Single-Cell Analysis Reveals Critical Kidney Cell Types Involved in Disease

Researchers at the University of Pennsylvania's Perelman School of Medicine have identified over 1,000 genes that could serve as potential targets for kidney disease treatment, according to a new study published in Science.

By developing the most comprehensive genetic map of kidney function to date, the researchers have taken a significant step toward more precise diagnosis, prevention, and treatment of kidney disease. As part of this effort, they created a "Kidney Disease Genetic Scorecard," a tool that physicians can use to identify genes and variants most likely linked to kidney disease in individual patients.

Uncovering the Genetic Basis of Kidney Disease

"Kidney dysfunction is a major global health issue, and our findings shed new light on the specific genes and biological pathways that contribute to disease risk. Analyzing nearly 1,000 human kidney samples and studying hundreds of thousands of kidney cells individually provided a clearer picture of what’s happening at a molecular level," said Dr. Katalin Susztak, study co-senior author, professor of Renal-Electrolyte and Hypertension at Penn, and leader of the Penn/CHOP Kidney Innovation Center.

Chronic kidney disease affects nearly 10% of the global population, with cases on the rise. There is currently no cure, and available treatments only slow disease progression. Patients with advanced kidney disease often require dialysis or a kidney transplant once their kidneys can no longer filter blood, remove waste, or regulate electrolytes. According to the United Network for Organ Sharing (UNOS), approximately 90,000 people in the U.S. are waiting for a kidney transplant at any given time, and 13 die each day while waiting. However, insights from this study could help pave the way for new, more effective treatments or preventive strategies.

Identifying Key Kidney Cells

A major discovery from the study was the identification of proximal tubule cells as a focal point for disease-causing variants. These cells play a critical role in kidney function, including water and electrolyte reabsorption and the secretion of various compounds. Genetic variants affecting these cells can disrupt essential processes, increasing the risk of kidney disease.

"It’s essential to pinpoint which cells are truly relevant for disease. By generating single-cell profiles of thousands of kidney cells, we were able to zoom in and see how certain genetic variants interfere with key regulatory mechanisms," said Dr. Hongbo Liu, the study’s first author and assistant professor at the University of Rochester, who was previously a postdoctoral fellow in Penn’s Renal-Electrolyte and Hypertension division.

Beyond cellular analysis, the researchers examined broader genetic patterns and discovered that certain gene regions contained two types of variants: those that affect protein-coding instructions and non-coding variants that regulate protein production levels.

"That was a key breakthrough. More than 600 genes contained both types of variants, making them strong candidates for further study as potential causes of kidney disease. These genes should be prioritized for future research," Liu noted.

The Future of Kidney Disease Research

These findings lay the groundwork for future studies with direct clinical implications. Notably, some FDA-approved drugs for other conditions are known to interact with genes identified in the study. This raises the possibility of repurposing or refining existing treatments to slow kidney disease progression or even repair kidney damage.

The researchers also emphasized the potential for precision medicine, allowing for better identification of individuals at higher risk of developing kidney disease.

"While disease symptoms and outcomes can appear similar from patient to patient, our research continues to reveal how unique and varied the origins of diseases can be," Susztak said. "As medicine advances, treatments will likely become more personalized and tailored to each individual, increasing the chances of more effective therapies for serious conditions."