MDI Biological Laboratory
Biotechnology

Pioneering New Kidney-Grafting Techniques

  • January 10, 2024

New research published in the journal Bioengineering was led by former visiting scientists Leif Oxburgh, D.V.M., Ph.D. and Denise Marciano, M.D., Ph.D., and the MDI Bio Lab’s Iain Drummond, Ph.D.  Drummond calls the challenge of getting lab-grown kidney tissue to link with an organism's circulatory system and function properly a "plumbing problem." 

With more than 30 million people suffering from Chronic Kidney Disease (CKD) the hunt is on for alternatives to dialysis and the transplantation of donated kidneys. A growing body of research is focused on creating lab-grown kidney tissues that could be implanted in a CKD patient.

Medical and research scientists envision a limitless supply of replacement tissues which, derived from stem cells provided by patients themselves, would be better tolerated by their own immune systems.

Researchers are now able to grow small, human kidney tissues called “organoids” and engraft them in a larger mouse kidney. But getting them to fully function? Different story.

“It’s a plumbing problem,” says Drummond, Scientific Director of MDI Bio Lab’s Kathryn W. Davis Center for Regenerative Biology and Aging. “We know now that we can connect the pipes, at least partially. The issue is getting fluid to flow through.”

Mice are an experimental stand-in for human physiology when developing therapies that might eventually be tried in humans. And engrafted human kidney organoids have successfully joined up to the mouse’s vasculature – its blood vessel system.

Visiting Scientist Leif Oxburgh, D.V.M., Ph.D., participates in a panel at MDI Bio Lab in 2015

Visiting Scientist Leif Oxburgh, D.V.M., Ph.D., participates in a panel at MDI Bio Lab in 2015

But so far no one has been able to show that the engrafted organoid is doing actual work: filtering blood, making waste-containing urine, or moving it out of the engraftment and into the host kidney. Instead, fluid inside the engraftment appears to be hitting a biological clog, building up behind it and contributing to the engraftment’s disintegration after just a few weeks.

It’s one of many challenges of engineering replacement tissue structure and functionality that are being investigated by a consortium of more than 100 scientists in a project called (Re)Building a Kidney, or RBK. The project is funded by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), which is a branch of the National Institutes of Health;  Drummond, Oxburgh and Marciano are Principal Investigators of a $3.4 million, five-year grant from the program.

To test various techniques for improving the plumbing that’s needed to link human organoid and mouse kidney, their new publication describes a system for using a benign virus to deliver a payload of genetic material and growth-promoting molecules to the engraftment site.

That cocktail can be designed to mimic conditions associated with the generation of functional kidney tissue in a developing embryo – or the adult regeneration of tissue by animals that are able to do it, such as the zebrafish that Drummond specializes in.

The new research also proved out a method for detecting tell-tale genetic markers that would show that human-organoid produced urine is in fact, ending up in the mouse’s kidney, as desired.

Oxburgh is the Scientific Director of New York’s Rogosin Institute, which provides comprehensive clinical care at ten locations in New York. He envisions the system’s use by other research groups in the RBK consortium and worldwide.

“It’s a hard enough problem that you need multiple different groups with multiple, different candidate approaches to test,” he says. “If you don’t have a common platform, your data, your results, your experiments aren’t necessarily comparable with each other.”

Noting that the timeline between research and publication can be quite long – three years in this case – Oxburgh says he is already deploying the platform in his own experiments. So is Drummond.

“We now know ways to direct kidney tubule engraftment and, importantly, detect their contribution to kidney function,” Drummond says. “Getting fluid flowing through engrafted kidney tissue is the next step and will reveal a lot about how kidney cells mature and achieve their final functions.”