Abnormal Liver Biopsies of Donor Grafts in Pediatric Liver Transplantation: How Do They Fare?

BACKGROUND Little is known about outcomes of pediatric patients transplanted using donor liver grafts with abnormal biopsy results. We assessed donor liver biopsy data to report characteristics and outcomes of abnormal livers transplanted in pediatric patients. MATERIAL AND METHODS We identified pediatric patients who received a liver transplant from a biopsied deceased donor between 2015 and 2022 using the national database UNOS Standard Transplant Analysis and Research files. Recipients were excluded if they received multi-organ transplants or were lost to follow-up. Livers with ≤5% macrosteatosis, no fibrosis, and no inflammation were classified as normal livers (NL). Allografts with >5% macrosteatosis, any fibrosis, or any inflammation were considered abnormal livers (AL). Donor and recipient demographic data and outcomes were examined. RESULTS Of the 3808 total pediatric liver transplants in the study period, there were 213 biopsied donor liver allografts transplanted into pediatric recipients. Of those, 114 were NL and 99 were AL. 35.4% (35/99) of the AL had >5% macrosteatosis with a mean of 7.6±11.4%, 64.6% (64/99) had any inflammation, and 18.2% (18/99) had any fibrosis. AL donors were significantly older than NL donors. AL recipients had higher PELD scores. There were no significant differences in length of stay, rejection rates and causes, or allograft survival between AL and NL. Multivariable analysis revealed that inflammation was independently associated with a significantly greater risk for graft failure. CONCLUSIONS Outcomes of abnormal livers are excellent. Inflammation was an independent risk factor for poor graft prognosis. Donor biopsies in pediatric liver transplantation can be a useful adjunct to assess outcomes.

Multinational Analysis of Marginal Liver Grafts Based on the Eurotransplant Extended Donor Criteria.

OBJECTIVE: To evaluate the outcome of marginal liver grafts based on the Eurotransplant extended donor criteria (ECD) criteria. SUMMARY BACKGROUND DATA: Eurotransplant uses a broad definition of ECD criteria (age >65 years, steatosis >40%, BMI >30 kg/m2, ICU stay >7 days, DCD, and certain laboratory parameters) for allocating organs to recipients who have consented to marginal grafts. Historically, marginal liver grafts were associated with increased rates of dysfunction. METHODS: Retrospective cohort analysis using the German Transplant Registry (GTR) and the US Scientific Registry of Transplant Recipients (SRTR) from 2006-2016. Results were validated with recent SRTR data (2017-2022). Donors were classified according to the Eurotransplant ECD criteria, DCD was excluded. Data were analyzed with cut-off prediction, binomial logistic regression, and multivariate Cox regression. RESULTS: The study analyzed 92,330 deceased brain-dead donors (87% SRTR) and 70,374 transplants (87% SRTR) in adult recipients. Predominant ECD factors were donor age in Germany (30%) and BMI in the US (28%). Except for donor age, grafts meeting ECD criteria were not associated with impaired 1- or 3-year survival. Cut-offs had little to no predictive value for 30-day graft survival (AUROC 0.49 - 0.52) and were nominally higher for age (72 vs. 65 years) in Germany as compared to those defined by current Eurotransplant criteria. CONCLUSIONS: The outcome of transplanted grafts from higher risk donors was nearly equal to standard donors with Eurotransplant criteria failing to predict survival of marginal grafts. Modifying ECD criteria could improve graft allocation and potentially expand the donor pool.

A Contemporary Analysis of Mental Well-being Among Living Donor Kidney Applicants.

