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.

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.

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.

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.

Hepatocardiorenal syndrome in liver cirrhosis:Recognition of a new entity?

Emerging evidence and perspectives have pointed towards the heart playing an important role in hepatorenal syndrome(HRS),outside of conventional understanding that liver cirrhosis is traditionally considered the sole origin of a cascade of pathophysiological mechanisms directly affecting the kidneys in this context.In the absence of established heart disease,cirrhotic cardiomyopathy may occur more frequently in those with liver cirrhosis and kidney disease.It is a specific form of cardiac dysfunction characterized by blunted contractile responsiveness to stress stimuli and altered diastolic relaxation with electrophysiological abnormalities.Despite the clinical description of these potential cardiac-related complications of the liver,the role of the heart has traditionally been an overlooked aspect of circulatory dysfunction in HRS.Yet from a physiological sense,temporality(prior onset)of cardiorenal interactions in HRS and positive effects stemming from portosystemic shunting demonstrated an important role of the heart in the development and progression of kidney dysfunction in cirrhotic patients.In this review,we discuss current concepts surrounding how the heart may influence the development and progression of HRS,and the role of systemic inflammation and endothelial dysfunction causing circulatory dysfunction within this setting.The temporality of heart and kidney dysfunction in HRS will be discussed.For a subgroup of patients who receive portosystemic shunting,the dynamics of cardiorenal interactions following treatment is reviewed.Continued research to determine the unknowns in this topic is anticipated,hopefully to further clarify the intricacies surrounding the liver-heart-kidney connection and improve strategies for management.

Outcomes of liver transplantation in patients with hepatorenal syndrome

Hepatorenal syndrome(HRS) plays an important role in patients with liver cirrhosis on the wait list for liver transplantation(LT). The 1 and 5-year probability of developing HRS in cirrhotic with ascites is 20% and 40%, respectively. In this article, we reviewed current concepts in HRS pathophysiology, guidelines for HRS diagnosis, effective treatment options presently available, and controversies surrounding liver alone vs simultaneous liver kidney transplant(SLKT) in transplant candidates. Many treatment options including albumin, vasoconstrictors, renal replacement therapy, and eventual LT have remained a mainstay in the treatment of HRS. Unfortunately, even after aggressive measures such as terlipressin use, the rate of recovery is less than 50% of patients. Moreover, current SLKT guidelines include:(1) estimation of glomerular filtration rate of 30 m L/min or less for 4-8 wk;(2) proteinuria > 2 g/d; or(3) biopsy proven interstitial fibrosis or glomerulosclerosis. Even with these updated criteria there is a lack of consistency regarding longterm benefits for SLKT vs LT alone. Finally, in regards to kidney dysfunction in the post-transplant setting, an estimation of glomerular filtration rate < 60 mL /min per 1.73 m2 may be associated with an increased risk of patients having long-term end stage renal disease. HRS is common in patients with cirrhosis and those on liver transplant waitlist. Prompt identification and therapy initiation in transplant candidates with HRS may improve post-transplantation outcomes. Future studies identifying optimal vasoconstrictor regimens, alternative therapies, and factors predictive of response to therapy are needed. The appropriate use of SLKT in patients with HRS remains controversial and requires further evidence by the transplant community.

Current position of vasoconstrictor and albumin infusion for type 1 hepatorenal syndrome

Spontaneous bacterial peritonitis(SBP),refractory ascites,hepatorenal syndrome(HRS),hyponatremia and hepatic encephalopathy are complicationswhich frequently happen during a clinical course of decompensated cirrhosis.Splanchnic and peripheral vasodilatation,increased intrarenal vasoconstriction and impaired cardiac responsive function are pathological changes causing systemic and hemodynamic derangement.Extreme renal vasoconstriction leads to severe reduction of renal blood flow and glomerular filtration rate,which finally evolves into the clinical feature of HRS.Clinical manifestations of type 1 and type 2 HRS come to medical attention differently.Patients with type1 HRS present as acute kidney injury whereas those with type 2 HRS will have refractory ascites as the leading problem.Prompt diagnosis of type 1 HRS can halt the progression of HRS to acute tubular necrosis if the combined treatment of albumin infusion and vasoconstrictors is started timely.HRS reversal was seen in 34%-60%of patients,followed with decreasing mortality.Baseline serum levels of creatinine less than5 mg/dL,bilirubin less than 10 mg/dL,and increased mean arterial pressure of over 5 mmHg by day 3 of the combined treatment of vasoconstrictor and albumin are the predictors of good response.Type 1 HRS can be prevented in some conditions such as albumin infusion in SBP,prophylactic antibiotics for upper gastrointestinal hemorrhage,albumin replacement after large volume paracentesis in cirrhotic patients with massive ascites.The benefit of albumin infusion in infection with primary source other than SBP requires more studies.

