Effects of somatostatin on renal function in cirrhosis.

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.     

Hemodynamic, renal, and endocrine effects of acute inhibition of nitric oxide synthase in compensated cirrhosis.

To assess whether an increased production of nitric oxide is involved in the circulatory and renal alterations of cirrhosis, we evaluated systemic hemodynamics (echocardiography), renal hemodynamics, and sodium handling (lithium clearance method), plasma renin activity (PRA), aldosterone (PAC), and norepinephrine in 7 patients (3 men, mean age 65 +/- 2 years) with compensated cirrhosis, portal hypertension, and hyperdynamic circulation during intravenous N(G)-monomethyl-L-arginine (L-NMMA) (3 mg/kg bolus plus 0.05 mg/kg. min for 120 minutes) or placebo (the vehicle) in a randomized, placebo-controlled, crossover study. Administration of L-NMMA resulted in significant reductions in plasma and urinary nitrite levels and plasma cyclic guanosine monophosphate (cGMP), indicating effective inhibition of nitric oxide synthase. L-NMMA also significantly reduced cardiac index (-13%) and increased systemic vascular resistance (+26%), arterial pressure (+9%), renal blood flow (+12%), glomerular filtration rate (+12%), and sodium excretion (+25%). Changes in sodium excretion were caused by both enhanced filtered sodium load and reduced sodium reabsorption in the proximal tubule. Plasma norepinephrine significantly decreased in response to L-NMMA, and there was a trend for reductions in PRA and PAC. Placebo had no appreciable effect on any of the measured parameters. These results indicate that in patients with compensated cirrhosis, portal hypertension and hyperdynamic circulation inhibition of nitric oxide synthase corrects the altered systemic hemodynamics and improves renal function and sodium excretion.     

Hemodynamic, neurohumoral, and metabolic responses to amino acid infusion in patients with cirrhosis.

In patients with cirrhosis the renal response to amino acid infusion is controversial. In addition, the renal and systemic metabolic effects of amino acids are unknown. Therefore, the present study examined the effects of amino acids on renal hemodynamics, renal and systemic oxygen (O2) consumption, and hormones in patients with cirrhosis. Twelve patients received an 8% amino acid solution for 30 minutes at a rate providing 250 mg of amino acids/kg body wt. Renal blood flow increased by 45% (P less than 0.05) and the glomerular filtration rate by only 9% (P greater than 0.05). Renal vascular resistance decreased by 23% (P less than 0.05), and renal perfusion pressure did not change significantly. Renal and systemic O2 consumption and pulmonary artery plasma glucagon level significantly increased. There were no significant changes in plasma osmolality, plasma volume, and plasma atrial natriuretic peptide concentrations. In conclusion, the results show that amino acid-induced renal vasodilation caused hyperperfusion but not renal hyperfiltration in patients with cirrhosis. In addition, renal hyperemia was associated with renal and systemic hypermetabolism.     

Renal and hemodynamic effects of endothelin in anesthetized dogs

The effects of endothelin on systemic hemodynamics and renal functions were investigated in anesthetized dogs. Infusion of endothelin at a dose of 1 ng/kg/min decreased renal blood flow and increased renal vascular resistance and filtration fraction. Endothelin at doses higher than 10 ng/kg/min significantly decreased cardiac output, glomerular filtration rate, renal plasma flow, urine volume, and urinary sodium excretion. Mean arterial pressure showed a transient decrease at doses higher than 50 ng/kg/min. These results showed that endothelin in systemic administration has effects on renal functions as well as on systemic hemodynamics.     

Hemodynamic and sympathetic responses to human atrial natriuretic peptide infusion in patients with cirrhosis

