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Chronic kidney disease (CKD) is a major complication of liver transplantation (LT) associated with substantial morbidity and mortality. Knowing the drivers of post-LT kidney dysfunction-with a granular focus on the type, duration, and severity of pre-LT kidney disease-can highlight intervention opportunities and inform dual-organ allocation policies. We retrospectively analyzed predictors of safety net kidney after liver transplant (KALT) eligibility and kidney replacement therapy (KRT) for > 14 days after LT. Among 557 recipients of adult deceased-donor LT, 49% had normal kidney function, 25% had acute kidney injury (AKI), and 25% had CKD±AKI at the time of LT. A total of 36 (6.5%) qualified for KALT and 63 (11%) required KRT > 14 days. In univariable analysis, factors associated with KALT eligibility and KRT > 14 days, respectively, included stage 3 AKI (OR 7.87; OR 7.06), CKD±AKI (OR 4.58; OR 4.22), CKD III-V duration (OR 1.10 per week; OR 1.06 per week), and increasing CKD stage (stage III: OR 3.90, IV: OR 5.24, V: OR 16.8; stage III: OR 2.23, IV: OR 3.62, V: OR 19.4). AKI stage I-II and AKI duration in the absence of CKD were not associated with the outcomes. Pre-LT KRT had a robust impact on KALT eligibility (OR 4.00 per week) and prolonged post-LT KRT (OR 5.22 per week), with 19.8% of patients who received any pre-LT KRT ultimately qualifying for KALT. Eligibility for KALT was similar between those who received 0 days and ≤ 14 days of KRT after LT (2.1% vs. 2.9%, p = 0.53). In conclusion, the type, duration, and severity of pre-LT kidney dysfunction have unique impacts on post-LT kidney-related morbidity, and future research must use these novel classifications to study mitigation strategies.
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The Banff Working Group on Liver Allograft Pathology met in September 2022. Participants included hepatologists, surgeons, pathologists, immunologists, and histocompatibility specialists. Presentations and discussions focused on the evaluation of long-term allograft health, including noninvasive and tissue monitoring, immunosuppression optimization, and long-term structural changes. Potential revision of the rejection classification scheme to better accommodate and communicate late T cell-mediated rejection patterns and related structural changes, such as nodular regenerative hyperplasia, were discussed. Improved stratification of long-term maintenance immunosuppression to match the heterogeneity of patient settings will be central to improving long-term patient survival. Such personalized therapeutics are in turn contingent on a better understanding and monitoring of allograft status within a rational decision-making approach, likely to be facilitated in implementation with emerging decision-support tools. Proposed revisions to rejection classification emerging from the meeting include the incorporation of interface hepatitis and fibrosis staging. These will be opened to online testing, modified accordingly, and subject to consensus discussion leading up to the next Banff conference.
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Rechazo de Injerto , Trasplante de Hígado , Humanos , Rechazo de Injerto/etiología , Rechazo de Injerto/patología , Supervivencia de Injerto , AloinjertosRESUMEN
Over the last 50 years, liver transplantation has evolved into a procedure routinely performed in many countries worldwide. Those able to access this therapy frequently experience a miraculous risk-benefit ratio, particularly if they face the imminently life-threatening disease. Over the decades, the success of liver transplantation, with dramatic improvements in early posttransplant survival, has aggressively driven demand. However, despite the emergence of living donors to augment deceased donors as a source of organs, supply has lagged far behind demand. As a result, rationing has been an unfortunate focus in recent decades. Recent shifts in the epidemiology of liver disease combined with transformative innovations in liver preservation suggest that the underlying premise of organ shortage may erode in the foreseeable future. The focus will sharpen on improving equitable access while mitigating constraints related to workforce training, infrastructure for organ recovery and rehabilitation, and their associated costs. Research efforts in liver preservation will undoubtedly blossom with the aim of optimizing both the timing and conditions of transplantation. Coupled with advances in genetic engineering, regenerative biology, and cellular therapies, the portfolio of innovation, both broad and deep, offers the promise that, in the future, liver transplantation will not only be broadly available to those in need but also represent a highly durable life-saving therapy.
