Innovative Strategies for Liver Transplantation: The Role of Mesenchymal Stem Cells and Their Cell-Free Derivatives.

Despite being the standard treatment for end-stage liver disease, liver transplantation has limitations like donor scarcity, high surgical costs, and immune rejection risks. Mesenchymal stem cells (MSCs) and their derivatives offer potential for liver regeneration and transplantation. MSCs, known for their multipotency, low immunogenicity, and ease of obtainability, can differentiate into hepatocyte-like cells and secrete bioactive factors that promote liver repair and reduce immune rejection. However, the clinical application of MSCs is limited by risks such as aberrant differentiation and low engraftment rates. As a safer alternative, MSC-derived secretomes and extracellular vesicles (EVs) offer promising therapeutic benefits, including enhanced graft survival, immunomodulation, and reduced ischemia-reperfusion injury. Current research highlights the efficacy of MSC-derived therapies in improving liver transplant outcomes, but further studies are necessary to standardize clinical applications. This review highlights the potential of MSCs and EVs to address key challenges in liver transplantation, paving the way for innovative therapeutic strategies.

Outcomes of liver transplant for colorectal liver metastasis: a systematic review and meta-analysis.

BACKGROUND: Liver transplantation (LT) for nonresectable colorectal liver metastasis (NRCRLM) has become accepted for select patients meeting strict inclusion criteria. Advancements in patient selection and understanding of cancer biology may expand benefits to patients with colorectal liver metastasis (CRLM). In this meta-analysis, we sought to assess survival outcomes, recurrence patterns, and quality of life (QoL) after LT for CRLM. METHODS: PubMed, Embase, and Scopus databases were searched. A random-effect meta-analysis was conducted to obtain pooled overall survival (OS) and disease-free survival (DFS) rates and to compare QoL from baseline. Continuous data were analyzed, and standardized mean differences were reported. RESULTS: Overall, 16 studies (403 patients, 58.8% male sex) were included. The pooled 1-, 3-, and 5-year OS after LT for NRCRLM was 96% (95% CI: 92%-99%), 77% (95% CI: 62%-89%), and 53% (95% CI: 45%-61%), respectively. Moreover, the pooled 1-, 3-, and 5-year DFS was 58% (95% CI: 43%-72%), 33% (95% CI: 9%-61%), and 13% (95% CI: 4%-27%), respectively. Overall, 201 patients (49.8%) experienced recurrence during the follow-up period with the lungs being the most common site (45.8%). There was no significant differences in physical and emotional functioning, fatigue, and pain components of QoL at 6 months after LT compared with baseline (all P > .05). CONCLUSION: LT for NRCRLM demonstrated good OS outcomes with no differences in the QoL at 6 months after transplantation. Transplantation may represent a viable treatment option for NRCRLM.

The impact of county-level food access on the mortality and post-transplant survival among patients with steatotic liver disease.

BACKGROUND: The impact of county-level food access on mortality associated with steatotic liver disease, as well as post-liver transplant outcomes among individuals with steatotic liver disease, have not been characterized. METHODS: Data on steatotic liver disease-related mortality and outcomes of liver transplant recipients with steatotic liver disease between 2010 and 2020 were obtained from the Centers for Disease Control Prevention mortality as well as the Scientific Registry of Transplant Recipients databases. These data were linked to the food desert score, defined as the proportion of the total population in each county characterized as having both low income and limited access to grocery stores. RESULTS: Among 2,710 counties included in the analytic cohort, median steatotic liver disease-related mortality was 27.3 per 100,000 population (interquartile range 24.9-32.1). Of note, patients residing in counties with high steatotic liver disease death rates were more likely to have higher food desert scores (low: 5.0, interquartile range 3.1-7.8 vs moderate: 6.1, interquartile range, 3.8-9.3 vs high: 7.6, interquartile range 4.1-11.7). Among 28,710 patients who did undergo liver transplantation, 5,310 (18.4%) individuals lived in counties with a high food desert score. Liver transplant recipients who resided in counties with the worst food access were more likely to have a higher body mass index (>35 kg/m2: low food desert score, 17.3% vs highest food desert score, 20.1%). After transplantation, there was no difference in 2-year graft survival relative to county-level food access (food desert score: low: 88.4% vs high: 88.6%; P = .77). CONCLUSION: Poor food access was associated with a higher incidence rate of steatotic liver disease-related death, as well as lower utilization of liver transplants. On the other hand, among patients who did receive a liver transplant, there was no difference in 2-year graft survival regardless of food access strata. Policy initiatives should target the expansion of transplantation services to vulnerable communities in which there is a high mortality of steatotic liver disease.

