Solute-free Water Excretion Research Articles

Intravenous Conivaptan

*Conivaptan is an arginine vasopressin V1A and V2 receptor antagonist. The intravenous formulation is approved in the US for use in the treatment of euvolemic and hypervolemic hyponatremia. Conivaptan produces a dose-dependent electrolyte-sparing aquaresis (solute-free water excretion), increasing serum sodium levels. *In a randomized, double-blind, parallel-group, placebo-controlled, multicenter trial in adults with euvolemic or hypervolemic hyponatremia, the area under the serum sodium concentration-time curve over a 4-day treatment duration (primary endpoint) was significantly greater in intravenous conivaptan 40 mg/day recipients than in placebo recipients. *The total time during treatment that patients had serum sodium levels > or = 4 mEq/L above baseline was significantly longer in intravenous conivaptan than placebo recipients. In conivaptan recipients, an increase in serum sodium levels of > or = 4 mEq/L above baseline was achieved approximately 1 day after the first dose of the drug. *In addition, the mean change from baseline in free water clearance and effective water clearance over the first day of treatment was significantly greater with intravenous conivaptan than with placebo. *Given the nature of the treatment, the tolerability profile for intravenous conivaptan was generally acceptable in patients with hyponatremia. The most common adverse events were injection related (e.g. injection-site phlebitis), hypotension, and pyrexia.

Vasopressin and prostaglandin E 2 as regulators of renal function during children’s development

The main physicochemical parameters of blood serum (the osmolality and concentrations of Na+, K+, Ca2+, and Mg2+) determined in 314 children (from newborn infants to 17-year-old adolescents) and 25 adults were found to be virtually constant throughout the postnatal period, which was due to the high effectiveness of the systems responsible for their stabilization. From the first postnatal days until puberty, prostaglandin E2 (PGE2) and arginine vasopressin (AVP) are involved in the regulation of renal water excretion. In infants, during their first postnatal months, the excretion of solute-free water is correlated with the excretion of PGE2. Adult-type effects of AVP on the reabsorption of solute-free water were observed in children only after 12 postnatal months. A change in the reabsorption of ions in the thick ascending limb of Henle’s loop was shown to be involved in the regulation of the volume of urine excreted. AVP and PGE2 are also involved in the regulation of the distal segment of the nephron and collecting tubules, but their influence on the volume and composition of urine is age-dependent.

Hyponatremia in cirrhosis: clinical features and management

The presence of dilutional hyponatremia has a poor prognosis for survival in patients with cirrhosis and ascites. Effective and safe treatments are needed to improve prognosis in patients with cirrhosis and dilutional hyponatremia. The initial approach to management includes fluid restriction, low sodium diet, and minimizing the use of diuretics. In addition, the use of hypertonic saline should be avoided in patients with cirrhosis and dilutional hyponatremia. Furthermore, patients should be placed on the top of the list for liver transplantation if they are appropriate candidates. Although V2 arginine vasopressin receptor antagonists that selectively enhance solute-free water excretion in patients with cirrhosis seem very promising, two points must be considered in relation to the available data. First, although the results of phase-2 studies are encouraging, the efficacy and safety of these compounds should be further evaluated. Second, the clinical utility of these agents in cirrhosis has only been assessed in short-term studies. The long-term effects of these drugs remain unknown. Future research with these compounds should not only focus on the effects on serum sodium, but also on treatment and prevention of recurrence of ascites. In addition, the possible beneficial effects of these drugs in the prevention of hepatic encephalopathy would be worth studying.

Water and Sodium Retention in Edematous Disorders: Role of Vasopressin and Aldosterone

This article discusses the pathophysiology of sodium and water retention in edematous disorders with a particular focus on cardiac failure, cirrhosis, and pregnancy. The body fluid volume hypothesis, which emphasizes the dominant role of arterial baroreceptors in renal sodium and water excretion, is reviewed. With arterial underfilling, either due to a decrease in cardiac output or peripheral arterial vasodilation, the normal central inhibition of the sympathetic nervous system activity and baroreceptor-mediated, nonosmotic arginine vasopressin (AVP) release is attenuated. The resultant increase in renal adrenergic activity stimulates the renin-angiotensin-aldosterone system. Although the resultant increase in systemic vascular resistance compensates for the primary arterial underfilling, this activation of the neurohumoral axis results in diminished sodium and water delivery to the renal collecting duct sites of aldosterone, AVP, and natriuretic peptide action. This diminished distal sodium and water delivery will be discussed as an important factor in the failure to escape from the sodium-retaining effects of aldosterone, the resistance to the natriuretic and diuretic effects of natriuretic peptides, and the diminished maximal solute-free water excretion in patients with edema. The role of the nonosmotic AVP release in water retention and hypo-osmolality/hyponatremia has been demonstrated in patients and experimental animals by administering nonpeptide, orally active vasopressin V 2 receptor antagonists. These agents have been found to increase solute-free water excretion in patients with water-retaining, hyponatremic edema as well as in experimental animals.

