Phase I clinical trial of the feasibility and safety of direct peritoneal resuscitation in liver transplantation.

BACKGROUND: Direct peritoneal resuscitation (DPR) is associated with improved outcomes in trauma. Animal models suggest DPR has favorable effects on the liver. We sought to evaluate its safety and assess for improved outcomes in liver transplantation (LT). METHODS: LT patients with renal dysfunction and/or obesity were enrolled in a phase-I clinical trial. DPR lasted 8-24 â€‹h depending on postoperative disposition. Primary outcome was percent of patients completing DPR. Secondary outcomes evaluated complications. Controls with either obesity (control-1) or both risk factors (obesity â€‹+ â€‹renal dysfunction, control-2) were analyzed. RESULTS: Fifteen patients were enrolled (seven with both criteria and eight with obesity alone). DPR was completed in 87 â€‹% of patients, with one meeting stopping criteria. Controls included 45 (control-1) and 24 (control-2) patients. Return to operating room, graft loss, and late infections were lower with DPR. CONCLUSION: DPR appears to be safe in closed abdomens following LT, warranting a follow-up phase-II trial to assess efficacy.

Survival following liver transplantation: A population-based nested case-control study.

BACKGROUND: Liver transplantation is the gold standard treatment for end-stage liver disease. This study evaluates post-transplantation survival compared with the general population by quantifying standardized mortality ratios in a nested case-control study. METHODS: Controls were noninstitutionalized United States inhabitants from the National Longitudinal Mortality Study. Cases underwent liver transplantation from 1990 to 2007 identified through the Organ Procurement and Transplantation Network database. Propensity matching (5:1, nearest neighbor, caliper 0.1) identified controls based on age, sex, race, and state. The primary endpoint was 10-year survival. RESULTS: 62,788 cases were matched to 313,381 controls. The overall standardized mortality ratio was 2.46 (95% CI â€‹= â€‹2.44-2.48). The standardized mortality ratio was higher for males (2.59 vs. 2.25) and Hispanic patients (4.80). Younger patients and those transplanted earlier (1990-1995) had higher standardized mortality ratios. CONCLUSIONS: Liver recipients have a standardized mortality ratio 2.46 times higher than the general population. Long-term mortality has declined over time.

Retransplantation in Living Donor Liver Transplantation.

The need for retransplantation after living donor liver transplantation can occur early, mainly because of technical difficulties such as hepatic artery thrombosis or as a result of early allograft dysfunction as a symptom of small-for-size syndrome. Patients with autoimmune diseases may develop progressive graft failure from recurrent disease. The ethics of retransplantation can be complicated by the cause of the initial liver disease, which may be self-inflicted or the outcome of malignancy. This is especially true in countries without the availability of deceased donors for salvage, and a second living donor would be needed. Nevertheless, patients who experience early or late graft failure should be considered for retransplant if they are deemed acceptable candidates. When a living donor is required for retransplant, the equipoise between donor risk and autonomy and recipient outcome should be considered.

Association of procurement technique with organ yield and cost following donation after circulatory death.

Donation after circulatory death (DCD) could account for the largest expansion of the donor allograft pool in the contemporary era. However, the organ yield and associated costs of normothermic regional perfusion (NRP) compared to super-rapid recovery (SRR) with ex-situ normothermic machine perfusion, remain unreported. The Organ Procurement and Transplantation Network (December 2019 to June 2023) was analyzed to determine the number of organs recovered per donor. A cost analysis was performed based on our institution's experience since 2022. Of 43 502 donors, 30 646 (70%) were donors after brain death (DBD), 12 536 (29%) DCD-SRR and 320 (0.7%) DCD-NRP. The mean number of organs recovered was 3.70 for DBD, 3.71 for DCD-NRP (P < .001), and 2.45 for DCD-SRR (P < .001). Following risk adjustment, DCD-NRP (adjusted odds ratio 1.34, confidence interval 1.04-1.75) and DCD-SRR (adjusted odds ratio 2.11, confidence interval 2.01-2.21; reference: DBD) remained associated with greater odds of allograft nonuse. Including incomplete and completed procurement runs, the total average cost of DCD-NRP was $9463.22 per donor. By conservative estimates, we found that approximately 31 donor allografts could be procured using DCD-NRP for the cost equivalent of 1 allograft procured via DCD-SRR with ex-situ normothermic machine perfusion. In conclusion, DCD-SRR procurements were associated with the lowest organ yield compared to other procurement methods. To facilitate broader adoption of DCD procurement, a comprehensive understanding of the trade-offs inherent in each technique is imperative.

