Maximizing utility of nondirected living liver donor grafts using machine learning.

Objective: There is an unmet need for optimizing hepatic allograft allocation from nondirected living liver donors (ND-LLD). Materials and method: Using OPTN living donor liver transplant (LDLT) data (1/1/2000-12/31/2019), we identified 6328 LDLTs (4621 right, 644 left, 1063 left-lateral grafts). Random forest survival models were constructed to predict 10-year graft survival for each of the 3 graft types. Results: Donor-to-recipient body surface area ratio was an important predictor in all 3 models. Other predictors in all 3 models were: malignant diagnosis, medical location at LDLT (inpatient/ICU), and moderate ascites. Biliary atresia was important in left and left-lateral graft models. Re-transplant was important in right graft models. C-index for 10-year graft survival predictions for the 3 models were: 0.70 (left-lateral); 0.63 (left); 0.61 (right). Similar C-indices were found for 1-, 3-, and 5-year graft survivals. Comparison of model predictions to actual 10-year graft survivals demonstrated that the predicted upper quartile survival group in each model had significantly better actual 10-year graft survival compared to the lower quartiles (p<0.005). Conclusion: When applied in clinical context, our models assist with the identification and stratification of potential recipients for hepatic grafts from ND-LLD based on predicted graft survivals, while accounting for complex donor-recipient interactions. These analyses highlight the unmet need for granular data collection and machine learning modeling to identify potential recipients who have the best predicted transplant outcomes with ND-LLD grafts.

Association of Body Surface Area With Access to Deceased Donor Liver Transplant and Novel Allocation Policies.

Importance: Small waitlist candidates are significantly less likely than larger candidates to receive a liver transplant. Objective: To investigate the magnitude of the size disparity and test potential policy solutions. Design, Setting, and Participants: A decision analytical model was generated to match liver transplant donors to waitlist candidates based on predefined body surface area (BSA) ratio limits (donor BSA divided by recipient BSA). Participants included adult deceased liver transplant donors and waitlist candidates in the Organ Procurement and Transplantation Network database from June 18, 2013, to March 20, 2020. Data were analyzed from January 2021 to September 2021. Exposures: Candidates were categorized into 6 groups according to BSA from smallest (group 1) to largest (group 6). Waitlist outcomes were examined. A match run was created for each donor under the current acuity circle liver allocation policy, and the proportion of candidates eligible for a liver based on BSA ratio was calculated. Novel allocation models were then tested. Main Outcomes and Measures: Time on the waitlist, assigned Model for End-Stage Liver Disease (MELD) score, and proportion of patients undergoing a transplant were compared by BSA group. Modeling under the current allocation policies was used to determine baseline access to transplant by group. Simulation of novel allocation policies was performed to examine change in access. Results: There were 41 341 donors (24 842 [60.1%] male and 16 499 [39.9%] female) and 84 201 waitlist candidates (53 724 [63.8%] male and 30 477 [36.2%] female) in the study. The median age of the donors was 42 years (IQR, 28-55) and waitlist candidates, 57 years (IQR, 50-63). Females were overrepresented in the 2 smallest BSA groups (7100 [84.0%] and 7922 [61.1%] in groups 1 and 2, respectively). For each increase in group number, waitlist time decreased (234 days [IQR, 48-700] for group 1 vs 179 days [IQR, 26-503] for group 6; P < .001) and the proportion of the group undergoing transplant likewise improved (3890 [46%] in group 1 vs 4932 [57%] in group 6; P < .001). The smallest 2 groups of candidates were disadvantaged under the current acuity circle allocation model, with 37% and 7.4% fewer livers allocated relative to their proportional representation on the waitlist. Allocation of the smallest 10% of donors (by BSA) to the smallest 15% of candidates overcame this disparity, as did performing split liver transplants. Conclusions and Relevance: In this study, liver waitlist candidates with the smallest BSAs had a disadvantage due to size. Prioritizing allocation of smaller liver donors to smaller candidates may help overcome this disparity.

State of pediatric liver transplantation in the United States and achieving zero wait list mortality with ideal outcomes: A statement from the Starzl Network for Excellence in Pediatric Transplant Surgeon's Working Group.

