ABO Incompatible Living Donor Liver Transplantation in Children: A Single Centre Experience from India.

Background: In recent years, paediatric ABO incompatible (ABOi) living donor liver transplant (LT) has shown promising outcomes and can potentially eliminate organ shortage. This study aims to report paediatric ABOi LT experience, including short- and long-term outcomes. Methods: It is a single-centre retrospective study. Out of 108 LTs, 20 were done in children. We compared the outcomes between ABOi (n = 20) and non-ABOi (n = 220) paediatric living donor liver transplantation (LDLT) performed during the study period. All the children received pre-LT desensitization therapy comprising rituximab and plasmapheresis targeting pre-LT isohemagglutinin (IHA) titres of ≤1:16. Results: Out of 239 paediatric LDLTs from 2017 to 2022, 19 children (11 females) underwent 20 ABOi LTs (including one retransplant with an ABOi domino allograft) at a median age of 12 (12, 51) months, with the majority being biliary atresia (60%). The median change in CD19 cell%, CD20 cell%, and IHA titres after rituximab from day -14 to day -1 (before LT) was satisfactory. In the first 3 months following LT, acute cellular rejection, culture-proven sepsis, and biliary and vascular complications were seen in 10%, 20%, 20%, and 15%, respectively. None of the ABOi LT recipients developed antibody-mediated rejection. ABOi LT recipients, as compared to non-ABOi LT recipients, had a higher incidence of bile leaks and prolonged hospital stay, with the rest of the complications, including biliary strictures and long-term outcomes, being comparable. At a median follow-up of 21 (14, 33) months, 4 children expired (21%). Conclusion: ABOi LT in children shows excellent outcomes and can be performed safely with prior desensitization when a compatible liver is unavailable.

Influence of polymorphisms in TNF-α and IL1ß on susceptibility to alcohol induced liver diseases and therapeutic potential of miR-124-3p impeding TNF-α/IL1ß mediated multi-cellular signaling in liver microenvironment.

Background and aims: Alcoholic liver disease (ALD) is the leading cause of the liver cirrhosis related death worldwide. Excessive alcohol consumption resulting enhanced gut permeability which trigger sensitization of inflammatory cells to bacterial endotoxins and induces secretion of cytokines, chemokines leading to activation of stellate cells, neutrophil infiltration and hepatocyte injury followed by steatohepatitis, fibrosis and cirrhosis. But all chronic alcoholics are not susceptible to ALD. This study investigated the causes of differential immune responses among ALD patients and alcoholic controls (ALC) to identify genetic risk factors and assessed the therapeutic potential of a microRNA, miR-124-3p. Materials and methods: Bio-Plex Pro™ Human Chemokine analysis/qRT-PCR array was used for identification of deregulated immune genes. Sequencing/luciferase assay/ELISA detected and confirmed the polymorphisms. THP1 co-cultured with HepG2/LX2/HUVEC and apoptosis assay/qRT-PCR/neutrophil migration assay were employed as required. Results: The combined data analysis of the GSE143318/Bio-Plex Pro™ Human Chemokine array and qRT-PCR array revealed that six genes (TNFα/IL1ß/IL8/MCP1/IL6/TGFß) were commonly overexpressed in both serum/liver tissue of ALD-patients compared to ALC. The promoter sequence analysis of these 6 genes among ALD (n=322)/ALC (n=168) samples revealed that only two SNPs, rs361525(G/A) at -238 in TNF-α/rs1143627(C/T) at -31 in IL1ß were independently associated with ALD respectively. To evaluate the functional implication of these SNPs on ALD development, the serum level of TNF-α/IL1ß was verified and observed significantly higher in ALD patients with risk genotypes TNF-α-238GA/IL1ß-31CT+TT than TNF-α-238GG/IL1ß-31CC. The TNF-α/IL1ß promoter Luciferase-reporter assays showed significantly elevated level of luciferase activities with risk genotypes -238AA/-31TT than -238GG/-31CC respectively. Furthermore, treatment of conditioned medium of TNF-α/IL1ß over-expressed THP1 cells to HepG2/LX2/HUVEC cells independently showed enhanced level of ER stress and apoptosis in HepG2/increased TGFß and collagen-I production by LX2/huge neutrophil infiltration through endothelial layer. However, restoration of miR-124-3p in THP1 attenuated such inter-cellular communications and hepatocyte damage/collagen production/neutrophil infiltration were prohibited. Target analysis/luciferase-reporter assays revealed that both TNF-α/IL1ß were inhibited by miR-124-3p along with multiple genes from TLR4 signaling/apoptosis/fibrogenesis pathways including MYD88, TRAF3/TRADD, Caspase8/PDGFRA, TGFßR2/MCP1, and ICAM1 respectively. Conclusion: Thus, rs361525(G/A) in TNF-α and rs1143627(C/T) in IL1ß gene may be used as early predictors of ALD susceptibility among East Indian population. Impeding overexpressed TNF-α/IL1ß and various genes from associated immune response pathways, miR-124-3p exhibits robust therapeutic potential for ALD patients.

