|
1
|
Vitale G, Coscia K, Zavatta G, Morelli MC, Vicennati V. Secondary hyperaldosteronism and liver fibrosis in patients with compensated chronic liver disease or portal hypertension. Eur J Intern Med 2022; 99:118-120. [PMID: 35039214 DOI: 10.1016/j.ejim.2022.01.020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Revised: 01/03/2022] [Accepted: 01/07/2022] [Indexed: 11/03/2022]
Affiliation(s)
- Giovanni Vitale
- Internal Medicine Unit for the Treatment of Severe Organ Failure, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Policlinico di Sant'Orsola, Bologna, Italy.
| | - Kimberly Coscia
- Unit of Endocrinology and Prevention and Care of Diabetes, Department of Medical and Surgical Sciences (DIMEC), IRCCS Azienda Ospedaliero-Universitaria di Bologna, Policlinico di Sant'Orsola, Bologna, Italy.
| | - Guido Zavatta
- Unit of Endocrinology and Prevention and Care of Diabetes, Department of Medical and Surgical Sciences (DIMEC), IRCCS Azienda Ospedaliero-Universitaria di Bologna, Policlinico di Sant'Orsola, Bologna, Italy.
| | - Maria Cristina Morelli
- Internal Medicine Unit for the Treatment of Severe Organ Failure, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Policlinico di Sant'Orsola, Bologna, Italy.
| | - Valentina Vicennati
- Unit of Endocrinology and Prevention and Care of Diabetes, Department of Medical and Surgical Sciences (DIMEC), IRCCS Azienda Ospedaliero-Universitaria di Bologna, Policlinico di Sant'Orsola, Bologna, Italy.
| |
Collapse
|
|
2
|
Hsieh YC, Lee KC, Lei HJ, Lan KH, Huo TI, Lin YT, Chan CC, Schnabl B, Huang YH, Hou MC, Lin HC. (Pro)renin Receptor Knockdown Attenuates Liver Fibrosis Through Inactivation of ERK/TGF-β1/SMAD3 Pathway. Cell Mol Gastroenterol Hepatol 2021; 12:813-838. [PMID: 34087453 PMCID: PMC8340309 DOI: 10.1016/j.jcmgh.2021.05.017] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Revised: 05/25/2021] [Accepted: 05/25/2021] [Indexed: 12/14/2022]
Abstract
BACKGROUND & AIMS Activation of the (pro)renin receptor (PRR) up-regulates the expression of profibrotic genes in the kidney and heart. We aimed to investigate the role of PRR in hepatic fibrogenesis. METHODS Human hepatic PRR levels were measured in patients with or without liver fibrosis. PRR expression was analyzed in primary mouse hepatic stellate cells (HSCs). Experimental fibrosis was studied in thioacetamide (TAA)-treated or methionine choline-deficient (MCD) diet-fed C57BL/6 mice. Lentivirus-mediated PRR short hairpin RNA was used to knockdown hepatic PRR expression. Lentiviral vectors expressing PRR short hairpin RNA or complementary DNA from the α-smooth muscle actin promoter were used for myofibroblast-specific gene knockdown or overexpression. RESULTS PRR is up-regulated in human and mouse fibrotic livers, and in activated HSCs. Hepatic PRR knockdown reduced liver fibrosis by suppressing the activation of HSCs and expression of profibrotic genes in TAA or MCD diet-injured mice without significant changes in hepatic inflammation. Renin and prorenin increased the expression of PRR and production of TGF-β1 in human activated HSC Lieming Xu-2 cells, and knockdown of PRR inactivated Lieming Xu-2 cells with decreased production of transforming growth factor (TGF)-β1 and Mothers against decapentaplegic homolog 3 (Smad3) phosphorylation. Myofibroblast-specific PRR knockdown also attenuated liver fibrosis in TAA or MCD diet-injured mice. Mice with both myofibroblast-specific and whole-liver PRR knockdown showed down-regulation of the hepatic extracellular signal-regulated kinase (ERK)/TGF-β1/Smad3 pathway. Myofibroblast-specific PRR overexpression worsened TAA-induced liver fibrosis by up-regulating the ERK/TGF-β1/Smad3 pathway. CONCLUSIONS PRR contributes to liver fibrosis and HSC activation, and its down-regulation attenuates liver fibrosis through inactivation of the ERK/TGF-β1/Smad3 pathway. Therefore, PRR is a promising therapeutic target for liver fibrosis.
Collapse
Affiliation(s)
- Yun-Cheng Hsieh
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei, Taiwan; Department of Medicine, Taipei, Taiwan; Institute of Pharmacology, National Yang-Ming University School of Medicine, Taipei, Taiwan
| | - Kuei-Chuan Lee
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei, Taiwan; Department of Medicine, Taipei, Taiwan.
| | - Hao-Jan Lei
- Department of Medicine, Taipei, Taiwan; Division of General Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Keng-Hsin Lan
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei, Taiwan; Department of Medicine, Taipei, Taiwan; Institute of Pharmacology, National Yang-Ming University School of Medicine, Taipei, Taiwan
| | - Teh-Ia Huo
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei, Taiwan; Department of Medicine, Taipei, Taiwan; Institute of Pharmacology, National Yang-Ming University School of Medicine, Taipei, Taiwan
| | - Yi-Tsung Lin
- Department of Medicine, Taipei, Taiwan; Division of Infectious Disease, Department of Medicine, Taipei, Taiwan
| | - Che-Chang Chan
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei, Taiwan; Department of Medicine, Taipei, Taiwan
| | - Bernd Schnabl
- Department of Medicine, VA San Diego Healthcare System, San Diego, California
| | - Yi-Hsiang Huang
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei, Taiwan; Department of Medicine, Taipei, Taiwan
| | - Ming-Chih Hou
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei, Taiwan; Department of Medicine, Taipei, Taiwan
| | - Han-Chieh Lin
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei, Taiwan; Department of Medicine, Taipei, Taiwan
| |
Collapse
|
|
3
|
West CA, Sasser JM, Baylis C. The enigma of continual plasma volume expansion in pregnancy: critical role of the renin-angiotensin-aldosterone system. Am J Physiol Renal Physiol 2016; 311:F1125-F1134. [PMID: 27707703 PMCID: PMC6189751 DOI: 10.1152/ajprenal.00129.2016] [Citation(s) in RCA: 48] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2016] [Accepted: 09/29/2016] [Indexed: 12/27/2022] Open
Abstract
Pregnancy is characterized by avid renal sodium retention and plasma volume expansion in the presence of decreased blood pressure. Decreased maternal blood pressure is a consequence of reduced systemic vascular tone, which results from an increased production of vasodilators [nitric oxide (NO), prostaglandins, and relaxin] and decreased vascular responsiveness to the potent vasoconstrictor (angiotensin II). The kidneys participate in this vasodilatory response, resulting in marked increases in renal plasma flow and glomerular filtration rate (GFR) during pregnancy. In women, sodium retention drives plasma volume expansion (∼40%) and is necessary for perfusion of the growing uterus and fetus. For there to be avid sodium retention in the presence of the potent natriuretic influences of increased NO and elevated GFR, there must be modifications of the tubules to prevent salt wasting. The purpose of this review is to summarize these adaptations.
Collapse
Affiliation(s)
- Crystal A West
- Department of Medicine, Georgetown University, Washington, District of Columbia;
| | - Jennifer M Sasser
- Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi; and
| | - Chris Baylis
- Department of Physiology and Functional Genomics, University of Florida, Gainesville, Florida
| |
Collapse
|
|
4
|
Solà E, Ginès P. Challenges and Management of Liver Cirrhosis: Pathophysiology of Renal Dysfunction in Cirrhosis. Dig Dis 2015; 33:534-8. [PMID: 26159270 DOI: 10.1159/000375344] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
Kidney dysfunction is a common complication of patients with advanced cirrhosis and is associated with poor prognosis. Patients with advanced cirrhosis show circulatory dysfunction characterized by reduced systemic vascular resistance due to splanchnic arterial vasodilation, which is caused by portal hypertension. The progressive reduction in systemic vascular resistance leads to effective arterial hypovolemia. In order to maintain arterial pressure within normal limits in this setting, there is activation of systemic vasoconstrictor systems, including the renin-angiotensin-aldosterone system, sympathetic nervous system and, in late stages, nonosmotic hypersecretion of vasopressin. Although these systems have positive effects in maintaining arterial pressure, they have a negative influence on kidney function, leading to the retention of sodium and solute-free water, and in late stages of the disease an intense kidney vasoconstriction develops, leading to decrease of the glomerular filtration rate and the development of hepatorenal syndrome (HRS). Moreover, bacterial translocation and the existence of a systemic inflammatory state in patients with advanced cirrhosis may play a role in the impairment of circulatory function. HRS is a unique cause of kidney failure of functional origin that develops in patients with cirrhosis. However, besides HRS, patients with cirrhosis may develop kidney failure due to other causes, including bacterial infections, prerenal kidney failure, shock, use of nephrotoxic drugs or intrinsic kidney diseases. Considering the existence of circulatory dysfunction and some degree of kidney vasoconstriction, patients with advanced cirrhosis have fragile kidney function and are susceptible to easily developing kidney failure associated with other complications of the disease, particularly bacterial infections and gastrointestinal bleeding.
