Eltrombopag for Post-Transplant Poor Graft Function in East Asian Patients.

Poor graft function (PGF) is a serious, potentially life-threatening complication of allogeneic hematopoietic stem cell transplantation. Eltrombopag has shown multilineage responses in patients with refractory severe aplastic anemia, supporting the idea that it may improve cytopenia in patients with PGF. This retrospective, single center analysis included 8 Korean patients receiving eltrombopag for PGF. Median interval between transplant and eltrombopag treatment was 73 days, and the median duration treatment was 3.5 weeks. With median maximum daily dose of 50 mg, the time to best response was 93 days. Median hemoglobin increased from 8.2 g/dL to 10.9 g/dL, platelet from 18.5 × 109/L to 54 × 109/L, and absolute neutrophil count from 1.25 × 109/L to 3.32 × 109/L. In conclusion, eltrombopag is a good option for PGF in Korean patients, even at a lower dose compared to western patients.

Outcomes after heart retransplantation: A 50-year single-center experience.

OBJECTIVES: To evaluate outcomes after heart retransplantation. METHODS: From January 6, 1968, to June 2019, 123 patients (112 adult and 11 pediatric patients) underwent heart retransplantation, and 2092 received primary transplantation at our institution. Propensity-score matching was used to account for baseline differences between the retransplantation and the primary transplantation-only groups. Kaplan-Meier survival analyses were performed. The primary end point was all-cause mortality, and secondary end points were postoperative complications. RESULTS: Retransplantation recipient age was 39.6 ± 16.4 years, and donor age was 26.4 ± 11.2 years. Ninety-two recipients (74.8%) were male. Compared with recipients who only underwent primary heart transplantation, retransplantation recipients were more likely to have hypertension (44/73.3% vs 774/53.3%, P = .0022), hyperlipidemia (40/66.7% vs 447/30.7%, P < .0001), and require dialysis (7/11.7% vs 42/2.9%, P = .0025). The indications for heart retransplantation were cardiac allograft vasculopathy (32/80%), primary graft dysfunction (6/15%), and refractory acute rejection (2/5%). After matching, postoperative outcomes such as hospital length of stay, severe primary graft dysfunction requiring intra-aortic balloon pump or extracorporeal membrane oxygenation, cerebral vascular accident, respiratory failure, renal failure requiring dialysis, and infection were similar between the 2 groups. Matched median survival after retransplantation was 4.6 years compared with 6.5 years after primary heart transplantation (log-rank P = .36, stratified log-rank P = .0063). CONCLUSIONS: In this single-center cohort, the unadjusted long-term survival after heart retransplantation was inferior to that after primary heart transplantation, and short-term survival difference persisted after propensity-score matching. Heart retransplantation should be considered for select patients for optimal donor organ usage.

Obesity-related IL-18 Impairs T-Regulatory Cell Function and Promotes Lung Ischemia-Reperfusion Injury.

Rationale: Primary graft dysfunction (PGD) is a severe form of acute lung injury, leading to increased early morbidity and mortality after lung transplant. Obesity is a major health problem, and recipient obesity is one of the most significant risk factors for developing PGD. Objectives: We hypothesized that T-regulatory cells (Tregs) are able to dampen early ischemia-reperfusion events and thereby decrease the risk of PGD, whereas that action is impaired in obese recipients. Methods: We evaluated Tregs, T cells, and inflammatory markers, plus clinical data, in 79 lung transplant recipients and 41 liver or kidney transplant recipients and studied two groups of mice on a high-fat diet (HFD), which did ("inflammatory" HFD) or did not ("healthy" HFD) develop low-grade inflammation with decreased Treg function. Measurements and Main Results: We identified increased levels of IL-18 as a previously unrecognized mechanism that impairs Tregs' suppressive function in obese individuals. IL-18 decreases levels of FOXP3, the key Treg transcription factor, decreases FOXP3 di- and oligomerization, and increases the ubiquitination and proteasomal degradation of FOXP3. IL-18-treated Tregs or Tregs from obese mice fail to control PGD, whereas IL-18 inhibition ameliorates lung inflammation. The IL-18-driven impairment in Tregs' suppressive function before transplant was associated with an increased risk and severity of PGD in clinical lung transplant recipients. Conclusions: Obesity-related IL-18 induces Treg dysfunction that may contribute to the pathogenesis of PGD. Evaluation of Tregs' suppressive function together with evaluation of IL-18 levels may serve as a screening tool to identify obese individuals with an increased risk of PGD before transplant.