Hyponatremia Impairs Early Posttransplantation Outcome in Patients With Cirrhosis Undergoing Liver Transplantation

Hyponatremia is associated with reduced survival in patients with cirrhosis awaiting liver transplantation. However, it is not known whether hyponatremia also represents a risk factor of poor outcome after transplantation. We aimed to assess the effects of hyponatremia at the time of transplantation on posttransplantation outcome in patients with cirrhosis. Two-hundred forty-one consecutive patients with cirrhosis submitted to liver transplantation during a 4-year period (January 2000-December 2003) were included in the study. The main end point was survival at 3 months after transplantation. Secondary end points were complications within the first month after transplantation. Patients with hyponatremia (serum sodium lower than 130 mEq/L) had a greater incidence of neurologic disorders, renal failure, and infectious complications than patients without hyponatremia (odds ratio; 4.6, 3.4 and 2.7, respectively) within the first month after transplantation. By contrast, hyponatremia was not associated with an increased incidence of severe intra-abdominal bleeding, acute rejection, or vascular and biliary complications. Hyponatremia was an independent predictive factor of early posttransplantation survival. Three-month survival of patients with hyponatremia was 84% compared with 95% of patients without hyponatremia (P < .05). Survival was similar after 3 months. In patients with cirrhosis, the presence of hyponatremia is associated with a high rate of neurologic disorders, infectious complications, and renal failure during the first month after transplantation and reduced 3-month survival. In cirrhosis, hyponatremia should be considered not only a risk factor of death before transplantation but also a risk factor of impaired early posttransplantation outcome.

Aquaretic Effect of Lixivaptan, an Oral, Non-Peptide, Selective V2 Receptor Vasopressin Antagonist, in New York Heart Association Functional Class II and III Chronic Heart Failure Patients

The purpose of this study was to examine the renal effects of a V2 receptor arginine vasopressin (AVP) antagonist in heart failure. Arginine vasopressin has been implicated in the renal water retention and dilutional hyponatremia associated with chronic heart failure. We examined the effects of the oral, non-peptide, selective V2 receptor antagonist lixivaptan in 42 diuretic-requiring patients with mild-to-moderate heart failure in a randomized, double-blind, placebo-controlled, ascending single-dose study. After overnight fluid deprivation, patients received single-blind placebo on day -1 (baseline) and double-blind study medication (placebo [n = 12] or lixivaptan 10, 30, 75, 150, 250, or 400 mg [n = 5 per dose group]) on day 1, followed by 4 h of continued fluid restriction and additional 20 h with ad libitum fluid intake. At all but the 10-mg dose, lixivaptan produced a significant and dose-related increase in urine volume over 4 h, compared with placebo. During 24 h, increases in urine volume ranged from 1.8 l with placebo to 3.9 l after the 400-mg lixivaptan dose (p < 0.01). These increases in urine volumes were accompanied by significant increases in solute-free water excretion. At higher doses, serum sodium was significantly increased; AVP antagonism was well tolerated in these patients. These observations confirm a role for AVP in the renal water retention associated with heart failure and suggest that the V2 receptor antagonist lixivaptan may be a promising therapeutic agent for the treatment of heart failure.

Nonosmotic release of vasopressin and renal aquaporins in impaired urinary dilution in hypothyroidism

The purpose of this study was to examine protein expression of renal aquaporins (AQP) and ion transporters in hypothyroid (HT) rats in response to an oral water load compared with controls (CTL) and HT rats replaced with l-thyroxine (HT+T). Hypothyroidism was induced by aminotriazole administration for 10 wk. Body weight, water intake, urine output, solute and urea excretion, and serum and urine osmolality were comparable among the three groups at the conclusion of the 10-wk treatment period. One hour after oral gavage of water (50 ml/kg body wt), HT rats demonstrated significantly less water excretion, higher minimal urinary osmolality, and decreased serum osmolality compared with CTL and HT+T rats. Despite the hyposmolality, plasma vasopressin concentration was elevated in HT rats. These findings in HT rats were associated with an increase in protein abundance of renal cortex AQP1 and inner medulla AQP2. AQP3, AQP4, and the Na-K-2Cl cotransporter were also increased. Moreover, 1 h following the oral water load, HT rats demonstrated a significant increase in the membrane-to-vesicle fraction of AQP2 by Western blot analysis. The defect in urinary dilution in HT rats was reversed by the V(2) vasopressin antagonist OPC-31260. In conclusion, impaired urinary dilution in HT rats is primarily compatible with the nonosmotic release of vasopressin and increased protein expression of renal AQP2. The impairment of maximal solute-free water excretion in HT rats, however, appears also to involve diminished distal fluid delivery.