Background: Living donation is paramount for expanding the donor pool. The aim of this study was to assess changes over time in self-reported mental health of living donor kidney applicants in efforts to inform patient-centered discussions with potential donors. Methods: Kidney donor applications from 2017 through 2021 were compiled. Data included age, gender, race, ethnicity, applicant-recipient relationship, medical history, and medications. Trends over time were analyzed and post hoc analyses were performed. Results: During the study period, 2479 applicants to the living donor kidney program were evaluated; 73% of applicants were female individuals. More than half of applicants were not related to their intended recipient; this fraction increased from 46% in 2017 to 58% in 2021 (P < 0.01). A similar decline in family relations was not present among Black and Latino applicants. Of all applicants, 18% reported depression and 18% reported anxiety; 20% reported taking antidepressants or anxiolytics. Depression and anxiety increased 170% (P < 0.001) and 136% (P < 0.001) from 2018 to 2019, respectively; antidepressant and anxiolytic use rose 138% (P < 0.001) between 2018 and 2020. Conclusions: The profile of living donor applicants has changed in recent years, with approximately 1 in 5 requiring antidepressants or anxiolytics. Predonation counseling and postdonation monitoring are imperative to decrease adverse psychological outcomes for living donors.

A contemporary analysis of 20,086 deceased donor liver biopsies.

BACKGROUND: Pre-transplant deceased donor liver biopsy may impact decision making; however, interpretation of the results remains variable and depends on accepting center practice patterns. METHODS: In this cohort study, adult recipients from 04/01/2015-12/31/2020 were identified using the UNOS STARfile data. The deceased donor liver biopsies were stratified by risk based on degree of fibrosis, macrovesicular fat content, and level of portal infiltration (low-risk: no fibrosis, no portal infiltrates, and <30% macrosteatosis; moderate-risk: some fibrosis or mild infiltrates and <30% macrosteatosis; high-risk: most fibrosis, moderate/marked infiltrates, or ≥30% macrosteatosis). Graft utilization, donor risk profile, and recipient outcomes were compared across groups. RESULTS: Of the 51,094 donor livers available, 20,086 (39.3%) were biopsied, and 34,606 (67.7%) were transplanted. Of the transplanted livers, 14,908 (43.1%) were biopsied. The transplanted grafts had lower mean macrovesicular fat content (9.3% transplanted vs. 26.9% non-transplanted, P < 0.001) and less often had any degree of fibrosis (20.9% vs. 39.9%, P < 0.001) or portal infiltration (51.3% vs. 58.2%, P < 0.001) versus non-transplanted grafts. Post-transplant recipient LOS (14.2 days high-risk vs. 15.2 days low-risk, P = 0.170) and 1-year graft survival (90.5% vs. 91.7%, P = 0.137) did not differ significantly between high- versus low-risk groups. Kaplan-Meier survival estimates further revealed no differences in the 5-year graft survival across risk strata (P = 0.833). Of the 5178 grafts biopsied and turned down, PSM revealed 1338 (26.0%) were potentially useable based on biopsy results and donor characteristics. CONCLUSION: Carefully matched deceased donor livers with some fibrosis, inflammation, or steatosis ≥30% may be suitable for transplantation. Further study of this group of grafts may decrease turndowns of potentially useable organs.

From Patients to Providers: Assessing Impact of Normothermic Machine Perfusion on Liver Transplant Practices in the US.

BACKGROUND: Normothermic machine perfusion (NMP) of livers allows for the expansion of the donor pool and minimization of posttransplant complications. Results to date have focused on both donor and recipient outcomes, but there remains potential for NMP to also impact transplant providers. STUDY DESIGN: Using United Network for Organ Sharing Standard Transplant Analysis file data, adult deceased donors who underwent transplantation between January 1, 2016, and December 31, 2022, were identified. Transplanted livers were divided by preservation methods (static cold storage [SCS] and NMP) and case time (day-reperfusion 8 am to 6 pm ). Patient factors, transplant characteristics, and short-term outcomes were analyzed between Mahalanobis-metric-matched groups. RESULTS: NMP livers represented 742 (1.4%) of 52,132 transplants. NMP donors were more marginal with higher Donor Risk Index scores (1.78 ± 0.50 NMP vs 1.49 ± 0.38 SCS, p < 0.001) and donation after cardiac death frequency (36.9% vs 8.4%, p < 0.001). NMP recipients more often had model for end-stage liver disease (MELD) exception status (29.9% vs 23.4%, p < 0.001), lower laboratory MELD scores (20.7 ± 9.7 vs 24.3 ± 10.9, p < 0.001), and had been waitlisted longer (111.5 [21.0 to 307.0] vs 60.0 [9.0 to 245.0] days, p < 0.001). One-year graft survival (90.2% vs 91.6%, p = 0.505) was similar between groups, whereas length of stay was lower for NMP recipients (8.0 [6.0 to 14.0] vs 10.0 [6.0 to 16.0], p = 0.017) after adjusting for confounders. Notably, peak case volume occurred at 11 am with NMP livers (vs 9 pm with SCS). Overall, a higher proportion of transplants was performed during daytime hours with NMP (51.5% vs 43.0%, p < 0.001). CONCLUSIONS: NMP results in increased use of marginal allografts, which facilitated transplantation in lower laboratory MELD recipients who have been waitlisted longer and often have exception points. Importantly, NMP also appeared to shift peak caseloads from nighttime to daytime, which may have significant effects on the quality of life for the entire liver transplant team.

