Successful Sequential Liver and Isolated Intestine Transplantation for Mitochondrial Neurogastrointestinal Encephalopathy Syndrome: A Case Report.

BACKGROUND Mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE) is an autosomal recessive disease caused by thymidine phosphorylase deficiency leading to progressive gastrointestinal dysmotility, cachexia, ptosis, ophthalmoparesis, peripheral neuropathy and leukoencephalopathy. Although liver transplantation corrects thymidine phosphorylase deficiency, intestinal deficiency of the enzyme persists. Retrospective chart review was carried out to obtain clinical, biochemical, and pathological details. CASE REPORT We present a case of liver and subsequent intestine transplant in a 28-year-old man with MNGIE syndrome with gastrointestinal dysmotility, inability to walk, leukoencephalopathy, ptosis, cachexia, and elevated serum thymidine. To halt progression of neurologic deficit, he first received a left-lobe partial liver transplantation. Although his motor deficit improved, gastrointestinal dysmotility persisted, requiring total parenteral nutrition. After exhaustive intestinal rehabilitation, he was listed for intestine transplantation. Two-and-half years after liver transplantation, he received an intestine transplant. At 4 years after LT and 20 months after the intestine transplant, he remains off parenteral nutrition and is slowly gaining weight. CONCLUSIONS This is the first reported case of mitochondrial neurogastrointestinal encephalomyopathy to undergo successful sequential liver and intestine transplantation.

Deceased Donor Flush Volume Similar for Histidine-Tryptophan-Ketoglutarate and University of Wisconsin at a Single US Organ Procurement Organization: Adult and Pediatric Data.

BACKGROUND: Histidine-tryptophan-ketoglutarate (HTK) and University of Wisconsin (UW) solutions are the two primary solid-organ preservation solutions used in the United States (>95%), but flush volumes vary markedly by region and center. This study analyzes data from a single organ procurement organization (OPO) to determine the actual clinical flush volumes used for HTK and UW for liver and pancreas grafts. METHODS: All procurements at Indiana Donor Network were analyzed (2016-2020), and data were extracted from the on-site records. Variables included procuring center, solution, volumes, and vessels flushed. Brand and generic versions were considered equivalent. No clinical transplant outcomes were available. RESULTS: Data were analyzed from 875 liver and 192 pancreas procurements by over 70 U.S. centers representing 10 of 11 UNOS regions. The large majority of liver grafts were preserved with HTK (n=810, 93%; UW n=93, 7%). All liver donors received an aortic flush (100%), while portal vein flush was 14% in-situ and 88% back table. For liver grafts, the median volume of infused solution was less for HTK when compared to UW (4225mL vs 5500mL, p=0.04). For pancreas procurement, 100% received aortic flush of the graft, with median HTK and UW volumes being equivalent (3000mL; p=0.85). Pediatric organs were flushed with markedly higher weight-based volumes. CONCLUSIONS: Flush volumes for HTK and UW are similar at one midwestern OPO, with data comprised of procurements performed by centers from across the U.S. These data demonstrate that low-volume HTK flush is commonly used, and this practice may be considered as a cost-saving measure.

Comparative analysis of whole vs. split liver transplantation in infants.

BACKGROUND: Liver transplantation (LT) in infants can be challenging due to their small size and small vasculature. Although both whole LT (WLT) and split LT (SLT) have been described in infants, the head-to-head comparison of these techniques in this population is sparse. METHODS: We retrospectively analyzed the records of all patients with age ≤1 year at Indiana University between 2016 and 2022. All SLT were left lateral segment grafts split in situ. RESULTS: A total of 24 infants were transplanted, with 11 SLT and 13 WLT. The median follow-up time was 52.1 months. Donor and recipient characteristics were comparable except for donor age (19 years vs. 2 years; p < .01) and weight (64 kg vs. 14.2 kg; p < .01). Early allograft dysfunction, primary nonfunction, and hepatic artery thrombosis developed more frequently in the WLT group. There were no biliary complications. There were two early deaths (2 and 4 days) in the WLT group. One-year graft survival (100% vs. 77%; p = .10) and patient survival (100% vs. 85%; p = .18) were numerically higher in the SLT group. CONCLUSIONS: SLT with LLS offers a safe and viable option for liver transplantation in infants and is associated with a trend toward superior outcomes. SLT should be considered as a strategy to reduce waitlist times for infants in the absence of small, deceased donors for WLT.