Effects of contrast media on renal function in patients with cirrhosis: a prospective study.

Patients with cirrhosis are frequently submitted to radiological procedures that require the administration of contrast media. Contrast media is a well-known cause of renal failure, particularly in the presence of some predisposing conditions. However, it is not known whether cirrhosis constitutes a risk factor for contrast media-induced renal failure. The aim of this study was to assess the possible nephrotoxicity of contrast media in patients with cirrhosis. In a first protocol, renal function was evaluated with sensitive methods (glomerular filtration rate using iothalamate I 125 clearance and renal plasma flow using iodohippurate I 131 clearance) before and 48 hours after the administration of contrast media in 31 patients with cirrhosis (20 with ascites, 5 with renal failure). Solute-free water clearance, urine sodium, prostaglandins, and markers of tubular damage were also measured. The administration of contrast media was not associated with significant changes in renal function tests, neither in the whole group of patients nor in patients with ascites or renal failure. Urinary prostaglandin E2 and N-acetyl-beta-D-glucosaminidase increased significantly, but sodium and solute-free water excretion remained unchanged. In a second protocol, a different series of 60 patients with cirrhosis and renal failure were examined prospectively. No patient had renal failure due to contrast media. Only in 1 patient with septic shock was contrast media a possible contributing factor. In conclusion, the administration of contrast media is not associated with adverse effects on renal function in patients with cirrhosis. Cirrhosis does not appear to be a risk factor for the development of contrast media-induced nephrotoxicity.

Modulation of vasopressin antidiuretic action by renal alpha 2-adrenoceptors

It has been almost 40 years since the diuretic effect of alpha-adrenoceptor agonists was first demonstrated. Two possible mechanisms were proposed: inhibition of vasopressin secretion and antagonism of the cellular hydrosmotic actions of vasopressin. The debate could not be settled then for the lack of appropriate experimental models and pharmacological tools. Advances made in adrenoceptor pharmacology in the 1970s such as 1) subdivision of alpha-adrenoceptors into alpha 1- and alpha 2-subtypes; 2) development of selective agonists and antagonists; and 3) localization of both adrenoceptor subtypes in the kidney, including the proximal and collecting tubules, stimulated new research. With regard to renal adrenoceptors, selective alpha 2-agonists have been shown to induce diuresis in dogs and rats. Whereas in the dog the increase in urine flow results mostly from an increase in osmolal clearance, in the rat the diuresis results in large part from an increase in the excretion of solute-free water. In vitro studies on isolated collecting tubules from rats and rabbits (none from dogs) have shown that alpha 2-agonists inhibit vasopressin-induced adenosine 3',5'-cyclic monophosphate formation and that this effect is mediated by the inhibitory guanine nucleotide regulatory protein and abolished by pertussis toxin treatment. In vivo evidence in support of such a mechanism was presented from conscious Brattleboro homozygous rats in which a selective alpha 2-agonist inhibited the antidiuretic effect of exogenous vasopressin, and this effect was abolished by pertussis toxin. The physiological importance of renal alpha 2-adrenoceptors was identified by use of adrenal medullectomized rats and the alpha 2-antagonist, yohimbine.(ABSTRACT TRUNCATED AT 250 WORDS)

Renal mechanisms of human alpha-atrial natriuretic peptide in man.

