By 2050, organ transplantation will be radically transformed—from a scarce, donor-dependent therapy into a diverse ecosystem of biological and technological solutions. Patients will receive organs from genetically engineered pigs, bioprinting labs, or even their own regenerated cells, while many others may avoid transplantation altogether through regenerative medicine, gene editing, and artificial organ implants. Advances in AI-driven allocation, precision medicine, and opt-out donation policies will expand access and efficiency, though disparities may persist between rich and poor regions. As bioengineered and artificial organs blur the boundaries between human, animal, and machine, the ethical, psychological, and cultural dimensions of identity, equity, and mortality will become central. Ultimately, the future of end-stage organ disease lies not only in replacing organs but in redefining what it means to heal, live, and thrive beyond biological limits.

Regulatory T cells (Tregs)—discovered by Shimon Sakaguchi, Mary Brunkow, and Fred Ramsdell, who were awarded the 2025 Nobel Prize—are central to inducing immune tolerance and preventing organ transplant rejection. These CD4⁺FoxP3⁺ cells suppress alloimmune responses through multiple mechanisms (IL-10, TGF-β secretion; CTLA-4–mediated dendritic cell modulation; IL-2 consumption; cytotoxic effects on effector T cells). Clinically, higher Treg levels correlate with better graft survival and fewer rejection episodes. Early-phase trials in kidney and liver transplantation show that adoptive Treg infusions are safe, reduce acute rejection, and allow lowering of toxic immunosuppressive drugs. Approaches include polyclonal Tregs, donor-specific Tregs (darTregs), low-dose IL-2 to expand Tregs in vivo, and cutting-edge CAR-engineered Tregs for precise graft targeting. Key challenges remain—maintaining Treg stability and specificity, avoiding off-target immunosuppression, and overcoming complex cell manufacturing. Future directions focus on CAR/FOXP3-engineered “super Tregs,” orthogonal IL-2 systems for selective in vivo expansion, biomaterial-based delivery, and scalable Treg production from thymus or iPSCs. These advances aim to achieve durable, donor-specific tolerance with minimal lifelong immunosuppression—potentially transforming transplant care.

Desensitization has transformed kidney transplantation for patients with high immunologic risk by lowering or removing antibodies that would otherwise cause graft loss. Pre- and peri-transplant plasmapheresis (therapeutic plasma exchange) with low-dose intravenous immunoglobulin (IVIG), sometimes combined with B-cell depletion (rituximab) or newer agents (imlifidase, bortezomib, daratumumab), is standard for HLA- or ABO-incompatible living and deceased donor transplants. Plasmapheresis is also first-line therapy for antibody-mediated rejection and for recurrent focal segmental glomerulosclerosis (FSGS), where early, intensive sessions can induce remission; resistant cases may benefit from lipoprotein apheresis. Highly sensitized patients are identified by elevated panel reactive antibody (PRA/cPRA) levels; allocation systems now prioritize these candidates, but desensitization remains key when compatible organs are unavailable. Pediatric protocols aim to minimize apheresis burden while maintaining good graft survival. In parallel, xenotransplantation—especially gene-edited pig kidneys—is entering early human trials; here, preemptive or rescue plasmapheresis/IVIG has shown utility in controlling anti-pig antibody responses. Emerging strategies target long-lived plasma cells, complement pathways, and precise antibody monitoring to make incompatible and xenogeneic transplantation safer and more durable.

When a deceased-donor offer arrives, the on-call surgeon rapidly weighs donor organ quality, recipient need, and logistics within OPTN/UNOS policy. For kidneys, decisions hinge on KDPI, creatinine/AKI course, machine-pump metrics, procurement biopsy (e.g., glomerulosclerosis/arteriosclerosis), HLA antibodies/virtual or physical crossmatch, and the patient’s wait time/sensitization; kidneys tolerate longer cold ischemia and can be deferred a few hours if needed. For livers, the focus is MELD/urgency, donor stability (pressors/arrest), DCD status and warm ischemia, steatosis by appearance/biopsy, extreme transaminases, size match, and the ability to transplant quickly (short cold time ± normothermic perfusion), with far less emphasis on HLA. Logistics—distance/transport mode, OR and team readiness, projected cold ischemia, and availability of perfusion—can tip the balance for either organ. Donor infections (e.g., HCV NAT+) are acceptable with informed consent and modern antivirals; ABO compatibility is mandatory (liver ABO-incompatible only in rare emergencies). UNOS DonorNet, offer filters, image/biopsy sharing, and emerging AI triage tools streamline evaluation, while center-specific protocols and national metrics encourage timely, appropriate acceptance rather than reflexive decline. Ethically, surgeons balance utility and equity—accepting enough risk to save the right patient now without wasting scarce grafts—recognizing that kidney transplantation is comparatively elective in timing, whereas liver transplantation is often urgent and less forgiving of delay.

