Sofosbuvir plus glecaprevir/pibrentasvir as salvage therapy after liver transplantation in NS5A inhibitor-experienced patients. A case series.

BACKGROUND: Treatment of chronic hepatitis C virus (HCV) infection with direct-acting antivirals achieves a sustained virologic response rate higher than 95%. However, virologic failure remains a clinical challenge, and data on retreatment are limited, especially in special populations such as liver transplant (LT) recipients. OBJECTIVES: This study evaluated the sofosbuvir plus glecaprevir-pibrentasvir (GLE/PIB) regimen in LT recipients who had failed to a nonstructural protein 5A (NS5A) inhibitor-based regimen. MATERIAL AND METHODS: Retrospective study of 111 liver transplant recipients between January 2018 and December 2020; 18 patients presented with HCV recurrent infection after LT, out of whom three had a history of at least one NS5A inhibitor-based regimen. Salvage therapy with sofosbuvir plus GLE/PIB was started for 12 weeks; baseline characteristics and outcomes were recorded. RESULTS: All three patients (100%) achieved an undetectable HCV viral load 12 weeks after treatment completion. No serious adverse events were observed. CONCLUSION: In our series, sofosbuvir plus GLE/PIB for 12 weeks is an effective and safe salvage therapy after LT in patients previously treated with NS5A inhibitors.

ANTECEDENTES: El tratamiento del virus de la hepatitis C (VHC) crónica con antivirales de acción directa logra tasas de respuesta virológica sostenida superiores a 95 %. Sin embargo, el manejo del fracaso virológico sigue siendo un desafío clínico y la evidencia sobre el retratamiento es limitada, especialmente en poblaciones como los receptores de trasplante hepático (TH). OBJETIVO: Este estudio evaluó el régimen de sofosbuvir más glecaprevir/pibrentasvir (GLE/PIB) en receptores de TH en quienes falló el régimen basado en inhibidores de la proteína no estructural 5A (NS5A). MATERIAL Y MÉTODOS: Estudio retrospectivo de 111 pacientes trasplantados entre enero de 2018 y diciembre de 2020; 18 pacientes presentaron infección recurrente por VHC posterior al TH, tres de ellos tuvieron antecedentes de al menos un régimen basado en inhibidores de NS5A. Se inició terapia de rescate con sofosbuvir más GLE/PIB durante 12 semanas posterior al TH; se registraron las características basales de los pacientes y sus desenlaces. RESULTADOS: En los tres pacientes se logró obtener una carga viral indetectable de VHC a las 12 semanas de finalizar el tratamiento. No se observaron eventos adversos graves. CONCLUSIÓN: En nuestra serie, sofosbuvir más GLE/PIB durante 12 semanas demostró ser una terapia de rescate efectiva y segura posterior al TH en pacientes previamente tratados con inhibidores de NS5A.

Low-dose aspirin confers protection against acute cellular allograft rejection after primary liver transplantation.

This study investigated the effect of low-dose aspirin in primary adult liver transplantation (LT) on acute cellular rejection (ACR) as well as arterial patency rates. The use of low-dose aspirin after LT is practiced by many transplant centers to minimize the risk of hepatic artery thrombosis (HAT), although solid recommendations do not exist. However, aspirin also possesses potent anti-inflammatory properties and might mitigate inflammatory processes after LT, such as rejection. Therefore, we hypothesized that the use of aspirin after LT has a protective effect against ACR. This is an international, multicenter cohort study of primary adult deceased donor LT. The study included 17 high-volume LT centers and covered the 3-year period from 2013 to 2015 to allow a minimum 5-year follow-up. In this cohort of 2365 patients, prophylactic antiplatelet therapy with low-dose aspirin was administered in 1436 recipients (61%). The 1-year rejection-free survival rate was 89% in the aspirin group versus 82% in the no-aspirin group (hazard ratio [HR], 0.77; 95% confidence interval [CI], 0.63-0.94; p = 0.01). The 1-year primary arterial patency rates were 99% in the aspirin group and 96% in the no-aspirin group with an HR of 0.23 (95% CI, 0.13-0.40; p < 0.001). Low-dose aspirin was associated with a lower risk of ACR and HAT after LT, especially in the first vulnerable year after transplantation. Therefore, low-dose aspirin use after primary LT should be evaluated to protect the liver graft from ACR and to maintain arterial patency.