Recipient and surgical factors trigger severe primary graft dysfunction after heart transplant.

BACKGROUND: Primary graft dysfunction (PGD) is a major cause of early mortality following heart transplant (HT). The International Society for Heart and Lung Transplantation (ISHLT) subdivides PGD into 3 grades of increasing severity. Most studies have assessed risk factors for PGD without distinguishing between PGD severity grade. We sought to identify recipient, donor and surgical risk factors specifically associated with mild/moderate or severe PGD. METHODS: We identified 734 heart transplant recipients at our institution transplanted between January 1, 2012 and December 31, 2018. PGD was defined according to modified ISHLT criteria. Recipient, donor and surgical variables were analyzed by multinomial logistic regression with mild/moderate or severe PGD as the response. Variables significant in single variable modeling were subject to multivariable analysis via penalized logistic regression. RESULTS: PGD occurred in 24% of the cohort (n = 178) of whom 6% (n = 44) had severe PGD. One-year survival was reduced in recipients with severe PGD but not in those with mild or moderate PGD. Multivariable analysis identified 3 recipient factors: prior cardiac surgery, recipient treatment with ACEI/ARB/ARNI plus MRA, recipient treatment with amiodarone plus beta-blocker, and 3 surgical factors: longer ischemic time, more red blood cell transfusions, and more platelet transfusions, that were associated with severe PGD. We developed a clinical risk score, ABCE, which provided acceptable discrimination and calibration for severe PGD. CONCLUSIONS: Risk factors for mild/moderate PGD were largely distinct from those for severe PGD, suggesting a differing pathophysiology involving several biological pathways. Further research into mechanisms underlying the development of PGD is urgently needed.

Resolving the graft ischemia-reperfusion injury during liver transplantation at the single cell resolution.

Ischemia-reperfusion injury (IRI) remains the major reason for impaired donor graft function and increased mortality post-liver transplantation. The mechanism of IRI involves multiple pathophysiological processes and numerous types of cells. However, a systematic and comprehensive single-cell transcriptional profile of intrahepatic cells during liver transplantation is still unclear. We performed a single-cell transcriptome analysis of 14,313 cells from liver tissues collected from pre-procurement, at the end of preservation and 2 h post-reperfusion. We made detailed annotations of mononuclear phagocyte, endothelial cell, NK/T, B and plasma cell clusters, and we described the dynamic changes of the transcriptome of these clusters during IRI and the interaction between mononuclear phagocyte clusters and other cell clusters. In addition, we found that TNFAIP3 interacting protein 3 (TNIP3), specifically and highly expressed in Kupffer cell clusters post-reperfusion, may have a protective effect on IRI. In summary, our study provides the first dynamic transcriptome map of intrahepatic cell clusters during liver transplantation at single-cell resolution.

Percutaneous RVAD with the Protek Duo for severe right ventricular primary graft dysfunction after heart transplant.

Right ventricular primary graft dysfunction after heart transplant is a serious life-threatening condition. The severe form, refractory to maximal medical therapy, has traditionally required temporary mechanical support through veno-arterial extracorporeal membrane oxygenation or central right ventricular support. The Protek Duo is a dual lumen cannula recently introduced in the market, which allows for the institution of a percutaneous right ventricular support. We present the first promising case series of the use of this novel support in patients with right ventricular primary graft dysfunction after heart transplant.

Ventilation parameters and early graft function in double lung transplantation.

