Versatile, in-line optical oxygen tension sensors for continuous monitoring during ex vivo kidney perfusion.

Integration of physiological sensing modalities within tissue and organ perfusion systems is becoming a steadily expanding field of research, aimed at achieving technological breakthrough innovations that will expand the sites and clinical settings at which such systems can be used. This is becoming possible in part due to the advancement of user-friendly optical sensors in recent years, which rely both on synthetic, luminescent sensor molecules and inexpensive, low-power electronic components for device engineering. In this article we report a novel approach towards enabling automated, continuous monitoring of oxygenation during ex vivo organ perfusion, by combining versatile flow cell components and low-power, programmable electronic readout devices. The sensing element comprises a 3D printed, miniature flow cell with tubing connectors and an affixed oxygen-sensing thin film material containing in-house developed, brightly-emitting metalloporphyrin phosphor molecules embedded within a polymer matrix. Proof-of-concept validation of this technology is demonstrated through integration within the tubing circuit of a transportable medical device for hypothermic oxygenated machine perfusion of extracted kidneys as a model for organs to be preserved as transplants.

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.

Successful Extension of Vascularized Composite Allograft Perfusion Cold Storage to 24 h in a Rat Hindlimb Transplant Model.

Background: Vascularized composite allograft transplantation is a treatment option for complex tissue injuries; however, ischemia reperfusion injury and high acute rejection rates remain a challenge. Hypothermic machine perfusion using acellular storage perfusate is a potential solution. This study evaluated the University of Wisconsin Kidney Preservation Solution-1 (KPS-1) compared with normal saline (NS) for preservation of donor rat hindlimbs subjected to 24 h of ex vivo perfusion cold storage. Methods: Hindlimbs were subjected to 24-h perfusion cold storage with heparinized KPS-1 (n = 6) or heparinized NS (n = 6). Flow, resistance, and pH were measured continuously. At the end of the 24-h period, tissue was collected for histological analysis of edema and apoptosis. Results: KPS-1 perfused limbs showed significantly less edema than the NS group, as evidenced by lower limb weight gain (P < 0.001) and less interfascicular space (P < 0.001). KPS-perfused muscle had significantly less cell death than NS-perfused muscle based on terminal deoxynucleotidyl transferase dUTP nick-end labeling (P < 0.001) and cleaved caspase-3 staining (P = 0.045). During hypothermic machine perfusion, a significant decrease in pH over time was detected in both groups, with a significantly greater decline in pH in the KPS-1 group than in the NS group. There were no significant differences overall and over time in flow rate or vascular resistance between the KPS and NS groups. Conclusions: Perfusion with KPS-1 can successfully extend vascularized composite allograft perfusion cold storage for 24 h in a rat hindlimb model without significant edema or cell death.

The effect of donor graft type on survival after liver transplantation for hepatoblastoma in children.

BACKGROUND: Liver transplantation (LT) is the only potentially curative option for children with unresectable hepatoblastoma (HBL). Although post-transplant outcomes have improved in the contemporary era, the impact of donor graft type on survival remains unclear. METHODS: Using the United Network for Organ Sharing database (02/2002-06/2021), demographics, clinical characteristics, and patient and graft survival were analyzed in children (<18 years) who underwent LT for HBL according to donor graft type. The Kaplan-Meier method, log-rank tests, and Cox regression modeling were used to evaluate the effect of whole, partial, and split deceased donor liver transplantation (DDLT) and living donor liver transplantation (LDLT) on patient and graft survival. RESULTS: A total of 590 pediatric HBL LT recipients (344 whole graft DDLT; 62 partial graft DDLT; 139 split graft DDLT; 45 LDLT) were included. During 2012-2021 the proportion of LDLTs for HBL decreased to about 5% compared with about 11% during 2002-2011. No significant differences were identified by donor graft type in either patient survival (log-rank test, p = .45) or graft survival (log-rank test, p = .69). The results remained similar during the 2002-2011 era, while during the 2012-2021 era, split graft DDLT was associated with decreased graft loss risk versus whole graft DDLT (hazard ratio: 0.48, 95% confidence interval: 0.23-0.99, p = .046) without any other significant between-group differences. CONCLUSIONS: Utilizing non-whole liver grafts can increase access to LT in children with unresectable HBL while ensuring favorable outcomes. LDLT is underutilized in children with HBL in the United States, and efforts to explore LDLT options should be undertaken.

