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In 2013, the Human Immunodeficiency Virus Organ Policy Equity (HOPE) Act was passed to permit the conduct of research on the transplantation of organs from donors infected with human immunodeficiency virus (HIV) into recipients who are HIV-positive. The HOPE Act workshop had many objectives including the discussion of the ethical issues involved in HIV-positive to HIV-positive transplantation, the informed consent process, and the role of independent advocates in the context of HIV to HIV transplantation. As of 2018, 22 transplant hospitals are approved, or undergoing approval, to perform HIV-positive to HIV-positive transplant surgeries, and this number is expected to grow. This study aims to: (i) briefly review the history and research of HIV+ transplantation prior to the HOPE Act, (ii) describe the ethical principles supporting the HOPE Act, (iii) characterize the informed consent process, and (iv) provide guidance regarding the role of independent advocates in the context of HIV-positive to HIV-positive transplantation.

Background The prevalence of atrial fibrillation (AF) in patients undergoing renal (RT) or liver transplantation (LT) has increased during the last decades. Yet, there is still uncertainty on the association between AF and patient and graft survival. Methods Multiple electronic databases were searched using various combinations of keywords and MeSH terms pertinent to the exposure (AF), and outcomes (graft and patient survival). Randomized or quasi-randomized controlled studies, cohort and case-control studies on adults with documented AF undergoing RT or LT were included. The quality of studies was assessed using the Newcastle-Ottawa Assessment Scale. When appropriate, data on the primary and secondary outcomes were pooled in a meta-analysis using the random-effect model. The Odds ratio was used for patients undergoing LT and the hazard ratio was used for patients who underwent renal transplantation. Results A total of 50,362 publications were identified. Six studies, with a total of 136,331 patients, satisfied the inclusion criteria. LT was performed on 2861 patients and RT was performed on 133,470 recipients. Overall, AF affected 6652 (4.8%) transplant recipients. Among them, 153 received a LT and 6499 underwent RT. The OR for mortality after LT was 2.375 (95% CI; 1.532–3.682) (P = 0.000) in AF(+) recipients and the HR was 1.859 (95% CI; 1.031–3.354) (P = 0.039) after RT. The OR for graft loss in AF(+) after LT r was 1.088 (95% CI; 0.311–3.804) (P = 0.894) and the HR for graft loss was 1.632 (95% CI; 1.200–2.218) (P = 0.002) after RT. Conclusions To the best of our knowledge, this is the first systematic review and meta-analysis to explore the association between AF and patient and graft survival after RT or LT. Our findings suggest that the presence of AF is associated with inferior patient survival. For renal transplant recipients, AF is also associated with inferior graft survival.

The multifactorial etiology of pulmonary hypertension (PH) in end-stage renal disease (ESRD) includes patients with and without elevated pulmonary vascular resistance (PVR). We explored the prognostic implication of this distinction by evaluating pretransplant ESRD patients who underwent right heart catheterization and echocardiography. Demographics, clinical data, and test results were analyzed. All-cause mortality data were obtained. Median follow-up was 4 years. Of the 150 patients evaluated, echocardiography identified 99 patients (66%) with estimated pulmonary artery (PA) systolic pressure > 36 mm Hg, which correlated poorly with mortality (HR = 1.28, 95% CI 0.72-2.27, P = .387). Right heart catheterization identified 88 (59%) patients with mean PA pressure ≥ 25 mm Hg. Of these, 70 had PVR ≤ 3 Wood units and 18 had PVR > 3 Wood units. Survival analysis demonstrated a significant prognostic effect of an elevated PVR in patients with high mean PA pressures (HR = 2.26, 95% CI 1.07-4.77, P = .03), while patients with high mean PA pressure and normal PVR had equivalent survival to those with normal PA pressure. Despite the high prevalence of PH in ESRD patients, elevated PVR is uncommon and is a determinant of prognosis in patients with PH. Patients with normal PVR had survival equivalent to those with normal PA pressures.

Tissue plasminogen activator (tPA) has been reported to treat intraoperative pulmonary thromboembolism (PTE) during liver transplantation (LT). However, tPA administration is often delayed due to fear of uncontrolled bleeding and storage in a refrigerator outside of operating rooms. Various dosages of tPA were used. We hypothesize that a policy of tPA storage and low dosage use improves patient outcomes. At a transplantation center, a multidisciplinary committee has implemented a tPA policy since April 2014, which includes the following: (1) timely administering of low-dose tPA (0.5-4 mg) for intraoperative PTE; (2) keeping 2 vials of tPA (2 mg/vial) in the operating room at room temperature; and (3) transferring unused tPA vials to the cardiology catheterization laboratory for next-day use. A prospective observational study was conducted to record the incidence and outcome of PTE during LTs. Over the next 19 months, 99 adult deceased donor LTs were performed with 1 (1.0%) intraoperative PTE. A 45-year-old woman with hepatitis C developed PTE within 5 minutes after graft reperfusion. A 2-mg tPA was immediately administered via a central venous line with hemodynamic improvement and clot lysis. Thromboelastography was normalized in 90 minutes. Five LT cases developing intraoperative PTE have been reported to receive “standard” dosages of tPA (20-110 mg) or urokinase (4400 IU/kg), which were administered more than 20 minutes after the diagnosis of PTE. One intraoperative death and one later mortality were noted with intracranial hemorrhages/infarction of 3 cases. The multidisciplinary low-dose tPA policy for PTE was suggested to be effective.