BACKGROUND: Liver transplant is a life-saving therapy that can restore quality life for several pediatric liver diseases. However, it is not available to all children who need one. Expertise in medical and surgical management is heterogeneous, and allocation policies are not optimally serving children. Technical variant grafts from both living and deceased donors are underutilized. METHODS: Several national efforts in pediatric liver transplant to improve access to and outcomes from liver transplant for children have been instituted and include adjustments to allocation policies, UNOS-sponsored collaborative improvement projects, and the emergence of national learning networks to study ongoing challenges in the field the Surgical Working group of the Starzl Network for Excellence in Pediatric Transplantation (SNEPT) discusses key issues and proposes potential solutions to eliminate the persistent wait list mortality that pediatric patients face. RESULTS: A discussion of the factors impacting pediatric patients' access to liver transplant is undertaken, along with a proposal of several measures to ensure equitable access to life-saving liver transplant. CONCLUSIONS: Pediatric liver transplant wait list mortality can and should be eliminated. Several measures, including collaborative efforts among centers, could be leveraged to acheive this goal.

Acute liver failure secondary to acute antibody mediated rejection after compatible liver transplant: A case report.

BACKGROUND: The liver has traditionally been regarded as resistant to antibody-mediated rejection (AMR). AMR in liver transplants is a field in its infancy compared to kidney and lung transplants. In our case we present a patient with alpha-1-antitrypsin disease who underwent ABO compatible liver transplant complicated by acute liver failure (ALF) with evidence of antibody mediated rejection on allograft biopsy and elevated serum donor-specific antibodies (DSA). This case highlights the need for further investigations and heightened awareness for timely diagnosis. CASE SUMMARY: A 56 year-old woman with alpha-1-antitrypsin disease underwent ABO compatible liver transplant from a deceased donor. The recipient MELD at the time of transplant was 28. The flow cytometric crossmatches were noted to be positive for T and B lymphocytes. The patient had an uneventful recovery postoperatively. Starting on postoperative day 5 the patient developed fevers, elevated liver function tests, distributive shock, renal failure, and hepatic encephalopathy. She went into ALF with evidence of antibody mediated rejection with portal inflammation, bile duct injury, endothelitis, and extensive centrizonal necrosis, and C4d staining on allograft biopsy and elevated DSA. Despite various interventions including plasmapheresis and immunomodulating therapy, she continued to deteriorate. She was relisted and successfully underwent liver retransplantation. CONCLUSION: This very rare case highlights AMR as the cause of ALF following liver transplant requiring retransplantation.

Building a Utility-based Liver Allocation Model in Preparation for Continuous Distribution.

BACKGROUND: The current model for end-stage liver disease-based liver allocation system in the United States prioritizes sickest patients first at the expense of long-term graft survival. In a continuous distribution model, a measure of posttransplant survival will also be included. We aimed to use mathematical optimization to match donors and recipients based on quality to examine the potential impact of an allocation system designed to maximize long-term graft survival. METHODS: Cox proportional hazard models using organ procurement and transplantation network data from 2008 to 2012 were used to place donors and waitlist candidates into 5 groups of increasing risk for graft loss (1-lowest to 5-highest). A mixed integer programming optimization model was then used to generate allocation rules that maximized graft survival at 5 and 8 y. RESULTS: Allocation based on mathematical optimization improved 5-y survival by 7.5% (78.2% versus 70.7% in historic cohort) avoiding 2271 graft losses, and 8-y survival by 9% (71.8% versus 62.8%) avoiding 2725 graft losses. Long-term graft survival for recipients within a quality group is highly dependent on donor quality. All candidates in groups 1 and 2 and 43% of group 3 were transplanted, whereas none of the candidates in groups 4 and 5 were transplanted. CONCLUSIONS: Long-term graft survival can be improved using a model that allocates livers based on both donor and recipient quality, and the interaction between donor and recipient quality is an important predictor of graft survival. Considerations for incorporation into a continuous distribution model are discussed.

Acute Graft-Versus-Host Disease After Orthotopic Liver Transplantation: Predicting This Rare Complication Using Machine Learning.

