Size Matching Deceased Donor Livers: The Tampa General Measurement System.

BACKGROUND: No reliable or standardized system exists for measuring the size of deceased donor livers to determine whether they will fit appropriately into intended recipients. METHODS: This retrospective, single-center study evaluated the efficacy of Tampa General Hospital's size-matching protocol for consecutive, deceased donor liver transplantations between October 2021 and November 2022. Our protocol uses cross-sectional imaging at the time of organ offer to compare the donor's right hepatic lobe size with the recipient's right hepatic fossa. Outcomes were analyzed, including large-for-size syndrome, small-for-size syndrome, early allograft dysfunction, primary nonfunction, graft survival, and patient survival. RESULTS: We included 171 patients in the study. The donor liver physically fit in all the patients except one whose pretransplant imaging was outdated. One patient (0.6%) had large-for-size syndrome, none had small-for-size syndrome, 15 (10%) had early allograft dysfunction, and none had primary nonfunction. There were 11 (7%) patient deaths and 11 (7%) graft failures. CONCLUSION: Our measurement system is fast and effective. It reliably predicts whether the donor liver will fit in the intended recipient and is associated with low rates of early allograft dysfunction.

The sex disparity in liver transplantation.

PURPOSE OF THE REVIEW: This review describes the sex disparity in liver transplantation (LT) and explains its underlying causes. RECENT FINDINGS: There is a small but persistent sex disparity in transplant rate and waitlist mortality that disappears once women are listed as Status 1. Allocation systems that could replace the Model for End Stage Liver Disease (MELD)-Na with scores less reliant on serum creatine and muscle mass have the potential to alleviate part of the sex disparity. Women perform worse on frailty assessments and are more likely to have nonalcoholic steatohepatitis (NASH). A diagnosis of NASH is compounding risk factor for frailty. SUMMARY: Women remain disadvantaged in their access to LT despite multiple evolutions of the allocation system. An allocation system that relies less heavily on serum creatinine could partially alleviate the sex disparity. As NASH becomes more prevalent and frailty becomes more important in listing decisions, we may also need to carefully consider differences in the manifestations of frailty between the genders.

Living Donor Versus Deceased Donor Pediatric Liver Transplantation: A Systematic Review and Meta-analysis.

Reduced-size deceased donors and living donor liver transplantation (LDLT) can address the organ shortage for pediatric liver transplant candidates, but concerns regarding technical challenges and the risk of complications using these grafts have been raised. The aim of this study was to compare outcomes for pediatric LDLT and deceased donor liver transplantation (DDLT) via systematic review. METHODS: A systematic literature search was performed to identify studies reporting outcomes of pediatric (<18 y) LDLT and DDLT published between 2005 and 2019. A meta-analysis was conducted to examine peri- and postoperative outcomes using fixed- and random-effects models. RESULTS: Overall, 2518 abstracts were screened, and 10 studies met criteria for inclusion. In total, 1622 LDLT and 6326 DDLT pediatric patients from 4 continents were examined. LDLT resulted in superior patient survival when compared with DDLT at 1, 3, and 5 y post-LT (1-y hazard ratio: 0.58, 95% confidence interval [CI] 0.47-0.73, P < 0.0001). Similarly, LDLT resulted in superior graft survival at all time points post-LT when compared with DDLT (1-y hazard ratio: 0.56 [95% CI 0.46-0.68], P < 0.0001]. The OR for vascular complications was 0.73 (95% CI 0.39-1.39) and 1.31 (95% CI 0.92-1.86) for biliary complications in LDLT compared with DDLT, whereas LDLT was associated with lower rates of rejection (OR: 0.66 [95% CI 0.45-0.96], P = 0.03). CONCLUSIONS: This meta-analysis demonstrates that LDLT may offer many advantages when compared with DDLT in children and suggests that LDLT should continue to be expanded to optimize outcomes for pediatric LT candidates.

Potential association between public medical insurance, waitlist mortality, and utilization of living donor liver transplantation: An analysis of the Scientific Registry of Transplant Recipients.