Impact of gut microbiota on liver transplantation.

The gut microbiota has been gaining attention due to its interactions with the human body and its role in pathophysiological processes. One of the main interactions is the "gut-liver axis," in which disruption of the gut mucosal barrier seen in portal hypertension and liver disease can influence liver allograft function over time. For example, in patients who are undergoing liver transplantation, preexisting dysbiosis, perioperative antibiotic use, surgical stress, and immunosuppressive use have each been associated with alterations in gut microbiota, potentially impacting overall morbidity and mortality. In this review, studies exploring gut microbiota changes in patients undergoing liver transplantation are reviewed, including both human and experimental animal studies. Common themes include an increase in Enterobacteriaceae and Enterococcaceae species and a decrease in Faecalibacterium prausnitzii and Bacteriodes, while a decrease in the overall diversity of gut microbiota after liver transplantation.

Pleural Effusion and Malnutrition Are Associated With Worse Early Outcomes After Liver Transplant.

INTRODUCTION: Pulmonary complications after liver transplantation (LT) have previously been associated with longer hospital stays and ventilator time, and higher mortality. This study reports the outcomes for a specific pulmonary complication, pleural effusion, in LT recipients. METHODS: Records from a single transplant center were analyzed retrospectively for all adult LT patients. Patients with documented pleural effusion by radiographic imaging within 30 days pre- or post-transplant were considered as cases. Outcomes included length of hospital stay, discharge disposition, hospital readmission, discharge with home oxygen, and 1-year survival. RESULTS: During the 4-year study period, 512 LTs were performed, with 107 patients (21%) developing a peri-transplant pleural effusion. In total, 49 patients (10%) had a pre-transplant effusion, 91 (18%) had a post-transplant effusion, and 32 (6%) had both. Characteristics associated with the presence of any pleural effusion included an increasing model for end-stage liver disease score, re-transplantation, diagnosis of alcoholic liver disease, low protein levels, and sarcopenia. Effusion patients had longer hospital stays (17 vs 9 days, P < .001) and higher likelihood of discharge to a care facility (48% vs 21%, P < .001). Ninety-day readmission occurred in 69% of effusion patients (vs 44%, P < .001). One-year patient survival with any effusion was 86% (vs 94%, P < .01). CONCLUSIONS: Overall, 21% of recipients developed a clinically significant peri-transplant pleural effusion. Pleural effusion was associated with worse outcomes for all clinical measures. Risk factors for the development of pleural effusion included higher MELD score (>20), re-transplantation, alcoholic liver disease, and poor nutrition status, including poor muscle mass.

Hepatic Ischemia/Reperfusion Injury After Liver Transplantation Is Not Associated with Early Impairment of Left Ventricular Ejection Fraction.

BACKGROUND Early myocardial dysfunction is a known complication following liver transplant. Although hepatic ischemia/reperfusion injury (hIRI) has been shown to cause myocardial injury in rat and porcine models, the clinical association between hIRI and early myocardial dysfunction in humans has not yet been established. We sought to define this relationship through cardiac evaluation via transthoracic echocardiography (TTE) on postoperative day (POD) 1 in adult liver transplant recipients. MATERIAL AND METHODS TTE was performed on POD1 in all liver transplant patients transplanted between January 2020 and April 2021. Hepatic IRI was stratified by serum AST levels on POD1 (none: <200; mild: 200-2000; moderate: 2000-5000; severe: >5000). All patients had pre-transplant TTE as part of the transplant evaluation. RESULTS A total of 173 patients underwent liver transplant (LT) between 2020 and 2021 and had a TTE on POD 1 (median time to echo: 1 day). hIRI was present in 142 (82%) patients (69% mild, 8.6% moderate, 4% severe). Paired analysis between pre-LT and post-LT left ventricular ejection fraction (LVEF) of the entire study population demonstrated no significant decrease following LT (mean difference: -1.376%, P=0.08). There were no significant differences in post-LT LVEF when patients were stratified by severity of hIRI. Three patients (1.7%) had significant post-transplant impairment of LVEF (<35%). None of these patients had significant hIRI. CONCLUSIONS hIRI after liver transplantation is not associated with immediate reduction in LVEF. The pathophysiology of post-LT cardiomyopathy may be driven by extra-hepatic triggers.

