The study, coordinated by Luca Rampoldi, professor at the University Vita-Salute San Raffaele and group leader of the Division of Genetics and Cell Biology at IRCCS Ospedale San Raffaele, and Olivier Devuyst, professor and researcher at the Institute of Physiology at the University of Zurich, shed new light on chronic kidney disease, a condition that affects millions of people worldwide each year.

Researchers identified a new (intermediate-effect) variant of the UMOD gene, already known as a possible cause of the development of chronic kidney disease, thus providing new insights regarding the genetic architecture of the disease, with future prospects for treatment for affected patients.

The discovery was published a few weeks ago in the prestigious scientific journal PNAS.

What is chronic kidney disease

Chronic Kidney Disease (CKD) is a disease condition affecting the kidney that causes progressive and irreversible organ failure. It has a global prevalence estimated at more than 10 percent of the population, and the numbers are steadily increasing. Several million individuals are affected in Italy alone, with a very high social and health burden. Treatment options are unfortunately limited and consist solely, in the most advanced stage of the disease, of dialysis and organ transplantation.

"As for the possible causes of CKD, there is a strong genetic predisposition to the disease: that's why deciphering its genetic architecture is crucial. In my laboratory, we have been trying for years to study the mechanisms at the origin of kidney disease with the aim of developing increasingly effective therapeutic strategies," explains Luca Rampoldi.

UMOD gene in chronic kidney disease

Under the scientists' lens is a gene of particular interest, called UMOD, which codes for uromodulin, the most abundant protein excreted in urine, and which is critical in protecting the kidneys from stones and urinary tract infections.

Variants of the UMOD gene identified to date were of 2 types:

• rare high-effect mutations, which affect 2% of CKD patients and inevitably lead to kidney failure;
• frequent low-effect variants, which are much more prevalent, being present in 80% of the population, contributing to the risk of developing CKD in later life in combination with other genetic and environmental factors.

This study revealed the existence of intermediate variants, both in terms of their frequency in the population and their risk of developing kidney failure.

The study's finding

"This study was a collaboration with Prof. Devuyst's group and involved several research groups and international consortia, as well as families and patients. We combined several research techniques, from population genetics to cell biology, from in silico prediction to the use of databases and biobanks, to identify, for the first time, a variant of the UMOD gene that modifies a single protein residue and has an intermediate effect," Rampoldi specifies.

This genetic variant, detected in ~1:1,000 individuals of European descent, was associated with an approximately 4-fold increased risk of severe renal failure in the populations analyzed (100,000 Genomes Project, UK Biobank).

"Identifying a novel intermediate-effect variant of UMOD allowed us to complete the spectrum of genetic risk associated with variants of this gene to develop kidney disease and, in the future, could have important implications for genetic testing and counseling. The approach taken could also be applied to other genetic diseases," Rampoldi concludes.