Glycyrrhizin attenuates renal inflammation in a mouse Con A-hepatitis model via the IL-25/M2 axis.

Glycyrrhizin (GL) has immunoregulatory effects on various inflammatory diseases including hepatitis and nephritis. However, the mechanisms underlying the anti-inflammatory effect of GL on renal inflammation are not fully understood. Hepatorenal syndrome (HRS) is a functional acute renal impairment that occurs in severe liver disease, and we found that kidney injury also occurs in Con A-induced experimental hepatitis in mice. We previously found that GL can alleviate Con A-induced hepatitis by regulating the expression of IL-25 in the liver. We wanted to investigate whether GL can alleviate Con A-induced nephritis by regulating IL-25. IL-25 regulates inflammation by modulating type 2 immune responses, but the mechanism by which IL-25 affects kidney disease remains unclear. In this study, we found that the administration of GL enhanced the expression of IL-25 in renal tissues; the latter promoted the generation of type 2 macrophages (M2), which inhibited inflammation in the kidney caused by Con A challenge. IL-25 promoted the secretion of the inhibitory cytokine IL-10 by macrophages but inhibited the expression of the inflammatory cytokine IL-1ß by macrophages. Moreover, IL-25 downregulated the Con A-mediated expression of Toll-like receptor (TLR) 4 on macrophages. By comparing the roles of TLR2 and TLR4, we found that TLR4 is required for the immunoregulatory effect of IL-25 on macrophages. Our data revealed that GL has anti-inflammatory effects on Con A-induced kidney injury and that the GL/IL-25/M2 axis participates in the anti-inflammatory process. This study suggested that GL is a potential therapeutic for protecting against acute kidney injury.

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

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

Endotoxemia-enhanced renal vascular reactivity to endothelin-1 in cirrhotic rats.

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 (ETA) antagonist abrogated the LPS-enhanced renal vascular response in CBDL rats ( P < 0.001). There were significantly lower inducible nitric oxide synthase (iNOS) expression but higher ETA and phosphorylated extracellular signal-regulated kinase (p-ERK) expressions in renal medulla of endotoxemic CBDL rats ( P < 0.05). We concluded that LPS-induced renal iNOS inhibition, ETA upregulation, and subsequent ERK signaling activation may participate in renal vascular hyperreactivity in cirrhosis. ET-1-targeted therapy may be feasible in the control of HRS. NEW & NOTEWORTHY Hepatorenal syndrome (HRS) occurred in advanced cirrhosis after large-volume paracentesis or bacterial peritonitis. We demonstrated that intraperitoneal lipopolysaccharide (LPS) enhanced renal vascular reactivity to endothelin-1 (ET-1) in cirrhotic rats, accompanied by inducible nitric oxide synthase inhibition, endothelin receptor type A (ETA) upregulation, and subsequent extracellular signal-regulated kinase activation in renal medulla. Pretreatment with ETA antagonist abrogated the LPS-enhanced renal vascular response in common bile duct ligation rats. These findings suggest that further clinical investigation of ET-1-targeted therapy may be feasible in the control of HRS.

Terlipressin, a vasoactive prodrug recommended in hepatorenal syndrome, is an agonist of human V1, V2 and V1B receptors: Implications for its safety profile.

Terlipressin is recommended as a gold standard to treat hepatorenal syndrome complicating liver cirrhosis. It is presented as a specific V1A receptor agonist, beyond its enzymatic conversion into lysine8-Vasopressin (LVP), able to counteract the splanchnic vasodilation. However, the complete pharmacological characterization of this drug with respect to the different vasopressin receptor subtypes is missing. We studied terlipressin intrinsic properties, focusing not only on V1A, but also on other vasopressin receptor subtypes. The experimental studies were conducted on rat and human cellular models. Binding experiments were performed on rat liver membranes and CHO cells transfected with the different human vasopressin receptor subtypes. Agonist status was assessed from inositol phosphate or cyclic AMP assays, and measurement of intracellular calcium variations, performed on cultured vascular smooth muscle cells from rat aorta and human uterine artery and CHO cells. Terlipressin binds to the rat and human V1A receptors with an affinity in the micromolar range, a value 120 fold lower than that of LVP. It induces a rapid and transient intracellular calcium increase, a robust stimulation of phospholipase C but with reduced maximal efficiencies as compared to LVP, indicating a partial V1A agonist property. In addition, terlipressin is also a full agonist of human V2 and V1B receptors, with also a micromomolar affinity. CONCLUSIONS: Terlipressin is a non-selective vasopressin analogue, exhibiting intrinsic agonist properties. Its full V2 receptor agonism may result in renal effects potentially aggravating water retention and hyponatremia of cirrhosis.

