Two research projects at the Vall d'Hebron Research Institute (VHIR) have received funding from the Senefro Foundation of the Spanish Society of Nephrology (SEN). In total, the SEN has selected six projects from the over thirty proposals submitted, three clinical projects and three basic research investigations. Each research project will receive 24,000 euros to develop their initiatives. On one side, the research of Dr. Conxita Jacobs, principal investigator of the Nephrology and Renal Transplantation group at VHIR, aimed at optimising the C5b9 deposition test to monitor complex glomerulopathies, has been awarded in the category of clinical project. On the other, in the basic research category has been selectes a project led by Dr. Anna Meseguer, head of the Renal Physiopathology group at VHIR, which seeks to find biomarkers of progression and therapeutic solutions for patients suffering from Familial Hypomagnesaemia with Hypercalciuria and Nephrocalcinosis (HFHHN), an ultra-rare renal disease that currently lacks specific treatment.

Study of phenotypic variability in patients with an ultra-rare disease to identify new therapeutic targets.

HFHHN is an ultra-rare kidney disease caused by mutations in the CLDN16 and CLDN19 genes, with an incidence of less than one person per million population. Affected individuals experience an inexorable progression to chronic kidney disease and renal replacement therapy (dialysis and transplantation) early in life. In the Spanish population, the affected gene is CLDN19. Congenital eye defects that limit vision to varying degrees are also characteristic. Currently, there is no specific treatment for this disease, there is only mitigation of symptoms.

Dr. Meseguer's group is working to identify the mechanisms responsible for the progression of the disease in patients who present a very aggressive course compared to others who, although they have the same mutation, even if they are siblings, have milder affectation. On one hand, a complete analysis of patients and controls by whole exome sequencing (WES) has identified gene variants associated with very aggressive phenotypes, previously defined as those who have suffered a very rapid loss of kidney function requiring a transplant before 5 years of life. Analysis of these gene variants would identify a subgroup of high-risk patients who should undergo more frequent medical follow-up and monitoring.

Another approach has been the identification of miRNAs differentially expressed in urinary exosomes between patients with different degrees of disease progression and healthy controls, which may serve as biomarkers and also as therapeutic targets. The new project aims to validate these gene variants and biomarkers in other cohorts (France and Poland), as well as to develop cellular systems suitable for drug screening and repurposing and for testing therapies directed at specific targets (miRNA among others). The research team postulates that other tubulopathies that share common features with HFHHN, such as Dent's disease, could also benefit from this research.

A test to improve the management of complex glomerulopathic diseases

The complement system is part of the immune system and acts as a bridge between innate and acquired immunity. Several studies have found a direct or indirect relationship between this system and various glomerular pathologies, diseases that affect the structures responsible for filtering blood in the kidneys. Following this link, an ex vivo deposition test for C5b9, a protein complex formed during the activation of the complement system, has been developed and shown to be effective in monitoring Atypical Uremic Haemolytic Syndrome. Dr Jacobs' team aims to optimise the test so that it can be automated and to study whether it is possible to extend its use to other complex glomerulopathies such as lupus or membranous nephropathy. In addition to providing a better tool to monitor various glomerular pathologies, a greater understanding of the role of the complement system in these diseases may open up therapeutic opportunities for certain patients, as it might identify those who could benefit from therapy with existing complement system blockers.

The Spanish Society of Nephrology has also awarded Dr Jacobs a grant for a three-month stay at a foreign centre; she is currently at the Universitätsklinikum hospital in Aachen, Germany.