Intraoperative hemodialysis with supra- and infradiaphragmatic catheters for liver transplantation.

PURPOSE: The benefits of intraoperative dialysis during orthotopic liver transplantation remain controversial. In patients with anuric renal failure and portopulmonary hypertension, maintaining venous return during caval clamping and unclamping along with minimizing fluid overload is critical to avoiding right ventricular strain and failure. CLINICAL FEATURES: We present the case of a 54-yr-old female who underwent orthotopic liver transplantation for alcohol-related liver disease with acute decompensation including severe hepatorenal syndrome (anuric requiring dialysis), probable hepatopulmonary syndrome, moderate pulmonary hypertension (right ventricular systolic pressure, 44 mm Hg), hepatic encephalopathy (grade 2), and esophageal varices. Prior to incision, pulmonary arterial pressures were 48/28 (mean, 35) mm Hg with a central venous pressure of 30 mm Hg, cardiac output of 7.4 L·min-1, and pulmonary vascular resistance of 98 dynes·sec·cm-5. In the context of right ventricular strain and volume overload observed on transthoracic echocardiography, we inserted an additional dialysis catheter into the right femoral vein. We initiated dialysis using the two catheters as a circuit (femoral line to the dialysis machine; blood was reinjected via the subclavian line) acting as a limited venovenous bypass, allowing right ventricular offloading and hemodialysis throughout the case. We removed 4.5 L via hemodialysis during the surgery, while avoiding acidosis, hyperkalemia, and sodium shifts. The patient tolerated reperfusion adequately despite pre-existing right ventricular dilation and dysfunction. CONCLUSION: We report on the use two hemodialysis catheters in a patient undergoing orthotopic liver transplantation as a circuit for simultaneous anuric hepatorenal syndrome and moderate pulmonary hypertension with right ventricular dilation and dysfunction. We believe this technique was instrumental in the patient's successful transplant.

RéSUMé: OBJECTIF: Les avantages de la dialyse peropératoire pendant une transplantation hépatique orthotopique demeurent controversés. Chez la patientèle atteinte d'insuffisance rénale anurique et d'hypertension portopulmonaire, il est essentiel de maintenir le retour veineux pendant le clampage et le déclampage de la veine cave ainsi que de minimiser la surcharge hydrique, afin d'éviter la déformation et l'insuffisance ventriculaires droites. CARACTéRISTIQUES CLINIQUES : Nous présentons le cas d'une femme de 54 ans qui a bénéficié d'une transplantation hépatique orthotopique pour une maladie hépatique liée à l'alcool avec une décompensation aiguë comprenant un syndrome hépatorénal sévère (anurie nécessitant une dialyse), un syndrome hépatopulmonaire probable, une hypertension pulmonaire modérée (pression systolique ventriculaire droite, 44 mm Hg), une encéphalopathie hépatique (grade 2) et des varices œsophagiennes. Avant l'incision, les pressions artérielles pulmonaires étaient de 48/28 (moyenne, 35) mm Hg avec une pression veineuse centrale de 30 mm Hg, un débit cardiaque de 7,4 L·min−1 et une résistance vasculaire pulmonaire de 98 dynes·sec·cm−5. Dans le contexte de la déformation ventriculaire et de la surcharge volémique droites observées à l'échocardiographie transthoracique, nous avons inséré un cathéter de dialyse supplémentaire dans la veine fémorale droite. Nous avons amorcé la dialyse en créant un circuit avec les deux cathéters (ligne fémorale en direction de l'appareil de dialyse; sang réinjecté via la ligne sous-clavière) agissant comme un pontage veino-veineux limité, permettant la décharge du ventricule droit et l'hémodialyse tout au long du cas. Nous avons retiré 4,5 L par hémodialyse pendant la chirurgie, tout en évitant l'acidose, l'hyperkaliémie et les changements en sodium plasmatique. La patiente a toléré la reperfusion de manière adéquate malgré la dilatation et le dysfonctionnement préexistants du ventricule droit. CONCLUSION: Nous rapportons l'utilisation de deux cathéters d'hémodialyse pour créer un circuit chez une patiente bénéficiant d'une transplantation hépatique orthotopique pour le traitement d'un syndrome hépatorénal anurique simultané à une hypertension pulmonaire modérée avec dilatation et dysfonctionnement du ventricule droit. Nous pensons que cette technique a joué un rôle déterminant dans la réussite de la greffe chez la patiente.

The use of urinary kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin for diagnosis of hepato-renal syndrome in advanced cirrhotic patients.