Background: Recent studies have reported a significant decrease in wound problems and hospital stay in obese patients undergoing renal transplantation by robotic-assisted minimally invasive techniques with no difference in graft function. Objective: Due to the lack of cost-benefit studies on the use of robotic-assisted renal transplantation versus open surgical procedure, the primary aim of our study is to develop a Markov model to analyze the cost-benefit of robotic surgery versus open traditional surgery in obese patients in need of a renal transplant. Methods: Electronic searches will be conducted to identify studies comparing open renal transplantation versus robotic-assisted renal transplantation. Costs associated with the two surgical techniques will incorporate the expenses of the resources used for the operations. A decision analysis model will be developed to simulate a randomized controlled trial comparing three interventional arms: (1) continuation of renal replacement therapy for patients who are considered non-suitable candidates for renal transplantation due to obesity, (2) transplant recipients undergoing open transplant surgery, and (3) transplant patients undergoing robotic-assisted renal transplantation. TreeAge Pro 2017 R1 TreeAge Software, Williamstown, MA, USA) will be used to create a Markov model and microsimulation will be used to compare costs and benefits for the two competing surgical interventions. Results: The model will simulate a randomized controlled trial of adult obese patients affected by end-stage renal disease undergoing renal transplantation. The absorbing state of the model will be patients' death from any cause. By choosing death as the absorbing state, we will be able simulate the population of renal transplant recipients from the day of their randomization to transplant surgery or continuation on renal replacement therapy to their death and perform sensitivity analysis around patients' age at the time of randomization to determine if age is a critical variable for cost-benefit analysis or cost-effectiveness analysis comparing renal replacement therapy, robotic-assisted surgery or open renal transplant surgery. After running the model, one of the three competing strategies will result as the most cost-beneficial or cost-effective under common circumstances. To assess the robustness of the results of the model, a multivariable probabilistic sensitivity analysis will be performed by modifying the mean values and confidence intervals of key parameters with the main intent of assessing if the winning strategy is sensitive to rigorous and plausible variations of those values. Conclusions: After running the model, one of the three competing strategies will result as the most cost-beneficial or cost-effective under common circumstances. To assess the robustness of the results of the model, a multivariable probabilistic sensitivity analysis will be performed by modifying the mean values and confidence intervals of key parameters with the main intent of assessing if the winning strategy is sensitive to rigorous and plausible variations of those values. [JMIR Res Protoc 2018;7(3):e74]

The kidney wait list has outgrown the supply of available organs every year. Efforts are being made to minimize discard rate of organs. One such area is the use of kidneys with glomerular microthrombi (MT). We retrospectively examined graft/patient outcomes in 28 cases with MT in pre-implantation biopsies. All patients had follow-up of at least 36 months, or until graft loss or death. In total, 17 of the 18 patients who underwent follow-up biopsy within 90 days of transplantation had cleared all MT. Most patients had excellent long-term graft function. On a closer review of the biopsies included in our study, we found that even in the organs with the most widespread thrombosis, the median percentage of glomeruli with more than 50 percentage of the capillary loops occluded was 8% (range 0-17%). The current practice of mentioning the % of glomeruli with thrombi cannot adequately capture the extent of donor organ pathology, as the actual % glomerular area involved can vary greatly from case to case. Future studies should attempt to quantify donor thrombi by a more robust method and revisit the issue of using clinico-pathologic parameters to predict allograft function in the setting of MT.

BACKGROUND Noncompressible hemorrhage of the torso remains a challenging surgical dilemma. Stent graft repair requires endovascular expertise, imaging, and inventory that are not available within the critical window of massive hemorrhage. We developed a retrievable stent graft for rapid hemorrhage. We further investigated a radiofrequency (RF) positioning approach as a possible alternative to the logistics of fluoroscopy. METHODS A retrievable stent graft was constructed with a novel "petal and stem" design from nitinol and covered with a sleeve of electrospun polyurethane. The stent graft was tested using an in vitro model of simulated hemorrhage. Next, the stent graft was examined in vivo using a porcine model of noncompressible hemorrhage. The stent was examined for hemorrhage control in a porcine model of either aortic or caval injury. An RF reader was assembled from an Arduino processor while RF tags were affixed to the ends of the stent graft. Detection accuracy of a handheld RF wand for an RF tag was quantified both in vitro and through tissue. RESULTS The retrievable RESCUEstent graft was deployed within minutes and rapidly controlled traumatic hemorrhage angiographically in both aortic injury (n = 3) and caval injury (n = 2). Stent grafts were easily recaptured in both models in under 15 seconds. The LED light of a handheld RF detector illuminated when positioned directly over an RF tag. The RF detection approach revealed positioning accuracy to within 1 cm of the intended target, despite tissue interference. CONCLUSION This study demonstrates the rapid deployment and retrieval of a RESCUE stent graft as well as the ability to tamponade injuries of the aorta and cava. In addition, this study demonstrates the feasibility of RF tags to guide stent placement through tissue. More rigorous models are needed to define the effectiveness of this approach in the setting of vascular injury and shock.

Purpose The perceptions and expectations of students on the surgery clerkship were evaluated and compared with those of surgical residents and faculty. Methods A voluntary and anonymous survey was distributed to third year medical students, general surgery residents, and surgery faculty. Statistical analysis was performed using the χ 2 and Cochran-Mantel-Haenszel tests ( P value Results Medical students, surgery residents and faculty largely agreed on student responsibilities during morning rounds. However, more students (96.9%) than residents (86.2%) and faculty (77.3%) believed they should be writing progress notes, and fewer students (85%) than residents (100%) and faculty (95.5%) thought they should be taught during morning rounds ( P P = 0.04, respectively). The expected and actual educational experience on the surgical clerkship was similar. The amount of instruction provided each week by residents and faculty was similar to the amount expected by students; each group believed that surgical residents were good educators. Students, residents, and faculty agreed on many essential skills for a student to learn by the clerkship’s end; however, more students (85.8%) than residents (58.6%) and faculty (68.2%) viewed identifying surgical complications as an essential skill ( P Conclusions Overall, the expectations of the medical students, surgical residents, and surgical faculty on the surgery clerkship were well matched. However, there were some instances where the students thought they should be more involved in patient care than did the residents and the faculty. It is important for surgical educators to be aware of these discrepancies to fully maximize the educational experience of medical students.