Disparities in bile duct injury care.

BACKGROUND: An international group proposed a standardized terminology to report outcomes after bile duct repair. Data on this surgical complication vary depending on the center and country where patients are treated. The aim of this work is to show disparities in the care process of bile duct injury between patients from two different income-level countries, using a standard terminology of outcomes and clinical reporting. METHODS: A retrospective review comparing primary repair and re-repaired cases performed in an upper middle-income country (UMIC) versus primary repair cases treated in a high-income country (HIC) was performed. All pertinent data included in the tabular reporting system and outcomes classification were collected. Patients' characteristics were reported by calculating descriptive statistics. RESULTS: A total of 261 patients from UMIC (148 (56%) primary repair and 113 (44%) re-repair) were compared with 122 primary repair from HIC. Open cholecystectomy (55.4% vs 3.3%) and more E4 injuries (37.8% vs 19.7%) were found in the UMIC group. More Accordion 3 and higher complications were present in the UMIC primary and repair groups, as well as more episodes of postoperative acute cholangitis. Eleven patients were listed for liver transplant in the UMIC re-repair group. Primary patency by the end of the index treatment period was present in 217 (83%) of the full UMIC cohort. Median time to loss of primary patency was not reached in the primary repair, and was 3.8 years in the re-repair group. Patency was below HIC primary repaired cases. CONCLUSIONS: Standardized reporting outcomes after primary repair are applicable to re-repaired patients and are helpful to compare different populations, showing better outcomes in HIC. Measures of surgical access disparities exist among the process of bile duct injury care.

Molecular analysis provides further evidence that Chitayat syndrome is caused by the recurrent p.(Tyr89Cys) pathogenic variant in the ERF gene.

Chitayat syndrome (CHYTS, MIM #617180) is a rare autosomal dominant clinical condition caused by a single missense pathogenic variant in the ERF gene (19q13.2, MIM*611888), which encodes the ETS2 Repressor Factor (ERF) protein. The characteristic features reported to date for this condition are facial dysmorphism, hyperphalangism and respiratory complications during the newborn period. Herein, we report the sixth patient worldwide with a confirmed molecular diagnosis of CHYTS. Our documentation of pectus carinatum, hypoplastic phalanges (as in two previously described patients), and lack of hyperphalangism broadens the phenotypic spectrum of CHYTS. Moreover, our identification of a heterozygous mutation [c.266A>G or p.(Tyr89Cys)] [rs886041001] in this patient provides further evidence that this condition is caused by a recurrent pathogenic variant in ERF.

Unique association of hypochondroplasia with craniosynostosis and cleft palate in a Mexican family.

Hypochondroplasia (HCH) is a skeletal dysplasia caused by an abnormal function of the fibroblast growth factor receptor 3. Although believed to be relatively common, its prevalence and phenotype are not well established owing to its clinical, radiological, and genetic heterogeneity. Here we report on a molecularly proven HCH family with an affected father and two children. The siblings (male and female) with HCH also had craniosynostosis and cleft palate, respectively. The present report supports the conclusion that the full clinical spectrum of HCH is not completely delineated. It also suggests that secondary, as yet unknown, modifying factors can influence the final phenotype.

An unusual type of biliar cyst: A case report.

 We present the case of a 56-yr-old woman with vague abdominal pain of approximately 5 months duration. An ultrasound study showed moderate dilation of the common bile duct. Magnetic resonance cholangiopancreatography confirmed a cystic dilatation of the right hepatic duct with intra and extra hepatic component. The patient underwent right hepatectomy and complete excision of the cyst. Microscopically, the cyst wall was formed by fibrous tissue with mild acute and chronic inflammatory infiltrate, the inner surface showed a single layer of columnar epithelium and extensive squamous metaplasia without atypia, wich expressed p63 and high molecular weight cytoqueratin (34BE12).

Changes in frequency of delayed graft function in deceased donor renal transplant recipient in a tertiary care center in Mexico.

