Over the past several months, a small number of patients have received genetically modified pig kidneys. Three of the four procedures were performed at Massachusetts General Hospital (MGH) in Boston. The MGH medical team reported that a novel immunosuppressive strategy using an investigational therapy, tegoprubart, helped make these transplants possible. Tegoprubart therapy targets CD40 ligand (CD40L), a key co-stimulatory immune pathway. 

“The field of xenotransplantation is entering clinical trials and continues in preclinical studies in nonhuman primates,” said Jay A. Fishman, MD, associate director of the Transplantation Center and the director of the Transplant Infectious Disease & Compromised Host Program at MGH. “One of the cardinal lessons of innovation in transplantation is that one size does not fit all. We need to be able to individualize immunosuppression and infectious prophylaxis for the needs of each patient.”

Recent single-cell and multiomic kidney analyses now allow clinicians to better identify graft rejection and detect microbes (human-origin or zoonotic).

“These data provide a platform for uniform immune and infectious analysis of xenotransplant recipients and represent an important step toward analysis and understanding of xenotransplants,” Fishman told Medscape Medical News.

Investigators hope that advances in genetically edited donor pigs and novel immunosuppression will pave the way for broader clinical trials. However, widespread adoption will take time. The team cautions against overselling pig kidney transplants to the public.

“The field will require further preclinical and clinical trials to assure success and safety,” said Fishman, who also serves as president-elect of the International Xenotransplantation Association.

Meeting an Urgent Demand for Donor Organs

Tatsuo Kawai, MD, PhD, director of the Legorreta Center for Clinical Transplant Tolerance at MGH and a professor of surgery at Harvard Medical School in Boston, noted that because donor organ availability remains severely limited, xenotransplantation represents the most promising strategy to address the organ shortage.

“Only about 30% of patients on the kidney waitlist ultimately receive a transplant, with wait times ranging from 4-10 years depending on the state. Tragically, many patients on dialysis die while still waiting for a suitable organ,” Kawai told Medscape Medical News.

Three classes of genetic modifications have been adopted to improve compatibility and support long-term function in human recipients: elimination of three glycan antigens to prevent hyperacute immune rejection, insertion of seven human transgenes to regulate immune response, and inactivation of endogenous retroviruses in the porcine genome to enhance safety.

“We still need to determine the optimal genetic modifications in donor pigs and refine immunosuppressive strategies,” Kawai added. “At present, intensive immunosuppression and additional medications are required to prevent and manage complications. I anticipate it will take 3-5 years before this can be established as a viable treatment option for patients.”

Input From Patients on Dialysis

Heather Murphy, MA, medical project director at the National Kidney Foundation, leads xenotransplantation initiatives and works closely with leading centers and regulatory bodies to ensure that patient perspectives are incorporated. Early research, she said, suggests xenotransplantation could one day provide an additional, sustainable organ source.

“Patients facing long wait times on dialysis may eventually have another option when a compatible human kidney isn’t available. While still experimental, these studies are helping us understand how to improve safety, reduce rejection, and bring us closer to clinical application,” Murphy told Medscape Medical News.

Earlier this year, the US FDA granted an Investigational New Drug application to initiate a clinical trial evaluating EGEN-2784, a genetically engineered porcine-derived kidney, in patients with end-stage kidney disease (ESKD). A phase 1/2/3 study is underway to assess the safety, tolerability, and efficacy of EGEN-2784 through 24 weeks post-transplant in dialysis-dependent adults aged 50 years or older with ESKD and on the kidney waitlist.

“It’s an important milestone, but we’re still at the beginning,” Murphy said. “Right now, it doesn’t change how doctors and patients talk about treatment. Dialysis and human kidney transplants remain the standard. What it does change is the sense of possibility. It shows progress toward a future where patients may have more options, and that’s a source of hope.”

Fishman, Kwai, and Murphy reported having no financial disclosures.

John Schieszer, MA, is an award-winning national journalist and podcast broadcaster of The Medical Minute. He can be reached at medicalminutes@gmail.com.