes of deaths for patients with chronic kidney disease (CKD). This is concerning because in the last 2 decades, the prevalence of CKD has increased dramatically. This means that more people are prone to devastating CV events, and this CV risk increases with worsening CKD severity despite receiving guideline directed treatments (GDMT). We aim to mitigate residual CV risk in CKD patients, especially those who are not experiencing acute CV events. We hypothesize that in patients with CKD, activation of P2Y12 receptors on platelets triggers leukocytes to release inflammatory cytokines, such as IL-1β, thus contributing to inflammation and residual CV risk. We observed platelet P2Y12 receptor-dependent inflammation in CKD patients. Further, our preliminary data indicate that IL-1β immune pathways are overexpressed in circulating leukocytes of CKD patients despite receiving GDMT; this overexpression correlates with inflammatory burden. Ticagrelor, a platelet P2Y12 antagonist, plus aspirin decreased levels of inflammatory cytokines IL-1β and IL-1α in CKD patients (n = 25) who did not have any CV indication for the drug. Thus, we propose that inflammation in CKD can be managed with ticagrelor monotherapy, thereby reducing residual CV risk in CKD. We propose a large clinical trial to test whether ticagrelor decreases inflammatory cytokines, such as IL-1β, and surrogate risk of CV events in CKD (Aim 1). We will enroll 180 patients with CKD receiving GDMT to determine whether ticagrelor, prescribed in a randomized double-blind placebo-controlled fashion, reduces inflammatory burden, endothelial dysfunction, and albuminuria after 42 days. We predict that ticagrelor monotherapy will reduce serum IL-1β and other cytokines in CKD patients, and this reduction will improve endothelial function and albuminuria. To address the mechanisms of observed drug effect, we will use bulk RNA sequencing to determine how ticagrelor alters leukocyte gene expression in CKD compared with matched controls with normal kidney function (Aim 2.1). We predict that ticagrelor will inhibit platelets, resulting in favorable reprogramming of leukocyte gene expression of immune pathways. We will also perform in vitro studies to test direct effects of ticagrelor- and placebo-treated CKD platelets on secretion of IL- 1β from leukocytes obtained from the matched controls (Aim 2.2). Pathophysiology differs in CKD patients, and these differences may determine patients’ underlying inflammatory burden, residual CV risk and potential treatments to offset it. Aim 1 will reveal CKD subgroups who are strong candidates for ticagrelor to reduce inflammation and surrogate CV risk. Aim 2 will reveal molecular changes to leukocytes that drive inflammation in CKD and are amenable to ticagrelor monotherapy. Doing so will directly inform use of leukocytes from blood samples to identify candidates for ticagrelor in CKD. More broadly, learning these mechanisms would guide new strategies to manage residual CV risk in CKD when there are no treatments to do so.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $700,797 )
2026	2026	UNIVERSITY OF ARKANSAS FOR MEDICAL SCIENCES	4301 W MARKHAM ST	LITTLE ROCK	AR	72205	PULASKI	USA	Cardiovascular Diseases Research	000	1	9/10/2026	NEW	$700,797
														Subtotal = $700,797

Grand Total All Awards = $700,797

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Effect of Platelet Inhibition with Ticagrelor to Reduce Inflammation and Surrogate Cardiovascular Markers in Patients with Chronic Kidney Disease

Award Number: R01HL187306

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/10/2026

PERIOD OF PERFORMANCE END DATE: 07/31/2031

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