To determine the potential usefulness of atrial natriuretic peptide (ANP) in patients with cirrhosis, we examined the effects of the infusion of a low dose of alpha-human ANP (alpha hANP, 25 ng.kg-1.min-1 for 30 min) on renal, splanchnic, systemic hemodynamics and sympathetic outflow in eight patients. Pulmonary arterial plasma ANP concentrations increased from 59 +/- 9 to 328 +/- 41 pg/ml (mean +/- S.E., p less than 0.05). Mean values of glomerular filtration rate and renal plasma flow were not significantly changed. Individual renal plasma flow responses differed from one patient to another. Renal plasma flow increased in two patients, decreased in three and did not change in the other patients. Renal plasma flow changes were correlated with basal renal plasma flow values (r = -0.938, p less than 0.05) but not with arterial pressure changes or renal vein plasma norepinephrine concentration changes. Azygos blood flow increased from 0.43 +/- 0.10 to 0.63 +/- 0.13 l/min (p less than 0.05) and the hepatic-venous pressure gradient decreased from 19.9 +/- 1.5 to 17.5 +/- 2.9 mmHg in post-infusion (p less than 0.05). Mean arterial pressure decreased significantly by 18% and cardiac output by 12%. Systemic vascular resistance and pulmonary arterial plasma norepinephrine concentrations were not significantly modified. Thus, in patients with cirrhosis, alpha hANP appears to have a direct vasodilating action on renal arterioles when basal renal vascular tone is high. In addition, although alpha hANP might exert a portal hypotensive action, alpha hANP induced arterial hypotension as a result of both low cardiac output and a lack of increased sympathetic vascular tone. The arterial hypotensive action may, thus, limit the therapeutic use of low doses of alpha hANP in cirrhotic patients.     

Effects of Nitric Oxide Inhibition by Methylene Blue in Cirrhotic Patients with Ascites

Increased endogenous nitric oxide production has been proposed as an important mediator of the peripheral arterial vasodilation and the hyperdynamic circulation in cirrhosis, whereas a decreased intrahepatic production of nitric oxide has been implicated in the pathogenesis of portal hypertension. The present study investigated the possible beneficial effects of methylene blue, which is a potent inhibitor of guanylate cyclase and nitric oxide synthase, on hyperdynamic circulation and renal function in cirrhotic patients with ascites together with the effects on portal hemodynamics. Twenty patients were evaluated at baseline and during 2 consecutive 4-hr periods after the administration of methylene blue at a dose of 3 mg/kg (10 patients) or placebo (10 patients). Mean arterial pressure, heart rate, cardiac output, systemic vascular resistance, plasma active renin, plasma aldosterone, plasma antidiuretic hormone, serum urea, serum creatinine, serum sodium, urinary flow rate, glomerular filtration rate, effective renal plasma flow, portal flow volume, and portal vein velocity were not modified by methylene blue or placebo. Urinary sodium excretion, fractional sodium excretion and serum nitric oxide levels were significantly decreased 4 hr after methylene blue administration (P < 0.05), to return toward basal levels over a further 4-hr period. It is concluded that methylene blue, at the dose used in the present study, has no effect on systemic and portal hemodynamics in cirrhotic patients with ascites. The reduction in renal sodium excretion, in the absence of changes in renal function and hemodynamics, suggests, at least partly, a direct antinatriuretic effect of methylene blue.     

The effects of chronic treatment with octreotide versus octreotide plus midodrine on systemic hemodynamics and renal hemodynamics and function in nonazotemic cirrhotic patients with ascites

OBJECTIVES: The adrenergic agonist midodrine improved circulatory and renal dysfunction when acutely administered in nonazotemic cirrhotic patients with ascites while its combination with octreotide has recently been proposed as an effective treatment of type 1 hepatorenal syndrome (HRS). However, the effects of octreotide on systemic hemodynamics and renal function in cirrhotic patients are controversial. This study evaluated the effects of chronic treatment with octreotide versus octreotide plus midodrine on systemic hemodynamics and renal hemodynamics, and function in nonazotemic cirrhotic patients with ascites. METHODS: Twenty-five patients were studied at baseline and 11 days after administration of subcutaneous octreotide 300 mug, b.i.d. alone (n = 12) or together with oral midodrine 7.5 mg, t.i.d. (n = 13). RESULTS: Octreotide did not improve systemic hemodynamics whereas the addition of midodrine significantly decreased cardiac index (CI) and heart rate (HR), and increased mean arterial pressure (MAP) and systemic vascular resistance (SVR). Octreotide caused a decrease in renal vascular resistance (RVR) and increased renal blood flow (RBF) but significantly reduced glomerular filtration rate. The association of midodrine to octreotide did not modify renal hemodynamics and function as compared to baseline while it caused an almost significant minor increase in RVR and a significant minor decrease in RBF as compared to octreotide alone. Consequently, a significant minor increase in glomerular filtration rate was demonstrated. The plasma values of active renin, aldosterone, and glucagon were significantly reduced in either group. CONCLUSIONS: Octreotide does not improve systemic hemodynamics in nonazotemic cirrhotic patients with ascites while it impairs renal function. On the other hand, the addition of midodrine can ameliorate the hyperdynamic circulation without inducing renal dysfunction in these patients.     

