Enzyme technology enables first successful blood type conversion in kidney transplant

The first successful human transplant of a kidney converted from blood type A to universal type O used special enzymes developed at the University of British Columbia to help prevent a mismatch and rejection of the organ.

Published today in Nature Biomedical Engineering, the achievement marks a major step toward helping thousands of patients get kidney transplants sooner.

In a first-in-human experiment, the enzyme-converted kidney was transplanted into a brain-dead recipient with consent from the family, allowing researchers to observe the immune response without risking a life.

For two days, the kidney functioned without signs of hyperacute rejection, the rapid immune reaction that can destroy an incompatible organ within minutes. By the third day, some blood-type markers reappeared, triggering a mild reaction, but the damage was far less severe than in a typical mismatch, and researchers saw signs that the body was beginning to tolerate the organ.

"This is the first time we've seen this play out in a human model," said Dr. Stephen Withers, UBC professor emeritus of chemistry who co-led the enzyme development. "It gives us invaluable insight into how to improve long-term outcomes."

The breakthrough is the result of more than a decade of work. In the early 2010s, Dr. Withers and colleague Dr. Jayachandran Kizhakkedathu, a UBC professor in the department of pathology and laboratory medicine and the Centre for Blood Research, were focused on making universal donor blood by stripping away the sugars that define blood types.

Those same sugars, or antigens, coat organ blood vessels. If a recipient's immune system detects the wrong antigen, it attacks. Type-O patients-more than half of kidney waitlists-can only receive type-O organs, yet type-O kidneys are often given to others because they're universally compatible. As a result, type-O patients typically wait two to four years longer, and many die waiting.

Traditional methods for overcoming blood-type incompatibility in transplants require days of intensive treatment to strip antibodies and suppress a recipient's immune system-and require organs from living donors. This new approach changes the organ rather than the patient, meaning transplants could be performed faster, with fewer complications, and for the first time could unlock the use of blood-type mismatched organs from deceased donors-when every hour can determine whether a patient lives or dies.

The key to this approach is the 2019 discovery by the UBC team of two highly efficient enzymes that remove the sugar that defines type-A blood, effectively converting it to type O.

"These enzymes are highly active, highly selective, and work at very low concentrations," said Dr. Kizhakkedathu. "That made the whole concept feasible."

The next challenge was applying this to whole organs, achieved in 2022 when a Toronto team showed lungs could be converted. After successful tests on blood, then lungs and kidneys (with the University of Cambridge) outside the body, the question remained: Could an enzyme-converted organ survive inside a human immune system?

The answer came in late 2023 on an overseas trip for Dr. Kizhakkedathu. "Our collaborators showed me their data where, using our enzymes, they had converted a human kidney and transplanted it into a brain-dead recipient. It was working beautifully." He stayed up late to call Dr. Withers first thing in the B.C. morning. "I was so thrilled. It was a dream moment."

Blood-type antigens act like nametags on cells, and the UBC enzymes act as molecular scissors, snipping off the 'nametag' that marks type A and revealing type O beneath.

It's like removing the red paint from a car and uncovering the neutral primer. Once that's done, the immune system no longer sees the organ as foreign."

Dr. Stephen Withers, UBC professor emeritus of chemistry

Regulatory approval for clinical trials is the next hurdle, and the partner UBC spin-off company Avivo Biomedical will lead development of these enzymes for transplant application and to enable the creation of universal donor blood on demand for transfusion medicine.

The potential is enormous. "This is what it looks like when years of basic science finally connect to patient care," said Dr. Withers. "Seeing our discoveries edge closer to real-world impact is what keeps us pushing forward."