Early United States experience with liver donation after circulatory determination of death using thoraco-abdominal normothermic regional perfusion: A multi-institutional observational study.

Mortality on the liver waitlist remains unacceptably high. Donation after circulatory determination of death (DCD) donors are considered marginal but are a potentially underutilized resource. Thoraco-abdominal normothermic perfusion (TA-NRP) in DCD donors might result in higher quality livers and offset waitlist mortality. We retrospectively reviewed outcomes of the first 13 livers transplanted from TA-NRP donors in the US. Nine centers transplanted livers from eight organ procurement organizations. Median donor age was 25 years; median agonal phase was 13 minutes. Median recipient age was 60 years; median lab MELD score was 21. Three patients (23%) met early allograft dysfunction (EAD) criteria. Three received simultaneous liver-kidney transplants; neither had EAD nor delayed renal allograft function. One recipient died 186 days post-transplant from sepsis but had normal presepsis liver function. One patient developed a biliary anastomotic stricture, managed endoscopically; no recipient developed clinical evidence of ischemic cholangiopathy (IC). Twelve of 13 (92%) patients are alive with good liver function at 439 days median follow-up; one patient has extrahepatic recurrent HCC. TA-NRP DCD livers in these recipients all functioned well, particularly with respect to IC, and provide a valuable option to decrease deaths on the waiting list.

Early US experience with cardiac donation after circulatory death (DCD) using normothermic regional perfusion.

BACKGROUND: Given the shortage of suitable donor hearts for cardiac transplantation and the growing interest in donation after circulatory death (DCD), our institution recently began procuring cardiac allografts from DCD donors. METHODS: Between October 2020 and March 2021, 15 patients with heart failure underwent cardiac transplantation using DCD allografts. Allografts were procured using a modified extracorporeal membrane oxygenation circuit for thoracic normothermic regional perfusion (TA-NRP) and were subsequently transported using cold static storage. Data collection and analysis were performed with institutional review board approval. RESULTS: The mean age of the DCD donors was 23 ± 7 years and average time on TA-NRP was 56 ± 8 minutes. Total ischemic time was 183 ± 31 minutes and distance from transplant center was 373 ± 203 nautical miles. Recipient age was 55 ± 14 years, with 8 (55.3%) recipients on durable left ventricular assist device support. Post-transplant, 6 (40%) recipients experienced mild left ventricle primary graft dysfunction (PGD-LV), 3 (20%) recipients experienced moderate PGD-LV, and no recipients experienced severe PGD-LV. Postoperative transthoracic echocardiogram demonstrated left ventricular ejection fraction >55% in all recipients. One recipient (6.6%) developed International Society for Heart and Lung Transplantation 2R acute cellular rejection on first biopsy. At last follow-up, all 15 recipients were alive past 30-days. CONCLUSIONS: Cardiac DCD provides an opportunity to increase the availability of donor hearts for transplantation. Utilizing TA-NRP with cold static storage, we have extended the cold ischemic time of DCD allografts to almost 3 hours, allowing for inter-hospital organ transport.

Early Outcomes of Multivisceral Transplant Using Hepatitis C-Positive Donors.

BACKGROUND: In the era of direct-acting antiviral therapies, hepatitis C-positive organs offer a strategy to expand the donor pool. Heart failure patients with concomitant renal insufficiency benefit from combined heart/kidney transplant. In 2017, we began utilizing organs from hepatitis C donors for heart/kidney transplants. METHODS: Characteristics and outcomes of heart/kidney transplants were collected at our institution from 2012 through 2019. We determined patient cohorts by donor hepatitis C antibody status, antibody positive (HCV+) vs antibody negative (HCV-). Outcomes of interest include survival, postoperative allograft function, and waitlist time. Summary and descriptive statistics, as well as survival analyses, were performed. RESULTS: Thirty-nine patients underwent heart/kidney transplantation from 2012-2019. Twelve patients received HCV+ organs, and 27 patients received HCV- organs with minimal differences in donor and recipient cohort characteristics. Recipients who consented to receive HCV+ organs had a shorter median waitlist time. HCV+ and HCV- groups had similar perioperative and early postoperative cardiac function and similar rates of delayed renal graft function. HCV+ recipients demonstrated higher creatinine levels at 3 months posttransplant compared with HCV- recipients, but by 1-year post-transplant, creatinine levels in both groups were similar. The groups had similar 30-day and 1-year survival. CONCLUSIONS: This study is a single-center series of heart/kidney transplant using HCV+ donors. When the potential increased risk of early postoperative renal dysfunction is balanced against similar survival and decreased waitlist time, the results suggest that HCV+ donors are an important source of transplantable organs for heart/kidney transplantation.

