Protective effect of long-chain polyunsaturated fatty acids on hepatorenal syndrome in rats

BACKGROUND Hepatorenal syndrome(HRS)is the most prevalent form of acute kidney injury in cirrhotic patients.It is characterized by reduced renal blood flow and represents the most severe complication in cirrhotic patients with advanced disease.Previous research has indicated that antioxidants can delay the onset of a hyperdynamic circulatory state in cirrhosis and improve renal function in HRS patients.Regular omega-3 supplementation has significantly reduced the risk of liver disease.This supplementation could represent an additional therapy for individuals with HRS.AIM To evaluated the antioxidant effect of omega-3 polyunsaturated fatty acid supplementation on the kidneys of cirrhotic rats.METHODS Secondary biliary cirrhosis was induced in rats by biliary duct ligation(BDL)for 28 d.We used 24 male Wistar rats divided into the following groups:I(control);II(treated with omega-3,1 g/kg of body weight);III(BDL treated with omega-3,1 g/kg of body weight);and IV(BDL without treatment).The animals were killed by overdose of anesthetic;the kidneys were dissected,removed,frozen in liquid nitrogen,and stored in a freezer at-80℃for later analysis.We evaluated oxidative stress,nitric oxide(NO)metabolites,DNA damage by the comet assay,cell viability test,and apoptosis in the kidneys.Data were analyzed by one-way analysis of variance,and means were compared using the Tukey test,with P≤0.05.RESULTS Omega-3 significantly decreased the production of reactive oxygen species(P<0.001)and lipoperoxidation in the kidneys of cirrhotic rats treated with omega-3(P<0.001).The activity of the antioxidant enzymes superoxide dismutase and catalase increased in the BDL+omega-3 group compared to the BDL group(P<0.01).NO production,DNA damage,and caspase-9 cleavage decreased significantly in the omega-3-treated BDL group.There was an increase in mitochondrial electrochemical potential(P<0.001)in BDL treated with omega-3 compared to BDL.No changes in the cell survival index in HRS with omega-3 compared to the control group(P>0.05)were observed.CONCLUSION The study demonstrates that omega-3 can protect cellular integrity and function by increasing antioxidant enzymes,inhibiting the formation of free radicals,and reducing apoptosis.

Clinical and pathophysiological understanding of the hepatorenal syndrome:Still wrong or still not exactly right?

The hepatorenal syndrome(HRS)is one major extrahepatic complication of endstage liver diseases.While circulatory dysregulation is considered as primary etiology for HRS,cirrhosis-related(systemic)inflammation and/or cardial dysfunction may also play a key pathogenic role in HRS development.Exclusion of other causes of acute kidney injury(AKI)is required for diagnosis of HRS-AKI by the definition of the International Club of Ascites.However,the pathophysiology of HRS is not understood completely and there are still limited therapeutic options.Reversibility of renal dysfunction after liver transplantation indicates that HRS-AKI is a functional disorder caused by altered cellular function.The interplay between systemic inflammation and the onset of kidneyrelated hypometabolism may have a key role and needs to be studied in depth.This minireview challenges simplified views of the HRS in the context of diagnostics and therapy stressing the need for further evidence to advance the knowledge on this syndrome.

Recent advances in pathophysiology,diagnosis and management of hepatorenal syndrome:A review

Hepatorenal syndrome with acute kidney injury(HRS-AKI)is a form of rapidly progressive kidney dysfunction in patients with decompensated cirrhosis and/or acute severe liver injury such as acute liver failure.Current data suggest that HRS-AKI occurs secondary to circulatory dysfunction characterized by marked splanchnic vasodilation,leading to reduction of effective arterial blood volume and glomerular filtration rate.Thus,volume expansion and splanchnic vasoconstriction constitute the mainstay of medical therapy.However,a significant proportion of patients do not respond to medical management.These patients often require renal replacement therapy and may be eligible for liver or combined liver-kidney transplantation.Although there have been advances in the management of patients with HRS-AKI including novel biomarkers and medications,better-calibrated studies,more widely available biomarkers,and improved prognostic models are sorely needed to further improve diagnosis and treatment of HRS-AKI.