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Predicción , Trasplante de Hígado , Trasplante de Hígado/tendencias , Trasplante de Hígado/métodos , Humanos , Obtención de Tejidos y Órganos/tendencias , Preservación de Órganos/métodos , Preservación de Órganos/tendenciasAsunto(s)
Trasplante de Riñón , Trasplante Homólogo , Aloinjertos , Rechazo de Injerto/patología , Biopsia , Riñón/patologíaRESUMEN
BACKGROUND AND AIMS: Existing tools for perioperative risk stratification in patients with cirrhosis do not incorporate measures of comorbidity. The Hospital Frailty Risk Score (HFRS) is a widely used measure of comorbidity burden in administrative dataset analyses. However, it is not specific to patients with cirrhosis, and application of this index is limited by its complexity. APPROACH AND RESULTS: Adult patients with cirrhosis who underwent nontransplant abdominal operations were identified from the National Inpatient Sample, 2016-2018. Adjusted associations between HFRS and in-hospital mortality and length of stay were computed with logistic and Poisson regression. Lasso regularization was used to identify the components of the HFRS most predictive of mortality and develop a simplified index, the cirrhosis-HFRS. Of 10,714 patients with cirrhosis, the majority were male, the median age was 62 years, and 32% of operations were performed electively. HFRS was associated with an increased risk of both in-hospital mortality (OR=6.42; 95% CI: 4.93, 8.36) and length of stay (incidence rate ratio [IRR]=1.79; 95% CI: 1.72, 1.88), with adjustment. Using lasso, we found that a subset of 12 of the 109 ICD-10 codes within the HFRS resulted in superior prediction of mortality in this patient population (AUC = 0.89 vs. 0.79, p < 0.001). CONCLUSIONS: While the 109-component HFRS was associated with adverse surgical outcomes, 12 components accounted for much of the association between the HFRS and mortality. We developed the cirrhosis-HFRS, a tool that demonstrates superior predictive accuracy for in-hospital mortality and more precisely reflects the specific comorbidity pattern of hospitalized patients with cirrhosis undergoing general surgery procedures.
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Fragilidad , Mortalidad Hospitalaria , Tiempo de Internación , Cirrosis Hepática , Humanos , Masculino , Femenino , Cirrosis Hepática/cirugía , Cirrosis Hepática/complicaciones , Cirrosis Hepática/mortalidad , Cirrosis Hepática/epidemiología , Persona de Mediana Edad , Medición de Riesgo/métodos , Fragilidad/epidemiología , Fragilidad/complicaciones , Anciano , Tiempo de Internación/estadística & datos numéricos , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/etiología , Factores de Riesgo , Comorbilidad , Abdomen/cirugía , Estados Unidos/epidemiologíaRESUMEN
Mouse models have been instrumental in understanding mechanisms of transplant rejection and tolerance, but cross-study reproducibility and translation of experimental findings into effective clinical therapies are issues of concern. The Mouse Models in Transplantation symposium gathered scientists and physician-scientists involved in basic and clinical research in transplantation to discuss the strengths and limitations of mouse transplant models and strategies to enhance their utility. Participants recognized that increased procedure standardization, including the use of prespecified, defined endpoints, and statistical power analyses, would benefit the field. They also discussed the generation of new models that incorporate environmental and genetic variables affecting clinical outcomes as potentially important. If implemented, these strategies are expected to improve the reproducibility of mouse studies and increase their translation to clinical trials and, ideally, new Food and Drug Administration-approved drugs.