Collapse
Affiliation(s)
- Elsa Solà
- Liver Unit, Hospital Clinic, University of Barcelona School of Medicine, IDIBAPS, CIBERehd and Instituto Reina Sofía de Investigación Nefrológica (IRSIN), Barcelona, Spain
| | | |
Collapse
|
|
5
|
King VL, English VL, Bharadwaj K, Cassis LA. Angiotensin II Stimulates Sympathetic Neurotransmission to Adipose Tissue. Physiol Rep 2013; 1. [PMID: 24224084 PMCID: PMC3818081 DOI: 10.1002/phy2.14] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Angiotensin II (AngII) facilitates sympathetic neurotransmission by regulating norepinephrine (NE) synthesis, release, and uptake. These effects of AngII contribute to cardiovascular control. Previous studies in our laboratory demonstrated that chronic AngII infusion decreased body weight of rats. We hypothesized that AngII facilitates sympathetic neurotransmission to adipose tissue and may thereby decrease body weight. The effect of chronic AngII infusion on the NE uptake transporter and NE turnover was examined in metabolic (interscapular brown adipose tissue, ISBAT; epididymal fat, EF) and cardiovascular tissues (left ventricle, LV; kidney) of rats. To examine the uptake transporter saturation isotherms were performed using [3H]nisoxetine (NIS). At doses that lowered body weight, AngII significantly increased ISBAT [3H]NIS binding density. To quantify NE turnover, alpha-methyl-para-tyrosine (AMPT) was injected in saline-infused, AngII-infused, or saline-infused rats that were pair-fed to food intake of AngII-infused rats. AngII significantly increased the rate of NE decline in all tissues compared to saline. The rate of NE decline in EF was increased to a similar extent by AngII and by pair feeding. In rats administered AngII and propranolol, reductions in food and water intake and body weight were eliminated. These data support the hypothesis that AngII facilitates sympathetic neurotransmission to adipose tissue. Increased sympathetic neurotransmission to adipose tissue following AngII exposure is suggested to contribute to reductions in body weight.
Collapse
Affiliation(s)
- Victoria L King
- Division of Cardiology, University of Kentucky, Lexington, KY 40536
| | | | | | | |
Collapse
|
|
6
|
Shirai Y, Yoshiji H, Noguchi R, Kaji K, Aihara Y, Douhara A, Moriya K, Namisaki T, Kawaratani H, Fukui H. Cross talk between toll-like receptor-4 signaling and angiotensin-II in liver fibrosis development in the rat model of non-alcoholic steatohepatitis. J Gastroenterol Hepatol 2013; 28:723-730. [PMID: 23301938 DOI: 10.1111/jgh.12112] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/14/2012] [Indexed: 12/11/2022]
Abstract
BACKGROUND AND AIM The innate immune system, including toll-like receptor-4 (TLR4) signaling cascade and angiotensin-II (AT-II) play important roles in the progression of liver fibrosis development; the cross talk between TLR4 and AT-II has not been elucidated yet. The aim of the current study was to elucidate the effect of AT-II type 1 receptor blocker (ARB), on the liver fibrosis development, especially in conjunction with the interaction of TLR4 and AT-II in the rat model of non-alcoholic steatohepatitis. METHODS Fischer 344 rats were fed a choline-deficient, L-amino-acid-defined diet for 8 weeks and the effects of losartan were elucidated in conjunction with activated hepatic stellate cells (Ac-HSC) activation, TLR4, nuclear factor-κB (NF-κB), and transforming growth factor-β (TGF-β) expressions. In vitro study was carried out to elucidate the effect of AT-II on several indices including TLR4, myeloid differentiation factor 88, NF-κB, and TGF-β expressions in the rat HSC. RESULTS ARB markedly inhibited liver fibrosis development along with suppression of the number of Ac-HSC and TGF-β. These inhibitory effects of ARB were almost in parallel with suppression of the hepatic TLR4 and NF-κB expressions. This in vitro study showed that AT-II significantly augmented the TLR4 expression in a dose- and time-dependent manner via AT-II type 1 receptor in the Ac-HSC. AT-II also augmented the lipopolysaccharide-induced myeloid differentiation factor 88 (MyD88), NF-κB, and TGF-β and these increments were attenuated by treatment with ARB. CONCLUSIONS These studies indicated that the cross talk between TLR4 signaling cascade and AT-II plays a pivotal role in liver fibrosis development in non-alcoholic steatohepatitis.
Collapse
Affiliation(s)
- Yusaku Shirai
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
7
|
Karimian G, Buist-Homan M, Mikus B, Henning RH, Faber KN, Moshage H. Angiotensin II protects primary rat hepatocytes against bile salt-induced apoptosis. PLoS One 2012; 7:e52647. [PMID: 23300732 PMCID: PMC3530435 DOI: 10.1371/journal.pone.0052647] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2012] [Accepted: 11/19/2012] [Indexed: 02/06/2023] Open
Abstract
Angiotensin II (AT-II) is a pro-fibrotic compound that acts via membrane-bound receptors (AT-1R/AT-2R) and thereby activates hepatic stellate cells (HSCs). AT-II receptor blockers (ARBs) are thus important candidates in the treatment of liver fibrosis. However, multiple case reports suggest that AT-1R blockers may induce hepatocyte injury. Therefore, we investigated the effect of AT-II and its receptor blockers on cytokine-, oxidative stress- and bile salt-induced cell death in hepatocytes. Primary rat hepatocytes were exposed to TNF-α/Actinomycin D, the ROS-generating agent menadione or the bile salts: glycochenodeoxycholic acid (GCDCA) and tauro-lithocholic acid-3 sulfate (TLCS), to induce apoptosis. AT-II (100 nmol/L) was added 10 minutes prior to the cell death-inducing agent. AT-1R antagonists (Sartans) and the AT-2R antagonist PD123319 were used at 1 µmol/L. Apoptosis (caspase-3 activity, acridine orange staining) and necrosis (Sytox green staining) were quantified. Expression of CHOP (marker for ER stress) and AT-II receptor mRNAs were quantified by Q-PCR. AT-II dose-dependently reduced GCDCA-induced apoptosis of hepatocytes (−50%, p<0.05) without inducing necrosis. In addition, AT-II reduced TLCS-induced apoptosis of hepatocytes (−50%, p<0.05). However, AT-II did not suppress TNF/Act-D and menadione-induced apoptosis. Only the AT-1R antagonists abolished the protective effect of AT-II against GCDCA-induced apoptosis. AT-II increased phosphorylation of ERK and a significant reversal of the protective effect of AT-II was observed when signaling kinases, including ERK, were inhibited. Moreover, AT-II prevented the GCDCA-induced expression of CHOP (the marker of the ER-mediated apoptosis).
Collapse
Affiliation(s)
- Golnar Karimian
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
| | | | | | | | | | | |
Collapse
|
|
8
|
Bellot P, García-Pagán JC, Francés R, Abraldes JG, Navasa M, Pérez-Mateo M, Such J, Bosch J. Bacterial DNA translocation is associated with systemic circulatory abnormalities and intrahepatic endothelial dysfunction in patients with cirrhosis. Hepatology 2010; 52:2044-52. [PMID: 20979050 DOI: 10.1002/hep.23918] [Citation(s) in RCA: 170] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2010] [Accepted: 08/06/2010] [Indexed: 12/12/2022]
Abstract
UNLABELLED Presence of bacterial DNA in noninfected patients with cirrhosis and ascites is associated with a marked inflammatory response including activation of the inducible form of nitric oxide synthase and release of nitric oxide, similar to that observed in patients with spontaneous bacterial peritonitis. Although presence of bacterial DNA is associated with an impaired prognosis, no information is available regarding its hemodynamic consequences. Systemic and hepatic hemodynamics before and after a liquid test meal were assessed in a series of 75 noninfected patients with cirrhosis (55 with ascites). Bacterial DNA was measured by polymerase chain reaction. Bacterial DNA was detected only in patients with ascites. Clinical data and liver function were similar in ascitic patients with presence (n = 21) or absence of bacterial DNA (n = 34). Bacterial-DNA(+) patients had significantly lower mean arterial pressure (P = 0.002) and systemic vascular resistance (P = 0.03) than bacterial-DNA(-) patients. Cardiac output, cardiopulmonary pressures, hepatic venous pressure gradient (HVPG), and hepatic blood flow were similar in both groups. Thirty minutes after the test meal, in response to increased blood flow caused by postprandial hyperemia, there was a significantly greater increase in HVPG and impaired hepatic vasorelaxation in bacterial-DNA(+) as compared with bacterial-DNA(-) patients, which indicates hepatic endothelial dysfunction. Indeed, the increase in HVPG after the test meal significantly correlated with serum bacterial DNA concentration. CONCLUSION Presence of bacterial DNA, a marker of bacterial translocation, is associated with aggravation of peripheral vasodilation and with worsening of intrahepatic endothelial dysfunction.
Collapse
Affiliation(s)
- Pablo Bellot
- Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clínic-Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain
| | | | | | | | | | | | | | | |
Collapse
|
|
9
|
Colmenero J, Bataller R, Sancho-Bru P, Domínguez M, Moreno M, Forns X, Bruguera M, Arroyo V, Brenner DA, Ginès P. Effects of losartan on hepatic expression of nonphagocytic NADPH oxidase and fibrogenic genes in patients with chronic hepatitis C. Am J Physiol Gastrointest Liver Physiol 2009; 297:G726-34. [PMID: 19628656 PMCID: PMC2763804 DOI: 10.1152/ajpgi.00162.2009] [Citation(s) in RCA: 94] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Angiotensin II promotes liver fibrogenesis by stimulating nonphagocytic NADPH oxidase (NOX)-induced oxidative stress. Angiotensin II type 1 (AT1) receptor blockers attenuate experimental liver fibrosis, yet their effects in human liver fibrosis are unknown. We investigated the effects of losartan on hepatic expression of fibrogenic, inflammatory, and NOX genes in patients with chronic hepatitis C (CHC). Fourteen patients with CHC and liver fibrosis received oral losartan (50 mg/day) for 18 mo. Liver biopsies were performed at baseline and after treatment. The degree of inflammation and fibrosis was evaluated by histological analysis (METAVIR). Collagen content was measured by morphometric quantification of Sirius red staining. Overall collagen content and fibrosis stage remained stable in the whole series, yet the fibrosis stage decreased in seven patients. Inflammatory activity improved in seven patients. The effect of losartan on hepatic expression of 31 profibrogenic and inflammatory genes and components of the NOX complex was assessed by quantitative PCR. Losartan treatment was associated with a significant decrease in the expression of several profibrogenic and NOX genes including procollagen alpha1(I) and alpha1(IV), urokinase-type plasminogen activator, metalloproteinase type 2, NOX activator 1 (NOXA-1) and organizer 1 (NOXO-1), and Rac-1. Losartan was well tolerated in all patients and was effective in attenuating the activity of the systemic renin-angiotensin system. No effects on serum liver tests or viral load were observed. We conclude that prolonged administration of losartan, an oral AT1 receptor blocker, is associated with downregulation of NOX components and fibrogenic genes in patients with CHC. Controlled studies are warranted to assess the effect of AT1 receptor blockers in chronic liver injury.
