Previous studies have shown that chronic kidney disease (CKD) increases the risk of deep vein thrombosis. Thrombosis is the formation of a blood clot, known as a thrombus, within a blood vessel. It prevents blood from flowing normally through the circulatory system. A new study by researchers at Boston University School of Medicine (BUSM) demonstrates a potential signaling pathway and enzyme that will help explain blood clot formation in chronic kidney diseases patients.

Their findings are published in the Journal of the American Society of Nephrology in a paper titled, “Indoleamine 2,3-dioxygenase-1, a Novel Therapeutic Target for Post-Vascular Injury Thrombosis in CKD,” and led by Vipul Chitalia, MD, PhD, associate professor of medicine at BUSM.

“We examined the role of indoleamine 2,3-dioxygenase-1 (IDO-1), a rate-limiting enzyme of kynurenine biogenesis, in CKD-associated thrombosis after vascular injury,” the researchers wrote.

The team observed IDO-1 expression in mice and human vessels. IDO-1−/− mice, IDO-1 inhibitors, an adenine-induced CKD, and carotid artery injury models were used.

“We have shown for the first time that a specific enzymatic pathway is altered in CKD patients. This pathway is regulated by 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,” explained Chitalia.

“Both global IDO-1−/− CKD mice and IDO-1 inhibitor in wild-type CKD mice showed reduced blood Kyn levels, TF expression in their arteries, and thrombogenicity compared with respective controls. Several advanced IDO-1 inhibitors downregulated TF expression in primary human aortic vascular smooth muscle cells specifically in response to uremic serum,” noted the researchers.

According to the team, the current FDA-approved antithrombotics do not work efficiently in CKD patients as they fail to target CKD-specific pathways. Moreover, these agents predispose patients to a 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.

“Leveraging genetic and pharmacologic manipulation in experimental models and data from human studies implicate [indoxyl sulfate] (IS) as an inducer of IDO-1 and a perpetuator of the thrombotic milieu and supports IDO-1 as an antithrombotic target in CKD,” concluded the researchers.

The researchers hope that IDO-1 inhibitors can be repurposed to prevent thrombotic complications in CKD patients.

Previous articleGastrointestinal Infections Trigger Protection of Gut Neurons from Subsequent Assault
Next articleAI Merged with Electrical Brain Stimulation Improves Human Brain Function