BACKGROUND: Delayed graft function (DGF) is defined as the need for dialysis within the first seven days of transplantation. The frequency of DGF has decreased in the last five years compared with the previous 20 years of the kidney transplant program at a Mexican referral hospital. OBJECTIVE: To determine the incidence and risk factors for DGF in the past five years (2009-2013). METHODS: We analyzed a retrospective cohort of renal transplant recipients from deceased donors at our hospital between March 2009 and May 2013 (Period 2), and compared the results with a previously evaluated cohort (Period 1, between January 1990 and February 2009). RESULTS: During the analyzed period, 78 deceased donor transplants were performed. The frequency of DGF was 9%. Multivariate analysis showed that recipient older age (OR: 1.074419; 95% CI: 1.0009-1.155116; p = 0.05), transoperative amines administration (OR: 7.73; 95% CI: 1.037-57.6; p = 0.046), and hypotension during surgery in the recipient (OR: 11.6; 95% CI: 1.33-100.8; p = 0.026) were risk factors for DGF. CONCLUSION: The incidence of DGF has significantly decreased in the past five years when compared to the previous 20 years in our hospital.

Segment 4 and the left lateral segment regeneration pattern after resection of the middle hepatic vein in a living donor right hepatectomy.

BACKGROUND: Inclusion of the middle hepatic vein (MHV) with a right hepatectomy (RH) in live donor liver transplantation improves venous drainage of the anterior sector of the graft. Its long-term effects on donor left liver (LL) regeneration are not well described. METHODS: Donors who underwent RH with MHV (MHV+, n = 12) were compared with donors who underwent RH with preservation of the MHV (MHV-, n = 24). Peri-operative complications and volume of the entire liver and individual segments were evaluated at 1 year post-donation. RESULTS: There was a trend towards a higher complication rate in the MHV+ group (41% versus 25%), without reaching statistical significance (P = 0.3). Males, high body mass index (BMI) and a smaller residual liver volume (RLV) were predictors for greater LL regeneration. MHV+ donors had impaired regeneration of segment 4 (S4) at 1 year, and compensatory greater left lateral segment regeneration. The absence of venous drainage of S4 (V4) to left hepatic vein (LHV) was a predictor of impaired S4 regeneration. CONCLUSIONS: Regeneration of S4 is impaired in MHV+ donors. Caution should be taken when considering MHV removal on donors with dominant S4, especially on those with potential increased demand for liver regeneration, such as males, higher BMI and a smaller RLV.

[Indications for liver transplant]. / Indicaciones de trasplante hepático.

Liver transplantation (LT) is the treatment of choice in selected patients with end-stage liver disease and in some with acute liver failure, hepatocellular carcinoma (HCC) and other diseases with no synthetic liver failure. Currently, LT has an overall survival > 90 % at 1 year. Proper selection of LT candidates is important given the shortage in organ donation. The allocation and priorization of organs to patients with chronic liver failure (CLF) in waiting lists, is determined by the MELD priority score (Model of End Stage Liver Disease). Indications for LT in patients with CLF are the same regardless of the etiology (any type of hepatic decompensation or development of HCC). Priority MELD is a variant to this classification used only in special cases such as in those with stable hepatopathy but severe extra-hepatic features (e.g., HCC or hepato-pulmonary syndrome). The indication for LT in patients with acute liver failure (ALF) and acute failure associated to chronic liver failure (ACLF) are not fully established; there are prognostic factors that may guide the decision for urgent LT and some centers, like the King's College Hospital criteria in the UK. Currently, LT is a therapeutic modality in some primary liver tumors (HCC, cholangiocarcinoma) and neuroendocrine liver metastatic tumors. These protocols have provided significant opportunities for long-term survival (> 70% at 5 years). The high demand and shortage of organs have fostered the development of new strategies to benefit more patients, such as the use of extended criteria donors, or "domino" transplants. This review focuses on the most relevant data on the different indications of LT.

Pre-transplant angiotensin II type 1receptor antibodies: a risk factor for decreased kidney graft function in the early post-transplant period?