Missing the Match: A National Survey Investigating Education in Renal Donor-Recipient Matching.

PURPOSE: Clinical judgment in renal donor organ and recipient selection is gained through fellowship and mentorship in early career. We aim to understand the past and current state of organ acceptance education. METHODS: We developed and distributed an anonymous, national survey to American Society of Transplant Surgeons faculty members and transplant surgery fellows in 2022. Survey questions explored in detail the evaluation of organ offers, the extent of formal education in organ evaluation, and attitudes regarding training adequacy. FINDINGS: Ninety-eight attending surgeons (65 men, 25 women, and 3 nonbinary) and 38 fellows (25 men, 6 women, and 2 nonbinary) responded. Seventy-eight percent of attending surgeons and 6% of fellows take primary organ offers. Forty-four percent of fellows report no didactic education in donor evaluation and recipient selection. Fellows report that discussion with attending surgeons (37.2%) and independent study of the literature (35.4%) are their primary modes of learning. Fellows call for additional clinical decision-making experience (47.3%), further didactic sessions (44.7%), and additional discussions with faculty (44.7%). Sixty-four percent of fellows and 55% of attendings felt their training provided adequate education about donor selection. CONCLUSION: Our responses suggest gaps in education regarding donor and recipient selection. Increased clinical experience and standardized education at the national level represent opportunities for improvement.

Liver Transplant as a Treatment of Primary and Secondary Liver Neoplasms.

Importance: Liver malignancies are an increasing global health concern with a high mortality. We review outcomes following liver transplant for primary and secondary hepatic malignancies. Observations: Transplant may be a suitable treatment option for primary and secondary hepatic malignancies in well-selected patient populations. Conclusions and Relevance: Many patients with primary or secondary liver tumors are not eligible for liver resection because of advanced underlying liver disease or high tumor burden, precluding complete tumor clearance. Although liver transplant has been a long-standing treatment modality for patients with hepatocellular carcinoma, recently transplant has been considered for patients with other malignant diagnoses. In particular, while well-established for hepatocellular carcinoma and select patients with perihilar cholangiocarcinoma, transplant has been increasingly used to treat patients with intrahepatic cholangiocarcinoma, as well as metastatic disease from colorectal liver and neuroendocrine primary tumors. Because of the limited availability of grafts and the number of patients on the waiting list, optimal selection criteria must be further defined. The ethics of organ allocation to individuals who may benefit from prolonged survival after transplant yet have a high incidence of recurrence, as well as the role of living donation, need to be further discerned in the setting of transplant oncology.

Liver transplantation access and outcomes: Impact of variations in liver-specific specialty care.

BACKGROUND: We sought to characterize the impact access to gastroenterologists/hepatologists has on liver transplantation listing, as well as time on the liver transplantation waitlist and post-transplant outcomes. METHODS: Liver transplantation registrants aged >18 years between January 1, 2004 and December 31, 2019 were identified from the Scientific Registry of Transplant Recipients Standard Analytic Files. The liver transplantation registration ratio was defined as the ratio of liver transplant waitlist registrations in a given county per 1,000 liver-related deaths. RESULTS: A total of 150,679 liver transplantation registrants were included. Access to liver transplantation centers and liver-specific specialty physicians varied markedly throughout the United States. Of note, the liver transplantation registration ratio was lower in counties with poor access to liver-specific care versus counties with adequate access (poor access 137.2, interquartile range 117.8-163.2 vs adequate access 157.6, interquartile range 127.3-192.2, P < .001). Among patients referred for liver transplantation, the cumulative incidence of waitlist mortality and post-transplant graft survival was comparable among patients with poor versus adequate access to liver-specific care (both P > .05). Among liver transplantation recipients living in areas with poor access, after controlling for recipient and donor characteristics, cold ischemic time, and model for end-stage liver disease score, the area deprivation index predicted graft survival (referent, low area deprivation index; medium area deprivation index, hazard ratio 1.52, 95% confidence interval 1.03-12.23; high area deprivation index, 1.45, 95% confidence interval 1.01-12.09, both P < .05). CONCLUSION: Poor access to liver-specific care was associated with a reduction in liver transplantation registration, and individuals residing in counties with high social deprivation had worse graft survival among patients living in counties with poor access to liver-specific care.