BACKGROUND: Currently, the primary graft dysfunction (PGD) score is used to measure allograft function in the early post-lung transplant period. Although PGD grades at later time points (T48 hours and T72 hours) are useful to predict mid- and long-term outcomes, their predictive value is less relevant within the first 24 hours after transplantation. This study aimed to evaluate the capability of PGD grades to predict prolonged mechanical ventilation (MV) and compare it with a model derived from ventilation parameters measured on arrival at the intensive care unit (ICU). METHODS: A retrospective single-center analysis of 422 double lung transplantations (LTxs) was performed. PGD was assessed 2 hours after arrival at ICU, and grades were associated with length of MV (LMV). In addition, peak inspiratory pressure (PIP), ratio of the arterial partial pressure of oxygen to fraction of inspired oxygen (P/F ratio), and dynamic compliance (cDyn) were collected, and a logistic regression model was created. The predictive capability for prolonged MV was calculated for both (the PGD score and the model). In a second step, the created model was externally validated using a prospective, international multicenter cohort including 102 patients from the lung transplant centers of Vienna, Toronto, and Budapest. RESULTS: In the retrospective cohort, a high percentage of extubated patients was reported at 24 hours (35.1%), 48 hours (68.0%), and 72 hours (80.3%) after transplantation. At T0 (time point defined as 2 hours after arrival at the ICU), patients with PGD grade 0 had a shorter LMV with a median of 26 hours (interquartile range [IQR]: 16-47 hours) than those with PGD grade 1 (median: 42 hours, IQR: 27-50 hours), PGD grade 2 (median: 37.5 hours, IQR: 15.5-78.5 hours), and PGD grade 3 (median: 46 hours, IQR: 27-86 hours). However, IQRs largely overlapped for all grades, and the value of PGD to predict prolonged MV was poor. A total of 3 ventilation parameters (PIP, cDyn, and P/F ratio), determined at T0, were chosen on the basis of clinical reasoning. A logistic regression model including these parameters predicted prolonged MV (>72 hours) with an optimism-corrected area under the curve (AUC) of 0.727. In the prospective validation cohort, the model proved to be stable and achieved an AUC of 0.679. CONCLUSIONS: The prediction model reported in this study combines 3 easily obtainable variables. It can be employed immediately after LTx to quantify the risk of prolonged MV, an important early outcome parameter.

Extracorporeal Membrane Oxygenation after Heart Transplantation: Impact of Type of Cannulation.

BACKGROUND: Primary graft dysfunction (PGD) is a common cause of early death after heart transplantation (htx). The use of extracorporeal life support (ECLS) after htx has increased during the last years. It is still discussed controversially whether peripheral cannulation is favorable compared to central cannulation. We aimed to compare both cannulation techniques. METHODS: Ninety patients underwent htx in our department between 2010 and 2017. Twenty-five patients were treated with ECLS due to PGD (10 central extracorporeal membrane oxygenator [cECMO] and 15 peripheral extracorporeal membrane oxygenator [pECMO] cannulation). Pre- and intraoperative parameters were comparable between both groups. RESULTS: Thirty-day mortality was comparable between the ECLS-groups (cECMO: 30%; pECMO: 40%, p = 0.691). Survival at 1 year (n = 18) was 40 and 30.8% for cECMO and pECMO, respectively. The incidence of postoperative renal failure, stroke, limb ischemia, and infection was comparable between both groups. We also did not find significant differences in duration of mechanical ventilation, intensive care unit stay, or in-hospital stay. The incidence of bleeding complications was also similar (cECMO: 60%; pECMO: 67%). Potential differences in support duration in pECMO group (10.4 ± 9.3 vs. 5.7 ± 4.7 days, p = 0.110) did not reach statistical significance. CONCLUSIONS: In patients supported for PGD, peripheral and central cannulation strategies are safe and feasible for prolonged venoarterial ECMO support. There was no increase in bleeding after central implantation. With regard to the potential complications of a pECMO, we think that aortic cannulation with tunneling of the cannula and closure of the chest could be a good option in patients with PGD after htx.

Chest X-ray Sizing for Lung Transplants Reflects Pulmonary Diagnosis and Body Composition and Is Associated With Primary Graft Dysfunction Risk.

