Donor Diabetes and Prolonged Cold Ischemia Time Synergistically Increase the Risk of Graft Failure After Liver Transplantation

BACKGROUND: Both prolonged cold ischemia time (CIT) and donor history of diabetes mellitus (DM) are associated with reduced graft survival after liver transplantation. However, it is unknown whether the adverse effect of prolonged CIT on posttransplant graft survival is more pronounced after transplant with DM versus non-DM donor grafts. METHODS: The study sample included 58 226 liver transplant recipients (2002-2015) from the Scientific Registry of Transplant Recipients. Multivariable Cox survival regression with interaction analysis was used to quantify the extent to which history of donor DM (n = 6478) potentiates the adverse effect of prolonged ( \u3e /=8 hours) CIT (n = 18 287) on graft survival. RESULTS: Donor DM and CIT 8 hours or longer were each associated with increased risk of graft failure (GF) (adjusted hazard ratio [aHR], 1.19; 95% confidence interval [CI], 1.06-1.35 and aHR, 1.42; 95% CI, 1.32-1.53, respectively) compared with transplanted grafts without either risk factor. However, the combination of DM and CIT 8 hours or longer was associated with a higher risk of GF than either factor alone (aHR, 1.79; 95% CI, 1.55-2.06) and had a synergy index of 1.30. The interaction was significant on a multiplicative scale in the later postoperative period, days 31 to 365 (P = 0.047). CONCLUSIONS: These results suggest that liver grafts from DM donors are more susceptible to the adverse effects of prolonged CIT than livers from non-DM donors. We need to be cognizant that they are more susceptible to ischemic injury, and this may be considered during the allocation process

Single-Center Experience With Liver Transplant Using Donors With Very High Transaminase Levels

OBJECTIVES: Elevation of transaminases has been used as a marker of hepatic ischemic injury and as a crucial parameter for liver graft assessment. However, analysis of serum transaminases has limitations regarding the quantitative assessment of liver necrosis and is not a reliable predictor of outcomes. MATERIALS AND METHODS: We retrospectively reviewed the medical records of all liver transplants (N = 238) performed at the UMass Memorial Medical Center from 2009 to 2013. RESULTS: Fourteen liver grafts showed high peak aminotransferases alanine aminotransferase (ALT) and aspartate aminotransferase (AST) at \u3e 1000 U/L. This high aminotransferase group was compared with 224 donors with low transaminase levels (ALT/AST \u3c 1000 U/L). The high transaminase donors had a median peak AST level of 3216 U/L (range, 1823-13?030 U/L) and ALT level of 2677 U/L (range, 812-7080 U/L). The high transaminase donors showed higher levels of lactate dehydrogenase, international normalized ratio, total bilirubin, and gamma-glutamyltransferase compared with low transaminase donors; however, only lactate dehydrogenase results reached statistical significance. None of the grafts from the high transaminase donors showed primary nonfunction. Three-year graft and patient survival rates were similar in both groups (75% vs 80% [P = .48] and 72% vs 82% [P = .33], respectively). In an analysis of the discard rate of livers over a 10-year period in the United States using the Scientific Registry of Transplant Recipients database, the discard rate of livers with high aminotransferase levels was 69.14% compared with 22.23% for livers with low transaminase levels. CONCLUSIONS: Liver grafts from donors with high transaminase levels can lead to clinical results that are similar to liver grafts from donors who had lower peak transaminase levels

Clinical relevance of rapid FOXF1-targeted sequencing in patients suspected of alveolar capillary dysplasia with misalignment of pulmonary veins

Alveolar capillary dysplasia with misalignment of pulmonary Veins (ACDMPV) is a lethal congenital lung disorder that presents shortly after birth with respiratory failure and therapy-resistant pulmonary hypertension. It is associated with heterozygous point mutations and genomic deletions that involve the FOXF1 gene or its upstream regulatory region. Patients are unresponsive to the intensive treatment regiments and suffer unnecessarily, because ACDMPV is not always timely recognized and histological diagnosis is invasive and time-consuming. Here, we demonstrate the usefulness of a non-invasive, fast genetic test for FOXF1 variants that we previously developed to rapidly diagnose ACDMPV and reduce the time of hospitalization.</p

Application of the New Classification on Patients with a Disorder of Sex Development in Indonesia

Disorder of sex development (DSD) patients in Indonesia most often do not receive a proper diagnostic evaluation and treatment. This study intended to categorize 88 Indonesian patients in accordance with the new consensus DSD algorithm. Diagnostic evaluation including clinical, hormonal, genetic, imaging, surgical, and histological parameters was performed. Fifty-three patients were raised as males, and 34 as females. Of 22 patients with 46, XX DSD, 15 had congenital adrenal hyperplasia, while in one patient, an ovarian Leydig cell tumor was found. In all 58 46, XY DSD patients, 29 were suspected of a disorder of androgen action (12 with an androgen receptor mutation), and in 9, gonadal dysgenesis was found and, in 20, severe hypospadias e.c.i. Implementation of the current consensus statement in a resource-poor environment is very difficult. The aim of the diagnostic workup in developing countries should be to end up with an evidence-based diagnosis. This is essential to improve treatment and thereby to improve the patients' quality of life

Prolonged hypothermic machine perfusion enables daytime liver transplantation - an IDEAL stage 2 prospective clinical trial

