Study reveals innate immune barriers to long-term pig kidney transplant survival

Pioneering research led by Brazilians describes the immune system's reactions in detail in the first living patient to receive a genetically modified pig kidney transplant. This paves the way for the search for therapies that can prevent organ rejection.

The study demonstrates the feasibility of this type of graft but indicates that controlling initial rejection alone is insufficient. This is because even with immunosuppressants, continuous activation of innate immunity – the body's first line of defense, especially macrophages, which react to any threat – can compromise long-term survival.

Through transcriptomic, proteomic, metabolomic, and spatial analyses, the scientists have determined that new strategies are necessary to achieve long-term survival and favorable clinical outcomes. They recommend combining therapies that target innate immunity with advanced genetic engineering in donor pigs. They also suggest preventing early T lymphocyte-mediated rejection and implementing more sensitive monitoring approaches.

Xenotransplantation involves transplanting organs, tissues, or cells from one animal species – mainly genetically modified pigs – to humans. It is considered a promising solution to organ shortages, but rejection has been a major challenge.

In March 2024, the first living patient to receive a pig kidney was a 62-year-old man with end-stage kidney disease who underwent surgery at Massachusetts General Hospital, which is affiliated with Harvard Medical School in Boston. Brazilian nephrologist Leonardo Riella, one of the article's corresponding authors, led the team. The article was published on January 8 in the scientific journal Nature Medicine. The patient died two months later; the probable cause was previous chronic myocardial fibrosis.

According to data from the Brazilian Ministry of Health, kidney transplants are in the highest demand in Brazil. In 2025, about 6,670 surgeries of this type were performed in the country.

Additionally, it is estimated that between 10 and 12 million Brazilians have some form of kidney disease, a figure that could rise as the population ages and the number of people with diabetes, high blood pressure, and obesity increases. In more severe cases, dialysis may be a temporary treatment option. Dialysis is an artificial process that removes waste and excess fluids from the body when the kidneys are not functioning properly.

"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, a professor and researcher at Massachusetts General Hospital and Harvard Medical School, as well as the corresponding author of the article, in an interview with Agência FAPESP.

Multiple perspectives

To comprehensively evaluate the response triggered by renal xenotransplantation, the researchers characterized the recipient's immune profile by cross-referencing information obtained from clinical analyses with information from proteomics and metabolomics, which includes sugars, lipids, amino acids, and other metabolites.

They observed that, in the first week after surgery, the patient's body recognized the transplanted organ as "foreign" and activated cellular rejection, a specific type of defense conducted mainly by T lymphocytes. This process can damage the transplanted organ and was identified and controlled with immunosuppressive drugs.

The study showed that although no more severe rejection (mediated by antibodies) occurred, the immune system remained partially active, especially in monocytes and macrophages. This reveals a central and hitherto underestimated role of innate immunity in xenotransplant rejection.

This rejection was not detected through blood tests. However, tests measuring DNA fragments from the transplanted organ in the bloodstream indicated kidney damage. Based on these results, the group suggests that levels of porcine donor-derived cell-free DNA (dd-cfDNA) could serve as a potential biomarker for this issue. In the case analyzed, the pig kidney had 69 genetic modifications to increase immune compatibility.

"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 explains.

Persistent activation of innate immunity was also observed, with signs of ongoing inflammation. Despite advances in treatment, the findings suggest that current treatments are still unable to fully control immune responses.

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."

Helder Nakaya, senior researcher at the Albert Einstein Jewish-Brazilian Hospital and one of the authors of the article

Nakaya is a professor at the University of São Paulo's School of Pharmaceutical Sciences (FCF-USP) and receives support from FAPESP for the project "Integrative Biology Applied to Human Health." This project aims to develop innovative approaches to analyze epidemiological databases, map disease transmission hotspots, integrate transcriptome data with clinical and immunological information, and use machine learning to interpret and analyze microscopic images.

He is also the principal investigator at the Center for Research on Inflammatory Diseases (CRID), a FAPESP Research, Innovation, and Dissemination Center (RIDC).

"Due to our work developing various analytical tools, including single-cell analysis, we were invited by Harvard researchers to work on the integrated multiomic analysis of these thousands of molecules," adds Nakaya, who has advocated for creating an advanced school specializing in this type of analysis.

In November 2025, a different group of scientists affiliated with U.S. institutions published research evaluating the rejection of a pig kidney transplanted into a brain-dead person (read the article at www.nature.com/articles/s41586-025-09847-6).