Implications of drug intoxication on donor utilization and outcomes in liver transplantation.

INTRODUCTION: This study evaluates the implications of drug intoxication (DI) on donor utilization and outcomes in liver transplantation (LT). METHODS: The UNOS STAR database was evaluated for all potential donors and adult, first-time, whole LT between 2005 and 2019. Logistic regression analyses evaluated liver utilization; proportional hazards modeling assessed risk of 1-year graft loss. RESULTS: A total of 132 783 potential donors (10 205, 7.7% from DI), and 90 612 adult LT were identified (7490, 8.3% from DI). DI donors had median age 32 years (IQR 26-40 years, p < .001), were 42.6% female (n = 4346), and 15.5% were DCD donors (n = 1583). Utilization of DI donors changed over time, such that by 2015-2019 they were the most likely donor cause of death (COD) to be utilized. Among LT recipients, there were insignificant differences (<2% variance) in age, gender, ethnicity, and etiology of liver disease according to donor COD. Recipients with MELD scores >30 more frequently received grafts from donors with trauma (23.8%) and DI (21.8%) versus cardiovascular (20.0%) and CVA/stroke (19.9%, p < .001). Among DBD donors, DI-COD was associated with superior 1-year graft survival compared to donors from trauma (HR 1.172, 95% CI 1.057-1.300) and CVA/stroke (HR 1.404, 95% CI 1.264-1.561, p < .001). Donor COD was not significantly associated with 1-year graft loss among DCD donors. CONCLUSIONS: There is an increased likelihood of donor utilization when COD is drug overdose and an increased likelihood of 1-year graft survival compared to donors from trauma, CVA/stroke, and other COD.

The Promise of Complement Therapeutics in Solid Organ Transplantation.

Transplantation is the ideal therapy for end-stage organ failure, but outcomes for all transplant organs are suboptimal, underscoring the need to develop novel approaches to improve graft survival and function. The complement system, traditionally considered a component of innate immunity, is now known to broadly control inflammation and crucially contribute to induction and function of adaptive T-cell and B-cell immune responses, including those induced by alloantigens. Interest of pharmaceutical industries in complement therapeutics for nontransplant indications and the understanding that the complement system contributes to solid organ transplantation injury through multiple mechanisms raise the possibility that targeting specific complement components could improve transplant outcomes and patient health. Here, we provide an overview of complement biology and review the roles and mechanisms through which the complement system is pathogenically linked to solid organ transplant injury. We then discuss how this knowledge has been translated into novel therapeutic strategies to improve organ transplant outcomes and identify areas for future investigation. Although the clinical application of complement-targeted therapies in transplantation remains in its infancy, the increasing availability of new agents in this arena provides a rich environment for potentially transformative translational transplant research.

Incidence and Outcomes of Simultaneous Thoracoabdominal Triple Organ Transplantation in the United States.

BACKGROUND: This study aims to evaluate patient outcomes of simultaneous triple organ transplants, which may provide insight into optimal donor allocation while maximizing recipient benefit. METHODS: Triple organ transplants and their corollary dual organ transplants were identified using the United Network for Organ Sharing database. Triple organ transplants evaluated included heart-lung-kidney (n = 12) and heart-liver-kidney (n = 37). Heart-lung-kidney recipients were compared with heart-lung (n = 325), lung-kidney (n = 91), and heart-kidney (n = 2022) groups. Heart-liver-kidney recipients were compared with heart-liver (n = 451), liver-kidney (n = 10422), and heart-kidney (n = 2517) recipients. Patient survival outcomes were calculated using the Kaplan-Meier method and compared using log-rank tests. RESULTS: Patients undergoing triple organ transplants showed similar 10-year survival as their corresponding dual organ transplant cohorts. Patient survival estimate at 10 years for the heart-lung-kidney group was 45%, with no statistically significant difference in survival when compared with dual organ groups (P = .16). Survival estimates at 10 years for the heart-liver-kidney group was 49%, with no statistically significant difference in survival when compared with dual organ groups (P = .06). CONCLUSION: Despite the surgical burden of adding a third organ transplant, heart-liver-kidney and heart-lung-kidney have similar survival outcomes to dual organ equivalents and represent a reasonable allocation option in well-selected patients.