Angiotensin II type 1 receptor antibodies (AT1Rab) are associated to a significantly lower graft survival and a higher risk of acute rejection after kidney transplantation. This study aimed to evaluate graft function and BPAR during the 1st year post-transplant (PT) in adult kidney transplant recipients (KTR), between 03/2009 and 08/2012. Pre-KT sera were screened for AT1Rab (ELISA) and HLA-DSA (Luminex). Three groups were analyzed: AT1Rab only (n = 13); HLA-DSA only (n = 8); and no AT1Rab or HLA-DSA (n = 90). No differences were observed in clinical characteristics across groups. A higher percentage of BPAR was observed in the AT1Rab positive group, but this difference was not significant. KTR with AT1Rab had a lower mean eGFR (20 mL/min/1.73m2) when compared to KTR with no Abs at 12 months. The significant difference in eGFR was observed since the 1st month PT. Multivariate analysis showed 4 factors independently and significantly associated with eGFR at 12mos PT: BPAR (-18.7 95%, CI -28.2 to -9.26, p<0.001), AT1Rab (-10.51, CI -20.9 to -0.095, p = 0.048), donor age (-0.42, CI -0.75 to -0.103 p = 0.010), and recipient age (-0.36, CI -0.67 to -0.048, p = 0.024). In this study AT1Rab in pre-transplant sera from KTR, was an independent and significant risk factor contributing to a lower eGFR 12 months. PT. This finding deserves to be confirmed in a larger KTR population.

Three-dimensional Liver Model Application for Liver Transplantation.

BACKGROUND: Children are removed from the liver transplant waitlist because of death or progressive illness. Size mismatch accounts for 30% of organ refusal. This study aimed to demonstrate that 3-dimensional (3D) technology is a feasible and accurate adjunct to organ allocation and living donor selection process. METHODS: This prospective multicenter study included pediatric liver transplant candidates and living donors from January 2020 to February 2023. Patient-specific, 3D-printed liver models were used for anatomic planning, real-time evaluation during organ procurement, and surgical navigation. The primary outcome was to determine model accuracy. The secondary outcome was to determine the impact of outcomes in living donor hepatectomy. Study groups were analyzed using propensity score matching with a retrospective cohort. RESULTS: Twenty-eight recipients were included. The median percentage error was -0.6% for 3D models and had the highest correlation to the actual liver explant (Pearson's R = 0.96, P < 0.001) compared with other volume calculation methods. Patient and graft survival were comparable. From 41 living donors, the median percentage error of the allograft was 12.4%. The donor-matched study group had lower central line utilization (21.4% versus 75%, P = 0.045), shorter length of stay (4 versus 7 d, P = 0.003), and lower mean comprehensive complication index (3 versus 21, P = 0.014). CONCLUSIONS: Three-dimensional volume is highly correlated with actual liver explant volume and may vary across different allografts for living donation. The addition of 3D-printed liver models during the transplant evaluation and organ procurement process is a feasible and safe adjunct to the perioperative decision-making process.

Liver transplantation in Latin America: reality and challenges.

Healthcare systems in Latin America are broadly heterogeneous, but all of them are burdened by a dramatic rise in liver disease. Some challenges that these countries face include an increase in patients requiring a transplant, insufficient rates of organ donation, delayed referral, and inequitable or suboptimal access to liver transplant programs and post-transplant care. This could be improved by expanding the donor pool through the implementation of education programs for citizens and referring physicians, as well as the inclusion of extended criteria donors, living donors and split liver transplantation. Addressing these shortcomings will require national shifts aimed at improving infrastructure, increasing awareness of organ donation, training medical personnel, and providing equitable access to care for all patients.

Orthotopic liver transplantation for adults with Alagille syndrome.

INTRODUCTION: Alagille syndrome (AGS) is an inherited multisystem disorder, and liver transplantation (LT) may be required in pediatric patients with AGS (P-AGS). There are limited data regarding the outcomes of LT in adults with AGS (A-AGS). AIM: To determine and compare the outcomes of LT in A-AGS vs. P-AGS as well as A-AGS vs. adults with biliary atresia (A-BA). METHODS: Adults (>18 yr), with AGS and BA, and children (≤18 yr), with AGS who underwent isolated first LT between 10/1987 and 5/2008, were identified from the UNOS database. RESULTS: Forty-four of 79,400 adults transplanted for AGS were compared with 407 P-AGS and 56 A-BA, respectively. A-AGS patients had a significantly higher rate of encephalopathy, lower serum albumin, and higher serum creatinine in comparison with P-AGS. One- and five-yr patient and graft survival in A-AGS who underwent LT were not significantly different in comparison with either P-AGS or A-BA (A-AGS patient survival: 95.5%, 90.9%, P-AGS: 88. 7%, 86.2%, A-BA: 89.3%, 87.5%; A-AGS graft survival: 84.1%, 79. 5%, P-AGS: 80.3%, 76%. 1%, A-BA: 82.1%, 78.6%, respectively). CONCLUSION: The outcome of first LT in A-AGS is excellent compared with the overall reported adult patient and graft survival. Although A-AGS were sicker than P-AGS at transplant, their outcomes were comparable with that of P-AGS.

