atrial-natriuretic-factor and Hepatorenal-Syndrome

The circulatory disturbances seen in advanced cirrhosis lead to the development of ascites, which can become refractory to diet and medical therapy. These abnormalities may progress and cause a functional renal failure known as the hepatorenal syndrome. Management of refractory ascites and hepatorenal syndrome is a therapeutic challenge, and if appropriate, liver transplantation remains the best treatment. New therapeutic options have recently appeared, including the transjugular intrahepatic portosystemic shunt and selective splanchnic vasoconstrictor agents, which may improve renal function and act as a bridge to transplantation.

Topics: Ascites; Atrial Natriuretic Factor; Cardiotonic Agents; Dopamine; Hepatorenal Syndrome; Humans; Liver Transplantation; Paracentesis; Peritoneovenous Shunt; Portasystemic Shunt, Transjugular Intrahepatic; Prostaglandins, Synthetic; Vasoconstrictor Agents

Natriuretic peptides (NP) constitute hormonal systems of great clinical impact. This report deals with Urodilatin (URO), a renal natriuretic peptide type A. From the gene of NP type A, a message for the preprohormone is transcribed in heart and kidney. The cardiac prohormone CDD/ANP-1-126 is synthesized in the heart atrium and processed during exocytosis forming the circulating hormone CDD/ANP-99-126. URO (CDD/ANP 95-126) is a product from the same gene, but differentially processed in the kidney and detected only in urine. Physiologically, URO acts in a paracrine fashion. After release from distal tubular kidney cells into the tubular lumen, URO binds to luminal receptors (NPR-A) in the collecting duct resulting in a cGMP-dependent signal transduction. cGMP generation is followed by an interaction with the amiloriode-sensitive sodium channel which induces diuresis and natriuresis. In this way, URO physiologically regulates fluid balance and sodium homeostasis. Moreover, URO excretion and natriuresis are in turn dependent on several physiological states, such as directly by sodium homeostasis. Pharmacologically, URO at low dose administered intravenously shows a strong diuretic and natriuretic effect and a low hypotensive effect. Renal, pulmonary, and cardiovascular effects evoked by pharmacological doses indicate that URO is a putative drug for several related diseases. Clinical trials show promising results for various clinical indications. However, the reduction in hemodialysis/hemofiltration in patients suffering from ARF following heart and liver transplantation, derived from preliminary trials recruiting a small number of patients, was not confirmed by a multicenter phase II study. In contrast, data for the prophylactic use of URO in this clinical setting suggest a better outcome for the patients. Furthermore, treatment of asthmatic patients showed a convincingly beneficial effect of URO on pulmonary function. Patients with congestive heart failure may also profit from URO treatment, as it increases stroke volume and PCWP. Moreover, preliminary results from recent studies indicate that URO may also be effective in patients suffering from hepato-renal syndrome.

Topics: Acute Kidney Injury; Amino Acid Sequence; Atrial Natriuretic Factor; Diuretics; Heart Failure; Hepatorenal Syndrome; Humans; Molecular Sequence Data; Peptide Fragments; Second Messenger Systems