Endothelin-specific antibodies decrease blood pressure and increase glomerular filtration rate and renal plasma flow in spontaneously hypertensive rats.

OBJECTIVE: Studies were undertaken to clarify the pathophysiologic significance of endogenous endothelin in the control of blood pressure and renal hemodynamics in spontaneously hypertensive rats (SHR). DESIGN: The technique of passive immunization was used to neutralize endogenous endothelin in order to estimate the contribution of endothelin to the in vivo control of blood pressure and renal hemodynamics. METHODS: Endothelin-specific antibodies were administered intravenously into anesthetized SHR and Wistar-Kyoto (WKY) rats, and the effects upon blood pressure and renal function (renal plasma flow and glomerular filtration rate) assessed. Using the same antibodies, baseline plasma levels of endothelin in both strains of rats were determined by radioimmunoassay. RESULTS: Infusion of endothelin-specific antibodies into SHR decreased mean arterial pressure by approximately 10% and renal vascular resistance and renal vascular resistance by approximately 35%. Glomerular filtration rate and renal plasma flow both increased by approximately 50% over control. In contrast, infusion of normal rabbit serum into SHR or of endothelin-specific antibodies into WKY rats did not result in any significant change in renal hemodynamics or arterial blood pressure. Baseline plasma levels of immunoreactive endothelin in SHR were significantly lower than those in WKY rats. CONCLUSION: These results suggest that endothelin plays an important role in the modulation of systemic blood pressure and renal function in SHR.     

Plasma cytokines, glomerular filtration rate and adipose tissue cytokines gene expression in chronic kidney disease (CKD) patients

Background and AimSystemic inflammation is a hallmark of chronic kidney disease (CKD) and obesity represents a major risk factor for CKD. We investigated the relationship between plasma interleukin-6 (IL-6) and tumour necrosis factor-α (TNF-α) and the glomerular filtration rate (GFR) in 75 stage 2–5 CKD patients.Methods and ResultsWe studied the steady-state relationship between plasma and subcutaneous adipose tissue (SAT) gene expression of the same cytokines in 19 patients and in 17 well-matched healthy subjects (HS) and compared SAT gene expression of these cytokines and of two additional cytokines (IL-1β and IL-8) in CKD patients and in HS.Plasma IL-6 and TNF-α were higher in CKD patients than in HS (P < 0.001). IL-6 was similarly increased in patients with mild, moderate and severe CKD and largely independent of the GFR (r = ?0.03, P = NS). TNF-α was inversely related to GFR, which was the first factor in rank (β = ?0.37, P = 0.001) explaining the variability in TNF-α in CKD. SAT messenger RNA (mRNA) levels of IL-6, TNF-α, IL- β and IL-8 were similar in CKD patients and in HS. Plasma and SAT mRNA levels of IL-6 and TNF-α levels were largely unrelated.ConclusionsPlasma IL-6 rises early in CKD and does not show any further increase at more severe stages of CKD, whereas TNF-α is inversely associated with the GFR indicating a substantial difference in the dynamics of the relationship between these cytokines and renal function. Cytokines are not overexpressed in SAT in these patients, and circulating IL-6 and TNF-α are dissociated from the corresponding mRNA levels in SAT, both in CKD patients and in HS.     