Adenovirus-Related Fulminant Liver Failure After Kidney Transplantation.

BACKGROUND Human adenovirus is a well-known pathogen that can potentially lead to severe infection in immunocompromised patients. Adenovirus infections in solid-organ transplant recipients can range from asymptomatic to severe, prolonged, disseminated disease, and have a significant impact on morbidity, mortality, and graft survival. The clinical manifestations vary from asymptomatic and flu-like illness to severe life-threatening viremia with multi-organ failure. Post-transplant adenovirus infection is well described in kidney recipients, but in adult liver transplant recipients the impact of the virus is not well described. In this report, a case of disseminated adenovirus infection with subsequent fatal acute liver failure in a post-kidney transplant patient is presented. CASE REPORT A 51-year-old man underwent a deceased kidney transplantation for focal segmental glomerulosclerosis. Shortly after the kidney transplantation, he received multiple plasmapheresis with additional steroid treatments for cellular rejection and reoccurrence of his primary kidney disease. Three weeks after the kidney transplant, he developed a disseminated adenovirus infection with subsequent acute liver failure. Despite the early diagnosis and aggressive treatment, the patient died. CONCLUSIONS Patients with organ transplantation with autoimmune background etiology are usually over-immunosuppressed to avoid early rejection. In this population, opportunistic infections are not rare. Fever, general malaise, and transplant organ dysfunction are the first signs of bacterial or viral infection. Early infectious diseases work-up, including tissue biopsy, is fundamental to establish a diagnosis. Broad antibiotic and possible antiviral aggressive treatment are mandatory.

Clinical Aspect of Cytokines and Chemokines in Liver Transplant.

BACKGROUND: The objective of this prospective observational study was to determine whether a transplanted liver graft releases proinflammatory cytokines and chemokines on reperfusion and to determine the relationship between these molecules and subsequent ischemic reperfusion injury and acute kidney injury. METHODS: Blood samples from 66 consecutive patients undergoing liver transplant were analyzed for cyto- and chemokines at different time frames before and after liver transplant. Ischemic reperfusion injury was defined based on the peak levels of arginine transaminase and divided into 3 groups: mild, moderate, and severe. Acute kidney injury was defined according to the latest Kidney Disease: Improving Global Outcomes classification. RESULTS: For more than 40 different cyto/chemokines and growth factors, a certain pattern of expression was observed in all patients with ischemic reperfusion injury. G-SCF, IP10, and HSP90a were significantly elevated in all patients with ischemic reperfusion injury. On the other hand, eotaxin and MCP1 levels were markedly elevated in patients without ischemic reperfusion, suggesting a possible cytoprotective effect. We identified cold ischemia, macrosteatosis > 30%, postreperfusion syndrome, and postoperative use of 2 or more vasoactive agents as independent risk factors for ischemic reperfusion injury. CONCLUSIONS: Ischemia reperfusion injury is accompanied by distinct innate and adaptive immune cytokine signatures before and after transplant. It can be used for therapeutic intervention with goal to improve post-transplant graft outcomes.

Liver Transplantation in Recipients With Class III Obesity: Posttransplant Outcomes and Weight Gain.

BACKGROUND: There has been a dramatic increase in obesity in the United States. Several studies have reported conflicting results for the impact of obesity on outcomes of liver transplantation (LT). This study aims to assess the impact of obesity on LT and changes in body mass index (BMI) after transplantation. METHODS: All adult LTs performed at Indiana University between 2001 and 2018 were reviewed. BMIs of recipients were subdivided into 6 categories. Survival outcomes were compared across the subgroup. BMI was followed up in a cohort of patients from 2008 to 2018. RESULTS: Among 2024 patients, 25% were in class I obesity, 9.3% were in class II obesity, and 1.1% were in class III obesity. There was no significant difference in patient and graft survival at 10-y follow-up with respect to BMI. Among 1004 patients in the subgroup, BMI of all groups except the underweight group declined in the first 3 mo postoperatively; however, the BMI of all groups except the class III obesity group returned to the pre-LT level by 2 y and reached a plateau by 5 y. In the class III obesity group, there was a significant increase in body weight at 5 y. CONCLUSIONS: Class III obesity was not associated with higher mortality in our cohort. Because our cohort is small, it may be underpowered to detect a smaller difference in outcome. From our observation, obesity should not be considered a contraindication for LT. Post-LT interventions are required to prevent significant weight gain for the class III obesity group.