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Modelos Animales de Enfermedad , Animales , Ratones , Humanos , Rechazo de Injerto/prevención & control , Rechazo de Injerto/etiología , Trasplante de Órganos , Modelos Animales , Reproducibilidad de los Resultados , Trasplante/métodosRESUMEN
BACKGROUND & AIMS: Successful immunosuppression withdrawal (ISW) is possible for a subfraction of liver transplant (LT) recipients but the factors that define the risk of ISW failure are largely unknown. One candidate prognostic factor for ISW success or operational tolerance (OT) is longer time between LT and ISW which we term "pre-withdrawal time". To clarify the impact of pre-withdrawal time span on subsequent ISW success or failure, we conducted a systematic review with meta-analysis. METHODS: We systematically interrogated the literature for LT recipient ISW studies reporting pre-withdrawal time. Eligible articles from Embase, Medline, and the Cochrane Central Register of Controlled Trials were used for backward and forward citation searching. Pre-withdrawal time individual patient data (IPD) was requested from authors. Pooled mean differences and time-response curves were calculated using random-effects meta-analyses. RESULTS: We included 17 studies with 691 patients, 15 of which (620 patients) with IPD. Study-level risk of bias was heterogeneous. Mean pre-withdrawal time was greater by 427 days [95% confidence interval (CI) 67-788] in OT compared to non-OT patients. This increase was potentiated to 799 days (95% CI 369-1229) or 1074 days (95% CI 685-1463) when restricting analysis to adult or European study participants. In time-response meta-analysis for adult or European ISW candidates, likelihood of OT increased by 7% (95% CI 4-10%) per year after LT (GRADE low- and moderate-certainty of evidence, respectively). CONCLUSIONS: Our data support the impact of pre-withdrawal time in ISW decision-making for adult and European LT recipients. PROSPERO REGISTRATION: CRD42021272995.
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Trasplante de Hígado , Adulto , Humanos , Terapia de Inmunosupresión/efectos adversos , Tolerancia InmunológicaRESUMEN
OBJECTIVE: To create a blueprint for surgical department leaders, academic institutions, and funding agencies to optimally support surgeon-scientists. BACKGROUND: Scientific contributions by surgeons have been transformative across many medical disciplines. Surgeon-scientists provide a distinct approach and mindset toward key scientific questions. However, lack of institutional support, pressure for increased clinical productivity, and growing administrative burden are major challenges for the surgeon-scientist, as is the time-consuming nature of surgical training and practice. METHODS: An American Surgical Association Research Sustainability Task Force was created to outline a blueprint for sustainable science in surgery. Leaders from top NIH-sponsored departments of surgery engaged in video and in-person meetings between January and April 2023. A strength, weakness, opportunities, threats analysis was performed, and workgroups focused on the roles of surgeons, the department and institutions, and funding agencies. RESULTS: Taskforce recommendations: (1) SURGEONS: Growth mindset : identifying research focus, long-term planning, patience/tenacity, team science, collaborations with disparate experts; Skill set : align skills and research, fill critical skill gaps, develop team leadership skills; DEPARTMENT OF SURGERY (DOS): (2) MENTORSHIP: Chair : mentor-mentee matching/regular meetings/accountability, review of junior faculty progress, mentorship training requirement, recognition of mentorship (eg, relative value unit equivalent, awards; Mentor: dedicated time, relevant scientific expertise, extramural funding, experience and/or trained as mentor, trusted advisor; Mentee : enthusiastic/eager, proactive, open to feedback, clear about goals; (3) FINANCIAL SUSTAINABILITY: diversification of research portfolio, identification of matching funding sources, departmental resource awards (eg, T-/P-grants), leveraging of institutional resources, negotiation of formalized/formulaic funds flow investment from academic medical center toward science, philanthropy; (4) STRUCTURAL/STRATEGIC SUPPORT: Structural: grants administrative support, biostats/bioinformatics support, clinical trial and research support, regulatory support, shared departmental laboratory space/equipment; Strategic: hiring diverse surgeon-scientist/scientists faculty across DOS, strategic faculty retention/ recruitment, philanthropy, career development support, progress tracking, grant writing support, DOS-wide research meetings, regular DOS strategic research planning; (5) COMMUNITY AND CULTURE: Community: right mix of faculty, connection surgeon with broad scientific community; Culture: building research infrastructure, financial support for research, projecting importance of research (awards, grand rounds, shoutouts); (6) THE ROLE OF INSTITUTIONS: Foundation: research space co-location, flexible start-up packages, courses/mock study section, awards, diverse institutional mentorship teams; Nurture: institutional infrastructure, funding (eg, endowed chairs), promotion friendly toward surgeon-scientists, surgeon-scientists in institutional leadership positions; Expectations: RVU target relief, salary gap funding, competitive starting salaries, longitudinal salary strategy; (7) THE ROLE OF FUNDING AGENCIES: change surgeon research training paradigm, offer alternate awards to K-awards, increasing salary cap to reflect market reality, time extension for surgeon early-stage investigator status, surgeon representation on study section, focused award strategies for professional societies/foundations. CONCLUSIONS: Authentic recommitment from surgeon leaders with intentional and ambitious actions from institutions, corporations, funders, and society is essential in order to reap the essential benefits of surgeon-scientists toward advancements of science.