Acute graft-versus-host disease (GVHD) is a rare complication after orthotopic liver transplantation (OLT) that carries high mortality. We hypothesized that machine-learning algorithms to predict rare events would identify patients at high risk for developing GVHD. To develop a predictive model, we retrospectively evaluated the clinical features of 1938 donor-recipient pairs at the time they underwent OLT at our center; 19 (1.0%) of these recipients developed GVHD. This population was divided into training (70%) and test (30%) sets. A total of 7 machine-learning classification algorithms were built based on the training data set to identify patients at high risk for GVHD. The C5.0, heterogeneous ensemble, and generalized gradient boosting machine (GGBM) algorithms predicted that 21% to 28% of the recipients in the test data set were at high risk for developing GVHD, with an area under the receiver operating characteristic curve (AUROC) of 0.83 to 0.86. The 7 algorithms were then evaluated in a validation data set of 75 more recent donor-recipient pairs who underwent OLT at our center; 2 of these recipients developed GVHD. The logistic regression, heterogeneous ensemble, and GGBM algorithms predicted that 9% to 11% of the validation recipients were at high risk for developing GVHD, with an AUROC of 0.93 to 0.96 that included the 2 recipients who developed GVHD. In conclusion, we present a practical model that can identify patients at high risk for GVHD who may warrant additional monitoring with peripheral blood chimerism testing.

Donor-Recipient BSA Matching Is Prognostically Significant in Solitary and En Bloc Kidney Transplantation From Pediatric Circulatory Death Donors.

BACKGROUND: As the rate of early postoperative complications decline after transplant with pediatric donation after circulatory death (DCD) kidneys, attention has shifted to the long-term consequences of donor-recipient (D-R) size disparity given the pernicious systemic effects of inadequate functional nephron mass. METHODS: We conducted a retrospective cohort study using Organ Procurement and Transplantation Network data for all adult (aged ≥18 y) recipients of pediatric (aged 0-17 y) DCD kidneys in the United States from January 1, 2004 to March 10, 2020. RESULTS: DCD pediatric allografts transplanted between D-R pairs with a body surface area (BSA) ratio of 0.10-0.70 carried an increased risk of all-cause graft failure (relative risk [RR], 1.36; 95% confidence interval [CI], 1.10-1.69) and patient death (RR, 1.32; 95% CI, 1.01-1.73) when compared with pairings with a ratio of >0.91. Conversely, similar graft and patient survivals were demonstrated among the >0.70-0.91 and >0.91 cohorts. Furthermore, we found no difference in death-censored graft survival between all groups. Survival analysis revealed improved 10-y patient survival in recipients of en bloc allografts (P = 0.02) compared with recipients of single kidneys with D-R BSA ratios of 0.10-0.70. A similar survival advantage was demonstrated in recipients of solitary allografts with D-R BSA ratios >0.70 compared with the 0.10-0.70 cohort (P = 0.02). CONCLUSIONS: Inferior patient survival is likely associated with systemic sequelae of insufficient renal functional capacity in size-disparate DCD kidney recipients, which can be overcome by appropriate BSA matching or en bloc transplantation. We therefore suggest that in DCD kidney transplantation, D-R BSA ratios of 0.10-0.70 serve as criteria for en bloc allocation or alternative recipient selection to optimize the D-R BSA ratio to >0.70.

Donor CMV Reactivation as a Novel Risk Factor for CMV Replication in Seropositive Liver Transplant Recipients.

Risk factors for cytomegalovirus (CMV) viremia in CMV seropositive liver transplant recipients are incompletely defined and have focused primarily on recipient factors. We hypothesized that active CMV replication (CMV viremia) in seropositive donors might increase the risk for CMV viremia in recipients, as reported for other viruses in organ transplantation. METHODS: From January 3, 2009, to July 27, 2015, stored plasma from consecutive CMV seropositive liver donors was retrospectively tested for CMV viremia by PCR. From April 20, 2012, to July 27, 2015, CMV seropositive recipients of a liver transplant from the donors during this time period received preemptive therapy for CMV prevention (valganciclovir therapy for CMV viremia ≥250 IU/mL). The association of recipient factors and donor CMV viremia with viremia in recipients was assessed. RESULTS: Among 317 CMV-seropositive donors, CMV viremia was detected in 11 (3.5%) and was associated with longer time to collection after admission and bacteremia. Among 115 CMV-seropositive liver recipients, 5 (4.3%) received an organ from a donor with CMV viremia. Donor CMV viremia was independently associated with higher incidence of CMV viremia ≥250 IU/mL and shorter time to onset of CMV viremia ≥250 IU/mL in recipients: 4 (80%) versus 26 (23.6%), P = 0.02, and hazard ratio 8.55 (2.60-28.10), P = 0.003, respectively. CONCLUSION: Donor CMV reactivation is associated with CMV viremia in seropositive orthotopic liver transplant recipients receiving preemptive therapy, identifying a novel potential risk factor for CMV infection in seropositive liver transplant recipients. Future studies should independently validate and assess these findings in other organ transplant settings.