BACKGROUND: Chronic liver disease is a common and important clinical problem.Hepatorenal syndrome (HRS) is a life threatening complication. Serum creatinine (Cr) remains the only conventional indicator of renal function. However, the interpretation of serum Cr level can be confounded by malnutrition and reduced muscle mass often observed in patients with severe liver disease. Here, we present a cross-sectional study to explore the sensitivity and specificity of other markers as urinary KIM-1 and NGAL for cases of HRS. METHODS: Cross-sectional study was conducted on 88 patients who were admitted to Alexandria main university hospital. Enrolled patients were divided in two groups; group 1: patients with advanced liver cirrhosis (child B and C) who have normal kidney functions while group 2: patients who developed HRS. Stata© version 14.2 software package was used for analysis. RESULTS: Group 1 included 18 males and 26 females compared to 25 males and 19 females in group 2 (p = 0.135). Only the urinary KIM-1 showed a statistically significant difference between both groups in the multivariate logistic regression analysis adjusted for gender, serum bilirubin, serum albumin, INR, serum K, AST and ALT levels. CONCLUSION: In conclusion, our study aligns with prior research, as seen in the consistent findings regarding Urinary NGAL elevation in cirrhotic patients with AKI. Urinary KIM-1, independent of Urinary NGAL, may have a role in precisely distinguishing between advanced liver cirrhosis and HRS and merits further exploration.

Hepatorenal Syndrome Type 1: Diagnosis and Treatment.

Hepatorenal syndrome (HRS) is a feared complication in patients with advanced cirrhosis and is associated with significant morbidity and mortality. While recognized as a distinct physiologic condition for well over one hundred years, a lack of objective diagnostic tests has made the diagnosis one of exclusion. Since 1979, multiple sets of diagnostic criteria have been proposed. Though varying in detail, the principal intent of these criteria is to identify patients with severe, functional acute kidney injury that is unresponsive to volume resuscitation and exclude those with structural injury. However, accurate differential diagnosis remains challenging. Recently, multiple urinary biomarkers of kidney injury, including neutrophil gelatinase-associated lipocalin, have been studied as a means of objectively phenotyping etiologies of acute kidney injury in patients with cirrhosis. Along with markers reflecting tubular functional integrity, including the fractional excretion of sodium, injury markers will likely be incorporated into future diagnostic criteria. Making an accurate diagnosis is critical, as therapeutic options exist for HRS but must be given in a timely manner and only to those patients likely to benefit. Terlipressin, an analog of vasopressin, is the first line of therapy for HRS in much of the world and has recently been approved for use in the United States. Significant questions remain regarding the optimal dosing strategy, metrics for titration, and the potential role of point-of-care ultrasound to help guide concurrent albumin administration.

Association of left ventricular diastolic dysfunction with inflammatory activity, renal dysfunction, and liver-related mortality in patients with cirrhosis and ascites.

Left ventricular diastolic dysfunction (LVDD) is the predominant cardiac abnormality in cirrhosis. We investigated the association of LVDD with systemic inflammation and its impact on renal function, occurrence of hepatorenal syndrome (HRS) and survival in patients with cirrhosis and ascites. We prospectively enrolled 215 patients with cirrhosis and ascites. We evaluated the diagnosis and grading of LVDD by Doppler echocardiography, inflammatory markers, systemic hemodynamics, vasoactive factors, radioisotope-assessed renal function and blood flow, HRS development and liver-related mortality. LVDD was diagnosed in 142 (66%) patients [grade 2/3: n  = 61 (43%)]. Serum lipopolysaccharide-binding protein (LBP), plasma renin activity (PRA) and glomerular filtration rate (GFR) were independently associated with the presence of grade 2/3 LVDD and the severity of diastolic dysfunction. Serum tumor necrosis factor-α, cardiac output and plasma noradrenaline were also independently associated with the presence of grade 2/3 LVDD. The diastolic function marker E / e ' was strongly correlated with serum LBP ( r  = 0.731; P  < 0.001), PRA ( r  = 0.714; P  < 0.001) and GFR ( r  = -0.609; P  < 0.001) among patients with LVDD. The 5-year risk of HRS development and death was significantly higher in patients with grade 2/3 LVDD compared to those with grade 1 (35.5 vs. 14.4%; P  = 0.01 and 53.3 vs. 28.2%; P  = 0.03, respectively). The occurrence and severity of LVDD in patients with cirrhosis and ascites is closely related to inflammatory activity. Advanced LVDD is associated with baseline circulatory and renal dysfunction, favoring HRS development, and increased mortality.

Allopurinol Prevents Cirrhosis-Related Complications: A Quadruple Blind Placebo-Controlled Trial.