Postoperative liver function tests can predict anastomotic dysfunction after bile duct injury repair.

Liver function tests help in the follow-up of postoperative patients with iatrogenic bile duct injury. There is not clear evidence regarding their predictive role on anastomosis dysfunction. We describe our experience with postoperative liver function tests and a predictive model of long-term patency after repair. This is retrospective cohort study of patients with bilioenteric anastomosis for bile duct injury and their long-term follow-up. A binomial logistic regression model was performed to ascertain the effects of the grade of bile duct injury and liver function test in the postoperative period. A total of 329 patients were considered for the analysis. In the logistic regression model two predictor variables were statistically significant for anastomosis stenosis: type of bilioenteric anastomosis and alkaline phosphatase levels. A ROC curve analysis was made for alkaline phosphatase with an area under the curve of 0.758 (95% CI 0.67-0.84). A threshold of 323 mg/dL was established (OR 6.0, 95% CI 2.60-13.83) with a sensitivity of 75%, specificity of 67%, PPV of 20%, NPV of 96%, PLR of 2.27 and NLR of 0.37. Increased alkaline phosphatase (above 323 mg/dL) after the fourth operative week was found to be a predictor of long-term dysfunction.

Hepatic transplant during SARS-CoV-2 (COVID-19) pandemic. A literature review.

ANTECEDENTES: En diciembre de 2019 se identificó en la ciudad de Wuhan, China, un nuevo beta coronavirus, el SARS-CoV-2, como agente causal de neumonía grave, conocida como COVID-19, lo cual ha provocado medidas estrictas de aislamiento, cierre de programas de trasplante hepático y la necesidad de modificar los protocolos de tratamiento. OBJETIVO: Documentar la información publicada sobre el impacto de la COVID-19 en la población con antecedente de trasplante hepático y establecer un protocolo de tratamiento. MÉTODO: Se buscaron en PubMed los términos MeSH "SARS-CoV-2", "COVID-19", "trasplante hepático" y "tratamiento". RESULTADOS: Hasta el momento se ha demostrado en la población con trasplante hepático una mayor facilidad para adquirir el virus, sin una diferencia en la mortalidad al compararla con la población general. La inmunosupresión debe continuar, sin suspender los inhibidores de la calcineurina. Del tratamiento específico, los esteroides son los que han demostrado el mayor beneficio clínico y una disminución de la mortalidad. CONCLUSIÓN: El trasplante hepático no se asocia de manera independiente a una mayor mortalidad. Otros factores, además del trasplante, deben tomarse en cuenta al momento de establecer la gravedad. BACKGROUND: In December 2019, a new beta coronavirus, SARS-CoV-2, was identified in the city of Wuhan, China, as a causative agent of severe pneumonia, known as COVID-19, which has led to strict isolation measures, closure of liver transplantation programs and the need to modify treatment protocols. OBJECTIVE: Document the information published so far on the impact of COVID-19 in the population with a history of liver transplantation and establish a treatment protocol. METHOD: MeSH terms were searched for "SARS-CoV-2", "COVID-19", "liver transplantation" and "treatment". RESULTS: Up to now, a greater ease in acquiring the virus has been shown in the liver transplant population, without a difference in mortality when compared to the general population. Immunosuppression should continue at the minimum tolerated levels, without suspending calcineurin inhibitors. Of the specific treatment, steroids are those that have shown the greatest clinical benefit and decreased mortality. CONCLUSION: Liver transplantation is not independently associated with higher mortality. Factors other than transplantation must be taken into account when considering the risk of severity.