Textbook outcome: A novel metric in heart transplantation outcomes.

OBJECTIVE: Assessing heart transplant program quality using short-term survival is insufficient. We define and validate the composite metric textbook outcome and examine its association with overall survival. METHODS: We identified all primary, isolated adult heart transplants in the United Network for Organ Sharing/Organ Procurement and Transplantation Network Standard Transplant Analysis and Research files from May 1, 2005, to December 31, 2017. Textbook outcome was defined as length of stay 30 days or less; ejection fraction greater than 50% during 1-year follow-up; functional status 80% to 100% at 1 year; freedom from acute rejection, dialysis, and stroke during the index hospitalization; and freedom from graft failure, dialysis, rejection, retransplantation, and mortality during the first year post-transplant. Univariate and multivariate analyses were performed. Factors independently associated with textbook outcome were used to create a predictive nomogram. Conditional survival at 1 year was measured. RESULTS: A total of 24,620 patients were identified with 11,169 (45.4%, 95% confidence interval, 44.7-46.0) experiencing textbook outcome. Patients with textbook outcome were more likely free from preoperative mechanical support (odds ratio, 3.504, 95% confidence interval, 2.766 to 4.439, P < .001), free from preoperative dialysis (odds ratio, 2.295, 95% confidence interval, 1.868-2.819, P < .001), to be not hospitalized (odds ratio, 1.264, 95% confidence interval, 1.183-1.349, P < .001), to be nondiabetic (odds ratio, 1.187, 95% confidence interval, 1.113-1.266, P < .001), and to be nonsmokers (odds ratio, 1.160, 95% confidence interval,1.097-1.228, P < .001). Patients with textbook outcome have improved long-term survival relative to patients without textbook outcome who survive at least 1 year (hazard ratio for death, 0.547, 95% confidence interval, 0.504-0.593, P < .001). CONCLUSIONS: Textbook outcome is an alternative means of examining heart transplant outcomes and is associated with long-term survival. The use of textbook outcome as an adjunctive metric provides a holistic view of patient and center outcomes.

Liver transplantation for elderly patients with early-stage hepatocellular carcinoma.

BACKGROUND: Although liver resection is a viable option for patients with early-stage hepatocellular carcinoma (HCC), liver transplantation is the optimal treatment. The aim of this study was to identify characteristics of liver transplantation for elderly patients, and to assess the therapeutic benefit derived from liver transplantation over liver resection. METHODS: This was a population-based study of patients undergoing liver transplantation for HCC in the USA between 2004 and 2018. Data were retrieved from the National Cancer Database. Elderly patients were defined as individuals aged 70 years and over. Propensity score overlap weighting was used to control for heterogeneity between the liver resection and liver transplantation cohorts. RESULTS: Among 4909 liver transplant recipients, 215 patients (4.1 per cent) were classified as elderly. Among 5922 patients who underwent liver resection, 1907 (32.2 per cent) were elderly. Elderly patients who underwent liver transplantation did not have a higher hazard of dying during the first 5 years after transplantation than non-elderly recipients. After propensity score weighting, liver transplantation was associated with a lower risk of death than liver resection. Other factors associated with overall survival included diagnosis during 2016-2018, non-white/non-African American race, and α-fetoprotein level over 20 ng/dl. CONCLUSION: Elderly patients with HCC should not be excluded from liver transplantation based on age only. Transplantation leads to favourable survival compared with liver resection.

Updates and Expert Opinions on Liver Transplantation for Gastrointestinal Malignancies.

