A study led by the Renal Pathophysiology group at the Vall d’Hebron Research Institute (VHIR) has identified a protein that could help explain why Dent disease, a rare kidney disease, progresses very differently among patients. The work was carried out in collaboration with the Paediatric Nephrology Department of Vall d’Hebron University Hospital and the European Molecular Biology Laboratory (EMBL) in Heidelberg (Germany), and was supported by the Dent Disease Association (ASDENT). The results have been published in the Journal of Translational Medicine.

Dent disease is a rare kidney disease caused by genetic alterations that affect the functioning of the proximal tubule of the kidney. In approximately 60% of cases, the disease is caused by mutations in the CLCN5 gene, which encodes the ClC-5 protein. This protein is involved in the reabsorption of proteins in the kidney, preventing them from being lost in the urine. When there is a mutation in ClC-5, it does not function properly, meaning that low-molecular-weight proteins and small molecules cannot be reabsorbed. This causes progressive deterioration of kidney function in patients, eventually requiring dialysis or a kidney transplant. Currently, there is no curative treatment for the disease.

In addition, there is considerable variability in the severity of disease progression among patients: while some maintain stable kidney function for decades, others experience a more rapid decline that will lead to kidney failure, requiring dialysis or a transplant. The study recently published by VHIR investigated the mechanisms that could explain these differences, which have so far been poorly understood.

The team worked with kidney proximal tubule cell lines carrying different pathogenic mutations in ClC-5 and studied the proteins that interact with ClC-5. Among these proteins, they identified SEC22B, which is necessary for ClC-5 to reach the cell membrane and endosomes correctly, where it performs its function. “It is not only important for ClC-5 to have the correct structure, but also for it to reach the right place within the cell. With this study, we have seen that when SEC22B is altered, ClC-5 does not reach its destination correctly and, therefore, cannot function normally,” explain Dr. Mónica Durán and Andrea Casal, researchers in the Renal Pathophysiology group at VHIR.

Based on these results, the researchers propose that SEC22B could act as a modifier of the Dent disease phenotype. “If a person has alterations in both ClC-5 and SEC22B, they could have a more severe condition than a person who only has mutations in ClC-5. Therefore, alterations in SEC22B could help explain part of the phenotypic variability that we observe among patients with Dent disease,” highlights Dr. Gerard Cantero, principal investigator of the Renal Pathophysiology group at VHIR. The findings also raise the possibility that mutations in SEC22B may play a causal role in the disease in some patients in whom it has so far not been possible to identify the genetic cause, despite having a phenotype compatible with Dent disease.

A potential biomarker of Dent disease

In addition to helping understand variability among patients, the study also highlights the potential of SEC22B as a urinary marker of the disease. As part of this work, a pilot study was conducted in which the protein was found to be increased in patients’ urine and could therefore be used as a non-invasive biomarker of Dent disease. In this regard, further studies will investigate whether SEC22B could be useful as a predictive biomarker of disease progression. “The possibility of having a biomarker from a urine sample could open up new avenues for providing patients with more accurate diagnosis and prognosis,” concludes Dr. Anna Meseguer, who was head of the Renal Pathophysiology group at VHIR until 2025.

The work was supported by the Dent Disease Association (ASDENT), a non-profit organisation founded in 2011 with the aim of raising funds for research into Dent disease. For more than ten years, it has collaborated on VHIR projects focused on this disease. The work was also funded by the Carlos III Health Institute, the Mizutani Foundation for Glycoscience, the SENEFRO Foundation and the Ministry of Science and Innovation.