Yale Researchers Target Hidden Trigger of Kidney Scarring

Nearly one in seven adults in the United States lives with chronic kidney disease, a condition that often advances quietly until serious damage has occurred. While diabetes and high blood pressure are well-known culprits, researchers have long puzzled over why some kidneys fail faster than others.

At Yale, physician-scientist Madhav Menon, MBBS, MD, has been pursuing that question for more than a decade. His latest study, published in Nature Communications with collaborators at the Icahn School of Medicine at Mount Sinai and the University at Buffalo, pinpoints a key genetic clue: a common mutation in a gene called Shroom3, carried by roughly 40% of people in the U.S.

“It’s not a comorbidity,” Menon explains. “It’s a predisposition. If you already have diabetes or hypertension, this variant increases your likelihood of developing kidney disease. It adds an extra layer of risk on top of what you already have.”

The Shroom3 gene helps kidney cells maintain their structure. But when it’s overactive, excess Shroom3 appears to set off fibrosis — the buildup of scar tissue that replaces healthy, working cells. Menon’s group wanted to understand how this happens.

“Basically, having extra Shroom3 in the kidney is what we think drives disease,” he says. “When you have the mutation, you make more of the protein in particular kidney cells, and that excess seems to cause damage after injury from any cause.”

The team found that Shroom3 has both helpful and harmful roles. Instead of blocking the entire protein, which could disrupt normal kidney function, they focused on separating its good and bad effects and only targeting the elimination of its bad impact.

“We hypothesized that the good effects come from one part of the protein and the bad effects from another,” says Menon. “If we can pull them apart, then we can design drugs that target only the bad effect and protect the good.”

Their research identified a specific region of the protein responsible for fibrosis and showed that targeting just that part could prevent scarring in animal models. “Right now,” Menon says, “we’re showing proof of concept that you can target only part of this protein— the interaction it has downstream from that region—and get benefit in kidney fibrosis, scarring, and CKD without risking the adverse effects.”

Because Shroom3 variants are so common, Menon hopes this work will one day help identify and protect people most at risk. His lab is now refining the drug compound, testing its safety and potency in additional models, and preparing for human organoid studies. In about five years, Menon hopes that they will be ready for human trials.

Even at this early stage, Menon’s motivation remains deeply clinical. “Patients who self-identify with these mutations email me, ‘Is there anything new for scarring? Is there any cure?’ This work gives me hope that one day we can say yes to these patients—that we can slow down kidney disease progression in those at risk.”

For Menon, that goal captures a broader shift toward precision nephrology, medicine that tailors prevention and treatment to each patient’s genes. “We’re now going mutation by mutation, finding the problem and fixing exactly that problem,” he says. “This is precision medicine, and it’s the future of how we’ll treat kidney disease.”

Nephrology is one of 10 sections in the Yale Department of Internal Medicine. Committed to excellence in patient care, research, and education, the section’s faculty and trainees aim to be national and international leaders in academic nephrology. To learn more, visit Nephrology.