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ISSN / EISSN : 0041-1337 / 1534-6080
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, Grace-Hyun J. Kim, Heather D. Jones, Allison L. Ramsey, Olawale Amubieya, Fereidoun Abtin, Lila Pourzand, Jihey Lee, Michael Y. Shino, Ariss DerHovanessian, et al.
Background: Chronic lung allograft dysfunction (CLAD) phenotype determines prognosis and may have therapeutic implications. Despite the clarity achieved by recent consensus statement definitions, their reliance on radiologic interpretation introduces subjectivity. The Center for Computer Vision and Imaging Biomarkers at UCLA has established protocols for chest HRCT based computer-aided quantification of both interstitial disease and air-trapping. We applied quantitative image analysis (QIA) at CLAD onset to demonstrate radiographic phenotypes with clinical implications. Methods: We studied 47 first bilateral lung transplant recipients at UCLA with chest HRCT performed within 90 days of CLAD onset and 47 no-CLAD control HRCTs. QIA determined the proportion of lung volume affected by interstitial disease and air-trapping in total lung capacity and residual volume images, respectively. We compared QIA scores between no-CLAD and CLAD, and between phenotypes. We also assigned radiographic phenotypes based solely on QIA, and compared their survival outcomes. Results: CLAD onset HRCTs had more lung affected by interstitial disease (p=0.003) than no-CLAD controls. Bronchiolitis obliterans syndrome (BOS) cases had lower scores for interstitial disease as compared to probable restrictive allograft syndrome (RAS) (p<0.0001) and mixed CLAD (p=0.02) phenotypes. BOS cases had more air-trapping than probable RAS (p<0.0001). Among phenotypes assigned by QIA, the relative risk of death was greatest for mixed (RR 11.81), followed by RAS (RR 6.27) and BOS (RR 3.15). Conclusions: Chest HRCT QIA at CLAD onset appears promising as a method for precise determination of CLAD phenotypes with survival implications.
, Casper Vrij, Pieter Vermeersch, Jan Van Elslande, Sofie Vets, Katrien Lagrou, Robin Vos, Johan van Cleemput, Ina Jochmans, Diethard Monbaliu, et al.
Background: There is paucity of data on the prevalence, adequate timing and outcome of solid organ transplantation after SARS-CoV-2 infection and the kinetics of IgG antibodies in these patients. Methods: SARS-CoV-2 anti-nucleocapsid (N) IgG and PCR via nasopharyngeal swab were analyzed in all patients within 24h before liver and/or kidney transplantation. Kinetics of IgG antibodies were analysed and compared with an immune-competent cohort. Results: Between May 1st 2020 and March 18th 2021, 168 patients underwent liver and/or kidney transplantation in our centre, of which 11 (6.54%) patients with previous SARS-CoV-2 infection were identified. Median interval between SARS-CoV-2 infection and transplantation was 4.5 months (range 0.9-11). After a median post-transplant follow-up of 4.9 months, 10 out of 11 patients were alive without clinical signs of viral shedding or recurrent or active infection. One patient without symptom resolution at time of transplantation died after combined liver-kidney transplantation. In 9 out of 11 patients with previously PCR confirmed infection, SARS-CoV-2 anti-N and anti-spike (S) IgG were detectable at day of transplantation. Absolute levels of anti-N and anti-S IgG were positively correlated, declined over time in all patients and were significantly lower compared with immune-competent individuals. All patients remained anti-S IgG positive until last post-transplant follow-up, while three patients became anti-N negative. Conclusions: We observed an uncomplicated course of liver and/or kidney transplantation after SARS-CoV-2 infection in selected patients. Although having lower absolute IgG antibody levels than immune-competent individuals, all seroconverted patients remained anti-S IgG positive. These encouraging data need validation in larger studies.
