Oxazolone and ethanol induce colitis in non-obese diabetic-severe combined immunodeficiency interleukin-2Rγ(null) mice engrafted with human peripheral blood mononuclear cells.

Oxazolone-induced colitis in mice has become a recognized model to study the efficacy of therapeutics targeting the immunological response underlying the development of inflammatory bowel disease. However, this model cannot be used when therapeutics designed to address human targets do not interact with the respective murine counterpart. In this study, we examined the induction of oxazolone mediated colitis in non-obese diabetic-severe combined immunodeficiency interleukin-2Rγ(null) (NOD-SCID IL2Rγ(null)) mice engrafted with human peripheral blood mononuclear cells (hPBMC) derived from patients suffering from ulcerative colitis (UC), atopic dermatitis (AD) and healthy volunteers. NOD-SCID IL2Rγ (null) mice were engrafted with hPBMC followed by challenge with oxazolone or ethanol vehicle. Mice developed the same symptoms as observed previously in immunocompetent mice. The clinical activity score increased and the colon architecture was characterized by the development of oedema, fibrosis, crypt loss and dense infiltration of predominantly T cells into the lamina propria. Fluorescence activated cell sorter (FACS) analysis of lymphocytes in the colon identified natural killer (NK) T cells as a major constituent. In contrast to studies with immunocompetent mice, we observed the same phenotype in the group challenged with ethanol vehicle. The phenotype was most pronounced in mice engrafted with PBMC derived from a patient suffering from UC, suggesting that the immunological history of the donors predisposes the engrafted mice to react to ethanol. The model described here has the potential to study the efficacy of therapeutics targeting human lymphocytes in a model which is more reflective of the human disease. In addition, it might be developed to elucidate molecular mechanisms underlying the disease.

Intrarenal resistance index as a prognostic parameter in patients with liver cirrhosis compared with other hepatic scoring systems.

BACKGROUND AND AIMS: Patients with advanced liver cirrhosis who develop renal dysfunction have a poor prognosis. Elevated intrarenal resistance indices (RIs) due to renal vascular constriction have been described before in cirrhotic patients. In the current study, we prospectively investigated the course of intrarenal RIs and compared their prognostic impact with those of the Model for End-Stage Liver Disease (MELD) and the Child-Pugh scores. METHODS: Sixty-three patients with liver cirrhosis underwent a baseline visit which included a sonographic examination and laboratory tests. Forty-four patients were prospectively monitored. The end points were death or survival at the day of the follow-up visit. RESULTS: In 28 patients, a follow-up visit was performed after 22 ± 8 months (group 1). Sixteen patients died during follow-up after 12 ± 8 months (group 2). Group 2 patients showed a significantly higher baseline RI (0.76 ± 0.05) than group 1 patients (RI = 0.72 ± 0.06; p < 0.05). As shown by receiver operating characteristic analysis, the RI and the MELD score achieved similar sensitivity and specificity [area under the curve (AUC): 0.722; 95% confidence interval (95% CI): 0.575-0.873 vs. AUC: 0.724; 95% CI: 0.575-0.873, z = 0.029, n.s.] in predicting survival and were superior to the Child-Pugh score (AUC: 0.677; 96% CI: 0.518-0.837). CONCLUSION: The RI is not inferior in sensitivity and specificity to the MELD score. Cirrhotic patients with elevated RIs have impaired short- and long-term survival. The RI may help identify high-risk patients that require special therapeutic care.

Effectiveness of a novel endoscopy training concept.

