Inflammatory processes link the kidneys and the heart

People with chronic kidney disease (CKD) have a significantly increased risk of dying from cardiovascular disease. They also suffer from a chronic inflammatory response, the causes of which are as yet only partially understood. Oxalic acid (oxalate) has, until now, been known primarily for its role in the formation of kidney stones. The molecule is a natural component of the body’s metabolism, is found in certain foods and is normally excreted via the kidneys in the urine. However, when kidney function is impaired, oxalate accumulates in the body and can drive inflammatory processes.

The Department of Experimental Biomedicine II at Würzburg University Hospital (UKW), in collaboration with the Experimental and Clinical Research Centre (ECRC) – a joint venture between Charité – University Medicine Berlin and the Max Delbrück Centre in Berlin – investigated the immunological mechanisms linking oxalate-induced kidney damage to systemic inflammation and cardiovascular damage.

An oxalate-rich diet triggered inflammation and heart damage in mice

“In our research project, a diet enriched with oxalate activated the immune system systemically in mice. This means that the inflammatory processes spread throughout the entire body. This resulted not only in kidney damage but also in pathological changes to the heart, which reduced cardiac function,” reports Dr Hendrik Bartolomaeus. The scientist, who is part of Professor Alma Zernecke-Madsen’s team at the UKW, shares the role of last author of the study with Dr Nicola Wilck from the ECRC.

The team has now published its findings in the journal Cardiovascular Research. Bartolomaeus had previously worked in Wilck’s laboratory.

The more oxalate, the more pro-inflammatory immune cells

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

In the next step, the team investigated what happens when IL-17A is specifically blocked. “In the animal model, several disease symptoms improved at once,” says Nicola Wilck. “The mice’s kidneys functioned better, inflammation and fibrosis were reduced, and there was less damage to the heart. We are thus describing a pathway that could potentially be targeted therapeutically: oxalate–IL-17A–cardiorenal damage.” The study thus mechanistically links elevated oxalate levels to IL-17A-mediated inflammation, cellular metabolism and cardiorenal organ damage.

“All in all, our findings show that oxalate not only damages the kidneys but can also contribute to the development of cardiovascular diseases via IL-17A and inflammatory processes,” summarises lead author Moritz Wimmer from the ECRC. Oxalate can therefore no longer be regarded merely as a crystal-forming substance that causes local damage to the kidneys. Rather, it represents a systemic burden on the immune system and metabolism, according to Wimmer.

New prospects for anti-inflammatory therapies

Clinically, this means that elevated oxalate levels may not only place a strain on the kidneys but, via inflammatory processes, also directly affect the cardiovascular system. The research could therefore help to better identify patients with kidney disease who are at increased cardiovascular risk, interpret biomarkers more accurately and develop new anti-inflammatory treatment strategies.

Large patient cohorts are to confirm these findings

What’s next? Co-authors of the current study – Professor Felix Knauf and his team from Charité – Universitätsmedizin Berlin and the Mayo Clinic – have already demonstrated in large patient cohorts that oxalate levels are frequently elevated in people with impaired kidney function. Furthermore, high oxalate levels were associated with an increased risk of cardiovascular complications.

As a next step, the researchers now wish to investigate whether the inflammatory mechanisms they have identified can also be detected in larger cohorts of patients with CKD. To this end, they are currently analysing data on systemic inflammation, the progression of CKD and cardiovascular complications.

Hendrik Bartolomaeus says: “A key aspect will be determining to what extent the observed IL-17A-mediated inflammatory pathway is specific to oxalate. Perhaps similar mechanisms also contribute to the development of cardiovascular damage in other causes of kidney disease.” Nicola Wilck adds: “In the long term, we hope to gain a better understanding of which inflammatory pathways in chronically damaged kidneys can be targeted therapeutically and which patients might benefit most from this.”

The project was funded by the German Research Foundation as part of the Collaborative Research Centres 1365 “Renoprotection” and 1470 “HFpEF”, as well as by the Federal Ministry of Research, Technology and Space as part of the TAhRget collaborative project.

Publication

Moritz I Wimmer, Martin Reichel, Arne Thiele, Alex Yarritu, Ariana Matz-Rauch, Harithaa Anandakumar, Luisa Hernandez Götz, Till Robin Lesker, Olena Potapenko, Natnael Gebremedhin, Wibke Anders, Sarah V Liévano Contreras, Rongling Wang, Felix Behrens, Bernd Hoppe, Olivia Nonn, Gabriele G Schiattarella, Franz Schaefer, Johannes Holle, Till Strowig, Alma Zernecke, Kai-Uwe Eckardt, Felix Knauf, Nicola Wilck, Hendrik Bartolomaeus, ‘Interleukin-17A mediates cardiorenal injury in oxalate nephropathy’, Cardiovascular Research, 2026; cvag158, https://doi.org/10.1093/cvr/cvag158