Donor and recipient genetics: Implications for the development of posttransplant diabetes mellitus.

Posttransplant diabetes mellitus (PTDM) is a prevalent complication of liver transplantation and is associated with cardiometabolic complications. We studied the consequences of genetic effects of liver donors and recipients on PTDM outcomes, focusing on the diverse genetic pathways related to insulin that play a role in the development of PTDM. One thousand one hundred fifteen liver transplant recipients without a pretransplant diagnosis of type 2 diabetes mellitus (T2D) and their paired donors recruited from 2 transplant centers had polygenic risk scores (PRS) for T2D, insulin secretion, and insulin sensitivity calculated. Among recipients in the highest T2D-PRS quintile, donor T2D-PRS did not contribute significantly to PTDM. However, in recipients with the lowest T2D genetic risk, donor livers with the highest T2D-PRS contributed to the development of PTDM (OR [95% CI] = 3.79 [1.10-13.1], P = .035). Recipient risk was linked to factors associated with insulin secretion (OR [95% CI] = 0.85 [0.74-0.98], P = .02), while donor livers contributed to PTDM via gene pathways involved in insulin sensitivity (OR [95% CI] = 0.86 [0.75-0.99], P = .03). Recipient and donor PRS independently and collectively serve as predictors of PTDM onset. The genetically influenced biological pathways in recipients primarily pertain to insulin secretion, whereas the genetic makeup of donors exerts an influence on insulin sensitivity.

Biliary complications after adult-to-adult living-donor liver transplantation: An international multicenter study of 3633 cases.

In living-donor liver transplantation, biliary complications including bile leaks and biliary anastomotic strictures remain significant challenges, with incidences varying across different centers. This multicentric retrospective study (2016-2020) included 3633 adult patients from 18 centers and aimed to identify risk factors for these biliary complications and their impact on patient survival. Incidences of bile leaks and biliary strictures were 11.4% and 20.6%, respectively. Key risk factors for bile leaks included multiple bile duct anastomoses (odds ratio, [OR] 1.8), Roux-en-Y hepaticojejunostomy (OR, 1.4), and a history of major abdominal surgery (OR, 1.4). For biliary anastomotic strictures, risk factors were ABO incompatibility (OR, 1.4), blood loss >1 L (OR, 1.4), and previous abdominal surgery (OR, 1.7). Patients experiencing biliary complications had extended hospital stays, increased incidence of major complications, and higher comprehensive complication index scores. The impact on graft survival became evident after accounting for immortal time bias using time-dependent covariate survival analysis. Bile leaks and biliary anastomotic strictures were associated with adjusted hazard ratios of 1.7 and 1.8 for graft survival, respectively. The study underscores the importance of minimizing these risks through careful donor selection and preoperative planning, as biliary complications significantly affect graft survival, despite the availability of effective treatments.

Novel Benchmark for Adult-to-Adult Living-donor Liver Transplantation: Integrating Eastern and Western Experiences.

OBJECTIVE: To define benchmark values for adult-to-adult living-donor liver transplantation (LDLT). BACKGROUND: LDLT utilizes living-donor hemiliver grafts to expand the donor pool and reduce waitlist mortality. Although references have been established for donor hepatectomy, no such information exists for recipients to enable conclusive quality and comparative assessments. METHODS: Patients undergoing LDLT were analyzed in 15 high-volume centers (≥10 cases/year) from 3 continents over 5 years (2016-2020), with a minimum follow-up of 1 year. Benchmark criteria included a Model for End-stage Liver Disease ≤20, no portal vein thrombosis, no previous major abdominal surgery, no renal replacement therapy, no acute liver failure, and no intensive care unit admission. Benchmark cutoffs were derived from the 75th percentile of all centers' medians. RESULTS: Of 3636 patients, 1864 (51%) qualified as benchmark cases. Benchmark cutoffs, including posttransplant dialysis (≤4%), primary nonfunction (≤0.9%), nonanastomotic strictures (≤0.2%), graft loss (≤7.7%), and redo-liver transplantation (LT) (≤3.6%), at 1-year were below the deceased donor LT benchmarks. Bile leak (≤12.4%), hepatic artery thrombosis (≤5.1%), and Comprehensive Complication Index (CCI ® ) (≤56) were above the deceased donor LT benchmarks, whereas mortality (≤9.1%) was comparable. The right hemiliver graft, compared with the left, was associated with a lower CCI ® score (34 vs 21, P < 0.001). Preservation of the middle hepatic vein with the right hemiliver graft had no impact neither on the recipient nor on the donor outcome. Asian centers outperformed other centers with CCI ® score (21 vs 47, P < 0.001), graft loss (3.0% vs 6.5%, P = 0.002), and redo-LT rates (1.0% vs 2.5%, P = 0.029). In contrast, non-benchmark low-volume centers displayed inferior outcomes, such as bile leak (15.2%), hepatic artery thrombosis (15.2%), or redo-LT (6.5%). CONCLUSIONS: Benchmark LDLT offers a valuable alternative to reduce waitlist mortality. Exchange of expertise, public awareness, and centralization policy are, however, mandatory to achieve benchmark outcomes worldwide.