Delayed diagnosis of bronchobiliary fistula complicating a pediatric living donor liver transplantation: a case report.

Bronchobiliary fistula (BBF) is a very rare condition in children. Only a few pediatric BBF cases have been reported, in the context of a ruptured hydatid cyst or liver abscess. BBF after living donor liver transplantation (LDLT) has not been reported in the pediatric literature. We report a 7-year-old female child with Wilson disease, who developed BBF post-LDLT. She had a clinically uneventful course in the immediate post-transplant period. She was readmitted on postoperative day (POD) 75 with a productive cough and respiratory difficulty, which was diagnosed as bilioptysis secondary to BBF. Endoscopic retrograde cholangiopancreaticography was attempted but failed. Exploratory laparotomy showed a fistula from the strictured biliary anastomotic site to the right thoracic cavity; it was excised, and a Roux-en-Y hepaticojejunostomy was performed. She tolerated the procedure well and remained clinically well on follow-up through POD 185. BBF is extremely rare in children. This is the first case report of BBF in a child following LDLT. BBF requires a high index of suspicion for a timely intervention to prevent subsequent complications.

Anesthesia and Critical Care for the Prediction and Prevention for Small-for-size Syndrome: Guidelines from the ILTS-iLDLT-LTSI Consensus Conference.

BACKGROUND: During the perioperative period of living donor liver transplantation, anesthesiologists and intensivists may encounter patients in receipt of small grafts that puts them at risk of developing small for size syndrome (SFSS). METHODS: A scientific committee (106 members from 21 countries) performed an extensive literature review on aspects of SFSS with proposed recommendations. Recommendations underwent a blinded review by an independent expert panel and discussion/voting on the recommendations occurred at a consensus conference organized by the International Liver Transplantation Society, International Living Donor Liver Transplantation Group, and Liver Transplantation Society of India. RESULTS: It was determined that centers with experience in living donor liver transplantation should utilize potential small for size grafts. Higher risk recipients with sarcopenia, cardiopulmonary, and renal dysfunction should receive small for size grafts with caution. In the intraoperative phase, a restrictive fluid strategy should be considered along with routine use of cardiac output monitoring, as well as use of pharmacologic portal flow modulation when appropriate. Postoperatively, these patients can be considered for enhanced recovery and should receive proactive monitoring for SFSS, nutrition optimization, infection prevention, and consideration for early renal replacement therapy for avoidance of graft congestion. CONCLUSIONS: Our recommendations provide a framework for the optimal anesthetic and critical care management in the perioperative period for patients with grafts that put them at risk of developing SFSS. There is a significant limitation in the level of evidence for most recommendations. This statement aims to provide guidance for future research in the perioperative management of SFSS.

Domino liver transplantation for maple syrup urine disease in children: A single-center case series.