Galectin-3 in biliary atresia and other pediatric cholestatic liver diseases.

AIMS: Biliary atresia (BA) is characterized by intrahepatic inflammation and rapid progression of liver fibrosis. Galectin-3, a beta-galactoside binding protein, is a key regulator of inflammation and fibrosis. The aim of this study was to characterize circulating and hepatic Galectin-3 levels in children with BA. METHODS: Plasma and liver samples were obtained from children with early BA at time of Kasai hepatoportoenterostomy, late BA at time of transplant, early and late other cholestatic liver diseases (CLD), and controls. Plasma Galectin-3 was measured using standard enzyme-linked immunoassay. Liver tissue was analyzed with multiplex immunohistochemistry and quantified using whole slide analysis. Statistical comparisons were made using nonparametric testing. RESULTS: Plasma Galectin-3 in late BA was significantly higher than in early BA (20.82 [12.45-30.46] vs. 11.30 [8.74-16.83] ng/mL, p = 0.0096). Galectin-3 levels correlated with markers of disease severity and interleukin-6. There were significantly more Galectin-3+ M2 macrophages in late BA in comparison to late other CLD (162 [157-233] vs. 49 [33-59] cells/mm2, p = 0.03). The number of Galectin-3+ M2 macrophages correlated with the number of activated hepatic stellate cells and bile duct proliferation. CONCLUSIONS: Plasma Galectin-3 is higher in late BA at time of transplant in comparison to early BA at time of Kasai. The number of Galectin-3 expressing M2 macrophages in late BA is elevated relative to late other CLD and was associated with other prognostic histological findings. Galectin-3 targeted therapy may be beneficial in slowing disease progression to cirrhosis in children with BA.

Modern-era successful liver transplantation outcomes in children with hepatic undifferentiated embryonal sarcoma.

BACKGROUND: Hepatic undifferentiated embryonal sarcoma (HUES) is the third most common primary hepatic malignancy in children. If unresectable, liver transplantation (LT) is the only curative option. Historically, HUES LT outcomes were not favorable; however, modern-era data are lacking. We aimed to describe LT outcomes in children with HUES and compared with LT outcomes in children transplanted for hepatoblastoma (HBL) and non-malignancy indications. METHODS: Children 18 years or younger with HUES who underwent LT from 1987 to 2021 were identified from the Scientific Registry of Transplant Recipients database. Graft and patient survival were studied in HUES and LT recipients with HBL and non-malignancy indications using Kaplan-Meier analysis. Cox regression was used to compare patient and graft survival among groups, controlling for confounders. RESULTS: Twenty-one children with HUES underwent LT during the study period with a median age at LT of 10 years (IQR: 8-12 years). One and five-year patient survival for HUES recipients was not significantly different from that of recipients with HBL (p = .3) or non-malignancy diagnoses (p = .6). There were no deaths due to HUES recurrence. In multivariable Cox regression, HUES did not increase risk of either patient or graft loss as compared to HBL (HR 2.36, p = .2) or non-malignancy indications (HR 0.74, p = .7). CONCLUSION: LT outcomes are more favorable in patients with HUES than historically described, and similar to LT outcomes of patients with HBL and non-malignancy indications. Transplant should be considered for HUES patients with unresectable localized tumors.

Development and in-vivo validation of a portable phosphorescence lifetime-based fiber-optic oxygen sensor.

Oxygenation is a crucial indicator of tissue viability and function. Oxygen tension ([Formula: see text]), i.e. the amount of molecular oxygen present in the tissue is a direct result of supply (perfusion) and consumption. Thus, measurement of [Formula: see text] is an effective method to monitor tissue viability. However, tissue oximetry sensors commonly used in clinical practice instead rely on measuring oxygen saturation ([Formula: see text]), largely due to the lack of reliable, affordable [Formula: see text] sensing solutions. To address this issue we present a proof-of-concept design and validation of a low-cost, lifetime-based oxygen sensing fiber. The sensor consists of readily-available off-the shelf components such as a microcontroller, a light-emitting diode (LED), an avalanche photodiode (APD), a temperature sensor, as well as a bright in-house developed porphyrin molecule. The device was calibrated using a benchtop setup and evaluated in three in vivo animal models. Our findings show that the new device design in combination with the bright porphyrin has the potential to be a useful and accurate tool for measuring [Formula: see text] in tissue, while also highlighting some of the limitations and challenges of oxygen measurements in this context.

