Michael Kueht

Time-of-day-dependent dietary fat consumption influences multiple cardiometabolic syndrome parameters in mice

Background:Excess caloric intake is strongly associated with the development of increased adiposity, glucose intolerance, insulin resistance, dyslipidemia, and hyperleptinemia (that is the cardiometabolic syndrome). Research efforts have focused attention primarily on the quality (that is nutritional content) and/or quantity of ingested calories as potential causes for diet-induced pathology. Despite growing acceptance that biological rhythms profoundly influence energy homeostasis, little is known regarding how the timing of nutrient ingestion influences development of common metabolic diseases.Objective:To test the hypothesis that the time of day at which dietary fat is consumed significantly influences multiple cardiometabolic syndrome parameters.Results:We report that mice fed either low- or high-fat diets in a contiguous manner during the 12 h awake/active period adjust both food intake and energy expenditure appropriately, such that metabolic parameters are maintained within a normal physiologic range. In contrast, fluctuation in dietary composition during the active period (as occurs in human beings) markedly influences whole body metabolic homeostasis. Mice fed a high-fat meal at the beginning of the active period retain metabolic flexibility in response to dietary challenges later in the active period (as revealed by indirect calorimetry). Conversely, consumption of high-fat meal at the end of the active phase leads to increased weight gain, adiposity, glucose intolerance, hyperinsulinemia, hypertriglyceridemia, and hyperleptinemia (that is cardiometabolic syndrome) in mice. The latter perturbations in energy/metabolic homeostasis are independent of daily total or fat-derived calories.Conclusions:The time of day at which carbohydrate versus fat is consumed markedly influences multiple cardiometabolic syndrome parameters.

Inferior outcomes on the waiting list in low volume pediatric heart transplant centers

Low case volume has been associated with poor outcomes in a wide spectrum of procedures. Our objective was to study the association of low case volume and worse outcomes in pediatric heart transplant centers, taking the novel approach of including waitlist outcomes in the analysis. We studied a cohort of 6482 candidates listed in the Organ Procurement and Transplantation Network for pediatric heart transplantation between 2002 and 2014; 4665 (72%) of the candidates underwent transplantation. Candidates were divided into groups according to the average annual transplantation volume of the listing center during the study period: more than 10, six to 10, three to five, or fewer than three transplantations. We used multivariate Cox regression analysis to identify independent risk factors for waitlist and posttransplantation mortality. Of the 6482 candidates, 24% were listed in low‐volume centers (fewer than three annual transplantations). Of these listed candidates in low‐volume centers, only 36% received a transplant versus 89% in high‐volume centers (more than 10 annual transplantations) (p < 0.001). Listing at a low‐volume center was the most significant risk factor for waitlist death (hazard ratio [HR] 4.5, 95% confidence interval [CI] 3.5–5.7 in multivariate Cox regression and HR 5.6, CI 4.4–7.3 in multivariate competing risk regression) and was significant for posttransplantation death (HR 1.27, 95% CI 1.0–1.6 in multivariate Cox regression). During the study period, one‐fourth of pediatric transplant candidates were listed in low‐volume transplant centers. These children had a limited transplantation rate and a much greater risk of dying while on the waitlist.

Impact of Pretransplant Bridging Locoregional Therapy for Patients with Hepatocellular Carcinoma Within Milan Criteria Undergoing Liver Transplantation: Analysis of 3601 Patients from the US Multicenter HCC Transplant Consortium

