New genetic map offers hope for more precise diagnosis and treatment of kidney disease

Over 1,000 genes may serve as possible treatment targets for individuals with kidney disease, according to a new study, published in Science, from researchers at the Perelman School of Medicine at the University of Pennsylvania. By creating the most complete and detailed genetic "map" of kidney function to date, the researchers have paved the way for more precise diagnosing of kidney disease, strategies to prevent it, and ways to treat it. In addition, they also created a "Kidney Disease Genetic Score card" that doctors can use with their patients to see what specific genes and variants may be most likely tied to a particular patient's kidney disease.

Kidney dysfunction is a major global health issue, and our findings shed new light on the specific genes and biological pathways that underlie disease risk. Studying close to 1,000 human kidney samples and hundreds of thousands of kidney cells one by one was key to offering a clearer picture of what is going on 'behind the scenes.'"

Katalin Susztak, MD, PhD, MSc, co-senior author, leader of the Penn/CHOP Kidney Innovation Center, and professor of Renal-Electrolyte and Hypertension at Penn

Chronic kidney disease affects nearly 10 percent of the world's population and incidence is rising. There is no cure and current treatments only slow disease progression. Ultimately, a person with the disease usually requires dialysis or a transplant once their kidneys cannot keep up with the body's need to filter blood, remove waste, and regulate electrolytes. At any point, there are approximately 90,000 people waiting for a kidney transplant according to the United Network for Organ Sharing (UNOS). In addition, 13 people die in the US every day waiting for a kidney. But with insights from this research, new effective or preventive treatments could be on the horizon.

Zeroing in on critical kidney cells

Among the findings, Susztak and her colleagues discovered that proximal tubule cells are one "hotbed" of disease-causing variants. These cells play various kidney-function roles including reabsorption of water and electrolytes, and secretion of different chemicals and compounds, so variants in these cells could lead to disease by impeding these essential functions.

"It's critical to pinpoint which cells are truly relevant for disease," said first author Hongbo Liu, PhD, a former postdoctoral fellow in the division of Renal Electrolyte and Hypertension at Penn who is now a research assistant professor at the University of Rochester. "By creating single-cell profiles of thousands of kidney cells, we were able to 'zoom in' and find how certain genetic variants disrupt the regulatory machinery in key kidney cell types."

In addition to zooming in, researchers also looked at the bigger picture and saw some gene regions had two kinds of variants, variants in the coding or instructions to build essential bodily proteins, and variants that don't code for a protein or change its sequence that can control how much of a protein is made.

"That was a key breakthrough from this study," said Liu. "More than 600 genes had these two variant types, and having more than one variant type makes us strongly suspect the genes as causes of kidney disease. Among the genes we highlighted, genes with both variant types should be the first to be studied further."

The future of kidney disease research

These findings set the stage for research that could directly impact the clinical care of people with or at risk of kidney disease. In fact, there are FDA-approved drugs, for other conditions, that are also known to influence some of the genes from this study. That means scientists should study whether repurposing or refining some already available drugs could potentially halt this disease's progression or even repair the kidneys.

In addition, along with the ability to understand those at greater risk of developing kidney disease, the researchers said their work represents the potential and power of precision medicine.

"While outcomes and symptoms from diseases are often very similar patient to patient, the more research we do into our bodies' mechanisms and genes, the more we understand how unique and varied origins of diseases can be," said Susztak. "There is a strong likelihood that medicine will continue to become more personalized and tailored to each person, and that means a greater chance future treatments for serious illnesses and conditions will be more effective."

This research is supported by grants from the National Institutes of Health (P50DK114786, DK076077, DK087635, DK132630, DK105821).