Cardiovascular, renal, and endocrine response to atrial natriuretic peptide in angiotensin II mediated hypertension

Studies done in vitro have demonstrated that atrial natriuretic peptide (ANP) antagonizes angiotensin II-mediated contraction of vascular smooth muscle. The present studies were designed to examine the in vivo actions of ANP in acute angiotensin II-mediated hypertension. The cardiovascular, renal, and hormonal effects of intravenous ANP were evaluated in anesthetized normotensive (n = 6) and hypertensive (n = 6) dogs. In both groups, ANP (3.0 micrograms/kg bolus, 0.3 micrograms/kg/min continuous infusion) reduced arterial pressure and cardiac output without changing systemic vascular resistance. ANP specifically reduced renal vascular resistance and increased sodium excretion. The natriuresis observed was greater in hypertensive than in normotensive dogs. This occurred without a significant change in glomerular filtration rate or aldosterone. The ANP-mediated reduction in arterial pressure was associated with an increase in circulating arginine vasopressin and catecholamines but not in renin. These studies demonstrate that ANP-mediated hypotension results from a reduction in cardiac output without changing systemic vascular resistance, ANP acts as a specific renal vasodilator, ANP-mediated natriuresis can occur without alteration in glomerular filtration rate or aldosterone, and ANP specifically inhibits the release of renin without inhibiting the release of other circulating vasoconstrictors.     

Portosystemic myelopathy: Spastic paraparesis after portosystemic shunting

Objective. In patients with cirrhosis and spontaneous bacterial peritonitis (SBP), the use of intravenous albumin has been shown to prevent deterioration of renal function and to decrease the mortality rate, but the mechanisms remain unclear. The purpose of this study was to characterize the mechanisms of action of albumin with the focus on endotoxin and cytokines. Material and methods. Thirty patients with SBP were divided into two groups. Group 1 received antibiotics and albumin infusion (20% 50 cc every day for 3 days) and Group 2 received antibiotic treatment only. Twenty-four cirrhotic patients with sterile ascites were enrolled in Group 3 and received albumin infusion (20% 50 cc every day for 3 days). Plasma and ascitic fluid concentrations of endotoxin, nitric oxide products (NOx), tumor necrosis factor (TNF)-α, and interleukin (IL)-6 were analyzed before and after treatments, respectively. Results. Combination therapy of albumin and antibiotics can significantly (p<0.01) reduce plasma levels of TNF-α and IL-6, and ascitic fluid levels of endotoxin, TNF-α and IL-6 in cirrhotic patients with SBP. Without the addition of albumin to an antibiotic regimen, the plasma and ascitic fluid levels of NOx increased significantly in patients with SBP (p=0.005 and p=0.004, respectively). Conclusions. The results confirm that the beneficial effects of albumin are related to the reduction of the levels of TNF-α and NOx in both plasma and ascitic fluid. The infusion of albumin continuously for 3 days in addition to antibiotic treatment at the time of SBP detection is recommended as an effective therapy for patients with cirrhosis and SBP.     

Renal and systemic hemodynamics in experimental cirrhosis in rats: relation to hepatic function

The onset of sodium retention in the phenobarbital and carbon tetrachloride model of cirrhosis in the rat is preceded by a linear decrease in hepatic function as measured by the aminopyrine breath test. Sodium retention occurs when liver function decreases below a critical threshold. Changes in systemic hemodynamics may be responsible for initiating the development of renal sodium retention. The objective of this study was to investigate the relationship between hepatic function and systemic and renal hemodynamics of experimental cirrhosis in rats maintained on a constant salt diet. Cirrhosis was induced in phenobarbital-treated rats by weekly administration of carbon tetrachloride. The aminopyrine breath test served as a measure of hepatic function. Three groups of animals were studied to evaluate the contribution of changes in systemic and renal hemodynamics to the onset of sodium retention: a group with sodium retention and aminopyrine breath test results just below the critical threshold, a group without sodium retention and aminopyrine breath test results just above the critical threshold and a phenobarbital-treated control group. In each group, urinary sodium excretion, renal plasma flow, glomerular filtration rate, mean arterial pressure and arterial and renal venous plasma renin activities were determined. A progressive, significant reduction in mean arterial pressure was seen, comparing controls with the other two groups. No differences in renal plasma flow were observed between the three groups, but glomerular filtration rate and filtration fraction were slightly reduced in the sodium-retaining group compared with the non-retaining group and controls.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of a 7-day treatment with midodrine in non-azotemic cirrhotic patients with and without ascites