Effects of Polysaccharides from Enteromorpha prolifera on Hepatorenal Syndrome in Mice

[Objectives]This study was conducted to evaluate the protective effect of polysaccharides from Enteromorpha prolifera(PEP)on mice with hepatorenal syndrome induced by carbon tetrachloride.[Methods]A mouse hepatorenal syndrome model was induced by carbon tetrachloride.The serum levels of lipid,total antioxidant capacity,liver and kidney function,pathological changes of liver and kidney were selected to clarity the effectiveness of PEP on hepatorenal syndrome in mice.[Results]PEP effectively lowered the serum levels of lipid,increased total antioxidant capacity,improved liver and kidney injury,and alleviated pathological changes of liver and kidney of mice induced by carbon tetrachloride.[Conclusions]PEP has a potent preventive effect on hepatorenal syndrome induced by carbon tetrachloride in mice,which provides theoretical support for future clinical application of PEP.

Hepatorenal syndrome

Hepatorenal syndrome (HRS) is a "functional" and reversible form of renal failure that occurs in patients with advanced chronic liver disease. The distinctive hallmark feature of HRS is the intense renal vasoconstriction caused by interactions between systemic and portal hemodynamics. This results in activation of vasoconstrictors and suppression of vasodilators in the renal circulation. Epidemiology, pathophysiology, as well as current and emerging therapies of HRS are discussed in this review.

Bile duct ligation in rats: A reliable model of hepatorenal syndrome?

The two most widely used experimental models of advanced liver disease are the administration of carbon tetrachloride, and common bile duct ligation (BDL), however, neither has been systematically evaluated as a model of hepatorenal syndrome (HRS). The BDL model in rats, studied at diverse time points, induced a progressive renal dysfunction without structural changes in the kidney. The authors concluded that BDL is a good model for further studies of HRS and its treatment. However, the renal impairment observed at the acute phase of the BDL model is based on a different pathophysiology than that of HRS. Specifi cally, in acute obstructive jaundice, cholemia predominates over parenchymal liver disease (reversible at this stage without portal hypertension or cirrhosis) and independently induces negative inotropic and chronotropic effects on the heart, impaired sympathetic vasoconstriction response and profound natriuresis and diuresis that might lead to volume depletion. In addition, systemic endotoxemia contributes to the prerenal etiology of renal impairment and promotes direct nephrotoxicity and acute tubular necrosis. On the other hand, the renal failure observed in the chronic BDL model (with development of biliary cirrhosis, portal hypertension and ascites) shares pathophysiological similarities with HRS, but the accordance of the chronic BDL model to the diagnostic criteria of HRS (e.g. absence of spontaneous bacterial peritonitis, no renal function improvement after plasma volume expansion) should have been confirmed. In conclusion, we think that the BDL model is not suitable for the study of the natural history of HRS, but the chronic BDL model might be valid for the study of established HRS and its potential therapies.

Acute kidney injury and hepatorenal syndrome in cirrhosis

Acute kidney injury(AKI)in cirrhosis,including hepatorenal syndrome(HRS),is a common and serious complication in cirrhotic patients,leading to significant morbidity and mortality.AKI is separated into two categories,non-HRS AKI and HRS-AKI.The most recent definition and diagnostic criteria of AKI in cirrhosis and HRS have helped diagnose and prognosticate the disease.The pathophysiology behind non-HRS-AKI and HRS is more complicated than once theorized and involves more processes than just splanchnic vasodilation.The common biomarkers clinicians use to assess kidney injury have significant limitations in cirrhosis patients;novel biomarkers being studied have shown promise but require further studies in clinical settings and animal models.The overall management of non-HRS AKI and HRS-AKI requires a systematic approach.Although pharmacological treatments have shown mortality benefit,the ideal HRS treatment option is liver transplantation with or without simultaneous kidney transplantation.Further research is required to optimize pharmacologic and nonpharmacologic approaches to treatment.This article reviews the current guidelines and recommendations of AKI in cirrhosis.

