Kidney xenotransplant: immunosuppression and rejection
Table of contents
A 62-year-old man has been on hemodialysis for four years due to chronic kidney disease secondary to diabetes and hypertension. He has a working fistula, but he is highly sensitized after transfusions and a previous failed transplant, and antibodies against human antigens make finding a compatible donor unlikely. The transplant team presents him for screening in a research protocol with a genetically edited pig kidney. He wants to know whether it is safe, what medicines he will take and what can go wrong. The scene is fictional and was written for teaching.
This text uses the scenario as a clinical reasoning setting for students and health professionals. Pig kidney xenotransplantation is still experimental, and access in the United States happens through studies under FDA authorization and through expanded access case by case (Yamanaka and colleagues, 2026). The text does not replace the protocol team, the informed consent form or the rules of your country's agency. If you play the case of the day on NEXO, you will recognize the challenge: deciding with clues that arrive in sequence and with a lot of uncertainty.
Key points
- The kidneys used in people come from pigs with several genetic edits, which remove carbohydrate antigens and add human genes for complement and coagulation regulation.
- The basis of the edits is the removal of three antigens: alpha-Gal, Neu5Gc and Sd(a), linked to antibody-mediated rejection.
- In the United States, there is no pig kidney approved for routine use, and the EXPAND study (NCT06878560) has been recruiting since October 2025.
- The reports describe intense induction with lymphocyte depletion and complement blockade, followed by maintenance with tacrolimus, mycophenolate and corticosteroid, sometimes with anti-CD154 antibody.
- Cellular rejection can appear in the first week, even with low lymphocytes in the blood, and biopsy guides treatment.
- Porcine endogenous retroviruses and porcine cytomegalovirus require screening of the animal and lifelong surveillance of the recipient.
Why this is a reasoning scenario
The shortage of organs is the underlying problem. Many patients on dialysis die on the waiting list or become too sick to receive a kidney, and dialysis brings significant morbidity and mortality (Ribas and colleagues, 2026). Xenotransplantation tries to answer this with organs from animals bred for that purpose. Even those who will never join a protocol may see one of these patients in the emergency department, on dialysis or on the ward, and need to understand what the patient received.
The scenario is good for training because it brings together several difficult decisions. You have to weigh the risk of staying on dialysis against the risk of a new procedure. You have to know the immunosuppression, which is more intense than that of an ordinary transplant. And you have to recognize rejection and infection in an organ that is not human. The post on signs, symptoms and history shows how to organize the history, and the post on diagnostic uncertainty helps decide when the evidence is still scarce.
What the scene teaches
The scene trains five habits. The first is separating what is routine from what is research. The second is checking inclusion and exclusion criteria instead of presuming eligibility. The third is knowing the logic of immunosuppression. The fourth is suspecting rejection early and requesting biopsy. The fifth is remembering that infection surveillance lasts a lifetime.
What is not at stake
The text does not discuss surgical technique in detail nor promise results. The doses cited come from published reports of a single patient and serve to show the logic of treatment, not to guide prescription. Each protocol defines its own regimen.
What an edited pig kidney is
The pig kidney has size and function similar to those of the human kidney, but the immune system recognizes its cells as foreign. Without genetic edits, natural antibodies against sugars on the pig surface activate complement and destroy the organ in minutes or hours, the so-called hyperacute rejection (Yamanaka and colleagues, 2026).
The three basic edits
In pigs bred for xenotransplantation, the triple knockout of GGTA1, CMAH and B4GALNT2 is the base modification (Yamanaka et al., 2026). Removing GGTA1 eliminates the alpha-Gal antigen and inhibits hyperacute rejection; removing CMAH eliminates Neu5Gc and reduces late rejection and endothelial injury; removing B4GALNT2 reduces antibody binding to the Sd(a) antigen (Yamanaka et al., 2026).
