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Perelman School of Medicine on Jan. 20. Credit: Devansh Raniwala

Researchers at the Perelman School of Medicine identified over 1,000 genes that could serve as potential treatment targets for kidney disease in a newly published study.

The study marks the most complete and detailed genetic map of kidney function developed thus far. The findings are likely to improve the diagnosis, prevention, and treatment of kidney disease — which affects more than one in seven U.S. adults, according to the National Kidney Foundation — and were based on a close study of about 1,000 human kidney samples and hundreds of thousands of kidney cells. 

First author Hongbo Liu, a former postdoctoral fellow in the division of Renal Electrolyte and Hypertension at Penn, told Penn Medicine News that by creating single-cell profiles of thousands of kidney cells, the researchers were able to figure out how certain genetic variants disrupt the regulatory machinery in key kidney cells types.

The research team also took a step back to see the bigger picture. They found that certain kidney cells, called proximal tubule cells — which help control water, electrolytes, and waste removal — are a “hotbed” area where disease-causing genetic changes tend to occur.

The study also found that some gene regions contain two types of changes — one that helps build important proteins and another that controls how much of the protein is made. Identifying both types in key genes is important, as it could play a role in causing kidney disease.

Renal-Electrolyte and Hypertension professor Katalin Susztak — who also leads the Penn/CHOP Kidney Innovation Center — told The Daily Pennsylvanian that assembling and analyzing such a comprehensive genetic map for kidney disease was no easy feat. The project involved combining different datasets, even though they varied in quality and format. To ensure accurate results and avoid mistakes, the team used careful statistical and computational methods.

“We had to integrate two very different kinds of datasets: patient records from about 2.5 million people from large biobanks like Penn Medicine Biobank, UK Biobank, and the Million Veteran Program, and detailed tissue-level data from around 4,000 human kidney samples we collected in our lab,” Susztak said.

Genetic variants were identified through large-scale genome-wide association studies that allowed researchers to look at how these genetic variants influence open chromatin regions and gene expression specifically in kidney tissues, according to Susztak.

By combining statistical evidence from patient studies with functional data from kidney samples, researchers were able to determine which genetic variants are truly important in causing or advancing kidney disease.

This “genetic map” for kidney function will help doctors intervene earlier, provide preventive care, and develop treatments that target the genetic causes of kidney disease. With these genetic scorecards, clinicians can easily identify harmful genetic changes and the genes involved. 

“This will help develop personalized approaches — whether it’s early screening, preventive measures, or targeted therapies — so treatments become tailored to each person’s genetic makeup, improving outcomes dramatically,” Susztak added.

Based on the team’s findings, there are 160 genes linked to kidney disease that already have FDA-approved medications available, making drug repurposing a promising possibility. 

“We’re actively seeking collaborations with pharmaceutical companies, biotech firms, and academic institutions to bring these discoveries closer to the clinic,” Susztak said.

The research team hopes to confirm their findings about genes related to kidney disease through other studies and experiments. Future research could explore how gene-editing technologies, like CRISPR, might be used to directly correct harmful genes linked to kidney disease.

“Beyond gene editing, artificial intelligence and machine learning can also help us uncover complex genetic interactions, predict disease progression more accurately, and even identify new therapeutic targets,” Susztak said.