Cause of heart disease spurred by kidney syndrome found, neutralized

by Elizabethe Holland Durando
Cause of heart disease spurred by kidney syndrome found, neutralized
Senior author Keith A. Hruska with other School of Medicine scientists involved in the research. From left, Michael Seifert, MD, Olga Agapova, PhD, Hruska, Toshifumi Sugatani, PhD, DDS, and first author Yifu Fang, MD. Credit: Robert Boston

Chronic kidney disease affects 26 million Americans, but its sufferers are more likely to die of heart disease than kidney problems. However, it hasn't been clear just how kidney disease causes heart disease or what could be done to stop it.

But a new study in mice and people by researchers at Washington University School of Medicine in St. Louis has pinpointed the cause of a kidney-related syndrome also linked to heart disease. Further, they have discovered how to neutralize a protein produced by the kidney that spurs heart disease, illuminating a new approach to tackling health problems brought on by kidney disease.

The findings one day could improve the health and survival rates of those suffering from -mineral bone disorder (CKD-MBD), according to the study's senior author, Keith A. Hruska, MD, a kidney specialist at the School of Medicine.

"We've shown that kidney disease causes diseases of the and heart—and has targets that could be used therapeutically to treat associated heart problems," Hruska said. "And this discovery, serendipitously, shows that antibody-based drugs currently in clinical development potentially could be used to reduce deaths from related heart disease, as well as skeletal and other afflictions caused by CKD-MBD."

The research is available online Feb. 27 in the Journal of the American Society of Nephrology.

CKD-MBD is a common problem in people with kidney disease. In addition to weakening the bones, CKD-MBD shifts hormone levels in the blood, increasing the risk of heart disease.

To understand the link between kidney disease and heart disease, the researchers set out to see and study CKD-MBD at its inception, early in the course of kidney disease. What they found, in mouse models of diabetes with kidney disease, was that with even a very mild kidney injury CKD-MBD would be initiated.

This would happen because as soon as the kidney detected disease or an injury to itself, it would attempt to repair it, behaving much as it does during embryonic development. But in doing so, it would produce and circulate proteins that would harm other parts of the body, including the heart, essentially causing far more harm than good.

For example, the researchers found that kidney injury would spur a surge of the kidney protein Dkk1 in the circulation. Left unchecked, the protein can cause the hardening, or calcifying, of blood vessels, eventually leading to heart disease. But when the scientists neutralized the protein with an antibody, they were surprised to find that problems with blood vessels, including vascular calcification, were prevented.

"Neutralizing Dkk1 with an antibody actually corrects the skeletal and vascular disorders associated with kidney disease," said Hruska, a professor of pediatrics, of medicine and of cell biology and physiology.

The researchers also analyzed levels of Dkk1 in 38 patients with mild kidney disease, finding elevated levels of not only Dkk1 and other related proteins but also of the hormone FGF23, an indicator of heart disease onset. This follows the same pattern as seen in the mouse models, supporting the notion that findings in the laboratory could be applied clinically.

When the authors of the study combined the antibody against Dkk1 with phosphate binders—medications that reduce the absorption of harmful phosphates into a patient's blood—they were able to prevent the increase in FGF23 along with preventing vascular disease.

An antibody to Dkk1 currently is being used in clinical trials for multiple myeloma. Hruska wants to see it developed as a therapeutic to treat the heart and skeletal problems associated with CKD-MBD. And there are other antibodies with similar potential to fight kidney disease, he said.

"The fundamental issue here is that kidney disease directly causes cardiovascular disease through this attempt at trying to repair the injured, diseased kidney," Hruska explained. "And we are hopeful that neutralization of these factors may become a viable therapy for associated with . This could be a significant paradigm shift forward."

More information: Fang Y, Ginsberg C, Seifert M, Agapova O, Sugatani T, Register TC, Freedman BI, Monier-Faugere M, Malluche H, Hruska KA. "CKD-Induced Wingless/Integration1 Inhibitors and Phosphorus Cause the CKD-Mineral and Bone Disorder. "Journal of the American Society of Nephrology. Online Feb. 27, 2014.

add to favorites email to friend print save as pdf

Related Stories

Kidney patients may gain from less salt

Jan 31, 2014

(Medical Xpress)—Reducing salt consumption may help prolong the lives of patients with chronic kidney disease, a study from The University of Queensland study has found

Recommended for you

Ebola reveals shortcomings of African solidarity

16 hours ago

As Africa's leaders meet in Ethiopia to discuss the Ebola crisis, expectations of firm action will be tempered by criticism over the continent's poor record in the early stages of the epidemic.

Second bird flu case confirmed in Canada

Jan 30, 2015

The husband of a Canadian who was diagnosed earlier this week with bird flu after returning from a trip to China has also tested positive for the virus, health officials said Friday.

What exactly is coronavirus?

Jan 30, 2015

The conflicts in Syria and Iraq are straining public health systems and public health efforts meant to prevent and detect the spread of infectious diseases. This is generating a "perfect storm" of conditions for outbreaks. Among the infections raising concern is Middle East Respiratory Syndrome, caused by a type of coronavirus, which emerged in 2012. ...

Scientists find Ebola virus is mutating

Jan 30, 2015

(Medical Xpress)—Researchers working at Institut Pasteur in France have found that the Ebola virus is mutating "a lot" causing concern in the African countries where the virus has killed over eight thous ...

User comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.