When Kidneys Fail, The Heart Pays The Price, Scientists Explain Why

Why do more than half of patients with chronic kidney disease (CKD) ultimately die of heart problems? Scientists may now have an answer. New research suggests that diseased kidneys release substances into the bloodstream that directly poison the heart, offering a breakthrough explanation for the long-observed but poorly understood link between kidney failure and cardiovascular death.

The researchers, at UVA Health and Mount Sinai, say the discovery could let doctors identify people at risk and develop new treatments to help prevent and treat heart failure for these patients.

“Kidney and heart disease can develop silently, so they are often discovered only after damage has already been done,” said researcher Uta Erdbrugger, an internal medicine physician-scientist with the University of Virginia School of Medicine’s Division of Nephrology. “Our findings can help to identify patients at risk for heart failure earlier, enabling earlier treatment and improved outcomes.”

Cardiovascular disease causes over 50% of deaths in patients with CKD. The study holds importance in the context of India, which had the second-highest number of people with CKD in 2023 at 138 million, following China at 152 million, according to a global study published in The Lancet journal.

The link between chronic kidney disease (CKD) and cardiovascular problems has been well documented, with the severity of cardiovascular disease correlating directly with CKD. But scientists have struggled to understand why, partly because shared risk factors such as obesity and hypertension muddy the waters when it comes to determining cause and effect.

Scientists had, until now, been unable to pinpoint any kidney-specific risk factor that could be causing toxicity in the heart. But the new research from Erdbrugger and colleagues identifies a culprit: particles called “circulating extracellular vesicles” produced in diseased kidneys.

Extracellular vesicles are produced by almost all cells and serve as important messengers by carrying proteins and other materials to other cells. But the extracellular vesicles produced in kidneys with CKD carry small, non-coding RNA called miRNA that are toxic to the heart, the researchers determined.

In lab mice, blocking the extracellular vesicles from circulating significantly improved heart function and alleviated heart failure. The scientists also looked at blood plasma samples donated by patients with CKD and by healthy patients, and confirmed the presence of harmful extracellular vesicles in the CKD patients.

“Doctors always wondered how organs such as the kidney and heart communicate with each other. We show that EVs from the kidney can travel to the heart and be toxic,” Erdbrugger said. “We are just at the beginning to understand this communication.” The findings are published in the scientific journal Circulation.

The results, said Erdbrügger, suggest that scientists may be able to develop a blood test to identify CKD patients at high risk for serious heart problems. They also may be able to target the circulating extracellular vesicles to treat or prevent the poisonous effects on the heart.

“Our hope is to develop novel biomarkers and treatment options for our kidney patients at risk for heart disease,” she said. “Potentially our work will improve precision medicine for CKD and Heart failure patients, so that each patient gets the exact treatment they need.”

The research team also consisted of Xisheng Li, Nikhil Raisinghani, Alex Gallinat, Carlos G. Santos-Gallego, Shihong Zhang, Sabrina La Salvia, Seonghun Yoon, Hayrettin Yavuz, Anh Phan, Alan Shao, Michael Harding, David Sachs, Carol Levy, Navneet Dogra, Rupangi Vasavada, Nicole Dubois, and Susmita Sahoo.