Preserved 2-y Liver Transplant Outcomes Following Simultaneous Thoracoabdominal DCD Organ Procurement Despite Effects on Liver Utilization Rate.

Background: Current techniques for donation after circulatory determination of death (DCD) heart procurement, through either direct procurement and machine perfusion or thoracoabdominal normothermic regional perfusion (NRP), have demonstrated excellent heart transplant outcomes. However, the impact of thoracoabdominal DCD (TA-DCD) heart procurement on liver allograft outcomes and utilization is poorly understood. Methods: One hundred sixty simultaneous heart and liver DCD donors were identified using the United Network for Organ Sharing/Organ Procurement and Transplantation Network database between December 2019 and July 2021. Liver outcomes from TA-DCD donors were stratified by heart procurement technique and evaluated for organ utilization, graft survival, and patient survival. Results were compared with abdominal-only DCD (A-DCD; n = 1332) and donation after brain death (DBD; n = 12 891) liver transplants during the study interval. Kaplan-Meier methods with log-rank testing were used to evaluate patient and graft survival. Results: One hundred thirty-three of 160 livers procured from TA-DCD donors proceeded to transplant. TA-DCD donors were younger (mean 28.26 y; P < 0.0001) with lower body mass index (mean 26.61; P < 0.0001) than A-DCD and DBD donors. TA-DCD livers had equivalent patient survival ( P = 0.893) and superior graft survival (P = 0.009) compared with A-DCD. TA-DCD livers had higher rates of organ discard for long warm ischemia time (37.0%) than A-DCD (20.5%) and DBD (0.5%; P < 0.0001), with direct procurement and machine perfusion procurements leading to a higher discard rate (18.5%) than NRP procurements (7.4%). Conclusions: Liver transplants after TA-DCD donation demonstrated equivalent patient outcomes and excellent graft outcomes. NRP procurements resulted in the lowest rate of organ discard after DCD donation and may represent an optimal strategy to maximize organ utilization.

Drug Overdose and Cardiovascular Deaths Among Deceased Organ Donors: Implications for Donor Utilization and Data Reporting.

BACKGROUND The present study evaluated expanded cause of death (COD) definitions and its implications on donor utilization for solid organ transplantation. MATERIAL AND METHODS The OPTN Standard Transplant and Research file was queried for potential donors between 2005 and 2019. Donor- and organ-specific utilization were evaluated. Expanded donor COD were identified: trauma, cardiovascular (CV), cerebrovascular accident (CVA) or stroke, drug intoxication (DI), anoxia not otherwise specified (NOS), and other. Descriptive analyses and multivariable logistic regression analyses for donor utilization were performed. RESULTS Among 132 783 potential donors identified, the most common COD was CVA/Stroke (n=44 707, 33.7%), followed by trauma (n=43 356, 32.7%), CV (n=20 053, 15.1%), anoxia-NOS (n=12 261, 9.2%), DI (n=10 205, 7.7%), and other causes (n=2201, 1.7%). Significant differences between CV, DI, and anoxia-NOS groups existed for donor age, sex, ethnicity, body mass index, and comorbidities. Donors from trauma had the highest unadjusted utilization rate (97.2%) while CV donors had the lowest (90.1%). Multivariable analysis of brain-dead donors (DBD) showed that compared to trauma, donors from DI had higher likelihood of utilization (odds ratio 1.217, 95% 1.025-1.446) while CV donors were lower (OR 0.717, 95% CI 0.642-0.800, P<0.001). Among donation after circulatory death (DCD) donors, there was decreased utilization compared to trauma for both CV (OR 0.607, 95% CI 0.523-0.705) and DI (OR 0.754, 95% CI 0.603-0.914, P<0.001). CONCLUSIONS Current COD definitions should be expanded to capture significant differences in the donor population. DI donors are the fastest growing cohort and the most likely utilized DBD donors, while trauma donors remain the most likely utilized DCD donors.