BACKGROUND: Domino liver transplant (DLT) represents another type of liver donor to expand the donor pool. Recent reports of successful DLT in children with maple syrup urine disease (MSUD) show promising long-term outcomes. METHODS: It was a retrospective study. All children with MSUD were paired with either recipients with end-stage liver disease (ESLD) or non-MSUD metabolic disease. Each pair underwent simultaneous liver transplant (LT), where the MSUD recipient received the graft from a living-related donor and the liver explanted from the MSUD donor was transplanted to the respective paired domino recipient. We report our experience regarding the techniques and outcomes of DLT at our center. RESULTS: Eleven children with MSUD and 12 respective DLT recipients were enrolled, one of which was domino split-liver transplantation. DLT recipients included seven ESLD, two propionic acidemia (PA), one glycogen storage disease(GSD) type-1, one GSD type-3, and one Citrullinemia. Post-LT ICU and hospital stays were comparable (p > .05). Patient and graft survival was 100% and 66.6% in the MSUD group and DLT recipients at a mean follow-up of 13.5 and 15 months. There was no death in the MSUD group as compared to four in the DLT group. The amino acid levels rapidly normalized after the LT in the children with MSUD and they tolerated the normal unrestricted diet. No vascular, biliary, or graft-related complications were seen in the post-transplant period. No occurrence of MSUD was noted in DLT recipients. CONCLUSION: DLTs have excellent post-surgical outcomes. DLT should be strongly considered and adopted by transplant programs worldwide to circumvent organ shortage.

Strategies for ABO Incompatible Liver Transplantation.

Liver transplantation (LT) is a definitive treatment for the decompensated liver cirrhosis and fulminant liver failure. With limited availability of cadaveric liver allograft, ABO incompatible (ABOi) living donor liver transplantation (LDLT) plays an important part in further expansion of donor pool. Over the years, with the introduction of Rituximab and improving desensitisation protocol, outcomes of ABOi LDLT are on par with ABO compatible LT. However, ABOi LDLT protocol varies markedly from centre to centre. Intravenous Rituximab followed by plasmapheresis or immunoadsorption effectively reduce ABO isoagglutinins titre before transplant, thereby reducing the risk of antibody mediated rejection in the post-transplant period. Local infusion therapy and splenectomy are not used routinely at most of the centres in Rituximab era. Post-transplant immunosuppression usually consists of standard triple drug regime, and tacrolimus trough levels are targeted at higher level compared to ABO compatible LT. Introduction of newer therapies like Belatacept and Obinutuzumab hold promise to further improve outcomes and reduce the risk of antibody mediated rejection related complications. ABOi LT in emergency situations like acute liver failure and deceased donor LT is challenging due to limited time period for desensitisation protocol before transplant, and available evidence are still limited but encouraging.

Living Donor Liver Transplantation Alone Is Not Inferior to Combined Kidney Liver Transplant for Cirrhotic Patients With Chronic Kidney Disease.

BACKGROUND: Chronic kidney disease (CKD) is common in patients with chronic liver disease (CLD) as is acute kidney injury (AKI). The differentiation between CKD vs AKI is often difficult and sometimes the both may coexist. A combined kidney-liver transplant (CKLT) may result in a kidney transplant in patients whose renal function is likely to recover or at least who have stable renal function post-transplant. We retrospectively enrolled 2742 patients who underwent living donor liver transplant at our center from 2007 to 2019. METHODS: This audit was carried out in liver transplant recipients with CKD 3 to 5 who underwent either liver transplant alone (LTA) or CKLT to look at outcomes and long-term evolution of renal function. Forty-seven patients met the medical eligibility criteria for CKLT. Of the 47 patients, 25 underwent LTA and the rest 22 underwent CKLT. The diagnosis of CKD was made according to the Kidney Disease: Improving Global Outcomes classification. RESULTS: Preoperative renal function parameters were comparable between the 2 groups. However, CKLT patients had significantly lower glomerular filtration rates (P = .007) and higher proteinuria (P = .01). Postoperatively, renal function, and comorbidities were comparable between the 2 groups. Survival was similar at 1, 3, and 12 months, respectively (log-rank; P = .84, = .81, and = .96, respectively). At the end of the study period, 57% of patients who survived in LTA groups had stabilized renal function (Creatinine = 1.8 ± 0.6 mg/dL). CONCLUSIONS: Liver transplant alone is not inferior to CKLT in living donor situations. Renal dysfunction is stabilized in the long term whereas long-term dialysis may be carried out in others. Living donor liver transplantation alone is not inferior to CKLT for cirrhotic patients with CKD.