Differential in Kidney Graft Years on the Basis of Solitary Kidney, Simultaneous Liver-Kidney, and Kidney-after-Liver Transplants.

BACKGROUND: The number of simultaneous liver-kidney (SLK) transplants has significantly increased in the United States. There has also been an increase in kidney-after-liver transplants associated with 2017 policy revisions aimed to fairly allocate kidneys after livers. SLK and kidney-after-liver candidates are prioritized in allocation policy for kidney offers ahead of kidney-alone candidates. METHODS: We compared kidney graft outcomes of kidney-alone transplant recipients with SLK and kidney-after-liver transplants using paired kidney models to mitigate differences among donor risk factors. We evaluated recipient characteristics between transplant types and calculated differential graft years using restricted mean survival estimates. RESULTS: We evaluated 3053 paired donors to kidney-alone and SLK recipients and 516 paired donors to kidney-alone and kidney-after-liver recipients from August 2017 to August 2022. Kidney-alone recipients were younger, more likely on dialysis, and Black race. One-year and 3-year post-transplant kidney graft survival for kidney-alone recipients was 94% and 86% versus SLK recipients 89% and 80%, respectively, P < 0.001. One-year and 3-year kidney graft survival for kidney-alone recipients was 94% and 84% versus kidney-after-liver recipients 93% and 87%, respectively, P = 0.53. The additional kidney graft years for kidney-alone versus SLK transplants was 21 graft years/100 transplants (SEM=5.0) within 4 years post-transplantation, with no significant difference between kidney-after-liver and kidney-alone transplants. CONCLUSIONS: Over a 5-year period in the United States, SLK transplantation was associated with significantly lower kidney graft survival compared with paired kidney-alone transplants. Most differences in graft survival between SLK and kidney-alone transplants occurred within the first year post-transplantation. By contrast, kidney-after-liver transplants had comparable graft survival with paired kidney-alone transplants.

Early predictors of prolonged intensive care utilization following liver transplantation.

INTRODUCTION: Creatinine, bilirubin, and fibrinolysis resistance are associated with multi-organ dysfunction and likely risk factors for prolonged intensive care unit (pICU) stay following liver transplantation (LT). We hypothesize postoperative day-1 (POD-1) labs will predict pICU. METHODS: LT recipients had clinical laboratories and viscoelastic testing with tissue plasminogen activator thrombelastography (tPA TEG) to quantify fibrinolysis resistance (LY30) on POD-1. pICU was defined as one week or longer in the ICU. Logistic regression was used to identify the relationship between POD-1 labs and pICU. RESULTS: Of 304 patients, 50% went to the ICU, with 15% experiencing pICU. Elevated creatinine (OR 6.6, P â€‹< â€‹0.001) and low tPA TEG LY30 (OR 3.7, P â€‹= â€‹0.004) were independent predictors of pICU after controlling for other risk factors. A 9-fold increase in the rate of 90-day graft loss (19% vs 2% p â€‹< â€‹0.001) was observed patients who had these risk factors for pICU. CONCLUSION: Elevated creatine and fibrinolysis resistance are associated with pICU and poor outcomes following LT.

Reassessing the survival benefit of deceased donor liver transplantation: retrospective cohort study.