Human genes added
In addition to the knockouts, the pigs receive human genes. CD46, CD55 and CD59 regulate complement; other genes, such as thrombomodulin and the endothelial protein C receptor, help control coagulation (Yamanaka et al., 2026). The kidney used in a study with a brain-dead donor came from a pig with 10 modifications: knockout of the growth hormone receptor and of the three antigens, and expression of CD55, CD46, thrombomodulin, protein C receptor, CD47 and heme oxygenase 1 (Cheung et al., 2024). The knockout of the growth hormone receptor serves to limit organ growth after transplantation (Yamanaka et al., 2026).
The pig with 69 edits
Another design uses the Yucatan minipig, blood type O, with 69 edits: knockout of the three carbohydrate antigens, seven human transgenes inserted at a single site in the genome and inactivation of 59 copies of porcine endogenous retrovirus (PERV) (Anand et al., 2023). It was a kidney of this type, called EGEN-2784, that a 62-year-old man received at Massachusetts General Hospital (Ribas et al., 2026). Miniature breeds are also studied to solve the problem of organ growth (Yamanaka et al., 2026).
In non-human primates, kidneys from pigs with 10 edits and inactivated PERV reached a maximum survival of 758 days, with a median of 176 days (Yamanaka et al., 2026). Studies in brain-dead donors, including with minipigs in China, showed that the edits prevent hyperacute rejection, but these models are short-lived (Wang et al., 2024), (Pan et al., 2024).
Regulatory status and ongoing studies
United States. The FDA defines xenotransplantation as the transplantation, implantation or infusion into a human recipient of live cells, tissues or organs of animal origin, or of human material that has had contact with them outside the body (FDA, xenotransplantation page). No pig kidney is approved for routine use. First, there were rescue procedures through expanded access, evaluated case by case (Yamanaka et al., 2026). Then, in early 2025, the FDA authorized the first investigational new drug (IND) application for a formal study, designed to start with 6 patients and reach up to 50, with safety as the primary objective, primary assessment at 24 weeks and lifelong follow-up (Yamanaka et al., 2026).
In the ClinicalTrials.gov registry, the EXPAND study (NCT06878560), by United Therapeutics, evaluates the kidney with 10 genetic edits in patients with end-stage kidney disease (ClinicalTrials.gov, NCT06878560). It is a phase 1/2, single-group study, with 50 estimated participants, start on October 29, 2025 and status of active recruitment in the latest update, of March 27, 2026 (ClinicalTrials.gov, NCT06878560). The same sponsor registered EXTEND (NCT07224763), with a pig kidney and thymus with GGTA1 knockout, also recruiting (ClinicalTrials.gov, NCT07224763).
Other countries. Outside the United States, any use depends on the agency and the ethics committees of each country. In China, groups have published transplants of kidneys from edited minipigs into brain-dead recipients (Wang et al., 2024). In any country, participation only happens within an approved protocol.
The table summarizes the stages described in the sources.
| Stage | What it is | Source |
|---|---|---|
| Non-human primates | Kidneys from pigs with 10 edits and inactivated PERV; maximum survival of 758 days | (Yamanaka et al., 2026) |
| Brain-dead donor | Studies of days to weeks, with biopsies and molecular analyses | (Cheung et al., 2024), (Schmauch et al., 2026) |
| Expanded access | Rescue procedures assessed case by case | (Yamanaka et al., 2026) |
| Study under IND | EXPAND, phase 1/2, 50 estimated participants, start on 10/29/2025 | (ClinicalTrials.gov, NCT06878560) |
| Kidney with thymus | EXTEND, pig kidney and thymus with GGTA1 knockout, recruiting | (ClinicalTrials.gov, NCT07224763) |
Who can enter a protocol
Choosing well who enters a protocol is part of safety. An analysis of data from the American registry proposed identifying patients at higher risk of dying or leaving the waiting list before receiving a human kidney, considering age at inclusion, diabetes, time on the waiting list, blood type and previous transplant (Ata et al., 2025). The idea is to offer xenotransplantation to those with little chance of receiving a human organ in time.
EXPAND criteria
The EXPAND registry lists, among other criteria (ClinicalTrials.gov, NCT06878560):
- Hemodialysis for at least 6 months, with a working access.
