Acute kidney injury in patients with cirrhosis: Acute Disease Quality Initiative (ADQI) and International Club of Ascites (ICA) joint multidisciplinary consensus meeting.

Patients with cirrhosis are prone to developing acute kidney injury (AKI), a complication associated with a markedly increased in-hospital morbidity and mortality, along with a risk of progression to chronic kidney disease. Whereas patients with cirrhosis are at increased risk of developing any phenotype of AKI, hepatorenal syndrome (HRS), a specific form of AKI (HRS-AKI) in patients with advanced cirrhosis and ascites, carries an especially high mortality risk. Early recognition of HRS-AKI is crucial since administration of splanchnic vasoconstrictors may reverse the AKI and serve as a bridge to liver transplantation, the only curative option. In 2023, a joint meeting of the International Club of Ascites (ICA) and the Acute Disease Quality Initiative (ADQI) was convened to develop new diagnostic criteria for HRS-AKI, to provide graded recommendations for the work-up, management and post-discharge follow-up of patients with cirrhosis and AKI, and to highlight priorities for further research.

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.

Inequity in organ allocation for patients awaiting liver transplantation: Rationale for uncapping the model for end-stage liver disease.

BACKGROUND & AIM: The goal of organ allocation is to distribute a scarce resource equitably to the sickest patients. In the United States, the Model for End-stage Liver Disease (MELD) is used to allocate livers for transplantation. Patients with greater MELD scores are at greater risk of death on the waitlist and are prioritized for liver transplant (LT). The MELD is capped at 40 however, and patients with calculated MELD scores >40 are not prioritized despite increased mortality. We aimed to evaluate waitlist and post-transplant survival stratified by MELD to determine outcomes in patients with MELD >40. METHODS: Using United Network for Organ Sharing data, we identified patients listed for LT from February 2002 through to December 2012. Waitlist candidates with MELD ⩾40 were followed for 30days or until the earliest occurrence of death or transplant. RESULTS: Of 65,776 waitlisted patients, 3.3% had MELD ⩾40 at registration, and an additional 7.3% had MELD scores increase to ⩾40 after waitlist registration. A total of 30,369 (46.2%) underwent LT, of which 2,615 (8.6%) had MELD ⩾40 at transplant. Compared to MELD 40, the hazard ratio of death within 30days of registration was 1.4 (95% CI 1.2-1.6) for patients with MELD 41-44, 2.6 (95% CI 2.1-3.1) for MELD 45-49, and 5.0 (95% CI 4.1-6.1) for MELD ⩾50. There was no difference in 1- and 3-year survival for patients transplanted with MELD >40 compared to MELD=40. A survival benefit associated with LT was seen as MELD increased above 40. CONCLUSIONS: Patients with MELD >40 have significantly greater waitlist mortality but comparable post-transplant outcomes to patients with MELD=40 and, therefore, should be given priority for LT. Uncapping the MELD will allow more equitable organ distribution aligned with the principle of prioritizing patients most in need. Lay summary: In the United States (US), organs for liver transplantation are allocated by an objective scoring system called the Model for End-stage Liver Disease (MELD), which aims to prioritize the sickest patients for transplant. The greater the MELD score, the greater the mortality without liver transplant. The MELD score, however, is artificially capped at 40 and thus actually disadvantages the sickest patients with end-stage liver disease. Analysis of the data advocates uncapping the MELD score to appropriately prioritize the patients most in need of a liver transplant.

Effects of recipient size and allograft type on pediatric liver transplantation for biliary atresia.