BACKGROUND: The Affordable Care Act (ACA) and subsequent Medicaid expansion has increased utilization of public health insurance. Living donor liver transplantation (LDLT) increases access to transplant and is associated with improved survival but consistently represents < 5% of LT in the United States. STUDY DESIGN: National registry data were analyzed to evaluate the impact of insurance payor on waitlist mortality and LDLT rates at LDLT centers since implementation of the ACA. RESULTS: Public insurance [Medicare RR 1.18 (1.13-1.22) P < .001, Medicaid RR 1.22 (1.18-1.27) P < .001], Latino ethnicity (P < .001), and lower education level (P = .02) were associated with increased waitlist mortality at LDLT centers. LDLT recipients were more likely to have private insurance (70.4% vs. 59.4% DDLT, P < .001), be Caucasian (92.1% vs. 83% DDLT, P < .001), and have post-secondary education (66.8% vs. 54.1% DDLT, P < .001). Despite 78% of LDLT centers being located in states with Medicaid expansion, there was no change in LDLT utilization among recipients with Medicaid (P = .196) or Medicare (P = .273). CONCLUSION: Despite Medicaid expansion, registry data suggests that patients with public medical insurance may experience higher waitlist mortality and underutilize LDLT at centers offering LDLT. It is possible that Medicaid expansion has not increased access to LDLT.

Pediatric kidney transplantation, a technical update.

PURPOSE OF REVIEW: Pediatric kidney transplantation is the definitive therapy for infants and children suffering from renal failure. It is a distinct endeavor demanding specialized care for optimal results. This includes a dedicated preoperative workup accounting for unique predisposing urologic conditions, specialized surgical techniques, and careful hemodynamic monitoring and maintenance. RECENT FINDINGS: Historically, size-matched renal allografts from pediatric donors to pediatric recipients suffered from poor outcomes. Advances in surgical technique performed at high volume centers have shown that these operations can be performed safely, helping expand the donor pool for these patients. Concurrently, transplantation of increasingly small for size infants with complex medical and surgical backgrounds has become a reality. SUMMARY: On a policy front, efforts to expand access to size-matched organs, combined with advances in medical management and immunosuppression have seen pediatric renal transplantation reach new heights. Now, these breakthroughs are heightened by the ability to transplant such organs into the smallest infants. The net result will be diminished transplant waiting times and, accordingly, improved quality of life and longevity for children suffering from renal failure.

The evolving role of ECMO in liver transplantation.

PURPOSE OF REVIEW: To review the indications for extra-corporeal membrane oxygenation (ECMO) in liver transplantation (LT) recipients and their optimal management on ECMO. RECENT FINDINGS: Recent studies have reported a 30-40% survival rate among LT recipients that receive ECMO. Increasingly, case reports have documented successful outcomes of LT performed for patients on preoperative ECMO. Outcomes appear to be superior with patients in the immediate peri-LT period with reversible causes of severe, acute respiratory, and/or cardiovascular collapse. Mortality is most commonly secondary to infection. Volume optimization with CRRT may improve outcomes and perfusion to the graft, especially for patients on veno-arterial ECMO. There is little consensus on management of anticoagulation in these patients, but it can likely be held temporarily when the patient is coagulopathic and/or experiencing bleeding complications. SUMMARY: ECMO should be considered in the peri-LT period for patients with severe, acute, and reversible causes of respiratory and/or cardiovascular collapse, with acceptable outcomes in patients that would otherwise not be expected to survive. Management of the post-LT patient on ECMO is challenging with a slowly enlarging body of literature to inform decision making.

Pediatric kidney transplantation in the United States.