BACKGROUND AND STUDY AIMS: Training standards in gastrointestinal endoscopy are poorly defined even though different simulators are increasingly used for skills training. In 2001 a new training concept called "GATE--gastroenterological education-training endoscopy" was established, which provides a combination of background theory, video demonstrations, and simulator training. We aimed to evaluate the acceptance and training effect of this training model. METHODS: In total, 98 physicians participating in four training courses were included. Data were collected on baseline characteristics, acceptance (5-point Likert scale), and pre- and post-course knowledge through a structured questionnaire (A-type and Pick-N multiple choice questions). A total of 13 trainees were randomly selected for additional simulator assessment of training effects on manual skills (5-point Likert scale). RESULTS: A total of 78 trainees (80%) provided complete data sets. The evaluation showed a positive acceptance of the training program (value 1 and 2, Likert scale); for example, 88% of participants suggested the inclusion of the GATE course as an obligatory part of endoscopic education. There was a significant improvement in theoretical knowledge in the post-test set compared with the pre-test set (mean 3.27 ±1.30 vs. 1.69 ±1.01 points; P<0.001). The training effect on practical skill showed a significant reduction in time needed for a procedure (445 ±189 s vs. 274 ±129 s; P<0.01). The mean assessment rating for practical skills improved from 3.05 ±0.65 at baseline to 2.52 ±0.59 on Likert scale ( P=0.085). CONCLUSIONS: The integrated GATE training improved theoretical knowledge and manual skill. The GATE courses have been accredited by the German Society of Gastroenterology, underlining the demand for implementing preclinical training courses in endoscopic training.

Acute postinfectious glomerulonephritis associated with Campylobacter jejuni enteritis - a case report and review of the literature on C. jejuni's potential to trigger immunologically mediated renal disease.

Kidney disease is a rare complication of Campylobacter jejuni (C. jejuni) enteritis. We here present the case of an 18-year-old male patient with crampy abdominal pain, vomiting, diarrhea, and fever. Three weeks later urinalysis revealed mild proteinuria and hematuria and a marked raise in serum creatinine was observed. Renal biopsy demonstrated acute endocapillary glomerulonephritis with mesangial IgM (immunoglobuline M) deposits. Extensive workup revealed no signs of skin or joint disease, thus excluding Henoch-Schönlein purpura. Due to persistent abdominal discomfort further gastro-enterological tests were performed and eventually Campylobacter jejuni was isolated from the patient's feces. In the absence of other precipitating factors for renal diseases we presumed an association between the bacterial infection and this postinfectious glomerulonephritis. Over a time period of 6 months the patient's kidney function normalized completely. However, long-term prognosis remains unclear. In addition to the case report, we conducted a review of the literature with results underlining Campylobacter jejuni's potential to trigger various types of immune mediated kidney diseases.

[Acute renal failure in patients with liver cirrhosis--what to do? An update]. / Akutes Nierenversagen bei Patienten mit Leberzirrhose--was tun? Ubersicht.

A lot of patients suffering from liver cirrhosis show a decreased renal perfusion and glomerular filtration rate. An impaired renal function is the result of complex e.g. hemodynamic disturbances, resulting of the chronic liver disease. This explains its disposition to renal dysfunction and the higher incidence of acute renal failure in liver cirrhosis. In the case of renal failure hepatorenal syndrome, apart from prerenal, renal and postrenal causes, should be included in the differential diagnosis especially when signs of portal hypertension are apparent regarding its high mortalityand fatal prognosis requiring an immediate therapeutically approach. Special attention must be due to preventive strategies to avoid renal deterioration. This includes simple steps e.g. a careful election of medication but also an adequate therapy of infection-associated complications in patients with liver cirrhosis.

Endothelin-3 like immunoreactivity in plasma of patients with cirrhosis of the liver.

A highly specific and sensitive radioimmunoassay (RIA) has been established for determination of endothelin-3 like immunoreactivity in human plasma to investigate its possible role in hemodynamic alterations due to liver disease. Crossreactivity with other endothelin isoforms was always below 4 %, the lower detection limit following extraction on Sep-Pak C18 cartridges was 0.5 pg/ml. The concentration of endothelin-3 (mean +/- SEM) was 4.16 +/- 0.56 pg/ml (n = 13) in plasma of patients with cirrhosis of the liver, three fold higher than in age matched controls (1.35 +/- 0.27 pg/ml, n = 12, p less than 0.01). Plasma immunoreactivity was confirmed to be endothelin-3 related by reverse-phase HPLC. These data could suggest a role of plasma endothelin-3 in circulatory changes, as they occur in cirrhosis of the liver.

Prevention of infectious complications after transjugular intrahepatic portosystemic shunt in cirrhotic patients with a single dose of ceftriaxone.