The field of renal transplantation has undergone major advancements with regard to organ selection, preservation, and allocation; patient selection; and short- and long-term immunosuppressive management. However, despite these strides, the procedure of renal allograft implantation has remained relatively unchanged for the past 40 years. Cadaveric whole-organ pancreas transplantation is done as part of a simultaneous pancreas/kidney transplant, after kidney transplantation (pancreas after previous successful cadaveric or living-donor renal transplant), or as a sole procedure.

Donation after cardiac death has been adopted to address the critical shortage of donor organs for transplant. Recovery of these organs is hindered by low blood flow that leads to permanent organ injury. We propose a novel approach to isolate the perfusion of the abdominal organs from the systemic malperfusion of the dying donor. We reasoned that this design could improve blood flow to organs without open surgery, while respecting the ethical principle that cardiac stress not be increased during organ recovery. Conditions within the stent were analysed using a computational fluid dynamics (CFD) method and validated on two prototypes in vitro. The hydrodynamic pressure drop across the stent was measured as 0.14-0.22 mmHg, which is a negligible influence. Device placement studies were also conducted on swine model fluoroscopically. All these results demonstrated the feasibility of rapidly isolating the perfusion to abdominal organs using a compartmentalised stent graft design.

Living donor kidney transplantation (LDKT) is the optimal treatment for end-stage kidney disease (ESKD). The evaluation process for a kidney transplant is complex, time consuming, and burdensome to the ESKD patient. Also, race disparities exist in rates of transplant evaluation completion, transplantation, and LDKT. In December 2012 our transplant center implemented a streamlined, one-day evaluation process, dubbed Kidney Transplant Fast Track (KTFT). This paper describes the protocol of a two-part study to evaluate the effectiveness of KTFT at increasing transplant rates (compared to historical controls) and the TALK intervention (Talking About Live Kidney Donation) at increasing LDKT during KTFT. All participants will receive the KTFT evaluation as part of their usual care. Participants will be randomly assigned to TALK versus no-TALK conditions. Patients will undergo interviews at pre-transplant work-up and transplant evaluation. Transplant status will be tracked via medical records. Our aims are to: (1) test the efficacy and cost effectiveness of the KTFT in reducing time to complete kidney transplant evaluation, and increasing kidney transplant rates relative to standard evaluation practices; (2) test whether TALK increases rates of LDKT during KTFT; and (3) determine whether engaging in a streamlined and coordinated-care evaluation experience within the transplant center reduces negative perceptions of the healthcare system. The results of this two-pronged approach will help pave the way for other transplant centers to implement a fast-track system at their sites, improve quality of care by transplanting a larger number of vulnerable patients, and address stark race/ethnic disparities in rates of LDKT.

Background Hepatic ischemia/reperfusion (I/R) injury is a serious complication of liver surgery and transplantation. Regulation of this injury response occurs at the cellular and molecular levels. Previous studies have shown that interleukin-6 (IL-6) is a negative regulator of the acute inflammatory injury occurring as a result of hepatic I/R. The signal transducer and activator of transcription-3 (STAT3) is a key target of receptor signaling for IL-6. Both IL-6 and STAT3 have been implicated in the protective effects of ischemic preconditioning of the liver. However, there have been no studies that have directly addressed the potential role of STAT3 in regulating acute inflammatory liver injury induced by I/R. In the current study, we investigated whether blockade of STAT3 phosphorylation altered the injury response to hepatic I/R injury. Methods Male Balb/c mice were subjected to 90 min of partial hepatic ischemia followed by reperfusion with or without treatment with specific inhibitors of STAT3 activation, AG490 (selective JAK2 inhibitor), or STATTIC (direct inhibitor of STAT3 phosphorylation). Mice were sacrificed at 8 and 24 h after reperfusion. Results STAT3 activation was induced by I/R. This activation was partially inhibited by administration of AG490 and almost completely abrogated by treatment with STATTIC. Despite the blockade of STAT3, neither AG490 nor STATTIC had any effect on acute liver injury induced by I/R. Treatment with STATTIC did reduce hepatic neutrophil accumulation. Conclusion The data suggest that STAT3 is not a central regulator of acute liver injury induced by I/R.

Background Nonalcoholic fatty liver disease (NAFLD) refers to an increasingly diagnosed condition involving triglyceride accumulation into hepatocytes resulting in a broad spectrum of liver injury. The progression of NAFLD, a relatively benign condition, to nonalcoholic steatohepatitis (NASH) involves the hepatic infiltration of inflammatory cells and subsequent hepatocellular injury. Ischemia/reperfusion (I/R) injury of the liver is a major complication of liver resection, hepatic trauma, and liver transplantation. To date, there have been no studies that have evaluated the effects of hepatic I/R on models of NASH. Objective Evaluate the effects of hepatic I/R on a mouse model of NASH. Methods A mouse model of progressive NASH was developed and evaluated using C57BL/6 mice fed a methionine choline deficient diet for 3, 6, 9, and 12 wk. Mice subsequently underwent 90 min of partial hepatic ischemia with reperfusion of 1, 4, and 8 h. Mice were sacrificed after the indicated periods, and blood and liver samples were taken for analysis. Results Mice fed the MCD diet showed a rapid induction of hepatic steatosis, inflammation, and fibrosis by 3 wk that persisted over the 12-wk period of diet, as demonstrated by histologic examination, alanine aminotransferase (ALT), and liver content of myeloperoxidase (MPO). The response to I/R in livers with progressive NASH fed MCD diet for 3, 6, 9, and 12 wk showed marked neutrophil recruitment and hepatocyte necrosis. Conclusion These data suggest the inflammatory response from I/R is augmented in livers with NASH histopathology compared with normal liver.