INTRODUCTION: Currently in the United States, deceased donor liver transplant (DDLT) allocation priority is based on the model for end-stage liver disease including sodium (MELD-Na) score. The United Network for organ sharing's 'Share-15' policy states that candidates with MELD-Na scores of 15 or greater have priority to receive local organ offers compared to candidates with lower MELD-Na scores. Since the inception of this policy, major changes in the primary etiologies of end-stage liver disease have occurred and previous assumptions need to be recalibrated. METHODS: The authors retrospectively analyzed the Scientific Registry of Transplant Recipients database between 2012 and 2021 to determine life years saved by DDLT at each interval of MELD-Na score and the time-to-equal risk and time-to-equal survival versus remaining on the waitlist. The authors stratified our analysis by MELD exception points, primary disease etiology, and MELD score. RESULTS: On aggregate, compared to remaining on the waitlist, a significant 1-year survival advantage of DDLT at MELD-Na scores as low as 12 was found. The median life years saved at this score after a liver transplant was estimated to be greater than 9 years. While the total life years saved were comparable across all MELD-Na scores, the time-to-equal risk and time-to-equal survival decreased exponentially as MELD-Na scores increased. CONCLUSION: Herein, the authors challenge the perception as to the timing of DDLT and when that benefit occurs. The national liver allocation policy is transitioning to a continuous distribution framework and these data will be instrumental to defining the attributes of the continuos allocation score.

A model for calculating the long-term estimated post-transplant survival of deceased donor liver transplant patients.

BACKGROUND: The estimated long-term survival (EPTS) score is used for kidney allocation. A comparable prognostic tool to accurately quantify EPTS benefit in deceased donor liver transplant (DDLT) candidates is nonexistent. METHODS: Using the Scientific Registry of Transplant Recipients (SRTR) database, we developed, calibrated, and validated a nonlinear regression equation to calculate liver-EPTS (L-EPTS) for 5- and 10-year outcomes in adult DDLT recipients. The population was randomly split (70:30) into two discovery (N = 26,372 and N = 46,329) and validation cohorts (N = 11,288 and N = 19,859) for 5- and 10-year post-transplant outcomes, respectively. Discovery cohorts were used for variable selection, Cox proportional hazard regression modeling, and nonlinear curve fitting. Eight clinical variables were selected to construct the L-EPTS formula, and a five-tiered ranking system was created. FINDINGS: Tier thresholds were defined and the L-EPTS model was calibrated (R2 = 0.96 [5-year] and 0.99 [10-year]). Patients' median survival probabilities in the discovery cohorts for 5- and 10-year outcomes ranged from 27.94% to 89.22% and 16.27% to 87.97%, respectively. The L-EPTS model was validated via calculation of receiver operating characteristic (ROC) curves using validation cohorts. Area under the ROC curve was 82.4% (5-year) and 86.5% (10-year). INTERPRETATION: L-EPTS has high applicability and clinical utility because it uses easily obtained pre-transplant patients characteristics to accurately discriminate between those who are likely to receive a prolonged survival benefit and those who are not. It is important to evaluate medical urgency alongside survival benefit and placement efficiency when considering the allocation of a scarce resource. FUNDING: There are no funding sources related to this project.

Addressing sex-based disparities in solid organ transplantation in the United States - a conference report.

Solid organ transplantation provides the best treatment for end-stage organ failure, but significant sex-based disparities in transplant access exist. On June 25, 2021, a virtual multidisciplinary conference was convened to address sex-based disparities in transplantation. Common themes contributing to sex-based disparities were noted across kidney, liver, heart, and lung transplantation, specifically the existence of barriers to referral and wait listing for women, the pitfalls of using serum creatinine, the issue of donor/recipient size mismatch, approaches to frailty and a higher prevalence of allosensitization among women. In addition, actionable solutions to improve access to transplantation were identified, including alterations to the current allocation system, surgical interventions on donor organs, and the incorporation of objective frailty metrics into the evaluation process. Key knowledge gaps and high-priority areas for future investigation were also discussed.

Postoperative fibrinolytic resistance is associated with early allograft dysfunction in liver transplantation: A prospective observational study.

