Study links oxalate to systemic inflammation and heart damage

Oxalic acid might do more than just contribute to the formation of kidney stones — it may also be an underappreciated driver of inflammation and heart damage in people with impaired kidney function. Researchers from Berlin and Würzburg report their findings in ​“Cardiovascular Research.”

People with chronic kidney disease (CKD) have a significantly increased risk of dying from cardiovascular disease. They also suffer from chronic inflammation, the causes of which are still only partly understood. Oxalic acid (oxalate) has so far been known primarily for its role in the formation of kidney stones. The molecule is a natural metabolic by-product of the body, is found in certain foods, and is normally excreted by the kidneys in urine. However, when kidney function is impaired, oxalate accumulates in the body and can promote inflammatory processes.

The Experimental Biomedicine II department at Würzburg University Hospital (UKW), together with the Experimental and Clinical Research Center (ECRC), a joint institution of Charité – Universitätsmedizin Berlin and the Max Delbrück Center, investigated the immunological mechanisms linking oxalate-induced kidney damage with systemic inflammation and cardiovascular injury.

"In our research project, an oxalate-enriched diet activated the immune system systemically in mice. In other words, inflammatory processes spread throughout the body. This led not only to kidney damage, but also to pathological changes in the heart that reduced cardiac function," says Dr. Hendrik Bartolomaeus. The scientist, who is part of Professor Alma Zernecke-Madsen's team at UKW, shares senior authorship of the study with Dr. Nicola Wilck of ECRC. The study was published in "Cardiovascular Research." Bartolomaeus previously worked in Wilck's laboratory.

More oxalate, more pro-inflammatory immune cells

The team identified the cytokine interleukin-17A (IL-17A) as a key factor. IL-17A is produced by certain immune cells and can amplify inflammation. The researchers found that oxalate promoted IL-17A production and disrupted the energy metabolism of immune cells. Elevated IL-17A levels were also detected in patients with the rare inherited metabolic disorder primary hyperoxaluria, in which enzyme defects cause the liver to produce too much oxalate.

The team also investigated what happens when IL-17A is specifically blocked. "In the animal model, several signs of disease improved simultaneously," says Wilck. "The mice's kidneys functioned better, inflammation and fibrosis declined, and heart damage was reduced. We therefore describe a potentially therapeutically targetable axis: oxalate–IL-17A–cardiorenal injury." The study thus mechanistically links elevated oxalate levels with IL-17A-mediated inflammation, cellular metabolism, and cardiorenal organ damage.

Overall, our results show that oxalate not only damages the kidneys, but also contributes to cardiovascular disease through IL-17A and inflammatory processes. Oxalate can therefore no longer be viewed solely as a crystal-forming substance that locally damages the kidneys. Rather, it represents a systemic burden on the immune system and metabolism."

Moritz Wimmer first author, ECRC

New prospects for anti-inflammatory therapies

Clinically, this means that elevated oxalate levels may not only burden the kidneys, but also directly affect the cardiovascular system through inflammatory processes. The work could therefore help identify kidney disease patients at particularly high cardiovascular risk, enable more targeted interpretation of biomarkers, and support the development of new anti-inflammatory therapeutic strategies.

What comes next? Co-authors Professor Felix Knauf and his team at Charité – Universitätsmedizin Berlin and the Mayo Clinic have already shown in large patient cohorts that oxalate levels are often elevated in people with impaired kidney function. High oxalate levels were also associated with an increased risk of cardiovascular complications.

The researchers now plan to investigate whether the inflammatory mechanisms they identified can also be detected in larger cohorts of patients with CKD. They are analyzing data on systemic inflammation, CKD progression, and cardiovascular complications. "A key question will be to what extent the observed IL-17A-mediated inflammatory axis is specific to oxalate. Similar mechanisms may also contribute to cardiovascular damage in other causes of kidney disease," says Bartolomaeus.

 Wilck adds: "In the long term, we want to better understand which inflammatory pathways in chronically damaged kidneys can be targeted therapeutically and which patients are most likely to benefit."

The project was funded by the German Research Foundation (DFG) through Collaborative Research Centers (SFB) 1365 "Renoprotection" and SFB 1470 "HFpEF", and by the German Federal Ministry for Research, Technology and Space (BMFTR) through the TahRget collaborative project.