The process of liver repair and regeneration following hepatic injury is complex and relies on a temporally coordinated integration of several key signaling pathways. Pathways activated by members of the CXC family of chemokines play important roles in the mechanisms of liver repair and regeneration through their effects on hepatocytes. However, little is known about the signaling pathways utilized by CXC chemokine receptors in hepatocytes. Here we review our current understanding of the pathways involved in both CXC chemokine receptor signaling in other cell types, most notably neutrophils, and similar pathways operant during hepatocyte proliferation/liver regeneration in order to formulate a basis for the function of CXC chemokine receptor signaling in hepatocytes.

Background. The efficacy of plasma cell targeted therapies for antibody-mediated rejection (AMR) has not been defined in detail. The purpose of this study was to compare early and late acute AMR in terms of immunologic characteristics and responses with proteasome inhibitor (PI) therapy. Methods. Renal transplant recipients with acute AMR were treated with PI-based regimens. Early acute AMR was defined as occurring within 6 months posttransplant. Immunodominant donor-specific antibody (iDSA) was defined as the DSA with the highest level. Results. Results are expressed as early or late acute AMR. Thirty AMR episodes (13 early, 17 late) were treated in 12 and 16 patients. Early but not late AMR was associated with presensitization. Late AMR iDSA levels were higher, and specificities were primarily class II (DQ being most frequent). Early AMR patients demonstrated greater reduction in iDSA at 7, 14, and 30 days and at the posttreatment nadir (81.5%+21.2% vs. 51.4%+27.6%; P

Previous studies have shown that CXC chemokines containing Glu-Leu-Arg (ELR) in their amino-terminus stimulate hepatocyte proliferation and liver regeneration after partial hepatectomy. These ELR+CXC chemokines bind to two receptors, CXCR1 and CXCR2. Previous work has shown that CXCR2 is involved in the proliferative effects of CXC chemokines. However, the function of CXCR1 during the regenerative response has not been studied. The aim of the current study was to investigate the role of CXCR1 in liver regeneration after partial hepatectomy. C57BL/6 (wild type) or CXCR1-/- mice were subjected to 70% partial hepatectomy or sham surgery and sacrificed on day 2 and 4 after operation. There were no significant differences in liver-to-body weight ratio or hepatocyte proliferation. The data suggest that CXCR1 does not mediate the proliferative effects of ELR+ CXC chemokines during liver regeneration after partial hepatectomy.

Ischemia/reperfusion (I/R) of the liver often occurs as a result of liver resection surgery, transplantation, and trauma and is a primary cause of subsequent liver dysfunction (1-3). The recovery and regeneration of the liver after I/R is associated with the temporal expression of cell cycle control proteins (4). Recent data from our laboratory has demonstrated that this process is regulated by signaling through CXC chemokine receptor-2 (CXCR2) (5). These studies demonstrated that deletion or pharmacological blockade of CXCR2 increased hepatocyte proliferation and liver regeneration in association with increased activation of the transcription factors, nuclear factor-κB (NF-κB) and signal transducer and activator of transcription-3 (STAT3). Furthermore, we showed that ligands of CXCR2 have direct, dose-dependent effects on hepatocytes to regulate cell death or proliferation (5). The ligands for CXCR2 are comprised of a subclass of CXC chemokines which possess the amino acid sequence Glu-Leu-Arg (ELR motif) in the amino terminus (6, 7). However, CXCR2 is not the only receptor for ELR+ CXC chemokines. In humans, CXC chemokine receptor-1 (CXCR1) also binds many of these ligands and has both overlapping and independent functions to CXCR2 (8-13). The murine homolog of human CXCR1 remained elusive for many years, but the gene for murine CXCR1 was recently cloned and characterized (14, 15). Murine CXCR1 shares 64% and 89% homology at the amino acid level with human CXCR1 and murine CXCR2, respectively (15). Murine CXCR1 has been shown to bind to multiple CXC chemokines (16), but it is unknown if the receptor is expressed in the liver during injury. In the present study, we sought to determine if CXCR1 plays a functional role in the injury and recovery from hepatic I/R.

Background Hepatic ischemia/reperfusion (I/R) injury is a principal consideration of trauma, resectional liver surgery, and transplantation. Despite improvements in supportive care, hepatic I/R injury continues to negatively impact patient outcomes because of significant tissue damage and organ dysfunction. CXC chemokines have been implicated as key mediators in the deleterious inflammatory cascade after hepatic I/R and also as important, beneficial regulators of liver recovery and regeneration. As such, their potential to mediate both beneficial and detrimental effects on hepatocytes makes them a key target for therapy. Herein, we provide a review of the inflammatory mechanisms of hepatic I/R injury, with a focus on the divergent functions of CXC chemokines in this response compared with other liver insults, and offer an explanation of this apparent paradox. Data sources MEDLINE and PubMed. Conclusions CXC chemokines are key mediators of both the inflammatory response to hepatic I/R as well as the recovery from this injury. Their contrasting functions in the regeneration of liver mass after an ischemic insult indicates that therapeutic manipulation of these mediator pathways should differ depending on the surgical milieu.