Hepatorenal syndrome:Update on diagnosis and therapy

Hepatorenal syndrome(HRS) is a manifestation of extreme circulatory dysfunction and entails high morbidity and mortality.A new definition has been recently recommended by the International Club of Ascites,according to which HRS diagnosis relies in serum creatinine changes instead that on a fixed high value.Moreover,new data on urinary biomarkers has been recently published.In this sense,the use of urinary neutrophil gelatinase-associated lipocalin seems useful to identify patients with acute tubular necrosis and should be employed in the diagnostic algorithm.Treatment with terlipressin and albumin is the current standard of care.Recent data show that terlipressin in intravenous continuous infusion is better tolerated than intravenous boluses and has the same efficacy.Terlipressin is effective in reversing HRS in only 40%-50% of patients.Serum bilirubin and creatinine levels along with the increase in blood pressure and the presence of systemic inflammatory response syndrome have been identified as predictors of response.Clearly,there is a need for further research in novel treatments.Other treatments have been assessed such as noradrenaline,dopamine,transjugular intrahepatic portosystemic shunt,renal and liver replacement therapy,etc.Among all of them,liver transplant is the only curative option and should be considered in all patients.HRS can be prevented with volume expansion with albumin during spontaneous bacterial peritonitis and after post large volume paracentesis,and with antibiotic prophylaxis in patients with advanced cirrhosis and low proteins in the ascitic fluid.This manuscript reviews the recent advances in the diagnosis and management of this life-threatening condition.

Pentoxifylline:A first line treatment option for severe alcoholic hepatitis and hepatorenal syndrome?

Although favourable results of pentoxifylline （PTX） used in treatment of severe alcoholic hepatitis patients with a Maddrey discriminant function score ≥ 32 have been previously reported, it is not currently recommended as a first line treatment for alcoholic hepatitis owing to lack of evidence for its efficacy as compared to the standard treatment with corticosteroids. In a very recent issue of World Journal of Gastroenterology, Dr. De BK and colleagues compared for the first time the two treatment modalities head to head in a randomized controlled study, demonstrating the advantage of PTX over corticosteroids in terms of patients＇ survival and risk-benefit profile. The advantage of PTX over corticosteroids in survival of patients with severe alcoholic hepatitis was found to be related to the prevention of hepatorenal syndrome in their study. This study raises the question of the use of PI-X as a standard treatment for severe alcoholic hepatitis. Considering the fact that PTX presented a spectacular efficiency in prevention of hepatorenal syndrome in their study as well as that previous studies have shown that this effect is possibly related to a primary renoprotective action because it is irrelevant of tumor necrosis factor-c~ synthesis inhibition or improved liver function, we tempted to speculate that PXT might be an effective option for prevention and/or treatment of hepatorenal syndrome complicating other forms of advanced liver disease. This attractive theory remains to be elucidated by pressing future studies in view of the lack of effective treatment modalities for hepatorenal syndrome.

Development and validation of a prognostic model for patients with hepatorenal syndrome:A retrospective cohort study

BACKGROUND Hepatorenal syndrome(HRS)is a severe complication of cirrhosis with high mortality,which necessitates accurate clinical decision.However,studies on prognostic factors and scoring systems to predict overall survival of HRS are not enough.Meanwhile,a multicenter cohort study with a long span of time could be more convincing.AIM To develop a novel and effective prognostic model for patients with HRS and clarify new prognostic factors.METHODS We retrospectively enrolled 1667 patients from four hospitals,and 371 eligible patients were finally analyzed to develop and validate a novel prognostic model for patients with HRS.Characteristics were compared between survivors and non-survivors,and potential prognostic factors were selected according to the impact on 28-d mortality.Accuracy in predicting 28-d mortality was compared between the novel and other scoring systems,including Model for End-Stage Liver Disease(MELD),Chronic Liver Failure-Sequential Organ Failure Assessment(CLIF-SOFA),and Chinese Group on the Study of Severe Hepatitis BAcute-on-Chronic Liver Failure(COSSH-ACLF).RESULTS Five prognostic factors,comprised of gender,international normalized ratio,mean corpuscular hemoglobin concentration,neutrophil percentage,and stage,were integrated into a new score,GIMNS;stage is a binary variable defined by the number of failed organs.GIMNS was positively correlated with MELD,CLIFSOFA,and COSSH-ACLF.Additionally,it had better accuracy[area under the receiver operating characteristic curve(AUROC):0.830]than MELD(AUROC:0.759),CLIF-SOFA(AUROC:0.767),and COSSH-ACLF(AUROC:0.759)in the derivation cohort(P<0.05).It performed better than MELD and CLIF-SOFA in the validation cohort(P<0.050)and had a higher AUROC than COSSH-ACLF(P=0.122).CONCLUSION We have developed a new scoring system,GIMNS,to predict 28-d mortality of HRS patients.Mean corpuscular hemoglobin concentration and stage were first proposed and found to be related to the mortality of HRS.Additionally,the GIMNS score showed better accuracy than MELD and CLIF-SOFA,and the AUROC was higher than that of COSSH-ACLF.