A pilot study to evaluate renal hemodynamics in cirrhosis by simultaneous glomerular filtration rate, renal plasma flow, renal resistive indices and biomarkers measurements.

BACKGROUND: Renal hemodynamic measurements are complicated to perform in patients with cirrhosis, yet they provide the best measure of risk to predict hepatorenal syndrome (HRS). Currently, there are no established biomarkers of altered renal hemodynamics in cirrhosis validated by measured renal hemodynamics. METHODS: In this pilot study, simultaneous measurements of glomerular filtration rate (GFR), renal plasma flow (RPF), renal resistive indices and biomarkers were performed to evaluate renal hemodynamic alterations in 10 patients with cirrhosis (3 patients without ascites, 5 with diuretic-sensitive and 2 diuretic-refractory ascites). RESULTS: Patients with diuretic-refractory ascites had the lowest mean GFR (36.5 ml/min/1.73 m(2)) and RPF (133.6 ml/min/1.73 m(2)) when compared to those without ascites (GFR 82.9 ml/min/1.73 m(2), RPF 229.9 ml/min/1.73 m(2)) and with diuretic-sensitive ascites (GFR 82.3 ml/min/1.73 m(2), RPF 344.1 ml/min/1.73 m(2)). A higher mean filtration fraction (FF) (GFR/RPF 0.36) was noted among those without ascites compared to those with ascites. Higher FF in patients without ascites is most likely secondary to the vasoconstriction in the efferent glomerular arterioles (normal FF ~0.20). In general, renal resistive indices were inversely related to FF. While patients with ascites had lower FF and higher right kidney main and arcuate artery resistive indices, those without ascites had higher FF and lower right kidney main and arcuate artery resistive indices. While cystatin C and ß2-microglobulin performed better compared to Cr in estimating RPF, ß-trace protein, ß2-microglobulin, and SDMA, and (SDMA+ADMA) performed better in estimating right kidney arcuate artery resistive index. CONCLUSION: The results of this pilot study showed that identification of non-invasive biomarkers of reduced RPF and increased renal resistive indices can identify cirrhotics at risk for HRS at a stage more amenable to therapeutic intervention and reduce mortality from kidney failure in cirrhosis.

[Pain management in patients with liver cirrhosis]. / Tratamiento del dolor en el paciente con cirrosis hepática.

Pain management in patients with liver cirrhosis is a real challenge and is often inadequate due to a lack of therapeutic efficacy or the high incidence of adverse effects. The focus of treatment differs depending on whether the pain is acute or chronic and involves understanding the causative pathophysiological mechanism. Analgesics should be started with the minimum effective dose and should be titrated slowly with avoidance of polypharmacy. Adverse effects must be monitored, especially sedation and constipation, which predispose the patient to the development of hepatic encephalopathy. The first-line drug is paracetamol, which is safe at doses of 2-3g/day. Non-steroidal anti-inflammatory agents are contraindicated because they can cause acute renal failure and/or gastrointestinal bleeding. Tramadol is a safe option for moderate-severe pain. The opioids with the best safety profile are fentanyl and hydromorphone, with methadone as an alternative. Topical treatment can reduce oral drug consumption. In neuropathic pain the first-line therapeutic option is gabapentin. The use of antidepressants such as amitriptyline can be considered in some patients. Interventional techniques are a valuable tool in moderate to severe pain, since they allow a reduction in drug therapy and consequently its adverse effects. Psychological treatment, physical therapy and rehabilitation should be considered as part of multimodality therapy in the management of chronic pain.