Collapse
Affiliation(s)
- Jordi Colmenero
- 1Liver Unit, Institut Clínic de Malalties Digestives i Metabòliques, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica En Red de Enfermedades Hepáticas y Digestivas (CIBERehd), University of Barcelona, Catalonia, Spain; and
| | - Ramón Bataller
- 1Liver Unit, Institut Clínic de Malalties Digestives i Metabòliques, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica En Red de Enfermedades Hepáticas y Digestivas (CIBERehd), University of Barcelona, Catalonia, Spain; and
| | - Pau Sancho-Bru
- 1Liver Unit, Institut Clínic de Malalties Digestives i Metabòliques, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica En Red de Enfermedades Hepáticas y Digestivas (CIBERehd), University of Barcelona, Catalonia, Spain; and
| | - Marlene Domínguez
- 1Liver Unit, Institut Clínic de Malalties Digestives i Metabòliques, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica En Red de Enfermedades Hepáticas y Digestivas (CIBERehd), University of Barcelona, Catalonia, Spain; and
| | - Montserrat Moreno
- 1Liver Unit, Institut Clínic de Malalties Digestives i Metabòliques, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica En Red de Enfermedades Hepáticas y Digestivas (CIBERehd), University of Barcelona, Catalonia, Spain; and
| | - Xavier Forns
- 1Liver Unit, Institut Clínic de Malalties Digestives i Metabòliques, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica En Red de Enfermedades Hepáticas y Digestivas (CIBERehd), University of Barcelona, Catalonia, Spain; and
| | - Miquel Bruguera
- 1Liver Unit, Institut Clínic de Malalties Digestives i Metabòliques, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica En Red de Enfermedades Hepáticas y Digestivas (CIBERehd), University of Barcelona, Catalonia, Spain; and
| | - Vicente Arroyo
- 1Liver Unit, Institut Clínic de Malalties Digestives i Metabòliques, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica En Red de Enfermedades Hepáticas y Digestivas (CIBERehd), University of Barcelona, Catalonia, Spain; and
| | - David A. Brenner
- 2University of California San Diego School of Medicine, La Jolla, California
| | - Pere Ginès
- 1Liver Unit, Institut Clínic de Malalties Digestives i Metabòliques, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica En Red de Enfermedades Hepáticas y Digestivas (CIBERehd), University of Barcelona, Catalonia, Spain; and
| |
Collapse
|
|
10
|
Herath CB, Warner FJ, Lubel JS, Dean RG, Jia Z, Lew RA, Smith AI, Burrell LM, Angus PW. Upregulation of hepatic angiotensin-converting enzyme 2 (ACE2) and angiotensin-(1-7) levels in experimental biliary fibrosis. J Hepatol 2007; 47:387-95. [PMID: 17532087 PMCID: PMC7114685 DOI: 10.1016/j.jhep.2007.03.008] [Citation(s) in RCA: 126] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2006] [Revised: 02/09/2007] [Accepted: 03/05/2007] [Indexed: 12/12/2022]
Abstract
BACKGROUND/AIMS Angiotensin-converting enzyme 2 (ACE2), its product, angiotensin-(1-7) and its receptor, Mas, may moderate the adverse effects of angiotensin II in liver disease. We examined the expression of these novel components of the renin angiotensin system (RAS) and the production and vasoactive effects of angiotensin-(1-7) in the bile duct ligated (BDL) rat. METHODS BDL or sham-operated rats were sacrificed at 1, 2, 3 and 4 weeks. Tissue and blood were collected for gene expression, enzyme activity and peptide measurements. In situ perfused livers were used to assess angiotensin peptide production and their effects on portal resistance. RESULTS Hepatic ACE2 gene and activity (P<0.0005), plasma angiotensin-(1-7) (P<0.0005) and Mas receptor expression (P<0.01) were increased following BDL compared to shams. Perfusion experiments confirmed that BDL livers produced increased angiotensin-(1-7) (P<0.05) from angiotensin II and this was augmented (P<0.01) by ACE inhibition. Whilst angiotensin II increased vasoconstriction in cirrhotic livers, angiotensin-(1-7) had no effect on portal resistance. CONCLUSIONS RAS activation in chronic liver injury is associated with upregulation of ACE2, Mas and hepatic conversion of angiotensin II to angiotensin-(1-7) leading to increased circulating angiotensin-(1-7). These results support the presence of an ACE2-angiotensin-(1-7)-Mas axis in liver injury which may counteract the effects of angiotensin II.
Collapse
Affiliation(s)
- Chandana B Herath
- Department of Medicine, The University of Melbourne, Austin Health, Heidelberg, Vic., Australia
| | | | | | | | | | | | | | | | | |
Collapse
|
|
11
|
Abstract
There is an increasing body of evidence to suggest that the RAS (renin–angiotensin system) contributes to tissue injury and fibrosis in chronic liver disease. A number of studies have shown that components of a local hepatic RAS are up-regulated in fibrotic livers of humans and in experimental animal models. Angiotensin II, the main physiological effector molecule of this system, mediates liver fibrosis by stimulating fibroblast proliferation (myofibroblast and hepatic stellate cells), infiltration of inflammatory cells, and the release of inflammatory cytokines and growth factors such as TGF (transforming growth factor)-β1, IL (interleukin)-1β, MCP (monocyte chemoattractant protein)-1 and connective tissue growth factor. Furthermore, blockade of the RAS by ACE (angiotensin-converting enzyme) inhibitors and angiotensin type 1 receptor antagonists significantly attenuate liver fibrosis in experimental models of chronic liver injury. In 2000 ACE2 (angiotensin-converting enzyme 2), a human homologue of ACE, was identified. ACE2 efficiently degrades angiotensin II to angiotensin-(1–7), a peptide which has recently been shown to have both vasodilatory and tissue protective effects. This suggests that ACE2 and its products may be part of an alternate enzymatic pathway in the RAS, which counterbalances the generation and actions of angiotensin II, the ACE2–angiotensin-(1–7)–Mas axis. This review focuses on the potential roles of the RAS, angiotensin II and ACE2 in chronic liver injury and fibrogenesis.
Collapse
Affiliation(s)
- Fiona J Warner
- A. W. Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, Camperdown, NSW, Australia.
| | | | | | | |
Collapse
|
|
12
|
De Minicis S, Brenner DA. NOX in liver fibrosis. Arch Biochem Biophys 2007; 462:266-72. [PMID: 17531188 PMCID: PMC2727549 DOI: 10.1016/j.abb.2007.04.016] [Citation(s) in RCA: 120] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2007] [Revised: 04/10/2007] [Accepted: 04/11/2007] [Indexed: 12/13/2022]
Abstract
NADPH oxidase is a multi-protein complex producing reactive oxygen species (ROS) both in phagocytic cells, being essential in host defense, and in non-phagocytic cells, regulating intracellular signalling. In the liver, NADPH oxidase plays a central role in fibrogenesis. A functionally active form of the NADPH oxidase is expressed not only in Kupffer cells (phagocytic cell type) but also in hepatic stellate cells (HSCs) (non-phagocytic cell type), suggesting a role of the non-phagocytic NADPH oxidase in HSC activation. Consistent with this concept, profibrogenic agonists such as Angiotensin II (Ang II) and platelet derived growth factor (PDGF), or apoptotic bodies exert their activity through NADPH oxidase-activation in HSCs. Both pharmacological inhibition with DPI and genetic studies using p47(phox) knockout mice provided evidence for a central role of NADPH oxidase in the regulation of HSC-activity and liver fibrosis. In addition to the p47(phox) component, only Rac1 has been identified as a functional active component of the NADPH oxidase complex in HSCs.
Collapse
Affiliation(s)
- Samuele De Minicis
- Department of Medicine, Columbia University, College of Physicians and Surgeons, New York, NY 10026
| | - David A. Brenner
- Department of Medicine, Columbia University, College of Physicians and Surgeons, New York, NY 10026
| |
Collapse
|
|
13
|
The Role of the Renin-Angiotensin System in Hepatic Fibrosis. FRONTIERS IN RESEARCH OF THE RENIN-ANGIOTENSIN SYSTEM ON HUMAN DISEASE 2007. [PMCID: PMC7121340 DOI: 10.1007/978-1-4020-6372-5_6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
|
|
14
|
Hernández-Guerra M, López E, Bellot P, Piera C, Turnes J, Abraldes JG, Bosch J, García-Pagán JC. Systemic hemodynamics, vasoactive systems, and plasma volume in patients with severe Budd-Chiari syndrome. Hepatology 2006; 43:27-33. [PMID: 16374846 DOI: 10.1002/hep.20990] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Budd-Chiari syndrome (BCS) causes postsinusoidal portal hypertension, which leads to complications similar to those observed in cirrhosis. However, no studies have investigated whether patients with BCS develop the hyperdynamic circulatory syndrome present in patients with cirrhosis who have portal hypertension. We evaluated systemic and cardiopulmonary hemodynamics, plasma renin activity, aldosterone and norepinephrine levels, and plasma volume in patients with BCS admitted for complications of portal hypertension. BCS patients had mean systemic and cardiopulmonary pressures and cardiac indices that were within the normal range but were significantly different from those of a group of patients with cirrhosis matched by sex, body surface, and liver function (cardiac index 3.1 +/- 0.7 vs. 4.9 +/- 1.2 L.min(-1).m(-2); P < .001; systemic vascular resistance [SVR] index, 2,189 +/- 736 vs. 1,377 +/- 422 dyne.s.cm(-5).m(-2), P < .001). Despite normal systemic vascular resistance, BCS patients had activation of the neurohumoral vasoactive systems, as evidenced by increased plasma renin activity, aldosterone and norepinephrine levels (15.0 +/- 21.5 ng/mL . h, 76.7 +/- 106.8 ng/dL, 586 +/- 868 pg/mL; respectively) and plasma volume expansion. The analysis of individual BCS patients identified that 7 of the 21 patients actually had reduced SVR index. These patients had the greatest plasma volume expansion. A significant inverse correlation between plasma volume and SVR index was observed. In conclusion, patients with BCS had activation of vasoactive neurohumoral systems and expanded plasma volume. This outcome was observed even though most of these patients did not exhibit systemic vasodilation and cardiac output was not increased, in marked contrast with what is observed in patients with cirrhosis.