Background: Liver transplantation is traditionally performed around the clock to minimize organ ischemic time. However, the prospect of prolonging preservation times holds the potential to streamline logistics and transform liver transplantation into a semi-elective procedure, reducing the need for nighttime surgeries. Dual hypothermic oxygenated machine perfusion (DHOPE) of donor livers for 1–2 h mitigates ischemia-reperfusion injury and improves transplant outcomes. Preclinical studies have shown that DHOPE can safely extend the preservation of donor livers for up to 24 h. Methods: We conducted an IDEAL stage 2 prospective clinical trial comparing prolonged (≥4 h) DHOPE to conventional (1–2 h) DHOPE for brain-dead donor livers, enabling transplantation the following morning. Liver allocation to each group was based on donor hepatectomy end times. The primary safety endpoint was a composite of all serious adverse events (SAE) within 30 days after transplantation. The primary feasibility endpoint was defined as the number of patients assigned and successfully receiving a prolonged DHOPE-perfused liver graft. Trial registration at: WHO International Clinical Trial Registry Platform, number NL8740. Findings: Between November 1, 2020 and July 16, 2022, 24 patients were enrolled. The median preservation time was 14.5 h (interquartile range [IQR], 13.9–15.5) for the prolonged group (n = 12) and 7.9 h (IQR, 7.6–8.6) for the control group (n = 12; p = 0.01). In each group, three patients (25%; 95% CI 3.9–46%, p = 1) experienced a SAE. Markers of ischemia-reperfusion injury and oxidative stress in both perfusate and recipients were consistently low and showed no notable discrepancies between the two groups. All patients assigned to either the prolonged group or control group successfully received a liver graft perfused with either prolonged DHOPE or control DHOPE, respectively. Interpretation: This first-in-human clinical trial demonstrates the safety and feasibility of DHOPE in prolonging the preservation time of donor livers to enable daytime transplantation. The ability to extend the preservation window to up to 20 h using hypothermic oxygenated machine preservation at a 10 °C temperature has the potential to reshape the landscape of liver transplantation. Funding: University Medical Center Groningen, the Netherlands.</p

The impact of point mutations in the human androgen receptor : classification of mutations on the basis of transcriptional activity

Peer reviewedPublisher PD

The genetic diagnosis of rare endocrine disorders of sex development and maturation : a survey among Endo-ERN centres

Differences of sex development and maturation (SDM) represent a heterogeneous puzzle of rare conditions with a large genetic component whose management and treatment could be improved by an accurate classification of underlying molecular conditions, and next-generation sequencing (NGS) should represent the most appropriate approach. Therefore, we conducted a survey dedicated to the use and potential outcomes of NGS for SDM disorders diagnosis among the 53 health care providers (HCP) of the European Reference Network for rare endocrine conditions. The response rate was 49% with a total of 26 HCPs from 13 countries. All HCPs, except 1, performed NGS investigations for SDM disorders on 6720 patients, 3764 (56%) with differences of sex development (DSD), including 811 unexplained primary ovarian insufficiency, and 2956 (44%) with congenital hypogonadotropic hypogonadism (CHH). The approaches varied from targeted analysis of custom gene panels (range: 11-490 genes) in 81.5% of cases or whole exome sequencing with the extraction of a virtual panel in the remaining cases. These analyses were performed for diagnostic purposes in 21 HCPs, supported by the National Health Systems in 16 cases. The likelihood of finding a variant ranged between 7 and 60%, mainly depending upon the number of analysed genes or criteria used for reporting, most HCPs also reporting variants of uncertain significance. These data illustrate the status of genetic diagnosis of DSD and CHH across Europe. In most countries, these analyses are performed for diagnostic purposes, yielding highly variable results, thus suggesting the need for harmonization and general improvements of NGS approaches.publishersversionPeer reviewe

Prolonged hypothermic machine perfusion enables daytime liver transplantation - an IDEAL stage 2 prospective clinical trial

Background: Liver transplantation is traditionally performed around the clock to minimize organ ischemic time. However, the prospect of prolonging preservation times holds the potential to streamline logistics and transform liver transplantation into a semi-elective procedure, reducing the need for nighttime surgeries. Dual hypothermic oxygenated machine perfusion (DHOPE) of donor livers for 1–2 h mitigates ischemia-reperfusion injury and improves transplant outcomes. Preclinical studies have shown that DHOPE can safely extend the preservation of donor livers for up to 24 h. Methods: We conducted an IDEAL stage 2 prospective clinical trial comparing prolonged (≥4 h) DHOPE to conventional (1–2 h) DHOPE for brain-dead donor livers, enabling transplantation the following morning. Liver allocation to each group was based on donor hepatectomy end times. The primary safety endpoint was a composite of all serious adverse events (SAE) within 30 days after transplantation. The primary feasibility endpoint was defined as the number of patients assigned and successfully receiving a prolonged DHOPE-perfused liver graft. Trial registration at: WHO International Clinical Trial Registry Platform, number NL8740. Findings: Between November 1, 2020 and July 16, 2022, 24 patients were enrolled. The median preservation time was 14.5 h (interquartile range [IQR], 13.9–15.5) for the prolonged group (n = 12) and 7.9 h (IQR, 7.6–8.6) for the control group (n = 12; p = 0.01). In each group, three patients (25%; 95% CI 3.9–46%, p = 1) experienced a SAE. Markers of ischemia-reperfusion injury and oxidative stress in both perfusate and recipients were consistently low and showed no notable discrepancies between the two groups. All patients assigned to either the prolonged group or control group successfully received a liver graft perfused with either prolonged DHOPE or control DHOPE, respectively. Interpretation: This first-in-human clinical trial demonstrates the safety and feasibility of DHOPE in prolonging the preservation time of donor livers to enable daytime transplantation. The ability to extend the preservation window to up to 20 h using hypothermic oxygenated machine preservation at a 10 °C temperature has the potential to reshape the landscape of liver transplantation. Funding: University Medical Center Groningen, the Netherlands.</p