Do funding sources influence long-term patient survival in pediatric liver transplantation?

BACKGROUND: Socioeconomic status has been associated with inferior outcomes after multiple surgical procedures, but has not been well studied with respect to pediatric liver transplantation. This study evaluated the impact of insurance status (as a proxy for socioeconomic status) on patient and allograft survival in pediatric first-time liver transplant recipients. METHODS: Our retrospective analysis of the UNOS data base from January 2002 through September 2017 revealed 6997 pediatric patients undergoing first-time isolated liver transplantation. A mixed Cox proportional hazards model adjusted for donor, recipient, and program characteristics determined the RR of insurance status on allograft and patient survival. All results were considered significant at P < .05. All statistical results were obtained using R version 3.5.1 and coxme version 2.2-10. RESULTS: Medicaid status had a significant negative impact on long-term survival after controlling for multiple covariates. Pediatric patients undergoing first-time isolated liver transplantation with Medicaid insurance had a RR of 1.42 [confidence interval: 1.18-1.60] of post-transplant death. CONCLUSION: Pediatric patients undergoing first-time isolated liver transplantation have multiple risk factors that may impact long-term survival. Having Medicaid insurance almost doubles the chances of dying post-liver transplant. This patient population may require more global support post-transplant to improve long-term survival.

Machine Perfusion Decreases Delayed Graft Function in Donor Grafts With High Kidney Donor Profile Index.

OBJECTIVES: Kidney transplant is the optimal treatment for patients with end-stage renal disease. The effects of using machine perfusion for donor kidneys with varying Kidney Donor Profile Index scores are unknown. We sought to assess the impact of machine perfusion on the incidence of delayed graft function in different score groups of kidney grafts classified with the Kidney Donor Profile Index. MATERIALS AND METHODS: We conducted a retrospective analysis from January 2008 through September 2017 of adult recipients (≥ 18 years old) undergoing kidney-only transplant from deceased donors. All transplant recipients were followed until December 2017. Recipients who received multiorgan transplants or kidneys from living donors were excluded from our analyses. Recipients were divided according to 5 donor categories of Kidney Donor Profile Index scores (0-20, 21-40, 41-60, 61-80, and 81-100). Logistic regression analysis was performed for each score group to determine the effects of machine perfusion on development of delayed graft function within each score group. RESULTS: Our study included 101222 recipients who met the inclusion criteria. Multivariate analysis revealed that machine perfusion was associated with significantly decreased development of delayed graft function only in donors with high-risk profiles: the 61 to 80 score group (odds ratio = 0.83; confidence interval, 0.78-0.89) and the 81 to 100 score group (odds ratio = 0.72; confidence interval, 0.67-0.78). CONCLUSIONS: Machine perfusion is beneficial in reducing delayed graft function only in donor kidneys with a higher risk profile.

Use of SARS-CoV-2-infected deceased organ donors: Should we always "just say no?"

In the context of a rapidly evolving pandemic, multiple organizations have released guidelines stating that all organs from potential deceased donors with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection should be deferred, including from otherwise medically eligible donors found to have mild or asymptomatic SARS-CoV-2 discovered on routine donor screening. In this article, we critically examine the available data on the risk of transmission of SARS-CoV-2 through organ transplantation. The isolation of SARS-CoV-2 from nonlung clinical specimens, the detection of SARS-CoV-2 in autopsy specimens, previous experience with the related coronaviruses SARS-CoV and MERS-CoV, and the vast experience with other common RNA respiratory viruses are all addressed. Taken together, these data provide little evidence to suggest the presence of intact transmissible SARS-CoV in organs that can potentially be transplanted, specifically liver and heart. Other considerations including ethical, financial, societal, and logistical concerns are also addressed. We conclude that, for selected patients with high waitlist mortality, transplant programs should consider accepting heart or liver transplants from deceased donors with SARS-CoV-2 infection.