BACKGROUND: Complications associated with liver cirrhosis are various and potentially fatal. The treatment options to counteract hepatic decompensation are limited. Therefore, the study aimed to explore the use of allopurinol in preventing the recurrence of liver cirrhosis-related complications. METHODS: One hundred patients with hepatic decompensation were randomized into 1:1 ratio to receive either allopurinol 300 mg or placebo tablets once daily for 6 months. The primary endpoint was the incidence of cirrhosis-related complications (overt ascites, spontaneous bacterial peritonitis, variceal bleeding, hepatorenal syndrome, and hepatic encephalopathy). RESULTS: Six months following treatment, allopurinol reduced the relative risk (RR) of any first complication experienced after enrollment by 56% (hazard ratio [HR] 0.44; 95% confidence interval [CI], 0.27-0.62); P ˂ .001). Allopurinol decreased the RR of overt ascites by 67% (HR 0.33; 95% CI, 0.0098-0.94); P = .039] and reduced the RR of spontaneous bacterial peritonitis by about 75% (HR 0.25; 95% CI, 0.05-0.76; P = .01). Likewise, allopurinol was linked to an 80% reduction in the RR of developing hepatorenal syndrome (HR 0.2; 95% CI, 0.04-0.87; P = .033). CONCLUSION: Allopurinol significantly decreased the recurrence of overall liver cirrhosis-related complications. Therefore, allopurinol may constitute a promising agent for patients with hepatic decompensation. These positive outcomes could be a result of its ability to reduce bacterial translocation and inflammation. GOV IDENTIFIER: NCT005545670.

Lenvatinib plus pembrolizumab versus lenvatinib plus placebo for advanced hepatocellular carcinoma (LEAP-002): a randomised, double-blind, phase 3 trial.

BACKGROUND: Systemic therapies have improved the management of hepatocellular carcinoma, but there is still a need to further enhance overall survival in first-line advanced stages. This study aimed to evaluate the addition of pembrolizumab to lenvatinib versus lenvatinib plus placebo in the first-line setting for unresectable hepatocellular carcinoma. METHODS: In this global, randomised, double-blind, phase 3 study (LEAP-002), patients aged 18 years or older with unresectable hepatocellular carcinoma, Child Pugh class A liver disease, an Eastern Cooperative Oncology Group performance status of 0 or 1, and no previous systemic treatment were enrolled at 172 global sites. Patients were randomly assigned (1:1) with a central interactive voice-response system (block size of 4) to receive lenvatinib (bodyweight <60 kg, 8 mg/day; bodyweight ≥60 kg, 12 mg/day) plus pembrolizumab (200 mg every 3 weeks) or lenvatinib plus placebo. Randomisation was stratified by geographical region, macrovascular portal vein invasion or extrahepatic spread or both, α-fetoprotein concentration, and Eastern Cooperative Oncology Group performance status. Dual primary endpoints were overall survival (superiority threshold at final overall survival analysis, one-sided p=0·019; final analysis to occur after 532 events) and progression-free survival (superiority threshold one-sided p=0·002; final analysis to occur after 571 events) in the intention-to-treat population. Results from the final analysis are reported. This study is registered with ClinicalTrials.gov, NCT03713593, and is active but not recruiting. FINDINGS: Between Jan 17, 2019, and April 28, 2020, of 1309 patients assessed, 794 were randomly assigned to lenvatinib plus pembrolizumab (n=395) or lenvatinib plus placebo (n=399). Median age was 66·0 years (IQR 57·0-72·0), 644 (81%) of 794 were male, 150 (19%) were female, 345 (43%) were Asian, 345 (43%) were White, 22 (3%) were multiple races, 21 (3%) were American Indian or Alaska Native, 21 (3%) were Native Hawaiian or other Pacific Islander, 13 (2%) were Black or African American, and 46 (6%) did not have available race data. Median follow up as of data cutoff for the final analysis (June 21, 2022) was 32·1 months (IQR 29·4-35·3). Median overall survival was 21·2 months (95% CI 19·0-23·6; 252 [64%] of 395 died) with lenvatinib plus pembrolizumab versus 19·0 months (17·2-21·7; 282 [71%] of 399 died) with lenvatinib plus placebo (hazard ratio [HR] 0·84; 95% CI 0·71-1·00; stratified log-rank p=0·023). As of data cutoff for the progression-free survival final analysis (April 5, 2021), median progression-free survival was 8·2 months (95% CI 6·4-8·4; 270 events occurred [42 deaths; 228 progressions]) with lenvatinib plus pembrolizumab versus 8·0 months (6·3-8·2; 301 events occurred [36 deaths; 265 progressions]) with lenvatinib plus placebo (HR 0·87; 95% CI 0·73-1·02; stratified log-rank p=0·047). The most common treatment-related grade 3-4 adverse events were hypertension (69 [17%] of 395 patients in the lenvatinib plus pembrolizumab group vs 68 [17%] of 395 patients) in the lenvatinib plus placebo group), increased aspartate aminotransferase (27 [7%] vs 17 [4%]), and diarrhoea (25 [6%] vs 15 [4%]). Treatment-related deaths occurred in four (1%) patients in the lenvatinib plus pembrolizumab group (due to gastrointestinal haemorrhage and hepatorenal syndrome [n=1 each] and hepatic encephalopathy [n=2]) and in three (1%) patients in the lenvatinib plus placebo group (due to gastrointestinal haemorrhage, hepatorenal syndrome, and cerebrovascular accident [n=1 each]). INTERPRETATION: In earlier studies, the addition of pembrolizumab to lenvatinib as first-line therapy for advanced hepatocellular carcinoma has shown promising clinical activity; however, lenvatinib plus pembrolizumab did not meet prespecified significance for improved overall survival and progression-free survival versus lenvatinib plus placebo. Our findings do not support a change in clinical practice. FUNDING: Eisai US, and Merck Sharp & Dohme, a subsidiary of Merck.