Progressive oliguric renal failure (designated "hepatorenal syndrome") commonly complicates the course of patients with advanced hepatic disease. Despite the severe derangement of renal function and ominous prognosis when renal failure develops, minimal and inconsistent pathologic abnormalities of the kidneys are found at autopsy. Furthermore, the kidneys, if transplanted, are capable of normal function, which supports the concept that the renal failure is functional and potentially reversible. In contrast to patients with classical acute failure (ATN), hepatorenal syndrome patients manifest characteristic alterations of renal function including (1) relatively hyperosmolar urine; (2) high creatinine urine:plasma ratio, and (3) a very low urine sodium concentration (< 10 mEq/L). The past several years have witnessed newer insights into both the pathophysiology and the therapeutics of this syndrome. The application of newer methodology such as tracer kinetics has more rigorously delineated the role of a number of pathogenic mechanisms including activation of the sympathetic nervous system. The characterization of endothelin and the nitric oxide-arginine pathway and their roles in biology and medicine has provided additional new insights with regard to the pathogenesis of hepatorenal syndrome. For example, nitric oxide has been proposed to constitute a mediator of both the hyperdynamic circulation and renal failure. Finally, recently initiated therapeutic approaches lend a note of optimism to the future management of a syndrome that is so often incompatible with recovery. These include the acceptance of orthotopic liver transplantation as definitive treatment for patients with end-stage liver disease and attempts to improve renal function by countervailing the decreases in systemic vascular resistance while minimizing concomitant increments in renal vascular resistance. Hopefully, ongoing and future clinical trials will establish the precise contribution of each of these treatment modalities and their respective roles in the therapeutic armamentarium.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Atrial Natriuretic Factor; Diagnosis, Differential; Drainage; Endothelins; Endotoxins; Hepatorenal Syndrome; Humans; Immersion; Kidney; Liver Transplantation; Nitric Oxide; Peritoneovenous Shunt; Prostaglandins; Radionuclide Imaging; Renal Circulation; Renal Dialysis; Renin-Angiotensin System; Sympathetic Nervous System; Thromboxane-A Synthase; Vasoconstrictor Agents; Xenon Radioisotopes

Topics: Ascites; Atrial Natriuretic Factor; Constriction, Pathologic; Hepatorenal Syndrome; Humans; Renal Artery; Renin-Angiotensin System

Topics: Ascites; Atrial Natriuretic Factor; Hemodynamics; Hepatorenal Syndrome; Humans; Liver Cirrhosis; Renin-Angiotensin System; Vasodilator Agents; Vasopressins

A new appreciation of the hemodynamic, hormonal, and neural derangements associated with unexplained renal failure in patients with severe liver disease has led to a reappraisal of the limited therapeutic approaches to the hepatorenal syndrome. Although the prognosis generally remains dismal, specific supportive measures are now available for the management of selected patients.

Topics: Atrial Natriuretic Factor; Diagnosis, Differential; Hemodynamics; Hepatorenal Syndrome; Humans; Immersion; Kidney Diseases; Liver Cirrhosis; Prognosis; Renal Circulation; Sympathetic Nervous System; Uremia

Topics: Atrial Natriuretic Factor; Endotoxins; Hepatorenal Syndrome; Humans; Kidney; Kidney Diseases; Prostaglandins; Renin-Angiotensin System; Sympathetic Nervous System

This review examines current understanding about the patient with moderately advanced cirrhosis of the liver and his or her transition to hepatorenal syndrome (HRS). Special emphasis is given to three areas of ongoing research. Atrial natriuretic factor's role in the pathogenesis of salt and water retention is examined, as well as its role in determining volume status in these patients. The current literature regarding prostaglandins (PGs) is reviewed, with emphasis on how vasodilatory PGs appear first to help maintain homeostasis in advanced cirrhosis and how vasoconstrictor thromboxane may then be involved in the transition to HRS. Finally, new findings regarding the liver hormone glomerulopressin are examined, and how deficient release of this may lead to the decrease in glomerular filtration rate seen in HRS.

Topics: Animals; Atrial Natriuretic Factor; Eicosanoic Acids; Glucuronates; Hepatorenal Syndrome; Hormones; Humans; Kidney Diseases; Liver Cirrhosis

A treatment to induce a sustained increase in glomerular filtration rate in patients with hepatorenal syndrome has not yet been identified. Thus, the aim of the present study was to investigate the effects of terlipressin for 2 days on the glomerular filtration rate in patients with cirrhosis and hepatorenal syndrome.. A double-blind, cross-over randomized study was performed in nine patients. Patients received terlipressin (2 mg/day for 2 days) and a placebo for 2 days in a randomized order.. Terlipressin administration significantly increased creatinine clearance (from 15+/-2 ml/min to 27+/-4 ml/min) and urine output (from 628+/-67 ml/day to 811+/-76 ml/day), but did not significantly change urinary sodium concentrations. Urinary sodium excretion was not significantly different after placebo administration (0.6+/-0.1 mmol/24 h) and terlipressin administration (9.3+/-7.2 mmol/24 h). Terlipressin administration significantly decreased plasma concentrations of renin and aldosterone but not atrial natriuretic peptide levels. Placebo elicited no significant effects.. This study shows that 2-day terlipressin administration increases the glomerular filtration rate in patients with cirrhosis and hepatorenal syndrome.