A Retrospective Evaluation of Changing Health Characteristics Amongst Deceased Organ Donors in the United States.

BACKGROUND: The availability of suitable donor organs remains a limiting factor to performing life-saving transplant operations. This study evaluates changes in the health of the donor population and its influence on organ use in the United States. METHODS: A retrospective analysis was performed using the OPTN STAR data file from 2005 to 2019. Three donor eras were defined: 1) 2005 to 2009, 2) 2010 to 2014, and 3) 2015 to 2019. The primary outcome was donor use, defined as transplantation of at least one solid organ. Descriptive analyses were performed, and associations of donor use were examined with multivariable logistic regression models. P values <.01 were considered significant. RESULTS: The cohort included 132,783 potential donors of which 124,729 (93.9%) were used for transplantation. Donor median age was 42 years (interquartile range 26-54), 53,566 (40.3%) were female, and 88,209 (66.4%) were White, 21,834 (16.4%) were black, and 18,509 (13.9%) were Hispanic. Compared with donors from Eras 1 and 2, donors in Era 3 were younger (P < .001), had higher body mass index (BMI) (P < .001), increased rates of diabetes mellitus (DM) (P < .001), hepatitis C virus (HCV) positivity (P < .001) and more comorbidities (P < .001). Multivariable modeling found donor BMI, DM, hypertension, and HCV status as health factors significantly associated with donor use. Compared with Era 1, there was increased use in Era 3 of donors with BMI ≥30 kg/m2, DM, hypertension, HCV-positive status, and donors with ≥3 comorbidities. CONCLUSIONS: Despite an increasing prevalence of chronic health problems in the donor population, donors with multiple comorbid conditions are more likely to be used for transplantation in recent years.

Use of a donor-derived cell-free DNA assay to monitor treatment response in pediatric renal transplant recipients with allograft rejection.

BACKGROUND: Detection of donor-derived cell-free DNA (dd-cfDNA) reliably identifies allograft rejection in pediatric and adult kidney transplant (KT) recipients. Here, we evaluate the utility of dd-cfDNA for monitoring response to treatment among pediatric renal transplant recipients suffering graft rejection. METHODS: 58 pediatric transplant recipients were enrolled between April 2018 and March 2020 and underwent initial dd-cfDNA testing to monitor for rejection. Allograft biopsy was performed for dd-cfDNA scores >1.0%. Patients with histologically proven rejection formed the study cohort and underwent appropriate treatment. Results of dd-cfDNA, serum creatinine (SCr), biopsy findings, and treatment outcomes were evaluated. Standard statistical analyses were applied. RESULTS: Nineteen of 58 (31%) patients had dd-cfDNA score >1.0%, of which 18 (94.7%) had biopsy-proven rejection. Median dd-cfDNA value was 1.90% (interquartile range 1.43%-3.23%), and biopsy results showed 11 patients (61.1%) with antibody-mediated rejection (AMR), 2 patients (11.1%) with T-cell mediated rejection (TCMR), and 5 patients (27.7%) with mixed AMR/TCMR. SCr at time of biopsy was 1.28 ± 1.09 mg/dl. Following treatment, dd-cfDNA scores decreased for all types of rejection but still remained >1.0% in both AMR (1.50% [0.90%-3.10%]) and mixed (1.40% [0.95%-4.15%]) groups. Repeat dd-cfDNA values were <1.0% for patients with TCMR (0.20%-0.28%). SCr showed minimal change from pre-treatment levels regardless of rejection subtype. CONCLUSIONS: Patients with TCMR may be reliably followed by dd-cfDNA; however, it remains unclear whether persistently elevated dd-cfDNA levels in AMR is a reflection of ongoing subclinical rejection or an inherent limitation of the assay's utility.