Renal damage in Hepatorenal Syndrome: A still unsolved issue.

Acute kidney injury (AKI) is a common complication of cirrhosis, burdened by high morbidity and mortality rates and progression to chronic kidney disease. Hepatorenal syndrome (HRS) is a peculiar type of functional AKI observed in cirrhotic patients with ascites. HRS diagnosis is still clinical, once pre-renal azotemia and intrinsic kidney damage have been excluded by applying well-established and internationally adopted criteria. HRS is considered reversible because of the absence of intrinsic renal damage. However, HRS reversibility has been questioned, due to the lack of response to treatment with vasoconstrictors plus albumin in a relevant percentage of patients and to the persistence of renal dysfunction in HRS patients who underwent liver transplantation (LT). Indeed, LT is the only ultimate treatment, as it solves both liver failure and portal hypertension. Thus, the presence of renal damage in HRS can be hypothesized. In this scenario, neutrophil gelatinase-associated lipocalin (NGAL), one of the most promising biomarkers, may help in characterizing the type of renal injury, distinguishing between HRS and acute tubular necrosis. This review gathers the available evidence in favor and against the presence of structural lesions in HRS in terms of either renal histology and urinary biomarkers with a particular focus on NGAL. The ability to properly characterize which component of renal dysfunction prevails - functional rather than structural - entails a relevant clinical impact for the treatment of these patients, both in terms of medical therapy and liver vs. combined liver-kidney transplantation.

Treatment and outcome of hepatorenal syndrome in Japan: a retrospective cohort study using a national inpatient database.

BACKGROUND: Hepatorenal syndrome (HRS) is a life-threatening complication of end-stage liver disease. This study aimed to clarify the status of HRS in Japan by analyzing the Japanese Diagnosis Procedure Combination database. METHODS: Patients hospitalized for cirrhosis and HRS from July 2010 to March 2019 were sampled. They were divided into two groups according to their prognosis upon discharge: the transplant-free survival group and the death or liver transplantation group. The two groups' baseline patient characteristics and treatments were compared. RESULTS: The mean age of the 1,412 participants was 67.3 years (standard deviation: 12.3 years), and 65.4% were male. The Child-Pugh grades was B and C in 18.8% and 81.2%, respectively. Hepatocellular carcinoma was present in 27.1% of the patients, and the proportion of spontaneous bacterial peritonitis was 2.3%. Albumin, noradrenaline, and dopamine were administered to 57.9%, 8.0%, and 14.9% of the patients, respectively; 7.0% of the patients underwent renal replacement therapy; and 5.0% were admitted to the intensive care unit. Intravenous antibiotics were administered to 30.8% of the patients. A total of 925 patients (65.5%) died or underwent liver transplantation. In addition to a higher proportion of patients with poor baseline liver function, the death or liver transplantation group included more males, patients with hepatocellular carcinoma, and those with spontaneous bacterial peritonitis. CONCLUSIONS: HRS in Japan has a high mortality rate. Albumin was administered to over 50% of participants. Although noradrenaline is recommended in Japanese clinical guidelines, dopamine was more frequently used as a vasoconstrictor in clinical practice.

Diagnosis and Management of Cirrhosis and Its Complications: A Review.

