Taurine-induced diuresis and natriuresis in cirrhotic patients with ascites

Life Sciences, Vol. 54, No. 21, pp. 1585-1593, 1991 Copyright * 1994 F_asevierScience Ltd Printed in the USA. All rights re~rved

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TAURINE-INDUCED DIURESIS AND NATRIURESIS IN CIRRHOTIC PATIENTS WITH ASCITES Silvia Gentile, Enrico Bologna, David Terracina and Mario Angelico Department of Medicine, Fatebenefratelli Hospital, Isola Tiberina, Rome, and Chair of Gastroenterology, University of Catania, Italy (Received in final form March 9, 1994) Summary Taurine is a non-protein sulfur aminoacid widely distributed in mammalian tissues, with poorly understood functions. Taurine administration has a variety of hemodynamic effects, including improvement of cardiac function and suppression of sympathetic activity. Increased urinary volume and sodium excretion have been reported in taurine-fed hamsters. Since patients with ascitic liver cirrhosis have severe hemodynamic and renal abnormalities potentially sensitive to taurine feeding, we evaluated the effects of the i.v. infusion oftaurine on urinary flow and sodium excretion and on the hormones involved in the control of hydrosaline homeostatis. Eight cirrhotic patients with tense ascites were given an i.v. bolus of taurine (16 lamoles in 40 ml of saline). The next day patients were given saline only, as a control. Diuresis, urinary sodium and plasma renin activity, aldosterone, atrial natriuretic peptide and arginin vasopressine were measured for the following 6 hrs. Plasma taurine increased ten fold after infusion, then decreased exponentially. No side effects were recorded. After taurine, but not after saline, there was a prompt and significant increase in both urinary volume and sodium excretion. Diuresis increased from 340-a:43 to 817~:116 lal/min (p<0.01); urinary sodium from 13.8+3 to 26.3+4 lamoles/min (p<0.05). Both values returned to normal after 2-3 hrs. Taurine infusion caused a concomitant significant decrease in plasma renin activity (from 7.7+2.2 to 4.3+1.9 ng/ml/hr, p<0.05) and aldosterone (from 588±47 to 348+89 pg/ml, p<0.05), but no changes in atrial natriuretic peptide and arginin vasopressine. We conclude that i.v. taurine infusion in ascitic cirrhosis promotes a transient diuresis and natriuresis, apparently through the inhibition of the renin-aldosterone axis. Key Words: taurine, ascitic cirrhosis, urinary sodium, diuresis

Taurine, (2-aminoethanesulfonic acid) is a non-protein sulfur aminoacid widely distributed in mammalian tissues (1,2). Apart from the well known function on bile acid conjugation, which has been estimated to consume only one percent of the available taurine (3,4), no definite functions have been estabilished for the remaining 99 percent of the free aminoacid. However, the extraordinary