BACKGROUND: Donor-recipient oversizing based on predicted total lung capacity (pTLC) is associated with a reduced risk of primary graft dysfunction (PGD) following lung transplant but the effect varies with the recipient's diagnosis. Chest x-ray (CXR) measurements to estimate actual total lung capacity (TLC) could account for disease-related lung volume changes, but their role in size matching is unknown. METHODS: We reviewed adult double lung transplant recipients 2007-2016 and measured apex-to-costophrenic-angle distance (=lung height) on pretransplant donor and recipient CXRs (oversized donor-recipient ratio >1; undersized ≤1]. We tested the relationship between recipient lung height to actual TLC; between lung height ratio and donor/recipient characteristics; and between both lung height ratio or pTLC ratio and grade 3 PGD with logistic regression. RESULTS: Two hundred six patients were included and 32 (16%) developed grade 3 PGD at 48 or 72 hours. Recipient lung height was related to TLC (r2=0.7297). Pulmonary diagnosis, donor BMI, and recipient BMI were the major determinants of lung height ratio (AUC 0.9036). Lung height ratio oversizing was associated with increased risk of grade 3 PGD (odds ratio, 2.51; 95% confidence interval, 1.17-5.47; P = 0.0182) in this cohort, while pTLC ratio oversizing was not. CONCLUSIONS: CXR lung height estimates actual TLC and reflects pulmonary diagnosis and body composition. Oversizing via CXR lung height ratio increased PGD risk moreso than pTLC-based oversizing in our cohort.

Use of Organs for Heart Transplantation after Rescue Allocation: Comparison of Outcome with Regular Allocated High Urgent Recipients.

BACKGROUND: The number of patients waiting for heart transplantation (HTx) is exceeding the number of actual transplants. Subsequently, waiting times are increasing. One possible solution may be an increased acceptance of organs after rescue allocation. These organs had been rejected by at least three consecutive transplant centers due to medical reasons. METHODS: Between October 2010 and July 2019, a total of 139 patients underwent HTx in our department. Seventy (50.4%) of the 139 patients were transplanted with high urgency (HU) status and regular allocation (HU group); the remaining received organs without HU listing after rescue allocation (elective group, n = 69). RESULTS: Donor parameters were comparable between the groups. Thirty-day mortality was comparable between HU patients (11.4%) and rescue allocation (12.1%). Primary graft dysfunction with extracorporeal life support occurred in 26.9% of the elective group with rescue allocated organs, which was not inferior to the regular allocated organs (HU group: 35.7%). No significant differences were observed regarding the incidence of common perioperative complications as well as morbidity and mortality during 1-year follow-up. CONCLUSIONS: Our data support the use of hearts after rescue allocation for elective transplantation of patients without HU status. We could show that patients with rescue allocated organs showed no significant disadvantages in the early perioperative morbidity and mortality as well at 1-year follow-up.

Methane supplementation improves graft function in experimental heart transplantation.

BACKGROUND: Maintenance of cell viability during cold storage is a key issue in organ transplantation. Methane (CH4) bioactivity has recently been recognized in ischemia/reperfusion conditions; we therefore hypothesized that cold storage in CH4-enriched preservation solution can provide an increased defense against organ dysfunction during experimental heart transplantation (HTX). METHODS: The hearts of donor Lewis rats were stored for 60 minutes in cold histidine-tryptophan-ketoglutarate (Custodiol [CS]) or CH4-saturated CS solution (CS-CH4) (n = 12 each). Standard heterotopic HTX was performed, and 60 minutes later, the left ventricular (LV) pressure-volume relationships LV systolic pressure (LVSP), systolic pressure increment (dP/dtmax), diastolic pressure decrement, and coronary blood flow (CBF) were measured. Tissue samples were taken to detect proinflammatory parameters, structural damage (by light microscopy), endoplasmic reticulum (ER) stress, and apoptosis markers (CCAAT/enhancer binding protein [C/EBP] homologous protein, GRP78, glycogen synthase kinase-3ß, very low-density lipoprotein receptor, caspase 3 and 9, B-cell lymphoma 2, and bcl-2-like protein 4), whereas mitochondrial functional changes were analyzed by high-resolution respirometry. RESULTS: LVSP and dP/dtmax increased significantly at the largest pre-load volumes in CS-CH4 grafts as compared with the CS group (114.5 ± 16.6 mm Hg vs 82.8 ± 4.6 mm Hg and 3,133 ± 430 mm Hg/s vs 1,739 ± 169 mm Hg/s, respectively); the diastolic function and CBF (2.4 ± 0.4 ml/min/g vs 1.3 ± 0.3 ml/min/g) also improved. Mitochondrial oxidative phosphorylation capacity was more preserved (58.5 ± 9.4 pmol/s/ml vs 27.7 ± 6.6 pmol/s/ml), and cytochrome c release was reduced in CS-CH4 storage. Signs of HTX-caused myocardial damage, level of ER stress, and the transcription of proapoptotic proteins were significantly lower in CS-CH4 grafts. CONCLUSION: The addition of CH4 during 1 hour of cold storage improved early in vitro graft function and reduced mitochondrial dysfunction and activation of inflammation. Evidence shows that CH4 reduced ER stress-linked proapoptotic signaling.