Importance: Cirrhosis affects approximately 2.2 million adults in the US. From 2010 to 2021, the annual age-adjusted mortality of cirrhosis increased from 14.9 per 100 000 to 21.9 per 100 000 people. Observations: The most common causes of cirrhosis in the US, which can overlap, include alcohol use disorder (approximately 45% of all cases of cirrhosis), nonalcoholic fatty liver disease (26%), and hepatitis C (41%). Patients with cirrhosis experience symptoms including muscle cramps (approximately 64% prevalence), pruritus (39%), poor-quality sleep (63%), and sexual dysfunction (53%). Cirrhosis can be diagnosed by liver biopsy but may also be diagnosed noninvasively. Elastography, a noninvasive assessment of liver stiffness measured in kilopascals, can typically confirm cirrhosis at levels of 15 kPa or greater. Approximately 40% of people with cirrhosis are diagnosed when they present with complications such as hepatic encephalopathy or ascites. The median survival time following onset of hepatic encephalopathy and ascites is 0.92 and 1.1 years, respectively. Among people with ascites, the annual incidence of spontaneous bacterial peritonitis is 11% and of hepatorenal syndrome is 8%; the latter is associated with a median survival of less than 2 weeks. Approximately 1% to 4% of patients with cirrhosis develop hepatocellular carcinoma each year, which is associated with a 5-year survival of approximately 20%. In a 3-year randomized clinical trial of 201 patients with portal hypertension, nonselective ß-blockers (carvedilol or propranolol) reduced the risk of decompensation or death compared with placebo (16% vs 27%). Compared with sequential initiation, combination aldosterone antagonist and loop diuretics were more likely to resolve ascites (76% vs 56%) with lower rates of hyperkalemia (4% vs 18%). In meta-analyses of randomized trials, lactulose was associated with reduced mortality relative to placebo (8.5% vs 14%) in randomized trials involving 705 patients and reduced risk of recurrent overt hepatic encephalopathy (25.5% vs 46.8%) in randomized trials involving 1415 patients. In a randomized clinical trial of 300 patients, terlipressin improved the rate of reversal of hepatorenal syndrome from 39% to 18%. Trials addressing symptoms of cirrhosis have demonstrated efficacy for hydroxyzine in improving sleep dysfunction, pickle brine and taurine for reducing muscle cramps, and tadalafil for improving sexual dysfunction in men. Conclusions and Relevance: Approximately 2.2 million US adults have cirrhosis. Many symptoms, such as muscle cramps, poor-quality sleep, pruritus, and sexual dysfunction, are common and treatable. First-line therapies include carvedilol or propranolol to prevent variceal bleeding, lactulose for hepatic encephalopathy, combination aldosterone antagonists and loop diuretics for ascites, and terlipressin for hepatorenal syndrome.

Treatment of Severe Acute on Chronic Liver Failure: Management of Organ Failures, Investigational Therapeutics, and the Role of Liver Transplantation.

Acute on chronic liver failure (ACLF) is a unique syndrome that afflicts patients with chronic liver disease and results in high short-term mortality, in the setting of organ system failures. Given this prognosis, there is an urgent need to understand risk factors for this condition, for appropriate medical management of organ failures, and for selection criteria for patients who may benefit from liver transplantation (LT). Although several definitions exist to identify ACLF, all of them are designed to identify patients with uniquely high mortality. Currently, management of severe ACLF relies on best supportive care for specific organ failures. Thromboelastography should guide the evaluation of coagulation pathways and hyperfibrinolysis in ACLF; prophylactic blood product transfusions and thrombopoetin agonists are not recommended. Combination therapy with terlipressin and albumin has been shown to be efficacious in the management of the hepatorenal syndrome but should be administered with caution in patients with ACLF-3. Recent data have characterized the role of beta-blockers and transjugular intrahepatic portosystemic shunt placement in the management of ACLF. Investigational therapies such as extracorporeal liver support and hepatocyte stem cell therapies have shown promise; larger scale studies may better define the subpopulations of patients with ACLF mostly likely to benefit from these evolving therapeutics. Regarding LT in ACLF, data suggest that even patients with 3 or more organ system failures may have a 1-year survival >80%. However, further efforts are needed to understand the predictors of post-LT survival to facilitate LT criteria for this condition.

Hepatorenal syndrome: a historical appraisal of its origins and conceptual evolution.