BACKGROUND/AIMS: Splanchnic arterial vasodilatation has been causally related with hyperdynamic circulation and impaired natriuresis in advanced cirrhosis and has also been suggested to be responsible for the subtle sodium retention in pre-ascitic cirrhosis. This study evaluated the effects of a 7-day treatment with the alpha1-adrenergic agonist midodrine in non-azotemic cirrhotic patients with and without ascites. METHODS: Thirty-nine cirrhotic patients were studied at baseline and 7 days after administration of oral midodrine 10mg, t.i.d. (11 without and 12 with ascites) or placebo (8 without and 8 with ascites). RESULTS: A significant increase in urine sodium excretion was noted after midodrine administration in patients without and with ascites, in line with significant increases in mean arterial pressure and systemic vascular resistance, and significant decreases in cardiac output and heart rate. Significant increases in glomerular filtration rate, filtration fraction, and urine volume and significant decreases in plasma renin activity and aldosterone were observed in patients with ascites. Placebo had no effect in any study group. CONCLUSIONS: The administration of midodrine for 7 days improves systemic haemodynamics and sodium excretion in non-azotemic cirrhotic patients without or with ascites. In patients with ascites, but not in those without ascites, these effects are associated with a suppression of the activity of the renin-angiotensin-aldosterone system, suggesting that the increase in natriuresis is related to the improvement in the effective arterial blood volume.     

Diltiazem maintains renal vasodilation without hyperfiltration in hypertension: Studies in essential hypertensive man and the spontaneously hypertensive rat

Summary The systemic and renal hemodynamic effects of diltiazem were determined in patients with mild to moderately severe essential hypertension and in rats with spontaneous hypertension (SHR). Seven patients were treated for one full year (300 mg/day, average dose) and 10 SHR and 10 normotensive Wistar-Kyoto (WKY) rats received 1 and 2 mg/ kg, intravenously. In both man and rat with genetic hypertension, arterial pressure was reduced through a fall in total peripheral resistance without associated reflexive increases in heart rate and cardiac index; and the patients demonstrated no change in plasma volume. In both man and the SHR: renal blood flow increased (in SHR not statistically significant) as arterial pressure and renal vascular resistance fell; glomerular filtration rate (GFR) remained unchanged and the filtration fraction (FF) significantly fell; and calculated intrarenal hemodynamic indices (using the Gomez formulae) demonstrated falls in afferent and efferent glomerular arteriolar pressures and resistances and in intraglomerular pressures, thereby explaining the unchanged GFRs and the decline in FF. These findings in both hypertensive man and rat are in contrast with those of the normotensive WKY that only demonstrated a fall in afferent glomerular arteriolar resistance. Thus, these data demonstrate that diltiazem controlled arterial pressure in both forms of genetic hypertension associated with falls in systemic and renal arteriolar resistances and with improved intrarenal hemodynamics without glomerular hyperfiltration.     

Terlipressin in hepatorenal syndrome: Evidence for present indications

Hepatorenal syndrome (HRS) is the most frequent life threatening complication of advanced liver failure and cirrhosis. HRS results from a functional renal dysfunction due to circulatory disturbances in patients with advanced liver disease and portal hypertension. Reduction in the effective circulating blood volume and hence hypoperfusion of the kidney is the basic underlying common pathogenetic mechanism for the development of hepatorenal syndrome. The prognosis for HRS remains very poor with types 1 and 2-both having an expected survival time of 2 weeks and 6 months, respectively. Although the available data are derived from studies including a limited number of patients mainly affected by type 1 HRS, vasoconstrictor drugs, in particular the vasopressin analog Terlipressin, seem to be the most effective approach for the management of HRS. Associated with albumin infusion, these drugs have been shown to lead to reduced mortality and improved renal function in HRS. Terlipressin administration significantly increases mean arterial pressure and systemic vascular resistance; while the heart rate, cardiac output, HVPG and portal venous blood flow decrease significantly. This decrease correlates well with the decrease in plasma renin activity. Thus the vasoconstrictor effect of Terlipressin reverses the basic pathology of HRS by reducing the plasma renin activity. The improvement in hemodynamics with Terlipressin is associated with an increase in glomerular filtration rate and deactivation of the vasoconstrictor and sodium-conserving hormones with reduced activity of the RAAS resulting in increased natriuresis. Terlipressin thus reverses HRS and is useful in bridging the patient to liver transplantation and may hence indirectly improve survival. Patients with HRS who show an improvement in renal function with Terlipressin and albumin seem to have an excellent post-transplantation outcome similar to that of patients without HRS. Thus, the use of Terlipressin has been shown to be safe, with minimal side effects that usually disappear after dose reduction, and results in an improved outcome in patients with HRS.     

