Faculty Bibliography

BACKGROUND:Left-sided kidneys are preferred for living donor kidney transplant (LDKT) because their longer renal vein leads to greater technical ease. Nevertheless, right-sided nephrectomies are performed when favorable for donors. We evaluated national and center-level trends in right living donor nephrectomy. METHODS:We used SRTR data to identify all LDKTs from 1995-2024 and calculated annual proportions of right kidneys. Then analyzing the contemporary 10-year period (2015-2024), we calculated the Pearson correlation coefficient between center-level LDKT volume and proportion of right-sided nephrectomies. We also assessed the effect of Kidney paired donation (KPD) on proportion of right kidneys used at the center and national levels. We also compared the incidence of delayed graft function (DGF) and 90-day graft failure. RESULTS:= 0.02). KPDs involved a greater proportion of right kidneys compared to direct donations (12% vs. 11%, p = 0.003). Additionally, even in the contemporary era, right-sided LDKTs had higher incidence of DGF (2.4% vs. 1.3%) and 90-day graft failure (8.7% vs. 5.2%) compared to left-sided LDKTs (both p < 0.01). CONCLUSIONS:Center-level variation in right LDKTs likely reflects different thresholds in accepting anatomic complexity or split function and is independent from overall center volume. Further, despite advances in laparoscopic LDKT, right kidneys remain associated with early graft dysfunction in the contemporary era.

Organ shortage remains a major challenge in transplantation, and gene-edited pig organs offer a promising solution^1-3. Despite gene-editing, the immune reactions following xenotransplantation can still cause transplant failure⁴. To understand the immunological response of a pig-to-human kidney xenotransplantation, we conducted large-scale multi-omics profiling of the xenograft and the host's blood over a 61-day procedure in a brain-dead human (decedent) recipient. Blood plasmablasts, natural killer (NK) cells, and dendritic cells increased between postoperative day (POD)10 and 28, concordant with expansion of IgG/IgA B-cell clonotypes, and subsequent biopsy-confirmed antibody-mediated rejection (AbMR) at POD33. Human T-cell frequencies increased from POD21 and peaked between POD33-49 in the blood and xenograft, coinciding with T-cell receptor diversification, expansion of a restricted TRBV2/J1 clonotype and histological evidence of a combined AbMR and cell-mediated rejection at POD49. At POD33, the most abundant human immune population in the graft was CXCL9+ macrophages, aligning with IFN-γ-driven inflammation and a Type I immune response. In addition, we see evidence of interactions between activated pig-resident macrophages and infiltrating human immune cells. Xenograft tissue showed pro-fibrotic tubular and interstitial injury, marked by S100A6⁵, SPP1⁶ (Osteopontin), and COLEC11⁷, at POD21-POD33. Proteomics profiling revealed human and pig complement activation, with decreased human component after AbMR therapy with complement inhibition. Collectively, these data delineate the molecular orchestration of human immune responses to a porcine kidney, revealing potential immunomodulatory targets for improving xenograft survival.

Xenotransplantation of genetically-modified pig kidneys offers a solution to the scarcity of organs for end-stage renal disease patients.¹ We performed a 61-day alpha-Gal knock-out pig kidney and thymic autograft transplant into a nephrectomized brain-dead human using clinically approved immunosuppression, without CD40 blockade or additional genetic modification. Hemodynamic and electrolyte stability and dialysis independence were achieved. Post-operative day (POD) 10 biopsies revealed glomerular IgM and IgA deposition, activation of early complement components and mesangiolysis with stable renal function without proteinuria, a phenotype not seen in allotransplantation. On POD 33, an abrupt increase in serum creatinine was associated with antibody-mediated rejection and increased donor-specific IgG. Plasma exchange, C3/C3b inhibition and rabbit anti-thymocyte globulin (rATG), completely reversed xenograft rejection. Pre-existing donor-reactive T cell clones expanded progressively in the circulation post-transplant, acquired an effector transcriptional profile and were detected in the POD 33 rejecting xenograft prior to rATG treatment. This study provides the first long-term physiologic, immunologic, and infectious disease monitoring of a pig-to-human kidney xenotransplant and indicates that pre-existing xenoreactive T cells and induced antibodies to unknown epitope(s) present a major challenge, despite significant immunosuppression. It also demonstrates that a minimally gene-edited pig kidney can support long-term life-sustaining physiologic functions in a human.

With U.S. Food and Drug Administration (FDA) clearance of clinical trials of kidney xenotransplantation (XTx) in living humans, understanding the recipient experience is critical. Semi-structured interviews with the three living XTx recipients identified core domains of the recipient experience, including quality of life (QoL), fears about XTx, and healthcare team communication and support. Transcribed interviews were analyzed by two qualitative researchers using an inductive thematic approach and were mapped onto the Warwick Patient Experience Model, a validated framework to assess key aspects of patient satisfaction with the healthcare experience. All three recipients (53-year-old female; 66-year-old male; 54-year old male) described a restoration of hope, contrasted with their poor quality of life on dialysis. They emphasized that access to XTx and graft survival requires mutual confidence and commitment between recipients and healthcare teams. XTx recipients use dialysis as a point of reference when describing changes in their post-transplant QoL and seemed well-situated to handle the possibility of graft failure. These insights may aid in the creation of decision aids and educational materials tailored to the specific needs of XTx recipients.