The Association Between Macroscopic Arteriosclerosis of the Renal Artery, Microscopic Arteriosclerosis, Organ Discard, and Kidney Transplant Outcome.

BACKGROUND: During organ retrieval, surgeons estimate the degree of arteriosclerosis and this plays an important role in decisions on organ acceptance. Our study aimed to elucidate the association between macroscopic renal artery arteriosclerosis, donor kidney discard, and transplant outcome. METHODS: We selected all transplanted and discarded kidneys in the Netherlands between January 1, 2000, and December 31, 2015, from deceased donors aged 50 y and older, for which data on renal artery arteriosclerosis were available (n = 2610). The association between arteriosclerosis and kidney discard, the relation between arteriosclerosis and outcome, and the correlation between macroscopic and microscopic arteriosclerosis were explored. RESULTS: Macroscopic arteriosclerosis was independently associated with kidney discard (odds ratio [OR], 1.36; 95% confidence interval [CI], 1.02-1.80; P = 0.03). Arteriosclerosis (any degree) was not significantly associated with delayed graft function (OR, 1.16; 95% CI, 0.94-1.43; P = 0.16), estimated glomerular filtration rate 1-y posttransplant (B, 0.58; 95% CI, -2.07 to 3.22; P = 0.67), and long-term graft survival (hazard ratio, 1.07; 95% CI, 0.86-1.33; P = 0.55). There was a significant association between mild arteriosclerosis and primary nonfunction (OR, 2.14; 95% CI, 1.19-3.84; P = 0.01). We found no correlation between macroscopic and histological arteriosclerosis, nor between histological arteriosclerosis and transplant outcome. CONCLUSIONS: Macroscopic arteriosclerosis of the renal artery was independently associated with kidney discard and somewhat associated with primary nonfunction posttransplant. However, there was no effect of arteriosclerosis on delayed graft function, estimated glomerular filtration rate at 1 y, or long-term graft survival. Our results are valid only after inevitable exclusion of discarded kidneys that had on average more arteriosclerosis. Hence, conclusions should be interpreted in the light of this potential bias.

Azithromycin prophylaxis after lung transplantation is associated with improved overall survival.

BACKGROUND: Azithromycin prophylaxis (AP) in lung transplant recipients has been shown to reduce the composite end-point of death or chronic lung allograft dysfunction (CLAD) onset but without a clear effect on overall survival. Our program began using AP in 2010. We sought to evaluate the association between AP and survival and the risk of CLAD and baseline lung allograft dysfunction (BLAD). METHODS: We studied double lung recipients transplanted between 2004 and 2016. We defined AP as chronic use of azithromycin initiated before CLAD onset. We analyzed the association between AP and death or retransplant using Cox regression with adjustment for potential confounders. We further used Cox and logistic models to assess the relationship between AP and post-transplant CLAD onset and BLAD, respectively. RESULTS: A total of 445 patients were included, and 344 (77%) received AP (median time from transplant: 51 days). Patients receiving AP were more likely to receive induction with interleukin-2 receptor antagonists (57% vs 35%; p < 0.001). AP was associated with improved survival (hazard ratio [HR]: 0.59; 95% confidence interval [CI]: 0.42-0.82; p = 0.0020) in our fully adjusted model, with a reduced adjusted risk of BLAD (odds ratio: 0.53; 95% CI: 0.33-0.85; p = 0.0460) but no clear reduction in the adjusted risk of CLAD (HR: 0.69; 95% CI: 0.47-1.03; p = 0.0697). CONCLUSIONS: AP is associated with improved survival after lung transplantation, potentially through improved baseline function. These findings build on prior trial results and suggest that AP is beneficial for lung transplant recipients.

Longitudinal lung function measurements in single lung transplant recipients with chronic lung allograft dysfunction.

