Pioneering research led by Brazilian scientists has provided new insights into the immune response following the transplantation of a genetically modified pig kidney into a living human patient. The study, published on January 8 in Nature Medicine, describes in detail how the immune system reacts to such xenotransplants and suggests that current methods to prevent organ rejection may not be sufficient for long-term survival.
The first living recipient of a pig kidney was a 62-year-old man with end-stage kidney disease who underwent surgery at Massachusetts General Hospital, affiliated with Harvard Medical School, in March 2024. The patient died two months later from what was likely pre-existing chronic myocardial fibrosis.
The research team used transcriptomic, proteomic, metabolomic, and spatial analyses to evaluate the immune response. Their findings indicate that while immunosuppressants can control initial rejection—primarily mediated by T lymphocytes—the innate immune system remains active. This ongoing activation, particularly involving macrophages and monocytes, could compromise the long-term success of xenotransplantation.
"The main finding of the study was the detailed, unprecedented, high-resolution characterization of the human immune response following the transplantation of a genetically modified pig kidney into a living patient. The results show that, for xenotransplantation to become a safe and lasting clinical option, controlling only adaptive immunity, as we traditionally do in transplants between humans, is insufficient. Specific strategies must also be developed to modulate the innate immune response and ensure the prolonged survival of xenogeneic grafts in humans," said Thiago Borges, professor and researcher at Massachusetts General Hospital and Harvard Medical School and corresponding author of the article.
The researchers observed that cellular rejection occurred within the first week after surgery but was managed with immunosuppressive drugs. However, they found persistent activity in components of innate immunity that traditional blood tests did not detect. Instead, measuring DNA fragments from the transplanted organ in the bloodstream revealed ongoing damage to the kidney.
"We demonstrated that DNA fragments from the pig kidney circulating in the patient's blood can be used as a sensitive and noninvasive marker of rejection. This opens up the possibility of monitoring the graft in real time, which potentially reduces the need for biopsies," Borges explained.
Despite no evidence of more severe antibody-mediated rejection during this period—and with 69 genetic modifications made to increase compatibility—the study highlighted continued inflammation linked to innate immunity.
"This study was important because it provided a broad view of all the molecular and cellular changes that occurred during the transplant. This can help guide and improve the efficiency of immunosuppression," said Helder Nakaya, senior researcher at Albert Einstein Jewish-Brazilian Hospital and co-author.
Nakaya is also involved with FAPESP-supported projects focused on integrative biology applied to human health. These initiatives aim to develop innovative approaches for analyzing epidemiological data and integrating various types of biological information using advanced analytical tools such as single-cell analysis.
In Brazil, demand for kidney transplants remains high; about 6,670 surgeries were performed in 2025 according to data from Brazil’s Ministry of Health. Between 10 million and 12 million Brazilians are estimated to have some form of kidney disease—a number expected to rise due to aging demographics and increased prevalence of diabetes, hypertension, and obesity. For those with severe cases where kidneys fail entirely or nearly so, dialysis serves as an interim solution until transplantation becomes possible.
Xenotransplantation is being explored globally as one way to address organ shortages but faces significant challenges related to immune rejection. In November 2025 another group published research on pig-to-human kidney transplants involving brain-dead recipients (see www.nature.com/articles/s41586-025-09847-6).
The authors recommend combining therapies targeting both adaptive and innate immunity along with further advances in genetic engineering for donor pigs. They also call for more sensitive monitoring techniques—such as tracking donor-derived cell-free DNA—to better detect early signs of rejection.