Perioperative dysfunction of the fibrinolytic system may play a role in adverse outcomes for liver transplant recipients. There is a paucity of data describing the potential impact of the postoperative fibrinolytic system on these outcomes. Our objective was to determine whether fibrinolysis resistance (FR), on postoperative day one (POD-1), was associated with early allograft dysfunction (EAD). We hypothesized that FR, quantified by tissue plasminogen activator thrombelastography, is associated with EAD. Tissue plasminogen activator thrombelastography was performed on POD-1 for 184 liver transplant recipients at a single institution. A tissue plasminogen activator thrombelastography clot lysis at 30 minutes of 0.0% was identified as the cutoff for FR on POD-1. EAD occurred in 32% of the total population. Fifty-nine percent (n=108) of patients were categorized with FR. The rate of EAD was 42% versus 17%, p <0.001 in patients with FR compared with those without, respectively. The association between FR and EAD risk was assessed using multivariable logistic regression after controlling for known risk factors. The odds of having EAD were 2.43 times (95% CI, 1.07-5.50, p =0.03) higher in recipients with FR [model C statistic: 0.76 (95% CI, 0.64-0.83, p <0.001]. An additive effect of receiving a donation after circulatory determination of death graft and having FR in the rate of EAD was observed. Finally, compared with those without FR, recipients with FR had significantly shorter graft survival time ( p =0.03). In conclusion, FR on POD-1 is associated with EAD and decreased graft survival time. Postoperative viscoelastic testing may provide clinical utility in identifying patients at risk for developing EAD, especially for recipients receiving donation after circulatory determination of death grafts.

Viscoelastic Management of Coagulopathy during the Perioperative Period of Liver Transplantation.

Viscoelastic testing (VET) in liver transplantation (LT) has been used since its origin, in combination with standard laboratory testing (SLT). There are only a few, small, randomized controlled trials that demonstrated a reduction in transfusion rates using VET to guide coagulation management. Retrospective analyses contrasting VET to SLT have demonstrated mixed results, with a recent concern for overtreatment and the increase in postoperative thrombotic events. An oversight of many studies evaluating VET in LT is a single protocol that does not address the different phases of surgery, in addition to pre- and postoperative management. Furthermore, the coagulation spectrum of patients entering and exiting the operating room is diverse, as these patients can have varying anatomic and physiologic risk factors for thrombosis. A single transfusion strategy for all is short sighted. VET in combination with SLT creates the opportunity for personalized resuscitation in surgery which can address the many challenges in LT where patients are at a paradoxical risk for both life-threatening bleeding and clotting. With emerging data on the role of rebalanced coagulation in cirrhosis and hypercoagulability following LT, there are numerous potential roles in VET management of LT that have been unaddressed.

An evaluation of the organ procurement and transplantation network's expanded post-transplant performance metrics.

On July 14, 2022, the Organ Procurement and Transplantation Network's (OPTN) Membership and Professional Standards Committee (MPSC) approved bylaws including two new post-transplant performance evaluation metrics, the 90-day (90D) and 1-year conditional on the 90-day (1YC90D) graft survival hazard ratio (HR). These metrics have replaced the previous 1-year (1Y) unconditional, post-transplant graft survival HR and are used to nationally rank and identify programs for MPSC review. The MPSC's policies have major implications for all transplant programs, providers, and patients across the United States. Herein we show two significant limitations with the new evaluation criteria, arbitrary censoring periods and interdependence in the new performance metrics. We have demonstrated a strong and consistent inverse correlation between the new evaluation metrics, thus proving a lack of independence. Moreover, these two evaluation criteria are interdependent even at nominal HRs. Thus, the 90D cohort can be used to accurately predict whether the 1YC90D is above or below a given HR threshold. This could alter practice behaviors and the timing of patient event reporting, which may result in many unintended consequences related to clinical practice. Here we provide the first evidence that this new evaluation system will lead to a significant increase in the number of programs flagged for MPSC review. When this occurs, the cost of operating a transplant program will increase without a clear demonstration of an increased accuracy in identifying problematic programs.

