What began as research to increase the scarce therapeutic options for cystinuria, a rare genetic disease affecting 1 person in 7,000, could become a potential solution for millions of people around the world suffering from kidney stones (5-10% of the world’s population).
A team from IDIBELL and the UB has been studying L-Ergothioneine, a natural antioxidant, for years, as a compound capable of reducing the formation of cystine stones in the kidneys in mouse models. Now, thanks to the latest research carried out by the team, they have found that the benefits of this antioxidant are extensible to other types of kidney stones, especially the most common type: calcium oxalate stones, which represent 70-80% of the cases of global kidney lithiasis. The study, published in Antioxidants & Redox Signaling, reveals that the antioxidant not only slows down the growth of kidney stones, but also protects the organ from inflammation and cell damage, attacking the root of the problem and offering a safer therapeutic alternative with fewer side effects.
The research has been led by Dr. Clara Mayayo, researcher at IDIBELL and the UB; Dr. Raúl Estévez, principal investigator of the group of Physiology and Pathology of the Glia-neurone functional relationship at IDIBELL, the UB and CIBERER; and Dr. Virginia Nunes. This is the posthumous study by Dr. Nunes, who was a founding member, program coordinator and group leader at IDIBELL, as well as professor at the Department of Physiological Sciences of the Faculty of Medicine and Health Sciences of the UB, dedicating her entire research life to the study of minority diseases. Researchers from the Institut de Recerca Sant Joan de Déu, CIBERER, CIBEROBN, IRB Barcelona and the Universitat de València have also collaborated. In addition, the study has been funded by the Carlos III Health Institute and La Marató de TV3, also receiving institutional support from the CERCA program of the Generalitat de Catalunya.
A natural compound that attacks the root of the problem in renal lithiasis
L-Ergothioneine, identified almost 100 years ago, is a natural antioxidant obtained daily from the diet. Virginia Nunes and Raúl Estévez’s team began studying its antioxidant properties and their impact on cystinuria, finally proving in 2021 that it was a realistic and safe therapeutic option, of very low toxicity, which could allow the chronic treatment of patients with cystinuria and manage to delay or prevent the appearance of cystine stones (article). In the same year, L-Ergothioneine was designated as an orphan drug for the treatment of this rare disease, and later a clinical trial could be initiated to validate this new preventive treatment for cystinuria (article).
The key to the success of L-Ergothioneine is the way it attacks the root of the problem. Regardless of the type of stone being formed in the kidney, either by aggregation of cystine amino acids (in the case of cystinuria) or by crystallization of calcium and oxalate in the urine (in the case of the most common stones), the process damages the mitochondria and generates oxidative stress at the cellular level that inflames the kidney tissue and facilitates the appearance of crystals. “Mitochondrial dysfunction and oxidative stress are one of the main drivers of the different types of renal lithiasis”, explains Dr. Clara Mayayo, researcher at IDIBELL and the UB. “And L-Ergothionine solves it fully: the molecule is transported directly to the kidney and reverses the oxidative stress that may exist, restoring the functioning of the mitochondria”, details Mayayo.
“Correcting two of the main defects of renal lithiasis -mitochondrial dysfunction and oxidative stress- is the best therapeutic strategy that could be developed, and we have been able to verify that it works,” adds Dr. Raúl Estévez. According to the results obtained in mouse models, in cystinuria, L-Ergothioneine reduces cystine precipitation by more than 60%. When combined with a penicillin derivative (D-penicillamine), the effect is additive and exceeds 80% reduction in cystine precipitate. “It is not only the success in dissolving stones, but also that this antioxidant preserves the kidney and protects it from damage,” says Dr. Estévez. “By restoring the kidney balance, it helps the kidney repair itself and reduce the inflammation it had suffered,” he concludes. The team has been able to confirm that all these effects are equally effective in experimental models with calcium oxalate stones.
Cystinuria, a rare disease
Cystinuria is a rare and hereditary disease characterized by the recurrent appearance of cystine stones in the kidney and urinary tracts throughout the patient’s life, seriously affecting quality of life. Until now, preventive treatments were ineffective and with strong adverse effects, and many patients abandoned it and ended up going through various surgical procedures of stone extraction since childhood.
For these patients, the efficacy and extremely low toxicity of L-Ergothioneine make it a very promising option. Although the expansion of treatment to common kidney stones opens a huge range of possibilities, the initial objective is still the same: to offer a respectable solution to patients with cystinuria. This reinforces REMMA Bellvitge’s commitment to research into rare adult diseases, such as cystinuria, ensuring innovative solutions for patients who often have few therapeutic alternatives. “L-Ergothioneine is especially promising for these patients because, being a natural compound present in the diet, it has almost zero toxicity,” explains Dr. Mayayo. This would allow people with cystinuria to take it chronically to prevent the formation of stones and protect the kidney before damage appears, with guarantees and safety. Now it is necessary to validate it in clinical trials.
The Bellvitge Biomedical Research Institute (IDIBELL) is a research center established in 2004 specialized in cancer, neuroscience, translational medicine, and regenerative medicine. It counts on a team of more than 1.500 professionals who, from 73 research groups, publish more than 1.400 scientific articles per year. IDIBELL is participated by the Bellvitge University Hospital and the Viladecans Hospital of the Catalan Institute of Health, the Catalan Institute of Oncology, the University of Barcelona, and the City Council of L’Hospitalet de Llobregat.
IDIBELL is a member of the Campus of International Excellence of the University of Barcelona HUBc and is part of the CERCA institution of the Generalitat de Catalunya. In 2009 it became one of the first five Spanish research centers accredited as a health research institute by the Carlos III Health Institute. In addition, it is part of the “HR Excellence in Research” program of the European Union and is a member of EATRIS and REGIC. Since 2018, IDIBELL has been an Accredited Center of the AECC Scientific Foundation (FCAECC).