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Investigación Biomédica , Cirujanos , Humanos , Estados Unidos , Mentores , Docentes , Centros Médicos Académicos , Movilidad Laboral , National Institutes of Health (U.S.)Asunto(s)
Sistema Cardiovascular , Trasplante de Riñón , Nefrología , Trasplante de Órganos , Humanos , RiñónRESUMEN
Introduction: Donation after circulatory death (DCD) liver transplantation (LT) makes up well less than 1% of all LTs with a Model for End-Stage Liver Disease (MELD)≥35 in the United States. We hypothesized DCD-LT yields acceptable ischemia-reperfusion and reasonable outcomes for recipients with MELD≥35. Methods: We analyzed recipients with lab-MELD≥35 at transplant within the UCSF (n=41) and the UNOS (n=375) cohorts using multivariate Cox regression and propensity score matching. Results: In the UCSF cohort, five-year patient survival was 85% for DCD-LTs and 86% for matched-Donation after Brain Death donors-(DBD) LTs (p=0.843). Multivariate analyses showed that younger donor/recipient age and more recent transplants (2011-2021 versus 1999-2010) were associated with better survival. DCD vs. DBD graft use did not significantly impact survival (HR: 1.2, 95%CI 0.6-2.7). The transaminase peak was approximately doubled, indicating suggesting an increased ischemia-reperfusion hit. DCD-LTs had a median post-LT length of stay of 11 days, and 34% (14/41) were on dialysis at discharge versus 12 days and 22% (9/41) for DBD-LTs. 27% (11/41) DCD-LTs versus 12% (5/41) DBD-LTs developed a biliary complication (p=0.095). UNOS cohort analysis confirmed patient survival predictors, but DCD graft emerged as a risk factor (HR: 1.5, 95%CI 1.3-1.9) with five-year patient survival of 65% versus 75% for DBD-LTs (p=0.016). This difference became non-significant in a sub-analysis focusing on MELD 35-36 recipients. Analysis of MELD≥35 DCD recipients showed that donor age of <30yo independently reduced the risk of graft loss by 30% (HR, 95%CI: 0.7 (0.9-0.5), p=0.019). Retransplant status was associated with a doubled risk of adverse event (HR, 95%CI: 2.1 (1.4-3.3), p=0.001). The rejection rates at 1y were similar between DCD- and DBD-LTs, (9.3% (35/375) versus 1,541 (8.7% (1,541/17,677), respectively). Discussion: In highly selected recipient/donor pair, DCD transplantation is feasible and can achieve comparable survival to DBD transplantation. Biliary complications occurred at the expected rates. In the absence of selection, DCD-LTs outcomes remain worse than those of DBD-LTs.