Corresponding author: Mario Angelico, MD, Via Luigi Perna 51, 00142 Rome, Italy

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abundance of taurine in several tissues, such as heart (5) and brain (5,6,7), the demonstration of its essentiality in some animal species (2) and the presence of efficient mechanisms for cellular uptake (8), transport (9) and conservation (10) of taurine have led to the search for other important physiological functions. From among a variety of biochemical and metabolic functions which have been attributed to taurine, we were attracted: a) by the complex hemodynamic effects of taurine (cardiac, vascular and renal) shown in humans (11,12) and in various animal species (10); b) by the recent observation that taurine administration promotes both diuresis and natriuresis in the 14.6 bio syrian hamster strain (13), an experimental model of hereditary cardiomyopathy (14), possibly via an increased production or release of atrial natriuretic peptide. Ascitic liver cirrhosis is characterized by severe hemodynamic and renal abnormalities (15), potentially sensitive to taurine feeding. Very few reports have explored taurine metabolism in liver cirrhosis (16), and virtually none in relation to hemodynamic and renal functions. Hence, this study was designed to explore the effect of the acute intravenous infusion of taurine on the renal water and sodium handling in patients with liver cirrhosis and the possible relationships with the regulatory hormonal systems. Materials and Methods Patients. Ten patients with liver cirrhosis, 6 males and 4 females, ranging in age from 39 to 74 years (mean±SE:61.8±3.5 yrs) and three normal volunteers, 2 males and one female aged 61.7+5.9, were included in the study. The etiology of the liver disease was alcoholic in 5 patients, cryptogenic in 3 and posthepatitis B in two. All patients had tense ascites and evidence of sodium retention (urinary sodium excretion lower than 40 mEq/day), and a history of ascites lasting from two months to five years prior to the study. The diagnosis was based, in all cases, on physical examination (presence of spider teleangectasia, palmar erythema, abdominal venous collaterals and splenomegaly), presence of abnormal liver tests and ultrasonographic and/or endoscopic evidence of portal hypertention. In 5 patients the diagnosis was confirmed by liver biopsy. Three patients were classified as group B according to Child-Pugh criteria, and seven as group C. None of the patients had had previous episodes of variceal bleeding, hepatic encephalopathy, renal failure, nor a recent history of alcohol abuse. Study Protocol. Patients were studied at least five days after discontinuation of any drug and restriction of salt intake to 40 mEq/day. All patients gave their informed consent to the following study protocol. The day before the study a bladder catheter was positioned and the urinary excretion was measured using a disposable collecting system (Ureofix-500, Brawn Milscinger, Germany), which allows the precise monitoring of the urinary flow per unit of time. After an adequate basal urinary excretion had been measured (baseline data are the average of four consecutive 15 min periods diluted in 40 ml of saline. Eight patients received a standard dose of 2 g of taurine (16 ~tmoles). The next morning, five of these patients were given 40 ml of saline alone, which served as a control. Other two cirrhotic patients were also studied twice, but received 1 g (8 lamoles) and 4 g (32 ~tmoles) of taurine, respectively, in two consecutive days. The three normal subjects were studied only with a single infusion of 2 g (16 lamoles) of taurine. Patients and subjects remained fasted and without drinking throughout the study period and were asked to stand in the supine position.

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Clinical, Biochemical and Hormonal Data. The following clinical, biochemical and hormonal data were measured before and after regular time intervals following the infusion of taurine or saline: urinary excretion, systolic and diastolic blood pressure and heart rate; BUN, serum creatinine, hematocrit and plasma ammonia (conventional methods); plasma and urinary sodium, potassium (atomic absorption) and osmolality (freezing point osmometer); plasma taurine concentration (Beckman 6300 Aminoacid Analyzer after plasma deproteinization with sulfosalicylic acid). All specimens for measurement of plasma hormones were centrifuged at 2 °C (15 min, 2000 g) immediately after collection and the plasma stored at -30 °C until time of analysis. Plasma renin activity (PRA), aldosterone (PA) and arginin vasopressine (AVP) were measured by specific radioimmunoassays (17-19). Atrial natriuretic peptide (ANP) was determined by a specific radioimmunoassay kit (Peninsula Laboratories, Belmont, CA) employing rabbit antibodies againest anti-synthetic alpha-human ANP (20). Data are expressed as means + SE. Statistical difference were evaluated by ANOVA to determine the F statistic. When the F statistic was significant, Student's "t" test was used to calculate the level of significance. Data were also analyzed by linear regression. Results Effect of Taurine Infusion on Clinical and Biochemical Data. No side effects were recorded during or after taurine infusion. As shown in Table I, the infusion of 16 ~tmoles of taurine in cirrhotic patients caused an initial, appoximately ten fold, increase of plasma taurine concentration, which then dereased exponentially, but still remained within a pharmacological range after 2 hrs. The infusion did not cause significant changes in blood pressures and heart rate, nor in BUN, serum creatinine, plasma sodium and plasma or urinary osmolality. Similary, these parameters did not change after the infusion of either 8 or 32 ~tmoles of taurine, nor after the infusion of 16 ~tmoles in the 3 normal subjects studied. A prompt increase in both urinary volume (fig. 1) and urinary sodium excretion occurred in all cirrhotic patients following the administration of taurine at any dosage used. After infusion of saline we only observed a slight increase of UNa immediately after infusion. After 30 and 60 minutes UNa decreased. UV and UNa increased slightly, but not significantly, after taurine infusion in normal subjects. In the cirrhotic patients, the average diuresis (UV) after administration of 16 lamoles of taurine rose from 340.5+42.9 ul/min at baseline to 816.7±116 (p<0.01) and 800.0±94 (p<0.01) after 15 and 30 min, respectively. Then it slowly decreased, to approximate the basal values after 2 hrs (330.2+57). A significant linear correlation (r=0.44; p=0.028) was observed between taurine concentration in plasma and urinary volume in these patients (fig. 2). The infusion of 32 ~tmoles of taurine in two patients (fig. 3) caused an increase in diuresis of the same order of magnitude as the former standard dose: this effect was approximately the double than that observed after giving 8 lamoles to the same patients. As despicted in fig. 4, in cirrhotic patients receiving 16 ~moles of taurine, the average urinary sodium excreation (UNa) rose from baseline values of 13.8+3.0 ~tmoles/min to 26.3±4.1 (p<0.05) after 30 min, then it decreased to approach the basal values after 3 hrs (14.5±2.4). A similar increase was observed after the infusion of 32 ~tmoles of taurine and only a slight change after 8 lamoles.