Objective: To evaluate the effect of pretransplant bridging locoregional therapy (LRT) on hepatocellular carcinoma (HCC) recurrence and survival after liver transplantation (LT) in patients meeting Milan criteria (MC). Summary Background Data: Pre-LT LRT mitigates tumor progression and waitlist dropout in HCC patients within MC, but data on its impact on post-LT recurrence and survival remain limited. Methods: Recurrence-free survival and post-LT recurrence were compared among 3601 MC patients with and without bridging LRT utilizing competing risk Cox regression in consecutive patients from 20 US centers (2002–2013). Results: Compared with 747 LT recipients not receiving LRT, 2854 receiving LRT had similar 1, 3, and 5-year recurrence-free survival (89%, 77%, 68% vs 85%, 75%, 68%; P = 0.490) and 5-year post-LT recurrence (11.2% vs 10.1%; P = 0.474). Increasing LRT number [3 LRTs: hazard ratio (HR) 2.1, P < 0.001; 4+ LRTs: HR 2.5, P < 0.001), and unfavorable waitlist alphafetoprotein trend significantly predicted post-LT recurrence, whereas LRT modality did not. Treated patients achieving complete pathologic response (cPR) had superior 5-year RFS (72%) and lower post-LT recurrence (HR 0.52, P < 0.001) compared with both untreated patients (69%; P = 0.010; HR 1.0) and treated patients not achieving cPR (67%; P = 0.010; HR 1.31, P = 0.039), who demonstrated increased recurrence compared with untreated patients in multivariate analysis controlling for pretransplant and pathologic factors (HR 1.32, P = 0.044). Conclusions: Bridging LRT in HCC patients within MC does not improve post-LT survival or HCC recurrence in the majority of patients who fail to achieve cPR. The need for increasing LRT treatments and lack of alphafetoprotein response to LRT independently predict post-LT recurrence, serving as a surrogate for underlying tumor biology which can be utilized for prioritization of HCC LT candidates.

Effects of an early referral system on liver transplantation for hepatoblastoma at Texas Children's Hospital.

The purposes of this study were to analyze the effects of an ERS on time to transplantation and to describe our centers experience with OLT for HB. Patients who received OLT for HB between 2000 and 2013 were included. Patient and allograft characteristics, chemotherapy regimens, and prior surgical therapies were examined. The interval between diagnosis and OLT prior to and following the institution of an ERS for transplant was compared. Survival and tumor recurrence were analyzed. Nineteen patients received OLT for HB (mean age 33 months). All children received grafts from deceased donors. Two patients underwent prior resections. Tumor recurred in four patients (21.1%). Both patients who received salvage transplants experienced post‐OLT recurrence. Three of the four recurrences occurred in spite of adjuvant chemotherapy. There were three deaths: two from metastatic disease. One‐ and five‐yr survivals were 86.1% and 73.8%. After the institution of the ERS, the mean interval between tissue diagnosis and OLT was significantly reduced. Our series of 19 patients demonstrates a 21% recurrence of HB following OLT despite chemotherapy. Five‐yr survival reached 73.8%. A system of early referral can effectively reduce times between diagnosis and transplant.

Liver transplant length of stay (LOS) index: A novel predictive score for hospital length of stay following liver transplantation

An index to predict hospital length of stay after liver transplantation could address unmet clinical needs. Length of stay is an important surrogate for hospital costs and efforts to limit stays can preserve our healthcare resources. Here, we devised a scoring system that predicts hospital length of stay following liver transplantation. We used univariate and multivariate analyses on 73 635 adult liver transplant recipient data and identified independent recipient and donor risk factors for prolonged hospital stay (>30 days). Multiple imputation was used to account for missing variables. We identified 22 factors as significant predictors of prolonged hospital stay, including the most significant risk factors: intensive care unit (ICU) admission (OR 1.75, CI 1.58‐1.95) and previous transplant (OR 1.60, CI 1.47‐1.75). The length of stay (LOS) index assigns weighted risk points to each significant factor in a scoring system to predict prolonged hospital stay after liver transplantation with a c‐statistic of 0.75. The LOS index demonstrated good discrimination across the entire population, dividing the cohort into tertiles, which had odds ratios of 2.25 (CI 2.06‐2.46) and 7.90 (7.29‐8.56) for prolonged hospital stay (>30 days). The LOS index utilizes 22 significant donor and recipient factors to accurately predict hospital length of stay following liver transplantation. The index further demonstrates the basis for a clear clinical recommendation to mitigate risk of long hospitalization by minimizing cold ischemia time.