The majority of pediatric patients with end-stage liver disease receive a transplant with a whole liver (WL) allograft. However, smaller recipients with biliary atresia (BA) may have improved outcomes with deceased donor partial liver (DDPL) or living donor allografts. This study compares the national outcomes for liver transplantation in BA, with attention to the interaction between liver allograft type and recipient size. From January 2, 2002 to December 30, 2014, 2123 pediatric patients underwent a primary liver transplant for BA. The majority of transplants (53%) were performed with a WL allograft. Utilization of a WL allograft increased from 42% of recipients weighing ≤ 7 kg to 74% of recipients weighing > 14 kg. The 1-, 5-, and 10-year graft survival in recipients weighing ≤7 kg was significantly superior for living donor liver transplantation (LDLT) (91%, 88%, 84%) and DDPL allografts (90%, 84%, 77%) compared with WL allografts (79%, 75%, 74%; P = 0.005). The 1-, 5-, and 10-year graft survival in recipients weighing >14 kg trended toward being inferior in recipients of DDPL allografts (85%, 85%, 71%) compared with WL allografts (96%, 91%, 86%; P = 0.06). Furthermore, the incidence of vascular thrombosis was highest in WL (13%) compared with LDLT (6%) and DDPL (5%) recipients ≤ 7 kg (P = 0.002). Liver retransplantation was also highest in WL (16%) compared with LDLT (9%) and DDPL (9%) recipients ≤ 7 kg (P = 0.02). In conclusion, strong consideration should be given to the use of technical variant allografts in small recipients with BA requiring liver transplantation. Liver Transplantation 23 221-233 2017 AASLD.

Intraoperative hemodialysis during liver transplantation: a decade of experience.

Liver transplantation (LT) for patients with renal dysfunction is frequently complicated by major fluid shifts, acidosis, and electrolyte and coagulation abnormalities. Continuous renal replacement therapy (CRRT) has been previously shown to ameliorate these problems. We describe the safety and clinical outcomes of intraoperative hemodialysis (IOHD) during LT for a group of patients with high Model for End-Stage Liver Disease (MELD) scores. We performed a retrospective study at our institution of patients who underwent IOHD from 2002 to 2012. Seven hundred thirty-seven patients underwent transplantation, and 32% received IOHD. The mean calculated MELD score was 37, with 38% having a MELD score ≥ 40. Preoperatively, 61% were in the intensive care unit, 19% were mechanically ventilated, 43% required vasopressor support, and 80% were on some form of renal replacement therapy at the time of transplantation, the majority being on CRRT. Patients on average received 35 U of blood products and 4.8 L of crystalloids without significant changes in hemodynamics or electrolytes. The average urine output was 450 ml, and the average amount of fluid removal with dialysis was 1.8 L. The 90-day patient and dialysis-free survival rates were 90% and 99%, respectively. One-year patient survival rates based on the pretransplant renal replacement status and the MELD status were not statistically different. This is the first large study to demonstrate the safety and feasibility of IOHD in a cohort of critically ill patients with high MELD scores undergoing LT with good patient and renal outcomes.

Impact of the etiology of acute kidney injury on outcomes following liver transplantation: acute tubular necrosis versus hepatorenal syndrome.

Acute kidney injury (AKI) at the time of liver transplantation (LT) has been associated with increased morbidity and mortality. In patients with potentially reversible renal dysfunction, predicting whether there will be sufficient return of native kidney function is sometimes difficult. Previous studies have focused mainly on the effect of the severity of renal dysfunction or the duration of pretransplant dialysis on posttransplant outcomes. We performed a retrospective analysis of patients who underwent LT at our center after Model for End-Stage Liver Disease-based allocation so that we could determine the impact of the etiology of AKI [acute tubular necrosis (ATN) versus hepatorenal syndrome (HRS)] on post-LT outcomes. The patients were stratified according to the severity of AKI at the time of LT as described by the Risk, Injury, Failure, Loss, and End-Stage Kidney Disease (RIFLE) classification: risk, injury, or failure. The RIFLE failure group was further subdivided according to the etiology of AKI: HRS or ATN. The patient survival and renal outcomes 1 and 5 years after LT were significantly worse for those with ATN. At 5 years, the incidence of chronic kidney disease (stage 4 or 5) was statistically higher in the ATN group versus the HRS group (56% versus 16%, P < 0.001). A multivariate analysis revealed that the presence of ATN at the time of LT was the only variable associated with higher mortality 1 year after LT (P < 0.001). Our study is the first to demonstrate that the etiology of AKI has the greatest impact on patient and renal outcomes after LT.

Medical management of hepatorenal syndrome.

Hepatorenal syndrome (HRS) is defined as the occurrence of renal dysfunction in a patient with end-stage liver cirrhosis in the absence of another identifiable cause of renal failure. The prognosis of HRS remains poor, with a median survival without liver transplantation of <6 months. However, understanding the pathogenesis of HRS has led to the introduction of treatments designed to increase renal perfusion and mean arterial blood pressure using vasopressors and albumin, which has led to improvement in renal function in ∼50% of patients.