BACKGROUND: Phenotyping chronic lung allograft dysfunction (CLAD) in single lung transplant (SLTX) recipients is challenging. The aim of this study was to assess the diagnostic and prognostic value of longitudinal lung function tests in SLTX recipients with CLAD. METHODS: A total of 295 SLTX recipients were analyzed and stratified according to native lung physiology. In addition to spirometry, measurements of static lung volumes and lung capacities were used to phenotype patients and to assess their prognostic value. Outcome was survival after CLAD onset. Patients with insufficient clinical information were excluded (n = 71). RESULTS: Of 224 lung transplant recipients, 105 (46.9%) developed CLAD. Time to CLAD onset (hazard ratio [HR]: 0.82, 95% CI: 0.74-0.90; p < 0.001), severity of CLAD at onset (HR: 0.97, 95% CI: 0.94-0.99; p = 0.009), and progression after onset of CLAD (HR: 1.03, 95% CI: 1.00-1.05; p = 0.023) were associated with outcome. Phenotypes at onset were bronchiolitis obliterans syndrome (BOS) (59.1%), restrictive allograft syndrome (RAS) (12.4%), mixed phenotype (6.7%), and undefined phenotype (21.9%). Survival estimates differed significantly between phenotypes (p = 0.004), with RAS and mixed phenotype being associated with the worst survival, followed by BOS and undefined phenotype. Finally, a higher hazard for mortality was noticed for RAS (HR: 2.34, 95% CI: 0.99-5.52; p = 0.054) and mixed phenotype (HR: 3.30, 95% CI: 1.20-9.11; p = 0.021) while controlling for time to CLAD onset and severity of CLAD at onset. CONCLUSIONS: Phenotyping CLAD in SLTX remains challenging with a high number of patients with an undefined phenotype despite comprehensive lung function testing. However, phenotyping is of prognostic value. Furthermore, early, severe, and progressive CLADs are associated with worse survival.

Engraftment Syndrome and Acute Graft-versus-Host Disease: A Meta-Analysis.

Engraftment syndrome (ES) has been associated with the surge of neutrophils and cytokines, which is similar to the presumed underlying pathophysiology behind acute graft-versus-host disease (aGVHD). However, there has been no meta-analysis to evaluate the association; therefore, the team attempted to verify an association between ES and aGVHD through meta-analysis. The team searched for titles of articles in MEDLINE (PubMed), the Cochrane Library, and the EMBASE database up until December 2018 that evaluated the association between ES and aGVHD and conducted a random effect meta-analysis of 8 studies involving a total of 1,945 participants to report the pooled odds ratio (OR) for association of ES and aGVHD. The team found a significantly increased odds of developing aGVHD in patients with ES with the pooled OR of 2.76 (95% confidence interval [CI]: 1.64-4.63) and an I2= 64.5%. In conclusion, patients with ES have significantly higher odds of developing aGVHD compared to patients without ES.

Early graft dysfunction after liver transplant: Comparison of different diagnostic criteria in a single-center prospective cohort / Disfunción temprana del injerto tras trasplante hepático: Comparación de varios criterios diagnósticos en un estudio unicéntrico, prospectivo y de cohorte

OBJECTIVE: Comparison of different diagnostic criteria for early liver allograft dysfunction (EAD) and their capability to predict mortality. DESIGN: Single-center, prospective, cohort study. SETTINGS: ICU in a Regional Hospital with a liver transplant program since 1997. PATIENTS: 253 consecutive patients admitted to our ICU immediately after liver transplantation between 2009 and 2015. Variables of interest: Differences in the incidence of EAD and its relation with ICU, Hospital and 2-year mortality depending on the definition applied using as comparator the UNOS (United Network for Organ Sharing) primary non-function criterion. RESULTS: The incidence of early liver allograft dysfunction according to UNOS was 13.8%, to Makowka 6.3%, to Ardite 10.7%, to Nanashima 20.6%, to Dhillon 30.8% and to MEAF 13.4%. Kappa test did not show a good correlation among these criteria. EAD was related with ICU mortality for all diagnostic criteria except Dhillon but only UNOS, Makowka and MEAF were associated with 2-year mortality. Hospital mortality was poorly predicted by all criteria except for the MEAF score. CONCLUSIÓN: We found a poor agreement between different criteria analyzed for the diagnosis of EAD. In our population, the MEAF score showed the best relationship with short- and long-term mortality