Prevalence and clinical characteristics of alpha-1 antitrypsin deficiency in liver explants in a Mexican cohort.

INTRODUCTION: Alpha-1 antitrypsin deficiency (AATD) is a risk factor for liver disease. PASD-positive inclusions have been found unexpectedly in approximately 10% of liver explants in patients with no previous diagnosis of AATD, particularly, in patients with non-alcoholic steatohepatitis (NASH), supporting a synergistic mechanism of liver injury between AATD and environmental factors. We aimed to determine the clinical characteristics of mestizo patients in which AATD was diagnosed before or after liver transplantation. METHODS: Liver explants of patients with cryptogenic, alcoholic, and NAFLD/NASH cirrhosis undergoing orthotopic liver transplantation (OLT) were included. Liver histopathology was assessed by two expert pathologists. Hematoxylin and eosin staining, PASD staining, and confirmatory AAT immunohistochemistry were performed. In explants with positive histopathology, genotyping for SERPINA1 was performed. RESULTS: A total of 180 liver transplants were performed during the study period. Of these, 44 patients with cryptogenic cirrhosis, NASH, and alcoholic cirrhosis were included. Of these patients, two liver explants (4.5%) had PASD-positive inclusions stain and confirmatory immunochemistry. During the period evaluated, another two patients with a diagnosis of AATD before the OLT were also included. The four patients had overweight or obesity, three had type 2 diabetes mellitus, and two developed liver steatosis after the OLT. CONCLUSION: AATD was found to be an infrequent finding in patients with cryptogenic, NASH/NAFLD, and alcoholic cirrhosis in our population. However, it is important to consider this entity as it may represent an additional factor in the appearance and progression of liver fibrosis in patients with metabolic syndrome.

Every allograft needs a silver lining.

The development of chronic allograft rejection is based on the hypothesis that cumulative, time-dependent tissue injury eventually leads to a fibrotic response. In this issue of the JCI, Babu and colleagues found that alloimmune-mediated microvascular loss precedes tissue damage in murine orthotopic tracheal allografts (see the related article beginning on page 3774). The concept that injury to the endothelium may precede airway fibrosis suggests that interventions to maintain vascular integrity may be important, especially in the case of lung transplantation. Further, for all solid organ allografts, it is possible that the key to long-term allograft survival is physiological vascular repair at early times following transplantation.

CD40-induced signaling in human endothelial cells results in mTORC2- and Akt-dependent expression of vascular endothelial growth factor in vitro and in vivo.

We have examined CD40-dependent signals in endothelial cells (EC) mediating the expression of vascular endothelial growth factor (VEGF) and VEGF-induced angiogenesis. We treated confluent cultures of EC with soluble CD40L (sCD40L), and by Western blot found a marked increase in the phosphorylation of Akt, 4EBP-1, and S6K1, compared with untreated cells. EC were transfected with a full-length VEGF promoter-luciferase construct and cultured in the absence or presence of rapamycin and sCD40L. We found that rapamycin, which blocks mTORC1 and mTORC2 signaling, inhibited sCD40L-mediated transactivation of VEGF. In addition, by Western blot, we found that the transfection of EC with small interfering RNA (siRNA) to rictor (to inhibit mTORC2), and not raptor (to inhibit mTORC1), inhibited sCD40L-dependent protein expression of VEGF. In additions, we found that basal levels of phosphorylated Akt as well as VEGF were increased in EC transfected with the raptor siRNA. Also, rapamycin failed to inhibit VEGF promoter activation, as well as VEGF protein expression in EC transfected with a constitutively active construct of Akt, further demonstrating that mTORC1 is not necessary for CD40- and Akt-induced expression of VEGF. Finally, we injected human CD40L-transfected fibroblasts or mock transfectants into human skin on SCID mice. We found that the injection of CD40L transfectants, but not mock cells, resulted in VEGF expression and mediated a marked angiogenesis reaction, and this response was reduced in mice treated with rapamycin. Together, these observations indicate that mTORC2 and Akt facilitate CD40-inducible expression of VEGF in EC, which is of clinical importance in tumor growth and the progression of chronic inflammatory diseases.