PURPOSE OF REVIEW: Pediatric kidney transplantation has made great strides over the preceding years. It has become an accepted and successful remedy for thousands of patients worldwide. For best outcomes, it must be viewed and treated as a distinct entity from adult transplantation with focus on the unique challenges particular to its cohort. RECENT FINDINGS: Although efforts have been made to decrease geographic disparity and increase allograft access throughout, an unintended consequence has been prolonged wait times for pediatric patients. Concurrently, ideally size-matched organs from older pediatric donors are also being bypassed. Nevertheless, advances in surgical technique and a better understanding of the limits of donor-recipient pairing have facilitated continued usage of adult kidneys for both infants and small for age children. Immunosuppression optimization has meant mean allograft survival measured in decades. SUMMARY: Enhanced access is needed to better size-matched organs for pediatric recipients, helping diminish wait times for the youngest patients, and improving their long-term prognosis. Longitudinal multicenter studies are needed to help standardize protocols, especially as it relates to optimal surgical and perioperative management. Advances in immunosuppression will continue to enhance patient and graft survival while minimizing adverse effects.

Liver Transplantation in Patients with Sickle Cell Disease in the United States.

BACKGROUND: Up to 30% of patients with sickle cell disease (SCD) develop chronic liver disease via etiologies including sickle cell hepatopathy, acquired viral hepatitis, or secondary hemochromatosis. It is unclear how many patients with SCD ultimately undergo liver transplantation (LT) and what factors are associated with survival after LT. In this study, we examined LT outcomes in these patients by reviewing the Scientific Registry of Transplant Recipients (SRTR) and our institutional experience. METHODS: Analysis of the SRTR identified 23 LT recipients and five simultaneous liver and kidney transplantation (SLKT) recipients with SCD. Patient demographics and graft and patient survival were analyzed. Two patients with SCD at our institution underwent SLKT. RESULTS: Review of the SRTR revealed that recipients with SCD had significantly higher model for end-stage liver disease scores (33 versus 21, P = 0.004), preoperative intensive care unit admission (43.5% versus 19.1%, P = 0.007), preoperative dialysis (17.4% versus 4.9%, P = 0.009), and were more likely to be status 1 (26.1% versus 12.1%, P = 0.041) when compared with the reference population of African American LT recipients. Despite being higher risk at the time of LT, patients with SCD had equivalent posttransplant graft and patient survival when compared with the reference population (P = 0.5 and P = 0.2, respectively) and a 2:1 propensity score-matched group (P = 0.5 and P = 0.2, respectively). Two recent SLKT recipients with SCD from our institution have performed well with stable allograft function. CONCLUSIONS: Data from the SRTR demonstrate that patients with SCD can expect equivalent graft and patient survival after LT despite exhibiting more comorbidities at the time of LT. The low number of patients with SCD who underwent LT in the SRTR in comparison with the rate of chronic liver disease in this population raises the question as to whether a disparity in access to LT exists for this complex population.

Adjunctive use of hepatic angioembolization following hemorrhage control laparotomy.

BACKGROUND: Severe liver injuries pose a challenge to trauma surgeons. While the use of hepatic angioembolization (HAE) has been evaluated as a component of the nonoperative management of liver injury, little is known about the efficacy of postoperative HAE in patients who require hemorrhage control laparotomy (HCL) for liver injury. The purpose of this study is to evaluate the impact of HAE following HCL on patient survival. METHODS: This is a retrospective cohort study using the American College of Surgeons Trauma Quality Improvement Program database from January 2013 to December 2014. In propensity score matched (2:1) patients who underwent HCL-only or HCL + HAE, the impact of adjunctive use of HAE on patient survival was examined with the Cox proportional hazards regression analysis adjusting for transfusion requirement within 4 hours. We also performed a subgroup analysis in patients without severe traumatic brain injury (Abbreviated Injury Scale head ≤3). RESULTS: A total of 1,675 patients met our inclusion criteria. Of those, 75 (4.5%) patients underwent HAE after HCL (median hours to HAE, 5 hours after admission). In 225 propensity score-matched patients, the use of HAE following HCL was significantly associated with improved 24-hour mortality, but not in-hospital mortality. In the subgroup of patients without severe traumatic brain injury (n = 189), we observed significant survival benefits (24-hour and in-hospital mortality) associated with the adjunctive use of HAE. CONCLUSION: The results of our study suggest that the adjunctive use of HAE might improve survival of patients who require HCL for liver injury. Further prospective study to determine the indication for postoperative HAE is still warranted. LEVEL OF EVIDENCE: Therapeutic study, level III.