BACKGROUND:Multiorgan heart and kidney transplants (HKTx) performed for patients with end-stage heart failure and chronic kidney disease have increased in recent years. However, no established protocols exist on whether a heart and kidney from the same donor should be transplanted in the same operation versus 1-2 days apart. METHODS:Using SRTR data 1993-2023, we compared same-donor HKTx recipients with both transplants performed on the same day ("simultaneous") to recipients with kidney transplants performed within 1 day of the heart transplant ("staged"). We examined differences in weighted post-transplant clinical characteristics using average treatment effect. Post-transplant mortality and graft failure was also assessed using Kaplan-Meier curves and instrumental variable analysis adjusted for recipient characteristics and year of transplant. RESULTS:, p < 0.001). Weighted patient mortality, all cause heart failure (ACHF), and all cause kidney failure (ACKF) 4 years post-transplant were slightly lower for simultaneous versus staged HKTx recipients (17.1% vs. 19.9%, 17.2% vs. 20.1%, 20.8% vs. 24.7%). However, instrumental variable analysis found no meaningful differences in adjusted patient survival, ACHF, or ACKF by HKTx type. CONCLUSION/CONCLUSIONS:Simultaneous HKTx recipients have shorter hospital stays, decreased mortality, and higher rates of graft survival post-transplant compared to staged HKTx recipients, which may reflect favorable patient factors that enable both operations to be performed on the same day rather than an inherent benefit of simultaneous HKTx, given equivalent adjusted patient mortality, ACHF, and ACKF.

BACKGROUND:Porcine genome editing has revolutionized xenotransplantation, recently enabling the first pig-to-human heart xenotransplants. However, the xeno-immune response in heart xenografts remains largely unexplored. This study aimed to precisely characterize the xeno-immune response and injury in two heart xenografts, transplanted from 10-gene-edited pigs into brain-dead human recipients. METHODS:We analyzed xenograft biopsies at 66-hour post-reperfusion using a multimodal phenotyping approach combining: morphological evaluation, immunophenotyping, ultrastructural assessment, automated quantification of multiplex immunofluorescence staining and gene expression profiling. Xenografts before implantation and wild-type pig hearts with and without ischemia reperfusion injury and brain death were used as controls. RESULTS:Both xenografts showed evidence of endothelial activation and mild microvascular inflammation without capillary C4d deposition. Immune infiltrates were mainly composed of CD15+ and CD68+ innate immune cells. Ultrastructural assessment showed endothelial swelling with occasional intravascular leucocytes. Deep-learning based automated multiplex immunofluorescence analysis confirmed that microvascular inflammation was primarily associated with CD15+ and CD68+ innate immune cells. Both xenografts showed increased expression of genes and pathways associated with monocyte/macrophage activation, neutrophil activation, interferon-gamma response, natural killer cell burden, endothelial activation, apoptosis and injury repair. This phenotype was absent in all control pig hearts, independently from ischemia reperfusion injury and brain death. CONCLUSIONS:Multimodal phenotyping of pig-to-human heart xenografts revealed early signs of xeno-immune response, characterized by mild innate microvascular inflammation, endothelial activation, and molecular signature characteristic of antibody-mediated rejection. Developing such precision diagnostic system could improve graft monitoring in future clinical settings.

A specialty pharmacy mandate is a rule by insurance companies requiring patients to obtain "specialty" medications from specific pharmacies. This study's objective was to evaluate the impact of these mandates on patient care and the solid organ transplantation population. Two surveys were distributed to transplant professionals within the American Society of Transplantation Communities of Practice (AST COPs) and the International Transplant Nurses Society (ITNS). In total, 167 respondents were included (n = 105 AST COPs, n = 62 ITNS). Most of the AST COP cohort identified as pharmacists (76%), followed by physicians (13%). Most respondents from the ITNS cohort identified their role as nurse/coordinator (97%). Sixty-two percent of respondents from the AST COPs and 48% of respondents from ITNS reported delays in discharge due to specialty pharmacy mandates within the past 12 months. Over 60% described delays in initiation of drug therapy related to these mandates. Additionally, 18%-34% of patients required additional outpatient visits and/or readmissions related to medication access issues in the setting of specialty pharmacy mandates. Over 50% of the time, patients paid out of pocket for medications to allow discharge if an override was not possible. Specialty pharmacy mandates delayed discharges, increased cost, and puts undue strain on the healthcare system for solid organ transplant recipients.

PURPOSE OF REVIEW/OBJECTIVE:Recent advancements in genetic engineering have propelled the field of xenotransplantation from preclinical models to early compassionate use cases. As first-in-human clinical trials (FIHCTs) approach, we examine recent developments, ethical and regulatory challenges, immunological considerations, and the clinical infrastructure necessary for successful xenotransplantation trials. RECENT FINDINGS/RESULTS:Expanded access transplants of pig hearts, kidneys, and livers have identified key challenges. Heart xenotransplants revealed risks of antibody-mediated rejection and zoonotic infections, while kidney xenotransplants suggest that patient selection, rather than immune rejection, may have caused failures. While there has been a report of auxiliary liver transplantation conducted abroad, profound thrombocytopenia poses an obstacle. As FIHCTs draw near, critical clinical challenges include determining the optimal donor genetic constructs and immunosuppressive regimens. Enrollment criteria and patient selection pose additional complexity, alongside ethical concerns such as lifelong zoonosis monitoring. Only a limited number of centers have the expertise needed to conduct these complex trials. SUMMARY/CONCLUSIONS:Xenotransplantation holds great promise as a solution to organ shortages, but success in FIHCTs will require careful design, multidisciplinary collaboration, and strong infrastructure. Addressing immunologic, ethical, and patient selection challenges will be critical. With proper preparation, xenotransplantation could transform organ transplantation.