endothelin-1 and Hepatorenal-Syndrome

Endothelin (ET)-1 is a potent vasoconstrictor peptide with pro-inflammatory, mitogenic, and pro-fibrotic properties that is closely involved in both normal renal physiology and pathology. ET-1 exerts a wide variety of biological effects, including constriction of cortical and medullary vessels, mesangial cell contraction, stimulation of extracellular matrix production, and inhibition of sodium and water reabsorption along the collecting duct, effects that are primarily mediated in an autocrine/paracrine manner. Increasing evidence indicates that the ET system is involved in an array of renal disorders. These comprise chronic proteinuric states associated with progressive glomerular and tubulointerstitial fibrosis, including diabetic and hypertensive nephropathy, glomerulonephritis and others. In addition, ET-1 is causally linked to renal disorders characterized by increased renal vascular resistance, including acute ischaemic renal failure, calcineurin inhibitor toxicity, endotoxaemia, hepatorenal syndrome and others. Furthermore, derangement of the ET system may be involved in conditions associated with inappropriate sodium and water retention; for example, in congestive heart failure and hepatic cirrhosis. Both selective and non-selective ET receptor antagonist have been developed and tested in animal models with promising results. As key events in progressive renal injury like inflammation and fibrosis are mediated via both ET(A) and ET(B) receptors, while constrictor effects are primarily transduced by ET(A) receptors, dual ET receptor blockade may be superior over selective ET(A) antagonism. Several compounds have been developed with remarkable effects in several models of acute and progressive renal injury. Thus, clinical studies are required to assess whether these results can be confirmed in humans, hopefully leading to novel and effective therapeutic options with few side effects.

Topics: Acute Kidney Injury; Animals; Chronic Disease; Diabetic Nephropathies; Endothelin-1; Endothelins; Glomerulonephritis; Hepatorenal Syndrome; Humans; Hypertension; Ischemia; Kidney; Kidney Diseases; Kidney Transplantation; Receptors, Endothelin

Pathophysiology of endothelin-1, a vasoconstrictor and a mitogenic peptide, has been extensively investigated in recent years. The authors have examined the main clinical and experimental evidence regarding the involvement of this peptide in some medical emergencies, namely myocardial infarction, stroke and hepato-renal syndrome. Literature data suggest an emerging pathophysiological role for endothelin in such clinical conditions.

Topics: Emergencies; Endothelin-1; Hepatorenal Syndrome; Humans; Myocardial Infarction; Stroke

Renal vasoconstriction is a key factor in the development of hepatorenal syndrome (HRS) and may be secondary to increased activities of endothelin-1, a potent renal vasoconstrictor. To assess the effects of tezosentan, a nonselective endothelin receptor antagonist, on renal function in patients with type 2 HRS, six male patients, 56.3 +/- 2.5 years old, with cirrhosis and type 2 HRS were treated with tezosentan; ascending doses of 0.3, 1.0, and 3.0 mg/hour, each for 24 hours, were used for the initial 2 patients, but a constant dose of 0.3 mg/hour for up to 7 days was used for the remaining 4 patients. The glomerular filtration rate, renal plasma flow, 24-hour urinary volume, mean arterial pressure (MAP), heart rate, tezosentan levels, and vasoactive hormones were measured daily. Albumin was given as required. The study was stopped early because of concerns about the safety of tezosentan in type 2 HRS. Five patients discontinued the study early; one stopped within 4 hours because of systemic hypotension (MAP < 70 mm Hg), and 4 patients stopped at approximately 4 days because of concerns about worsening renal function (serum creatinine increased from 180 +/- 21 to 222 +/- 58 micromol/L, P > 0.05) and decreasing urine volume (P = 0.03) but without a significant change in MAP. The plasma tezosentan concentrations were 79 +/- 34 ng/mL at a steady state during infusion at 0.3 mg/hour. The plasma endothelin-1 concentrations increased from 2.7 +/- 0.3 pg/mL at the baseline to 19.1 +/- 7.3 pg/mL (P < 0.05).. An endothelin receptor blockade potentially can cause a deterioration in renal function in patients with cirrhosis and type 2 HRS. Caution should be taken in future studies using endothelin receptor antagonists in these patients.

Topics: Endothelin-1; Hemodynamics; Hepatorenal Syndrome; Humans; Kidney; Kidney Function Tests; Liver Cirrhosis; Male; Middle Aged; Pilot Projects; Pyridines; Sodium; Tetrazoles; Treatment Failure; Water

