Yale, Cambridge pioneer new way to make kidneys safe for transplant
The rise in diabetes and high blood pressure-related diseases has led to a major need for kidney transplants, but the quality of available organs has been on a steady decline. Now, a new procedure pioneered by Yale School of Medicine and the University of Cambridge shows promise for making rejected kidneys fit for transplant.
Working with human kidneys deemed unsuitable for transplant, the researchers identified why they were poor candidates, and were also able to reinvigorate and qualify them for clinical transplant.
The researchers report results in the July 6 edition of the American Journal of Transplantation, and are planning a clinical trial.
“There are more than 93,000 people currently waiting for a kidney donation,” said Jenna DiRito, a postdoctoral fellow in surgery at Yale and lead author of the research. “Meanwhile, about 20% of the donor organs that are recovered end up being discarded largely due to complications from the declining health of our donor population as a result of co-morbidities like obesity.”
Through a partnership with New England Donor Services and the Blood and Transplant Research Unit in Organ Donation at the University of Cambridge, the Yale-Cambridge team studied 39 kidneys declined by clinicians as unsuitable for transplantation to discover what was wrong with them and how they could be made usable.
Specifically, researchers kept observing vascular blockages in these kidneys after the organs sat in cold storage, and wanted to know why. These blockages, or “plugs,” prevented blood flow and impeded delivery of drugs that could repair the organs.
The researchers discovered that cold storage — the standard method for preserving organs — led to a buildup of fibrinogen, a protein associated with blood clots. When that happened, said co-author Gregory Tietjen, assistant professor of surgery (transplant) at Yale School of Medicine, “plugs formed that choked off the circulation and prevented delivery of additional therapeutics.”
They then studied the organs using a technique called normothermic machine perfusion (NMP), in which an organ is put on a pump and supplied with red blood cells, oxygen, and nutrients at normal body temperature, a technique Tietjen compares to “putting an organ on a treadmill and testing its fitness.” They found that plug-causing fibrinogen quickly left epithelial cells in the kidneys during NMP, Tietjen said. “In turn,” he said, “we were able to develop a regimen to treat the organ which led to significant improvements in organ function on the pump.”
Specifically, the researchers administered to the donor kidneys a combined regimen of plasminogen and tissue plasminogen activator — therapies typically used to dissolve blood clots — and saw both a significant reduction in markers of kidney injury and improvement in kidney function. They were able to successfully treat vascular plugging induced by the cold storage and make the organs safe for transplant.
They plan to launch a clinical trial with patients at Yale in early 2021, in which physicians will transplant kidneys repaired through the new process. It will mark the first use of NMP in a clinical trial of an organ transplant in the U.S., according to Tietjen.
“The pace of translation in organ transplants can be really fast thanks to our ability to study the human organs directly,” he said.
When available transplant organs aren’t used, Tietjen added, it’s not just a tragedy for would-be recipients, but for donor families as well.
“When a donor family loses a loved one, at least they can take solace in the fact that part of them saved another family from enduring the same tragedy,” he said. “But with all these discarded organs, donor families are denied that solace. We hope this research can help us better honor the profound gift that every donor organ represents.”