Hepatorenal syndrome: the 8th International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group.

INTRODUCTION: Renal dysfunction is a common complication in patients with end-stage cirrhosis. Since the original publication of the definition and diagnostic criteria for the hepatorenal syndrome (HRS), there have been major advances in our understanding of its pathogenesis. The prognosis of patients with cirrhosis who develop HRS remains poor, with a median survival without liver transplantation of less than six months. However, a number of pharmacological and other therapeutic strategies have now become available which offer the ability to prevent or treat renal dysfunction more effectively in this setting. Accordingly, we sought to review the available evidence, make recommendations and delineate key questions for future studies. METHODS: We undertook a systematic review of the literature using Medline, PubMed and Web of Science, data provided by the Scientific Registry of Transplant Recipients and the bibliographies of key reviews. We determined a list of key questions and convened a two-day consensus conference to develop summary statements via a series of alternating breakout and plenary sessions. In these sessions, we identified supporting evidence and generated recommendations and/or directions for future research. RESULTS: Of the 30 questions considered, we found inadequate evidence for the majority of questions and our recommendations were mainly based on expert opinion. There was insufficient evidence to grade three questions, but we were able to develop a consensus definition for acute kidney injury in patients with cirrhosis and provide consensus recommendations for future investigations to address key areas of uncertainty. CONCLUSIONS: Despite a paucity of sufficiently powered prospectively randomized trials, we were able to establish an evidence-based appraisal of this field and develop a set of consensus recommendations to standardize care and direct further research for patients with cirrhosis and renal dysfunction.

Long-Term Suitability of Left Gastric Artery Inflow for Arterial Perfusion of Living Donor Right Lobe Grafts.

Poorer than expected, living donor liver transplant outcomes are observed after recipient graft artery thrombosis. At grafting, the risk for later thrombosis is high if a dissected hepatic artery is used for standard reconstruction. Surgeon diagnosis of dissection requires nonstandard management with alternative technique in addition to microvascular expertise. Intimal flap repair with standard reconstruction is contingent on basis of a redo anastomosis. It is a suboptimal choice for living donor transplantation. Achieving goal graft arterial perfusion at first revascularization is crucial for superior outcomes. Managing dissection at grafting with nonstandard left gastric artery reconstruction is unreported. Our experience is limited, but this is our preferred alternative technique to standard hepatic artery reconstruction complicated by dissection. Here, we describe our two-case experience with left gastric arterialized grafts for management of dissection. Our living donor graft recipients with alternatively arterialized grafts are now 6- and 2-years posttransplant.

SPOT GRADE II: Clinical Validation of a New Method for Reproducibly Quantifying Surgical Wound Bleeding: Prospective, Multicenter, Multispecialty, Single-Arm Study.

The SPOT GRADE (SG), a Surface Bleeding Severity Scale, is a unique visual method for assessing bleeding severity based on quantitative determinations of blood flow. This study assessed the reliability of the SG scale in a clinical setting and collected initial data on the safety and efficacy of HEMOBLAST Bellows (HB), a hemostatic agent, in abdominal and orthopedic operations. Twenty-seven patients were enrolled across 3 centers and received the investigational device. Bleeding severity and hemostasis were independently assessed by 2 surgical investigators at baseline and at 3, 6, and 10 minutes after application of HB and compared for agreement. The mean paired κ statistic for assignment of SG scores was .7754. The mean paired κ statistics for determining eligibility for participation in the trial based on bleeding severity and the mean paired κ statistics determining the presence of hemostasis were .9301 and .9301, respectively. The proportion of patients achieving hemostasis within 3, 6, and 10 minutes of HB application were 50.0%, 79.2%, and 91.7%, respectively. There were no unanticipated adverse device effects and one possible serious adverse device effect, as determined by the Independent Data Monitoring Committee (IDMC). The reliability of the SG scale was validated in a clinical setting. Initial data on the safety and efficacy of HB in abdominal and orthopedic operations were collected, and there were no concerns raised by the investigators or the IDMC.