OBJETIVO: Comparar diferentes criterios diagnósticos de disfunción temprana del aloinjerto hepático y su capacidad para predecir mortalidad. DISEÑO: Estudio de cohortes prospectivo, unicéntrico. Ámbito: Unidad de Cuidados Intensivos de un Hospital Regional con programa de trasplante hepático desde 1997. PACIENTES: 253 pacientes consecutivos ingresados en nuestra UCI inmediatamente después del trasplante entre 2009-2015. Variables de interés: Incidencia de disfunción temprana del aloinjerto hepático según cada criterio diagnóstico, relación entre disfunción grave acorde a cada criterio y mortalidad en UCI, mortalidad hospitalaria y a los 2 años utilizando como comparador el criterio para fallo primario de la UNOS (United Network for Organ Sharing). RESULTADOS: La incidencia de disfunción temprana según UNOS fue 13.8%, Makowka 6.3%, Ardite 10.7%, Nanashima 20.6%, Dhillon 30.8% y MEAF 13.4%. El coeficiente kappa mostró una pobre correlación entre ellos. Todos los criterios, excepto el de Dhillon, mostraron relación con la mortalidad en la UCI, pero solo los criterios de UNOS, Makowka y MEAF se asociaron con la mortalidad a 2 años. Finalmente, la capacidad predictiva de la mortalidad hospitalaria fue baja para todos, excepto para MEAF. CONCLUSIÓN: Existe una pobre correlación entre diferentes criterios diagnósticos de disfunción temprana del injerto hepático. El MEAF muestra la mejor relación con el pronóstico a corto y largo plazo en nuestra población

Heart Transplantation From Brain Dead Donors: A Systematic Review of Animal Models.

Despite advances in mechanical circulatory devices and pharmacologic therapies, heart transplantation (HTx) is the definitive and most effective therapy for an important proportion of qualifying patients with end-stage heart failure. However, the demand for donor hearts significantly outweighs the supply. Hearts are sourced from donors following brain death, which exposes donor hearts to substantial pathophysiological perturbations that can influence heart transplant success and recipient survival. Although significant advances in recipient selection, donor and HTx recipient management, immunosuppression, and pretransplant mechanical circulatory support have been achieved, primary graft dysfunction after cardiac transplantation continues to be an important cause of morbidity and mortality. Animal models, when appropriate, can guide/inform medical practice, and fill gaps in knowledge that are unattainable in clinical settings. Consequently, we performed a systematic review of existing animal models that incorporate donor brain death and subsequent HTx and assessed studies for scientific rigor and clinical relevance. Following literature screening via the U.S National Library of Medicine bibliographic database (MEDLINE) and Embase, 29 studies were assessed. Analysis of included studies identified marked heterogeneity in animal models of donor brain death coupled to HTx, with few research groups worldwide identified as utilizing these models. General reporting of important determinants of heart transplant success was mixed, and assessment of posttransplant cardiac function was limited to an invasive technique (pressure-volume analysis), which is limitedly applied in clinical settings. This review highlights translational challenges between available animal models and clinical heart transplant settings that are potentially hindering advancement of this field of investigation.

Long-term Outcome in Severe Left Ventricular Primary Graft Dysfunction Post Cardiac Transplantation Supported by Early Use of Extracorporeal Membrane Oxygenation.

BACKGROUND: Severe primary graft dysfunction (PGD) is the leading cause of early death following cardiac transplantation. The early use of venoarterial extracorporeal membrane oxygenation (VA-ECMO) may facilitate graft rescue. However, the additional risks of its use are unknown. METHODS: We retrospectively reviewed the medical records of all adult patients who underwent cardiac transplantation from January 2009 to February 2016 at St Vincent's Hospital, Sydney, to evaluate risk factors for the use of VA-ECMO and related morbidity and long-term survival. RESULTS: One hundred ninety-two transplanted patients were identified, 49 (25%) of whom developed left or biventricular PGD requiring VA-ECMO. The total operation time (median 495 [interquartile range 139.8] versus 412.8 [132] min, P < 0.001), cardiopulmonary bypass time (220 [63] versus 176 [73] min, P < 0.001) and the presence of a previous sternotomy (29 [59%] versus 51 [36%], P = 0.019) were associated with the use of VA-ECMO. One-year survival in the VA-ECMO cohort was 71%. After a median follow-up time of 696 days (interquartile range 1201 d), survival was significantly higher in the non-ECMO group (P = 0.004) but not when conditioned on hospital survival (P = 0.34). Patients with shorter than median ECMO runtime (<108 h) had a similar long-term survival to patients who did not require ECMO (P = 0.559). In the ECMO cohort, multivariable logistic regression revealed baseline creatinine in µmol/L (odds ratio 0.99 [95% confidence interval 0.99-1.00], P = 0.019) and duration of ECMO support in days (odds ratio 0.65 [95% confidence interval 0.44-0.97], P = 0.034) were inversely and independently associated with 1-year survival. CONCLUSIONS: Short- and long-term survival of PGD supported with VA-ECMO was better than previously described. Early recovery of PGD on VA-ECMO support negates its negative impact on short- and long-term survival.