The hepatorenal syndrome (HRS), a progressive but potentially reversible deterioration of kidney function, constitutes a serious complication of hepatic decompensation. Coexistence of liver/kidney damage, mentioned in the dropsy literature, was highlighted by Richard Bright in 1827 and confirmed in 1840 by his contemporary nephrology pioneer Pierre Rayer. Cholemic nephrosis was described in 1861 by Friedrich Frerichs, and the renal tubular lesions of HRS by Austin Flint in 1863. The term "acute hepato-nephritis" was introduced in 1916 by Paul Merklen, and its chronic form was designated HRS by Marcel Dérot in 1930s. HRS then was applied to renal failure in biliary tract surgery and to cases of coexistent renal and hepatic failure of diverse etiology. The pathogenesis of HRS was elucidated during the 1950 studies of renal physiology. Notably, studies of salt retention in edema and its relation to regulating the circulating plasma volume by John Peters and subsequently Otto Gauer defined the concept of "effective blood volume" and the consequent elucidation of ascites formation in liver failure. Parallel studies of intrarenal hemodynamics demonstrated severe renal vasoconstriction and preferential cortical ischemia to account for the functional renal dysfunction of HRS. Dialysis and liver or combined liver-kidney transplantation transformed the fatal HRS of old into a treatable disorder by the 1970s. Elucidation of the pathogenetic mechanisms of renal injury and refinements in definition, classification, and diagnosis of HRS since then have allowed for earlier therapeutic intervention with combined i.v. albumin and vasoconstrictor therapy, enabling the continued improvement of patient outcomes.

Obeticholic acid ameliorates hepatorenal syndrome in ascitic cirrhotic rats by down-regulating the renal 8-iso-PGF2α-activated COX-TXA2 pathway.

BACKGROUNDS/AIMS: The present study explores the potential of chronic treatment with the Foresaid X receptor (FXR) agonist obeticholic acid (OCA), which inhibits oxidative stress-related pathogenesis, in ascitic cirrhotic rats with hepatorenal syndrome (HRS) developed 6 weeks after bile duct ligation (BDL). METHODS: Systemic, splanchnic, and renal hemodynamics and pathogenic cascades were measured in ascitic BDL and sham rats receiving 2-weeks of either vehicle or OCA treatments (sham-OCA and BDL-OCA groups), and NRK-52E cells, rat kidney tubular epithelial cells. RESULTS: Chronic OCA treatment significantly normalized portal hypertension, glomerular filtration rate, urine output, renal blood flow; decreased ascites, renal vascular resistance, serum creatinine, and the release of renal tubular damage markers, including urinary neutrophil gelatinase-associated lipocalin (uNGAL) and kidney injury moleculae-1 (uKim-1) in BDL-OCA rats. In the BDL group, inhibition of the renal oxidative stress (8-iso-PGF2α)-activated cyclooxygenase-thromboxane A2 [COX-TXA2] pathway, apoptosis, and tubular injury accompanied by a decrease in hyper-responsiveness to the vasoconstrictor 8-iso-PGF2α in perfused kidneys. In vitro experiments revealed that 8-iso-PGF2α induced oxidative stress, release of reactive oxygen species, and cell apoptosis, which were reversed by concomitant incubation with the FXR agonist. CONCLUSIONS: Through the inhibition of renal 8-iso-PGF2α production and the down-regulation of the COX-TXA2 pathway, our study suggests that chronic OCA treatment can ameliorate the HRS in ascitic cirrhotic rats. Thus, OCA is an agent with antioxidative stress, antivasoconstrictive, antiapoptotic properties which benefit ascitic, cirrhotic rats with systemic, hepatic, and renal abnormalities.

Transjugular intrahepatic portosystemic shunt and alfapump® system for refractory ascites in liver cirrhosis: Outcomes and complications.

BACKGROUND: Treatment of refractory ascites in liver cirrhosis is challenging. Transjugular intrahepatic portosystemic shunt and alfapump® have been proposed for the management, but few data comparing both exist. AIMS: The aim of this study was to evaluate the characteristics and outcomes of patients treated with transjugular intrahepatic portosystemic shunt and alfapump® for refractory ascites at our centre. METHODS: All consecutive patients were retrospectively reviewed for baseline characteristics, efficacy of treatment, complications and survival. RESULTS: In total, 19 patients with transjugular intrahepatic portosystemic shunt and 40 patients with alfapump® were included. Patients with transjugular intrahepatic portosystemic shunt had better liver function and less hepatic encephalopathy at baseline. Fifty-eight per cent of patients developed hepatic encephalopathy in the first six months after transjugular intrahepatic portosystemic shunt. In patients with alfapump®, renal function decreased and 58% developed prerenal impairment and 43% hepatorenal syndrome in the first six months. Alfapump® patients with new catheters required less reinterventions (26% versus 57% with old catheters, p = 0.049). Transplant-free survival at 1 year was 25% in alfapump® and 65% in transjugular intrahepatic portosystemic shunt. Hepatic encephalopathy predicted transplant-free survival in patients with alfapump® (hazard ratio 2.00, 95% confidence interval 0.99-4.02, p = 0.05). In a sensitivity analysis comparing patients with similar liver function, the rate of hepatorenal syndrome and prerenal impairment was higher in patients with alfapump® and these patients were hospitalised more frequently, whereas the rate of hepatic encephalopathy was similar in both treatment groups. CONCLUSIONS: Both transjugular intrahepatic portosystemic shunt and alfapump® were effective treatments for refractory ascites in cirrhosis. Patients treated with transjugular intrahepatic portosystemic shunt had a better one-year transplant-free survival but had less negative prognostic factors at baseline. Selecting patients without hepatic encephalopathy prior to implantation of an alfapump® might improve transplant-free survival.