BACKGROUND/AIMS: Patients with cirrhosis of the liver are prone to bacterial infections. Therapeutic interventions such as endoscopic sclerotherapy increase the risk of bacterial infections in these patients. Following insertion of a transjugular intrahepatic portosystemic shunt (TIPS), the incidence of severe bacterial infections was recently shown to be 20% after elective procedures. This finding suggests antibiotic prophylaxis with the TIPS procedure. Antibiotic prophylaxis using cefotiam or cefotaxime/ampicillin did not significantly reduce infectious complications. The aim of the present study was therefore to investigate the efficacy of two different doses of a long-acting cephalosporin in prevention of bacterial infection after TIPS. METHODOLOGY: Eighty-two patients with cirrhosis (age: 52 +/- 2 years) who underwent elective TIPS were randomized to receive a single i.v. dose of either 1 g or 2 g Ceftriaxone 1 hour before the intervention. Patients with evidence of or suspected infections and patients on antibiotic therapy within 7 days prior to TIPS were excluded. Body temperature was monitored t.i.d. for 1 week and white blood count (WBC) and C-reactive protein (CRP) were determined before TIPS and 1 day and 1 week after TIPS. RESULTS: Only 2 of 82 patients (2.6%) showed signs of infection following TIPS insertion: One of 40 patients receiving 1 g Ceftriaxone and 1 of 42 patients receiving 2 g Ceftriaxone prior to TIPS developed temperature > 38.5 degrees C. In the latter patient this was due to pneumonia. This patient received antibiotic treatment with imipenem for 10 days. Temperature in the other patient normalized within 12 hours and he did not require antibiotic treatment. No significant differences in temperature, WBC and CRP between the different doses of Ceftriaxone were observed. CONCLUSIONS: Prophylactic treatment with Ceftriaxone reduces the reported incidence of bacterial infections after TIPS in patients with cirrhosis of the liver. Prophylaxis with 1 g Ceftriaxone seems as efficacious as 2 g.

Effects of transjugular intrahepatic portosystemic shunt (TIPS) on quantitative liver function tests.

BACKGROUND/AIMS: The transjugular intrahepatic portosystemic stent-shunt (TIPS) has been established as a new effective treatment for portal hypertension in advanced liver disease. Impairment of liver function due to reduced portal venous perfusion is considered to be a major risk of TIPS, and the shunt leads to an increase in the incidence of hepatic encephalopathy (HE). Known complications, like the increase in the incidence of HE or TIPS stenosis, are diagnosed either clinically or by doppler ultrasound. It is not practicable to use quantitative liver function tests in the diagnostic work-up of HE, and medical or interventional therapy can be established after clinical diagnosis. Still, information is limited about the influence of TIPS on quantitative liver function tests in patients with liver cirrhosis. Therefore, the aim of this prospective study was to assess the effects of TIPS on various liver function tests. METHODOLOGY: Fifteen patients with liver cirrhosis, a hepatopetal portal flow before TIPS, and an uncomplicated course without stenosis after elective TIPS were analysed. Liver function was quantitatively measured using the [14C]aminopyrine breath test (ABT), considered to be independent of hepatic blood flow, the monoethylglycinexylidide test (MEGX), believed to be largely dependent on hepatic blood flow, serum bilirubin, serum albumin, and prothrombin time. Measurements were performed before, 1, 3 and 6 months after TIPS. RESULTS: TIPS decreased the portal venous pressure gradient from 31.0+/-2.0 cm (SEM) H2O to 16.9+/-1.8 cm H2O (p<0.01). One, 3 and 6 months after TIPS there was no significant deterioration of liver function as assessed by ABT, MEGX or serum bilirubin, serum albumin, and prothrombin time compared to baseline values before TIPS. ABT and MEGX were significantly correlated before TIPS (r=0.72; p<0.01) and after TIPS (r=0.76; p<0.05). CONCLUSIONS: These data show no significant deterioration of microsomal liver function as measured by the quantitative liver function tests ABT and MEGX over a period of 6 months after elective TIPS. In particular, there was no significant reduction of the MEGX-test considered to depend predominantly on hepatic blood flow. Thus, there is no need for the quantitative liver function tests ABT and MEGX in the routine management of patients following the TIPS procedure.

Q-T interval (QT(C)) in patients with cirrhosis: relation to vasoactive peptides and heart rate.