Normothermic machine perfusion for older transplant recipients.

INTRODUCTION: Elderly patients (≥65 years old) are increasingly undergoing liver transplantation and are more likely to be removed from the waitlist. Normothermic machine perfusion (NMP) holds promise in expanding the number of livers available for transplant and improving outcomes for marginal donors and recipients. We aimed to determine the impact of NMP on outcomes in elderly recipients at our institution and nationally using the UNOS database. METHODS: The use of NMP on outcomes in elderly recipients was reviewed using both the UNOS/SRTR database (2016-2022) and institutional data (2018-2020). Characteristics and clinical outcomes were compared between the NMP and static cold (control) groups within both populations. RESULTS: Nationally, using the UNOS/SRTR database, we identified 165 elderly recipients from 28 centers who received a liver allograft undergoing NMP and 4270 that underwent traditional cold static storage. NMP donors were older (48.3 vs. 43.4 years, p < 0.01), had similar rates of steatosis (8.5% vs 8.5%, p = 0.58), were more likely to be from a DCD (41.8% vs 12.3%, p < 0.01), and had a higher donor risk index (DRI; 1.70 vs. 1.60, p < 0.02). NMP recipients had similar age but had a lower MELD score at transplant (17.9 vs. 20.7, p = 0.01). Despite increased marginality of the donor graft, NMP recipients had similar allograft survival and decreased length of stay, even after accounting for recipient characteristics including MELD. Institutional data showed that 10 elderly recipients underwent NMP and 68 underwent cold static storage. At our institution, NMP recipients had a similar length of stay, rates of complications, and readmissions. CONCLUSIONS: NMP may mitigate donor risk factors that are relative contraindications for transplantation in elderly liver recipients, increasing the donor pool. The application of NMP in older recipients should be considered.

Interpersonal violence affecting the pediatric population: Patterns of injury and recidivism.

PURPOSE: We aim to describe interpersonal violence-related injury patterns in the pediatric trauma population and to identify predictors of recidivism. METHODS: In this retrospective analysis from a single institution, we included pediatric patients (≤17 years) treated (2006-2020) for traumatic injury related to interpersonal violence (IPV). Patient characteristics were compared among mechanism types and between recidivists and non recidivists using two sample t-tests, Wilcoxon rank-sum tests, and Pearson's chi-squared. Multivariate analysis was performed using logistic regression to identify predictors of repeat injury. RESULTS: We identified 635 pediatric patients who sustained injuries owning to IPV: firearm (N = 266), assault (stab/blunt; N = 243), and abuse (N = 126). The average age of the firearm, assault, and abuse groups was 15.5, 14.7, and 1.1 years (SD = 2.2, 3.4, 2.4 years), respectively. Majority of the overall cohort was male (77.5%) and publicly- or un insured (67.8%), with 28.0% being Black. Of the 489 firearm and assault patients who survived the first injury, 30 (6.1%) had repeat injury owning to IPV requiring treatment at our center with a median time of 40 months (IQR 17-62 months) between first and second injury. The majority of recidivists (83.3%) were victims of gun violence whereas the distribution between assault and firearm in the non recidivists was more even at 51 and 49%, respectively (p < 0.001). Eighteen (60.0%) of the recidivist patients had the same mechanism between the first and second injury. In the logistic regression analysis, Black race and firearm injury were associated with greater than 3-fold higher likelihood of repeat injury compared to white race after adjusting for age, sex, insurance, and child opportunity index. CONCLUSIONS: We found that survivors of firearm injuries and assault comprise a vulnerable patient cohort at risk for repeat injury, and Black race is an independent predictor of repeat injury owning to IPV. These findings provide guidance for developing violence prevention programs. TYPE OF STUDY: Retrospective Comparative Study LEVEL OF EVIDENCE: Level III.