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.

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.

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.

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

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.

clinical course and prognostic factors of hepatorenal syndrome:a retrospective single-center cohort study

AIM: To investigate clinical and biochemical features of hepatorenal syndrome(HRS), to assess short and long- term survival evaluating potential predictors of early mortality. METHODS: Sixty-two patients with liver cirrhosis and renal failure, defined as a serum creatinine value > 1.5 mg/dL on at least two measurements within 48 h, admitted to our tertiary referral Unit from 2001 to 201, were retrospectively reviewed. Among them, 33 patients(53.2%) fulfilled the revised criteria of the International Ascites Club for the diagnosis of HRS. Twenty-eight patients were treated with combinations of terlipressin and albumin, two with dopamine and al- bumin, and three with albumin alone. No patients were suitable for liver transplantation. Complete response was defined as normalization of creatinine levels to less than 1.5 mg/dL, partial response as a decrease of at least 50% but not to less than 1.5 mg/dL, no response as no reduction in creatinine or a decrease of less 50% compared to pre-treatment values. All of the patients were followed up for at least 1 year until January 2013. RESULTS: HRS type 1 was diagnosed in 15 patients(45.5%). Hepatitis C virus infection was the primary etiology(69.6%), followed by alcohol(15.2%), and cryptogenesis(15.2%). Complete response to therapy was obtained in only 3 cases(9.1%) and partial re- sponse in 7 patients(21.2%). Median survival was 30 d(range: 10-274) without significant differences be- tween type 1 and type 2 HRS. By univariate analysis, Child-Pugh class C(P = 0.009), presence of hepatocel- lular carcinoma(P = 0.04), low serum sodium(P = 0.02), high bilirubin values(P = 0.009) and high Model for End-stage Liver Disease(MELD) score(P = 0.03) were predictive factors of 30-d mortality. By multivari- ate analysis, only serum sodium < 132 mEq/L(OR = 31.39; P = 0.02) and MELD score > 27(OR = 18.72; P = 0.01) were independently associated with a survival of less than one month. CONCLUSION: HRS still has a poor prognosis, even when vasoactive drug therapies are extensively used.

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.

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.

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.

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.

Development of a rat model of D-galactosamine/lipopolysaccharide induced hepatorenal syndrome

AIM:To develop a practical and reproducible rat model of hepatorenal syndrome for further study of the pathophysiology of human hepatorenal syndrome. METHODS:Sprague-Dawley rats were intravenously injected with D-galactosamine and lipopolysaccharide(LPS) via the tail vein to induce fulminant hepatic failure to develop a model of hepatorenal syndrome. Liver and kidney function tests and plasma cytokine levels were measured after D-galactosamine/LPS administration,and hepatic and renal pathology was studied. Glomerular filtration rate was detected in conscious rats using micro-osmotic pump technology with fluorescein isothiocyanate-labelled inulin as a surrogate marker.RESULTS:Serum levels of biochemical indicators including liver and kidney function indexes and cytokines all significantly changed,especially at 12 h after D-galactosamine/LPS administration [alanine aminotransferase,3389.5 ± 499.5 IU/L; blood urea nitrogen,13.9 ± 1.3 mmol/L; Cr,78.1 ± 2.9 μmol/L; K+,6.1 ± 0.5 mmol/L; Na+,130.9 ± 1.9 mmol/L; Cl-,90.2 ± 1.9 mmol/L; tumor necrosis factor-α,1699.6 ± 599.1 pg/m L; endothelin-1,95.9 ± 25.9 pg/m L; P < 0.05 compared with normal saline control group]. Hepatocyte necrosis was aggravated gradually,which was most significant at 12 h after treatment with D-galactosamine/LPS,and was characterized by massive hepatocyte necrosis,while the structures of glomeruli,proximal and distal tubules were normal. Glomerular filtration rate was significantly decreased to 30%-35% of the control group at 12 h after D-galactosamine/LPS administration [Glomerular filtration rate(GFR)1,0.79 ± 0.11 m L/min; GFR2,3.58 ± 0.49 m L/min·kg BW-1; GFR3,0.39 ± 0.99 m L/min·g KW-1]. The decreasing timing of GFR was consistent with that of the presence of hepatocyte necrosis and liver and kidney dysfunction.CONCLUSION:The joint use of D-galactosamine and LPS can induce liver and kidney dysfunction and decline of glomerular filtration rate in rats which is a successful rat model of hepatorenal syndrome.

Is MELD score failing patients with liver disease and hepatorenal syndrome?

There is a need to reassess the application of MELD and the impact of renal insufficiency with consideration for developing an algorithm with exception points that would lead to timely allocation of livers to patients with hepatorenal syndrome prior to occurrence of permanent renal damage without jeopardizing post-transplant survival.