Protein Shows Promise for Anticoagulation in Chronic Kidney Disease

Physicians who treat patients with kidney disease often face a quandary: How to stop blood clots in kidney disease patients without causing bleeding complications. Now, researchers have discovered a protein that, when manipulated, could prevent these patients from developing blood clots, making it a possible alternative to heparin.

“This is in stark contrast to the current standard-of-care for chronic kidney disease (CKD) patients, and really is  groundbreaking work,” said Vipul Chitalia, MD, PhD, an author of the study and Associate Professor of Medicine at Boston University School of Medicine (BUSM). “This is the first report in chronic kidney patients where we can inhibit clotting without increasing the risk of bleeding,” he told Drug Topics.

In the article, published in Science Translational Medicine, Chitalia and his colleagues detailed how they made the discovery. The BUSM researchers developed an experimental model for late-stage kidney disease using animal models as well as samples from human patients.

They narrowed in on a regulatory protein, STUB1, which interacts with a blood vessel wall component called tissue factor (TF) that triggers the clotting cascade. STUB1 belongs to a class of molecules called ubiquitin ligases that tag proteins such as TF to be broken down for recycling. When the researchers boosted levels of STUB1, the amount of TF in mouse models of kidney disease declined, but without causing excessive bleeding.

“Our work establishes a new means of minimizing the uremic hyperthrombotic phenotype without altering the hemostatic balance, a long-sought-after combination in patients with chronic kidney disease,” Chitalia said. “We already identified the protein that regulates the clotting without affecting bleeding. If you manipulate that protein, you are likely to help with clotting without causing bleeding.”

The strategy offers a much-needed treatment alternative to heparin, the current standard of care, “which throws off the finely-tuned balance between pro-clotting and anticoagulant factors in blood vessels that work to keep fluid flowing while protecting against excessive bleeding after injuries,” according to a statement from BUSM.

After success in both animal and human models, the researchers are currently developing STUB1 as a drug, and are seeking pharmaceutical manufacturers to partner with, Chitalia told Drug Topics.

While Chitalia is optimistic about the protein being developed into a drug, he said that drug development could take between 5 and 10 years. “It is important to remember that cellular and murine-based studies require further confirmation in humans,” said co-senior investigator Katya Ravid, DSc, Professor of Medicine and Biochemistry at BUSM.

The study was funded by grants from the National Institutes of Health (NIH) and the Evans Center for Interdisciplinary Biomedical Research ARC on Thrombosis at Boston University.