Yanyao Liu, Zilun Lei, Hao Chai, Song Xiang, Yihua Wang, Ping Yan, Zhenrui Cao, Xingyu Pu, Zhongjun Wu
Background: Hepatic ischemia/reperfusion injury (IRI) is an unavoidable outcome of liver transplantation, during which neutrophil extracellular traps (NETs) may play a critical role in the IRI-induced immune response to inflammation. The purpose of this study was to identify the function of recombinant human thrombomodulin (rTM) in the remission of hepatic IRI after liver transplantation and elucidate the specific mechanism. Methods: NET formation was detected in the serum of liver transplantation patients and rats following liver transplantation. Hematoxylin-eosin (HE) staining, terminal deoxynucleotidyl transferase dUTP nick-end labelling (TUNEL) staining, immunohistochemistry and immunofluorescence were used to assess the effect of rTM on NET formation in vitro and in vivo. Results: We found that rTM markedly inhibited neutrophil formation in NETs, reduced apoptosis in hepatocytes, alleviated rat hepatic IRI and improved liver function. In vitro, rTM inhibited neutrophil formation in NETs, and lipopolysaccharide (LPS) (a Toll-like receptor (TLR)-4 agonist) reversed the inhibitory effect of rTM on NET formation. rTM blocked TLR-4 and the downstream extracellular signal-regulated kinase (ERK)/c-Jun NH2 terminal kinase (JNK) and nicotinamide adenine dinucleotide phosphate (NADPH)/ROS/peptidylarginine deiminase 4 (PAD4) signaling pathways to protect against hepatic IRI and inhibit NET formation. In addition, we demonstrated that combined treatment with rTM and an NADPH oxidative inhibitor had a better effect than either treatment alone. Conclusions: NETs are a potential therapeutic target in hepatic IRI, and rTM could be used to prevent IR-induced hepatic injury. In addition, cotargeting NETosis-related signaling pathways might be a novel therapeutic strategy for hepatic IRI treatment.
, Thin Thin Maw, Rishi Mehta, Juliet Emamaullee, Jim Kim, Emily Blodget, Jeffrey Kahn, Linda Sher, Yuri Genyk
Background: Coronavirus-19 disease (COVID-19) has resulted in significant morbidity and mortality in solid organ transplant recipients. In December 2020, at the peak of the Los Angeles outbreak, our center rapidly implemented a protocol to improve outpatient management and provide Bamlanivimab or Casirivimab-Imdevimab (COVID mAb therapies) to all eligible COVID-19 positive liver and kidney transplant recipients. Methods: A retrospective review of all abdominal organ transplant recipients who were COVID-19 PCR+ between 2/2020-2/2021 from our center was performed. Patient demographics, COVID-19 treatments, hospitalizations, and survival were reviewed. Patients were considered eligible for COVID mAb therapy if they meet outpatient criteria at the time of diagnosis. Results: In the study period, 121 kidney transplant recipients (KG) and 105 liver or combined liver/kidney transplant recipients (LG) were COVID-19 PCR+. Hospitalization rates were similar for the KG (45%) versus LG (35%) (p=.20) but mortality was higher for the KG (22%) when compared to LG (10%) (p=.02). Our programmatic response, including outpatient COVID mAb therapies, reduced hospitalizations (p=.01) and deaths (p=.01). 94 KG and 87 LG patients were identified as potentially eligible for COVID mAb therapy and 17 KG and 17 LG patients were treated. COVID mAb therapies reduced hospitalization from 32% to 15% (p=.045) and eliminated mortality (13% vs 0%, p=.04). Conclusions: An aggressive approach including outpatient COVID mAb therapy in the COVID+ abdominal organ transplant recipients significantly decreased hospitalization and death. Early outpatient intervention for COVID-19 disease in transplant patients should be considered where possible.
Dominic Mudiayi, Soroush Shojai, Ikechi Okpechi, Emily A. Christie, Kevin Wen, Mostafa Kamaleldin, Mohamed Elsadig Osman, Meaghan Lunney, Bhanu Prasad, Feng Ye, et al.
Background: Kidney transplantation (KT) is the optimal treatment for kidney failure and is associated with better quality of life and survival relative to dialysis. However, knowledge of the current capacity of countries to deliver KT is limited. This study reports on findings from the 2018 International Society of Nephrology Global Kidney Health Atlas (ISN-GKHA) survey, specifically addressing the availability, accessibility, and quality of KT across countries and regions. Methods: Data were collected from published online sources and a survey was administered online to key stakeholders. All country-level data were analyzed by ISN region and World Bank income classification. Results: Data were collected via a survey in 182 countries of which 155 answered questions pertaining to KT. Of these, 74% stated that KT was available, with a median incidence of 14 pmp (range: 0.04 to 70) and median prevalence of 255 pmp (range: 3 to 693). Accessibility of KT varied widely; even within high income countries, it was disproportionately lower for ethnic minorities. Universal health coverage of all KT treatment costs was available in 31% and 57% had a KT registry. Conclusions: There are substantial variations in KT incidence, prevalence, availability, accessibility, and quality worldwide, with the lowest rates evident in low- and lower-middle income countries. Understanding these disparities will inform efforts to increase awareness and the adoption of practices that will ensure high quality KT care is provided around the world. Supplemental Visual Abstract;
Zhitao Chen, Tielong Wang, Chuanbao Chen, Qiang Zhao, Yihao Ma, Yiwen Guo, Xitao Hong, Jia Yu, Changjun Huang, Weiqiang Ju, et al.