Collapse
Affiliation(s)
- Manuel Hernández-Guerra
- Hepatic Hemodynamic Laboratory, Institut de Malalties Digestives, Hospital Clinic, Institut d'Investigaciones Biomédiques August Pi i Sunyer, Barcelona, Spain
| | | | | | | | | | | | | | | |
Collapse
|
|
15
|
Fernández J, Monteagudo J, Bargallo X, Jiménez W, Bosch J, Arroyo V, Navasa M. A randomized unblinded pilot study comparing albumin versus hydroxyethyl starch in spontaneous bacterial peritonitis. Hepatology 2005; 42:627-34. [PMID: 16108036 DOI: 10.1002/hep.20829] [Citation(s) in RCA: 160] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The administration of albumin improves circulatory function, prevents hepatorenal syndrome, and reduces hospital mortality in patients with cirrhosis and spontaneous bacterial peritonitis. This randomized unblinded pilot study compared the effect of albumin (10 patients) and the synthetic plasma expander hydroxyethyl starch 200/0.5 (10 patients) on the systemic hemodynamics of patients with spontaneous bacterial peritonitis. Baseline measurements were performed within 12 hours after diagnosis of infection. Patients then received 2 doses of the volume expander (1.5 g/kg body weight after baseline measurements and 1 g/kg body weight on day 3). Measurements were repeated after infection resolution. Treatment with albumin was associated with a significant increase in arterial pressure and a suppression of plasma renin activity, indicating an improvement in circulatory function. This occurred in the setting of a significant expansion of central blood volume (increase in cardiopulmonary pressures and atrial natriuretic factor) and an increase in systolic volume and systemic vascular resistance. In contrast, no significant changes were observed in these parameters in patients treated with hydroxyethyl starch. Von Willebrand-related antigen plasma levels significantly decreased in patients treated with albumin but not in those treated with hydroxyethyl starch. Serum nitrates and nitrites increased in patients treated with hydroxyethyl starch but not in those treated with albumin. These data suggest an effect of albumin on endothelial function. In conclusion, albumin but not hydroxyethyl starch improves systemic hemodynamics in patients with spontaneous bacterial peritonitis. This effect is due not only to volume expansion but also to an action on the peripheral arterial circulation.
Collapse
Affiliation(s)
- Javier Fernández
- Liver Unit, IMDM and IDIBAPS, Hospital Clínic, University of Barcelona, Spain.
| | | | | | | | | | | | | |
Collapse
|
|
16
|
Li X, Meng Y, Yang XS, Mi LF, Cai SX. ACEI attenuates the progression of CCl 4-induced rat hepatic fibrogenesis by inhibiting TGF-β1, PDGF-BB, NF-κB and MMP-2,9. World J Gastroenterol 2005; 11:4807-11. [PMID: 16097048 PMCID: PMC4398726 DOI: 10.3748/wjg.v11.i31.4807] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: Angiotensin II has pro-fibrotic function in the liver. Blockade of the renin-angiotensin-aldosterone-system (RAAS) attenuates hepatic fibrosis. The aim of the present study was to determine the mechanism of angiotensin-converting enzyme inhibitor (ACEI) on the progression of rat hepatic fibrosis.
METHODS: Forty male Wistar rats were divided into three groups. Model group (Mo): The rats were injected subcutaneously with 40% of CCl4 0.25 mL/100 g. Perindopril group (Pe): The rats were injected subcutaneously with 40% of CCl4. Perindopril, equivalent to 2 mg/(kg昫), was administrated. Control group (Nc): the rats were treated with olive oil only. After 4 and 6 wk, the rats were killed. The liver sections were stained with Masson. The protein expressions of AT1R, TGF-β1 and PDGF-BB were examined by Western blot. Nuclear factor κB (NF-κB) DNA binding activity was examined by EMSA (Electrophoretic gel mobility shift assay). Matrix metalloproteinase-2,9 (MMP-2,9) activity was assessed by zymography. Serum laminin (LN) and hyaluronic acid (HA) were measured using radioimmunoassays.
RESULTS: Using Western blot, we clearly provided direct evidence for the expression of AT1R in liver. The expression was up-regulated when fibrogenesis occurred. Perindopril treatment significantly reduced mean fibrosis score, protein levels of AT1R, TGF-β1 and PDGF-BB, serum levels of HA and LN, and the activity of MMP-2,9. NF-κB DNA binding activity markedly increased in model group, perindopril treatment considerably reduced NF-κB DNA binding activity.
CONCLUSION: Perindopril attenuates CCl4-induced hepatic fibrogenesis of rat by inhibiting TGF-β1, PDGF-BB, NF-κB and MMP-2,9
Collapse
Affiliation(s)
- Xu Li
- Department of Emergency, Nanfang Hospital, Southern Medical University, Guangzhou 510515, Guangdong Province, China.
| | | | | | | | | |
Collapse
|
|
17
|
Ruiz-del-Arbol L, Monescillo A, Arocena C, Valer P, Ginès P, Moreira V, Milicua JM, Jiménez W, Arroyo V. Circulatory function and hepatorenal syndrome in cirrhosis. Hepatology 2005; 42:439-47. [PMID: 15977202 DOI: 10.1002/hep.20766] [Citation(s) in RCA: 382] [Impact Index Per Article: 19.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The pathogenic mechanism of hepatorenal syndrome is not well established. We investigated the circulatory function in cirrhosis before and after the development of hepatorenal syndrome. Systemic and hepatic hemodynamics and the activity of endogenous vasoactive systems were measured in 66 patients who had cirrhosis with tense ascites and normal serum creatinine levels; measurements were repeated at follow-up in 27 cases in whom hepatorenal syndrome had developed. At baseline, mean arterial pressure and cardiac output were significantly higher, and hepatic venous pressure gradient, plasma renin activity, and norepinephrine concentration were significantly lower in patients who did not develop hepatorenal syndrome compared with those presenting with this complication. Peripheral vascular resistance was decreased to the same extent in the two groups. Plasma renin activity and cardiac output were the only independent predictors of hepatorenal syndrome. Hepatorenal syndrome occurred in the setting of a significant reduction in mean arterial pressure (83 +/- 9 to 75 +/- 7 mmHg; P < .001), cardiac output (6.0 +/- 1.2 to 5.4 +/- 1.5 L/min; P < .01), and wedged pulmonary pressure (9.2 +/- 2.6 to 7.5 +/- 2.6 mmHg; P < .001) and an increase in plasma renin activity (9.9 +/- 5.2 to 17.5 +/- 11.4 ng/mL . hr; P < .001), norepinephrine concentration (571 +/- 241 to 965 +/- 502 pg/mL; P < .001), and hepatic venous pressure gradient. No changes were observed in peripheral vascular resistance. In conclusion, these data indicate that hepatorenal syndrome is the result of a decrease in cardiac output in the setting of a severe arterial vasodilation.
Collapse
Affiliation(s)
- Luis Ruiz-del-Arbol
- Hepatic Hemodynamic Unit, Gastroenterology Department, Hospital Ramón y Cajal, University of Alcalá, Ctra. de Colmenar Viejo Km. 9.1, 28034 Madrid, Spain.
| | | | | | | | | | | | | | | | | |
Collapse
|
|
18
|
Alessandria C, Ozdogan O, Guevara M, Restuccia T, Jiménez W, Arroyo V, Rodés J, Ginès P. MELD score and clinical type predict prognosis in hepatorenal syndrome: relevance to liver transplantation. Hepatology 2005; 41:1282-9. [PMID: 15834937 DOI: 10.1002/hep.20687] [Citation(s) in RCA: 232] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Important progress has been made recently regarding the pathogenesis and treatment of hepatorenal syndrome (HRS). However, scant information exists about factors predicting outcome in patients with cirrhosis and HRS. Moreover, the prognostic value of the model of end-stage liver disease (MELD) score has not been validated in the setting of HRS. The current study was designed to assess the prognostic factors and outcome of patients with cirrhosis and HRS. The study included 105 consecutive patients with HRS. Forty-one patients had type 1 HRS, while 64 patients had type 2 HRS. Patients with type 1 HRS not only had more severe liver and renal failure than type 2 patients, they also had greater impairment of circulatory function, as indicated by lower arterial pressure and higher activation of vasoconstrictor factors. In the whole series, the median survival was 3.3 months. In a multivariate analysis of survival, only HRS type and MELD score were associated with an independent prognostic value. All patients with type 1 HRS had a high MELD score (> or =20) and showed an extremely poor outcome (median survival: 1 mo). By contrast, the survival of patients with type 2 HRS was longer and dependent on MELD score (> or =20, median survival 3 mo; <20, median survival 11 mo; P < .002). In conclusion, the outcome of patients with cirrhosis and HRS can be estimated by using two easily available variables, HRS type and MELD score. These data can be useful in the management of patients with HRS, particularly for patients who are candidates for liver transplantation.
Collapse
Affiliation(s)
- Carlo Alessandria
- Liver Unit, Hospital Clínic, Universitat de Barcelona, Barcelona, Spain
| | | | | | | | | | | | | | | |
Collapse
|
|
19
|
Bataller R, Gäbele E, Parsons CJ, Morris T, Yang L, Schoonhoven R, Brenner DA, Rippe RA. Systemic infusion of angiotensin II exacerbates liver fibrosis in bile duct-ligated rats. Hepatology 2005; 41:1046-55. [PMID: 15841463 DOI: 10.1002/hep.20665] [Citation(s) in RCA: 135] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Recent evidence indicates that the renin-angiotensin system (RAS) plays a major role in liver fibrosis. Here, we investigate whether the circulatory RAS, which is frequently activated in patients with chronic liver disease, contributes to fibrosis progression. To test this hypothesis, we increased circulatory angiotensin II (Ang II) levels in rats undergoing biliary fibrosis. Saline or Ang II (25 ng/kg/h) were infused into bile duct-ligated rats for 2 weeks through a subcutaneous pump. Ang II infusion increased serum levels of Ang II and augmented bile duct ligation-induced liver injury, as assessed by elevated liver serum enzymes. Moreover, it increased the hepatic concentration of inflammatory proteins (tumor necrosis factor alpha and interleukin 1beta) and the infiltration of CD43-positive inflammatory cells. Ang II infusion also favored the development of vascular thrombosis and increased the procoagulant activity of tissue factor in the liver. Livers from bile duct-ligated rats infused with Ang II showed increased transforming growth factor beta1 content, collagen deposition, accumulation of smooth muscle alpha-actin-positive cells, and lipid peroxidation products. Moreover, Ang II infusion stimulated phosphorylation of c-Jun and p42/44 mitogen-activated protein kinase and increased proliferation of bile duct cells. In cultured rat hepatic stellate cells (HSCs), Ang II (10(-8) mol/L) increased intracellular calcium and stimulated reactive oxygen species formation, cellular proliferation and secretion of proinflammatory cytokines. Moreover, Ang II stimulated the procoagulant activity of HSCs, a newly described biological function for these cells. In conclusion, increased systemic Ang II augments hepatic fibrosis and promotes inflammation, oxidative stress, and thrombogenic events.