Relationships among endotoxemia, arterial pressure, and renal function in dogs

This study evaluated the effects of increasing plasma endotoxin (Difco 055:B5) concentration by intravenous and intrarenal infusion on renal hemodynamics and renal function. Plasma endotoxin was increased to 130-150 ng/ml (infusion rate of 32 micrograms/min) in two groups of dogs and changes in plasma endotoxin concentration were correlated with arterial pressure (AP), glomerular filtration rate (GFR), renal blood flow (RBF), and urinary sodium excretion (UNaV) for 4 hr. In group 1, intrarenal endotoxin infusion decreased AP, GFR, RBF, and UNaV equally between infused and contralateral noninfused kidneys. In dogs with unilateral renal denervation (group 2), intravenous endotoxin maximally decreased AP, GFR, RBF, and UNaV in both kidneys by 90 min. Despite continued endotoxin infusion, RBF and GFR then spontaneously increased after 90 min, and by 240 min these values were significantly greater in the innervated kidneys compared with denervated kidneys (P less than 0.05). In both groups of dogs, the spontaneous increase in GFR and RBF was associated with a spontaneous increase in arterial pressure. These data suggest that renal dysfunction during moderate endotoxemia may be mediated by systemic hemodynamic changes rather than by direct intrarenal toxicity and that renal innervation may protect against endotoxin-induced reductions in RBF and GFR.     

Natriuretic response to the combination of atrial natriuretic peptide and terlipressin in patients with cirrhosis and refractory ascites

Background/Aims: Refractory ascites, which occurs in certain patients with cirrhosis, is associated with a blunted natriuretic response to exogenous atrial natriuretic peptide (ANP). Since this blunting seems to be related to ANP-induced arterial hypotension, a vasoconstrictor, such as terlipressin (a vasopressin analogue), may restore natriuresis to exogenous ANP. Moreover, since cirrhosis-elicited vasolidation is thought to play a role in sodium retention, a vasoconstriction caused by terlipressin alone may lead to an increase in sodium excretion. This study aimed to evaluate the natriuretic response to either a combination of ANP with terlipressin or terlipressin alone in patients with cirrhosis and refractory ascites.Methods: Sixteen consecutive patients with cirrhosis and refractory ascites were randomly assigned to receive either a combination of terlipressin (1–2 mg, i.v. bolus) with ANP (35 ng/kg, i.v. bolus followed by 15 ng·kg⁻¹·min⁻¹ for 60 min) (n=8) or terlipressin alone (1–2 mg, i.v. bolus) (n=8). Sodium excretion and urine output, systemic, splanchnic and renal hemodynamics and renal oxygen consumption were measured before and during treatments.Results: Combined therapy did not change arterial pressure but significantly increased urinary sodium excretion and urine output. These effects were associated with a significant increase in glomerular filtration rate and a decrease in renal oxygen consumption. Terlipressin alone significantly increased arterial pressure but did not change urinary sodium excretion or urine output. Moreover, terlipressin did not change either glomerular filtration rate or renal oxygen consumption.Conclusions: The combination of exogeneous ANP with terlipressin, but not terlipressin alone, increases sodium excretion in patients with cirrhosis and refractory ascites.     