Topics: Atrial Natriuretic Factor; Blood Pressure; Cross-Over Studies; Double-Blind Method; Female; Glomerular Filtration Rate; Hepatorenal Syndrome; Humans; Liver Cirrhosis; Lypressin; Male; Middle Aged; Sodium; Terlipressin

We investigated left ventricular diastolic dysfunction (LVDD) and its relationship with circulatory function and prognosis in cirrhosis with portal hypertension and normal creatinine. Conventional and tissue Doppler (TDI) echocardiography, systemic and hepatic hemodynamics, and the activity of endogenous vasoactive systems (AEVS) were measured prospectively in 80 patients. Plasma renin activity (PRA; >4 ng/mL/hour) was used as a surrogate of effective arterial blood volume. Patients were followed up for 12 months. Thirty-seven patients had LVDD (19 with grade 1 and 18 with grade 2). Left ventricular hypertrophy, left atrial volume, AEVS, and natriuretic peptide levels were significantly greater in patients with LVDD than without LVDD. Patients with grade 2 LVDD, compared to grade 1 LVDD and without LVDD, had significantly lower mean arterial pressure and higher Model for End-Stage Liver Disease (MELD) score, E-wave transmitral/early diastolic mitral annular velocity (E/e' ratio), cardiopulmonary pressures, PRA, and natriuretic peptide levels. Systolic and cardiac chronotropic function were significantly lower in patients with grade 2 LVDD than without LVDD. LVDD was more frequent in patients with ascites and increased PRA than patients without ascites or with ascites but normal PRA. Fourteen patients with LVDD developed hepatorenal syndrome (HRS) type 1 on follow-up. Survival was different according to degree of LVDD (without LVDD: 95%; grade 1 LVDD: 79%; grade 2 LVDD: 39%; P < 0.001). Independent predictive factors of mortality were MELD score and E/e' ratio.. LVDD occurs simultaneously with other changes in cardiac structure and function and is associated with an impairment of effective arterial blood volume. LVDD is a sensitive marker of advanced cirrhosis, type 1 HRS development, and mortality.

Topics: Adult; Atrial Natriuretic Factor; Creatinine; Diastole; Female; Heart Rate; Hepatorenal Syndrome; Humans; Hypertension, Portal; Liver Cirrhosis; Male; Middle Aged; Prospective Studies; Renin; Severity of Illness Index; Ventricular Dysfunction, Left

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

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

The etiology of hepatorenal syndrome (HRS) is still incompletely understood, but the atriopeptin-renin-aldosterone system plays an important role in its pathogenesis. Since this system presents a circadian rhythmicity, the aim of the study was to investigate the circadian rhythm in the circulating concentrations of atriopeptin (atrial natriuretic peptide, pANP), plasma renin activity (PRA) and plasma aldosterone (pA) in patients with HRS, compared with healthy controls. Venous blood samples were drawn during the span of a whole day and every two hours from a peripheral vein in 10 healthy subjects and in 10 patients with HRS. The circulating concentrations of pANP, PRA and pA were determined by radioimmunoassay. Statistical analysis was carried out by the "cosinor" method. The controls presented a significant (p < 0.05) circadian rhythm for each variable, whereas no rhythm (p > 0.05) was found in HRS patients. The pANP, PRA and pA rhythms were significantly (p < 0.05) different between the two groups, HRS patients having higher mean daily concentrations and larger circadian variations of pANP, PRA and pA than controls. Significant relations (p < 0.05) were demonstrated between the mean daily concentrations of pANP and PRA (r = 0.79), PRA and pA (r = 0.73) and PRA and pA (r = 0.76) in the controls; on the contrary, the HRS patients showed only a significant (p < 0.05) positive relation between pANP and PRA (r = 0.71). These results confirm the previous observation that the atriopeptin-renin- aldosterone system presents a well-defined circadian time structure in healthy subjects, while the HRS patients present a complete loss of the secretory sequentiality and of the circadian rhythm, with desynchronization of the whole system. This great upset in the temporal and functional organizations of the system could play an important role in promoting and/or in maintaining the hydro-electrolyte unbalance of HRS.