- Age between 50 and 70 years, or between 40 and 49 years with very high sensitization (antibody panel of at least 99.9 percent).
- Ineligibility for transplantation with a human kidney, or inclusion on the waiting list without a living donor and with a higher probability of dying than of being transplanted within 5 years.
- Negative crossmatch with pig cells.
- Body mass index up to 35.
- Positive serology for cytomegalovirus and Epstein-Barr, vaccinations up to date, including against meningococcus, and residence within 3 hours of the center.
Pulmonary hypertension, advanced cardiovascular disease and the need for anticoagulation are among the exclusion criteria (ClinicalTrials.gov, NCT06878560). The man in the scene has compatible age, dialysis time and access, but the cardiac assessment will weigh heavily, because years of dialysis leave marks on the heart.
The heart of the patient on dialysis
In the recipient of the EGEN-2784 kidney, a fatal cardiac event occurred on day 51 (Ribas et al., 2026). The autopsy found no acute infarction, but chronic myocardial fibrosis, probably linked to the microvascular disease of prolonged dialysis, which may have favored arrhythmia (Ribas et al., 2026). The authors call for more studies on the role of graft-related systemic inflammation in cardiovascular risk (Ribas et al., 2026). For the scene, the lesson is clear: careful cardiac screening before and monitoring after.
The post on clinical decision-making helps choose the screening tests, and the post on differential diagnosis shows how to think about the causes of worsening after transplantation.
Immunosuppression: what the reports describe
Immunosuppression regimens in xenotransplantation are still being tested and vary between centers. What the reports have in common is intense induction, which reduces lymphocytes and blocks complement, followed by maintenance with several drugs.
The recipient of EGEN-2784
In the report by Ribas et al., induction included rabbit antithymocyte globulin, rituximab, high-dose corticosteroid and ravulizumab, an anti-C5 antibody (Ribas et al., 2026). Maintenance used tegoprubart, an anti-CD154 antibody with a modified Fc, together with tacrolimus, mycophenolic acid and prednisone (Ribas et al., 2026). The regimen reduced proteins and cells linked to the effector immune response, and the drop in creatinine and cystatin C accompanied the improvement in graft function (Ribas et al., 2026).
Studies with donors in brain death
In the model by Cheung et al., with a pig kidney with 10 edits, induction used antithymocyte globulin, rituximab and methylprednisolone, and maintenance used tacrolimus, mycophenolate mofetil and prednisone, a regimen with known safety in human transplants (Cheung et al., 2024). In the 61-day study by Schmauch et al., with a pig kidney and thymus with GGTA1 knockout, the review by Yamanaka describes induction with rituximab, antithymocyte globulin and methylprednisolone, and maintenance with eculizumab, antithymocyte globulin, belatacept, tacrolimus, mycophenolate and corticosteroid (Yamanaka et al., 2026), (Schmauch et al., 2026).
Why block complement
Molecular analyses showed increased lectin pathway molecules in the graft, which suggests that all three complement pathways, classical, alternative and lectin, may take part in rejection (Yamanaka and colleagues, 2026). So blocking just one pathway is not enough, and the pigs receive human complement regulatory genes in addition to the drugs (Yamanaka and colleagues, 2026).
Anyone caring for one of these patients outside the center should remember that tacrolimus levels, interactions and the effects of monoclonal antibodies follow the protocol rules. Any change must be agreed with the transplant team. The post on interprofessional clinical reasoning shows why pharmacy, nursing and nephrology need to talk to each other.
Rejection: recognizing and treating
Even with the edits and intense induction, rejection can appear. In the EGEN-2784 recipient, a Banff grade 2A T cell-mediated rejection appeared in the first week and was confirmed by biopsy on day 8 (Ribas and colleagues, 2026). This happened despite the marked drop in adaptive immune cells in the blood: the T lymphocytes vanished from the circulation, but not from every tissue (Ribas and colleagues, 2026).