Profiling immunologic risk for acute rejection in liver transplantation: Recipient age is an important risk factor

BACKGROUND Careful management of induction and maintenance of immunosuppression is paramount to prevent acute rejection in liver transplantation. A methodical analysis of risk factors for acute cellular rejection may provide a more comprehensive method to profile the immunologic risk of candidates. METHODS Using registry data from the Organ Procurement and Transplantation Network (OPTN), we identified 42,508 adult recipients who underwent orthotopic liver transplant (OLT) between 2002 and 2013. We excluded recipients with a blank entry for treated rejection. We analyzed this all inclusive cohort in addition to a subset of 27,493 patients with just tacrolimus immunosuppression. Multivariate logistic regression was used on both cohorts and identified independent risk factors for treated acute rejection at one year. RESULTS Recipient age (reference group was 40 to 60years) was a dominant risk factor for rejection in both cohorts and had a dose response relationship. The strongest risk factors in the inclusive cohort were: age 18-25 (OR 2.20), age 26-29 (OR 2.03), and primary biliary cholangitis (OR 1.55). The most protective factors were age 70 and older (OR 0.68), and age 65-69 (OR 0.70). The rates of rejection had a similar pattern. CONCLUSIONS Although prior studies have suggested age as a risk factor for rejection in liver transplantation, this is the first study of national-level data to demonstrate a robust dose dependent relationship between age and risk for rejection at one year. Clinicians should place significant weight on recipient age when they assess their recipients for the immunologic risk of rejection.

Portosystemic shunt as a bridge to liver transplantation in infants: A comparison of two techniques

Portosystemic shunts can serve as a bridge to liver transplantation in patients with end‐stage liver disease by providing portal decompression to treat life‐threatening variceal bleeding and prevent recurrent episodes until an organ becomes available. The conventional TIPS procedure, however, is technically challenging to perform in infants due to the small size of their intrahepatic vasculature. We report two cases of emergent creation of portosystemic shunts as a bridge to liver transplantation in infants with life‐threatening variceal bleeding using a conventional TIPS technique in the first case and a percutaneous DIPS technique in the other. Both procedures were successful at reducing the portosystemic pressure gradient and preventing further variceal bleeds until a liver transplant could be performed. The novel percutaneous DIPS procedure is a valuable alternative to the conventional TIPS in infants, as it is better suited for small or challenging intrahepatic vascular anatomy.

Are drowned donors marginal donors? A single pediatric center experience

Drowning, a common cause of death in the pediatric population, is a potentially large donor pool for OLT. Anecdotally, transplant centers have deemed these organs high risk over concerns for infection and graft dysfunction. We theorized drowned donor liver allografts do not portend worse outcomes and therefore should not be excluded from the donation pool. We reviewed our single‐center experience of pediatric OLTs between 1988 and 2015 and identified 33 drowned donor recipients. These OLTs were matched 1:2 to head trauma donor OLTs from our center. A chart review assessed postoperative peak AST and ALT, incidence of HAT, graft and recipient survival. Recipient survival at one year between patients with drowned donor vs head trauma donor allografts was not statistically significant (94% vs 97%, P=.63). HAT incidence was 6.1% in the drowned donor group vs 7.6% in the control group (P=.78). Mean postoperative peak AST and ALT was 683 U/L and 450 U/L for drowned donors vs 1119 U/L and 828 U/L in the matched cohort. These results suggest drowned donor liver allografts do not portend worse outcomes in comparison with those procured from head trauma donors.

A Surge in cadaveric liver donors and a national narcotic epidemic: Is there an association?