Telomerase Variants in Patients with Cirrhosis Awaiting Liver Transplantation.

Telomeres are repetitive DNA sequences that protect the ends of linear chromosomes, and they are maintained by a ribonucleoprotein complex called telomerase. Variants in genes encoding for telomerase components have been associated with a spectrum of disease in the lung, skin, bone marrow, and liver. Mutations in the telomerase reverse transcriptase and telomerase RNA component genes have been observed at a higher prevalence in patients with liver disease compared with the general population; however, the presence of variants in other components of the telomerase complex and their impact on clinical outcomes has not been explored. We evaluated 86 patients with end-stage liver disease for variants in an expanded panel of eight genes, and found that 17 patients (20%) had likely deleterious variants by in silico analysis. Seven unique likely deleterious variants were identified in the regulator of telomere elongation helicase 1 (RTEL1) gene that encodes for a DNA helicase important in telomere maintenance and genomic stability. In gene burden association analysis of their clinical data, the presence of any RTEL1 variant was associated with a 29% lower baseline white blood cell count (95% confidence interval [CI], -7% to -46%; P Value = 0.01) compared with patients without RTEL1 variants, and the presence of any exonic missense RTEL1 variant was associated with a 42% lower baseline platelet count (95% CI, -5% to -65%: P Value = 0.03). The presence of any telomerase variant was associated with an increased number of readmissions within 1 year after transplantation demonstrated by an incident rate ratio (IRR) of 3.15 (95% CI, 1.22 to 8.57). No association with survival was observed. Conclusion: Among patients who underwent liver transplantation, the presence of any exonic missense variant was associated with a longer postoperative length of stay with an IRR of 2.16 (95% CI, 1.31 to 3.68).

More Than Just Wait Time? Regional Differences in Liver Transplant Outcomes for Hepatocellular Carcinoma.

BACKGROUND: Regional allocation of deceased donor livers has led to variable wait times for hepatocellular carcinoma (HCC) patients on the liver transplant list. The purpose of our study was to evaluate how regional differences in wait time affect outcomes for HCC patients. METHODS: A retrospective, observational study was performed using the Organ Procurement and Transplantation Network database from February 27, 2002, to September 25, 2015. The cumulative incidences of transplant and waitlist death as well as intention-to-treat and posttransplant survival were evaluated for patients 18 years or older listed for deceased donor liver transplantation with stage II HCC exception points in each United Network for Organ Sharing region. A multivariable analysis of predictive factors for posttransplant survival was performed. RESULTS: Cumulative incidence of transplant decreased and cumulative incidence of waitlist death increased as regional wait time increased. Intention-to-treat survival decreased with increased regional wait time with long wait time regions 1, 5, and 9 having significantly lower intention-to-treat survival compared with many of the shorter wait time regions (P < 0.05). Wait time did not predict posttransplant survival. Significant predictive factors of posttransplant survival included alpha-fetoprotein, size of the largest tumor, number of tumors, age of the recipient, laboratory model for end-stage liver disease, donor risk index, period of transplantation, and region (P < 0.05). CONCLUSIONS: Wait time inequality affects waitlist mortality and intention-to-treat survival but does not affect posttransplant survival. Posttransplant survival is predicted by tumor biology, graft quality, recipient age, underlying liver function, and region. Regional environments of HCC care seem to drive posttransplant survival.

Balanced blood product transfusion during liver transplantation.