Protective effect of nitric oxide on hepatopulmonary syndrome from ischemia-reperfusion injury.

AIM: To evaluate immunological protection of nitric oxide (NO) in hepatopulmonary syndrome and probable mechanisms of ischemia-reperfusion (IR) injury in rat liver transplantation. METHODS: Sixty-six healthy male Wistar rats were randomly divided into three groups (11 donor/recipient pairs). In group II, organ preservation solution was lactated Ringer's solution with heparin 10, 000/µL at 4 °C. In groups I and III, the preservation solution added, respectively, L-arginine or N(G)-L-arginine methyl ester (L-NAME) (1 mmol/L) based on group II, and recipients were injected with L-arginine or L-NAME (50 mg/kg) in the anhepatic phase. Grafted livers in each group were stored for 6 h and implanted into recipients. Five rats were used for observation of postoperative survival in each group. The other six rats in each group were used to obtain tissue samples, and executed at 3 h and 24 h after transplantation. The levels of alanine aminotransferase (ALT), tumor necrosis factor (TNF)-α and NO metabolites (NOx) were detected, and expression of NO synthase, TNF-α and intercellular adhesion molecule 1 (ICAM-1) was examined by triphosphopyridine nucleotide diaphorase histochemical and immunohistochemical staining. RESULTS: By supplementing L-arginine to strengthen the NO pathway, a high survival rate was achieved and hepatic function was improved. One-week survival rate of grafted liver recipients in group I was significantly increased (28.8 ± 36.6 d vs 4 ± 1.7 d, P < 0.01) as compared with groups II and III. Serum levels of ALT in group I were 2-7 times less than those in groups II and III (P < 0.01). The cyclic guanosine monophosphate (cGMP) levels in liver tissue and NOx in group I were 3-4 times higher than those of group II after 3 h and 24 h reperfusion, while in group III, they were significantly reduced as compared with those in group II (P < 0.01). The levels of TNF-α in group I were significantly lower than in group II after 3 h and 24 h reperfusion (P < 0.01), while being significantly higher in group III than group II (P < 0.01). Histopathology revealed more severe tissue damage in graft liver and lung tissues, and a more severe inflammatory response of the recipient after using NO synthase inhibitor, while the pathological damage to grafted liver and the recipient's lung tissues was significantly reduced in group I after 3 h and 24 h reperfusion. A small amount of constitutive NO synthase (cNOS) was expressed in liver endothelial cells after 6 h cold storage, but there was no expression of inducible NO synthase (iNOS). Expression of cNOS was particularly significant in vascular endothelial cells and liver cells at 3 h and 24 h after reperfusion in group II, but expression of iNOS and ICAM-1 was low in group I. There was diffuse strong expression of ICAM-1 and TNF-α in group III at 3 h after reperfusion. CONCLUSION: The NO/cGMP pathway may be critical in successful organ transplantation, especially in treating hepatopulmonary syndrome during cold IR injury in rat orthotopic liver transplantation.

Hepatorenal syndrome: are we missing some prognostic factors?