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.

Uncontrolled donation after cardiac death kidney transplantation: Opportunity to expand the donor pool?

BACKGROUND: Compared to controlled donation after cardiac death (cDCD), uncontrolled DCD (uDCD) kidney transplantation remains an underutilized resource in the United States. However, it is unclear whether long-term allograft outcomes following uDCD are inferior to that of cDCD kidney transplantation. METHODS: From January 1995 to January 2018, the OPTN/UNOS database was queried to discover all reported cases of uDCD and cDCD kidney transplantation. Primary non-function, delayed graft function, ten-year graft and patient survival were compared among uDCD and cDCD patients. RESULTS: Rates of primary non-function (4.0% [uDCD] vs. 1.8% [cDCD], P < 0.001) and delayed graft function (51.1% [uDCD] vs. 41.7% [cDCD], P < 0.001) were higher following uDCD transplant. However, ten-year graft survival (47.5% [uDCD] vs. 48.4% [cDCD], P = 0.21) and patient survival were similar to cDCD transplantation (59.4% [uDCD] vs. 59.2% [cDCD], P = 0.32). CONCLUSION: Although initial allograft outcomes are inferior following uDCD, long-term durability of uDCD kidney allografts is on par to cDCD transplantation. Kidney allografts derived by uDCD may be a viable and durable option to increase the donor pool.

Can non-directed living liver donation help improve access to grafts and correct socioeconomic disparities in pediatric liver transplantation?

BACKGROUND: Each year, children die awaiting LT as the demand for grafts exceeds the available supply. Candidates with public health insurance are significantly less likely to undergo both deceased donor LT and D-LLD LT. ND-LLD is another option to gain access to a graft. The aim of this study was to evaluate if recipient insurance type is associated with likelihood of D-LLD versus ND-LLD LT. METHODS: The SRTR/OPTN database was reviewed for pediatric LDLT performed between January 1, 2014 (Medicaid expansion era) and December 31, 2019 at centers that performed ≥1 ND-LLD LDLT during the study period. A multivariable logistic regression was performed to assess relationship between type of living donor (directed vs. non-directed) and recipient insurance. RESULTS: Of 299 pediatric LDLT, 46 (15%) were from ND-LLD performed at 18 transplant centers. Fifty-nine percent of ND-LLD recipients had public insurance in comparison to 40% of D-LLD recipients (p = .02). Public insurance was associated with greater odds of ND-LLD in comparison to D-LLD upon multivariable logistic regression (OR 2.37, 95% CI 1.23-4.58, p = .01). CONCLUSIONS: ND-LLD allows additional children to receive LTs and may help address some of the socioeconomic disparity in pediatric LDLT, but currently account for only a minority of LDLT and are only performed at a few institutions. Initiatives to improve access to both D-LLD and ND-LLD transplants are needed.

Role of galectin-3 in the pathogenesis and progression of biliary atresia.

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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.

Pediatric Heart Transplant Waiting List Times in the US During the COVID-19 Pandemic.

This cohort study investigates the association between the COVID-19 pandemic and waiting list times among pediatric heart transplant recipients in the US.

Fibrinolysis resistance after liver transplant as a predictor of early infection.

BACKGROUND: Infection is a leading cause of morbidity in liver transplant (LT). Considering that the fibrinolytic system is altered in sepsis, we investigated the relationship between fibrinolysis resistance (FR) and post-transplant infection. METHODS: Fibrinolysis was quantified using thrombelastography (TEG) with the addition of tPA to quantify FR. FR was defined as LY30 = 0% and stratified as transient if present on POD1 or POD5 (tFR), persistent (pFR) if present on both, or no FR (nFR) if absent. RESULTS: 180 LT recipients were prospectively enrolled. 52 (29%) recipients developed infection. 72 had tFR; 37 had pFR; and 71 had nFR. Recipients with pFR had significantly greater incidence of infections (51% vs. 26% tFR vs. 20% nFR, p = 0.002). pFR was independently associated with increased odds of post-transplant infection (adjusted OR 3.39, p = 0.009). CONCLUSIONS: Persistent fibrinolysis resistance is associated with increased risk of post-transplant infection.