How it was treated.
Treatment included two steroid pulses, an antibody against the interleukin 6 receptor on day 8 and antithymocyte globulin on days 9 and 10, with an increase in tacrolimus and mycophenolic acid (Ribas and colleagues, 2026). In the methods description, the antibody was tocilizumab 8 mg/kg, the pulses were methylprednisolone 500 mg on days 9 and 10 and the antithymocyte globulin was given at 1.5 mg/kg (Ribas and colleagues, 2026). Because the biopsy showed C3 deposition, the doctors gave pegcetacoplan, a C3 inhibitor, from day 12 to day 28 (Ribas and colleagues, 2026). There was no sign of antibody-mediated rejection, and tocilizumab was not repeated (Ribas and colleagues, 2026).
Antibody-mediated rejection.
In the 61-day study, serial analysis identified molecular markers of antibody-mediated and T cell-mediated rejection, and followed their treatment and resolution (Schmauch and colleagues, 2026). In the few-day studies with brain-dead donors, the initial analysis of the biopsies showed no clear rejection, but the short duration may hide changes that appear later (Pan and colleagues, 2024).
Signs that call for attention.
For those following the patient, the signs are those of any transplant: falling urine output, rising creatinine, fever, pain in the graft. EXPAND includes filtration rate and proteinuria among the outcomes (ClinicalTrials.gov, NCT06878560). If the patient worsens, the course of action is to notify the protocol team, which decides on biopsy and treatment. The post on clinical deterioration on the ward shows how to escalate when vital signs change.
Infections and zoonosis risk
The xenotransplant recipient has two infection risks. The first is that of any heavily immunosuppressed patient, with opportunistic infections. The second is that of receiving agents from the pig itself.
Porcine endogenous retroviruses
PERVs are viral sequences integrated into the pig genome, and for that reason they do not go away with specific pathogen-free breeding (Yamanaka and colleagues, 2026). The ability to infect human cells in the laboratory creates a theoretical risk, but the real risk of transmission, persistent infection and disease in the organism is not yet clear (Yamanaka and colleagues, 2026). Inactivating several copies with the CRISPR technique has become an important safety point (Yamanaka and colleagues, 2026), and the Yucatan pig with 69 edits has 59 copies inactivated (Anand and colleagues, 2023). The FDA notes that retroviruses from other species can remain latent and cause disease years after infection (FDA, xenotransplantation page).
Porcine cytomegalovirus
In the first pig heart transplant, in 2022, porcine cytomegalovirus was detected in the patient, and its role in the loss of the organ was not clear (Sykes and Sachs, 2022). This type of infection can be avoided with stricter screening of the source pigs (Sykes and Sachs, 2022). Today, the donor animals are raised in a designated pathogen-free environment and tested with broad PCR panels (Yamanaka and colleagues, 2026).
Recipient surveillance
EXPAND includes zoonotic infection and opportunistic infection among the outcomes and provides for follow-up of up to 50 years (ClinicalTrials.gov, NCT06878560). Therefore, whoever attends the patient should record fever, collect cultures and notify the center, which may want samples to test for pig agents. The post about sepsis in nursing triage recalls how to act in the first hour.
How NEXO helps train this reasoning
In NEXO, the case of the day is fictional, with a real clinical presentation and up to six progressive clues, and you propose the diagnosis by searching for the ICD-10 code. Xenotransplantation is a good exercise because it forces you to separate evidence from hope and to recognize complications in a new field. The post about learning based on clinical cases explains why this format fixes knowledge.
Three exercises with cases
Change the age. Say whether he would enter EXPAND at 45 years old, with an antibody panel of 99.9 percent.
Change the heart. Say how pulmonary hypertension on the echocardiogram would change the screening.
Change the day. Say what to think if, on day 7, creatinine rose and urine output fell.
The post about diagnostic pause reminds you to stop before closing the management plan, and the post about simulation of care shows how to train the assessment step by step.