Human organ donor-derived vagus nerve biopsies allow for well-preserved ultrastructure and high-resolution mapping of myelinated and unmyelinated fibers.

The vagus nerve provides motor, sensory, and autonomic innervation of multiple organs, and electrical vagus nerve stimulation (VNS) provides an adjunctive treatment option for e.g. medication-refractory epilepsy and treatment-resistant depression. The mechanisms of action for VNS are not known, and high-resolution anatomical mapping of the human vagus nerve is needed to better understand its functional organization. Electron microscopy (EM) is required for the detection of both myelinated and unmyelinated axons, but access to well-preserved human vagus nerves for ultrastructural studies is sparse. Intact human vagus nerve samples were procured intra-operatively from deceased organ donors, and tissues were immediately immersion fixed and processed for EM. Ultrastructural studies of cervical and sub-diaphragmatic vagus nerve segments showed excellent preservation of the lamellated wall of myelin sheaths, and the axolemma of myelinated and unmyelinated fibers were intact. Microtubules, neurofilaments, and mitochondria were readily identified in the axoplasm, and the ultrastructural integrity of Schwann cell nuclei, Remak bundles, and basal lamina was also well preserved. Digital segmentation of myelinated and unmyelinated axons allowed for determination of fiber size and myelination. We propose a novel source of human vagus nerve tissues for detailed ultrastructural studies and mapping to support efforts to refine neuromodulation strategies, including VNS.

Combined liver-kidney transplantation with positive crossmatch: Role of delayed kidney transplantation.

BACKGROUND: Positive crossmatch (XM+) combined liver-kidney transplantation due to preformed donor-specific human leukocyte antigen antibodies has produced mixed results. We sought to understand the role of delayed kidney transplant approach in XM+ combined liver-kidney transplantations. METHODS: XM+ combined liver-kidney transplantations were retrospectively reviewed. T- and B-cell XM, complement-dependent cytotoxic crossmatch, and flow cytometric crossmatch were performed prospectively. RESULTS: Of 183 combined liver-kidney transplantations performed (2002-2019), 114 (62%) were with "delayed" kidney transplant approach and 19 (19 of 183, 10%) were XM+. Of 19 XM+ combined liver-kidney transplantations, kidney transplant was "delayed" in 14 by an average of 47 hours (range 24-64 hours) from liver transplant. There was a significant reduction in both class I (mean pre-liver transplant mean fluorescence intensity (MFI) 26,230 versus mean post-liver transplant and pre-delayed kidney transplant MFI 3,272, P = .01) and total MFI (mean pre-liver transplant MFI 27,233 vs mean post liver transplant and predelayed kidney transplant MFI 11,469, P = .01). However, there was no significant change in the MFI of class II donor-specific antibodies (mean pre-liver transplant MFI 17,899 versus post-liver transplant and pre-delayed kidney transplant MFI 14,341, P = .19). None of XM+ delayed kidney transplants had delayed graft function, and there was no antibody-mediated rejection. One-year patient survival for the XM+ combined liver-kidney transplantation with delayed kidney transplant approach was 92.9%, which is comparable to patient survival of XM- combined liver-kidney transplantation. Whereas patient survival in recipients before "delayed" approach ("simultaneous"; n = 5) was 40% when liver-kidney transplants were performed simultaneously (P = .06). CONCLUSION: In sensitized combined liver-kidney transplantation recipients, the "delayed" kidney transplant approach is associated with a significant reduction in total and class I donor-specific antibodies after liver transplant before kidney transplant, enabling therapeutic interventions such as plasmapheresis, if needed, providing optimal outcomes similar to crossmatch recipients.

Donor-recipient body size mismatch has no impact on outcomes after deceased donor whole liver transplantation: Role of donor liver size measurement.