Hepatorenal syndrome

Hepatorenal syndrome(HRS) is defined as a functional renal failure in patients with liver disease with portal hypertension and it constitutes the climax of systemic circulatory changes associated with portal hypertension.This term refers to a precisely specified syndrome featuring in particular morphologically intact kidneys,where regulatory mechanisms have minimised glomerular filtration and maximised tubular resorption and urine concentration,which ultimately results in uraemia.The syndrome occurs almost exclusively in patients with ascites.Type 1 HRS develops as a consequence of a severe reduction of effective circulating volume due to both an extreme splanchnic arterial vasodilatation and a reduction of cardiac output.Type 2 HRS is characterised by a stable or slowly progressive renal failure so that its main clinical consequence is not acute renal failure,but refractory ascites,and its impact on prognosis is less negative.Liver transplantation is the most appropriate therapeutic method,nevertheless,only a few patients can receive it.The most suitable "bridge treatments" or treatment for patients ineligible for a liver transplant include terlipressin plus albumin.Terlipressin is at an initial dose of 0.5-1 mg every 4 h by intravenous bolus to 3 mg every 4 h in cases when there is no response.Renal function recovery can be achieved in less than 50% of patients and a considerable decrease in renal function may reoccur even in patients who have been responding to therapy over the short term.Transjugular intrahepatic portosystemic shunt plays only a marginal role in the treatment of HRS.

Terlipressin improves pulmonary pressures in cirrhotic patients with pulmonary hypertension and variceal bleeding or hepatorenal syndrome

Terlipressin has been shown to improve both pulmonary and systemic hemodynamics in stable cirrhotic patients with pulmonary hypertension,whereas other vasoconstrictors may cause pulmonary pressures to deteriorate We investigated the pulmonary and systemic hemodynamic effects of the first terlipressin dose(2 mg) in 7 cirrhotic patients with PH presenting with variceal bleeding(n=4) or hepatorenal syndrome(n=3).Terlipressin decreased pulmonary vascular resistance(158.8±8.9 vs 186.5±13.9 dynes sec cm-5 ;P=0.003) together with an increase in systemic vascular resistance(2143± 126 vs 1643±126 dynes sec cm-5 ;P<0.001).Terlipressin should be the vasoconstrictor treatment of choice when patients present with variceal bleeding or HRS.

Management of hepatorenal syndrome

Hepatorenal syndrome （HRS） is defned as development of renal dysfunction in patients with chronic liver diseases due to decreased effective arterial blood volume. It is the most severe complication of cirrhosis because of its very poor prognosis. In spite of several hypotheses and research, the pathogenesis of HRS is still poorly understood. The onset of HRS is a progressive process rather than a suddenly arising phenomenon. Since there are no specifc tests for HRS diagnosis, it is diagnosed by the exclusion of other causes of acute kidney injury in cirrhotic patients. There are two types of HRS with different characteristics and prognostics. Type 1 HRS is characterized by a sudden onset acute renal failure and a rapid deterioration ofother organ functions. It may develop spontaneously or be due to some precipitating factors. Type 2 HRS is characterized by slow and progressive worsening of renal functions due to cirrhosis and portal hypertension and it is accompanied by refractory ascites. The only definitive treatment for both Type 1 and Type 2 HRS is liver transplantation. The most suitable bridge treatment or treatment for patients who are not eligible for transplantation is a combination of terlipressin and albumin. For the same purpose, it is possible to try hemodialysis or renal replacement therapies in the form of continuous veno-venous hemofiltration. Artificial hepatic support systems are important for patients who do not respond to medical treatment.Transjugular intrahepatic portosystemic shunt may be considered as a treatment modality for unresponsive patients to medical treatment. The main goal of clinical surveillance in a cirrhotic patient is prevention of HRS before it develops. The aim of this article is to provide an updated review about the physiopathology of HRS and its treatment.