Livers From Pediatric Donation After Circulatory Death Donors Represent a Viable and Underutilized Source of Allograft.

Despite increased numbers of donation after circulatory death (DCD) donors, pediatric DCD livers are underused. To investigate possible reasons for this discrepancy, we conducted a retrospective cohort study using 2 data sets from the Organ Procurement and Transplantation Network for all deceased liver donors and for all recipients of DCD liver transplants from March 8, 1993, to June 30, 2018. Pediatric (0-12 years) and adolescent (13-17 years) DCD donors were compared with those aged 18-40 years. We found that pediatric DCD allografts are recovered at a significantly lower rate than from 18-to-40-year-old donors (27.3% versus 56.3%; P < 0.001). However, once recovered, these organs are transplanted at a similar rate to those from the 18-to-40-year-old donor cohort (74.7% versus 74.2%). Significantly more pediatric DCD livers (odds ratio [OR], 3.75; confidence interval [CI], 3.14-4.47) were not recovered compared with adult organs, which were most commonly not recovered due to organ quality (10.2% versus 7.1%; P < 0.001). The 10-year relative risks (RRs) for graft failure and patient death were similar between pediatric and adult DCD donors, with adolescent DCD livers demonstrating improved outcomes. DCD livers transplanted into pediatric donors were protective against graft failure (RR, 0.46; 95% confidence interval [CI], 0.21-0.99) and patient death (RR, 0.16; 95% CI, 0.04-0.69). In conclusion, despite lower rates of recovery, pediatric DCD livers represent a viable organ source for certain adults and children.

The impact of public health service increased risk donors in pediatric liver transplantation.

Many transplant programs are reluctant to use organs from deceased donors designated as "PHS increased risk" due to misconceptions regarding the quality of those organs. This study evaluated the impact of PHS increased risk donors on patient and allograft survival in pediatric patients undergoing liver transplantation. Retrospective analysis of the UNOS database from January 2005 through September 2017 revealed 5615 pediatric patients who underwent isolated liver transplantation; of these, 5057 patients received primary isolated liver transplants and 558 patients received isolated liver retransplants. PHS increased risk organs were used in 6.7% and 5.4% of the children receiving primary isolated and retransplant livers, respectively. Cox proportional hazards models adjusted for donor and recipient characteristics determined the relative risk of PHS status on allograft and patient survival. Sicker children (those in ICU [P < .001] and on life support [P = .04]) were more likely to receive PHS increased risk donor organs. There were no differences in overall patient (P = .61) or allograft (P = .68) survival between pediatric patients receiving PHS positive vs PHS negative deceased donor organs; adjusted models also demonstrated no statistically significant differences in patient or allograft survival. Excellent patient and allograft survival can be accomplished with PHS increased risk organs.

Hyperammonemia syndrome due to Ureaplasma infection after liver-kidney transplant.

Hyperammonemia syndrome, with high levels of ammonia and neurologic dysfunction, is a syndrome with historically high mortality that may occur after solid organ transplantation. Recently, this has been associated with infection due to Ureaplasma, mostly following lung transplantation. We describe the first case of hyperammonemia syndrome due to Ureaplasma infection after liver-kidney transplantation. Our patient rapidly recovered after specific antibiotic treatment. It is important to consider these infections in the differential diagnosis for encephalopathy post-transplant, as these organisms often do not grow using routine culture methods and polymerase chain reaction testing is typically required for their detection. This is particularly critical after liver transplantation, where a number of other etiologies may be considered as a cause of hyperammonemia syndrome.

Adults transplanted as children as retransplant candidates: Analysis of outcomes support optimism in a population mislabeled as high risk.