Topics: Aldosterone; Atrial Natriuretic Factor; Circadian Rhythm; Female; Hepatorenal Syndrome; Humans; Linear Models; Liver Cirrhosis; Male; Middle Aged; Radioimmunoassay; Renin

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.. 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.. 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.. Urinary excretion of irET is not increased in cirrhotic patients with ascites and does not correlate with abnormalities in renal function.

Topics: Adult; Aldosterone; Ascites; Atrial Natriuretic Factor; Endothelins; Female; Hepatorenal Syndrome; Humans; Liver Cirrhosis; Male; Middle Aged; Norepinephrine; Renin; Vasopressins

In advanced cirrhosis and hepatorenal syndrome, peripheral vasodilation is a prominent feature and may be pathophysiologically relevant. To determine whether the potent vasodilator, calcitonin gene-related peptide (CGRP), circulates at abnormal levels in patients with these disorders, we observed eight patients with alcoholic cirrhosis and hepatorenal syndrome, seven with alcoholic cirrhosis and ascites without hepatorenal syndrome, and 10 healthy controls. Plasma CGRP levels were higher in patients with alcoholic cirrhosis and hepatorenal syndrome (364 +/- 166 pg/ml) than in healthy controls (143 +/- 54 pg/ml, p less than 0.01). In patients with cirrhosis and ascites without hepatorenal syndrome, plasma CGRP levels were less elevated (291 +/- 257 pg/ml, NS). The identity of immunoreactive CGRP and synthetic hCGRP was confirmed by high performance liquid chromatography. These results suggest that CGRP may play a role in hepatorenal syndrome. However, to establish whether circulating CGRP contributes to the hemodynamic change in hepatorenal syndrome requires study of a larger number of patients and additional control groups.

Topics: Atrial Natriuretic Factor; Calcitonin Gene-Related Peptide; Chromatography, High Pressure Liquid; Female; Hepatorenal Syndrome; Humans; Liver Cirrhosis, Alcoholic; Male; Middle Aged; Radioimmunoassay; Vasodilation

Functional renal failure of cirrhosis (FRFC) is a usually fatal syndrome of acute renal failure occurring in patients with advanced liver disease. Although not conclusively proven, most evidence suggests that renal arterial and arteriolar vasoconstriction is the cause of the renal failure in these patients. However, the mediators of the vasoconstriction remain unknown. Human atrial natriuretic factor (hANF) is a hormone with potent natriuretic, diuretic, and vasorelaxant properties. A deficiency of hANF could lead to renal arterial vasoconstriction and avid renal sodium retention as seen in FRFC. This study was undertaken to determine if patients with FRFC are deficient in circulating hANF. Seven patients with advanced alcoholic liver disease and renal failure of unknown cause (FRFC) were compared with 7 patients with advanced alcoholic liver disease, ascites, and normal serum creatinine as well as with 14 healthy volunteers. Plasma hANF was measured by radioimmunoassay. Plasma hANF was 742 +/- 227 pg/ml (mean +/- SEM) in patients with FRFC compared with 360 +/- 70 pg/ml in patients with liver disease and normal serum creatinine (p greater than 0.05) and 28 +/- 5.7 pg/ml in healthy volunteers (p less than 0.005 vs. FRFC and chronic liver disease, ascites, and normal serum creatinine). Thus, FRFC is not caused by a deficiency of circulating hANF. The elevated plasma hANF levels in patients with chronic liver disease and continued sodium retention may suggest a renal insensitivity to the natriuretic effects of hANF.

Topics: Adult; Atrial Natriuretic Factor; Creatinine; Female; Hepatorenal Syndrome; Humans; Kidney Diseases; Liver Cirrhosis, Alcoholic; Male; Middle Aged; Radioimmunoassay