Transplant oncology is a relatively new field in which transplantation is used to treat patients who would otherwise be unresectable. New anticancer treatment paradigms using tumor and transplant immunology and cancer immunogenomics are emerging. In turn, liver transplantation (LT) has become a potential therapy for certain patients with colorectal cancer (CRC) with liver metastasis, hepatocellular (HCC), cholangiocarcinoma (CCA), and metastatic neuroendocrine tumor (NET) of the liver. Although there are established criteria for LT in HCC, evidence regarding LT as a treatment modality for certain gastrointestinal malignancies is still debated. The aim of this review is to highlight updates in the role of LT for certain malignancies, including HCC, metastatic CRC, hilar CCA, and neuroendocrine tumor (NET), as well as contextualize LT use and discuss controversies in transplant oncology.

The Impact of a Liver Transplant Program on the Outcomes of Hepatocellular Carcinoma.

OBJECTIVE: We sought to evaluate the impact of liver transplantation (LT) programs on the prognosis of hepatocellular carcinoma (HCC) patients who underwent liver resection (LR) and noncurative intent treatment. BACKGROUND: LT programs have an array of resources and services that would positively affect the prognosis of patients with HCC. METHODS: Patients who underwent LT, LR, radiotherapy (RT), or chemotherapy (CTx) for HCC between 2004 and 2018 were included in the National Cancer Database. Institutions with LT programs were defined as those that performed 1 or more LT for at least 5 years. Centers were stratified by hospital volume. The impact of LT programs was assessed after propensity score matching to achieve covariate balance. RESULTS: A total of 71,735 patients were identified, of which 7997 received LT (11.1%), 12,683 LR (17.7%), 15,675 RT (21.9%), and 35,380 CTx (49.3%). Among a total of 1267 distinct institutions, 94 (7.4%) were categorized as LT programs. Designation as an LT program was also associated with a high volume of LR and noncurative intent treatment (both P <0.001). After propensity score matching, LT programs were associated with better survival among LR and noncurative intent treatment patients. Although hospital volume was also associated with improved prognosis, LT programs were associated with additional survival benefits in noncurative intent treatment. On the other hand, no such benefit was noted in patients who underwent LR. CONCLUSIONS: The presence of an LT program was associated with a higher volume of LR and noncurative intent treatment. Furthermore, designation as an LT program had a "halo effect" on the prognosis of patients undergoing RT/CTx that went beyond the procedure-volume effect.

Comparing Kidney Transplant Rates and Outcomes Among Adults With and Without Intellectual and Developmental Disabilities.

Importance: Improving equity in organ transplant access for people with intellectual and developmental disabilities (IDD) is a topic of social discourse in mainstream media, state legislation, and national legislation. However, few studies have compared evaluation rates, transplant rates, and outcomes among adults with and without IDD. Objective: To compare rates of kidney transplant and transplant-specific outcomes between propensity-score matched groups of adults with end-stage kidney disease (ESKD [also referred to as end-stage renal disease (ESRD)]) with and without co-occurring IDD. Design, Setting, and Participants: This retrospective cohort study included all Medicare inpatient and outpatient standard analytical files from 2013 through 2020. A total of 1 413 655 adult Medicare beneficiaries with ESKD were identified. Propensity-score matching was used to balance cohorts based on age, sex, race, follow-up duration, and Charlson Comorbidity Index. The matched cohorts consisted of 21 384 adults with ESKD (10 692 of whom had IDD) and 1258 kidney transplant recipients (629 of whom had IDD). Data were analyzed between June 1, 2022, and August 1, 2022. Exposure: IDD. Main Outcomes and Measures: Evaluation for kidney transplant, receipt of kidney transplant, perioperative complications, readmission, mortality, graft rejection, and graft failure. Results: Of the 21 384 propensity-score matched adults with ESKD, the median (IQR) age was 55 (43-65) years, 39.2% were male, 27.4% were Black, 64.1% were White, and 8.5% identified as another race or ethnicity. After propensity score matching within the ESKD cohort, 633 patients with IDD (5.9%) received a kidney transplant compared with 1367 of adults without IDD (12.8%). Adults with IDD were 54% less likely than matched peers without IDD to be evaluated for transplant (odds ratio, 0.46; 95% CI, 0.43-0.50) and 62% less likely to receive a kidney transplant (odds ratio, 0.38; 95% CI, 0.34-0.42). Among matched cohorts of kidney transplant recipients, rates of perioperative complications, readmission, and graft failure were similar for adults with and without IDD. Conclusions and Relevance: Using the largest cohort of adult kidney transplant recipients with IDD to date, the study team found that rates of evaluation and transplant were lower despite yielding equivalent outcomes. These data support consideration of adults with IDD for kidney transplant and underscore the urgent need for antidiscrimination initiatives to promote the receipt of equitable care for this population.