Hepatorenal syndrome (HRS), a severe complication of advanced cirrhosis, is defined as hypoperfusion of kidneys resulting from intense renal vasoconstriction in response to generalized systemic arterial vasodilatation. Nevertheless, the mechanisms have been barely investigated. Cumulative studies demonstrated renal vasodilatation in portal hypertensive and compensated cirrhotic rats. Previously, we identified that blunted renal vascular reactivity of portal hypertensive rats was reversed after lipopolysaccharide (LPS). This study was therefore conducted to delineate the sequence of renal vascular alternation and underlying mechanisms in LPS-treated cirrhotic rats. Sprague-Dawley rats were randomly allocated to receive sham surgery (Sham) or common bile duct ligation (CBDL). LPS was induced on the 28th day after surgery. Kidney perfusion was performed at 0.5 or 3 h after LPS to evaluate renal vascular response to endothelin-1 (ET-1). Endotoxemia increased serum ET-1 levels ( P < 0.0001) and renal arterial blood flow ( P < 0.05) in both Sham and CBDL rats. CBDL rats showed enhanced renal vascular reactivity to ET-1 at 3 h after LPS ( P = 0.026). Pretreatment with endothelin receptor type A (ET

Topics: Animals; Endothelin A Receptor Antagonists; Endothelin-1; Endotoxemia; Hepatorenal Syndrome; Lipopolysaccharides; Male; MAP Kinase Signaling System; Nitric Oxide Synthase Type II; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A; Renal Circulation; Vasodilation

To explore the role of tumor necrosis factor-alpha (TNF-alpha) in the pathogenesis of hepatorenal syndrome.. By isolated perfused kidney technique, rat kidneys were perfused at a constant flow. Changes in perfusion pressure (mmHg) were consecutively measured with multi-functional physiology recorder. After TNF-alpha or heparin treated 90 minutes, the perfusion pressure stimulated by endothelin-1 (ET-1) was detected.. TNF-alpha and heparin didn't modify the baseline perfusion pressure. When ET-1 was added at 2 nmol/L, the perfusion pressures increased to (47+/-9) mmHg, (97+/-36) mm Hg and (11+/-6) mm Hg in control, TNF-alpha and heparin (10mg/L) treated group, respectively, which were different among the three groups (t>or=3.811, P<0.01). No pathological damages were found in kidney tissues from all the groups after being stained with hematoxylin/eosin.. TNF-alpha plays an important role in the pathogenesis of hepatorenal syndrome by promoting renal vasoconstriction.

Topics: Animals; Calcium Channels; Endothelin-1; Heparin; Hepatorenal Syndrome; In Vitro Techniques; Inositol 1,4,5-Trisphosphate Receptors; Kidney; Male; Rats; Rats, Wistar; Receptors, Cytoplasmic and Nuclear; Renal Artery; Tumor Necrosis Factor-alpha; Vasoconstriction

Renal failure occurs in approximately 55% of patients with acute liver failure. We have previously shown that plasma endothelin 1 concentrations are elevated in patients with acute liver failure and the hepatorenal syndrome. There are few reported satisfactory animal models of liver failure together with functional renal failure. In this study, a rat model of acute liver failure induced by galactosamine that also develops renal failure was first characterised. This model was used to investigate the hypothesis that endothelin 1 is an important mediator involved in the pathogenesis of renal impairment that occurs in acute liver failure.. Acute liver failure was induced in male Sprague-Dawley rats by intraperitoneal injection of galactosamine together with treatment with the endothelin receptor antagonist Bosentan. Twenty four hour urine collections were made using a metabolic cage. Renal blood flow was measured in anaesthetised animals.. This model developed renal failure and liver failure in the absence of any significant renal pathology, and with an accompanying fall in renal blood flow. Plasma concentrations of endothelin 1 were increased twofold following the onset of liver and renal failure (p<0.05), and there was significant upregulation of the endothelin receptor A (ET(A)) in the renal cortex (p<0.05). Administration of Bosentan prevented the development of renal failure when given before or 24 hours after the onset of liver injury (p<0.05) but had no effect on liver injury itself, or on renal blood flow.. This study demonstrates that this animal model has many of the features needed to be regarded as a model of renal failure that occurs in acute liver failure. The observation that plasma levels of endothelin 1 and ET(A) receptors are increased and upregulated, and that renal failure is prevented by an endothelin antagonist supports the hypothesis originally put forward that ET(A) is important in the pathogenesis of renal failure that occurs in patients with acute liver failure.

Topics: Acute Disease; Analysis of Variance; Animals; Antihypertensive Agents; Biomarkers; Bosentan; Cells, Cultured; Endothelin Receptor Antagonists; Endothelin-1; Galactosamine; Hepatorenal Syndrome; Male; Microscopy, Electron; Osmolar Concentration; Rats; Rats, Sprague-Dawley; Renal Circulation; Statistics, Nonparametric; Sulfonamides; Up-Regulation