Low viscoelastic clot strength, platelet transfusions, and graft dysfunction are associated with persistent postoperative ascites following liver transplantation.

INTRODUCTION: High output, persistent ascites (PA) is a common complication following liver transplant (LT). Recent work has identified that platelets help maintain endothelial integrity and can decrease leakage in pathological states. We sought to assess the association of PA following LT with platelet count and platelet function. METHODS: Clot strength (MA) is a measure of platelet function and was quantified using thrombelastography (TEG). Total drain output following surgery was recorded in 24-h intervals during the same time frame as TEG. PA was considered >1 L on POD7, as that much output prohibits drain removal. RESULTS: 105 LT recipients with moderate or high volume preoperative ascites were prospectively enrolled. PA occurred in 28%. Platelet transfusions before and after surgery were associated with PA, in addition to POD5 TEG MA and POD5 MELD score. Patients with PA had a longer hospital length of stay and an increased rate of intraabdominal infections. CONCLUSION: Persistent ascites following liver transplant is relatively common and associated with platelet transfusions, low clot strength, and graft dysfunction.

Survival Benefit of Living-Donor Liver Transplant.

Importance: Despite the acceptance of living-donor liver transplant (LDLT) as a lifesaving procedure for end-stage liver disease, it remains underused in the United States. Quantification of lifetime survival benefit and the Model for End-stage Liver Disease incorporating sodium levels (MELD-Na) score range at which benefit outweighs risk in LDLT is necessary to demonstrate its safety and effectiveness. Objective: To assess the survival benefit, life-years saved, and the MELD-Na score at which that survival benefit was obtained for individuals who received an LDLT compared with that for individuals who remained on the wait list. Design, Setting, and Participants: This case-control study was a retrospective, secondary analysis of the Scientific Registry of Transplant Recipients database of 119 275 US liver transplant candidates and recipients from January 1, 2012, to September 2, 2021. Liver transplant candidates aged 18 years or older who were assigned to the wait list (N = 116 455) or received LDLT (N = 2820) were included. Patients listed for retransplant or multiorgan transplant and those with prior kidney or liver transplants were excluded. Exposures: Living-donor liver transplant vs remaining on the wait list. Main Outcomes and Measures: The primary outcome of this study was life-years saved from receiving an LDLT. Secondary outcomes included 1-year relative mortality and risk, time to equal risk, time to equal survival, and the MELD-Na score at which that survival benefit was obtained for individuals who received an LDLT compared with that for individuals who remained on the wait list. MELD-Na score ranges from 6 to 40 and is well correlated with short-term survival. Higher MELD-Na scores (>20) are associated with an increased risk of death. Results: The mean (SD) age of the 119 275 study participants was 55.1 (11.2) years, 63% were male, 0.9% were American Indian or Alaska Native, 4.3% were Asian, 8.2% were Black or African American, 15.8% were Hispanic or Latino, 0.2% were Native Hawaiian or Other Pacific Islander, and 70.2% were White. Mortality risk and survival models confirmed a significant survival benefit for patients receiving an LDLT who had a MELD-Na score of 11 or higher (adjusted hazard ratio, 0.64 [95% CI, 0.47-0.88]; P = .006). Living-donor liver transplant recipients gained an additional 13 to 17 life-years compared with patients who never received an LDLT. Conclusions and Relevance: An LDLT is associated with a substantial survival benefit to patients with end-stage liver disease even at MELD-Na scores as low as 11. The findings of this study suggest that the life-years gained are comparable to or greater than those conferred by any other lifesaving procedure or by a deceased-donor liver transplant. This study's findings challenge current perceptions regarding when LDLT survival benefit occurs.

The vexing triad of obesity, alcohol, and coagulopathy predicts the need for multiple operations in liver transplantation.