Collapse
Affiliation(s)
- Ramón Bataller
- Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7038, USA
| | | | | | | | | | | | | | | |
Collapse
|
|
20
|
Fernández J, Navasa M, Garcia-Pagan JC, G-Abraldes J, Jiménez W, Bosch J, Arroyo V. Effect of intravenous albumin on systemic and hepatic hemodynamics and vasoactive neurohormonal systems in patients with cirrhosis and spontaneous bacterial peritonitis. J Hepatol 2004; 41:384-90. [PMID: 15336440 DOI: 10.1016/j.jhep.2004.05.009] [Citation(s) in RCA: 101] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2003] [Revised: 04/29/2004] [Accepted: 05/07/2004] [Indexed: 12/11/2022]
Abstract
BACKGROUND/AIMS Albumin administration prevents renal failure and improves survival in spontaneous bacterial peritonitis. This study characterizes the mechanisms of action of albumin in this condition. METHODS Systemic and splanchnic hemodynamics, plasma renin activity and plasma concentration of interleukin-6, serum concentration of nitric oxide and ascitic fluid levels of nitric oxide and interleukin-6 were assessed at diagnosis and resolution of infection in 12 patients with spontaneous bacterial peritonitis treated with ceftriaxone plus albumin. At infection resolution there was a significant improvement in circulatory function, as indicated by a significant increase in mean arterial pressure (+8%, P=0.02), a fall in heart rate (-10%, P=0.01), a suppression of plasma renin activity (-67%, P=0.002) and a decrease in creatinine levels. These changes were related to both an increase in cardiac work (stroke work index: +18%, P=0.005) and in peripheral vascular resistance (+14%, P=0.05). The improvement in cardiac function was due to an increase in filling. No significant changes were observed in portal pressure or hepatic blood flow. CONCLUSIONS These results indicate that the beneficial effects of albumin administration on systemic hemodynamics and renal function in spontaneous bacterial peritonitis are related to both an improvement in cardiac function and a decrease in the degree of arterial vasodilation.
Collapse
Affiliation(s)
- Javier Fernández
- Liver Unit, IMD, IDIBAPS, Hospital Clínic, University of Barcelona, Barcelona, Spain.
| | | | | | | | | | | | | |
Collapse
|
|
21
|
Sansoé G, Silvano S, Mengozzi G, Todros L, Smedile A, Touscoz G, Rosina F, Rizzetto M. Inappropriately low angiotensin II generation: a factor determining reduced kidney function and survival in patients with decompensated cirrhosis. J Hepatol 2004; 40:417-23. [PMID: 15123355 DOI: 10.1016/j.jhep.2003.11.010] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2003] [Revised: 11/10/2003] [Accepted: 11/10/2003] [Indexed: 12/28/2022]
Abstract
BACKGROUND/AIMS Angiotensin II contributes to the post-glomerular arteriolar vasoconstriction which maintains the glomerular filtration rate (GFR) in renal hypoperfusion. To explore whether depressed angiotensin II generation, due to reduced angiotensinogen production or low angiotensin-converting enzyme (ACE) levels, could impair kidney function in advanced cirrhosis. METHODS We studied and prospectively followed up 21 diuretic-free ascitic cirrhotic patients, through these determinations: plasma levels of active renin (AR), renin activity (PRA), angiotensin II, ACE and aldosterone; renal clearances of sodium, inulin and para-aminohippurate; antipyrine clearance. Fifteen healthy subjects were also studied. RESULTS GFR distribution was bimodal, 10 patients had low GFR values (l-GFR group) and 11 had normal-GFR values (n-GFR group) (below and above 105 ml/min per 1.73 m(2) body surface area). Antipyrine clearance and Child-Pugh score did not differ in the two patient groups. l-GFR group had higher AR and PRA values, lower ACE levels and a significantly higher AR/Angiotensin II ratio than n-GFR group (all P<0.01). All 21 patients showed increased values of the AR/PRA ratio, i.e. subnormal angiotensinogen levels (P<0.03). The 18-month survival rates of l-GFR and n-GFR groups were 20 and 81% (P<0.02). CONCLUSIONS Low-GFR cirrhotic patients had a worse survival rate associated with more severe contraction of the effective arterial blood volume, higher AR/Angiotensin II ratio and lower ACE levels.
Collapse
Affiliation(s)
- Giovanni Sansoé
- Gastroenterology Unit, Gradenigo Hospital, C.so Regina Margherita 10, 10153 Torino, Italy.
| | | | | | | | | | | | | | | |
Collapse
|
|
22
|
Bataller R, Schwabe RF, Choi YH, Yang L, Paik YH, Lindquist J, Qian T, Schoonhoven R, Hagedorn CH, Lemasters JJ, Brenner DA. NADPH oxidase signal transduces angiotensin II in hepatic stellate cells and is critical in hepatic fibrosis. J Clin Invest 2003. [PMID: 14597764 DOI: 10.1172/jci200318212] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
Angiotensin II (Ang II) is a pro-oxidant and fibrogenic cytokine. We investigated the role of NADPH oxidase in Ang II-induced effects in hepatic stellate cells (HSCs), a fibrogenic cell type. Human HSCs express mRNAs of key components of nonphagocytic NADPH oxidase. Ang II phosphorylated p47phox, a regulatory subunit of NADPH oxidase, and induced reactive oxygen species formation via NADPH oxidase activity. Ang II phosphorylated AKT and MAPKs and increased AP-1 DNA binding in a redox-sensitive manner. Ang II stimulated DNA synthesis, cell migration, procollagen alpha1(I) mRNA expression, and secretion of TGF-beta1 and inflammatory cytokines. These effects were attenuated by N-acetylcysteine and diphenylene iodonium, an NADPH oxidase inhibitor. Moreover, Ang II induced upregulation of genes potentially involved in hepatic wound-healing response in a redox-sensitive manner, as assessed by microarray analysis. HSCs isolated from p47phox-/- mice displayed a blunted response to Ang II compared with WT cells. We also assessed the role of NADPH oxidase in experimental liver fibrosis. After bile duct ligation, p47phox-/- mice showed attenuated liver injury and fibrosis compared with WT counterparts. Moreover, expression of smooth muscle alpha-actin and expression of TGF-beta1 were reduced in p47phox-/- mice. Thus, NADPH oxidase mediates the actions of Ang II on HSCs and plays a critical role in liver fibrogenesis.
Collapse
Affiliation(s)
- Ramon Bataller
- Department of Medicine, Columbia University College of Physicians and Surgeons, 622 West 168th Street, New York, New York 10032, USA.
| | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
23
|
Bataller R, Schwabe RF, Choi YH, Yang L, Paik YH, Lindquist J, Qian T, Schoonhoven R, Hagedorn CH, Lemasters JJ, Brenner DA. NADPH oxidase signal transduces angiotensin II in hepatic stellate cells and is critical in hepatic fibrosis. J Clin Invest 2003; 112:1383-94. [PMID: 14597764 PMCID: PMC228420 DOI: 10.1172/jci18212] [Citation(s) in RCA: 425] [Impact Index Per Article: 19.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Angiotensin II (Ang II) is a pro-oxidant and fibrogenic cytokine. We investigated the role of NADPH oxidase in Ang II-induced effects in hepatic stellate cells (HSCs), a fibrogenic cell type. Human HSCs express mRNAs of key components of nonphagocytic NADPH oxidase. Ang II phosphorylated p47phox, a regulatory subunit of NADPH oxidase, and induced reactive oxygen species formation via NADPH oxidase activity. Ang II phosphorylated AKT and MAPKs and increased AP-1 DNA binding in a redox-sensitive manner. Ang II stimulated DNA synthesis, cell migration, procollagen alpha1(I) mRNA expression, and secretion of TGF-beta1 and inflammatory cytokines. These effects were attenuated by N-acetylcysteine and diphenylene iodonium, an NADPH oxidase inhibitor. Moreover, Ang II induced upregulation of genes potentially involved in hepatic wound-healing response in a redox-sensitive manner, as assessed by microarray analysis. HSCs isolated from p47phox-/- mice displayed a blunted response to Ang II compared with WT cells. We also assessed the role of NADPH oxidase in experimental liver fibrosis. After bile duct ligation, p47phox-/- mice showed attenuated liver injury and fibrosis compared with WT counterparts. Moreover, expression of smooth muscle alpha-actin and expression of TGF-beta1 were reduced in p47phox-/- mice. Thus, NADPH oxidase mediates the actions of Ang II on HSCs and plays a critical role in liver fibrogenesis.