BACKGROUND: Hepatorenal syndrome (HRS) is the functional renal failure associated with advanced cirrhosis and has also been described in fulminant hepatic failure. Without liver transplantation its prognosis is dismal. Our study included patients with type 1 HRS associated with cirrhosis, who were not liver transplant candidates. AIM: To identify variables associated with improved survival. METHODS: Sixty-eight patients fulfilled the revised Ascites Club Criteria for type 1 HRS. None of them was suitable for liver transplantation. All the patients were treated with combinations of: albumin, midodrine and octreotide, pressors, and hemodialysis. RESULTS: Median survival was 13 days for the whole group. Survival varied with the end-stage liver disease (ESLD) etiology: autoimmune, 49 days, cardiac cirrhosis, 22 days, idiopathic, 15.5 days, viral, 15 days, hepatitis C and alcohol, 14.5 days, alcohol 8 days, and neoplasia 4 days (p = 0.048). Survival of HRS associated with alcoholic liver disease versus other etiologies was not statistically significant (p = 0.1). Increased serum creatinine (p = 0.02) and urinary sodium 6-10 mEq/l (p = 0.027) at the initiation of therapy were prognostic factors for mortality. HRS treatment modalities (p = 0.73), use of dialysis (p = 0.56), dialysis modality (p = 0.35), use of vasopressors (p = 0.26), pre-existing renal disease (p = 0.49), gender (p = 0.90), and age (p = 0.57) were not associated with survival. CONCLUSIONS: We report for the first time ESLD etiology as a prognostic factor for survival. The renal function (expressed as serum creatinine) and urinary Na (<5 mEq/l) at the time of diagnosis were found to be associated with survival, suggesting that early treatment might increase survival.

[Correction of protein-energy metabolism in elderly patients with acute intestinal obstruction and hepatorenal dysfunction].

UNLABELLED: Infringements of a protein-energetic metabolism in hepatorenal complications are an actual problem in urgent surgery. MATERIAL: 358 patients with a acute surgical pathology of intestines were analysed, in 27.4% of patients infringements of functions of a liver and kidneys were revealed, necessity for normalization of the protein-energetic metabolism was noted in 47-70% of cases. RESULTS: As a result the scheme for protein-energetic metabolism correction was specified in depending of a kind of intestinal impassability and a degree of severity of surgical disease. The early correction of a protein-energetic metabolism in complex with the extracorporeal support methods of a detoxication has provided the expressed positive clinical effect.

TNFα-induced IP3R1 expression through TNFR1/PC-PLC/PKCα and TNFR2 signalling pathways in human mesangial cell.

BACKGROUND: Little information is available regarding the mechanisms involved in cytokine-induced type 1 inositol 1,4,5-trisphosphate receptor (IP(3)R1) expression in human mesangial cells (HMCs) in the occurrence of hepatorenal syndrome (HRS). Over-expression of IP(3)R1 would enhance both IP(3)-binding activity and sensitivity. We hypothesize that it is possible that increased IP(3)R1, induced by TNFα, would lead to increased IP(3) sensitivity in response to a variety of vasoconstrictors, and promote HMC contraction and thus lead to reduced GFP, promoting HRS occurrence and development. METHODS: Quantitative real-time polymerase chain reaction and immunoblot assay were used to examine the effects of TNFα on IP(3)R1 mRNA and protein expression. Several inhibitors of kinases, depletion PKC, over-expression of dominant-negative mutant of PKC and non-radioactive PKC assay were used to examine the mechanism of signal transduction of TNFα-regulated IP(3)R1 in HMCs. RESULTS: TNFα increased IP(3)R1 mRNA and protein expression in HMCs, an effect that was blocked by prolonged incubated chronic PMA, D609, safingol and also by transfection with domain-negative PKCα construct. TNFα activated and promoted autophosphorylation of the PKCα. In addition, both anti-TNFR1 and anti-TNFR2 antibodies blocked TNFα-induced IP(3)R1 protein expression, while only anti-TNFR1 antibodies but not anti-TNFR2 antibodies attenuated TNFα-induced PKCα activity. CONCLUSIONS: TNFα increased the expression of IP(3)R1, and this was mediated, at least in part, through the TNFR1/PC-PLC/PKCα and TNFR2 signalling pathways in HMCs.

[Hepato-renal syndrome and problem of protein-energy metabolism correction during urgent surgery of the abdominal organs].

Early connecting of hardware detoxification methods allow more efficient use of amino acid preparations for action. The use of efferent technology provides a full correction of protein and energy metabolism in the immediate surgical patients with complicated diseases of the abdominal cavity. This will reduce bed-day in patient and surgical mortality.