Chimerism—the coexistence of donor and recipient hematopoietic cells—has become central to understanding and inducing immune tolerance in solid organ transplantation. Early work by Owen, Medawar, and later Starzl revealed that donor “passenger leukocytes” can persist as microchimerism in recipients, reshaping the once one-way host-versus-graft paradigm into a bidirectional model. Stable mixed chimerism can induce central and peripheral tolerance by deleting or regulating donor-reactive lymphocytes, while microchimerism may help sustain long-term graft acceptance but is not uniformly protective. Clinical trials combining kidney or liver transplants with donor stem cell infusions have shown that mixed or even transient chimerism can allow safe withdrawal of immunosuppression, though challenges include toxic conditioning, GVHD risk, inconsistent predictability, and unclear biomarkers. Advances in non-myeloablative regimens, regulatory cell therapies, costimulation blockade, precision immune monitoring, and bioengineering hold promise for making chimerism-based tolerance safer and more broadly applicable.

Following a recent New York Times report that questioned the ethics and safety of donation after circulatory death (DCD), this episode clarifies how DCD and donation after brain death (DBD) actually work in U.S. organ procurement. We explain why DCD now accounts for ~43% of deceased donors (≈7,300 in 2024, 13,496 transplants) and how it complements the ~9,700 brain-dead donors who still provide most organs. We explore the surgical, ethical, and logistical safeguards that make procurement safe and trustworthy, the innovations (machine perfusion, NRP) that expand DCD use, and why expert procurement is the critical bridge that preserves organ quality, upholds public trust, and makes every transplant possible.

During normothermic machine perfusion (NMP), several red flags may prompt declining a liver for transplantation. The most critical biochemical warning is failure to clear lactate to <2–2.5 mmol/L within 2–3 hours, or a rebound rise after initial clearance, indicating poor hepatocellular metabolism. Persistent metabolic acidosis despite heavy bicarbonate support and sharply rising ALT/AST (especially ALT >6000 IU/L) reflect ongoing hepatocellular injury. Perfusion parameters such as low hepatic artery (<150 mL/min) or portal flow (<500 mL/min) at target pressures, or rising vascular resistance, signal microvascular dysfunction. Absent or minimal bile output and, more importantly, abnormal bile chemistry (acidic pH <7.4, high bile glucose nearly equal to perfusate) are strong predictors of biliary complications and graft non-viability. Morphological red flags include patchy discoloration, uneven perfusion, severe steatosis, or firm/nodular architecture. Histology, if available, showing extensive hepatocyte necrosis, endothelial injury, or cholangiocyte death further supports declining. While absolute thresholds vary between centers, the combination of failing metabolic recovery, poor perfusion, absent bile, and histologic injury reliably predicts a high risk of primary non-function or ischemic cholangiopathy, making such livers unsuitable for transplant.

Domino liver transplantation is a unique and innovative surgical strategy designed to expand the donor organ pool by utilizing the explanted liver from a patient with a non-cirrhotic metabolic liver disease—such as familial amyloid polyneuropathy or maple syrup urine disease—as a graft for a second recipient. While the donor liver carries a genetic or enzymatic defect, it remains structurally and functionally normal, and the recipient is carefully selected to minimize the risk or impact of the transmitted condition. Since its introduction in the mid-1990s, this technique has demonstrated excellent outcomes with comparable graft and patient survival to standard liver transplantation, particularly when meticulous surgical planning, appropriate donor-recipient matching, and long-term monitoring are ensured. Domino liver transplantation not only optimizes the utility of available organs but also embodies ethical complexity, requiring informed consent and ongoing surveillance to balance the benefits of life-saving transplantation against the potential late-onset effects of inherited metabolic diseases.

This episode of TTS Podcast explores “Smarter Organ Allocation: AI, Policy, and KDPI Optimization”, focusing on how recent U.S. policy reforms like continuous distribution, kidney expedited placement protocols, and updated scoring systems (KDPI, EPTS, MELD 3.0) are reshaping transplant equity and efficiency. It examines cutting-edge AI applications in donor-recipient matching, survival prediction, and real-time decision support, alongside integration with electronic health records and predictive analytics tools. By merging data-driven models with evolving allocation frameworks, these innovations aim to maximize graft utility, reduce organ discard, and ensure fairer access across all organ types, marking a transformative era in transplantation.

Vascular complications after liver transplantation – HAT, HVOO, and PVT – though infrequent, demand a high index of suspicion and aggressive management. Early Doppler ultrasound monitoring and prompt imaging are essential to detect these complications in their nascent stages. Advances in surgical techniques and interventional radiology have significantly improved outcomes: for example, timely IR procedures now salvage many grafts that previously would have been lost. Multidisciplinary care, involving transplant surgeons, hepatologists, interventional radiologists, and intensive care specialists, is required to optimize results. Moreover, preventive strategies – from meticulous surgical anastomoses to prophylactic anticoagulation in high-risk patients – are increasingly recognized as crucial in minimizing the incidence of these complications. By understanding the incidence, risk factors, and presentations of HAT, HVOO, and PVT, transplant teams can ensure early diagnosis and tailored interventions, thereby improving graft survival and patient outcomes in liver transplantation.