A Clinical Tool to Guide Selection and Utilization of Marginal Donor Livers With Graft Steatosis in Liver Transplantation.

BACKGROUND: Donor liver biopsy (DLBx) in liver transplantation provides information on allograft quality; however, predicting outcomes from these allografts remains difficult. METHODS: Between 2006 and 2015, 16 691 transplants with DLBx were identified from the Standard Transplant Analysis and Research database. Cox proportional hazard regression analyses identified donor and recipient characteristics associated with 30-d, 90-d, 1-y, and 3-y graft survival. A composite model, the Liver Transplant After Biopsy (LTAB) score, was created. The Mini-LTAB was then derived consisting of only donor age, macrosteatosis on DLBx, recipient model for end-stage liver disease score, and cold ischemic time. Risk groups were identified for each score and graft survival was evaluated. P values <0.05 were considered significant. RESULTS: The LTAB model used 14 variables and 5 risk groups and identified low-, mild-, moderate-, high-, and severe-risk groups. Compared with moderate-risk recipients, severe-risk recipients had increased risk of graft loss at 30 d (hazard ratio, 3.270; 95% confidence interval, 2.568-4.120) and at 1 y (2.258; 1.928-2.544). The Mini-LTAB model identified low-, moderate-, and high-risk groups. Graft survival in Mini-LTAB high-risk transplants was significantly lower than moderate- or low-risk transplants at all time points. CONCLUSIONS: The LTAB and Mini-LTAB scores represent guiding principles and provide clinically useful tools for the successful selection and utilization of marginal allografts in liver transplantation.

Clinical considerations in the management of non-alcoholic steatohepatitis cirrhosis pre- and post-transplant: A multi-system challenge.

Non-alcoholic steatohepatitis (NASH) is the most common chronic liver disease worldwide, and the fastest growing indication for liver transplantation in the United States. NASH is now the leading etiology for liver transplantation in women, the second leading indication for men, and the most common cause amongst recipients aged 65 years and older. Patients with end-stage liver disease related to NASH represent a unique and challenging patient population due the high incidence of associated comorbid diseases, including obesity, type 2 diabetes (T2D), and hypertension. These challenges manifest in the pre-liver transplantation period with increased waitlist times and waitlist mortality. Furthermore, these patients carry considerable risk of morbidity and mortality both before after liver transplantation, with high rates of T2D, cardiovascular disease, chronic kidney disease, poor nutrition, and disease recurrence. Successful transplantation for these patients requires identification and management of their comorbidities in the face of liver failure. Multidisciplinary evaluations include a thorough pre-transplant workup with a complete cardiac evaluation, control of diabetes, nutritional support, and even, potentially, consultation with a bariatric surgeon. This article provides a comprehensive review of the conditions and challenges facing patients with NASH cirrhosis undergoing liver transplantation and provides recommendations for evaluation and management to optimize them before liver transplantation to produce successful outcomes.

Higher thresholds for the utilization of steatotic allografts in liver transplantation: Analysis from a U.S. national database.

BACKGROUND: Historically, liver allografts with >30% macrosteatosis (MaS) on donor biopsy have been associated with early allograft dysfunction and worse graft survival; however, successful outcomes have been reported in small cohorts. This study proposes an elevated MaS threshold for organ utilization without detriment to graft survival. METHODS: The UNOS Standard Transplant Analysis and Research database was evaluated for transplants between 2006-2015. Graft survival up to 1-year was evaluated by Kaplan-Meier (KM) survival analyses, and by univariate and multivariable logistic regression analyses, including donor and recipient characteristics. Odds ratios (OR) with 95% confidence intervals (CI) for risk of graft loss are reported. RESULTS: Thirty-day risk of graft loss was increased with MaS as low as 10-19% (OR [95% CI] 1.301 [1.055-1.605], p<0.0001) and peaked with MaS 50-59% (2.921 [1.672-5.103]). At 1-year, risk of graft loss remained elevated with MaS 40-49% (1.465 [1.002-2.142]) and MaS 50-59% (1.978 [1.281-3.056], p = 0.0224). Multivariable models were created for Lower and Higher MELD recipients and MaS cutoffs were established. In Lower MELD recipients, organs with ≥50% MaS had increased risk of graft loss at 30 days (2.451 [1.541-3.897], p = 0.0008) and 1-year post-transplant (1.720 [1.224-2.418], p = 0.0125). Higher MELD recipients had increased risk of graft loss at 30 days with allografts showing MaS ≥40% (4.204 [1.440-5.076], p = 0.0016). At 1-year the risk remained increased, but MaS was not significant predictor of graft loss.048 [1.131-3.710], p = 0.0616). In both MELD cohorts, organs with MaS levels below threshold had similar survival to those transplanted without a donor biopsy. CONCLUSIONS: In conjunction with recipient selection, organs with MaS up to 50% may be safely used without detriment to outcomes.