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Líquidos Corporales , Enfermedad Hepática en Estado Terminal , Trasplante de Hígado , Humanos , Trasplante de Hígado/efectos adversos , Enfermedad Hepática en Estado Terminal/cirugía , Índice de Severidad de la Enfermedad , Donantes de TejidosRESUMEN
Autoimmune hepatitis (AIH) is a severe autoimmune disease, characterized by the presence of autoantibodies. However, the role of autoantibodies in the pathophysiology of AIH remains uncertain. Here, we employed Phage Immunoprecipitation-Sequencing (PhIP-Seq) to identify novel autoantibodies in AIH. Using these results, a logistic regression classifier was able to predict which patients had AIH, indicating the presence of a distinct humoral immune signature. To further investigate the autoantibodies most specific to AIH, significant peptides were identified relative to a broad array of controls (298 patients with non-alcoholic fatty liver disease (NAFLD), primary biliary cholangitis (PBC), or healthy controls). Top ranked autoreactive targets included SLA, the target of a well-recognized autoantibody in AIH, and disco interacting protein 2 homolog A (DIP2A). The autoreactive fragment of DIP2A shares a 9-amino acid stretch nearly identical to the U27 protein of HHV-6B, a virus found in the liver. In addition, antibodies against peptides derived from the leucine rich repeat N-terminal (LRRNT) domain of the relaxin family peptide receptor 1 (RXFP1) were highly enriched and specific to AIH. The enriched peptides map to a motif adjacent to the receptor binding domain, which is required for RXFP1 signaling. RXFP1 is a G protein-coupled receptor that binds relaxin-2, an anti-fibrogenic molecule shown to reduce the myofibroblastic phenotype of hepatic stellate cells. Eight of nine patients with antibodies to RXFP1 had evidence of advanced fibrosis (F3 or greater). Furthermore, serum from AIH patients positive for anti-RFXP1 antibody was able to significantly inhibit relaxin-2 signaling in the human monocytic cell line, THP1. Depletion of IgG from anti-RXFP1 positive serum abrogated this effect. These data provide supporting evidence that HHV6 plays a role in the development of AIH and point to a potential pathogenic role for anti-RXFP1 IgG in some patients. Identification of anti-RXFP1 in patient serum may enable risk stratification of AIH patients for fibrosis progression and lead to the development of novel strategies for disease intervention.
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INTRODUCTION: Although clinicians repeatedly measure ALT to assess allograft health in children with liver transplants, they generally make decisions based on single values or qualitative trends without quantitative aggregation or synthesis. We therefore aimed to derive and test a holistic ALT metric for the 5th post-transplant year (Yr 4-5) that may better guide clinical decision-making and/or population comparisons. METHODS: We derived the "adjusted mean Yr 4-5 ALT" for children transplanted in 2005-2016 by averaging the median ALT from each month. Patients in quartiles (Q1-4) defined by the adjusted mean Yr 4-5 ALT were compared by clinical variables, Yr 5-8 outcomes, and tacrolimus standard deviation (MLVI). RESULTS: For 97 children [49 male; 77 deceased donors; median (IQR) age at LT 2.5 (0.8-11.7) years], the 25th, 50th, and 75th percentile thresholds for adjusted mean Yr 4-5 ALT were 19, 28, and 47 U/L, respectively. Age, donor type, LT indication, rejection history, and mean tacrolimus levels did not differ between quartiles (Q). Children in Q4 had more Yr 4-5 acute rejection episodes (p < .01), higher Yr 4-5 MLVI (p < .01), and more Yr 5-8 for-cause liver biopsies (p < .01) than those in Q1 + Q2. Children in Q3 also had higher Yr 4-5 MLVI than Q1 + Q2 (p = .047). Rates of chronic rejection and therapeutic liver-related procedures were higher in Q4 but the difference did not reach significance. CONCLUSION: An integrated ALT metric calculated utilizing all available ALT values correlates with MLVI and future for-cause biopsies. Further study of this novel ALT metric as a predictor of clinical outcomes and descriptor of populations is warranted.