No Stone Left Unturned: Utilization of an Organ Procurement Organization Donor Surgeon at Procurement Reduces Discards of Marginal Liver Allografts.

BACKGROUND: The recent trend of organ procurement organizations (OPOs) employing independent surgeons for organ procurement has been developed with the goal of improving the supply of suitable organs for transplantation. We investigated the effects that the addition of an OPO-employed, organ-procurement specialist has on liver allograft discard rate, marginal organ utilization, and graft survival. METHODS: Organ Procurement and Transplant Network and OPO data were retrospectively studied between April 1, 2014' and July 31, 2019' within the Southwest Transplant Alliance donor service area. Liver procurements with an OPO-surgeon present (OPO-Present) were compared to those without the involvement of an OPO surgeon (OPO-Absent). Donor and recipient characteristics as well as outcomes were analyzed across groups using propensity score matching. RESULTS: In total 869 OPO-Present liver allografts had similar rates of discard (5.2%) compared to 771 OPO-Absent livers (5.8%). However, after adjusting for donor risk, OPO-Present livers had a lower propensity of discard compared to OPO-Absent (3.4% versus 7.6%, P < 0.05). OPO-Present livers were more likely to be shared nationally (11.0% versus 4.8%, P < 0.001). Outcome analysis showed allograft survival of OPO-Present livers at 5 y was comparable to OPO-Absent livers (79.5% versus 80%, P = 0.34). CONCLUSIONS: The presence of an OPO surgeon was associated with decreased liver allograft discard and increased utilization of marginal donor organs. The OPO surgeon's presence represents a potential strategy to increase organ utilization nationally.

Is there value in volume? An assessment of liver transplant practices in the United States since the inception of MELD.

BACKGROUND: Liver transplantation has increased in volume and provides substantial survival benefit. However, there remains a need for value-based assessment of this costly procedure. METHODS: Model for end stage liver disease era adult recipients were identified using United Network for Organ Sharing Standard Transplant Analysis file data (n = 75,988) and compared across time periods (period A: February 2002 to January 2007; B: February 2007 to January 2013; C: February 2013 to January 2019). Liver centers were divided into volume tertiles for each period (small, medium, large). Value for the index transplant episode was defined as percentage graft survival ≥1 year divided by mean posttransplant duration of stay. RESULTS: All centers increased value over time due to ubiquitous improvement in 1-year graft survival. However, large centers demonstrated the most significant value change (large +17% vs small +7.0%, P < .001) due to a -8.5% reduction in large centers duration of stay from period A to C, while small centers duration of stay remained unchanged (-0.1%). Large centers delivered higher value despite more complex care: older recipients (54.8 ± 10.3 vs 53.0 ± 11.4 years P < .001), fewer model for end stage liver disease exceptions (34.0% vs 38.2%, P < .001), higher rates of candidate portal vein thrombosis (10.1% vs 8.5%, P < .001) and prior abdominal surgery (43.4% vs 37.4%, P < .001), and more marginal donor utilization (donor risk index 1.45 ± 0.38 vs 1.36 ± 0.33, P < .001). Mahalanobis metric matching demonstrated that compared with small centers, large centers progressively shortened recipient duration of stay per transplant in each period (A: -0.36 days, P = .437; B: -2.14 days, P < .001; C: -2.49 days, P < .001). CONCLUSION: There is value in liver transplant volume. Adoption of value-based practices from large centers may allow optimization of health care delivery for this costly procedure.

Short-term kidney transplant outcomes from severe acute respiratory syndrome coronavirus 2 lower respiratory tract positive donors.