Introduction: Traditional liver transplant strategies with cold preservation usually result in ischemia reperfusion injury (IRI) to the donor liver. Regular normothermic machine perfusion (NMP) donor livers suffer IRI twice. Here, we aimed to introduce a novel technique called continuous normothermic machine perfusion (NMP) without recooling to avoid a second IRI and its application in livers from extended criteria donors (ECDs). Materials and methods: Seven donor livers transplanted following continuous NMP without recooling, 7 donor livers transplanted following standard NMP and 14 livers under static cold storage (SCS) were included in this study. Perioperative outcomes were recorded and analyzed between groups. Result: During the NMP without a recooling procedure, all livers cleared lactate quickly to normal levels in a median time of 100 minutes (IQR 60~180) and remained stable until the end of perfusion. In the NMP without recooling and standard NMP groups, posttransplant peak aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels were both significantly lower than those in the SCS group (P=0.0015 and 0.016, respectively). The occurrence rate of early allograft dysfunction (EAD) was significantly lower in the NMP without recooling group than in the SCS group (P=0.022), while there was no difference in the NMP group with or without recooling (P=0.462). Conclusion: Our pilot study revealed a novel technique designed to avoid secondary IRI. This novel technique is shown to have at least a comparable effect to the standard NMP, though more data are needed to show its superiority in the future.
, Amit K. Mathur, Bashar Aqel, Liu Yang, Timucin Taner, Julie K. Heimbach, Charles B. Rosen, Ricardo Paz-Fumagalli, C. Burcin Taner
Background: As the number of donation after circulatory death(DCD) liver transplants(LTs) performed in the United States continues to increase annually, there has been interest by policy makers to develop a more robust exception point safety net for patients who develop ischemic cholangiopathy(IC) following DCD LT. As such, there is a need for better understanding of the clinical course and long-term outcomes in patients who develop IC, as well as determining if IC can be classified into distinct categories with distinctly different clinical outcomes. Methods: All DCD LT performed at Mayo Clinic-Florida, Mayo Clinic-Arizona and Mayo Clinic-Rochester from 1/1999-3/2020 were included(N=770). Outcomes were compared between 4 distinct radiologic patterns of IC: Diffuse Necrosis(DN), Multifocal Progressive(MP), Confluence Dominant(CD) and Minor Form(MF). Results: In total N=88(11.4%) patients developed IC, of which N=42(5.5%) were listed for retransplantation (ReLT). Patients with DN and MP patterns suffered from frequent hospital admissions for cholangitis in the first year following DCD LT(median 3 and 2), were largely stent dependent(100% and 85.7%) and almost universally required ReLT. Patients with CD disease were managed with multiple stents and frequently recovered, ultimately becoming stent free without need for ReLT. Patients with the MF IC did well with limited need for stent placement or repeat procedures and did not require ReLT. Graft survival was different between the 4 distinct IC patterns(p<0.001). Conclusions: The present analysis provides a detailed analysis on the natural history and clinical course of IC. Patients developing IC can be classified into 4 distinct patterns with distinct clinical courses.
Julien De Wolf, Matthieu Glorion, Luc Jouneau, Jérôme Estephan, Jean-Jacques Leplat, Fany Blanc, Christophe Richard, Céline Urien, Antoine Roux, Morgan Le Guen, et al.
Background: Normothermic ex vivo lung perfusion (EVLP) increases the pool of donor lungs by requalifying marginal lungs refused for transplantation through the recovery of macroscopic and functional properties. However the cell response and metabolism occurring during EVLP generate a nonphysiological accumulation of electrolytes, metabolites, cytokines and other cellular byproducts which may have deleterious effects both at the organ and cell levels, with impact on transplantation outcomes. Methods: We analyzed the physiological, metabolic and genome-wide response of lungs undergoing a 6-hour EVLP procedure in a pig model in 4 experimental conditions: without perfusate modification, with partial replacement of fluid, and with adult or pediatric dialysis filters. Results: Adult and pediatric dialysis stabilized the electrolytic and metabolic profiles while maintaining acid-base and gas exchanges. Pediatric dialysis increased the level of IL-10 and IL-6 in the perfusate. Despite leading to modification of the perfusate composition, the 4 EVLP conditions did not affect the gene expression profiles which were associated in all cases with increased cell survival, cell proliferation, inflammatory response and cell movement, and with inhibition of bleeding. Conclusions: Management of EVLP perfusate by periodic replacement and continuous dialysis has no significant effect on the lung function nor on the gene expression profiles ex vivo. These results suggest that the accumulation of dialysable cell products does not significantly alter the lung cell response during EVLP, a finding that may have impact on EVLP management in the clinic.
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