Potential new pathway and enzyme responsible for thrombosis in CKD identified in new study

Patients with chronic kidney disease (CKD) are at a higher risk of clotting (thrombosis) than patients with normal kidney function after vascular procedures. This complication predisposes them to potentially fatal events such as myocardial ischemia (heart failure). Over the past decade, researchers from Boston University School of Medicine (BUSM) have discovered metabolites (uremic solutes/toxins) in the blood of patients with CKD as potent drivers of thrombosis. Now in a new study, these same researchers have discovered an important mediator of thrombosis in these patients.

"We have shown for the first time that a specific enzymatic pathway is altered in CKD patients. This pathway is regulated by an enzyme called Indoleamine 2,3-dioxygenase (IDO), which converts tryptophan amino acid to kynurenine, a potent pro-thrombotic metabolite in CKD patients. IDO1 can now be targeted as a potential treatment option," explains corresponding author Vipul Chitalia, MD, PhD, associate professor of medicine at BUSM.

According to the researchers, the current FDA approved antithrombotic do not work efficiently in CKD patients as they fail to target CKD-specific pathways. Moreover, these agents predispose patients at the higher risk of bleeding. "Therefore, a safe and effective antithrombotic for CKD patients is imminent. Addressing this huge unmet clinical need, our study defines a novel therapeutic target for heightened risk of thrombosis in CKD patients," said Chitalia.

While IDO-1 inhibitors are in clinical trials for other conditions, the researchers hope that they can be repurposed to prevent thrombotic complications in CKD patients.

These findings appear online in the Journal of the American Society of Nephrology.

This work was funded in part by the National Cancer Institute R01CA175382, NIH R01 HL132325 and Evans Faculty Merit award (to V. Chitalia), NHLBI R01HL136363 and NIH R01HL080442 (to K. Ravid), American Heart Association CAT-HD Center grant # 857078 (VCC and SL), T32 training grant in cardiovascular biology T32 HL007224-40 (to J. Walker), T32 training grant in immunobiology of trauma T32 GM086308-06A1 (to N. Arinze), and the Thrombosis to Hemostasis in Health and Disease Affinity Research Collaborative (Boston University, Evans Center For Interdisciplinary Biomedical Research).