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Uremic Toxins, a consequence of CKD, as key mediators of CKM-associated PAD

Award Number: K01DK146245
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 08/13/2026
PERIOD OF PERFORMANCE END DATE: 08/01/2031

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Uremic Toxins, a consequence of CKD, as key mediators of CKM-associated PAD - PROJECT SUMMARY/ABSTRACT Chronic kidney disease (CKD) affects 30 million Americans and increases the risk of cardiovascular disease (CVD). CVD and CKD are recognized through their intertwined biological, metabolic, and social risk factors–as the “Cardiovascular-Kidney-Metabolic (CKM) Syndrome.” CVD in CKM is characterized by early onset and premature mortality at a relatively higher glomerular filtration rate. A vast majority of U.S. adults have CKM stage 1 or higher, and 15% have advanced CKM stages. CKM is characterized by complications such as heart failure, myocardial infarction, and peripheral artery disease (PAD). PAD is also a public health problem; its combination with CKD results in a strikingly higher risk of adverse outcomes, such as gangrene. Despite CKM's profound implications, its pathogenic mediators remain elusive and, therefore, worthy of investigation. This proposal examines the role of solutes retained as a consequence of CKD as potential CKM mediators. CKD is characterized by the retention of a host of solutes termed uremic toxins, of which protein- derived uremic toxins are highly vasculotoxic. Our lab and others have uncovered the cardiovascular toxicity of tryptophan-derived uremic toxins, of which kynurenine is a potent pro-thrombotic, pro-inflammatory, and anti- angiogenic factor and imparted the highest risk for adverse limb events in human patients. The metabolites of Kynurenine also exert independent vasculotoxicity. This proposal comprehensively examines the role of tryptophan-derived uremic toxins and the enzymes responsible for their biogenesis in CKM. Aim 1 will examine endothelial functions in the presence of specific uremic toxins. The cells will be genetically engineered to change the levels of enzymes responsible for the generation of these toxins. Inhibitors of these enzymes will be employed. The effect of specific uremic toxins and their enzymes will be assessed on fundamental endothelial functions. Aim 2 represents the in vivo counterpart of Aim 1, where mice with the loss of activity of enzymes responsible for the biogenesis of these toxins will be subjected to the PAD model. An array of structural and functional assays will be performed to investigate the specific effect of enzymes on PAD progression and its impact on angiogenesis. Aim 3 will leverage the data from a longitudinal cohort of CKD patients where the toxin levels are determined by the onset of PAD or its complications. A risk model will be generated specifically to examine the contribution of uremic toxins in the risk of PAD progression along with other cardiometabolic covariates. The project will be spearheaded by PI, a vascular surgeon by training who is deeply passionate about translational science. The PI will be supported by an experienced mentoring team of established investigators to ensure the execution and timely completion of the project. The completion of the project will deepen uremic biology and uncover the role of specific uremic toxins in CKM pathogenesis, which can be leveraged in the future for biomarker discovery or to develop a therapeutic target.


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 = $152,777 )
2026	2026	BOSTON MEDICAL CENTER CORPORATION	1 BOSTON MEDICAL CTR PL	BOSTON	MA	02118	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	8/13/2026	NEW	$152,777
														Subtotal = $152,777

Grand Total All Awards = $152,777

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Uremic Toxins, a consequence of CKD, as key mediators of CKM-associated PAD

Award Number: K01DK146245

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 08/13/2026

PERIOD OF PERFORMANCE END DATE: 08/01/2031

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