Good outcomes of living donor liver transplant in primary sclerosing cholangitis: an experience from North India.

BACKGROUND: Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease. In the absence of effective medical therapy, liver transplant is the definitive treatment for advanced stage. However, recurrence of PSC after liver transplant is of concern which can lead to graft failure and may require retransplant. There are limited data on outcomes of living donor liver transplant (LDLT) in PSC. Also, in LDLT as donors are genetically related there can be an increased risk of recurrence. We conducted this retrospective study to analyze the outcomes of LDLT in PSC at a tertiary liver transplant center in north India. METHODS: We conducted a retrospective analysis of 3213 transplant recipients who underwent LDLT from January 2006 to May 2021. Of these 26 (0.80%) patients had PSC as indication for liver transplantation (PSC = 24, PSC-AIH overlap = 2). Data analysis was done to look for baseline demographics, clinical details, transplant outcomes, PSC recurrence, and survival. RESULTS: Mean age of study group was 42 (± 13.8) years and 19 patients (73.1%) were males. All patients had decompensated cirrhosis at the time of transplant. Mean CTP score and MELD score were 9.5 (± 1.8) and 18.9 (± 7.1), respectively. Sixteen patients received modified right lobe graft, seven extended right lobe graft and five patients received left lateral graft. Median graft weight and mean graft to recipient weight ratio (GRWR) were 633.5 (IQR 473.5-633.5) grams and 1.23 (± 0.42), respectively. Most common biliary anastomosis was hepaticojejunostomy, done in 19 (73.1%) while duct to duct anastomosis was performed in 7 (26.9%) patients. Median follow-up was 96 (36-123) months. One patient had ulcerative colitis and none had cholangiocarcinoma. Two (7.7%) patients had bile leak during early post-transplant period. Three (11.1%) patients developed graft rejection and were managed successfully with steroid pulses. Three patients died during early post-transplant period while seven deaths occurred during long-term follow-up including one death due to COVID-19. Five (21.73%) patients had recurrence of PSC of which two patients had graft loss including one after retransplantation. The one year graft and patient survival rate was 88.5%. CONCLUSION: LDLT can be performed in PSC with good long-term outcomes with a risk of PSC recurrence in about one-fifth patients.

Safety and feasibility of immediate tracheal extubation of small pediatric patients after living donor liver transplantation.

BACKGROUND: Immediate extubation is integral constituent of enhance recovery protocols. Purpose of this study was to examine success rates and safety of protocolized immediate extubation in pediatric living donor liver transplant recipients and to find out factors associated with non-immediate extubation in operation room. METHODS: We performed retrospective analysis for data of small (≤20 kg) pediatric patients transplanted between 2017 and 2019 (protocolized duration) and compared with data of transplants done between 2014 and 2016 (non-protocolized duration). Further, we compared data during each time duration between immediate extubation and non-immediate extubation group to find risk factors in that particular duration. RESULTS: Immediate extubation rates were significantly higher during protocolized duration compared with non-protocolized duration (85.52% vs. 48.29%, p < .001). Reintubation rates decreased during protocolized duration (10.9% vs. 4.6%). Hospital stays (20.47 ± 7.06 vs. 27.8 ± 6.2 days, p < .001) and mortality (13.2% vs. 28%, p = .04) were significantly decreased in protocolized duration. Higher age (OR: 2.85, 95% CI 1.22-6.67, p = .02), weight > 10 (OR: 4.37, 95% CI 1.16-16.46, p = .029) and high vasopressor support (OR: 32, 95% CI 6.4-160.13, p < .001) found as significant predictors of non-immediate extubation however only high vasopressor support found to be independent predictor during protocolized duration. CONCLUSIONS: Outcomes in pediatric transplants can be optimized by immediate extubation in majority of cases when protocolized as part of policy.