OBJECTIVE: Prolonged Q-T interval (QT) has been reported in patients with cirrhosis who also exhibit profound abnormalities in vasoactive peptides and often present with elevated heart rate (HR). The aim of this study was to relate QT to the circulating level of endothelins (ET-1 and ET-3) and calcitonin gene-related peptide (CGRP) in patients with cirrhosis. In addition, we studied problems with HR correction of QT. MATERIAL AND METHODS: Forty-eight patients with cirrhosis and portal hypertension were studied during a haemodynamic investigation. Circulating levels of ETs and CGRP were determined by radioimmunoassays. Correction of QT for HR above 60 beats per min was performed using the methods described by Bazett (QT(C)) and Fridericia (QT(F)). RESULTS: Prolonged QT(C) (above 440 ms), found in 56% of the patients, was related to the presence of significant portal hypertension and liver dysfunction (p < 0.05 to 0.001), but not to elevated ET-1, ET-3 or CGRP. When corrected according to Bazett, QT(C) showed no significant relation to differences in HR between patients (r = 0.07, ns). QTF showed some undercorrection of HR (r = -0.36; p < 0.02). During HR variation in the individual patient, QT(C) revealed a small but significant overcorrection (2.6 ms per heartbeat per min; p < 0.001). This value was significantly (p < 0.02) smaller with QTF (1.2 ms per heartbeat per min). CONCLUSIONS: The prolonged QT(C) in cirrhosis is related to liver dysfunction and the presence of portal hypertension, but not to the elevated powerful vasoconstrictor (ET-1) or vasodilator (CGRP, ET-3) peptides. The problems with correction of the QT for elevated HR in cirrhosis are complex, and the lowest HR should be applied for determination of the QT.

[Renal impairment in liver diseases]. / Extrahepatische Manifesta- tionen bei Lebererkrankungen: Niere.

Renal failure in patients with liver disease is mostly none-organic: prerenal failure or hepatorenal syndrome (HRS). In addition there is organic renal failure, mostly acute tubular necrosis (ATN). In order to avoid functional renal failure cautious diuretic treatment as well as intravenous albumin substitution following paracentesis are pivotal. For prophylaxis of HRS patients with spontaneous bacterial peritonitis shall be given albumin infusions in addition to antibiotic treatment. Patients with HRS type I exhibit a very poor prognosis. Liver transplantation is the only established therapy with long-term success. To bridge the time to transplantation TIPS or terlipressin and albumin can be used.

Endothelin and endothelin receptor antagonism in portopulmonary hypertension.

Portopulmonary hypertension (PPHT) is a rare but devastating complication in patients with portal hypertension, characterized by pulmonary arterial obliterative disease with a concomitant rise in pulmonary vascular resistance. A broad body of evidence has accumulated, indicating that endothelin (ET) peptides and their cognate receptors are causally involved in the pathophysiology of pulmonary arterial hypertension (PAH) owing to different aetiologies, including PPHT. In addition, the ET system may be involved in hepatic fibrotic remodelling and portal hypertension. Several experimental models have provided evidence that ET receptor antagonism may have therapeutic potential in PPHT. Initial experience has accumulated during the last 2 years, suggesting that targeting the ET system may have beneficial effects in the clinical setting. In these studies, the orally active, dual ET receptor antagonist bosentan improved pulmonary haemodynamics and functional capacity. These effects were sustained and occurred in the absence of adverse events. If these observations can be corroborated by controlled clinical trials, bosentan would offer several advantages over available therapies, which have major drawbacks owing to their invasive and demanding mode of application.

Hepatitis induced by Noni juice from Morinda citrifolia: a rare cause of hepatotoxicity or the tip of the iceberg?