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Trasplante de Hígado , Humanos , Niño , Masculino , Tacrolimus/uso terapéutico , Donantes de Tejidos , Rechazo de Injerto/diagnóstico , Rechazo de Injerto/epidemiología , Estudios RetrospectivosRESUMEN
OBJECTIVE: To compare conventional low-temperature storage of transplant donor livers [static cold storage (SCS)] with storage of the organs at physiological body temperature [normothermic machine perfusion (NMP)]. BACKGROUND: The high success rate of liver transplantation is constrained by the shortage of transplantable organs (eg, waiting list mortality >20% in many centers). NMP maintains the liver in a functioning state to improve preservation quality and enable testing of the organ before transplantation. This is of greatest potential value with organs from brain-dead donor organs (DBD) with risk factors (age and comorbidities), and those from donors declared dead by cardiovascular criteria (donation after circulatory death). METHODS: Three hundred eighty-three donor organs were randomized by 15 US liver transplant centers to undergo NMP (n = 192) or SCS (n = 191). Two hundred sixty-six donor livers proceeded to transplantation (NMP: n = 136; SCS: n = 130). The primary endpoint of the study was "early allograft dysfunction" (EAD), a marker of early posttransplant liver injury and function. RESULTS: The difference in the incidence of EAD did not achieve significance, with 20.6% (NMP) versus 23.7% (SCS). Using exploratory, "as-treated" rather than "intent-to-treat," subgroup analyses, there was a greater effect size in donation after circulatory death donor livers (22.8% NMP vs 44.6% SCS) and in organs in the highest risk quartile by donor risk (19.2% NMP vs 33.3% SCS). The incidence of acute cardiovascular decompensation at organ reperfusion, "postreperfusion syndrome," as a secondary outcome was reduced in the NMP arm (5.9% vs 14.6%). CONCLUSIONS: NMP did not lower EAD, perhaps related to the inclusion of lower-risk liver donors, as higher-risk donor livers seemed to benefit more. The technology is safe in standard organ recovery and seems to have the greatest benefit for marginal donors.
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BACKGROUND: Outcome data for the great majority of liver normothermic machine perfusion (NMP) cases derive from the strict confines of clinical trials. Detailed specifics regarding the intraoperative and early postoperative impact of NMP on reperfusion injury and its sequelae during real-world use of this emerging technology remain largely unavailable. METHODS: We analyzed transplants performed in a 3-month pilot period during which surgeons invoked commercial NMP at their discretion. Living donor, multi-organ, and hypothermic machine perfusion transplants were excluded. RESULTS: Intraoperatively, NMP (n = 24) compared to static cold storage (n = 25) recipients required less peri-reperfusion bolus epinephrine (0 vs. 60 µg; p < .001) and post-reperfusion fresh frozen plasma (2.5 vs. 7.0 units; p = .0069), platelets (.0 vs. 2.0 units; p = .042), and hemostatic agents (0% vs. 24%; p = .010). Time from incision to venous reperfusion did not differ (3.6 vs. 3.1; p = .095) but time from venous reperfusion to surgery end was shorter for NMP recipients (2.3 vs. 2.8 h; p = .0045). Postoperatively, NMP recipients required fewer red blood cell (1.0 vs. 4.0 units; p = .0083) and fresh frozen plasma (4.0 vs. 7.0 units; p = .046) transfusions, had shorter intensive care unit stays (33.5 vs. 58.4 h; p = .012), and experienced less early allograft dysfunction according to both the Model for Early Allograft Function Score (3.4 vs. 5.0; p = .0047) and peak AST within 10 days of transplant (619 vs. 1,181 U/L; p = .036). Liver acceptance for the corresponding recipient was conditional on NMP use for 63% (15/24) of cases. CONCLUSION: Real-world NMP use was associated with significantly lower intensity of reperfusion injury and intraoperative and postoperative care that may translate into patient benefit.
