Background Sirolimus, although not approved for heart transplant recipients (HTRs), is frequently prescribed off-label for mitigating calcineurin inhibitor-related toxicity and promoting graft survival. However, its adverse event profile and real-world outcome associations within specific immunosuppressive combinations remain unclear. Methods This retrospective pharmacovigilance study utilized data from the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS). To minimize confounding by concomitant medication, paired comparisons were restricted to regimens differing only by sirolimus use. Reporting odds ratios (RORs) and adjusted RORs (aRORs), controlling for demographic and geographic variables, were calculated for the composite outcome of transplant rejection or death. Each sirolimus-containing regimen was compared with its corresponding nonsirolimus reference. Results The sirolimus plus tacrolimus regimen showed lower disproportional reporting of transplant rejection or death than the tacrolimus regimen (ROR, 0.532 [95% CI, 0.284-0.994], P=0.048; aROR, 0.419 [95% CI, 0.218-0.804], P=0.009). In other tacrolimus-based regimens (tacrolimus plus mycophenolic acid, tacrolimus plus prednisone, and tacrolimus plus mycophenolic acid plus prednisone), sirolimus addition consistently showed RORs and aRORs <1.000, indicating a similar but nonsignificant trend toward lower reporting of transplant rejection or death. Conclusions This FAERS-based analysis suggested an association between sirolimus-containing regimens and lower disproportional reporting of transplant rejection or death among HTRs. These findings should be interpreted as hypothesis-generating, as spontaneous reporting data are susceptible to confounding and cannot establish causality. Prospective studies with detailed clinical data are needed to determine whether this association persists after adequate confounding control.
Renal retransplantation in the presence of extensive systemic venous thrombosis, lack of reliable vascular access and complex lower urinary tract pathology presents significant challenges. We report a 27-year-old male who presented for kidney retransplantation following chronic rejection of a previous graft. Pretransplant evaluation revealed extensive thrombosis involving central and peripheral venous systems, pericatheter thrombosis of a left femoral dialysis line, burn injury to the trunk, bilateral upper limbs and right lower limb, a previous gunshot injury to the right thigh, volume overload with dyselectrolytemia, panurethral stricture and infected allograft from first transplant. These challenges were approached stepwise by a multidisciplinary team. Peritoneal dialysis was initiated due to complexity in vascular access, and urethral reconstruction using buccal mucosal graft urethroplasty was performed to ensure a good urinary outflow tract along with transplant nephrectomy of the infected graft. The patient received desensitization therapy for donor-specific antibodies and positive crossmatch and orthotopic renal transplantation was performed after native left nephrectomy (due to extensive bilateral iliac vein thrombosis). The patient had excellent postoperative recovery with good allograft function. This case highlights the importance of careful multidisciplinary planning and staged approach for a successful renal retransplantation even in complicated clinical scenarios.
Xenotransplantation using genetically engineered porcine organs offers a solution to the global organ shortage. However, the extreme vulnerability of porcine xenografts to ischemia-reperfusion injury (IRI) poses a barrier that conventional transplant infrastructure cannot overcome. We evaluated the architectural, biological, economic, and regulatory frameworks of a xenotransplantation hybrid hospital (integrating donor swine procurement suites with human operating theaters) as a structural solution to xenogeneic IRI. We systematically reviewed evidence on interspecies molecular incompatibilities amplifying IRI, machine perfusion platforms, dual-track architectural biosafety, health economic modeling, and regulatory prerequisites. Interspecies incompatibilities involving thrombomodulin, tissue factor pathway inhibitor, von Willebrand factor-platelet glycoprotein Ib, CD73, and CD39 amplify xenogeneic IRI, yielding initial xenograft dysfunction rates up to 60% with cold storage versus 0% with perfusion. The hybrid hospital eradicates ischemia via structural colocation, dual-track ventilation separation, and airtight sterile transfer barriers. This framework complements genetic modification and perfusion. Break-even analysis projects parity with mobile perfusion models within 2 to 4 years at 30 to 60 annual procedures ($45,000–$80,000 per quality-adjusted life-year). Regulatory implementation requires dedicated legislation, 50-year biospecimen archives, and blockchain-based lifelong surveillance. The xenotransplantation hybrid hospital is a clinical necessity and an economic imperative, providing the foundation to overcome xenogeneic IRI and scale xenotransplantation safely.
Xenotransplantation using genetically engineered porcine organs has emerged as a transformative strategy to address the critical organ shortage crisis in Asia, where low deceased donation rates and high disease burden create a persistent supply-demand gap. This review examines the Asian perspective on xenotransplantation across five domains: sociocultural acceptance, technical advances in multigene-edited pig platforms, clinical protocol optimization for Asian recipients, regulatory harmonization through the Asian Xenotransplantation Association, and infrastructure development including hybrid clinical centers and capacity-building initiatives. Asian countries, particularly China, South Korea, and Japan, have demonstrated substantial progress in gene editing, designated pathogen-free breeding, and translational research. However, clinical success requires region-specific immunosuppressive protocols, pharmacogenomic adaptation, endemic infectious disease surveillance, and culturally sensitive public engagement. Regional collaboration through harmonized regulatory frameworks, multinational trial networks, and equitable access models will be essential to ensure that xenotransplantation benefits all Asian populations. This review proposes a distinct "Asian way" that integrates scientific excellence with cultural diversity and regional solidarity to shape the future of transplantation medicine.
Costimulation blockade of the CD40-CD154 pathway is among the most effective strategies for preventing allograft rejection, yet development of first-generation anti-CD154 antibodies was discontinued after thromboembolic complications. Higher-order immune complexes of soluble CD154 and anti-CD154 immunoglobulin G cross-link Fcγ receptor IIa (FcγRIIa) on platelets and activate them, localizing the liability to the fragment crystallizable region (Fc) rather than to the CD154-binding arm of the antibody. Engineering strategies address this by excluding the Fc altogether or silencing Fc function. Fc-free antagonists structurally preclude FcγRIIa cross-linking but forfeit neonatal Fc receptor (FcRn)-mediated recycling and size protection from glomerular filtration. Such antagonists must therefore recover both functions by other means. Size-based carriers recover only the second: conjugation of polyethylene glycol (PEG) to an anti-CD154 Fab′ extends its half-life from hours to weeks, as in dapirolizumab pegol, but leaves FcRn recycling unaddressed, while uncertainties remain regarding long-term PEG exposure. Albumin recovers both through FcRn-dependent recycling and its own molecular size, without engaging Fcγ receptors. Dazodalibep, an Fc-free albumin-fusion CD154 antagonist, was administered with belatacept to kidney transplant recipients in a single-arm phase 2a trial without thrombotic events, but the prespecified composite efficacy endpoint was not met.