[Correction of protein-energy metabolism in hepatorenal failure in surgical patients].

Infringements of a protein-energetic metabolism in hepatorenal complications are an actual problem in urgent surgery. 358 patients with a acute surgical pathology of intestines were analyzed, in 27.4% of patients infringements of functions of a liver and kidneys were revealed, necessity for normalization of the protein-energetic metabolism was noted in 47-70% of cases. As a result the scheme for protein-energetic metabolism correction was specified in depending of a kind of intestinal impassability and a degree of severity of surgical disease. The early correction of a protein-energetic metabolism in complex with the extracorporeal support methods of a detoxication has provided the expressed positive clinical effect.

Effects of terlipressin on the aquaretic system: evidence of antidiuretic effects.

The vasopressin analog terlipressin is believed to cause vasoconstriction selectively by V1 receptor stimulation. However, a possible antidiuretic effect by V2 receptor stimulation has never been ruled out. Twenty-two patients with ascites, including seven with refractory ascites, were included. The subjects were studied during a 400 ml/h oral water load before and after infusion of 2 mg of terlipressin (18 patients) or placebo infusion (4 patients). Effects on the V2 receptors were assessed by evaluating aquaporin (AQP)2 excretion, free water clearance (C(H2O)), urine osmolality (Uosm), and fractional distal water excretion (DFeH2O). After terlipressin the excretion of AQP2 increased by 89% [144 ng/mmol creatinine, 95% confidence interval (CI) 73-214 ng/mmol creatinine, P = 0.001]. C(H2O) decreased 1.05 ml/min (from 0.17 to -0.89 ml/min, P = 0.001), and DFeH2O decreased 37% (19 vs. 12; 95% CI 2-11, P = 0.01). Uosm increased by 27% (93 mosmol/kgH2O, 95% CI 23-164 mosmol/kgH2O, P = 0.02). Plasma sodium decreased 1.1 mmol/l (P < 0.01). An increase in AQP2 excretion and a decrease in C(H2O) and distal water excretion after terlipressin despite water loading is a clear indication of activation of the antidiuretic system (V2 receptor effect).

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 were placed 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 significant 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 fibrosis 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.

[Study on the expressions and roles of renal heat shock protein 72 and Toll-like receptor 4 in hepatorenal syndrome in rat].

OBJECTIVE: To explore the expressions and roles of renal heat shock protein 72(HSP72) and Toll-like receptor 4(TLR4) during development of hepatorenal syndrome in rat. METHODS: Following bile duct ligation (BDL), a biliary cirrhosis and hepatorenal syndrome rat model was reproduced. The blood, the renal and hepatic tissues of the rats were examined at 1, 2, 4 and 6 weeks (6 rats were used in each week) after BDL. Blood was withdrawn from the femoral vein and centrifuged. The plasma concentrations of alanine aminotransferase (ALT), total bilirubin (TBil), blood urea nitrogen (BUN) and creatinine (Cr) were measured, and those of the HSP72 and tumor necrosis factor-alpha (TNF-alpha) were assessed with enzyme linked immunosorbent assay (ELISA). After weighing liver and kidney and expressions of HSP72 and TLR4 in renal tissue were determined by reverse transcription-polymerase chain reaction (RT-PCR) and Western blotting. All data were compared with control group (C group). RESULTS: The plasma levels of ALT, TBil at each week and of BUN, Cr at 4 and 6 weeks were increased significantly (all P<0.05). The concentration of plasma HSP72 and the expressions of renal HSP72 mRNA and protein were lower (especially at 4 and 6 weeks, both P<0.01) in BDL rats compared with sham operation rats. But the plasma TNF-alpha levels and renal TLR4 (mRNA and protein) expressions were significantly higher than those of sham operation rats (all P<0.01). CONCLUSION: Decreased expression of renal HSP72 may contribute to activate the TLR4- initiating inflammatory signal pathway, attributing partly to the pathogenesis of hepatorenal syndrome in biliary cirrhosis.