OBJECTIVE: In this study, we aim to assess short-term allograft outcomes following deceased donor kidney transplantation from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) lower respiratory tract (LRT) nucleic acid testing (NAT) positive donors. METHODS: From September to December 2021, SARS-CoV-2 NAT positive organ donors, whose solid abdominal organs were transplanted at our academic medical center were identified. Donors were stratified into having tested positive for SARS-CoV-2 in an upper respiratory tract (URT) or LRT sample. For this study, the SARS-CoV-2 LRT NAT positive deceased kidney donors and their respective recipients were examined. Donor and recipient demographic data, coronavirus disease 2019 (COVID-19)-related history, patient outcomes, as well as postoperative graft function were evaluated. RESULTS: Thirteen SARS-CoV-2 positive deceased donors were identified. Of these, eight were LRT NAT positive and yielded nine kidneys. These allografts were successfully transplanted into vaccinated and unvaccinated recipients. All recipients received standard induction immunosuppression and did not receive any prophylactic therapy for SARS-CoV-2. Two recipients had delayed graft function. At 1-month post-transplant, there was no clinical evidence of donor-derived COVID-19 or graft loss, and all recipients were free from dialysis. CONCLUSION: We describe the first case series of SARS-CoV-2 LRT NAT positive deceased kidney donors for vaccinated and unvaccinated recipients with excellent short-term allograft outcomes and no clinical evidence of donor-derived COVID-19 post-transplantation. Given the increasing prevalence of SARS-CoV-2 in the population, utilization of SARS-CoV-2 LRT NAT positive deceased donors could be considered an acceptable source of organs for renal transplantation, especially as multi-center experiences and longer-term follow-up emerge.

Complications from ankle arthrodesis in diabetes-related Charcot foot syndrome.

INTRODUCTION: Charcot neuroarthropathy (CN) is an inflammatory arthropathy associated with bony destruction, dislocation, and deformity in patients with neuropathy. Surgical procedures involving foot and ankle in CN for deformity correction have been shown to result in high rate of complications. The purpose of this study was to compare post-operative outcomes and assess odds of complication after ankle arthrodesis among patients with diabetes-related Charcot neuroarthropathy, non-Charcot patients with diabetes, and non-Charcot patients without diabetes. METHODS: The PearlDiver Patient Records Database was queried for patients who underwent ankle fusion and maintained at least one year of post-operative follow-up. The following post-operative complications were assessed among groups: overall nonunion and amputation, one-year nonunion, amputation, and hardware removal, 90-day and 30-day surgical site infection, dehiscence, acute kidney injury, and pneumonia, and 90-day myocardial infarction and deep vein thrombosis. The odds and prevalence of each complication for each group were assessed and compared. RESULTS: Higher rates of amputation (OR 3.43, CI 2.89-4.06), hardware removal (OR 1.63, CI 1.45-1.83), wound dehiscence (OR 1.75, CI 1.44-2.13), acute kidney injury (OR 2.87, CI 2.32-3.54), pneumonia (OR 1.53, CI 1.13-2.07), and surgical site infection (OR 2.46, CI 2.12-2.85), were observed in patients with diabetes-related CN compared to non-Charcot patients with diabetes. In patients without CN, higher rates of nonunion (OR 1.38, CI 1.19-1.61), amputation (OR 2.26, CI 1.74-2.93), surgical site infection (OR 1.57, CI 1.30-1.90), and acute kidney injury (OR 1.57, CI 1.18-2.09) were observed in patients with diabetes compared to patients without diabetes. Time to hardware removal was significantly shorter in diabetes-related Charcot patients compared to non-Charcot patients without diabetes (368.0 ± 446.7 vs 438.5 ± 487.5 days, P < 0.001). CONCLUSION: Patients with diabetes demonstrated increased odds of nonunion, amputation, surgical site infection, and acute kidney injury compared to patients without diabetes. In the population of patients with diabetes, odds of most of these complications were further increased with the addition of Charcot diagnosis compared to patients without diabetes. Other local and multisystemic medical conditions, including pneumonia and wound dehiscence, also demonstrated increased odds in patients of CN. LEVEL OF EVIDENCE: Cohort study; Level of evidence, 3.