TIPS for management of portal-hypertension-related complications in patients with cirrhosis.

Portal hypertension is primarily due to liver cirrhosis, and is responsible for complications that include variceal bleeding, ascites and hepatorenal syndrome. The transjugular intrahepatic portosystemic shunt (TIPS) is a low-resistance channel between the portal vein and the hepatic vein, created by interventional radiology, that aims to reduce portal pressure. TIPS is a potential treatment for severe portal-hypertension-related complications, including esophageal and gastric variceal bleeding. TIPS is currently indicated as salvage therapy in this setting when patients fail to respond to standard endoscopic and medical treatment. More recently, early TIPS has been shown to be effective in decreasing risk of rebleeding after variceal hemorrhage and mortality in Child-Pugh B patients with active hemorrhage at endoscopy, and in Child-Pugh C patients. TIPS is also an efficient treatment for refractory ascites and hepatic hydrothorax. In contrast, the role of TIPS in the hepatorenal syndrome has not been precisely defined. The aim of this review was to specifically describe the current role of TIPS in management of portal hypertension in patients with cirrhosis.

Effectiveness of terlipressin for prevention of complications after major liver resection - A randomized placebo-controlled trial.

BACKGROUND: Elevated portal pressure in response to major liver resection is associated with impaired liver regeneration and increased postoperative complications. Terlipressin, a splanchnic vasoconstrictor used for treatment of hepatorenal syndrome, was tested for reduction of complications and renal protection after liver resection. METHODS: A randomized double-blinded placebo-controlled trial including patients undergoing elective major liver resection was performed. Terlipressin was administered to patients in the intervention group for five days. The primary outcome parameter was the incidence of a clinical composite endpoint of following liver specific complications 6 weeks after surgery: liver failure, ascites, bile leakage, intra-abdominal abscess and operative mortality. Postoperative kidney function was assessed as a secondary endpoint. RESULTS: 150 patients (mean age 63.4 years, 73.3% male) were included. No difference was found in the composite endpoint between the placebo and intervention group (32.8% versus 30.8%, relative risk 1.066, 95%CI 0.643 to 1.769, p = 0.85). Patients receiving terlipressin showed a significant lower decrease in postoperative estimated glomerular filtration rate compared to placebo (two way ANOVA, p = 0.005). CONCLUSION: Perioperative administration of terlipressin during major liver surgery did not affect a composite endpoint of liver specific complications, but significantly protected from postoperative deterioration of kidney function compared to placebo. CLINICALTRIALS. GOV IDENTIFIER: NCT01921985.

Mushroom intoxication, a fatal condition in Romanian children: Two case reports.

RATIONALE: Approximately 5000 species of wild mushroom are reported worldwide, of which 100 are documented as poisonous and <10 are fatal. The clinical picture of patients with wild mushroom intoxication depends mostly on the type of ingested mushroom, ranging from mild gastrointestinal symptoms to organ failure and death. PATIENT CONCERNS: We report 2 children, sister and brother admitted in our clinic for gastrointestinal symptoms: abdominal pain, nausea, vomiting, and diarrhea after wild mushroom ingestion. DIAGNOSIS: The laboratory tests revealed hepatic cytolysis syndrome, hyperbilirubinemia, impaired coagulation status, hypoalbuminemia, hypoglycemia, and electrolytic unbalances in both cases. Abdominal ultrasound showed hepatomegaly and ascites. INTERVENTION: After admission, both cases received penicillin by vein, activated charcoal, liver protectors, glucose, and electrolytes perfusions. Nevertheless, their status worsened and required the transfer to the pediatric intensive care unit for appropriate supportive measure. Therefore, therapeutic plasma exchange was initiated along with N-acetyl cysteine and hemostatic drugs. OUTCOMES: Despite all these therapeutic interventions, both cases developed hepatorenal syndrome and died after a couple of days from ingestion. LESSONS: Mushroom poisoning remains a public health problem in developing countries. Preventable strategies and education regarding the consumption of wild type mushrooms are essential for decreasing the morbidity and mortality rates in these areas.