Background Transplant recipients are at increased risk of malignancy; however, the influence of transplantation on cancer outcomes has not been rigorously defined. The purpose of this study was to examine the influence of transplantation on the outcomes of individual cancers. Methods De novo nonsmall cell lung cancer, colon cancer, breast cancer, prostate cancer, bladder cancer, renal cell cancer (RCC), and malignant melanoma data in 635 adult (>18 years of age) transplant recipients (from the Israel Penn International Transplant Tumor Registry) were compared with data from 1,282,984 adults in the general population (from the Surveillance, Epidemiology, and End Results database). Results Compared with the general population, transplant patients were more likely to have early stage (AJCC stage 0-II) RCC, but more advanced (AJCC stage >II) colon cancer, breast cancer, bladder cancer, and malignant melanoma. Compared with the general population, disease-specific survival was worse in the transplant population for colon cancer (all stages), nonsmall cell lung cancer (stage II), breast cancer (stage III), prostate cancer (stage II, III, and IV), bladder cancer (stage III), and RCC (stage IV). Multivariate analyses demonstrated transplantation to be a negative risk factor for survival for each cancer studied, and transplantation and cancer stage at diagnosis to be the most profound negative survival predictors. Conclusions These analyses indicate that, for several common cancers, transplant patients experience worse outcomes than the general population. The data also suggest that cancers in transplant recipients are more aggressive biologically at the time of diagnosis.

Background. Current antihumoral therapies in transplantation and autoimmune disease do not target the mature antibody-producing plasma cell. Bortezomib is a first in class proteosomal inhibitor, that is Food and Drug Administration approved, for the treatment of plasma cell-derived tumors that is multiple myeloma. We report the first clinical experience with plasma cell-targeted therapy (bortezomib) as an antirejection strategy. Methods. Eight episodes of mixed antibody-mediated rejection (AMR) and acute cellular rejection (ACR) in six transplant recipients were treated with bortezomib at labeled dosing. Monitoring included serial donor-specific antihuman leukocyte antigen antibody (DSA) levels and repeated allograft biopsies. Results. Six kidney transplant patients received bortezomib for AMR and concomitant ACR. In each case, bortezomib therapy provided (1) prompt rejection reversal, (2) marked and prolonged reductions in DSA levels, (3) improved renal allograft function, and (4) suppression of recurrent rejection for at least 5 months. Moreover, immunodominant DSA (iDSA) (i.e., the antidonor human leukocyte antigen antibody with the highest levels) levels were decreased by more than 50% within 14 days and remained substantially suppressed for up to 5 months. One or more additional DSA were present at lower concentrations (non-iDSA) in each patient and were also reduced to nondetectable levels. Bortezomib-related toxicities (gastrointestinal toxicity, thrombocytopenia, and paresthesias) were all transient. Conclusions. Bortezomib therapy: (1) provides effective treatment of AMR and ACR with minimal toxicity and (2) provides sustained reduction in iDSA and non-iDSA levels. Bortezomib represents the first effective antihumoral therapy with activity in humans that targets plasma cells.

Frailty is a known risk factor for major life-threatening liver transplant complications, deaths, and waitlist attrition. Whether frailty indicates risk for adverse outcomes in cirrhosis short of lethality is not well defined. We hypothesized that clinical measurements of frailty using gait speed and grip strength would indicate the risk of subsequent hospitalization for the complications of cirrhosis.We assessed frailty as gait speed and grip strength in a 1-year prospective study of 373 cirrhotic patients evaluated for or awaiting liver transplantation. We determined its association with the outcome of subsequent hospital days/100 days at risk for 7 major complications of cirrhosis. We tested potential covariate influences of Model for Endstage Liver Disease (MELD) and Child-Turcotte-Pugh (CTP) scores, age, sex, height, depression, narcotic use, vitamin D deficiency, and hepatocellular carcinoma using multivariable modeling.Patients experienced 2.14 hospital days/100 days at risk, or 7.81 days/year. Frailty measured by gait speed was a strong risk factor for hospitalization for all cirrhosis complications. Each 0.1 m/s gait speed decrease was associated with 22% greater hospital days (P0.001). Grip strength showed a similar but nonsignificant association. Gait speed remained independently significant when adjusted for MELD, CTP, and other covariates. At hospital costs of $4,000/day, patients with normal 1 m/s gait speed spent 6.2 days and $24,800/year; patients with 0.5 m/s speed spent 21.2 days and $84,800/year; and patients with 0.25 m/s speed spent 40.2 days and $160,800/year.Frailty as measured by gait speed is an independent and potentially modifiable risk factor for cirrhosis complications requiring hospitalization. The potential clinical value of frailty measurements to help define such risk merits broader evaluation.

Limited information is available on the pharmacokinetics of drugs in the donors and recipients following adult living donor liver transplantation (LDLT). Given that both the donors and recipients receive multiple drug therapies, it is important to assess the pharmacokinetics of drugs used in these patients.Pathophysiological changes that occur post-surgery and regulatory factors that may influence pharmacokinetics of drugs, especially hepatic drug metabolism and transport in both LDLT donors and the recipients are discussed. Pharmacokinetic data in animals with partial hepatectomy are presented. Clinical pharmacokinetic data of certain drugs in LDLT recipients are further reviewed.It takes up to six months for the liver volume to return to normal after LDLT surgery. In the LDLT recipients, drug exposure generally is higher with lower clearance during early period post-transplant; lower initial dosages of immunosuppressants are used than deceased donor liver transplant recipients during the first six months post-transplantation. In animals, the activities of hepatic drug metabolizing enzymes and transporters are known to be altered differentially during liver regeneration. Future studies on the actual hepatic function with reference to drug metabolism, drug transport, and biliary secretion in both LDLT donors and recipients are required.