Development of hepatorenal syndrome in bile duct ligated rats

AIM: To evaluate in bile duct ligated rats whether there were progressive alterations of renal function without changes in histopathology. METHODS: Male Wistar rats were submitted to sham-surgery or bile duct ligation (BDL) and divided according to the post-procedure time (2, 4 and 6-wk). To determine renal function parameters, rats wereplaced in metabolic cages and, at the end of the experiment, blood and urine samples were obtained. Histology and hydroxyproline content were analyzed in liver and renal tissue. RESULTS: Rats with 2 wk of BDL increased free water clearance (P = 0.02), reduced urinary osmolality (P = 0.03) and serum creatinine (P = 0.01) in comparison to the sham group. In contrast, rats at 6 wk of BDL showed features of HRS, including signif icant increase in serum creatinine and reductions in creatinine clearance, water excretion and urinary sodium concentration. Rats with 4 wk of BDL exhibited an intermediate stage of renal dysfunction. Progressive hepatic f ibrosis according to post-procedure time was confirmed by histology. The increased levels of liver hydroxyproline contrasted with the absence of structural changes in the kidney, as assessed by histology and unchanged hydroxyproline content in renal tissue. CONCLUSION: Our data show that BDL produced progressive renal dysfunction without structural changes in the kidney, characterizing HRS. The present model will be useful to understand the pathophysiology of HRS.

Hepatorenal syndrome: Update on diagnosis and treatment

Acute kidney injury(AKI) is a common complication in patients with end-stage liver disease and advanced cirrhosis regardless of the underlying cause. Hepatorenal syndrome(HRS), a functional form of kidney failure, is one of the many possible causes of AKI. HRS is potentially reversible but involves highly complex pathogenetic mechanisms and equally complex clinical and therapeutic management. Once HRS has developed, it has a very poor prognosis. This review focuses on the diagnostic approach to HRS and discusses the therapeutic protocols currently adopted in clinical practice.

Liver kidney crosstalk:Hepatorenal syndrome

The dying liver causes the suffocation of the kidneys,which is a simplified way of describing the pathophysiology of hepatorenal syndrome(HRS).HRS is characterized by reversible functional renal impairment due to reduced blood supply and glomerular filtration rate,secondary to increased vasodilators.Over the years,HRS has gained much attention and focus among hepatologists and nephrologists.HRS is a diagnosis of exclusion,and in some cases,it carries a poor prognosis.Different classifications have emerged to better understand,diagnose,and promptly treat this condition.This targeted review aims to provide substantial insight into the epidemiology,pathophysiology,diagnosis,and management of HRS,shed light on the various milestones of this condition,and add to our current understanding.

Therapeutic alternatives for the treatment of type 1 hepatorenal syndrome: A Delphi technique-based consensus

AIM To propose several alternatives treatment of type 1 hepatorenal syndrome(HRS-1) what is the most severe expression of circulatory dysfunction on patients with portal hypertension.METHODS A group of eleven gastroenterologists and nephrologists performed a structured analysis of available literature.Each expert was designated to review and answer a question.They generated draft statements for evaluation by all the experts.Additional input was obtained from medical community.In order to reach consensus,a modified three-round Delphi technique method was used.According to United States Preventive Services Task Force criteria,the quality of the evidence and level of recommendation supporting each statement was graded.RESULTS Nine questions were formulated.The available evidence was evaluated considering its quality,number of patients included in the studies and the consistency of its results.The generated questions were answered by the expert panel with a high level of agreement.Thus,a therapeutic algorithm was generated.The role of terlipressin and norepinephrine was confirmed as the pharmacologic treatment of choice.On the other hand the use of the combination of octreotide,midodrine and albumin without vasoconstrictors was discouraged.The role of several other options was also evaluated and the available evidence was explored and discussed.Liver transplantation is considered the definitive treatment for HRS-1.The present consensus is an important effort that intends to organize the available strategies based on the available evidence in the literature,the quality of the evidence and the benefits,adverse effects and availability of the therapeutic tools described.CONCLUSION Based on the available evidence the expert panel was able to discriminate the most appropriate therapeutic alternatives for the treatment of HRS-1.