Regional Variation in Utilization and Outcomes of Liver Allografts From Donors With High Body Mass Index and Graft Macrosteatosis: A Role for Liver Biopsy.

BACKGROUND: Obesity, defined as a high body mass index (hBMI) of 30 kg/m or greater, is a growing epidemic worldwide and is associated with multiple comorbidities. High BMI individuals account for an increasing portion of potential liver donors. Here we evaluate trends in the utilization and outcomes of hBMI donors on a national and regional level and the potential role of liver biopsy in donor evaluation. METHODS: United Network for Organ Sharing Standard Transplant Analysis and Research database was evaluated for deceased donor liver transplants between 2006 and 2016 across 11 Organ Procurement and Transplantation Network regions. High BMI donors were compared with lower BMI counterparts and evaluated for biopsy rates, utilization rates and allograft outcomes. Univariate and multivariable analyses were performed. RESULTS: Seventy-seven thousand fifty potential donors were identified and 60 200 transplants were evaluated. Utilization rates for hBMI donors were 66.1% versus 78.1% for lower BMI donors (P < 0.001). Pretransplant biopsy was performed more frequently in hBMI donors (52.1% vs 33.1%, P < 0.001) and macrosteatosis of 30% or greater was identified more often (21.1% vs 12.2%, P < 0.001). Biopsy performance increased utilization rate of hBMI donors in 7 of 11 Organ Procurement and Transplantation Network regions. region 6 showed the highest rate of biopsy performance, high rate of hBMI donor utilization, and highest 5-year estimated graft survival rates of all regions. CONCLUSIONS: High BMI donors have not previously been associated with worse graft survival in multivariable analyses; however, they are used much less frequently. Liver biopsy may increase the utilization rate of hBMI donors and improve donor selection. Further evaluation of regions with high rates of utilization and good outcomes is warranted.

Liver Transplant Survival Index for Patients with Model for End-Stage Liver Disease Score ≥ 35: Modeling Risk and Adjusting Expectations in the Share 35 Era.

BACKGROUND: The Share 35 policy for liver allocation prioritizes patients with Model for End-Stage Liver Disease (MELD) scores ≥ 35 for regional sharing of liver allografts. To better assess donor-recipient interactions and inform expectations, this study identified factors affecting graft survival independent of MELD score and derived a risk index for transplantation in the MELD ≥ 35 population. STUDY DESIGN: The United Network for Organ Sharing (UNOS) STAR database was evaluated for deceased donor liver transplants with recipients' MELD ≥ 35, between January 2006 and June 2016. Data were randomly split into test and validate cohorts. Four individual models of graft survival spanning 90 days to 5 years were evaluated with univariate and multivariate Cox proportional hazards analyses against donor- and recipient-specific characteristics. Significant factors were compiled to generate the Liver Transplant Survival Index (LTSI-35), and survival analyses were performed. RESULTS: Five risk groups (very low, low, moderate, high, and severe) were identified, with 1-year graft survival rates of 90.8% ± 0.2%, 89.3% ± 0.3%, 85.0% ± 0.3%, 79.8% ± 0.3%, and 70.3% ± 0.4% (p < 0.001 across groups), respectively. The greatest risk of graft loss was associated with donation after circulatory death (DCD) donors (1-year hazard ratio [HR] = 1.61 [95% CI 1.26 to 2.05], p = 0.001), recipients' requiring ventilator support (HR 1.32 [95% CI 1.17 to 1.51], p < 0.001), and recipient portal vein thrombosis (HR 1.21 [95% CI 1.03 to 1.42], p = 0.003). Subgroup analysis revealed increased risk of graft loss with graft macrosteatosis ≥ 30% on pre-donation biopsy at 90 days (HR 1.64 [1.33 to 1.99], p < 0.001). CONCLUSIONS: The LTSI-35 identifies risk factors for graft loss in a high-MELD population which, when combined, may portend worse outcomes. The LTSI-35 may be used to influence donor selection, organ allocation, and to inform expectations for allograft survival.