The role of donor-recipient body size mismatch (DRSM) on outcomes after whole liver transplantation (LT) is not clearly defined. At our center, in presence of considerable DRSM, objective assessment of the donor liver by a radiology or intraoperative evaluation by procuring surgeon was incorporated. To evaluate the impact of DRSM on graft outcomes with this approach, adult deceased donor whole liver transplants between July 2001 and December 2017 at our center were studied. DRSM was considered when the donor-recipient body surface area (BSA) ratio (DR-BSAr) was either <0.69 or >1.25. There were 54 (3.2%) transplants with DR-BSAr <0.69 and 61 (3.6%) with DR-BSAr >1.25. One-year graft survival was 85% vs. 89% vs. 89%; (p = .64) for transplants with DR-BSArs of <0.69, 0.69-1.25, and >1.25, respectively. Early allograft dysfunction (EAD) (28% vs. 27% vs. 37%; p = .07), post-transplant coagulopathy, bilirubinemia, and renal function were also comparable. In conclusion, with the actual measurement of the donor liver and recipient abdominal cavity, significant DRSM did not have a negative impact on early and long-term outcomes. Routine measurement of donor liver size by radiology may be incorporated in liver allocation to improve utilization.

Oncologic indications of liver transplantation and deceased donor liver allocation in the United States.

PURPOSE OF REVIEW: Liver transplantation is a standard therapy for certain liver cancers. The majority of liver transplantation in the United States is through deceased donor liver transplantation (DDLT). A significant disparity between the demand of livers and patients awaiting liver transplantation still remains, relying on United Network for Organ Sharing (UNOS) to make policies to determine priority amongst recipients, including for patients with liver cancer. We review the scope of liver transplantation in patients with liver cancer with a focus on hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (iCCA), and unresectable colorectal liver metastases (CRLM) with respect to current liver allocation policy. RECENT FINDINGS: Recently, liver allocation changed in the United States. Under the current allocation policy, select patients with HCC and hilar CCA (hCCA) receive priority with an exception score of median MELD score at transplant (MMAT)-3. There is scope for other liver cancers, such as iCCA and CRLM to be considered, as reasonable outcomes have been achieved in these patients outside of the United States through DDLT and living donor liver transplantation (LDLT). SUMMARY: With the growing experience of liver transplantation for nonconventional oncologic indications, the current policy for prioritization of liver cancer within deceased donor liver allocation may need to be re-evaluated.

Impact of Recipient Age in Combined Liver-Kidney Transplantation: Caution Is Needed for Patients ≥70 Years.

Elderly recipients (≥70 y) account for 2.6% of all liver transplants (LTs) in the United States and have similar outcomes as younger recipients. Although the rate of elderly recipients in combined liver-kidney transplant (CLKT) is similar, limited data are available on how elderly recipients perform after CLKT. METHODS: We have previously shown excellent outcomes in CLKT using delayed kidney transplant (Indiana) Approach (mean kidney cold ischemia time = 53 ± 14 h). Between 2007 and 2018, 98 CLKTs were performed using the Indiana Approach at Indiana University (IU) and the data were retrospectively analyzed. Recipients were subgrouped based on their age: 18-45 (n = 16), 46-59 (n = 34), 60-69 (n = 40), and ≥70 years (n = 8). RESULTS: Overall, more elderly patients received LT at IU (5.2%) when compared nationally (2.6%). The rate of elderly recipients in CLKT at IU was 8.2% (versus 2% Scientific Registry of Transplant Recipient). Recipient and donor characteristics were comparable between all age groups except recipient age and duration of dialysis. Patient survival at 1 and 3 years was similar among younger age groups, whereas patient survival was significantly lower in elderly recipients at 1 (60%) and 3 years (40%) (P = 0.0077). Control analyses (replicating Scientific Registry of Transplant Recipient's survival stratification: 18-45, 46-64, ≥65 y) showed similar patient survival in all age groups. CONCLUSIONS: Although LT can be safely performed in elderly recipients, extreme caution is needed in CLKT due to the magnitude of operation.

Isolated Intestine Transplantation for Autoimmune Enteropathy: A Case Report.