Too Much, Too Little, or Just Right? The Importance of Allograft Portal Flow in Deceased Donor Liver Transplantation.

BACKGROUND: While portal flow (PF) plays an important role in determining graft outcomes in living donor liver transplantation, its impact in deceased donor liver transplantation (DDLT) is unclear. The aim of this study was to investigate the correlations between graft PF and graft outcomes in DDLT. METHODS: We retrospectively investigated 1001 patients who underwent DDLT between January 2007 and June 2017 at our institution. The patients were divided into 3 groups according to hazard ratio for 1-year graft loss at each PF value, which was standardized with graft weight. Graft and recipient outcomes were compared between the groups. RESULTS: The low-PF group (PF < 65 mL/min/100 g, n = 210, P = 0.011) and the high-PF group (PF ≥ 155 mL/min/100 g, n = 159, P = 0.018) showed significantly poorer 1-year graft survival compared with the intermediate-PF group (PF ≥ 65 mL/min/100 g and < 155 mL/min/100 g, n = 632). The patients in the low-PF group had severe reperfusion injury and were more frequently complicated with primary nonfunction (P = 0.013) and early allograft dysfunction (P < 0.001) compared with the other groups. In contrast, the patients in the high-PF group had milder reperfusion injury, but had lower intraoperative hepatic artery flow with higher incidence of hepatic artery thrombosis (P = 0.043) and biliary complication (P = 0.041) compared with the other groups. CONCLUSIONS: These results suggest that intraoperative PF plays an important role in determining early graft outcomes after DDLT.

Can texture analysis in ultrashort echo-time MRI distinguish primary graft dysfunction from acute rejection in lung transplants? A multidimensional assessment in a mouse model.

BACKGROUND: Differentiation of early postoperative complications affects treatment options after lung transplantation. PURPOSE: To assess if texture analysis in ultrashort echo-time (UTE) MRI allows distinction of primary graft dysfunction (PGD) from acute transplant rejection (ATR) in a mouse lung transplant model. STUDY TYPE: Longitudinal. ANIMAL MODEL: Single left lung transplantation was performed in two cohorts of six mice (strain C57BL/6) receiving six syngeneic (strain C57BL/6) and six allogeneic lung transplants (strain BALB/c (H-2Kd )). FIELD STRENGTH/SEQUENCE: 4.7T small-animal MRI/eight different UTE sequences (echo times: 50-5000 µs) at three different postoperative timepoints (1, 3, and 7 days after transplantation). ASSESSMENT: Nineteen different first- and higher-order texture features were computed on multiple axial slices for each combination of UTE and timepoint (24 setups) in each mouse. Texture features were compared for transplanted (graft) and contralateral native lungs between and within syngeneic and allogeneic cohorts. Histopathology served as a reference. STATISTICAL TESTS: Nonparametric tests and correlation matrix analysis were used. RESULTS: Pathology revealed PGD in the syngeneic and ATR in the allogeneic cohort. Skewness and low-gray-level run-length features were significantly different between PGD and ATR for all investigated setups (P < 0.03). These features were significantly different between graft and native lung in ATR for most setups (minimum of 20/24 setups; all P < 0.05). The number of significantly different features between PGD and ATR increased with elapsing postoperative time. Differences in significant features were highest for an echo-time of 1500 µs. DATA CONCLUSION: Our findings suggest that texture analysis in UTE-MRI might be a tool for the differentiation of PGD and ATR in the early postoperative phase after lung transplantation. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2020;51:108-116.