LNK deficiency promotes acute aortic dissection and rupture.

Aortic dissection (AD) is a life-threatening vascular disease with limited treatment strategies. Here, we show that loss of the GWAS-identified SH2B3 gene, encoding lymphocyte adaptor protein LNK, markedly increases susceptibility to acute AD and rupture in response to angiotensin (Ang) II infusion. As early as day 3 following Ang II infusion, prior to the development of AD, Lnk-/- aortas display altered mechanical properties, increased elastin breaks, collagen thinning, enhanced neutrophil accumulation, and increased MMP-9 activity compared with WT mice. Adoptive transfer of Lnk-/- leukocytes into Rag1-/- mice induces AD and rupture in response to Ang II, demonstrating that LNK deficiency in hematopoietic cells plays a key role in this disease. Interestingly, treatment with doxycycline prevents the early accumulation of aortic neutrophils and significantly reduces the incidence of AD and rupture. PrediXcan analysis in a biobank of more than 23,000 individuals reveals that decreased expression of SH2B3 is significantly associated with increased frequency of AD-related phenotypes (odds ratio 0.81). Thus, we identified a role for LNK in the pathology of AD in experimental animals and humans and describe a new model that can be used to inform both inherited and acquired forms of this disease.

Mitochondrial Cyclophilin D in Vascular Oxidative Stress and Hypertension.

Vascular superoxide (O˙2 (-)) and inflammation contribute to hypertension. The mitochondria are an important source of O˙2 (-); however, the regulation of mitochondrial O˙2 (-) and the antihypertensive potential of targeting the mitochondria remain poorly defined. Angiotensin II and inflammatory cytokines, such as interleukin 17A and tumor necrosis factor-α (TNFα) significantly contribute to hypertension. We hypothesized that angiotensin II and cytokines co-operatively induce cyclophilin D (CypD)-dependent mitochondrial O˙2 (-) production in hypertension. We tested whether CypD inhibition attenuates endothelial oxidative stress and reduces hypertension. CypD depletion in CypD(-/-) mice prevents overproduction of mitochondrial O˙2 (-) in angiotensin II-infused mice, attenuates hypertension by 20 mm Hg, and improves vascular relaxation compared with wild-type C57Bl/6J mice. Treatment of hypertensive mice with the specific CypD inhibitor Sanglifehrin A reduces blood pressure by 28 mm Hg, inhibits production of mitochondrial O˙2 (-) by 40%, and improves vascular relaxation. Angiotensin II-induced hypertension was associated with CypD redox activation by S-glutathionylation, and expression of the mitochondria-targeted H2O2 scavenger, catalase, abolished CypD S-glutathionylation, prevented stimulation mitochondrial O˙2 (-), and attenuated hypertension. The functional role of cytokine-angiotensin II interplay was confirmed by co-operative stimulation of mitochondrial O˙2 (-) by 3-fold in cultured endothelial cells and impairment of aortic relaxation incubated with combination of angiotensin II, interleukin 17A, and tumor necrosis factor-α which was prevented by CypD depletion or expression of mitochondria-targeted SOD2 and catalase. These data support a novel role of CypD in hypertension and demonstrate that targeting CypD decreases mitochondrial O˙2 (-), improves vascular relaxation, and reduces hypertension.

Preoperative Predictors of 30-Day Mortality and Prolonged Length of Stay after Above-Knee Amputation.

BACKGROUND: The above-knee amputation (AKA) is an operation of last resort with high postoperative morbidity and mortality. This study identifies preoperative risk factors predictive of both 30-day mortality and extended length of stay (LOS) in AKA patients. METHODS: Two hundred ninety-five AKA patients from 2004 to 2013 from a single institution were retrospectively reviewed using a deidentified electronic medical record. Rationally selected factors potentially influencing 30-day mortality and LOS were chosen, including demographics, etiologies, vascular surgical history, lifestyle factors, comorbidities, and laboratory values. Variables trending with one of the end points on bivariate analysis (P ≤ 0.10) were entered into multivariate forward stepwise regression models to determine independence as a risk factor (P ≤ 0.05). Subgroup analysis of AKA patients without a traumatic, burn, or malignant etiology was similarly conducted. RESULTS: Within the 295 patient cohort, 60% of the patients were male, 18% were African American, mean age was 58 years and mean body mass index was 28 kg/m(2). The 30-day mortality rate was 9%, and mean postoperative LOS of discharged patients was 9.3 days. Upon logistic regression, thrombocytopenia (platelet count < 250 × 10(6)/mL, P < 0.001, odds ratio 6.1) and preoperative septic shock (P = 0.02, odds ratio 5.1) were identified as independent risk factors for 30-day mortality. Upon linear regression, burn etiology (P < 0.001, B = 15.8 days), leukocytosis (white blood cell count > 12 × 10(6)/mL, P < 0.001, B = 6.2 days), and guillotine amputation (P < 0.001, B = 7.6 days) were independently associated with prolonged LOS. Excluding patients with AKAs due to trauma, burn, or malignancy, only thrombocytopenia (platelet count < 250 × 10(6)/mL, P < 0.001, odds ratio 10.2) and leukocytosis (white blood cell count > 12 × 10(6)/mL, P = 0.01, B = 5.2 days) were independent risk factors for in-hospital mortality and prolonged LOS, respectively. CONCLUSIONS: Preoperative septic shock and thrombocytopenia are independent risk factors for 30-day mortality after AKA, while burn etiology, leukocytosis, and guillotine amputation contribute to prolonged LOS. Awareness of these risk factors may help enhance both preoperative decision making and expectations of the hospital admission.