Postoperative and Recurrent Hematuria after Pretransplant Core Needle Biopsy in Living Donor Kidney Transplant.

Background: Core needle and wedge biopsies are the two main pathologic ways to determine the suitability of a kidney allograft and to have a baseline allograft biopsy in case of future rejection. Case Presentation. A 57-year-old patient developed a renal arteriovenous fistula causing postoperative and recurrent hematuria after allograft pretransplant renal core needle biopsy and treated with selective Interventional radiology coil embolization. Conclusion: Delayed profound hematuria can be seen after pretransplant core needle renal biopsies and can recur again even after complete resolution, due to arteriovenous fistula formation in the renal calyceal system.

Liver Transplantation as a New Standard of Care in Patients With Perihilar Cholangiocarcinoma? Results From an International Benchmark Study.

OBJECTIVE: To define benchmark values for liver transplantation (LT) in patients with perihilar cholangiocarcinoma (PHC) enabling unbiased comparisons. BACKGROUND: Transplantation for PHC is used with reluctance in many centers and even contraindicated in several countries. Although benchmark values for LT are available, there is a lack of specific data on LT performed for PHC. METHODS: PHC patients considered for LT after Mayo-like protocol were analyzed in 17 reference centers in 2 continents over the recent 5-year period (2014-2018). The minimum follow-up was 1 year. Benchmark patients were defined as operated at high-volume centers (≥50 overall LT/year) after neoadjuvant chemoradiotherapy, with a tumor diameter <3 cm, negative lymph nodes, and with the absence of relevant comorbidities. Benchmark cutoff values were derived from the 75th to 25th percentiles of the median values of all benchmark centers. RESULTS: One hundred thirty-four consecutive patients underwent LT after completion of the neoadjuvant treatment. Of those, 89.6% qualified as benchmark cases. Benchmark cutoffs were 90-day mortality ≤5.2%; comprehensive complication index at 1 year of ≤33.7; grade ≥3 complication rates ≤66.7%. These values were better than benchmark values for other indications of LT. Five-year disease-free survival was largely superior compared with a matched group of nodal negative patients undergoing curative liver resection (n=106) (62% vs 32%, P <0.001). CONCLUSION: This multicenter benchmark study demonstrates that LT offers excellent outcomes with superior oncological results in early stage PHC patients, even in candidates for surgery. This provocative observation should lead to a change in available therapeutic algorithms for PHC.

Orthotopic Kidney Transplant as a Fifth Intra-Abdominal Organ after Two Previous Kidney and Two Previous Pancreas Transplants.

Background: Patients with more than two prior kidney transplant procedures pose unique surgical challenges. Once both the right and left retroperitoneal spaces have been dissected, intra-abdominal implantation is usually necessary. If the external iliac arteries have been used previously, it is sometimes necessary to use the aorta and vena cava for implantation. Gaining safe exposure in these cases can be complicated by history of prior laparotomy, adhesive disease, and other surgical histories. Case Presentation. A 58-year-old female with type 1 diabetes and end-stage renal disease presented for surgical evaluation for kidney transplant. Surgical history was notable for prior simultaneous kidney-pancreas transplant followed by both a living donor kidney transplant and a pancreas after kidney transplant. She had undergone both an allograft nephrectomy and an allograft pancreatectomy and currently had a nonfunctioning kidney in the left retroperitoneal position and a nonfunctioning pancreatic allograft on the right common iliac artery. The entire distal aortoiliac system was surgically inaccessible. She was listed for transplantation, and a cadaveric graft was allocated. Intraoperatively, severe lower abdominal and pelvic adhesions prevented any use of the iliac system. A left native nephrectomy was performed, and the allograft was implanted in the left orthotopic position. The native left renal vein was used for outflow, the donor renal artery was joined end-to-side to the infrarenal aorta, and a uretero-ureterostomy was created. The operation was uneventful. The allograft functioned without delay, and almost one year later, the GFR is approximately 50 mg/dL. Conclusion: The left orthotopic position can be a good choice for kidney transplant candidates with histories of prior complex lower abdominal surgery.