Successful use of intra-operative continuous renal replacement therapy in pediatric liver transplant recipients: Single center case series.

BACKGROUND: Acute kidney injury (AKI) is common in pediatric patients undergoing liver transplantation (LT), with an incidence 17%-55%. Fluid, metabolic, and acid-base aberrancies are often pronounced pre-operatively and further worsened by events during LT, making intra-operative continuous renal replacement therapy (CRRT) an option for critically ill LT recipients. METHODS: All pediatric LT performed at our institution who underwent intra-operative CRRT between January 2017 and August 2021 were included. Patient demographics and clinical data including graft outcomes, intra-operative findings, and timing and indications for CRRT were collected from the electronic medical record. RESULTS: CRRT was used in nine of the 76 (12%) pediatric LT performed at our center during the study period. Ages at LT ranged from 39 to 17.7 years. Recipients requiring CRRT were more likely to have acute liver failure, status 1A, and higher calculated MELD/PELD scores. CRRT was initiated pre-transplant in three recipients and continued post-transplant in six recipients. Median duration of CRRT was two (range 0-14) days. Indications included hyperammonemia (3/9), acidosis (3/9), fluid overload (6/9), and hyperkalemia (2/9). The CRRT group had a significantly longer post-transplant intensive care unit length of stay in comparison to those that did not require CRRT (median 6, range 3-40 days vs. median 3, range 0-121 days, p = .02], but there were no significant differences in reoperations, hospital length of stay, or recipient or graft survival. CONCLUSIONS: We demonstrate that CRRT can be safely performed in pediatric LT recipients, including young infants through adolescents.

Immediate extubation following pediatric liver transplantation.

BACKGROUND: Immediate extubation (IE) following pediatric liver transplantation is being increasingly performed. The aim of this study was to characterize the rate of IE at our institution and identify recipient factors predictive of IE. METHODS: All pediatric liver transplants performed at our institution between January 1, 2015 and December 31, 2020 were reviewed. Retransplants and multi-organ transplants were excluded. IE was defined as extubation in the operating room following transplant. Backward stepwise logistic regression at a p-value threshold of .05 was performed to identify variables associated with IE. RESULTS: IE was achieved in 58 (72%) of the 81 pediatric liver transplants. The IE cohort had significantly shorter ICU length of stay and overall hospital length of stay, though IE was not an independent predictor of posttransplant length of stay. Age <2 years, preoperative mechanical ventilation, and total intraoperative epinephrine and dopamine infusion requirements were significant, independent risk factors against IE. This multivariable model was highly predictive of IE (area under the curve = 0.89). CONCLUSIONS: We describe the highest rate of IE postpediatric liver transplantation that has been reported to date and identified significant risk factors against successful IE.

Living Donor Liver Transplant Center Volume Influences Waiting List Survival Among Children Listed for Liver Transplantation.

BACKGROUND: Pediatric living donor liver transplantation (LDLT) remains infrequently performed in the United States and localized to a few centers. This study aimed to compare pediatric waiting list and posttransplant outcomes by LDLT center volume. METHODS: The Scientific Registry of Transplant Recipients/Organ Procurement and Transplantation Network database was retrospectively reviewed for all pediatric (age <18 y) liver transplant candidates listed between January 1, 2009, and December 31, 2019. The average annual number of LDLT, deceased donor partial liver transplant (DDPLT), and overall (ie, LDLT + DDPLT + whole liver transplants) pediatric liver transplants performed by each transplant center during the study period was calculated. RESULTS: Of 88 transplant centers, only 44 (50%) performed at least 1 pediatric LDLT during the study period. LDLT, DDPLT, and overall transplant center volume were all positively correlated. LDLT center volume was protective against waiting list dropout after adjusting for confounding variables (adjusted hazard ratio, 0.92; 95% confidence interval, 0.86-0.97; P = 0.004), whereas DDPLT and overall center volume were not ( P > 0.05); however, DDPLT center volume was significantly protective against both recipient death and graft loss, whereas overall volume was only protective against graft loss and LDLT volume was not protective for either. CONCLUSIONS: High-volume pediatric LDLT center can improve waiting list survival, whereas DDPLT and overall volume are associated with posttransplant survival. Expertise in all types of pediatric liver transplant options is important to optimize outcomes.

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.