Systematic discovery and perturbation of regulatory genes in human T cells reveals the architecture of immune networks.

Gene regulatory networks ensure that important genes are expressed at precise levels. When gene expression is sufficiently perturbed, it can lead to disease. To understand how gene expression disruptions percolate through a network, we must first map connections between regulatory genes and their downstream targets. However, we lack comprehensive knowledge of the upstream regulators of most genes. Here, we developed an approach for systematic discovery of upstream regulators of critical immune factors-IL2RA, IL-2 and CTLA4-in primary human T cells. Then, we mapped the network of the target genes of these regulators and putative cis-regulatory elements using CRISPR perturbations, RNA-seq and ATAC-seq. These regulators form densely interconnected networks with extensive feedback loops. Furthermore, this network is enriched for immune-associated disease variants and genes. These results provide insight into how immune-associated disease genes are regulated in T cells and broader principles about the structure of human gene regulatory networks.

Impact of Donor and Recipient Clinical Characteristics and Hepatic Histology on Steatosis/Fibrosis Following Liver Transplantation.

BACKGROUND: Deceased donor and recipient predictors of posttransplant steatosis/steatohepatitis and fibrosis are not well known. Our aim was to evaluate the prevalence and assess donor and recipient predictors of steatosis, steatohepatitis, and fibrosis in liver transplantation recipients. METHODS: Using the immune tolerance network A-WISH multicenter study (NCT00135694), donor and recipient demographic and clinical features were collected. Liver biopsies were taken from the donor liver at transplant, and from recipients per protocol and for-cause (ie, abnormal transaminases and to rule out rejection) and were interpreted by a central pathologist. RESULTS: One hundred eighty-three paired donor/recipients liver biopsies at the time of transplant and posttransplant follow-up (median time 582 d; average time to last biopsies was 704 d [SD ± 402 d]) were analyzed. Donor steatosis did not influence recipient steatosis or fibrosis. Ten of 183 recipients had steatohepatitis on the last biopsy. Recipient body mass index at the time of liver biopsy was the most influential factor associated with posttransplant steatosis. Both donor and recipient metabolic syndrome features were not associated with graft steatosis. Untreated hepatitis C viral (HCV) infection was the most influential factor associated with the development of allograft fibrosis. CONCLUSIONS: In a large experience evaluating paired donor and recipient characteristics, recipient body mass index at the time of liver biopsy was most significantly associated with posttransplant steatosis. Untreated HCV etiology influenced graft fibrosis. Thus relative to untreated HCV, hepatic fibrosis in those with steatosis/steatohepatitis is less common though long-term follow-up is needed to determine the course of posttransplant fibrosis. Emphasis on recipient weight control is essential.

Appendiceal neurofibroma in a patient with neurofibromatosis 1 and recurrent abdominal infections from ventriculoperitoneal shunt: a case report.

Appendiceal neurofibromas are exceedingly rare, with neither experimental nor observational data to support evidence-based diagnosis or treatment. We describe the case of a 52-year-old woman with neurofibromatosis 1 (NF1) complicated by aqueductal stenosis and resultant hydrocephalus needing a ventriculoperitoneal shunt (VPS). She presented to the emergency department with abdominal pain and was found to have abnormalities in the right hemiabdomen on cross-section imaging, also a Staphylococcus epidermidis growth at the distal portion of the VPS. She was initially treated with two rounds of intravenous antibiotics and VPS removal without improvement. She ultimately underwent an appendectomy, which revealed pathologic evidence of NF. The appendectomy was key to ruling out malignancy, addressing further symptoms and preventing future malignant transformation. This case highlights the importance of including appendiceal neurofibromas in the differential diagnoses of abdominal pain in patients with NF1.

CRISPR screen in regulatory T cells reveals modulators of Foxp3.