1. Eight normal volunteers were studied on two separate days after being dehydrated overnight. Each volunteer received a background intravenous infusion of arginine vasopressin (5.5 X 10(-7) i.u. kg-1 min-1) on both days and also received an intravenous infusion of human alpha-atrial natriuretic peptide (15 pmol kg-1 min-1) plus carrier on one day and carrier alone on the other. The ensuing changes in blood pressure, in the excretion of urinary solutes, and in the excretion of solute-free water were recorded. 2. The infusion of atrial peptide had a small hypotensive effect, and increased the rate of excretion of sodium but not of potassium. There were no significant changes of urinary osmolality or of creatinine clearance. 3. The infusion of atrial peptide increased the rate of solute-free water reabsorption and did so in direct proportion to its effect of increasing sodium excretion. 4. A further six normal, dehydrated volunteers were studied on each of two days after taking 500 mg of lithium carbonate on the previous evening. On one day, they received an intravenous infusion of human alpha-atrial natriuretic peptide (15 pmol kg-1 min-1) plus carrier and on the other day they received carrier alone. The excretion of urinary electrolytes and the creatinine clearance were recorded. 5. The infusion of atrial peptide produced significant increases in the rates of excretion of both sodium and lithium, but there were no such changes of creatinine clearance. 6. Another six normal volunteers were studied on each of two days. On each day they drank 2 l of water over 30 min and then water to replace their urinary losses. They also received loading doses and maintenance infusions of inulin and sodium para-aminohippurate. Once a full water diuresis had become established, each subject received an infusion of human alpha-atrial natriuretic peptide (15 pmol kg-1 min-1) plus carrier on one day and carrier alone on the other, exactly as before. The excretion of sodium and solute-free water, and the clearances of inulin and para-amino-hippurate were recorded. 7. The infusion of atrial peptide increased the rates of excretion of both sodium and solute-free water. It also increased the clearance of inulin, but not that of para-aminohippurate. 8. These results suggest that, in our volunteers, infusion of human alpha-atrial natriuretic peptide increases sodium excretion mainly by increasing the delivery of sodium along the renal tubule from sites upstream of the loop of Henle.(ABSTRACT TRUNCATED AT 400 WORDS)

Thirst following water deprivation in humans.

The effect of 24-h water deprivation and subsequent drinking on systemic fluid balance and subjective sensations has been determined in human beings. The deprivation caused significant intracellular and extracellular depletions, thirst, and a dry unpleasant tasting mouth. During rehydration, subjects drank 65% of their total intake within 2.5 min. The marked decrease in drinking rate thereafter, and the alleviation of thirst, occurred before plasma dilution had become significant. This attenuation of drinking was subjectively attributed to stomach fullness. Presystemic factors may therefore be important for drinking termination in humans. Within 20 min systemic deficits were removed, but intermittent drinking continued at a low rate, reportedly to alleviate unpleasant oral sensations, Following rehydration, the concentrated urine of hydropenia had disappeared. However, the excretion of solute-free water varied between subjects. Plasma renin activity was significantly elevated by water deprivation, while after rehydration this activity had decreased to levels not significantly different from predeprivation values.

The actions of bradykinin and eledoisin in the canine isolated kidney: relationships to prostaglandins.

1. The effects of two vasodilator polypeptides, bradykinin and eledoisin, were studied in isolated blood-perfused canine kidneys before and after administration of indomethacin, an inhibitor of prostaglandin synthesis, Bradykinin, but not eledoisin, releases renal prostaglandins. 2. Before administration of indomethacin, bradykinin decreased urinary osmolality and increased free qater clearance, whereas eledoisin did not affect the excretion of solute-free water. After administration of indomethacin, the renal vasodilator action of bradykinin was reduced but the vasodilator action of eledoisin was unaffected. 3. Fractional excretion of sodium was not affected by bradykinin before but was increased after administration of indomethacin. Reduction in glomerular filtration rate contributed to changes in sodium excretion produced by bradykinin and eledoisin. 4. The release of prostaglandins from the kidney by bradykinin amplifies the renal vasodilator action of the kinin and possibly mediates its effect on excretion of solute-free water.

Mechanism of the antidiuretic effect associated with interruption of parasympathetic pathways.

The present experiments were undertaken to investigate the mechanism whereby the parasympathetic nervous system may be involved in the renal regulation of solute-free water excretion. The effects of interruption of parasympathetic pathways by bilateral cervical vagotomy were examined in eight normal and seven hypophysectomized anesthetized dogs undergoing a water diuresis. In the normal animals cervical vagotomy decreased free-water clearance (C(H2O)) from 2.59+/-0.4 se to -0.26+/-0.1 ml/min (P < 0.001), and urinary osmolality (U(osm)) increased from 86+/-7 to 396+/-60 mOsm/kg (P < 0.001). This antidiuretic effect was not associated with changes in cardiac output, renal perfusion pressure, glomerular filtration rate, renal vascular resistance, or filtration fraction and was not affected by renal denervation. A small but significant increase in urinary sodium and potassium excretion was observed after vagotomy in these normal animals. Pharmacological blockade of parasympathetic efferent pathways with atropine, curare, or both was not associated with an alteration in either renal hemodynamics or renal diluting capacity. In contrast to the results in normal animals, cervical vagotomy was not associated with an antidiuretic effect in hypophysectomized animals. C(H2O) was 2.29+/-0.26 ml/min before and 2.41+/-0.3 ml/min after vagotomy, and U(osm) was 88+/-9.5 mOsm/kg before vagotomy and 78+/-8.6 mOsm/kg after vagotomy in the hypophysectomized animals. Changes in systemic or renal hemodynamics or electrolyte excretion were also not observed after vagotomy in these hypophysectomized animals. On the basis of these results, we conclude that the antidiuretic effect associated with cervical vagotomy is initiated by interruption of parasympathetic afferent pathways and is mediated by increased endogenous release of vasopressin. This antidiuresis was also demonstrated to occur in the absence of renal nerves and alterations in systemic and renal hemodynamics.