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Trasplante de Hígado , Daño por Reperfusión , Humanos , Preservación de Órganos , Hígado , PerfusiónRESUMEN
Outcomes after liver transplantation have continuously improved over the past decades, but long-term survival rates are still lower than in the general population. The liver has distinct immunological functions linked to its unique anatomical configuration and to its harbouring of a large number of cells with fundamental immunological roles. The transplanted liver can modulate the immunological system of the recipient to promote tolerance, thus offering the potential for less aggressive immunosuppression. The selection and adjustment of immunosuppressive drugs should be individualised to optimally control alloreactivity while mitigating toxicities. Routine laboratory tests are not accurate enough to make a confident diagnosis of allograft rejection. Although several promising biomarkers are being investigated, none of them is sufficiently validated for routine use; hence, liver biopsy remains necessary to guide clinical decisions. Recently, there has been an exponential increase in the use of immune checkpoint inhibitors due to the unquestionable oncological benefits they provide for many patients with advanced-stage tumours. It is expected that their use will also increase in liver transplant recipients and that this might affect the incidence of allograft rejection. Currently, the evidence regarding the efficacy and safety of immune checkpoint inhibitors in liver transplant recipients is limited and cases of severe allograft rejection have been reported. In this review, we discuss the clinical relevance of alloimmune disease, the role of minimisation/withdrawal of immunosuppression, and provide practical guidance for using checkpoint inhibitors in liver transplant recipients.
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Trasplante de Hígado , Humanos , Inhibidores de Puntos de Control Inmunológico , Rechazo de Injerto , Terapia de Inmunosupresión , Inmunosupresores/uso terapéutico , Inmunología del Trasplante , Hígado/patología , InmunomodulaciónAsunto(s)
Grupo de Atención al Paciente , Ciencia , Tecnología , Humanos , Conducta Cooperativa , Liderazgo , Cultura OrganizacionalRESUMEN
Solid organ transplantation provides the best treatment for end-stage organ failure, but significant sex-based disparities in transplant access exist. On June 25, 2021, a virtual multidisciplinary conference was convened to address sex-based disparities in transplantation. Common themes contributing to sex-based disparities were noted across kidney, liver, heart, and lung transplantation, specifically the existence of barriers to referral and wait listing for women, the pitfalls of using serum creatinine, the issue of donor/recipient size mismatch, approaches to frailty and a higher prevalence of allosensitization among women. In addition, actionable solutions to improve access to transplantation were identified, including alterations to the current allocation system, surgical interventions on donor organs, and the incorporation of objective frailty metrics into the evaluation process. Key knowledge gaps and high-priority areas for future investigation were also discussed.
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Fragilidad , Trasplante de Órganos , Obtención de Tejidos y Órganos , Femenino , Humanos , Disparidades en Atención de Salud , Riñón , Donantes de Tejidos , Estados Unidos , Listas de EsperaRESUMEN
BACKGROUND: For children with liver transplants (LT), achieving an "ideal outcome" is a balancing act: too little immunosuppression begets graft injury; too much begets systemic complications. We aimed to delineate the parental perspective on this tightrope. METHODS: Parents of children with LT completed an internet-based survey about their child's immunosuppression. RESULTS: Children of respondents (n = 82) were a median 4 years from primary LT (range 0-22); 73% were on immunosuppression monotherapy. Parents' top concerns were related to immunosuppression complications; 46% were more concerned about immunosuppression complications than rejection; only 17% were more concerned about rejection than immunosuppression complications. Among parents of children on immunosuppression monotherapy, 29% still worried more about immunosuppression complications than rejection, 48% expressed equal concern for both. Time since LT (0-4 vs. >4 years) was not associated with concern level for rejection or immunosuppression complications. Caregivers were significantly more certain that their child's immunosuppression regimen was correct to prevent rejection than to mitigate complications (p < .005). CONCLUSION: Caregivers of children with LTs reported higher levels of concern and uncertainty about immunosuppression complications than rejection risk. Understanding parent and patient perspectives on IS, and incorporating them into immunosuppression counseling and decision-making, is critical to achieving truly "ideal" long-term outcomes.