Rational design of fiber forming supramolecular structures.

Recent strides in the development of multifunctional synthetic biomimetic materials through the self-assembly of multi-domain peptides and proteins over the past decade have been realized. Such engineered systems have wide-ranging application in bioengineering and medicine. This review focuses on fundamental fiber forming α-helical coiled-coil peptides, peptide amphiphiles, and amyloid-based self-assembling peptides; followed by higher order collagen- and elastin-mimetic peptides with an emphasis on chemical / biological characterization and biomimicry.

Drug-triggered and cross-linked self-assembling nanofibrous hydrogels.

Self-assembly of multidomain peptides (MDP) can be tailored to carry payloads that modulate the extracellular environment. Controlled release of growth factors, cytokines, and small-molecule drugs allows for unique control of in vitro and in vivo responses. In this study, we demonstrate this process of ionic cross-linking of peptides using multivalent drugs to create hydrogels for sustained long-term delivery of drugs. Using phosphate, heparin, clodronate, trypan, and suramin, we demonstrate the utility of this strategy. Although all multivalent anions result in good hydrogel formation, demonstrating the generality of this approach, suramin led to the formation of the best hydrogels per unit concentration and was studied in greater detail. Suramin ionically cross-linked MDP into a fibrous meshwork as determined by scanning and transmission electron microscopy. We measured material storage and loss modulus using rheometry and showed a distinct increase in G' and G″ as a function of suramin concentration. Release of suramin from scaffolds was determined using UV spectroscopy and showed prolonged release over a 30 day period. Suramin bioavailability and function were demonstrated by attenuated M1 polarization of THP-1 cells compared to positive control. Overall, this design strategy has allowed for the development of a novel class of polymeric delivery vehicles with generally long-term release and, in the case of suramin, cross-linked hydrogels that can modulate cellular phenotype.

Highly angiogenic peptide nanofibers.

Major limitations of current tissue regeneration approaches using artificial scaffolds are fibrous encapsulation, lack of host cellular infiltration, unwanted immune responses, surface degradation preceding biointegration, and artificial degradation byproducts. Specifically, for scaffolds larger than 200-500 µm, implants must be accompanied by host angiogenesis in order to provide adequate nutrient/waste exchange in the newly forming tissue. In the current work, we design a peptide-based self-assembling nanofibrous hydrogel containing cell-mediated degradation and proangiogenic moieties that specifically address these challenges. This hydrogel can be easily delivered by syringe, is rapidly infiltrated by cells of hematopoietic and mesenchymal origin, and rapidly forms an extremely robust mature vascular network. Scaffolds show no signs of fibrous encapsulation and after 3 weeks are resorbed into the native tissue. These supramolecular assemblies may prove a vital paradigm for tissue regeneration and specifically for ischemic tissue disease.

A nanostructured synthetic collagen mimic for hemostasis.

Collagen is a major component of the extracellular matrix and plays a wide variety of important roles in blood clotting, healing, and tissue remodeling. Natural, animal derived, collagen is used in many clinical applications but concerns exist with respect to its role in inflammation, batch-to-batch variability, and possible disease transfection. Therefore, development of synthetic nanomaterials that can mimic the nanostructure and properties of natural collagen has been a heavily pursued goal in biomaterials. Previously, we reported on the design and multihierarchial self-assembly of a 36 amino acid collagen mimetic peptide (KOD) that forms nanofibrous triple helices that entangle to form a hydrogel. In this report, we utilize this nanofiber forming collagen mimetic peptide as a synthetic biomimetic matrix useful in thrombosis. We demonstrate that nanofibrous KOD synthetic collagen matrices adhere platelets, activate them (indicated by soluble P-selectin secretion), and clot plasma and blood similar to animal derived collagen and control surfaces. In addition to the thrombotic potential, THP-1 monocytes incubated with our KOD collagen mimetic showed minimal proinflammatory cytokine (TNF-α or IL-1ß) production. Together, the data presented demonstrates the potential of a novel synthetic collagen mimetic as a hemostat.