Collapse
Affiliation(s)
- Ramon Bataller
- Department of Medicine, Columbia University College of Physicians and Surgeons, 622 West 168th Street, New York, New York 10032, USA.
| | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
24
|
Ruiz-del-Arbol L, Urman J, Fernández J, González M, Navasa M, Monescillo A, Albillos A, Jiménez W, Arroyo V. Systemic, renal, and hepatic hemodynamic derangement in cirrhotic patients with spontaneous bacterial peritonitis. Hepatology 2003; 38:1210-8. [PMID: 14578859 DOI: 10.1053/jhep.2003.50447] [Citation(s) in RCA: 307] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Spontaneous bacterial peritonitis (SBP) is frequently associated with renal failure. This study assessed if systemic and hepatic hemodynamics are also affected by this condition. Standard laboratory tests, tumor necrosis factor alpha (TNF-alpha) in plasma and ascitic fluid, plasma renin activity (PRA) and norepinephrine (NE), and systemic and hepatic hemodynamics were determined in 23 patients with SBP at diagnosis and after resolution of infection. Eight patients developed renal failure during treatment. At diagnosis of infection, patients developing renal failure showed significantly higher values of TNF-alpha, blood urea nitrogen (BUN), PRA and NE, peripheral vascular resistance, and hepatic venous pressure gradient (HVPG) and lower cardiac output than patients not developing renal failure. During treatment, a significant reduction in cardiac output and arterial pressure and increase in PRA and NE, HVPG, and Child-Pugh score were observed in the first group but not in the second. Peripheral vascular resistance remained unmodified in both groups. Changes in PRA and NE correlated inversely with changes in arterial pressure and directly with changes in BUN, Child-Pugh score, and HVPG. Five patients in the renal failure group developed encephalopathy, and 6 died. In the group without renal failure, none of the patients developed encephalopathy or expired. In conclusion, patients with SBP frequently develop a rapidly progressive impairment in systemic hemodynamics, leading to severe renal and hepatic failure, aggravation of portal hypertension, encephalopathy, and death. This occurs despite rapid resolution of infection and is associated with an extremely poor prognosis.
Collapse
Affiliation(s)
- Luis Ruiz-del-Arbol
- Liver Hemodynamic Unit, Department of Gastroenterology, Hospital Ramón y Cajal, University of Alcalá de Henares, Madrid, Spain.
| | | | | | | | | | | | | | | | | |
Collapse
|
|
25
|
Santos J, Planas R, Pardo A, Durández R, Cabré E, Morillas RM, Granada ML, Jiménez JA, Quintero E, Gassull MA. Spironolactone alone or in combination with furosemide in the treatment of moderate ascites in nonazotemic cirrhosis. A randomized comparative study of efficacy and safety. J Hepatol 2003; 39:187-92. [PMID: 12873814 DOI: 10.1016/s0168-8278(03)00188-0] [Citation(s) in RCA: 122] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND/AIMS The most rational treatment of moderate ascites is spironolactone alone or in combination with furosemide. However, it is unknown which of these two treatment schedules is preferable. METHODS One hundred nonazotemic cirrhotic patients with moderate ascites were randomly assigned to be treated with spironolactone and furosemide (Group 1: 50 patients) or with spironolactone alone (Group 2: 50 patients). If no response was obtained, the doses of diuretics were increased up to 400 mg/day of spironolactone and 160 mg/day of furosemide. In patients of group 2 not responding to 400 mg/day of spironolactone, furosemide was added. In cases with an excessive response, the dosage of diuretics was reduced. RESULTS The response rate (98% in Group 1 vs. 94% in Group 2), the rapidity of ascites mobilization and the incidence of complications induced by diuretic therapy was similar in both groups. The need to reduce the diuretic dosage was significantly higher in Group 1 than Group 2 (68% vs. 34%; P=0.002). CONCLUSIONS In the treatment of moderate ascites, spironolactone alone seems to be as safe and effective as spironolactone associated with furosemide. Since spironolactone alone requires less dose adjustment, it would be more suitable for treating ascites on an outpatient basis.
Collapse
Affiliation(s)
- Justiniano Santos
- Department of Gastroenterology, Hospital Universitari Germans Tri;as i Pujol, Carretera del Canyet, s/n, 08916, Badalona, Spain
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
26
|
Fukui H. Does angiotensin II type 1 receptor blockade offer a clinical advantage to cirrhotics with ascites? J Gastroenterol 2002; 37:235-7. [PMID: 11931541 DOI: 10.1007/s005350200029] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
|
|
27
|
Uriz J, Ginès P, Ortega R, Jiménez W, Cárdenas A, Calahorra B, Sort P, Fernández J, Bataller R, Arroyo V, Rivera F, Rodés J. Increased plasma levels of neuropeptide Y in hepatorenal syndrome. J Hepatol 2002; 36:349-55. [PMID: 11867178 DOI: 10.1016/s0168-8278(01)00286-0] [Citation(s) in RCA: 19] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
BACKGROUND/AIMS To investigate the relationship between neuropeptide Y (NPY), a potent renal vasoconstrictor peptide released upon marked stimulations of sympathetic nervous system (SNS), and renal and circulatory function in cirrhosis. METHODS Plasma levels of NPY (radioimmunoassay) and norepinephrine and renal function parameters were determined in 17 healthy controls, nine patients with cirrhosis without ascites, and 37 patients with cirrhosis and ascites, of whom 12 had hepatorenal syndrome (HRS). RESULTS Patients with ascites showed circulating levels of NPY similar to those of patients without ascites and controls (73+/-4, +/-4 and 68+/-4 pmol/l, respectively; NS). However, patients with HRS had significantly increased levels of NPY with respect to the other groups (110+/-6 pmol/l; P<0.001). NPY levels correlated inversely with renal plasma flow and glomerular filtration rate and directly with norepinephrine. In patients with HRS (n=6) treatment with terlipressin and albumin was associated with a marked improvement in circulatory and renal function and marked suppression of NPY and norepinephrine levels. CONCLUSIONS Patients with HRS have increased levels of NPY which are related to circulatory dysfunction and SNS activation and may contribute to renal vasoconstriction.
Collapse
Affiliation(s)
- Juan Uriz
- Liver Unit, Institut de Malalties Digestives, Hospital Clínic, Barcelona, Spain
| | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
28
|
Uriz J, Ginès P, Cárdenas A, Sort P, Jiménez W, Salmerón JM, Bataller R, Mas A, Navasa M, Arroyo V, Rodés J. Terlipressin plus albumin infusion: an effective and safe therapy of hepatorenal syndrome. J Hepatol 2000; 33:43-8. [PMID: 10905585 DOI: 10.1016/s0168-8278(00)80158-0] [Citation(s) in RCA: 241] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
BACKGROUND/AIM Ornipressin, a vasopressin analog with potent splanchnic vasoconstrictor action, has been shown to reverse hepatorenal syndrome. However, its usefulness in clinical practice is limited by frequent ischemic complications. The aim of this study was to assess the efficacy of terlipressin, an analog of vasopressin with a low profile of side effects, plus albumin in this condition. METHODS Nine consecutive patients with cirrhosis and hepatorenal syndrome were included in a pilot study of terlipressin (0.5-2 mg/4 h i.v.) therapy associated with iv albumin. RESULTS Treatment (9 days, range 5-15) was associated with a marked reduction of serum creatinine (3.9+/-0.7 to 1.3+/-0.1 mg/dl, p<0.001, mean+/-SE). Reversal of hepatorenal syndrome (reduction of creatinine below 1.5 mg/dl) was observed in seven of the nine patients. There was a remarkable improvement in circulatory function, with an increase in mean arterial pressure (68+/-2 to 80+/-4 mmHg, p<0.05) and suppression of vasoconstrictor systems activity (plasma renin activity and plasma norepinephrine decreased from 23+/-12 ng/ml x h and 1549+/-373 pg/ml to 3.5+/-2 ng/ml x h and 373+/-98 pg/ml, respectively, p<0.01 for both). No patient developed signs of intestinal, myocardial or distal ischemia. CONCLUSIONS Terlipressin associated with albumin appears to be a safe and effective treatment of hepatorenal syndrome.
Collapse
Affiliation(s)
- J Uriz
- Institut de Malalties Digestives, Hospital Clinic, University of Barcelona, Institut d'Investigacions Biomèdiques August Pi-Sunyer, Catalunya, Spain
| | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
29
|
Sort P, Navasa M, Arroyo V, Aldeguer X, Planas R, Ruiz-del-Arbol L, Castells L, Vargas V, Soriano G, Guevara M, Ginès P, Rodés J. Effect of intravenous albumin on renal impairment and mortality in patients with cirrhosis and spontaneous bacterial peritonitis. N Engl J Med 1999; 341:403-9. [PMID: 10432325 DOI: 10.1056/nejm199908053410603] [Citation(s) in RCA: 1000] [Impact Index Per Article: 38.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND In patients with cirrhosis and spontaneous bacterial peritonitis, renal function frequently becomes impaired. This impairment is probably related to a reduction in effective arterial blood volume and is associated with a high mortality rate. We conducted a study to determine whether plasma volume expansion with intravenous albumin prevents renal impairment and reduces mortality in these patients. METHODS We randomly assigned 126 patients with cirrhosis and spontaneous bacterial peritonitis to treatment with intravenous cefotaxime (63 patients) or cefotaxime and intravenous albumin (63 patients). Cefotaxime was given daily in dosages that varied according to the serum creatinine level, and albumin was given at a dose of 1.5 g per kilogram of body weight at the time of diagnosis, followed by 1 g per kilogram on day 3. Renal impairment was defined as nonreversible deterioration of renal function during hospitalization. RESULTS The infection resolved in 59 patients in the cefotaxime group (94 percent) and 62 in the cefotaxime-plus-albumin group (98 percent) (P=0.36). Renal impairment developed in 21 patients in the cefotaxime group (33 percent) and 6 in the cefotaxime-plus-albumin group (10 percent) (P=0.002). Eighteen patients (29 percent) in the cefotaxime group died in the hospital, as compared with 6 (10 percent) in the cefotaxime-plus-albumin group (P=0.01); at three months, the mortality rates were 41 percent (a total of 26 deaths) and 22 percent (a total of 14 deaths), respectively (P=0.03). Patients treated with cefotaxime had higher levels of plasma renin activity than those treated with cefotaxime and albumin; patients with renal impairment had the highest values. CONCLUSIONS In patients with cirrhosis and spontaneous bacterial peritonitis, treatment with intravenous albumin in addition to an antibiotic reduces the incidence of renal impairment and death in comparison with treatment with an antibiotic alone.