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Trasplante de Hígado , Niño , Humanos , Trasplante de Hígado/efectos adversos , Terapia de Inmunosupresión , Padres/psicología , Rechazo de Injerto/etiología , Rechazo de Injerto/prevención & control , Encuestas y CuestionariosRESUMEN
BACKGROUND AND AIMS: In otherwise near-normal appearing biopsies by routine light microscopy, next-generation pathology (NGP) detected close pairings (immune pairs; iPAIRs) between lymphocytes and antigen-presenting cells (APCs) that predicted immunosuppression weaning failure in pediatric liver transplant (LTx) recipients (Immunosuppression Withdrawal for Stable Pediatric Liver Transplant Recipients [iWITH], NCT01638559). We hypothesized that NGP-detected iPAIRs enrich for true immune synapses, as determined by nuclear shape metrics, intercellular distances, and supramolecular activation complex (SMAC) formation. APPROACH AND RESULTS: Intralobular iPAIRs (CD45 high lymphocyte-major histocompatibility complex II + APC pairs; n = 1167, training set) were identified at low resolution from multiplex immunohistochemistry-stained liver biopsy slides from several multicenter LTx immunosuppression titration clinical trials (iWITH; NCT02474199 (Donor Alloantigen Reactive Tregs (darTregs) for Calcineurin Inhibitor (CNI) Reduction (ARTEMIS); Prospective Longitudinal Study of iWITH Screen Failures Secondary to Histopathology). After excluding complex multicellular aggregates, high-resolution imaging was used to examine immune synapse formation ( n = 998). By enriching for close intranuclear lymphocyte-APC distance (mean: 0.713 µm) and lymphocyte nuclear flattening (mean ferret diameter: 2.1), SMAC formation was detected in 29% of iPAIR-engaged versus 9.5% of unpaired lymphocytes. Integration of these morphometrics enhanced NGP detection of immune synapses (ai-iSYN). Using iWITH preweaning biopsies from eligible patients ( n = 53; 18 tolerant, 35 nontolerant; testing set), ai-iSYN accurately predicted (87.3% accuracy vs. 81.4% for iPAIRs; 100% sensitivity, 75% specificity) immunosuppression weaning failure. This confirmed the presence and importance of intralobular immune synapse formation in liver allografts. Stratification of biopsy mRNA expression data by immune synapse quantity yielded the top 20 genes involved in T cell activation and immune synapse formation and stability. CONCLUSIONS: NGP-detected immune synapses (subpathological rejection) in LTx patients prior to immunosuppression reduction suggests that NGP-detected (allo)immune activity usefulness for titration of immunosuppressive therapy in various settings.
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Hurones , Linfocitos T , Humanos , Animales , Niño , Estudios Prospectivos , Estudios Longitudinales , Hígado , Células Presentadoras de Antígenos , Aloinjertos , Rechazo de Injerto/diagnóstico , Inmunosupresores/uso terapéuticoRESUMEN
Promoting immune tolerance to transplanted organs can minimize the amount of immunosuppressive drugs that patients need to take, reducing lifetime risks of mortality and morbidity. Regulatory T cells (Tregs) are essential for immune tolerance, and preclinical studies have shown their therapeutic efficacy in inducing transplantation tolerance. Here, we report the results of a phase 1/2 trial (ARTEMIS, NCT02474199) of autologous donor alloantigen-reactive Treg (darTreg) therapy in individuals 2 to 6 years after receiving a living donor liver transplant. The primary efficacy endpoint was calcineurin inhibitor dose reduction by 75% with stable liver function tests for at least 12 weeks. Among 10 individuals who initiated immunosuppression withdrawal, 1 experienced rejection before planned darTreg infusion, 5 received darTregs, and 4 were not infused because of failure to manufacture the minimal infusible dose of 100 × 106 cells. darTreg infusion was not associated with adverse events. Two darTreg-infused participants reached the primary endpoint, but an insufficient number of recipients were treated for assessing the efficacy of darTregs. Mechanistic studies revealed generalized Treg activation, senescence, and selective reduction of donor reactivity after liver transplantation. Overall, the ARTEMIS trial features a design concept for evaluating the efficacy of Treg therapy in transplantation. The mechanistic insight gained from the study may help guide the design of future trials.