Role of antidiuretic hormone in the abnormal water diuresis of anterior hypopituitarism in man.

To evaluate the role of antidiuretic hormone (ADH) in the defect in water excretion which is characteristic of glucocorticoid deficiency, the effects of hydrocortisone and ethanol upon urinary dilution during a sustained water load were studied in patients with anterior hypopituitarism. A spectrum of defects in urinary dilution was found in the seven patients with anterior hypopituitarism, and the subjects were separable into two groups. Four patients were unable to excrete a urine hypotonic to plasma (group I) while three diluted the urine (group II). In two of the group II patients, despite maintenance of hydration, urinary osmolality later rose to hypertonicity. Physiological doses of hydrocortisone improved urinary dilution in all patients. Submaximal doses of oral hydrocortisone, when given to the group I patients, converted their response to hydration to one characteristic of the group II patients, i.e., an initial hypotonic urine followed by a secondary rise to hypertonicity. Ethanol, a known inhibitor of ADH secretion, had no effect in the group I patients. When two of these patients were pretreated with sub-maximal doses of hydrocortisone, however, so that they were able to transiently dilute the urine, ethanol prevented the secondary rise in urine osmolality. Similarly, the administration of ethanol to the untreated group II patients, when the urine was hypotonic, improved diluting ability as characterized by a lowering of urinary osmolality and an increased excretion of solute-free water in all three patients. Hydrocortisone did not improve urinary dilution in three patients with complete hypophyseal diabetes insipidus and one with both anterior and posterior insufficiency receiving constant infusions of vasopressin. These data suggest, therefore, that inappropriately elevated levels of ADH play a major role in the defect in water excretion of anterior hypopituitarism. Glucocorticoids appear to be necessary for a normal neurohypophyseal response to inhibitory stimuli.

Renal response to pyrogen in normotensive and hypertensive man.

Pyrogen, when administered intravenously to normotensive and hypertensive men, produced initially vasoconstriction and subsequently marked renal vasodilatation, both resulting from direct effects on the renal vasculature. The absolute renal plasma flow, both during control observations and at the height of renal hyperemia, was greater in normotensives, but the percentage change was greater in hypertensive subjects. Extraction of p -aminohippurate diminished during renal hyperemia. Medullary renal plasma flow was higher in normotensive subjects both during control observations and at the height of renal hyperemia. Simultaneously with the development of renal hyperemia, sodium excretion increased without alterations in filtered load of sodium and was prompt in its development in normotensives and delayed in hypertensives. This is attributed to a transient, small, yet probably significant decrease in filtered load of sodium during vasoconstriction immediately following the administration of pyrogen. Simultaneously with the development of renal hyperemia, there was in both groups an increase in solute excretion and tubular reabsorption of solute-free water.

Restoration of water diuresis in addisonian patients by expansion of the volume of extracellular fluid.

Although the inability of patients with Addison's disease to excrete a water load is well known, the nature of this defect remains obscure. The effects of changing glomerular filtration rate (GFR) and solute excretion (UosmV) on water excretion in patients with adrenal insufficiency have recently been described (1). While an increase in these two variables leads to an increase in the excretion of water, the improvement is very small compared with that seen with carbohydrate-active steroids. In healthy persons expansion of the volume of extracellular fluid may increase the rate of excretion of solute-free water (CH2o) (2, 3). In patients with Addison's disease, when replacement therapy is stopped, the increase in urinary sodium excretion leads to a depletion of body fluids, and continues despite this depletion. It is possible that depletion of the volume of extracellular fluid (ECF) could limit the rate at which water is excreted. These experiments were designed to explore the effects of contraction and expansion of the volume of ECF on water excretion in adrenal insufficiency.