INTRODUCTION: One in four liver transplants (LT) require return to the operating room(R-OR) within 48 h of surgery. We hypothesize that donor, recipient, and intraoperative factors will predict R-OR. METHODS: LT recipients were enrolled in an observational study to measure coagulation with thrombelastography (TEG) were assessed with transplant recipient and donor variables for risk of R-OR. RESULTS: 160 recipients with a median age of 55 years and a MELD-Na of 22 were analyzed. R-OR occurred in 22%. Recipient BMI (p = 0.006), donor heavy alcohol use (p = 0.017), TEG MA (p = 0.013) during the anhepatic phase of surgery, TEG MA at anhepatic and 30-min after reperfusion (p < 0.05), and red blood cell transfusions (p < 0.001) were associated with R-OR. CONCLUSION: The vexing triad of recipient obesity, heavy donor alcohol use, and low TEG MA were associated with a high rate of R-OR. Strategies to reduce this sub-optimal combination of risk factors could reduce the frequency of unplanned re-operations.

Choledochoduodenostomy is associated with fewer post-transplant biliary complications compared to Roux-en-Y in primary sclerosing cholangitis patients.

BACKGROUND: For primary sclerosing cholangitis (PSC) patients undergoing liver transplantation (LT), a consensus regarding biliary reconstruction remains unresolved. Choledochoduodenostomy (CDD) represents an alternative to Roux-en-Y (RY) and duct-to-duct. We compared long-term post-transplant outcomes between CDD and RY. METHODS: This was a retrospective review of patients transplanted for PSC who received CDD or RY, with minimum 12-months follow-up. The primary outcome was need for biliary intervention, with either percutaneous transhepatic cholangiography (PTC) or endoscopic retrograde cholangiopancreatography (ERCP). Secondary outcomes included biliary stricture(s) and cholangitis admission(s). RESULTS: Ninety-three patients were transplanted between August 2004 and October 2019 (34 living donor [LDLT] and 59 deceased donor [DDLT]; 40 RY, 53 CDD). Need for either ERCP or PTC was similar (45.0% RY vs. 32.1% CDD, P = .203), though RY exhibited more anastomotic strictures (AS) (35.0% RY vs. 11.3% CDD, P = .006), which was also observed in LDLT subanalyses (50.0% LDLT/RY vs. 10.0% LDLT/CDD; P = .036). Cholangitis admissions were more frequent in RY versus CDD (37.5% vs. 15.1%, P = .013). CONCLUSIONS: CDD does not impart greater risk of biliary complications, and RY may have an incremental effect combined with LDLT status for predisposing to AS. CDD maintains standard endoscopic access without additional risk of biliary complications, thus should be considered when anatomically feasible.

Challenging the Traditional Paradigm of Supply and Demand in Pediatric Liver Transplantation Through Nondirected Living Donation: A Case Series.

A gap exists between the demand for pediatric liver transplantation and the supply of appropriate size-matched donors. We describe our center's experience with pediatric liver transplantation using anonymous nondirected living liver donors (ND-LLD). First-time pediatric liver transplant candidates listed at our center between January 2012 and June 2020 were retrospectively reviewed and categorized by donor graft type, and recipients of ND-LLD grafts were described. A total of 13 ND-LLD pediatric liver transplantations were performed, including 8 left lateral segments, 4 left lobes, and 1 right lobe. Of the ND-LLD recipients, 5 had no directed living donor evaluated, whereas the remaining 8 (62%) had all potential directed donors ruled out during the evaluation process. Recipient and graft survival were 100% during a median follow-up time of 445 (range, 70-986) days. Of ND-LLDs, 69% were previous living kidney donors, and 1 ND-LLD went on to donate a kidney after liver donation. Of the ND-LLDs, 46% were approved prior to the recipient being listed. Over time, the proportion of living donor transplants performed, specifically from ND-LLDs, increased, and the number of children on the waiting list decreased. The introduction of ND-LLDs to a pediatric liver transplant program can expand the benefit of living donor liver transplantation to children without a suitable directed living donor while achieving excellent outcomes for both the recipients and donors.