Cysteinyl-leukotrienes and the liver.

Leukotrienes are potent biological mediators implicated in an increasing number of disease processes. This review outlines the basic biology of leukotrienes and discusses recent developments in our understanding of the specific role of cysteinyl-leukotrienes (cLTs) in cholestasis, hepatic inflammation, portal hypertension, and the pathogenesis of the hepatorenal syndrome (HRS).

[Tumor necrosis factor-alpha enhances the effect of endothelin on renal vasoconstriction in isolated perfused rat kidney].

OBJECTIVE: To explore the role of tumor necrosis factor-alpha (TNF-alpha) in the pathogenesis of hepatorenal syndrome. METHODS: 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. RESULTS: 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. CONCLUSION: TNF-alpha plays an important role in the pathogenesis of hepatorenal syndrome by promoting renal vasoconstriction.

Severe systemic reaction to (99m)Tc-methylene diphosphonate: a case report.

We report an unusual severe systemic reaction that occurred in a woman after a (99m)Tc-methylene diphosphonate bone scan and for which no alternative explanation could be found. The bone scintigram showed diffusely increased uptake in the liver and kidneys accompanied by reversible dysfunction of these organs and dermatologic manifestations. We speculate that an immune-mediated mechanism may have caused this unusual reaction.

Analysis of cysteinyl leukotrienes in human urine: enhanced excretion in patients with liver cirrhosis and hepatorenal syndrome.

The cysteinyl leukotrienes, comprising leukotriene C4 and its metabolites, are biologically most active mediators, eliminated from the blood circulation by the liver and the kidneys. The urine of normal subjects and of patients with hepatic and/or renal failure was analysed for endogenous cysteinyl leukotrienes. The leukotriene metabolites were separated by reversed-phase high-performance liquid chromatography and subsequently quantified by radioimmunoassay. Leukotriene E4 was detected in all urine samples analysed. Its mean concentration increased from 0.3 nmol l-1 in healthy subjects to 0.8 nmol l-1 in patients with liver cirrhosis. In patients with hepatorenal syndrome leukotriene E4 averaged 7.8 nmol l-1; in addition, N-acetyl-leukotriene E4 was detected in an average amount of 1.5 nmol l-1. The mean leukotriene E4/creatinine ratio in urine increased from 0.02 in healthy subjects to 0.11 in patients with liver cirrhosis and to 1.2 mumol leukotriene E4 mol-1 creatinine in patients with hepatorenal syndrome. These results indicate that cysteinyl leukotrienes may play an important role in the mediator network responsible for the development of the hepatorenal syndrome in patients with severe liver disease.

Digitoxin in patients with hepatorenal insufficiency after repeated oral administration.

Following chronic oral administration of digitoxin 0.1 mg day-1 the pharmacokinetics of this glycoside were studied in seven patients with hepatorenal insufficiency and were compared with those of seven healthy volunteers. Liver cirrhosis of the patients was confirmed by liver biopsy. Mean creatinine clearance of the healthy subjects was 129.7 +/- 3.3 ml min-1 (mean +/- SEM), that of the patients was 25.6 +/- 20.4 ml min-1. Mean antipyrine clearance (parameter of oxidative liver function) was 49.7 +/- 6.0 ml min-1 in the volunteers and 22.0 +/- 2.9 ml min-1 in the patients. Plasma protein binding of digitoxin (PPB) was 95.0 +/- 1.1% in the patients and 96.7 +/- 0.6% in the healthy subjects (n.s.). Total body clearance of digitoxin (Cltot) was 0.0728 +/- 0.0120 ml min-1 kg-1 in the patients and 0.0615 +/- 0.0027 ml min-1 kg-1 in normals (n.s.]. Mean steady state plasma levels (Css) of the patients were 18.3 +/- 4.7 ng ml-1 and 15.8 +/- 1.3 ng ml-1 in the normals (n.s.). Our data obtained from chronic oral administration do not indicate a reduced total body clearance of digitoxin in patients with hepatorenal insufficiency.