Frailty with sarcopenia in cirrhosis causes liver transplant wait-list attrition and deaths. Regular physical activity is needed to protect patients with cirrhosis from frailty. We subjectively assess physical performance in selecting patients for transplant listing, but we do not know whether clinical assessments reflect the extent of activity patients actually perform. To investigate this question, 53 wait-listed patients self-assessed their performance of ordinary physical tasks using the Rosow-Breslau survey, and clinicians assessed their physical performance status with the Karnofsky index. We compared these assessments with actual activity measured using an accelerometer/thermal sensing armband worn from 4 to 7 days. We found that their measured activity was among the lowest reported in chronic disease, similar to that of patients with advanced chronic pulmonary disease or renal failure. Their percentages of waking hours spent in sedentary, light, and moderate-vigorous activity were 75.9% ± 18.9%, 18.9% ± 14.3%, and 4.9% ± 6.9%, respectively. Higher mean sedentary and lower mean moderate-vigorous activity was significantly associated with 9 wait-list deaths (P = 0.004). Compared with a range of 7000-13,000 steps/day in healthy adults, patients' mean steps/day were 3164 ± 2842. Both their activity percentage and step data were typical of other severely inactive populations. Neither their Rosow-Breslau scores (mean 2.3 ± 0.8, maximum 3.0) nor their Karnofsky scores (mean 79 ± 12, maximum 100) suggested major impairment or showed a correlation with patients' actual physical performance. In conclusion, physical activity in patients with cirrhosis wait-listed for transplantation is highly sedentary. Self-assessments and provider assessments of physical activity do not reliably indicate actual performance. Whether the gap between assessed and actual performance may be favorably modified by interventions to improve activity and ameliorate frailty merits further study. Liver Transplantation 22 1324-1332 2016 AASLD.

Background Vitamin D is a steroid hormone with multiple vital roles within the immune system. Various studies evaluated the influence of vitamin D on infections postrenal transplantation and found contrasting results. This study aimed to assess the relationship between vitamin D status and the incidence of infection in renal transplant recipients. Methods This is a retrospective cohort study of adult renal transplant recipients at the University of Pittsburgh Medical Center between 2005 and 2012. Patients were grouped as vitamin D sufficient (≥30 ng/mL) or deficient (

Muscle wasting, sarcopenia, is common in advanced cirrhosis and predicts adverse outcomes while awaiting and following liver transplantation. Frequent post-transplant worsening of sarcopenia has attracted recent interest. It is unknown whether this serious problem is an expected metabolic consequence of transplantation or results from confounding conditions such as recurrent allograft liver disease or avoidable post-transplant complications. To clarify this question, we studied pre- and post-transplant muscle mass in a retrospective cohort of 40 patients transplanted for three diseases - alcoholic cirrhosis, non-alcoholic steatohepatitis cirrhosis, and primary sclerosing cholangitis cirrhosis - in whom allograft disease recurrence was monitored and excluded, and who lacked common post-transplant muscle wasting complications such as sepsis, renal failure, ischemia, and cholestasis. We measured skeletal muscle index (SMI) using computed tomography before and 12-48 months after transplant. SMI as a categorical variable significantly improved, from 18 patients above the normal cutoff pre-transplant to 28 post-transplant (p = 0.008). SMI increases were greatest in patients with the lowest pre-transplant SMI (p < 0.01). As a continuous variable, mean SMI remained stable, with a non-significant trend toward improvement. We conclude that after liver transplantation sarcopenia does not progress but is arrested and frequently improves in the absence of confounding conditions.

Kidney transplantation is the preferred therapy for patients with end-stage renal disease (ESRD). With improvements in allograft and patient outcomes, patients with prior kidney allograft failures are increasingly becoming candidates for repeat transplantation.1 According to the annual Scientific Registry for Transplant Recipients (SRTR) report for the year 2011, approximately 12% of kidney transplant recipients had prior renal allograft failure.2 In addition, renal failure is common in recipients of other nonrenal solid organ transplants with rates of CKD of up to 16% and in those with CKD, an ESRD incidence of up to 30% over 36 months post-nonrenal organ transplantation which varies from organ to organ.3-6 With improvements in medical care, patients with nonrenal solid organ transplants are living longer to become candidates for kidney after solid organ transplantation.7 This group which constituted less than 1% of the waitlist candidates before 1995 increased to 3.3% in 2008 and were more likely to be listed preemptively (38% vs 21% in those without prior nonrenal solid organ transplantation).8 According to the SRTR annual report, 2.6% of transplants performed in year 2011 were in recipients of prior nonrenal solid organ transplants.2 Only a few previous studies have compared renal allograft outcomes in recipients who have undergone other solid organ transplants compared with those undergoing primary or repeat kidney transplantation. These previous studies were based on national databases with large center to center variations in practices and issues with nonuniform coding.9,10 The current study is a retrospective single-center study that analyzes specifically the renal allograft outcome after primary kidney, repeat kidney and kidney-after-other solid organ transplant. We evaluated various demographic, donor/recipient, and posttransplant variables across the 3 groups.

Interleukin (IL)-33 is a recently identified member of the IL-1 family that binds to the receptor, ST2L. In the current study, we sought to determine whether IL-33 is an important regulator in the hepatic response to ischemia/reperfusion (I/R). Male C57BL/6 mice were subjected to 90 minutes of partial hepatic ischemia, followed by up to 8 hours of reperfusion. Some mice received recombinant IL-33 (IL-33) intraperitoneally (IP) before surgery or anti-ST2 antibody IP at the time of reperfusion. Primary hepatocytes and Kupffer cells were isolated and treated with IL-33 to assess the effects of IL-33 on inflammatory cytokine production. Primary hepatocytes were treated with IL-33 to assess the effects of IL-33 on mediators of cell survival in hepatocytes. IL-33 protein expression increased within 4 hours after reperfusion and remained elevated for up to 8 hours. ST2L protein expression was detected in healthy liver and was up-regulated within 1 hour and peaked at 4 hours after I/R. ST2L was primarily expressed by hepatocytes, with little to no expression by Kupffer cells. IL-33 significantly reduced hepatocellular injury and liver neutrophil accumulation at 1 and 8 hours after reperfusion. In addition, IL-33 treatment increased liver activation of nuclear factor kappa light-chain enhancer of activated B cells (NF-κB), p38 mitogen-activated protein kinase (MAPK), cyclin D1, and B-cell lymphoma 2 (Bcl-2), but reduced serum levels of CXC chemokines. In vitro experiments demonstrated that IL-33 significantly reduced hepatocyte cell death as a result of increased NF-κB activation and Bcl-2 expression in hepatocytes. Conclusion: The data suggest that IL-33 is an important endogenous regulator of hepatic I/R injury. It appears that IL-33 has direct protective effects on hepatocytes, associated with the activation of NF-κB, p38 MAPK, cyclin D1, and Bcl-2 that limits liver injury and reduces the stimulus for inflammation. (HEPATOLOGY 2012)