Hepatorenal Syndrome.

Hepatorenal syndrome is a severe complication of end-stage cirrhosis characterized by increased splanchnic blood flow, hyperdynamic state, a state of decreased central volume, activation of vasoconstrictor systems, and extreme kidney vasoconstriction leading to decreased GFR. The contribution of systemic inflammation, a key feature of cirrhosis, in the development of hepatorenal syndrome has been highlighted in recent years. The mechanisms by which systemic inflammation precipitates kidney circulatory changes during hepatorenal syndrome need to be clarified. Early diagnosis is central in the management and recent changes in the definition of hepatorenal syndrome help identify patients at an earlier stage. Vasoconstrictive agents (terlipressin in particular) and albumin are the first-line treatment option. Several controlled studies proved that terlipressin is effective at reversing hepatorenal syndrome and may improve short-term survival. Not all patients are responders, and even in responders, early mortality rates are very high in the absence of liver transplantation. Liver transplantation is the only curative treatment of hepatorenal syndrome. In the long term, patients transplanted with hepatorenal syndrome tend to have lower GFR compared with patients without hepatorenal syndrome. Differentiating hepatorenal syndrome from acute tubular necrosis (ATN) is often a challenging yet important step because vasoconstrictors are not justified for the treatment of ATN. Hepatorenal syndrome and ATN may be considered as a continuum rather than distinct entities. Emerging biomarkers may help differentiate these two conditions and provide prognostic information on kidney recovery after liver transplantation, and potentially affect the decision for simultaneous liver-kidney transplantation.

Ischemic mass effect from biliary surgical clips.

Migrating surgical clips in the hepatic hilum are known causes of biliary stricture or obstruction, most often due to direct intraluminal obstruction or secondary stone formation. Two cases are reported on patients with previous cholecystectomies presenting with delayed symptoms of biliary tract stricture. Both patients were successfully treated with a resection of the strictured area and a Roux-en-Y hepatico-jejunostomy. Resected specimens grossly demonstrated surgical clips adjacent to the stricture, but not directly within the lumen, suggestive of an ischemic mass effect, which was supported by histology. In addition to the direct intraluminal obstruction and lithogenic effects of migratory surgical clips, "clipomas" due to an ischemic mass effect can also lead to biliary tract strictures.

Living donor liver transplantation: post-operative imaging follow-up of right lobe liver donors.

PURPOSE: To identify long-term post-operative imaging findings resulting from right lobe liver donation. METHODS: This retrospective imaging review consisted of 42 adults (20 males, 22 females, mean age 36.6 years, range 18.7-55.9 years) who underwent right lobe liver donation with pre- and post-operative imaging between 1999 and 2006. The mean follow-up period was 30.2 months (range 12.3-69.6 months). Follow-up imaging evaluation included assessment of the biliary tree, particularly isolated bile ducts draining to and terminating at the cut surface (orphan ducts). Three-dimensional volumetry of the liver remnant was also assessed. RESULTS: After liver donation, 29/42 (69%) participants demonstrated orphan ducts on follow-up imaging (95% confidence interval 52.9% to 82.4%). In those patients with orphan ducts, the main draining ducts were normal in 70% and dilated in 69%. Nearly all right lobe liver donors with orphan ducts had no clinical symptoms on follow-up (28/29); the only liver donor with clinical symptoms on follow-up was subsequently diagnosed with primary biliary cirrhosis. Mean regenerated liver volume was approximately 93%, with mean pre-operative total liver volume of 1552 ml (median 1504 ml, range 1040-2520 ml) and mean post-operative total liver volume of 1446 ml (median 1455 ml, range 964-2090 ml). CONCLUSIONS: Orphan ducts are changes that may be seen after liver donation. The presence of these findings in the absence of clinical symptoms or abnormal hepatic chemistries does not require further work-up and should not be considered pathologic.

Acute Kidney Injury After Liver Transplantation.