Surgery in Patients with Portal Hypertension.

Patients with portal hypertension will increasingly present for nontransplant surgery because of the increasing incidence of, and improving long-term survival for, chronic liver disease. Such patients have increased perioperative morbidity and mortality caused by the systemic pathophysiology of liver disease. Preoperative assessment should identify modifiable causes of liver injury and distinguish between compensated and decompensated cirrhosis. Risk stratification, which is crucial to preparing patients and their families for surgery, relies on scores such as Child-Turcotte-Pugh and Model for End-stage Liver Disease to translate disease severity into quantified outcomes predictions. Risk factors for postoperative complications should also be recognized.

Clinical utility of urinary neutrophil gelatinase-associated lipocalin and serum cystatin C in a cohort of liver cirrhosis patients with renal dysfunction: a challenge in the diagnosis of hepatorenal syndrome.

OBJECTIVES: This study aimed to assess urinary neutrophil gelatinase-associated lipocalin (uNGAL) and serum cystatin C (sCys C) in liver cirrhosis patients with renal dysfunction and to evaluate their role in the diagnosis of the hepatorenal syndrome (HRS). PATIENTS AND METHODS: Forty-five liver cirrhosis patients were enrolled in the study and they were divided into three groups; the first group included 15 patients with normal renal function, the second group included 15 patients with HRS; and the third group included 15 patients with chronic kidney disease (CKD). There was a fourth group, which included 15 healthy controls. Liver and renal function tests, as well as the estimated glomerular filtration rate were determined. uNGAL was measured using the enzyme-linked immunosorbent assay, and the uNGAL/urinary creatinine concentration (UCC) ratio was calculated. sCys C was measured using the particle-enhanced immunoturbidimetric assay. RESULTS: The ratios of uNGAL and uNGAL/UCC were the highest among HRS patients. The combined uNGAL/UCC ratio and sCys C improved the sensitivity of diagnosis to 93.33% and specificity to 76.67%, with the highest area under the curve of 0.944, 95% confidence interval of 0.879-1.0 (P<0.001). The three biomarkers could successfully identify HRS at the following cutoffs: 84.94 ng/ml, 0.6 ng/mg, and 1.6 mg/l, respectively. Significant positive correlations were found between uNGAL, uNGAL/UCC ratios as well as sCys C and KDIGO stage in liver cirrhosis patients with CKD. CONCLUSION: uNGAL and a better uNGAL/UCC ratio can be used alone or together with serum cystatin C as early biomarkers for HRS among patients with decompensated liver cirrhosis. Moreover, uNGAL, uNGAL/UCC as well as serum cystatin C could aid the prognostic assessment of cirrhotic patients with CKD.

Portal vein thrombosis prevalence and associated mortality in cirrhosis in a nationally representative inpatient cohort.

BACKGROUND AND AIM: Portal vein thrombosis (PVT) is increasingly common in cirrhotics, but its impact on mortality and outcomes is unclear. Studies evaluating PVT have been limited by small sample size. This study analyzes the trend of the prevalence of PVT and its associated mortality in hospitalized decompensated cirrhotics. METHODS: The Nationwide Inpatient Sample, the largest nationally representative database of hospital discharges, was queried from 1998 to 2014. Inpatients older than 18 years with decompensated cirrhosis were included, while those who received liver transplantation or had hepatocellular carcinoma were excluded. The primary outcomes were the trend in prevalence and associated mortality with PVT. Secondary outcomes included identifying risk factors of PVT and the effect of PVT on complications of portal hypertension. Multivariable logistic regression evaluated the outcomes. RESULTS: A total of 3 045 098 discharges were included, of which 1.5% had PVT. PVT prevalence increased from 0.7% to 2.4%, annual percent change of 9%. Mortality associated with PVT declined from 11.9% to 9.1%, annual percent change of -3.0%. In multivariable analysis controlling for factors associated with mortality in cirrhotics, PVT was associated with an increased risk of mortality (OR 1.12, P < 0.001). Multivariable logistic regression also demonstrated that PVT significantly increased the risk of acute kidney injury (OR 1.75, P < 0.001) and hepatorenal syndrome (OR 1.62, P < 0.001). CONCLUSIONS: The prevalence of PVT is increasing while its associated mortality is decreasing. However, PVT still is associated with risk of mortality and kidney injury, implying a significant impact on cirrhotic outcomes.