The hepatorenal syndrome (HRS) is characterized by renal vasoconstriction leading to deterioration of renal function in patients with liver disease. A possible role of endothelin-1 (ET-1) in the pathogenesis of HRS has been suggested, but a correlation between ET-1 plasma levels and the development of HRS as well as the recovery from HRS following OLT has not been shown yet. We performed longitudinal measurements of ET-1 plasma levels in four groups of patients, 5 patients with HRS before and after orthotopic liver transplantation (OLT), 10 patients without HRS undergoing OLT, 20 patients with chronic renal failure but without liver disease, and 12 healthy controls. Before OLT, plasma levels of ET-1 were higher in patients with HRS (19.5 +/- 8.6 ng/l, P < 0.001; n = 5) compared to patients without HRS (4.9 +/- 1.1 ng/l; n = 10), normals (1.2 +/- 0.18 ng/l; n = 12), and patients with chronic renal failure (2.4 +/- 0.4 ng/l; n = 20). Patients with HRS compared to patients without HRS had higher levels for creatinine (2.42 +/- 0.6 vs. 0.89 +/- 0.05 mg/dl, P < 0.05), creatinine clearance (107 +/- 9 ml/min vs. 44.6 +/- 5.5 ml/ min, P < 0.001), and bilirubin (11.4 +/- 3.8 vs. 3.7 +/- 1 mg/dl, P < 0.05) before OLT. Within one week after OLT, there was a rapid decrease in ET-1 levels in patients with HRS while creatinine and bilirubin levels decreased slower. Regression analysis revealed a weak correlation between serum creatinine and ET-1 (r = 0.192, P = 0.04) and a significant correlation between serum bilirubin and ET-1 (r = 0.395, P < 0.001). The means of the ET-1 levels decreases rapidly with improvement of liver function after OLT. Levels of ET-1 correlate with excretory liver function assessed by bilirubin. The fall in ET-1 levels preceding improvement of renal function further strengthens the concept of ET-1 being a causative factor in HRS.

Topics: Acute Kidney Injury; Analysis of Variance; Bilirubin; Biomarkers; Creatinine; Endothelin-1; Hepatorenal Syndrome; Humans; Kidney Failure, Chronic; Liver Failure; Liver Transplantation; Postoperative Complications; Reference Values; Time Factors

The pathogenesis of cirrhotic ascites and hepatorenal syndrome remains unresolved. The involvement of both endothelin-1 and atrial natriuretic peptide have recently been suggested. This study investigated the concentrations of serum endothelin and atrial natriuretic peptide in cirrhotic patients.. Seven healthy subjects and 31 cirrhotic patients were studied. Cirrhotic patients were divided into three groups: Group I, 16 cirrhotic patients without ascites; Group II, 10 cirrhotic patients with ascites, but without hepatorenal syndrome; and Group III, five cirrhotic patients with hepatorenal syndrome and ascites. Their sera were analyzed for endothelin-1 and atrial natriuretic peptide concentrations.. Cirrhotic patients with ascites, Group II and Group III, had higher plasma endothelin-1 concentrations (15.9 +/- 2.3 pg/ml and 24 +/- 2.1 pg/ml, respectively) than normal subjects and compensated cirrhotics (3.8 +/- 0.7 pg/ml and 6.4 +/- 1.1 pg/ml, respectively); p < 0.001). Atrial natriuretic peptide concentrations were also significantly higher in cirrhotic patients than in normal subjects (p < 0.025). Plasma endothelin-1 concentration had a negative correlation with creatinine clearance (r = -0.65, p < 0.001), as did atrial natriuretic peptide concentrations (r = -0.44, p = 0.012). Plasma endothelin-1 correlated significantly with atrial natriuretic peptide concentrations (r = 0.38, p = 0.035).. Both endothelin-1 and atrial natriuretic peptide concentrations were elevated in cirrhotic patients with ascites and hepatorenal syndrome. Endothelin-1 may have a negative impact on renal function. Our data also suggested that impaired responsiveness rather than impaired secretion of atrial natriuretic peptide is responsible for sodium retention in cirrhotic patients with ascites.

Topics: Adult; Aged; Ascites; Atrial Natriuretic Factor; Endothelin-1; Female; Hepatorenal Syndrome; Humans; Liver Cirrhosis; Male; Middle Aged

Endothelin, a potent vasoconstrictor, is thought to play a role in liver cirrhosis-related functional kidney failure. Our aim was to investigate the correlation between renal vasoconstriction, as detected by a Doppler ultrasound technique, and plasma concentrations of endothelin in cirrhotic patients. Fifty cirrhotic patients underwent Doppler examinations to detect renal vasoconstriction. The plasma concentration of endothelin was measured in 10 patients who exhibited vasoconstriction of the renal microvessels diagnosed by Doppler waveform analysis and was compared to that of patients in whom there was no sign of such vasoconstriction. No difference was observed in the plasma concentration of endothelin between patients in whom renal vasoconstriction was diagnosed and those in whom it was not. Our results suggested that the circulating endothelin does not reflect renal vasoconstriction, at least in the early phase of the functional renal failure associated with cirrhosis of the liver.

Topics: Endothelin-1; Hepatorenal Syndrome; Humans; Immunoenzyme Techniques; Kidney; Liver Cirrhosis; Microcirculation; Regression Analysis; Ultrasonography, Doppler, Duplex; Vascular Resistance; Vasoconstriction