Clinical and histopathologic features of antibody-mediated rejection among pediatric renal transplant recipients with preformed vs de novo donor-specific antibodies.

Preformed and de novo donor specific antibodies (pDSA and dnDSA) are risk factors for ABMR. This study compares the effects of pDSA vs dnDSA in pediatric kidney transplant recipients. Sixteen pediatric patients with biopsy-proven ABMR were evaluated. Strong DSA (MFI >10 000) was recorded at transplant, rejection, and follow-up. DSAs with the highest MFI were termed iDSAs. Allograft biopsies were scored according to Banff 2013 criteria. Seven of 16 (44%) patients had pDSA at transplant; 9 (56%) developed dnDSA. Patients with pDSA developed ABMR earlier (median = 63 vs 1344 days, P = .017), while patients with dnDSA were more likely to have strong Class II iDSA (100% vs 28%, P = .009). Viral infection or non-adherence was more common in patients developing dnDSA (88.8% vs 28.6%, P < .01). Pathology in those with pDSAs demonstrated worse transplant glomerulitis (g score 1.57 ± 0.98 vs 0.56 ± 0.73, P = .031); however, those with dnDSAs exhibited higher C4d+ ABMR (P = .013). Patients developing dnDSAs showed ABMR later post-transplant with predominance of HLA-Class II iDSAs. Inadequate immunosuppression likely contributes to dnDSA formation. Patients with no DSA who have unprotocolized decreases in immunosuppression should be screened for dnDSA as it could lead to early intervention and potentially better outcomes.

Effect of intermittent hypercapnia on respiratory control in rat pups.

Preterm infants are subject to fluctuations in blood gas status associated with immature respiratory control. Intermittent hypoxia during early postnatal life has been shown to increase chemoreceptor sensitivity and destabilize the breathing pattern; however, intermittent hypercapnia remains poorly studied. Therefore, to test the hypothesis that intermittent hypercapnia results in altered respiratory control, we examined the effects of daily exposure to intermittent hypercapnia on the ventilatory response to subsequent hypercapnic and hypoxic exposure in neonatal rat pups. Exposure cycles consisted of 5 min of intermittent hypercapnia (5% CO(2), 21% O(2), balance N(2)) followed by 10 min of normoxia. Rat pups were exposed to 18 exposure cycles each day for 1 week, from postnatal day 7 to 14. We analyzed diaphragm electromyograms (EMGs) from pups exposed to subsequent acute hypercapnic (5% CO(2)) and hypoxic (12% O(2)) challenges. In response to a subsequent hypercapnia challenge, there was no significant difference in the ventilatory response between control and intermittent hypercapnia-exposed groups. In contrast, intermittent hypercapnia-exposed rat pups showed an enhanced ventilatory response to hypoxic challenge with an increase in minute EMG to 118 +/- 14% of baseline versus 107 +/- 13% for control pups (p < 0.05). We speculate that prior hypercapnic exposure may increase peripheral chemoreceptor response to subsequent hypoxic exposures and result in perturbed neonatal respiratory control.