Chronic kidney disease (CKD) confers increased risk for cardiovascular disease (CVD). Targeting traditional CVD risk factors has not significantly improved outcomes in the CKD population, underscoring the need for improved understanding and identification of early risk factors amenable to treatment in the CKD population. Rigorous studies in animal models now support a role for T cells in the pathogenesis of heart failure induced by pressure overload and CKD. In addition, there is are several observational studies that demonstrate signs of repeated activation and altered function of T cells isolated from patients with advanced CKD. Children with CKD also accumulate T cells with altered surface expression of important co-signaling pathways, namely the gain of CD57 and the downregulation of CD28, which predict decreased reliance on co- signaling checkpoints for activation and suggest increased pro-inflammatory potential. Furthermore, preliminary data demonstrates an association between diastolic function and expression of CD57 or CD28 on T cells isolated from children with CKD. The overarching hypothesis for this proposal is that the uremic state alters T cell activity contributing to early cardiovascular remodeling. The experiments outlined in this proposal for a Pilot and Feasibility Clinical Research Grant in Kidney Diseases (R21) will test the hypothesis that T cell expression patterns of co-stimulatory/co-inhibitory pathways are associated with subclinical cardiac and vascular dysfunction during CKD. The study combines in-depth assessment for subclinical CVD with high-dimensional T cell phenotyping in pediatric CKD patients who lack confounding comorbidities often present in adults. A total of 40 children with advanced CKD (GFR < 30 mL/min/1.73m2) and 20 age- and gender-matched healthy controls will be recruited. T cell expression of CD57 (CD57+) and CD28 (CD28null) will be measured by flow cytometry. Clinically-acquired echocardiograms will be evaluated for diastolic function and novel measures of subclinical ventricular dysfunction (global longitudinal strain) to evaluate for associations between T cell expression of CD57 and CD28 with myocardial dysfunction. Carotid intimal media thickness (cIMT), pulse wave velocity (PWV) and flow-mediated dilation (FMD) studies will be performed in the same recruited subjects with CKD to interrogate the relationships between arterial thickening, arterial stiffness, and endothelial dysfunction, respectively, and T cell expression of CD57 and CD28. Finally, unsupervised clustering algorithms for high-dimensional flow cytometry data (SPADE, viSNE, and Citrus) will identify expression patterns of additional co-stimulatory and co-inhibitory receptors on CD57+ and CD28null T cells in CKD patients to provide insight into their functional capacity and identify potential future immunomodulatory strategies. Additional novel T cell populations will be identified in children with CKD compared to healthy controls, and their frequencies evaluated for associations with the cardiovascular measures. Data collected will establish premise for expanded translational and basic science studies.

Public Health Relevance

Chronic kidney disease (CKD) causes early death from a type of heart failure due to a thickened and stiff heart. Blood vessels can also be thickened and stiff during CKD. Our project is trying to better understand what risk factors for thickening and stiffening of the heart and blood vessels during CKD to find new ways of treating and preventing death from this type of heart failure. Our research focuses on how a particular type of immune cell, called the T cell, is affecting the health of the heart and blood vessels during CKD.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21DK123616-01
Application #
9877558
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Mendley, Susan Ruth
Project Start
2020-05-15
Project End
2022-02-28
Budget Start
2020-05-15
Budget End
2021-02-28
Support Year
1
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Emory University
Department
Neurology
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322