A 24-year-old female patient presented to her community hospital with mild elevations of serum transaminase and bilirubin levels. Because of multiple sclerosis, she was treated with interferon beta-1a for 6 weeks. After exclusion of viral hepatitis due to hepatitis A-E, interferon beta-1a was withdrawn under the suspicion of drug-induced hepatitis. One week later, she was admitted again to her community hospital with severe icterus. The transaminase and bilirubin levels were highly elevated, and a beginning impairment of the liver synthesis was expressed by a reduced prothrombin time. The confinement to our department occurred with a fulminant hepatitis and the suspicion of beginning acute liver failure. There was no evidence for hepatitis due to potentially hepatotoxic viruses, alcoholic hepatitis, Budd-Chiari syndrome, hemochromatosis, and Wilson's disease. In her serum there were high titers of liver-kidney microsomal type 1 autoantibody; the serum gamma globulin levels were in the normal range. Fine-needle aspiration biopsy of the liver ruled out an autoimmune hepatitis but showed signs of drug-induced toxicity. During the interview, she admitted that for 'general immune system stimulation' she had been drinking Noni juice, a Polynesian herbal remedy made from a tropical fruit (Morinda citrifolia), during the past 4 weeks. After cessation of the Noni juice ingestion, her transaminase levels normalized quickly and were in the normal range within 1 month.

[Advances in therapy for ascites and hepatorenal syndrome]. / Neues in der Therapie von Aszites und hepatorenalem Syndrom.

Sequential diuretic treatment of ascites with spironolactone and furosemide is equivalent to initial combination therapy. Orally applicable vasopressin-V2-receptor antagonists are an interesting novel therapeutic approach for the elimination of free water. The therapeutic efficacy for patients with cirrhosis and ascites is currently being investigated in phase II trials. Following paracentesis of up to 6 liters volume, infusion of 3.5 % saline is as effective as 20 % albumin. Another trial confirms the superiority of TIPS for the treatment of massive ascites, also demonstrating survival benefit. Determination of leukocyte esterase activity with a simple stix method may be helpful for the rapid and easy diagnosis of spontaneous bacterial peritonitis. Patients with hepatorenal syndrome seem to benefit from a combination of terlipressin and albumin whereas the effect of albumin dialysis on survival remains to be proven.

TIPS or vasoconstrictors for the treatment of hepatorenal syndrome type 1--effect on survival?

HRS is a serious complication in patients with cirrhosis and ascites and associated with a poor prognosis unless liver transplantation can be performed. Two different types of HES are being differentiated according to the clinical presentation: while HRS type I is characterised by rapid deterioration of renal function indicated by a two-fold increase of serum creatinine to values above 2.5 mg/dl or a decrease of creatinine clearance to values below 20 ml/min, HRS type II shows moderately increased serum creatinine above 1.5 mg/dl remaining stable over a longer period. The most prominent circulatory alterations in patients with chronic liver disease comprise portal hypertension and peripheral (mainly splanchnic) arterial vasodilation. This leads to a decreased centrally effective blood volume in cirrhotic patients. As a consequence, activation of sodium- and volume-retaining neurohumoral systems such as the renin-angiotensin-aldosterone system and the sympathetic nervous system and a non-osmotic release of arginine-vasopressin can be observed. These neurohumoral alterations induce renal sodium and water retention which are responsible for accumulation of ascites and deterioration of renal function. Recent therapeutic strategies of the hepatorenal syndrome take into account these pathophysiologic considerations: whereas the transjugular intrahepatic portosystemic shunt lowers portal hypertension, infusion of vasoactive drugs increases systemic vascular resistance in cirrhotic patients. Several uncontrolled trials have reported a positive effect of these strategies on renal function. The present analysis of combined data from these reports shows that this positive effect on renal function also may improve survival of patients with HRS type I.

Relation of endothelins to volume regulating neurohumoral systems in patients with cirrhosis of the liver.