In-hospital mortality of hepatorenal syndrome in the United States:Nationwide inpatient sample

BACKGROUND Hepatorenal syndrome(HRS)is a life-threatening condition among patients with advanced liver disease.Data trends specific to hospital mortality and hospital admission resource utilization for HRS remain limited.AIM To assess the temporal trend in mortality and identify the predictors for mortality among hospital admissions for HRS in the United States.METHODS We used the National Inpatient Sample database to identify an unweighted sample of 4938 hospital admissions for HRS from 2005 to 2014(weighted sample of 23973 admissions).The primary outcomes were temporal trends in mortality as well as predictors for hospital mortality.We estimated odds ratios from multilevel mixed effect logistic regression to identify patient characteristics and treatments associated with hospital mortality.RESULTS Overall hospital mortality was 32%.Hospital mortality decreased from 44%in 2005 to 24%in 2014(P<0.001),while there was an increase in the rate of liver transplantation(P=0.02),renal replacement therapy(P<0.001),length of hospital stay(P<0.001),and hospitalization cost(P<0.001).On multivariable analysis,older age,alcohol use,coagulopathy,neurological disorder,and need for mechanical ventilation predicted higher hospital mortality,whereas liver transplantation,transjugular intrahepatic portosystemic shunt,and abdominal paracentesis were associated with lower hospital mortality.CONCLUSION Although there was an increase in resource utilizations,hospital mortality among patients admitted for HRS significantly improved.Several predictors for hospital mortality were identified.

COVID-19 and hepatorenal syndrome

Coronavirus disease 2019(COVID-19)is a highly infectious disease which emerged into a global pandemic.Although it primarily causes respiratory symptoms for affected patients,COVID-19 was shown to have multi-organ manifestations.Elevated liver enzymes appear to be commonly observed during the course of COVID-19,and there have been numerous reports of liver injury secondary to COVID-19 infection.It has been established that patients with pre-existing chronic liver disease(CLD)are more likely to have poorer outcomes following COVID-19 infection compared to those without CLD.Co-morbidities such as diabetes,hypertension,obesity,cardiovascular and chronic kidney disease frequently co-exist in individuals living with CLD,and a substantial population may also live with some degree of frailty.The mechanisms of how COVID-19 induces liver injury have been postulated.Hepatorenal syndrome(HRS)is the occurrence of kidney dysfunction in patients with severe CLD/fulminant liver failure in the absence of another identifiable cause,and is usually a marker of severe decompensated liver disease.Select reports of HRS following acute COVID-19 infection have been presented,although the risk factors and pathophysiological mechanisms leading to HRS in COVID-19 infection or following COVID-19 treatment remain largely unestablished due to the relative lack and novelty of published data.Evidence discussing the management of HRS in highdependency care and intensive care contexts is only emerging.In this article,we provide an overview on the speculative pathophysiological me-chanisms of COVID-19 induced HRS and propose strategies for clinical diagnosis and management to optimize outcomes in this scenario.

Fractional excretion of sodium in hepatorenal syndrome:Clinical and pathological correlation

AIMTo determine the accuracy of fractional excretion of sodium (FeNa) in the diagnosis of hepatorenal syndrome (HRS). METHODSEighty-eight liver transplantation candidates with renal dysfunction and/or proteinuria were included in the study sample. The baseline characteristics of the patients were obtained. All the 88 patients underwent iothalamate glomerular filtration rate testing, 24-h urine collection for urinary sodium and protein excretions, random urine for sodium and creatinine testing, and percutaneous kidney biopsy. FeNa was calculated using the equation [(urine sodium &times; serum creatinine)/(serum sodium &times; urine creatinine)] &times; 100%. Diuretic use was recorded among the participants. Patients on renal replacement therapy were not included in the original sample. RESULTSSeventy-seven (87%) of the 88 patients had FeNa P = 0.4). FeNa P = 0.47). Calculated positive predictive value and negative predictive value for FeNa P = 0.41). CONCLUSIONFeNa 1%.