Kidneys remove waste products from the blood. If a person experiences acute failure in both kidneys, the resulting accumulation of waste can kill the patient in days. Although it doesn’t act as quickly, chronic kidney disease (CKD), in which the kidneys function less than optimally, can be just as fatal. Over time, heightened levels of waste circulating in a person’s bloodstream can cause cardiovascular disease and heart failure. But recently, a team of researchers sought to break the deadly link between CKD and cardiovascular disease. Their results, published in Science Translational Medicine, suggest that blocking an inflammation-inducing protein could be the key (1).
The dual nature of cardiovascular disease within CKD attracted Ana Maria Amaya Garrido, a molecular biologist currently at Institut des Maladies Métaboliques et Cardiovasculaires, to the project. While completing a master’s degree in biochemistry, she realized that she wanted her PhD research to lead directly to life-saving drugs. She just wasn’t sure which disease she wanted to focus on. “I was searching on the internet: different drugs, different diseases, epidemiological data,” she said. CKD caught her eye because the leading cause of death for patients with the condition is actually cardiovascular disease. “So, I said, ‘Okay, if I start in this field, I have two different diseases at the same time,’” she recalled.
Amaya Garrido moved to France to join Inserm’s Renal Fibrosis Lab and began working with pathophysiologist and proteomics specialist Julie Klein. Klein was happy to have another scientist interested in CKD because she wants this major public health burden to garner more attention. Together, the pair began looking for proteins associated with cardiovascular disease in blood samples from patients with CKD in an effort to identify therapeutic targets.
Some of these patients had cardiovascular disease, and some did not. The team compared both groups to see if there were any proteins that the patients expressed at different levels. Calprotectin, a protein well known as an indicator of inflammatory bowel disease, stood out. “I’ve done a lot of proteomics analysis, and I’ve never seen a protein so highly upregulated,” said Klein. “Usually when you do biology, you are always looking at really small things, and this was so big. It was kind of surprising.”
Klein and Amaya Garrido weren’t satisfied with associations, though. They treated mouse aortic rings and cells from human blood vessels with excess calprotectin and confirmed that the protein drove the calcification responsible for cardiovascular disease. Then they inhibited calprotectin with paquinimod, a compound that the FDA has approved as an orphan drug. The scientists showed that the drug prevented calcification in vitro. Finally, they administered paquinimod to mice that had undergone partial kidney removal to approximate the symptoms of CKD. The mice did not develop vascular calcification.
The researchers also administered paquinimod to mice that lacked the gene for ApoE, which helps carry cholesterol through the bloodstream. These mice tend to age quickly and develop atherosclerosis, a condition in which arteries harden because cholesterol-heavy plaque builds up along their inner walls. Atherosclerosis differs significantly from the calcification that occurs in patients with CKD. The blood vessels of these patients don’t develop plaques along their inner walls; instead, the vessel walls harden in the middle. Nevertheless, paquinimod reduced calcification in both mouse models. The results suggest that inhibiting calprotectin could effectively prevent vascular calcification not only in CKD but also more broadly.
The history of nephrology is littered with failures, but we have had several successes of late.
- Rajiv Agarwal, Indiana University School of Medicine
Amaya Garrido and Klein’s work thoroughly impressed Rajiv Agarwal, an Indiana University School of Medicine nephrologist who was not involved in the study. Now he’s curious to see what comes next. He said, “They’ve gone from patients to rodents. The only thing that’s missing is from rodents back to patients.”
Klein would love to see if paquinimod could save human lives, but she’s encountered a few roadblocks. For one, she’s not a clinician, and she’d need to work with someone who has that expertise. Her group has reached out to the company that owns paquinimod, but she hasn’t heard back. In the meantime, Klein would like to continue basic research on calprotectin, but it’s hard for her to get enough of the protein to run more tests. “Calprotectin is very expensive,” she said.
Agarwal, though, is enthusiastic about the continuation of this work. He thinks that these initial results indicate a brightening future for patients with kidney disease. “The history of nephrology is littered with failures, but we have had several successes of late,” said Agarwal. “This looks like a real, real positive study to me.”
References
- Amaya-Garrido, A. et al. Calprotectin is a contributor to and potential therapeutic target for vascular calcification in chronic kidney disease. Sci Transl Med 15, eabn5939 (2023).