Residents as Educators: A Modern Model.

Education during surgical residency has changed significantly. As part of the shifting landscape, the importance of an organized and structured curriculum has increased. However, establishing this is often difficult secondary to clinical demands and pressure both on faculty and residents. We present a peer-assisted learning model for academic institutions without professional non-clinical educations. The "resident as educator" (RAE) model empowers residents to be the organizers of the education curriculum. RAE is built on a culture of commitment to education, skill development and team building, allowing the upper level residents to develop and execute the curriculum. Several modules designed to address junior level residents and medical students' educational needs have been implemented, including (1) intern boot camp, (2) summer school, (3) technical skill sessions, (4) trauma orientation, (5) weekly teaching conferences, and (4) a fourth year medical student surgical preparation course. Promoting residents as educators leads to an overall benefit for the program by being cost-effective and time-efficient, while simultaneously promoting professional development of residents and a culture of education.

Inflammation, immunity, and hypertensive end-organ damage.

For >50 years, it has been recognized that immunity contributes to hypertension. Recent data have defined an important role of T cells and various T cell-derived cytokines in several models of experimental hypertension. These studies have shown that stimuli like angiotensin II, deoxycorticosterone acetate-salt, and excessive catecholamines lead to formation of effector like T cells that infiltrate the kidney and perivascular regions of both large arteries and arterioles. There is also accumulation of monocyte/macrophages in these regions. Cytokines released from these cells, including interleukin-17, interferon-γ, tumor necrosis factorα, and interleukin-6 promote both renal and vascular dysfunction and damage, leading to enhanced sodium retention and increased systemic vascular resistance. The renal effects of these cytokines remain to be fully defined, but include enhanced formation of angiotensinogen, increased sodium reabsorption, and increased renal fibrosis. Recent experiments have defined a link between oxidative stress and immune activation in hypertension. These have shown that hypertension is associated with formation of reactive oxygen species in dendritic cells that lead to formation of gamma ketoaldehydes, or isoketals. These rapidly adduct to protein lysines and are presented by dendritic cells as neoantigens that activate T cells and promote hypertension. Thus, cells of both the innate and adaptive immune system contribute to end-organ damage and dysfunction in hypertension. Therapeutic interventions to reduce activation of these cells may prove beneficial in reducing end-organ damage and preventing consequences of hypertension, including myocardial infarction, heart failure, renal failure, and stroke.

Lymphocyte adaptor protein LNK deficiency exacerbates hypertension and end-organ inflammation.

The lymphocyte adaptor protein LNK (also known as SH2B3) is primarily expressed in hematopoietic and endothelial cells, where it functions as a negative regulator of cytokine signaling and cell proliferation. Single-nucleotide polymorphisms in the gene encoding LNK are associated with autoimmune and cardiovascular disorders; however, it is not known how LNK contributes to hypertension. Here, we determined that loss of LNK exacerbates angiotensin II-induced (Ang II-induced) hypertension and the associated renal and vascular dysfunction. At baseline, kidneys from Lnk-/- mice exhibited greater levels of inflammation, oxidative stress, and glomerular injury compared with WT animals, and these parameters were further exacerbated by Ang II infusion. Aortas from Lnk-/- mice exhibited enhanced inflammation, reduced nitric oxide levels, and impaired endothelial-dependent relaxation. Bone marrow transplantation studies demonstrated that loss of LNK in hematopoietic cells is primarily responsible for the observed renal and vascular inflammation and predisposition to hypertension. Ang II infusion increased IFN-γ-producing CD8+ T cells in the spleen and kidneys of Lnk-/- mice compared with WT mice. Moreover, IFN-γ deficiency resulted in blunted hypertension in response to Ang II infusion. Together, these results suggest that LNK is a potential therapeutic target for hypertension and its associated renal and vascular sequela.