Since the implementation of the Model of End-stage Liver Disease score-based allocation system, the number of transplant candidates with impaired renal function has increased. The aims of this review are to present new insights in the definitions and predisposing factors that result in acute kidney injury (AKI), and to propose guidelines for the prevention and treatment of postliver transplantation (LT) AKI. This review is based on both systematic review of relevant literature and expert opinion. Pretransplant AKI is associated with posttransplant morbidity, including prolonged post-LT AKI which then predisposes to posttransplant chronic kidney disease. Prevention of posttransplant AKI is essential in the improvement of long-term outcomes. Accurate assessment of baseline kidney function at evaluation is necessary, taking into account that serum creatinine overestimates glomerular filtration rate. New diagnostic criteria for AKI have been integrated with traditional approaches in patients with cirrhosis to potentially identify AKI earlier and improve outcomes. Delayed introduction or complete elimination of calcineurin inhibitors during the first weeks post-LT in patients with early posttransplant AKI may improve glomerular filtration rate in high risk patients but with higher rates of rejection and more adverse events. Biomarkers may in the future provide diagnostic information such as etiology of AKI, and prognostic information on renal recovery post-LT, and potentially impact the decision for simultaneous liver-kidney transplantation. Overall, more attention should be paid to pretransplant and early posttransplant AKI to reduce the burden of late chronic kidney disease.

Differentiation Therapy Targeting the ß-Catenin/CBP Interaction in Pancreatic Cancer.

BACKGROUND: Although canonical Wnt signaling is known to promote tumorigenesis in pancreatic ductal adenocarcinoma (PDAC), a cancer driven principally by mutant K-Ras, the detailed molecular mechanisms by which the Wnt effector ß-catenin regulates such tumorigenesis are largely unknown. We have previously demonstrated that ß-catenin's differential usage of the Kat3 transcriptional coactivator cyclic AMP-response element binding protein-binding protein (CBP) over its highly homologous coactivator p300 increases self-renewal and suppresses differentiation in other types of cancer. AIM/METHODS: To investigate Wnt-mediated carcinogenesis in PDAC, we have used the specific small molecule CBP/ß-catenin antagonist, ICG-001, which our lab identified and has extensively characterized, to examine its effects in human pancreatic cancer cells and in both an orthotopic mouse model and a human patient-derived xenograft (PDX) model of PDAC. RESULTS/CONCLUSION: We report for the first time that K-Ras activation increases the CBP/ß-catenin interaction in pancreatic cancer; and that ICG-001 specific antagonism of the CBP/ß-catenin interaction sensitizes pancreatic cancer cells and tumors to gemcitabine treatment. These effects were associated with increases in the expression of let-7a microRNA; suppression of K-Ras and survivin; and the elimination of drug-resistant cancer stem/tumor-initiating cells.

Improved prediction of outcome in patients with severe acute pancreatitis by the APACHE II score at 48 hours after hospital admission compared with the APACHE II score at admission. Acute Physiology and Chronic Health Evaluation.

HYPOTHESIS: The 48-hour APACHE (Acute Physiology and Chronic Health Evaluation) II score is a better predictor of pancreatic necrosis, organ failure, and mortality in patients with severe acute pancreatitis than the score at hospital admission. DESIGN: A retrospective analysis of 125 patients with acute pancreatitis. SETTING: A tertiary public teaching hospital. PATIENTS: Patients with severe acute pancreatitis as defined by 3 or more Ranson criteria or a hospital stay of longer than 6 days. MAIN OUTCOME MEASURES: Pancreatic necrosis, organ failure, and mortality. RESULTS: A significant association was found between the 48-hour score and the presence of pancreatic necrosis (P<.001), organ failure (P =.001), and death (P<.001). By contrast, the APACHE II score at admission was significantly associated only with the presence of organ failure (P =.007). Deteriorating APACHE II scores over 48 hours were significantly associated with a fatal outcome (P =.03). The combined APACHE II score (defined as the sum of the admission and 48-hour scores) was significantly higher among nonsurvivors than survivors (P<.001), and was strongly associated with the presence of pancreatic necrosis (P =.001) and organ failure (P<.001). The 48-hour and combined scores accurately predicted outcome in 93% of the patients compared with 75% by the admission score. CONCLUSIONS: The 48-hour APACHE II score has improved predictive value compared with the admission score for identifying patients with severe acute pancreatitis who have a poor outcome. A deteriorating APACHE II score at 48 hours after admission may identify patients at risk for an adverse outcome.