Regulatory T (Treg) cells are required to control immune responses and maintain homeostasis, but are a significant barrier to antitumour immunity1. Conversely, Treg instability, characterized by loss of the master transcription factor Foxp3 and acquisition of proinflammatory properties2, can promote autoimmunity and/or facilitate more effective tumour immunity3,4. A comprehensive understanding of the pathways that regulate Foxp3 could lead to more effective Treg therapies for autoimmune disease and cancer. The availability of new functional genetic tools has enabled the possibility of systematic dissection of the gene regulatory programs that modulate Foxp3 expression. Here we developed a CRISPR-based pooled screening platform for phenotypes in primary mouse Treg cells and applied this technology to perform a targeted loss-of-function screen of around 500 nuclear factors to identify gene regulatory programs that promote or disrupt Foxp3 expression. We identified several modulators of Foxp3 expression, including ubiquitin-specific peptidase 22 (Usp22) and ring finger protein 20 (Rnf20). Usp22, a member of the deubiquitination module of the SAGA chromatin-modifying complex, was revealed to be a positive regulator that stabilized Foxp3 expression; whereas the screen suggested that Rnf20, an E3 ubiquitin ligase, can serve as a negative regulator of Foxp3. Treg-specific ablation of Usp22 in mice reduced Foxp3 protein levels and caused defects in their suppressive function that led to spontaneous autoimmunity but protected against tumour growth in multiple cancer models. Foxp3 destabilization in Usp22-deficient Treg cells could be rescued by ablation of Rnf20, revealing a reciprocal ubiquitin switch in Treg cells. These results reveal previously unknown modulators of Foxp3 and demonstrate a screening method that can be broadly applied to discover new targets for Treg immunotherapies for cancer and autoimmune disease.

Non-cardiac surgery in patients with continuous-flow left ventricular assist devices: a single institutional experience.

With improvements in life expectancy for patients with continuous-flow left ventricular assist devices (LVADs), non-cardiac surgeons will increasingly encounter surgical problems in this population. 209 patients underwent LVAD placement between 10/1/2007 and 6/1/2015 at a single institution. Survival was compared between patients who had non-cardiac surgery (NCS) during the initial LVAD implantation hospitalization (n=36) and those who had NCS only in subsequent hospitalizations (n=33). Postoperative complication rates were examined. Index admission NCS was associated with lower 5-year survival compared with subsequent admission NCS (27.1% vs 39.4%, p=0.017). In subsequent admissions, the risks of bleeding and infectious complications were the same for elective or urgent NCS, but the risk of death was higher in the urgent surgery group. We conclude that elective NCS can be performed with low risk of death or LVAD dysfunction after sufficient recovery of patients from LVAD implantation.

Complex wound management in ventricular assist device (VAD) patients: the role of aggressive debridement and vascularized soft tissue coverage.

BACKGROUND: Infections and complex wounds after ventricular assist device (VAD) placement can result in significant morbidity and mortality. The purpose of this study was to evaluate complex wound management in the VAD patient, and to describe a treatment protocol for these challenging and potentially mortal complications. METHODS: A retrospective study was performed to examine all patients who underwent continuous flow, second-generation VAD placement at the Hospital of the University of Pennsylvania between March 2008 and April 2013. RESULTS: Overall, 150 VADs were placed, with 12 (8%) patients requiring 15 operative interventions by the plastic surgery services. The most common indication for operative intervention was a complicated wound with VAD exposure (5/12, 41.7%). All patients underwent aggressive operative debridement, and 11/12 (92%) underwent vascularized soft tissue coverage. Flaps commonly utilized included rectus abdominus myocutaneous (n = 4), rectus abdominus muscle (n = 4), pectoralis major (n = 3), and omentum (n = 3). Three patients experienced complications which required a return to the operating room, including 1 flap loss, 1 hematoma, and 1 wound dehiscence requiring further soft tissue coverage. Salvage was achieved, yet a 50% mortality rate in follow-up was noted. CONCLUSION: Complex wound management in VAD patients can be achieved with aggressive debridement and vascularized soft tissue coverage, most commonly utilizing well-vascularized rectus abdominus muscle or omental flaps. Plastic surgeons should be familiar with the armamentarium at their disposal when approaching these challenging cases as VAD wound complications stand to become an increasingly prevalent issue.

Acute-on-chronic liver failure before liver transplantation: impact on posttransplant outcomes.

