New research sheds light on the potential cause of diabetic kidney disease

New paper describes the existence of a new version of diabetes—innate immune-driven Diabetes Mellitus caused by uPAR-D2D3

For years, researchers have worked to understand why some people with diabetes get kidney disease while others do not. A paper published in today’s edition of Science Translational Medicine may have uncovered the reason: the existence of a new type of diabetes.

In 2022, the Centers for Disease Control and Prevention estimated that 37.3 million Americans had been diagnosed with diabetes, making it one of the world’s most persistent metabolic endocrine illnesses. About a third of patients with diabetes will develop kidney disease in their lifetimes.

“In addition to Type I and Type II Diabetes Mellitus, our paper suggests the existence of a third type,” said Dr. Sanja Sever, an associate professor at Harvard Medical School and a senior corresponding author of the paper. “It’s an innate, immune-driven Diabetes Mellitus caused by a protein known as uPAR-D2D3.”

Researchers found that D2D3, an enzymatic fragment of uPAR, circulates in blood and binds to insulin-producing beta cells in the pancreas, thereby reducing insulin production. It also targets kidney cells which triggers kidney disease.

“We have always wondered why only a third of patients with Diabetes Mellitus get kidney disease,” said Dr. Jochen Reiser, president of the University of Texas Medical Branch and a senior corresponding author of the paper. “Our paper might have an explanation because uPAR-D2D3-driven pancreatic injury comes with kidney disease, harming both organs simultaneously.”

As a renowned physician-scientist, Reiser has been leading the effort to define the implications of uPAR—and its soluble form suPAR—in renal and cardiovascular diseases for more than 20 years.

While circulating suPAR is known to be a kidney disease risk factor, uPAR-D2D3 appears to be the culprit for mainly diabetic kidney disease, said Dr. Ke Zhu, a scientist at Rush University Medical Center in Chicago and one of the study’s lead authors.

“Our findings also indicate that an antibody that blocks the D2D3 protein can rescue the diabetic phenotypes in a novel mouse model, thus, opening a new avenue for drug therapy”,  said Zhu. “This is an astonishing discovery, as it could help in the development of a new treatment that can potentially reverse the damage caused by the uPAR-D2D3 protein, which may be a direct cause for diabetes and chronic kidney disease. These diseases continue to grow at an alarming rate with no new adequate treatments in sight, so this is good news for patients whose diabetes and kidney disease are caused by uPAR-D2D3 protein.”

“Our study posits that the D2D3 protein may serve as a potential therapeutic target,” said Dr. Kamalika Mukherjee, a co-first author of the study at Massachusetts General Hospital and Harvard Medical School.

The findings described in the study could have implications beyond diabetes and kidney disease, said Dr. Salim Hayek, a cardiologist who is the medical director of the University of Michigan Health Frankel Cardiovascular Center Clinics and another lead author of this project.

“This research dives into the notorious nexus of inflammation, diabetes and kidney disease,” said Hayek. “These conditions are strongly linked to cardiovascular disease, and our team has recently identified a role for suPAR in the pathophysiology of cardiovascular disease. Our discovery delineates the strong connections between these conditions and cardiovascular disease—a convergence orchestrated by suPAR. Recognizing suPAR as the common denominator could pave the way for revolutionary therapies that alleviate not just one, but a spectrum of interconnected ailments, fundamentally enhancing the wellbeing and health prospects for countless individuals.”

“Decades  of studies on uPAR and suPAR from us and others have revealed an enormous potential of regulating the interaction between the immune system and the kidney,” said Dr. Changli Wei, a professor at Rush University Medical Center who was part of initial effort to characterize uPAR-D2D3. “It is very exciting and energizing to see suPAR science coming closer to patients with each new study.”

Other contributing authors include and Mehmet M. Altintas from Rush University Medical Center; Agnieszka Collins, Changkyu Gu and Kristin Corapi from Harvard Medical School; Yong Wang from the University of Virginia; Sushrut S. Waikar from Boston University; Antonio C. Bianco from the University of Chicago; Alexander Koch from University Hopsital Aachen in Aachen, Germany; and Frank Tacke from Universitätsmedizin Berlin in Berlin, Germany.