Hipofam, the association for information and research on familial hypomagnesemia, renews its commitment to the research of the Renal Pathophysiology group of Vall d'Hebron Research Institute (VHIR), led by Dr. Anna Meseguer, with a new donation of 19,000 €. These funds allow the hiring of the predoctoral researcher Julieta Torchia, who is doing her doctoral thesis on the study of familial hypomagnesemia with hypercalciuria and nephrocalcinosis (HFHNC).

As Dr. Gema Ariceta explains, "familial hypomagnesemia syndrome with hypercalciuria and nephrocalcinosis is an autosomal recessive minority kidney disease characterized by loss of calcium and magnesium in the urine and impaired renal function. It is caused by mutations in the genes coding for Claudin-16 or Claudin-19, proteins located in the kidney and involved in the regulation of ionic permeability in the cells of the thick ascending limb of loop of Henle".

The project currently being developed in the Kidney Pathophysiology group is focused on understanding which biological processes are altered in this disease and analyzing the differences in the progression of the pathology to renal failure among different patients. Dr. Cristina Martínez, Dr. Gerard Cantero-Recasens and Julieta Torchia are also part of the research team. "Our main objective", continues Dr. Ariceta, "is to identify biomarkers of disease progression to distinguish patients at higher risk of developing chronic kidney disease and, therefore, may eventually require dialysis or transplantation, from those who will have a better evolution".

New biomarkers of disease progression

Among the possible alterations that could explain this differential progression, the Kidney Pathophysiology group has focused on studying alterations at the genome level (WES), microRNA profiles in urine extracellular vesicles (exosomes), and also the profile of the microbiota.

These results are currently being validated by other platforms in the same cohort of patients. In addition, this cohort has been extended with new patients from Spain who have joined the study. Collaborations have also been established with researchers from France (Georges Pompidou Hospital) and Poland (University Hospital Lublin) to include patient samples from other countries in the project. According to Julieta Torchia, "the confirmation of these results will allow the identification, from the moment of diagnosis, of those patients with the worst prognosis, which will facilitate closer and more personalized care".

In the course of the last year, miRNA molecules have also been identified in the urinary exosomes of patients that are associated with different features of the disease and may explain why patients with the same mutation evolve more rapidly to chronic kidney disease. These miRNAs are being studied in follow-up samples from the patients themselves to observe their correlation with disease progression, as well as in new patients incorporated into the study. Finally, the information generated by both omics techniques (genome and microRNA) has been analyzed using artificial intelligence algorithms to identify targets and therapeutic solutions for the disease.

Importantly, a collaboration with researchers from the Leiden University Medical Center (The Netherlands) is currently underway to develop two genetically modified animal models*. One model carries the pG20D mutation in Claudin 19, which is the most frequent in the Spanish population; and a second one in which the Claudin 19 gene is deleted. "These animal models will be very useful to deepen the mechanisms of progression of CCHF to chronic kidney disease and to test possible therapeutic strategies for an orphan disease that has no specific treatment, except for the support", says Dr. Meseguer.

"The role of the microbiota in the course of this pathology remains poorly understood", explains Dr. Cristina Martinez, Miguel Servet researcher who collaborates in this project in the Kidney Pathophysiology group at VHIR, "but our hypothesis is that alterations in the bacteria producing short-chain fatty acids could contribute to the progression of the disease and its protective effect at the renal level".

Hipofam and VHIR: a 9-year collaboration

The collaboration between Hipofam and VHIR began in 2015, and since then it has already made 12 donations like this one to reach a total amount of 184,000€. As Dr. Gerard Cantero-Recasens, principal investigator of the group, says "the involvement of patient associations like Hipofam is very important for the continuity of many lines of research as it allows us to hire new researchers to carry out research projects and, very importantly, to continue researching in the field of minority diseases". In addition, contributions from the Association for Information and Research on Genetic Renal Diseases (AIRG-E), the Spanish Society of Nephrology (SENEFRO) and the Instituto de Salud Carlos III (ISCIII) also joined the project.

Antonio Cabrera, president of Hipofam explains that, when they started this collaboration with VHIR, they did not know how they would do it to get the funds needed, but they did not hesitate for a moment to support the project. "We'll do it any way we can", they thought at the time. "Our dream was to have the disease investigated, but they didn't know how, and Dr. Ariceta proposed that we collaborate on a project for which ISCIII had granted them funds but more money was needed for personnel costs. It was a great opportunity".

They started from scratch, but they succeeded and the project became a reality day by day. They had some tough times, like during the pandemic when they couldn't organize anything to raise funds, but they still managed to get by. "Now, 9 years later, the researchers have come a long way, they have won several awards and recognitions and there are a lot of ideas on the table to continue growing the lines of research. We know that there is still a long way to go, but we look back and see everything that has been done, which is also a lot, and that helps us to move forward", says Antonio Cabrera, who assures that he has only one sentence in his head: "we are on the right track and it is only a matter of time, perseverance and a bit of luck".

*Institutional Declaration on the Use of Animals in Research