Collapse
Affiliation(s)
- P Sort
- Liver Unit, Institut de Malalties Digestives, Hospital Clínic, Barcelona, Catalunya, Spain
| | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
30
|
Elizalde JI, Moitinho E, García-Pagán JC, Cirera I, Escorsell A, Bandi JC, Jiménez W, Bosch J, Piqué JM, Rodés J. Effects of increasing blood hemoglobin levels on systemic hemodynamics of acutely anemic cirrhotic patients. J Hepatol 1998; 29:789-95. [PMID: 9833917 DOI: 10.1016/s0168-8278(98)80260-2] [Citation(s) in RCA: 23] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
BACKGROUND/AIMS In experimental portal hypertension, blood hemoglobin levels have been shown to influence the hyperdynamic circulatory state. The aim of this study was to assess the hemodynamic effects of increasing hemoglobin concentration in human portal hypertension. METHODS Sixteen cirrhotic patients recovering from a variceal bleeding episode were randomly assigned to receive two units of packed red cells or 500 ml of a protein solution. Systemic and portal hemodynamics, and rheological and hormonal parameters were measured at baseline and after expansion. RESULTS Both groups were similar with respect to the degree of liver failure, severity of the bleeding episode, activation of the endogenous vasopressor systems, and hemodynamic parameters. The administration of either erythrocytes or a protein solution prompted a similar increase in total blood volume and suppression of vasopressor systems. Both groups of patients experienced similar increases in wedged hepatic venous pressure. Hepatic venous pressure gradient was not significantly modified but tended to increase in erythrocyte-transfused patients. Cardiopulmonary pressures increased, but this increment was significant in the non-blood-transfused patients only. Cardiac output decreased in erythrocyte-transfused patients, while it increased in the group receiving a protein solution. Red blood cell transfusion resulted in an increase in systemic vascular hindrance (resistance/blood viscosity), whereas the administration of a protein solution prompted a decrease in this parameter, thus reflecting true vasoconstriction and vasodilation, respectively. CONCLUSIONS An increase in blood hemoglobin in acutely anemic cirrhotic patients attenuates their hyperdynamic circulation beyond viscosity-dependent changes, an effect which might be counteracted by the effects on portal venous pressure gradient.
Collapse
Affiliation(s)
- J I Elizalde
- Gastroenterology Department, Institut Clínic de Malalties Digestives, Hospital Clínic, Universitat de Barcelona, Spain
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
31
|
Krüger C, Rauh M, Dörr HG. Immunoreactive renin concentrations in healthy children from birth to adolescence. Clin Chim Acta 1998; 274:15-27. [PMID: 9681594 DOI: 10.1016/s0009-8981(98)00044-8] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
We establish normative data for immunoreactive renin concentration in serum of healthy children. In a retrospective study, surplus sera of 281 healthy children, aged 0-18 years, were collected from the laboratory. The determinations were performed with a commercially available two-site immunoradiometric assay. Functional sensitivity was 4.0 mU/l, inter-assay and intra-assay variance were 7.0-18.3% and 3.8-7.5%, respectively. In umbilical cord and during the first 4 days of life, renin concentrations (geometric mean) were significantly higher (P < 0.05) than in older infants and children [umbilical cord: 155.2 mU/l; newborn infants (2-4 days of life): 90.9; newborn infants (5-7 days of life): 32.5; 2 weeks-3 months: 40.8; 4 months-1 year: 54.5; 1-3 years: 46.3; 3-5 years: 48.5; 5-7 years: 51.6; 7-11 years: 38.5; 11-15 years: 37.7; 15-18 years: 31.9]. Newborn infants delivered by Caesarian section had significantly lower renin concentrations in umbilical cord than those delivered vaginally (P < 0.02). Considering the methodological advantages and disadvantages of plasma renin activity and renin concentration assays, renin measurement was at least as valuable and accurate as plasma renin activity determination.
Collapse
Affiliation(s)
- C Krüger
- Division of Endocrinology, Hospital for Children and Adolescents, University of Erlangen-Nürnberg, Erlangen, Germany
| | | | | |
Collapse
|
|
32
|
Bandi JC, Poch E, García-Pagán JC, Luca A, Jiménez W, Escorsell A, Rodés J. Platelet cytosolic calcium concentration in patients with liver cirrhosis. Relationship with hepatic and systemic hemodynamics. J Hepatol 1997; 27:824-9. [PMID: 9382969 DOI: 10.1016/s0168-8278(97)80319-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
BACKGROUND/AIMS Due to structural and functional similarities between platelets and vascular smooth muscle cells, platelet cytosolic calcium concentration ([Ca2+]i) has been suggested to be a useful tool to study regulatory mechanisms of peripheral vascular tone. The aim of the present study was to investigate platelet [Ca2+]i in patients with cirrhosis and whether this parameter is related with the systemic and splanchnic vasodilatation found in these patients. METHODS Seventeen patients with cirrhosis and eight age- and sex-matched controls were studied. Mean arterial pressure, cardiac output, femoral blood flow and basal and thrombin-stimulated platelet [Ca2+]i were measured. Cardiac output (thermal dilution), azygos blood flow, hepatic venous pressure gradient and hepatic blood flow were also measured in patients with cirrhosis. RESULTS Patients with cirrhosis had severe portal hypertension and a significantly higher cardiac output and femoral blood flow and a significantly lower systemic and femoral vascular resistance than controls. Patients with cirrhosis had a lower basal platelet [Ca2+]i than normal subjects. However, there was no relationship between platelet [Ca2+]i and any of the hemodynamic parameters that evaluate systemic or splanchnic vasodilatation. CONCLUSIONS This study shows that cirrhotic patients with portal hypertension have a significant reduction in platelet basal [Ca2+]i. The lack of correlation between platelet [Ca2+]i and hepatic and systemic hemodynamics does not support the use of platelet [Ca2+]i as a model to study mechanisms involved in the pathophysiology of the hyperdynamic circulation associated to portal hypertension.
Collapse
Affiliation(s)
- J C Bandi
- Nephrology Department, Hospital Clìnic i Provincial, University of Barcelona, Spain
| | | | | | | | | | | | | |
Collapse
|
|
33
|
Saló J, Fernández-Esparrach G, Ginès P, Ginès A, Guevara M, Sort P, Jiménez W, Arroyo V, Rivera F, Rodés J. Urinary endothelin-like immunoreactivity in patients with cirrhosis. J Hepatol 1997; 27:810-6. [PMID: 9382967 DOI: 10.1016/s0168-8278(97)80317-0] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
BACKGROUND/AIMS To investigate a possible relationship between the renal production of endothelin and the presence of renal dysfunction and activation of vasoactive systems in cirrhosis, the urinary excretion and the circulating plasma levels of immunoreactive endothelin (irET) and the plasma levels of vasoactive hormones were measured in 19 healthy subjects, 12 cirrhotic patients without ascites and 39 patients with ascites and different degrees of renal dysfunction. METHODS The urinary excretion and the circulating levels of irET were assessed after 5 days on a 40 mEq sodium diet and off diuretics. Renal function parameters and the plasma levels of vasoactive hormones were also measured. RESULTS Patients with and without ascites had similar values of urinary irET as compared with healthy subjects (30+/-3, 31+/-3 and 29+/-2 ng/day, respectively, p>0.10). By contrast, patients with ascites had higher circulating levels of irET (15+/-1.2 pg/ml) than patients without ascites and healthy subjects (11+/-1.6 and 5+/-0.4 pg/ml, p<0.01). In patients with cirrhosis, no correlation was found between urinary irET and circulating irET. Moreover, urinary irET did not correlate with liver tests, serum and urine sodium, glomerular filtration rate or vasoactive substances. Patients with hepatorenal syndrome had similar urinary irET to patients with ascites without hepatorenal syndrome. CONCLUSIONS Urinary excretion of irET is not increased in cirrhotic patients with ascites and does not correlate with abnormalities in renal function.
Collapse
Affiliation(s)
- J Saló
- Department of Medicine, Hospital Clínic i Provincial, University of Barcelona, Spain
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
34
|
Saló J, Ginès A, Ginès P, Piera C, Jiménez W, Guevara M, Fernández-Esparrach G, Sort P, Bataller R, Arroyo V, Rodés J. Effect of therapeutic paracentesis on plasma volume and transvascular escape rate of albumin in patients with cirrhosis. J Hepatol 1997; 27:645-53. [PMID: 9365040 DOI: 10.1016/s0168-8278(97)80081-5] [Citation(s) in RCA: 48] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
BACKGROUND/AIMS Circulatory abnormalities with activation of vasoconstrictor systems after large-volume paracentesis are generally considered secondary to an increased extravasation of fluid from the intravascular compartment to the extravascular space with subsequent reduction in plasma volume. To test this hypothesis, plasma volume, the transvascular escape rate of albumin, the absolute escape rate of albumin and the activity of vasoconstrictor systems were measured in 25 cirrhotic patients with ascites in baseline conditions and 2 days after total paracentesis with plasma volume expansion. METHODS Plasma volume and the transvascular escape rate of albumin, the fraction of albumin passing from the intravascular to the extravascular space per unit of time, were assessed through the plasma disappearance curve of radioiodinated human albumin. The absolute escape rate of albumin, the total flux of albumin from intravascular to extravascular space per unit of time, was also calculated. RESULTS Eight of the 25 patients (32%) developed marked activation of vasoconstrictor systems after paracentesis. In these patients, plasma renin activity and plasma norepinephrine concentration increased from 6.6+/-2 to 23.4+/-11 ng x ml(-1) x h(-1) and 776+/-229 to 989+/-258 pg/ml, respectively (p<0.05). No significant changes in these parameters were found in the remaining 17 patients. The activation of vasoconstrictor systems occurred in the absence of changes in plasma volume (3456+/-276 vs 3476+/-264 ml, NS), transvascular escape rate of albumin (10.4+/-1 vs 10.9+/-2%/h, NS) and absolute escape rate of albumin (9.9+/-1.9 vs 10.5+/-0.7 g/h, NS). CONCLUSIONS These results do not support a contraction of plasma volume as the mechanism responsible for activation of vasoconstrictor systems after paracentesis. Rather, the activation of vasoconstrictor systems in the absence of changes in plasma volume suggests that paracentesis accentuates the impairment of "effective" blood volume present in cirrhotic patients with ascites.