The limits of use of the game are described on the NEXO Economy page. If you research teaching of clinical reasoning, the page for Researchers explains how to get in touch. Professionals who write or review cases find information on Curator and on Creators, and institutions can learn about the proposal on the for partnerships page.
Frequently asked questions
Is kidney xenotransplantation already an approved treatment?
No. In the United States, it takes place in studies under FDA authorization and in expanded access case by case (Yamanaka and colleagues, 2026), (ClinicalTrials.gov, NCT06878560).
Why does the pig need genetic edits?
To remove antigens that cause hyperacute rejection and add human genes that regulate complement and coagulation (Yamanaka and colleagues, 2026).
What drugs does the recipient take?
The reports describe induction with lymphocyte depletion and complement blockade, and maintenance with tacrolimus, mycophenolate and corticosteroid, sometimes with anti-CD154 (Ribas and colleagues, 2026), (Cheung and colleagues, 2024).
Can rejection happen early?
Yes. In the recipient of EGEN-2784, there was confirmed cellular rejection on day 8 (Ribas and colleagues, 2026).
Can the pig transmit viruses?
There is a theoretical risk with endogenous retroviruses and a risk of porcine cytomegalovirus, which requires screening of the animal and surveillance of the recipient (Yamanaka and colleagues, 2026), (Sykes and Sachs, 2022).
Final checklist
- I confirmed that the procedure only takes place within an approved protocol.
- I checked the study inclusion and exclusion criteria, including dialysis time and access.
- I assessed the heart carefully before inclusion.
- I reviewed the induction and maintenance defined by the protocol and the drug interactions.
- I agreed with the center team on any change in immunosuppression.
- I taught the patient to recognize decreased urine, fever and pain in the graft.
- I remembered that fever calls for cultures and contact with the center, because of the risk of zoonosis.
- I gave guidance about follow-up for life.
Want to practice reasoning with progressive clues? Play the case of the day.
References
- Anand RP, Layer JV, Heja D, et al. Design and testing of a humanized porcine donor for xenotransplantation. Nature. 2023. PMID 37821590.
- Ata B, Montgomery RA, Ozyoruk YN, et al. A data-driven analysis of patient selection for xenotransplant human clinical trials. PLoS One. 2025. PMID 41325474.
- Cheung MD, Asiimwe R, Erman EN, et al. Spatiotemporal immune atlas of a clinical-grade gene-edited pig-to-human kidney xenotransplant. Nat Commun. 2024. PMID 38605083.
- Pan W, Zhang W, Zheng B, et al. Cellular dynamics in pig-to-human kidney xenotransplantation. Med. 2024. PMID 38776915.
- Ribas GT, Cunha AF, Avila JP, et al. Immune profiling in a living human recipient of a gene-edited pig kidney. Nat Med. 2026. PMID 41507576.
- Schmauch E, Piening BD, Dowdell AK, et al. Multi-omics analysis of a pig-to-human decedent kidney xenotransplant. Nature. 2026. PMID 41233547.
- Sykes M, Sachs DH. Progress in xenotransplantation: overcoming immune barriers. Nat Rev Nephrol. 2022. PMID 36198911.
- United Therapeutics. Study to Evaluate the Safety and Efficacy of the 10 GE Xenokidney in Patients With ESRD. ClinicalTrials.gov NCT06878560. Accessed 24/10/2026. Official source.
- United Therapeutics. Study to Evaluate the Safety and Efficacy of the GGTA1 KO Thymokidney in Patients With ESRD. ClinicalTrials.gov NCT07224763. Accessed 24/10/2026. Official source.
- U.S. Food and Drug Administration. Xenotransplantation. Content updated on 09/04/2026. Accessed 24/10/2026. Official source.
- Wang Y, Chen G, Pan D, et al. Pig-to-human kidney xenotransplants using genetically modified minipigs. Cell Rep Med. 2024. PMID 39317190.
- Yamanaka K, Kakuta Y, Miyagawa S, et al. Present Advances and Emerging Challenges in Kidney Xenotransplantation. J Clin Med. 2026. PMID 41827111.