NCATS-Funded Rare Disease Researchers Provide Key Data, Help Build New Kidney Atlas

Human kidney cross-section illustration sees veins and arteries. (Shutterstock)

February 29, 2024

Group’s work has yielded insights into kidney disease biology, improved diagnostics and more

Researchers recently announced what may be the most comprehensive human kidney cell and tissue catalog to date. The Kidney Tissue Atlas, part of the Kidney Precision Medicine Project (KPMP), promises to provide a better understanding of what leads to kidney disease progression and kidney failure. The new data, reported in Nature, allow researchers to compare healthy kidney cells to injured and diseased cells. The work provides a foundation for developing new treatments for chronic kidney disease and acute kidney injury.

The Atlas consists of 51 kidney cell types and 28 kidney “states” that represent injury or disease and more than 1 million cell “neighborhoods.” It also includes 3-D models of cells and their relationships with their environments.

For University of Michigan co-author Matthias Kretzler, M.D., Ph.D., the Atlas represents, in part, a culmination of years of studies on rare kidney disorders. Such studies have provided insights into the molecular details behind kidney diseases. The data were gathered over more than a decade through the Nephrotic Syndrome Study Network (NEPTUNE), which is part of the NCATS-led Rare Diseases Clinical Research Network. Both NCATS and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) support NEPTUNE. Kretzler serves as NEPTUNE’s principal investigator.

For nearly 15 years, NEPTUNE has set the standard for studying rare kidney disorders. Kidney tissue samples have been collected from more than 1,200 people with rare kidney disorders. Researchers have analyzed and catalogued data and recorded patient outcomes. Their work has led to a better understanding of the biology of both rare and common kidney diseases. The research also has helped improve diagnostics and treatments.

NEPTUNE’s long-term data on patients were especially key for the Kidney Tissue Atlas and the KPMP.

“We’ve mapped common biological pathways in the kidney and shown how gene activity in kidney disease can indicate good and bad long-term outcomes in both rare and common kidney diseases,” said Kretzler. “It’s an example of how studying rare diseases not only predicts who needs treatment for a rare disease but can also be useful for common diseases.”

Kretzler said that new technologies have allowed more thorough examinations of kidney tissue samples. Many new techniques are based on studies at the single-cell and tissue level. Researchers used such techniques to measure gene activity and compare more recent kidney biopsy data from KPMP studies to data from NEPTUNE tissue samples. NEPTUNE data include information about patient outcomes.

The importance of connections among rare and common diseases can’t be overstated, Kretzler said.

“While these data in the KPMP come from patients with diabetic kidney disease and other disorders, the long-term outcome data from NEPTUNE are in rare diseases,” he said. “These results teach us about shared biology for the loss of kidney function, which is relevant for both rare and common diseases.”

Personalized approaches, improved diagnostics

Over the last several years, NEPTUNE researchers have used their storehouse of patient data to determine new ways to connect patients with specific treatments. People may have the same broad diagnosis, but the biology of their specific diseases can differ.

The NEPTUNE Match trial uses the understanding of biology and genetics in nephrotic syndrome to assign patients to specific treatments that can target the causes of a disease. This will allow targeted treatments for diseases that all too often are treated in a one-size-fits-all way, explained NIDDK Program Director Susan Mendley, M.D. Nephrotic syndrome results from problems with the kidney’s filtering system. It includes such disorders as focal segmental glomerulosclerosis, minimal change disease and membranous nephropathy.

Kretzler is collaborating with scientists at the University of Washington to address this problem using a different approach. The researchers are creating organoids to study two rare kidney diseases. Organoids are tiny organ models grown from stem cells in a laboratory dish. They hope to use the models and organ-on-a-chip technology to better predict which drugs will work in specific groups of people. This ability could improve the design of clinical trials.

NEPTUNE researchers and clinicians also have moved the field forward in other ways.

“NEPTUNE’s work in nephrotic syndrome diseases has helped change how kidney biopsies can be used,” Mendley pointed out. “By applying molecular techniques to kidney biopsies, scientists can see genes that are expressed in different cell types,” she said. “The work has helped push diagnostic tools of kidney disease into the 21st century. It’s changed the landscape of what a kidney biopsy can reveal. We’ve gained insights into underlying disease mechanisms and progression. This has changed our understanding of a range of kidney diseases.”  

A group of NEPTUNE-supported researchers created a system to standardize how kidney biopsies are read and evaluated. The new approach could change the way biopsies are used to diagnose patients, predict the course of a disease and help select treatment options.

Other NEPTUNE-backed researchers have been trying to understand the development of a rare kidney disease that is more common in people of African ancestry. APOL1 kidney disease is a group of diseases driven by two versions of the APOL1 gene. These gene variants can put people at high risk for developing kidney disease. Yet only a small percentage of those with a high-risk genetic makeup develop the disease.

Reporting recently in Nature Communications, Matthew Sampson, M.D., at Boston Children’s Hospital, Simone Sanna-Cherchi, M.D., at Columbia University, and their colleagues may have found one reason why. They showed that some Black Americans with a high-risk version of the APOL1 gene also have a protective genetic variant that cancels out the extra risk. Those with the protective variant have a risk of developing kidney disease much closer to that of the general population. The finding may help in developing new treatment strategies.

“The NEPTUNE consortium’s many accomplishments demonstrate the importance of work by multidisciplinary teams of dedicated researchers and the broad impact of their research,” said NCATS program officer Tiina Urv, Ph.D. “NEPTUNE’s foundational studies in rare kidney disorders have changed the field.”