Collapse
Affiliation(s)
- J Saló
- Department of Medicine, Hospital Clínic i Provincial, Barcelona, Spain
| | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
35
|
Roding JHA, Weterings T, van der Heiden C. Plasma Renin Activity: Temperature Optimum at ∼45 °C. Clin Chem 1997. [DOI: 10.1093/clinchem/43.7.1243] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
|
|
36
|
Fernández-Esparrach G, Guevara M, Sort P, Pardo A, Jiménez W, Ginès P, Planas R, Lebrec D, Geuvel A, Elewaut A, Adler M, Arroyo V. Diuretic requirements after therapeutic paracentesis in non-azotemic patients with cirrhosis. A randomized double-blind trial of spironolactone versus placebo. J Hepatol 1997; 26:614-20. [PMID: 9075669 DOI: 10.1016/s0168-8278(97)80427-8] [Citation(s) in RCA: 61] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
BACKGROUND/AIMS Diuretic requirements after mobilization of ascites by paracentesis have never been assessed in cirrhosis. It is also unknown whether diuretics increase the incidence of postparacentesis circulatory dysfunction. The aim of this study was to investigate these features and to assess whether measurement of plasma renin activity and aldosterone prior to paracentesis predicts diuretic response after this procedure. METHODS Thirty-six patients with non-azotemic cirrhosis and ascites treated by total paracentesis plus i.v. albumin were randomly assigned to receive placebo (n=17) or spironolactone 225 mg/day (n=19) immediately after paracentesis and followed-up for 4 weeks. RESULTS Five patients (three in the placebo and two in the spironolactone group) abandoned the treatment prior to ascites recurrence or the end of the study due to complications or lack of compliance. The analysis was performed in the remaining 31 patients. Ascites recurrence was more common in the placebo group (13 cases, 93%) than in the spironolactone group (3 cases, 18%) (p<0.0001) and occurred within the first 2 weeks of follow-up in more than 50% of patients. Patients developing ascites in the spironolactone group had higher levels of renin (14.1, 20.6, 32.4 ng/ml per h) and aldosterone (120, 149, 288 ng/dl) than those who did not develop ascites (renin: 2.0+/-2.1 ng/ml per h; range 0.1-6.8; aldosterone: 43+/-38 ng/dl; range 4-116). Three patients in the placebo group and two in the spironolactone group developed postparacentesis circulatory dysfunction (defined as an increase in renin at the third day after paracentesis greater than 50% over baseline levels up to a value higher than 4 ng/ml per h). CONCLUSIONS Patients with cirrhosis treated by paracentesis should receive diuretics immediately after this procedure to prevent early recurrence of ascites. The administration of 225 mg/day of spironolactone is a good empiric treatment for non-azotemic patients with cirrhosis, because it is effective in most cases and does not increase the incidence of postparacentesis circulatory dysfunction. The determination of plasma levels of renin or aldosterone prior to paracentesis predicts the efficacy of spironolactone in the prevention of ascites recurrence.
Collapse
|
|
37
|
Saló J, Ginès A, Quer JC, Fernández-Esparrach G, Guevara M, Ginès P, Bataller R, Planas R, Jiménez W, Arroyo V, Rodés J. Renal and neurohormonal changes following simultaneous administration of systemic vasoconstrictors and dopamine or prostacyclin in cirrhotic patients with hepatorenal syndrome. J Hepatol 1996; 25:916-23. [PMID: 9007721 DOI: 10.1016/s0168-8278(96)80297-2] [Citation(s) in RCA: 36] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
BACKGROUND/AIMS Intravenous ornipressin in cirrhotic patients with hepatorenal syndrome causes marked improvement of systemic hemodynamics and suppression of plasma renin and norepinephrine but only moderate improvement of renal function. This study was designed to investigate whether these beneficial effects could be enhanced by the simultaneous administration of dopamine. The renal effects of the i.v. infusion of norepinephrine plus prostacyclin in patients with hepatorenal syndrome were also assessed. METHODS Renal plasma flow, glomerular filtration rate, free water clearance, sodium excretion and the plasma levels of renin and norepinephrine were measured in baseline conditions and during the administration of ornipressin (6 i.u./h) and ornipressin (6 i.u./h) plus dopamine (2 micrograms/kg.min) in nine patients with hepatorenal syndrome. Five additional patients with hepatorenal syndrome were studied prior to and following the administration of norepinephrine (0.45 +/- 0.1 microgram/kg.min) and norepinephrine (0.85 +/- 0.2 microgram/kg.min) plus prostacyclin (5 ng/kg.min). RESULTS Despite a significant increase in arterial pressure and marked suppression of plasma renin activity during ornipressin and ornipressin plus dopamine administration, no significant improvement in renal function was observed. Norepinephrine and norepinephrine plus prostacyclin also failed to increase renal perfusion and glomerular filtration rate. CONCLUSIONS The combined administration of systemic vasoconstrictors (ornipressin or norepinephrine) and vasodilators (dopamine or prostacyclin), at the doses used in the current study and for a short period of time, does not improve renal function in cirrhotic patients with hepatorenal syndrome. The current study does not confirm a potential role for ornipressin in the treatment of hepatorenal syndrome.
Collapse
Affiliation(s)
- J Saló
- Department of Medicine, Hospital Clínic i Provincial, Barcelona, Spain
| | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
38
|
Krüger C, Höper K, Weissörtel R, Hensen J, Dörr HG. Value of direct measurement of active renin concentrations in congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Eur J Pediatr 1996; 155:858-61. [PMID: 8891554 DOI: 10.1007/bf02282834] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
UNLABELLED In congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency, measurement of plasma renin activity (PRA) has been the method of choice in diagnosing salt loss and in monitoring adequacy of mineralocorticoid replacement therapy. Due to methodological problems in PRA determinations, direct immunoradiometric assays for the measurement of active renin concentration have been developed. We measured PRA and active renin concentrations simultaneously in 39 patients with CAH (30 salt-wasting, 9 simple virilizing) to evaluate the potential role of this new method in the management of this disease. PRA was determined with an enzymatic assay (sample volume: 2 x 1000 microliters plasma), active renin concentration with a direct immunoradiometric assay (sample volume: 2 x 200 microliters plasma or serum). We found a highly significant correlation between active renin and PRA in our patients (P < 0.001), as previously shown in healthy subjects. Active renin was as reliable as PRA to assess the quality of mineralocorticoid replacement. CONCLUSION In children, active renin determination is preferable to PRA determination because of methodological advantages and a smaller sample volume. It correlates well with PRA and determines the activation of the renin-angiotensin system as precisely as PRA. Active renin determination is useful in the surveillance of mineralocorticoid replacement therapy in CAH.
Collapse
Affiliation(s)
- C Krüger
- University Hospital for Children, University of Erlangen-Nürnberg, Germany
| | | | | | | | | |
Collapse
|
|
39
|
Llach J, Ginès P, Arroyo V, Salmerón JM, Ginès A, Jiménez W, Gaya J, Rivera F, Rodés J. Effect of dipyridamole on kidney function in cirrhosis. Hepatology 1993. [PMID: 8423042 DOI: 10.1002/hep.1840170112] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
Adenosine is a potent endogenous renal vasoconstrictor. To investigate the sensitivity of the renal circulation to adenosine in cirrhosis, we evaluated kidney function and vasoactive hormones in 20 patients with cirrhosis before and after administration of dipyridamole (0.4 mg/kg, intravenously), a drug that increases extracellular levels of adenosine. In patients with ascites and increased plasma renin activity (6.9 +/- 4.0 ng/ml.hr [mean +/- S.D.]) (n = 7), dipyridamole induced marked reductions in renal plasma flow (from 623 +/- 294 to 374 +/- 188 ml/min, p = 0.03), glomerular filtration rate (from 89 +/- 22 to 48 +/- 16 ml/min, p = 0.009), urine volume (from 7.1 +/- 2.1 to 1.5 +/- 1.1 ml/min, p = 0.0001), free water clearance (from 4.0 +/- 1.7 to 0.4 +/- 0.6 ml/min, p = 0.001) and sodium excretion (from 28 +/- 36 to 7 +/- 15 mu Eq/min, p = 0.05) in the absence of changes in arterial pressure, plasma renin activity and levels of aldosterone, norepinephrine and antidiuretic hormone. In patients without ascites (n = 5) and in patients with ascites and normal plasma renin activity (0.9 +/- 0.5 ng/ml.hr) (n = 8), renal plasma flow and glomerular filtration rate did not change significantly after dipyridamole administration, whereas excretion of sodium and free water was reduced. These results indicate that in cirrhotic patients with ascites and overactivity of the renin-angiotensin system, dipyridamole induces renal vasoconstriction in the absence of changes in systemic hemodynamics, suggesting that these patients are particularly sensitive to the renal vasoconstrictor effect of endogenous adenosine.
Collapse
Affiliation(s)
- J Llach
- Liver Unit, Hospital Clínic i Provincial, University of Barcelona, Catalunya, Spain
| | | | | | | | | | | | | | | | | |
Collapse
|
|
40
|
Ginès A, Salmerón JM, Ginès P, Jiménez W, Saló J, Piera C, Clària J, Rivera F, Arroyo V, Rodés J. Effects of somatostatin on renal function in cirrhosis. Gastroenterology 1992; 103:1868-74. [PMID: 1360435 DOI: 10.1016/0016-5085(92)91446-b] [Citation(s) in RCA: 40] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/02/2022]
Abstract
To investigate the renal effects of somatostatin in cirrhosis, renal function and plasma and urinary levels of endogenous neurohumoral vasoactive substances were measured in conditions of intravenous water overload (20 mL/kg body wt with 5% glucose) before and during the intravenous infusion of somatostatin (250-500 micrograms/h) in 6 cirrhotic patients without ascites and 17 nonazotemic cirrhotic patients with ascites. Somatostatin induced a significant reduction of renal plasma flow, glomerular filtration rate, and free water clearance in both groups of patients. In patients with ascites, somatostatin also reduced urinary sodium excretion. Changes in renal function were significantly more marked in patients with ascites than in those without ascites and occurred in the absence of changes in mean arterial pressure and plasma levels of renin, aldosterone, norepinephrine, antidiuretic hormone, and atrial natriuretic peptide. Somatostatin induced a significant reduction in the plasma concentration of glucagon and urinary excretion of prostaglandin E2 that was not related to changes in renal function. These findings indicate that somatostatin administration induces renal vasoconstriction and impairs glomerular filtration rate, free water clearance, and sodium excretion in cirrhosis by a mechanism unrelated to systemic hemodynamics and endogenous neurohumoral vasoactive systems.
Collapse
Affiliation(s)
- A Ginès
- Liver Unit, Hospital Clínic i Provincial, University of Barcelona, Spain
| | | | | | | | | | | | | | | | | | | |
Collapse
|