Autoimmune enteropathy is a rare disease characterized by chronic watery diarrhea, weight loss, and immune-mediated injury of the enterocolic mucosa. The clinicopathologic findings of this disease are variable, and timely diagnosis is challenging. It is usually managed medically. If medical management fails, surgical intervention is considered. This is a case report of a patient with autoimmune enteropathy mimicking collagenous enterocolitis. A 55-year-old man developed intestinal failure that manifested as profuse watery diarrhea, electrolyte disturbances, and weight loss. Initially, he was diagnosed with collagenous enterocolitis based on pathologic findings. Medical interventions were started, but the patient failed to show improvement. At 13 months after the onset of the disease, he was listed for isolated intestine transplantation (IITX) for intestinal failure. A healthy donor graft became available. IITX with chimney colostomy was performed. Based on the pathologic findings of the excised native small intestine, the patient was diagnosed with severe autoimmune enteropathy. The postoperative course was uneventful. By the third postoperative week, a full diet was tolerated and parenteral nutrition (PN) was weaned to end. He was discharged on postoperative day 34. Since discharge, he has been off PN, remaining on an enteral diet. This case is the first reported IITX performed on a patient with severe autoimmune enteropathy that was both curative and lifesaving. The present case confirms that IITX promptly restores gastrointestinal absorption in medically refractory autoimmune enteropathy. This observation provides clinicians with an effective treatment option in this challenging group of patients.

Tracheostomy Post Liver Transplant: Predictors, Complications, and Outcomes.

BACKGROUND Liver transplant (LT) patients have an increased risk of postoperative respiratory failure requiring tracheostomy. This study sought to characterize objective clinical predictors of tracheostomy. MATERIAL AND METHODS The records for 2017 LT patients at a single institution were reviewed. Patients requiring tracheostomy were first compared with all other patients. A case-control subgroup analysis was conducted in which 98 tracheostomy patients were matched with 98 non-tracheostomy LT patients. For the case-control study, muscle mass was assessed using preoperative computed tomography scans. RESULTS Among 2017 LT patients, 98 required tracheostomy (5%), with a 19% complication rate. Tracheostomy patients were older and had a higher model for end-stage liver disease score, a lower body mass index (BMI), and a greater smoking history. Tracheostomy patients had a longer hospital stay (45 vs. 10 days, P<0.001) and worse 1-year survival (65% vs. 91%, P<0.001). Ten-year Cox regression patient survival for tracheostomy patients was significantly worse (32% vs. 68%, P<0.001). In the case-control analysis, respiratory failure patients were older (P<0.01) and had a lower BMI (P=0.05). They also had a muscle mass deficit of -39% compared with matched LT controls (P<0.001). No significant differences were seen with pre-LT total protein or albumin or with forced expiratory volume in 1 s divided by forced vital capacity (FEV1/FVC) values. CONCLUSIONS Predictors for respiratory failure requiring post-LT tracheostomy include higher model for end-stage liver disease score, older age, lower BMI, greater smoking history, and worse sarcopenia. Patients requiring tracheostomy have dramatically longer hospital stays and worse survival.

Complex Abdominal Wound Healing After Multivisceral Retransplant: A Case Report on the Importance of Nutrition.

BACKGROUND: Intestinal transplantation (ITx) is performed as an isolated ITx or as a part of multivisceral transplantation for intestinal failure secondary to short gut syndrome, inflammatory bowel disease, trauma, and sequelae of chronic parenteral nutrition dependence. Wound complications after ITx are very common, and abdominal wound closure cannot be immediately achieved in half of cases. CASE PRESENTATION: A 25-year-old man sustained an abdominal crush injury causing complete loss of his small intestine, requiring an isolated ITx in March 2016. He lost his graft because of early exfoliative rejection in November 2016. Five months after enterectomy and the immunosuppression-free period, he underwent multivisceral retransplantation in April 2017. His post-transplant course was complicated by wound healing problems that improved with treatment of his malnutrition, quantified by increasing albumin, total protein, prealbumin, weight, body mass index, and total psoas muscle area over a period of 19 months after retransplant. CONCLUSION: To our knowledge, this is the first case described of long-term wound follow-up after a multivisceral (re)transplantation, with corresponding nutrition information and images of the wound.