Successful Embolization of Spleen through Gastroepiploic Artery in a Liver Transplant Recipient with Splenic Artery Ligation.

Partial splenic embolization (PSE) is a minimally invasive endovascular procedure for the treatment of hypersplenism. This procedure is normally done by catheterization of the splenic artery, which if ligated during surgery, makes the procedure very challenging. We present a case where the splenic artery had been ligated during liver transplant surgery, and the only major endovascular route to reach the spleen was through the hypertrophied tortuous gastroepiploic artery. Successful PSE in these patients suggests the feasibility of this procedure after splenic artery ligation and can thus help to spare a patient from the otherwise more invasive surgical splenectomy.

Do Natural Portosystemic Shunts Need to Be Compulsorily Ligated in Living Donor Liver Transplantation?

BACKGROUND: Natural portosystemic shunt ligation practices in liver transplant vary widely across transplant centres and are frequently undertaken to prevent the serious consequence of portal steal phenomenon. No concrete indications have so far been convincingly identified for their management in living donor liver transplant. METHODS: We retrospectively studied the outcome of 89 cirrhotic patients who either did (n = 63) or did not (n = 25) undergo shunt ligation during living donor liver transplantation between 2017 and 2020. RESULTS: The incidence of early allograft dysfunction/nonfunction (P = 1.0) and portal venous complications (P = 0.555) were similar between the two groups. Although overall complications, biliary complications, and the composite of Grade III and IV complications were significantly higher in the nonligated group (P = 0.015, 0.052 and 0.035), 1- year graft and patient survival were comparable between them (P = 0.524). CONCLUSION: We conclude that shunt ligation in living donor liver transplantation may not always be necessary if adequate portal flow, good vascular reconstruction, and good graft quality have been ensured.

Outcomes of Right and Left Hepatic Arterial Anastomosis in Right Lobe Living Donor Liver Transplant.

OBJECTIVES: Living donor liver transplant is a complex surgery with well-known complications. Here, we report the use of the right and left hepatic arteries of the recipient for anastomosis and the effects of each procedure on overall outcomes and any associated short-term or long-term biliary complications. MATERIALS AND METHODS: This was a prospective observational study with long-term follow-up of 200 patients (100 in the right hepatic artery group and 100 in the left hepatic artery group). RESULTS: The average donor age was 28.9 years in the left hepatic artery group and 30.9 years in the right hepatic artery group. Most of the donors (60%) were female. Overall, there was 10.5% mortality in the early postoperative period. Among survivors, there were more late strictures in the right hepatic artery group (29.7% vs 22.7%). Bile leak (P = .42), mortality (P = .71), and incidence of late-onset biliary strictures (P = .83) were less common in the left hepatic artery group. CONCLUSIONS: Left artery anastomosis was found to be technically safe and feasible and did not adversely affect patient outcome compared with right artery anastomosis. Left hepatic artery anastomosis may also reduce the incidence of the biliary complications compared with the right hepatic artery anastomosis.

Portal vein fenestration: a case report of an unusual portal vein developmental anomaly.

Portal vein anatomic variations are common in living donor liver transplantation. Portal vein fenestration, in which a segment of a vessel divides into at least two channels that reunite into a single distal lumen, has not yet been reported in the literature. Failure to identify this anomaly can lead to catastrophic events in donor liver hepatectomy. Herein, we report an unusual portal vein anomaly that was detected intraoperatively in a living liver donor.