The aim of the present study was to investigate the relationship between ET plasma concentrations and other hormonal systems in acute volume regulation of patients with cirrhosis. Ten healthy controls and 10 cirrhotic patients, five without and five with ascites were studied after 1 h in a sitting posture and subsequently subjected to 1 h head-out water immersion. Blood was collected for determinations of ET-1, ET-3, ANF, aldosterone, renin activity and noradrenaline. In addition, in 10 patients with compensated cirrhosis the effect of loop diuretics on ET-3, aldosterone and renin was studied. ETs in cirrhosis were significantly (P < 0.01) higher than in controls both before (ET-1, 19.6 +/- 1.3 pgmL-1 vs. 11.8 +/- 0.4 pgmL-1; ET-3, 18.5 +/- 1.4 pgmL-1 vs. 9.5 +/- 0.5 pgmL-1) and after water immersion (ET-1, 18.6 +/- 1.2 pgmL-1 vs. 12.4 +/- 0.3 pgmL-1; ET-3, 18.7 +/- 1.7 pgmL-1 vs. 10.0 +/- 0.5 pgmL-1). In cirrhotic patients, basal and immersion concentrations of ET-1 were significantly correlated to noradrenaline plasma concentrations (r = 0.79, P < 0.05). ET-3 plasma concentrations in cirrhosis were correlated to renin activity (r = 0.65, P < 0.05). Furthermore, ET-3 in cirrhosis was inversely correlated to systolic and mean arterial blood pressure (r = -0.55, P < 0.01 and r = -0.50, P < 0.05; respectively). To investigate the effect of hypovolaemia in compensated cirrhosis, 10 patients without ascites were studied before and after treatment with loop diuretics. In compensated cirrhosis ET-3 was significantly increased 6h after oral diuretic treatment (17.9 +/- 1.0 pgmL-1 vs. 15.5 +/- 0.4 pgmL-1, P < 0.001). The presented data demonstrate relations of endothelins, particularly of ET-3 to neurohumoral systems in patients with cirrhosis of the liver.

[Endothelin-1 and endothelin-3 in the plasma of dogs]. / Endothelin-1 und Endothelin-3 im Plasma des Hundes.

The endothelins represent a family of peptides with potent vasoconstrictory effects indicating a role in the regulation of vascular tone. An involvement of endothelins in the pathogenesis as well as pathophysiology of vascular diseases has been proposed. Therefore, the aim of the presented study was to develop the methodology to measure and characterize endothelin-1 (ET-1) and endothelin-3 (ET-3) in the plasma of dogs. Extraction of acidified plasma samples was performed by use of Sep-Pak C18 cartridges and plasma levels of ET-1- and ET-3-immunoreactivity (ET-1-IR; ET-3-IR) were determined by specific radioimmunoassays. The measured ET-immunoreactivities were verified by separation of plasma using high-pressure liquid chromatography (HPLC).

Evaluation of serum cystatin C concentration as a marker of renal function in patients with cirrhosis of the liver.

BACKGROUND AND AIMS: Diagnosis of moderately impaired renal function is of particular importance in patients with cirrhosis of the liver. Whereas patients with a markedly impaired glomerular filtration rate can be diagnosed easily by elevated serum creatinine concentrations, moderately reduced renal function may be missed by this conventional parameter. Recently, cystatin C has been suggested as a sensitive marker of renal function, independent of sex or muscle mass. Therefore, the aim of this study was to investigate the value of serum cystatin C concentration for the detection of moderately impaired renal function. METHODS: Ninety seven in-hospital patients with cirrhosis and a 24 hour creatinine clearance of at least 40 ml/min were investigated and divided into group 1 (creatinine clearance > or = 70 ml/min; n = 55) and group 2 (creatinine clearance 40-69 ml/min; n = 42). RESULTS: Serum cystatin C concentrations (mean (SD): 1.31 (0.51) v 1.04 (0.34) mg/l (p = 0.008)) and creatinine concentrations (1.03 (0.52) v 0.86 (0.22) mg/100 ml (p=0.03)) were higher in group 2 than in group 1; there was no significant difference in urea concentrations. Receiver-operator characteristics (ROC) revealed a differential diagnostic advantage of cystatin C over creatinine and urea. At cut off concentrations of 1.0 mg/l, 0.9 mg/100 ml, and 28 mg/100 ml, respectively, cystatin C, creatinine, and urea exhibited 69%, 45%, and 44% sensitivity (p<0.05). As patients with a small muscle mass or reduced physical activity could be particularly prone to overestimation of their renal function, separate analyses were performed for the subgroups of female and Child-Pugh class C patients, respectively. In both groups, discrimination between patients with moderately impaired and normal renal function was best with cystatin C. In female patients, sensitivity of cystatin C (77.8%) was superior (p<0.05) to that of creatinine (38.9%) and urea (41.2%). In Child-Pugh C patients, the ROC curve was significantly better for cystatin C than for creatinine. CONCLUSIONS: Serum cystatin C determination could be a valuable tool in patients with cirrhosis, particularly with Child-Pugh class C or in female patients, for early diagnosis of moderately impaired renal function.