INTRODUCTION: This study was conducted to determine whether an intra-operative ratio of at least 1:1:2 of fresh frozen plasma (FFP):platelets (PLTs):packed red blood cells (pRBCs) improves outcomes in orthotopic liver transplantation (OLT). METHODS: A single-center, retrospective study of deceased donor OLT recipients (MELD ≥15) requiring intra-operative pRBC transfusion (years 2013-2016). Patients were grouped into those receiving an intra-operative ratio of ≥1:1:2 of FFP:PLTs:pRBCs vs ratios <1:1:2. RESULTS: Patients in ≥1:1:2 group (n = 150) and patients in <1:1:2 group (n = 80) were matched for baseline characteristics (P > .05). Patients in the ≥1:1:2 group had lower pRBC and intra-operative blood product requirements (11 ± 0.5 vs 19 ± 1.4 units, P < .001, and 33 ± 1.3 vs 43 ± 3.3 units, P = .006, respectively), improved 1-month mortality (0 vs 8%, P = .002), improved 1-year survival (P = .004), less intra-operative cardiac arrest (3% vs 10%, P = .03), and shorter operating room time (389 ± 7.2 vs 431 ± 17.2 minutes, P = .03). After multivariate adjustment for baseline and intra-operative variables, balanced blood product transfusion (BBPT) was significantly associated with less intra-operative pRBC transfusion (95% confidence interval: 0.60-0.72). CONCLUSION: Balanced blood product transfusion is associated with reduced transfusion requirements in OLT.

Invasive fungal infections following liver transplantation.

PURPOSE OF REVIEW: The review outlines the microbiology, presentation, prophylactic strategies, resistance patterns, and consequences of invasive fungal infections (IFIs) in orthotopic liver transplantation (OLT) recipients. RECENT FINDINGS: There has been an increase in the proportion of non-albicans Candida causing IFIs. The biomarkers galactomannan and ß-D-glucan should not be routinely used in the diagnosis of IFIs in OLT recipients due to their limited accuracy. Echinocandins have emerged as noninferior to fluconazole and other prophylactic regimens. Their broad spectrum of activity and side-effect profile are appealing; however, the development of echinocandin resistance, especially in Candida glabrata has been highlighted as one of their limitations. SUMMARY: A significant decline in IFIs but an increase in IFIs caused by non-albicans Candida species has been observed in the model for end-stage liver disease era. Diagnostic tools remain limited. Studies continue to support antifungal prophylaxis individualized to recipient risk with echinocandins now established as an additional option for antifungal prophylaxis. The appropriate duration of antifungal prophylaxis remains ill-defined with some studies advocating targeted therapy based on clinical status and others more prolonged therapy beyond the historically common 4 weeks. However, prolonged therapy with echinocandins can result in resistance.

Antibody-mediated rejection: what is the clinical relevance?

PURPOSE OF REVIEW: The review outlines the diagnosis, clinical implications, and treatment strategies for acute and chronic antibody-mediated rejection (AMR) after orthotopic liver transplantation (OLT). RECENT FINDINGS: A combination of clinical work-up, histopathology, C4d staining, and donor-specific antibody (DSA) should be used to diagnose AMR. The differential diagnosis for idiopathic fibrosis now includes chronic AMR. Characterization of pathogenic DSA continues to progress. De-novo and persistent DSA, particularly of the IgG3 subtype, are associated with inferior long-term outcomes.The liver allograft may confer long-term immunologic benefits to the kidney allograft after simultaneous liver-kidney transplant.The more widespread use of rituximab has improved outcomes in ABO-incompatible OLT.Although larger long-term studies of treatment options are needed, compliance with tacrolimus-based immunosuppression and transfusion minimization are agreed upon preventive strategies. SUMMARY: AMR has evolved into an established pathology in OLT recipients. Acute AMR may lead to early graft loss whereas chronic AMR results in progressive fibrosis if unrecognized. DSAs, likely in the setting of predisposing environmental factors, appear to play a role in T cell-mediated rejection and long-term graft outcomes.

Clostridium Difficile Infection from a Surgical Perspective.