BACKGROUND: Acute decompensation in patients with chronic liver disease, resulting from acute kidney injury and infections, leads to significant morbidity and mortality. It is unclear whether patients who develop acute-on-chronic liver failure (ACLF) have poor outcomes after liver transplantation. METHODS: We performed a single-center retrospective cohort study of 332 patients to evaluate the effect of ACLF, defined as an acute rise in the Model for End-Stage Liver Disease score of more than 5 within 4 weeks before transplantation, on posttransplant outcomes including stage 4 chronic kidney disease, death, recurrent cirrhosis, or graft failure requiring retransplantation. RESULTS AND CONCLUSIONS: One hundred fifty-seven patients in the study had ACLF and 175 patients had no ACLF (non-ACLF) pretransplant. Thirty-four patients in the entire cohort received dual organs, 10 of them (29.4%) had ACLF. Seventy-six percent of the patients with ACLF had acute kidney injury as their reason for decompensation and 23.6% had an infection. Mean Model for End-Stage Liver Disease score at transplant was significantly different between the groups (ACLF 28.77 vs. non-ACLF 21.23, P<0.0001). A total of 16.6% of the patients achieved an estimated glomerular filtration rate (eGFR) less than 30 mL/min, 21% of patients died, 12.3% developed cirrhosis, and 7.5% received a second transplant. There was no difference in mean eGFR between the ACLF and non-ACLF cohorts at 3 years posttransplant (56.35 mL/min vs. 59.93 mL/min, respectively, P=0.27). On multivariate analysis, ACLF was not significantly associated with eGFR less than 30 mL/min, death, recurrent cirrhosis, or retransplantation when adjusted for potential confounders.

Chronic kidney disease after orthotopic liver transplantation: impact of hepatitis C infection.

BACKGROUND: Hepatitis C virus (HCV) infection has been shown to be a potential risk factor for the development of chronic kidney disease in liver transplant recipients. METHODS: We performed a retrospective cohort study of 307 patients with and without HCV cirrhosis and preserved pretransplant renal function (serum creatinine<1.5 mg/dL pretransplantation) to assess the impact of HCV on the incidence of posttransplant chronic kidney disease. Kaplan-Meier analysis was performed for time to development of estimated glomerular filtration rate (eGFR) less than 30 mL/min, need for dialysis, and mortality. RESULTS: One hundred eighty-one patients were transplanted for HCV cirrhosis and 126 recipients had other causes of liver disease. Mean model for end-stage liver disease scores were 21.64 in the HCV group and 21.30 in the non-HCV group (P=0.58); 51% of patients in the HCV cohort had hepatocellular carcinoma compared with 27% in the non-HCV cohort (P<0.001). Mean pretransplant serum creatinine level was 0.89 mg/dL in both groups. At 3 years posttransplant, eGFR did not differ between the HCV and non-HCV cohorts (64.96 mL/min vs. 66.09 mL/min; P=0.71). A total of 14.4% of the patients with HCV achieved an eGFR less than 30 mL/min compared with 10.3% of the patients without HCV (P=0.13). There was no difference between the cohorts with respect to requirement for dialysis (P=0.73) or deaths (P=0.08), including those that were liver related (P=0.15). CONCLUSIONS: Patients with HCV cirrhosis and normal preliver transplant renal function do not have worse posttransplant renal outcomes compared with those with other causes of liver disease.

Biologic and clinical features of benign solid and cystic lesions of the liver.

The widespread use of imaging analyses, either routinely or to evaluate symptomatic patients, has increased the detection of liver lesions (tumors and cysts) in otherwise healthy individuals. Although some of these incidentally discovered masses are malignant, most are benign and must be included in the differential diagnosis. The management of benign hepatic tumors ranges from conservative to aggressive, depending on the nature of the lesions. New imaging modalities, increased experience of radiologists, improved definition of radiologic characteristics, and a better understanding of the clinical features of these lesions have increased the accuracy of diagnoses and reduced the need for invasive diagnostic tests. These advances have led to constant adjustments in management approaches to benign hepatic lesions. We review the biologic and clinical features of some common hepatic lesions, to guide diagnosis and management strategies.

Approach to a liver mass.

Incidentally discovered liver masses are becoming more common with the increasing application and power of imaging techniques for the evaluation of abdominal conditions. Although such masses are often benign, conclusive diagnoses must be established in order to provide appropriate patient care. Various imaging modalities can be utilized to accurately diagnose such masses without resort to more invasive diagnostic measures.