Background We sought to determine the outcome predictors of 94 cirrhotic patients undergoing laparoscopic cholecystectomy (LC). Methods We performed a single-center, retrospective review of cirrhotic patients undergoing LC for symptomatic gallbladder disease. Statistical analysis was completed using the Chi-square, Wilcoxon rank-sum, and Student t tests as appropriate. Results Ninety-four procedures were completed. The median Child-Turcotte-Pugh (CTP) score was 6 (range, 5–12), and the average Model for End-Stage Liver Disease (MELD) score was 11 ± 5. Hepatitis C was the most common etiology of liver disease (50%) followed by Laennec's cirrhosis (22%). The average length of stay was 2.6 ± 4.3 days; 21% were outpatient procedures. The conversion rate was 11%. Conversion risk factors were decreased serum albumin, increased MELD score, and blood loss. Morbidity occurred in 32 patients. Predictors of morbidity were decreases in serum albumin, increases in International Normalized Ratio (INR) and CTP score, and the number of intraoperative red blood cell transfusions. Mortality occurred in 4 patients. Increased INR, CTP score, CTP class, the number of intraoperative blood and platelet transfusions were predictors of mortality. Conclusion LC can be safely performed in cirrhotic patients with appropriate patient selection. Liver synthetic function, operative blood loss, transfusion requirement, CTP, and MELD scores may be used to predict outcomes in these patients.

Item does not contain fulltext BACKGROUND: Positive surgical role models influence medical students to pursue a career in surgery. However, the perception by role models of their own effectiveness has yet to be examined. In this study, we evaluated the influence of surgical role models on medical student career choice, and how these role models perceive themselves. METHODS: We distributed a voluntary and anonymous survey to third-year medical students, general surgery resident applicants, general surgery residents, and attending surgery faculty during the 2010-2011 academic year. We performed statistical analysis using the chi-square and Cochran-Mantel-Haenszel tests (P < 0.05 was significant). RESULTS: Medical students and resident applicants agreed that faculty and residents are important in shaping the career paths of students. The applicants were more likely to agree than were students that clerkship role models (P = 0.0049) and mentors (P = 0.0035) affected their interest in surgery. The applicants were also more likely to agree than the students that attending surgeons (P = 0.0004), senior (P = 0.0019) and junior (P = 0.0028) surgery residents served as positive role models. Although the surgical faculty and residents agreed with the students that each level of the surgical team served as positive role models, they did not agree as strongly with the students that they have an important role in shaping students' career path (P < 0.0001). CONCLUSIONS: Surgical faculty and residents serve as positive role models for medical students. They have an essential role in shaping students' career paths and should be more cognizant of their influence, which may draw a student toward or lead them away from the field of surgery. 01 oktober 2012

Ischemia/reperfusion (I/R) injury of the liver is a major complication of hemorrhagic shock, liver resection and transplantation (1) (2). It is widely accepted that there are two distinct phases in hepatic I/R injury. The first phase of injury occurs during the initial few hours after reperfusion and is related to the production of reactive oxygen species from Kupffer cells, leading to mild hepatocellular injury (3) (4). The late phase injury is initiated by inflammatory mediators released by activated Kupffer cells and hepatocytes. These mediators, including interleukin (IL)- 12/23, tumor necrosis factor-α (TNF-α) and IL-1, induce the expression of CXC chemokines and adhesion molecules which recruit activated neutrophils from the liver microcirculation to the parenchyma (5) (6) (7) (8) (9) (10). These neutrophils then contribute to hepatocyte and vascular endothelial cell injury by releasing of oxidants and proteases (11) (4). The expression of inflammatory mediators contributing to this response is largely controlled by the transcription factor nuclear factor (NF)-κB. Based on a number of recent studies, it appears that the role of NF-κB in the hepatic response to I/R is cell-specific, such that NF-κB activation in Kupffer cells and endothelial cells promotes inflammatory gene expression, whereas activation in hepatocytes promotes cell survival (12–16). A recent study has suggested a connection between acute liver pathology and an NF-κB-associated receptor-ligand system (17). This system includes the receptor activator of NF-κB (RANK) (18) (19), its ligand, RANKL (18), and the decoy receptor for RANKL, osteoprotegerin (OPG) (20). Although the study focused on the roles of RANKL/OPG system in osteoporosis caused by liver transplantation, the data suggest that hepatic I/R may affect RANKL and OPG expression (17). Moreover another study has shown that RANKL/OPG system is involved in chronic liver diseases, such as primary biliary cirrhosis and chronic hepatitis C, and suggested that liver inflammation may induce RANKL and OPG expression (21). Since NF-κB activation is known to play pivotal roles in hepatic I/R injury and the interaction of RANK and RANKL appears to have a direct relationship with hepatic inflammation, we sought to determine the role of RANK/RANKL/OPG system in the hepatic pathophysiological response to I/R.