Relation between severity of liver disease and renal oxygen consumption in patients with cirrhosis

BACKGROUND: Worsening cirrhosis may lead to increased renal O2 metabolism caused by activation of neurohumoral antinatriuretic substances. AIMS: To evaluate the relation between the severity of liver disease, sodium excretion, and neurohumoral antinatriuretic substances on the one hand and renal O2 metabolism on the other in patients with cirrhosis. METHODS: Renal O2 consumption and haemodynamics as well as plasma concentrations of noradrenaline, renin, and aldosterone were measured. Investigations were performed in 14 patients with Pugh's grade A, 43 with grade B, and 29 with grade C liver disease. RESULTS: Renal O2 consumption significantly increased with the severity of cirrhosis (grade A, 8.9 (1.6); grade B, 15.5 (1.3); grade C, 18.0 (1.5) ml/min/m2). Plasma concentrations of noradrenaline, renin, and aldosterone significantly increased while mean arterial presssure and systemic vascular resistance significantly decreased with the severity of the disease. A significant inverse correlation was found between renal O2 consumption and sodium excretion. A significant direct correlation was found between plasma levels of noradrenaline and aldosterone on the one hand and renal O2 consumption on the other. Renal blood flow and the glomerular filtration rate did not differ significantly between patients with grade C and grade A or B disease. CONCLUSIONS: This study shows for the first time that, in patients with cirrhosis, worsening of the disease is associated with an increase in renal O2 consumption. The results suggest that increased renal O2 consumption is due to renal tubular sodium retention caused by increased levels of neurohumoral antinatriuretic substances. This neurohumoral activation is related to cirrhosis induced vasodilation.     

Effect of the severity of liver disease on renal hemodynamics and renal oxygen consumption in patients with cirrhosis]

In patients with cirrhosis, it has been shown that abnormal systemic and splanchnic hemodynamics and systemic oxygen (O2) consumption are related to the severity of liver disease. Little is known on the relationship between the severity of cirrhosis, on one hand, and renal hemodynamics and O2 consumption, on the other. We measured renal hemodynamics and renal O2 consumption in 31 patients Pugh's grade A and B and in 13 patients grade C. Systemic and splanchnic hemodynamics as well as systemic O2 consumption were studied. Renal blood flow, glomerular filtration rate, and renal O2 consumption were not significantly different between grades A and B and grade C patients. The renal fraction of systemic O2 consumption was higher (11.4 +/- 5.9 vs 7.9 +/- 4.1 percent respectively; P less than 0.05) and the systemic O2 consumption (111 +/- 23 vs 128 +/- 26 ml.min-1.m-2 respectively; P less than 0.05) lower in patients with grade C than in grades A and B patients. The degree of systemic hyperkineticism and portal hypertension was related to the severity of cirrhosis. In our patients, renal hemodynamics and renal O2 consumption were not related to the severity of cirrhosis. However, liver failure was associated with an increased renal fraction of systemic O2 consumption due to unchanged renal O2 consumption and decreased systemic O2 consumption.     

Vascular,hemodynamic and renal effects of low‐dose losartan in rats with secondary biliary cirrhosis

Background: In cirrhosis, splanchnic and systemic vasodilatation induce a hyperdynamic circulatory dysfunction, portal hypertension and renal sodium retention. This vasodilatation is in part because of an impaired vascular response to α1‐adrenoceptor agonists. Recently, the angiotensin II type 1‐receptor antagonist losartan has been shown to attenuate portal hypertension. We hypothesized that losartan decreases portal pressure by counteracting the impaired vascular responsive to α1‐adrenoceptor agonists. Methods: We studied, in rats with secondary biliary cirrhosis and sham‐operated rats, the effect of 0.5 and 10 mg losartan/kg × day on aortic responsiveness to α1‐adrenoceptor stimulation with methoxamine and angiotensin II (myograph), splanchnic and systemic hemodynamics (colored microspheres), plasma noradrenaline levels and kidney function. Results: In cirrhotic rats, 10 mg losartan/kg × day completely inhibited aortic contractility to angiotensin II, decreased vascular resistance and arterial pressure and induced renal failure. In contrast, 0.5 mg losartan/kg × day only partially inhibited aortic contractility to angiotensin II, but improved aortic contractility to methoxamine, increased splanchnic and systemic vascular resistance, decreased portal pressure, decreased plasma norepinephrine levels and induced natriuresis. Conclusions: In cirrhotic rats, losartan at a very low dose increases splanchnic vascular resistance, decreases portal pressure and improves kidney function, possibly by an increased vascular responsiveness to α1‐adrenoceptor agonists.