Spinal Stroke following Kidney Transplant.

Complications are a part of surgery. Spinal infarctions are a dreaded complication of aortic surgery. We present a patient who developed a spinal infarct after a kidney transplant. We were unable to find a causative factor in our search for etiology. In our review of the literature, we were unable to find a similar report. We present this case report to highlight a rare complication of kidney transplantation and to reinforce that patients requiring kidney transplant are complex patients with multiple comorbidities that can cause a multitude of complications in the periop period.

Textbook Outcome as a Quality Metric in Liver Transplantation.

Quality in liver transplantation (LT) is currently measured using 1-y patient and graft survival. Because patient and graft survival rates now exceed 90%, more informative metrics are needed. Textbook outcomes (TOs) describe ideal patient outcomes after surgery. This study critically evaluates TO as a quality metric in LT. Methods: United Network for Organ Sharing data for 25 887 adult LT recipients were used to define TO as patient and graft survival >1 y, length of stay ≤10 d, 0 readmissions within 6 mo, absence of rejection, and bilirubin <3 mg/dL between months 2 and 12 post-LT. Univariate analysis identified donor and recipient characteristics associated with TO. Covariates were analyzed using purposeful selection to construct a multivariable model, and impactful variables were incorporated as linear predictors into a nomogram. Five-year conditional survival was tested, and center TO rates were corrected for case complexity to allow for center-level comparisons. Results: The national average TO rate is 37.4% (95% confidence interval, 36.8%-38.0%). The hazard ratio for death at 5 y for patients who do not experience TO is 1.22 (95% confidence interval, 1.11-1.34; P ≤ 0.0001). Our nomogram predicts TO with a C-statistic of 0.68. Center-level comparisons identify 31% of centers as high performing and 21% of centers as below average. High rates of TO correlate only weakly with center volume. Conclusions: The composite quality metric of TO after LT incorporates holistic outcome measures and is an important measure of quality in addition to 1-y patient and graft survival.

Safely Expanding the Liver Donor Pool by Utilization of Organs from Donation after Circulatory Death with Comparable Results to Donation After Brain Death, a Large Single-Center Experience.

BACKGROUND: Use of livers donated after circulatory death (DCD) is one way to expand the donor pool. Our center has aggressively incorporated use of DCD liver grafts into practice. We examined our center and national outcomes as well as national DCD liver utilization. METHODS: Liver transplants performed at our center and nationally from 11/2016 through 9/2020 were compared. Primary outcomes were patient and graft survival, and national DCD liver utilization. RESULTS: For our center, DCD and donation after brain death (DBD) donors were similar except DCD donors were younger (37 vs 40 years; p < 0.05). Recipient Na-MELD (20 vs 24; p < 0.0001) and cold ischemia time (4.63 vs 5.18 h; p < 0.05) were lower in DCD recipients. There were no significant differences in 1-year patient and graft survival between DCD and DBD liver recipients locally. Nationally, there was a difference in 1-year graft survival year (89.4% vs 92.4%, p < 0.0001) but patient survival was similar between groups. The proportion of DCD livers recovered and transplanted widely varied among organ procurement organizations (OPOs) and transplant centers. CONCLUSIONS: Similar outcomes for DCD and DBD liver recipients should encourage centers and OPOs nationwide to expand utilization of DCD livers.

Machine perfusion of kidney allografts affects early but not late graft function.

BACKGROUND: Hypothermic machine perfusion (HMP) parameters are influenced by donor variables which further affect recipient outcome. Interplay between these parameters can help to predict kidney performance on pump and the long term outcome. METHODS: All the kidneys transplanted at our center between May 2013 through November 2017 were included in the study. Donor and recipient data was obtained from internal database. Multiple logistic regression models with backward selection were used to determine significant donor and pump variables. RESULTS: Donor BMI, KDPI, age and donor sex had a significant association with pump flow. Donor sex, donor type, KDPI and age had significant effect on RI. Diastolic pressure and KDPI were significantly associated with DGF. Duration on pump, KDPI, flow, donor creatinine and type of donor were significantly associated with day 5 creatinine. KDPI was significantly associated with Day 365 creatinine. CONCLUSION: HMP effects early graft function while the long term function depends on donor parameters.