Hepatic ischemia/reperfusion (I/R) injury is a frequently encountered complication in a variety of clinical scenarios including liver transplantation, major hepatic resection, abdominal trauma surgery and hemorrhagic shock. In the late nineteenth century, Dr. James Hogarth Pringle, a celebrated surgeon, developed a technique in which the blood flow through the hepatic artery and portal vein was occluded in order to achieve hemostasis during abdominal surgery for hemorrhage associated with liver trauma. This technique was later named the Pringle maneuver. With the growth in the field of hepatobiliary surgery, this technique of total vascular occlusion was adapted and has enabled surgeons to perform complex procedures such as orthotropic liver transplantation and large liver resections and repairs that otherwise would have resulted in massive hemorrhage and certain death.

Nonalcoholic fatty liver disease (NAFLD) refers to an increasingly diagnosed condition involving triglyceride accumulation in hepatocytes, resulting in a broad spectrum of liver injury. This injury ranges from simple hepatic steatosis, steatohepatitis, and chronic fibrosis to cirrhosis, and pathologically resembles alcoholic hepatitis in individuals without extensive alcohol use.1 This disease process has become progressively more prevalent and it is important that clinicians are fully aware of its pathophysiology and clinical implications. The term nonalcoholic fatty liver disease was introduced by Schaffner and Thaler2 in 1986 and is the current terminology used to describe a progressive spectrum of liver disease beginning with simple steatosis and leading to non-alcoholic steatohepatitis (NASH), fibrosis, and ultimately, cirrhosis (Fig. 1). Figure 1 Histologic progression of nonalcoholic fatty liver disease from simple steatosis to cirrhosis. The term nonalcoholic steatohepatitis was coined by Ludwig and colleagues3 in 1980 to describe a cohort of 20 patients with no history of alcohol abuse but with liver biopsies demonstrating fatty change, lobular inflammation, focal necrosis, and Mallory bodies consistent with alcoholic hepatitis. These patients were predominantly female and moderately obese. Nonalcoholic steatohepatitis is the term currently used to describe patients in whom simple steatosis has progressed to histologic evidence of inflammation, including hepatocyte ballooning, mixed acute and chronic lobular inflammation, and zone 3 perisinusoidal fibrosis.4,5 Progression of NAFLD, a relatively benign condition, to NASH is characterized by hepatic infiltration of inflammatory cells and subsequent hepatocellular injury. This inflammatory phase distinguishes NASH from simple NAFLD.6,7 Recent clinical observations have shown a clear link between development of NASH and presence of the metabolic syndrome. The metabolic syndrome is defined as insulin resistance, hypertension, dyslipidemia, and visceral obesity,8–11 and some have suggested that NAFLD be considered an additional feature of the metabolic syndrome.12 There is evidence that inflammatory changes seen in the metabolic syndrome might be an important feature of the progression of NAFLD to NASH. Obesity and insulin resistance have been found to be associated with a chronic state of systemic inflammation involving abnormal cytokine release, secondary mediators, and signaling pathways.13–15 The pathophysiology of the progression of NAFLD to NASH has yet to be fully elucidated. The first insult is the production and accumulation of triglycerides in the liver. This is primarily due to the presence of insulin resistance and hyperinsulinemia resulting in dysregulated lipogenesis and lipolysis peripherally and increased hepatic fatty acid synthesis.16 This results in simple steatosis. Progression to NASH is thought to evolve by way of a “2-hit” phenomenon17 (Fig. 2). The primary insult is lipid accumulation leading to development of steatosis, and the second is oxidative stress and lipid peroxidation resulting in cytokine-mediated recruitment and retention of inflammatory cells. Multiple cytokines, chemokines, and adipokines have been implicated in the development of NASH, including leptin,18–21 adiponectin,21,22 tumor necrosis factor–α,23,24 resistin,25,26 interluekin-6,27 and others. Figure 2 Progression of nonalcoholic fatty liver disease demonstrating the 2-hit hypothesis. The first hit consists of lipid accumulation resulting in simple benign steatosis. This primes the liver for a second hit, which can be multifactorial. This 2-hit process ...

Ciliated hepatic foregut cysts are uncommon solitary cysts of the liver that originate from the embryologic foregut. Clinically and radiographically, these lesions can be difficult to distinguish from neoplasms. Recent reports have demonstrated that ciliated hepatic foregut cysts may undergo dysplastic progression, supporting the argument to excise these cysts when discovered. Fewer than 100 cases have been described in the literature since the first description of a ciliated hepatic foregut cyst in 1857. We present a patient who recently underwent laparoscopic excision of a ciliated hepatic foregut cyst, review the literature, and propose the rationale for attempting removal of these cysts via a laparoscopic approach.

The effect of de novo DSA detected at the time of acute cellular rejection (ACR) and the response of DSA levels to rejection therapy on renal allograft survival were analyzed. Kidney transplant patients with acute rejection underwent DSA testing at rejection diagnosis with DSA levels quantified using Luminex single-antigen beads. Fifty-two patients experienced acute rejection with 16 (31%) testing positive for de novo DSA. Median follow-up was 27.0 +/- 17.4 months postacute rejection. Univariate analysis of factors influencing allograft survival demonstrated significance for African American race, DGF, cytotoxic PRA20% (current) and/or50% (peak), de novo DSA, C4d and repeat transplantation. Multivariate analysis showed only de novo DSA (6.6-fold increased allograft loss risk, p = 0.017) to be significant. Four-year allograft survival was higher with ACR (without DSA) (100%) than mixed acute rejection (ACR with DSA/C4d) (65%) or antibody-mediated rejection (35%) (p0.001). Patients with50% reduction in DSA within 14 days experienced higher allograft survival (p = 0.039). De novo DSAs detected at rejection are associated with reduced allograft survival, but prompt DSA reduction was associated with improved allograft survival. DSA should be considered a potential new end point for rejection therapy.