BACKGROUND: The incidence and the severity of Clostridium difficile infection (CDI) have increased significantly over the last decade, especially in high-risk populations such as patients with inflammatory bowel disease (IBD). Surgeons must be able to both identify and minimize the risk of CDI in their own surgical patients and determine which CDI patients will benefit from surgery. PURPOSE: We sought to define the risk factors, compare the treatment options, define the surgical indications, and identify factors that affect surgical outcomes for CDI based on the currently available literature. RESULTS: Antibiotic use, exposure to the C. difficile bacteria, IBD, and higher levels of co-morbidity are all risk factors for CDI. The majority of CDI can be treated with antibiotics. Severe or fulminant colitis, however, has a high potential for poor outcome, but experience and some data suggest a lower mortality rate with colectomy rather than with continued medical treatment. Open total abdominal colectomy with end ileostomy is typically the preferred surgical strategy. It is often difficult to determine which patients will fail medical management as some may not manifest clinical signs of severe infection. Surrogate parameters of failure of medical therapy include respiratory and/or renal insufficiency, age greater than 60 years, peripheral vascular disease, congestive heart failure, and coagulopathy, all of which have been associated with worse surgical outcomes. Evidence suggests that in appropriately selected patients, colectomy performed before the development of shock requiring vasopressors, respiratory failure, renal failure, multi-organ dysfunction, and mental status changes may reduce mortality of the most severe forms of colitis. For less severe or recurrent presentations, creation of a loop ileostomy with intra-operative colonic lavage, fecal microbiota transfer, and C. difficile vaccinations are being discussed but have only been studied in small case-controlled series. CONCLUSIONS: Prevention, containment, and non-surgical treatment are the cornerstone of management for CDI. However, the most severe forms with toxic colitis benefit from involvement of a surgical team. Swift open total abdominal colectomy with end ileostomy in patients with severe or fulminant C. difficile colitis has the best chance to reduce mortality if it is not delayed until shock, end organ damage, vasopressor requirement, mental status changes develop. Less aggressive approaches may be appropriate for milder and refractory forms but require further study before their applicability can be determined.

Sunitinib inhibits MEK/ERK and SAPK/JNK pathways and increases sodium/iodide symporter expression in papillary thyroid cancer.

BACKGROUND: Sunitinib malate (Sutent, Pfizer, Inc.; SU11248) is a selective, multitargeted inhibitor of receptor tyrosine kinases and has been shown to inhibit receptors for VEGF, PDGF, KIT, FLT3, and RET. The objective of this study was to determine the effects of sunitinib on signal transduction pathways and on gene expression of iodide-metabolizing proteins in papillary cancer cells with the RET/PTC1 rearrangement. METHODS: We investigated the effects of sunitinib on cell growth, signal transduction pathways, and thyroid-specific gene expression in papillary thyroid cancer (PTC) cell lines that had the RET/PTC1 rearrangement. RESULTS: Sunitinib inhibited proliferation of RET/PTC1 subclones in a time- and dose-related manner. The mean 50% lethal concentration in the RET/PTC1 subclones was 1.81 microM. Incubation of RET/PTC1 cells with 1 microM sunitinib inhibited their migration potential and transformed their morphology. Sunitinib inhibited RET autophosphorylation at Y1062 and the activation of signal transducer and activator of transcription 3 by blocking Y705 phosphorylation. Sunitinib caused cell cycle arrest in the G0/G1 phase and dephosphorylation of retinoblastoma protein, but did not induce apoptosis. Western blot analysis of the p38, MEK/ERK, and SAPK/JNK mitogen-activated protein kinase signal transduction pathways showed that sunitinib blocked ERK 1/2 and JNK phosphorylation in the cytoplasm. Sunitinib treatment of RET/PTC1 cell lines, in combination, with forskolin induced expression of the sodium (Na)/iodide (I) symporter (NIS) and the transcription factors that bind the NIS upstream enhancer. Mechanistically, the inhibition of both MEK/ERK and SAPK/JNK cytoplasmic pathways individually and in combination caused an increase in NIS gene expression. CONCLUSION: Sunitinib appears to target the cytosolic MEK/ERK and SAPK/JNK pathways in the RET/PTC1 cell lines, suggesting that blocking these pathways is at least part of the mechanism by which sunitinib inhibits cell proliferation and causes stimulation of NIS gene expression in RET/PTC1 cells.