After years of decline, there has been a recent surge in deceased donor liver allografts available for transplantation. Following the peak year of donation in 2006 with 28.7 liver donors per million population (pmp), from 2006 to 2012 the liver donors fell to 25.8 donors pmp. Inexplicably, a surge in liver donors commenced in 2013 and continued to rise with over 31 liver donors pmp in 2016, despite a nearly constant death rate in this interval. At the same time, we have a wellpublicized raging narcotic epidemic. According to the Centers for Disease Control and Prevention (CDC), the number of overdoses involving narcotics has quadrupled since 1999. This epidemic has had a profound impact, even affecting global metrics like life expectancy. We hypothesize that these 2 observations, surging deceased donors and the raging narcotic epidemic, have an association. Increasing numbers of deceased donors from drug overdoses has been well documented in the literature. We conducted our own analysis using all donors for liver transplantation in the United States from 2002 to 2016 who were 18 years of age (n5 93,400). We normalized the liver donors per capita per year by using US census population data. Using the most up-to-date data available, our analysis demonstrates from 2002 to 2016, the number of donors who died from drug intoxication increased by 1155% (0.34 to 4.27 ppm; P< 0.001). Although a significant rise, this increase in donors from drug overdoses does not account for the overall surge in deceased donors. According to our analysis, it accounts for just 34% of the total increase in donors. We suspect that the increasing national prevalence of drug abuse has a greater impact on deceased donation than these statistics project. We conducted an in-depth chart review of 200 consecutive donors offered to our institution (adult recipients only) in 2016 to further investigate the association between the donor surge and narcotic epidemic. We found only 6% of these donors were classified as drug intoxications. However, 47% of the entire donor pool had evidence of drug abuse (excluding alcohol abuse), either from social history or urine toxicology screens; 32/200 (16%) donors had a social history positive for drug abuse, 22/200 (11%) had positive toxicology screens, and 40/200 (20%) had both a positive social history and toxicology screen. Also, 24% of the positive toxicology screens were positive for cocaine and 35% for opiates. Regarding the United Network for Organ Sharing (UNOS) data (all eligible donors not just donors for liver transplantation), the proportion of CDC high-risk donors increased from 3.7% in 2002 to 24.7% in 2016 (P< 0.001) and hepatitis C donors increased from 2.3% to 6.3% (P< 0.001). This suggests that a staggering proportion of donors have evidence of drug involvement and that an increasing national prevalence of drug abuse will have an impact on the donor pool far beyond the number of UNOSdocumented drug intoxications. The novel contribution of this analysis is that, since social histories elicited from family members are notoriously inaccurate and only 55% of deceased donors in our review had toxicology screens, the impact of drug abuse on the donor pool may be even greater than previously thought. Abbreviations: CDC, Centers for Disease Control and Prevention; CNS, central nervous system; pmp, per million population; UNOS, United Network for Organ Sharing.

Liver transplantation as definitive treatment of an unresectable mesenchymal hamartoma in a child with Beckwith–Wiedemann Syndrome

Abstract Mesenchymal liver hamartomas are benign tumors that can cause life-threatening abdominal distension and carry a risk for malignant transformation. In this case report, we describe a 13-month-old male with Beckwith–Wiedemann Syndrome (BWS) who presented with multiple mesenchymal liver hamartomas causing severe intra-abdominal mass effect. Imaging revealed six large multi-locular cystic lesions, ranging from 3.8 to 8.9 cm in diameter. The large size and spread of the tumors necessitated liver transplantation for complete removal. The patient successfully underwent cadaveric piggyback liver transplantation at 25 months of age. He was alive at 16-month follow-up without evidence of tumor recurrence or graft rejection. Histological examination of the hepatic masses revealed mucinous epithelial lining and abundant hepatocytes in varying stages of differentiation, supporting the diagnosis of mesenchymal hamartoma. To the best of our knowledge, this is the first reported case of liver transplantation in a patient with BWS as definitive treatment for unresectable mesenchymal liver hamartoma.