Adult liver transplant programs have heretofore been hesitant to perform liver retransplantation in adult patients who underwent primary liver transplantation as a child (P_A). Areas of concern include: (a) potential disruption in care when transferring from a pediatric to an adult transplant center; (b) generally inferior outcomes of retransplantation; (c) reputation of young adults for non-adherence to post-transplant regimen; and (d) potential higher work effort for equivalent outcomes. To examine these concerns, we reviewed data on all US liver adult retransplants from 10/01/1987 to 9/30/2017. We propensity matched the P_A patients to patients who received both primary and retransplantation as adults (A_A), with ≥550 days between transplants. A mixed Cox proportional hazards model with program size and time period of transplantation as random variables revealed that retransplantation of P_A patients produced no significantly different graft survival or patient survival rates than retransplantation of the matched A_A patients. Therefore, inferior rates of liver retransplantation in these patients and concerns about continuity of care in changing transplant programs are not as believed in the wider liver transplant community. In conclusion, liver transplant centers should be optimistic about retransplanting adults who received their primary transplants as children.

New Evidence Supporting Increased Use of Split Liver Transplantation.

BACKGROUND: Young children and small-statured candidates are dying on liver candidate waitlists. The Organ Procurement and Transplantation Network and United Network for Organ Sharing have proposed a split liver (SL) variance encouraging transplant programs to split more livers to aid these smaller statured candidates. METHODS: We evaluated the US experience of splitting donor livers during 2002-2016. The results of our analysis provide new evidence to support this variance. RESULTS: During 2002-2016, SL grafts from 935 donors were transplanted into 1870 recipients. Controlling for recipient factors and using time period and program identification as random variables, a multivariable mixed Cox proportional hazards model for graft failure revealed that donor aged 3-10 years had a relative risk (RR) of 3.94 (2.86-5.44), and donor aged >30 years had a RR of 1.94 (1.59-2.35) for graft failure. Donor-to-recipient body surface area ratio <0.90 had a RR of 1.40 (1.13-1.75). Programs with experience transplanting <23 SLs had a RR of 1.43 (1.21-1.75). The same program transplanting both split segments had a RR of 1.38 (1.20-1.59). CONCLUSIONS: Splitting protocols based on these findings could improve graft survival after SL transplantation, which would encourage programs to opt into splitting more livers. The new protocols may consider donor age restrictions, necessary program experience, donor with body surface area appropriate for recipient, and improved logistical factors to share segments between transplant programs. The result would likely be a drastic reduction in liver waitlist deaths for young children and small-statured candidates.

Living Donation Versus Donation After Circulatory Death Liver Transplantation for Low Model for End-Stage Liver Disease Recipients.

In this era of organ scarcity, living donor liver transplantation (LDLT) is an alternative to using deceased donors, and in Western countries, it is more often used for recipients with low Model for End-Stage Liver Disease (MELD) scores. We sought to compare the patient survival and graft survival between recipients of liver transplantation from living donors and donation after circulatory death (DCD) donors in patients with low MELD scores. This is a retrospective cohort analysis of adult liver transplant recipients with a laboratory MELD of ≤20 who underwent transplantation between January 1, 2003 and March 31, 2016. Recipients were categorized by donor graft type (DCD or LDLT), and recipient and donor characteristics were compared. Ten-year patient and graft survival curves were calculated using Kaplan-Meier analyses, and a mixed-effects model was performed to determine the contributions of recipient, donor, and center variables on patient and graft survival. There were 36,705 liver transplants performed: 32,255 (87.9%) from DBD donors, 2166 (5.9%) from DCD donors, and 2284 (6.2%) from living donors. In the mixed-effects model, DCD status was associated with a higher risk of graft failure (relative risk [RR], 1.27; 95% confidence interval [CI], 1.16-1.38) but not worse patient survival (RR, 1.27; 95% CI, 0.96-1.67). Lower DCD center experience was associated with a 1.21 higher risk of patient death (95% CI, 1.17-1.25) and a 1.13 higher risk of graft failure (95% CI, 1.12-1.15). LDLT center experience was also predictive of patient survival (RR, 1.03; 95% CI, 1.02-1.03) and graft failure (RR, 1.05; 95% CI, 1.05-1.06). In conclusion, for liver transplant recipients with low laboratory MELD, LDLT offers better graft survival and a tendency to better patient survival than DCD donors.