Long-term therapy and retreatment of hepatorenal syndrome type 1 with ornipressin and dopamine.

Peripheral vasodilation is considered an important factor in the pathophysiology of the hepatorenal syndrome (HRS). Therefore, the aim of this study was to evaluate the therapeutic potential of the vasoconstrictor ornipressin plus dopamine in the treatment of the most severe form of HRS, namely HRS type 1. Seven cirrhotic patients (creatinine clearance 15 +/- 1 mL/min, UNaV 7 +/- 2 mmol/24 h) with HRS type 1 were included in the study after normalization of central venous pressure with intravenous albumin and low-dose dopamine had failed to prevent further deterioration of renal function. Ornipressin was given continuously (intravenous 6 IU/h) in combination with dopamine (2-3 microgram/kg/min) until creatinine clearance had increased to above 40 mL/min or adverse events prevented further treatment. HRS was reverted in 4 of 7 patients after 5 to 27 days (creatinine clearance 51 +/- 4 mL/min, UNaV 47 +/- 11 mmol/24 h) of treatment. Withdrawal was necessary in 1 patient after 15 days because of intestinal ischemia. Treatment failure was observed in 2 of 7 patients (creatinine clearance 19 +/- 10 mL/min, UNaV 8 +/- 3 mmol/24 h). Two of 4 responders had recidivant HRS 2 and 8 months after initial therapy, respectively. HRS in 1 of these patients was reverted with 18 days of ornipressin retreatment. The other patient had to be withdrawn from ornipressin after 2 hours because of ventricular tachyarrhythmia. Altogether, 3 of 7 patients survived HRS type 1, 1 after successful ornipressin therapy and liver transplantation, 1 with 2 successful courses of ornipressin, and 1 with liver transplantation after ornipressin treatment had failed. Thus, ornipressin plus dopamine can be a useful therapeutic option in patients with HRS type 1, especially as bridge to liver transplantation.

Endothelin-1 and -3 plasma concentrations in patients with cirrhosis: role of splanchnic and renal passage and liver function.

Increased as well as decreased plasma concentrations of the endothelins, endogenous vasoactive peptides, have been reported in cirrhosis. This might be caused by alterations of hepatic or renal clearance or release. Therefore, the aim of the current study was to investigate the influence of splanchnic and renal passage and of liver function on plasma concentrations of endothelin-1 (ET-1) and endothelin-3 (ET-3) in patients with cirrhosis compared with controls. Eighteen patients with cirrhosis and 8 normotensive controls of similar age were investigated. Arterial and venous plasma samples were obtained simultaneously, and ET-1 and ET-3 concentrations were determined in extracted plasma by two separate radioimmunoassays. Arterial as well as hepatic and renal venous concentrations of ET-1 in cirrhosis (17.8 +/- 0.8 pg/mL, 19.1 +/- 0.9 pg/mL, and 16.8 +/- 0.8 pg/mL) were significantly (P < .001) higher than in controls (9.2 +/- 1.7 pg/mL, 9.0 +/- 2.0 pg/mL, and 8.4 +/- 1.9 pg/mL, respectively). The same held true for the corresponding ET-3 plasma concentrations in cirrhosis (19.3 +/- 1.6 pg/mL, 20.5 +/- 1.5 pg/mL, and 18.4 +/- 1.5 pg/mL, respectively) compared with controls (11.1 +/- 1.8 pg/mL, 11.3 +/- 1.5 pg/mL, and 10.1 +/- 1.7 pg/mL, respectively; P < .01). There was a significant (P < .05) renal net extraction of ET-1 and ET-3 in cirrhosis. In contrast, a significant (P < .05) net release of ET-1 and ET-3 (2.40 +/- 0.80 ng/min and 1.75 +/- 1.16 ng/min) during splanchnic passage was observed in cirrhosis, but not in controls (-0.24 +/- 0.51 ng/min, and -0.46 +/- 0.64 ng/min).(ABSTRACT TRUNCATED AT 250 WORDS)