Advanced Kidney Organoids Produce Early-Stage Plumbing Needed for Removing Waste

Team led by experts at Cincinnati Children's overcomes an obstacle that has limited the potential value of lab-grown mini-kidneys

CINCINNATI, May 8, 2025 /PRNewswire/ -- Each human kidney has about 1 to 2 million filtering units called nephrons that help purify our blood and remove waste products from the body. But those filters can only do so much without the ductwork necessary to send the waste out of the organ to ultimately be flushed out as urine.

In an achievement that was far more complex to achieve than it might sound, researchers now say they have figured out how to make tiny human kidney organoids that generate a critical initial plumbing connection between nephrons and tubule structures that can carry away waste. Details were published May 8, 2025 in the journal Cell Stem Cell.

"A number of research labs, including our own, have developed kidney organoids that successfully produce nephrons. However, a persistent limitation has been that these organoids lack a collecting duct system, which is required to carry fluid out of the nephron. This has been a fundamental barrier to producing physiologically competent human kidney tissue," says Kyle McCracken, MD, PhD, corresponding author for the study and a member of Center for Stem Cell and Organoid Medicine (CuSTOM)

The team included first author Min Shi, MD, PhD, Division of Nephrology and Hypertension, and 14 co-authors, including 11 experts from Cincinnati Children's and three researchers with Brigham and Women's Hospital, Boston, and the Harvard Stem Cell Institute.

Their two-year project included growing two specialized tissue types from separate lines of stem cells, then establishing the elusive conditions required to allow the maturing cells to signal each other at the right moment to become receptive to fusing together. The team then conducted a series of experiments to confirm and analyze the results down to genes involved at the single-cell level.

Challenges ahead

The team reports that the improved kidney organoids achieved a major step, but remain short of fully replicating the functions of a human kidney. For example, the connected nephron-tubule pairs remain disorganized. They do not yet form an organized tree-like structure of many twigs and branches leading to a single exit point—a ureter—which would be needed for kidney organoids to properly eliminate wastes.

In the lab, these organoids also do not have a system to filter blood plasma, another critical component of kidney physiology. However, the study shows that when these improved tissues are transplanted into mice, they do connect themselves into to the mouse circulatory system, and this led to fluid accumulating in the collecting ducts.

So how close are these kidney organoids to fully mimicking naturally formed kidneys?

"Most of the right cell types are present, but there are still major challenges to overcome before organoids are able to generate urine," McCracken says. "Normally, fluid is filtered into the kidneys from the blood by the body's blood pressure. But in a lab dish, there is no such force to drive the fluid into the tubules. Incorporating this feature remains an immense technical hurdle." 

Next steps 

In addition to further work on the entry end of the kidney organoids, the team is working on how to organize the collecting ducts into a tree-like structure. They also are working on questions of scale.

"Our organoids contain only a few hundred nephrons, and realistically thousands or tens of thousands would be required to mount a meaningful function in a mouse. Hundreds of thousands to 1 million or more would be needed for people," McCracken says.

Although human-ready repair tissues remain years away, the creation of the first kidney organoid system with real collecting ducts will allow scientists to further study diseases that mostly involve the collecting ducts. And by studying what happens when these tissues are transplanted in mice, scientists hope to learn even more about making more sophisticated and potentially functional kidney organoids.

"In this system, all we had to do was supply the correct cell types, which then knew how to organize themselves and connect to one another, just as it occurs in kidney development," McCracken says "This is really encouraging because it suggests we do not have to micro-engineer all aspects of the seemingly impossible complexity of the kidney. Rather, we can rely on using basic developmental principles to program the self-organizing properties into the cells, which is the major theme guiding the work in our lab."

About the study

Cincinnati Children's co-authors included Brittney Crouse, BS, Nambirajan Sundaram, PhD, Naomi Pode Shakked, MD, PhD, Konrad Thorner, MS, Nathaniel King, Parna Dutta, BS, Vinothini Govindarajah, PhD, Raphael Kopan, PhD, Cristina Cebrian, PhD, Christopher Mayhew, PhD, and Michael Helmrath, MD.

This work also included contributions from the Cincinnati Children's Pluripotent Stem Cell Facility, Information Services for Research facility, Bio-Imaging and Analysis Facility, Integrated Pathology Research Facility and the Research Flow Cytometry Facility.

Funding sources included the Cincinnati Children's Research Foundation, the Pediatric Center of Excellence in Nephrology at Washington University, a pilot grant through the (Re)Building a Kidney Consortium, and ATLAS-D2K Center.  

SOURCE Cincinnati Children's Hospital Medical Center