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TABLE I Effect of the Intravenous Infusion of 16/amoles of Taurine on Heart Rate, Blood Pressure, Plasma Taurine Concentration and Urinary Osmolality in Cirrhotic Patients with Ascites.

Heart Rate (beats/min) Syst. Pressure (mm Hg) Diast. Pressure (mm Hg) Plasma Taurine (gmol/L) Urin. Osmol (mOsm/kg)

Baseline

Minutes after Taurine Infusion 15 min. 30 min. 60 min.

80.4±3 123±5 7Y2±4 55.4±7 619±56

81.6±4 119±6 72.9±3 734±60* 677±46

79.4±3 121+6 72.5±4 449-3:31 ° 656±95

79.6±3 122±5 72.2±3 360-3:73 6554-64

120 min. 80.7+4 120a:6 73.8±4 190±74625±55

* p
Baseline PRA PA AVP ANP

(ng/ml/hr) (pg/ml) (pg/ml) (ng/ml)

7.0±2 577±47 3.6±1 77±5

Minutes after Taurine Infusion 15 min. 30 min. 60 min.

120 min.

5.7± 2 528±131 3.6±1 72+4

3.1±2" 348±89 3.8±1 69±5

4.3±1" 483±133 3.3±1 67±2

4.74-2* 466±120" 4.4±1 69±3

* p<0.05 from baseline values Taurine infusion caused a prompt and persistent decrease in PRA and PA concentration, which reached the statistical significance. No significant changes were recorded in AVP and ANP levels after taurine. Hormonal variations observed in the two patients who received 8 and 32 ~tmoles of taurine were comparable to those found after infusion of the standard dose. Discussion The objective of this study was to ascertain whether the intravenous administration of taurine, in a single pharmacological dose, to patients with decompensated liver cirrhosis has any effect on the renal or hormonal abnormalities causing sodium and water retention in this condition.

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The rationale for making this hypothesis was given us by recent reports demostrating the involvement of taurine in the regulation of vascular tone and myocardial and renal functions, which need to be here briefly discussed. Taurine is an essential aminoacid in cats (21) and probably also in humans (22), which has been implicated in many biological and metabolic functions. Bile acid conjugation is the best known of these functions, yet only an insignificant fraction of body taurine is utilized by this pathway (3). The bulk of body taurine is confined within specific tissues, such as the myocardium, retina, brain and renal cortex, where it is highly concentrated by energy-dependent trasport mechanisms under, at least partial, adrenergic control (22,24). The exact role of these taurine pools is unknown, despite the increasing data in support of a major role oftaurine in the control of cellular osmolality and cell volume (25,26). There are at least three aspects of taurine metabolism which may be expected to have some impact on renal water and sodium handling. The first is that taurine behaves as an antiadrenergic drug. Studies in both hypertensive rats (27) and men with borderline hypertension (28) have show that chronic administration of taurine exerts an hypotensive effect, apparently through the inhibition of the sympathoadrenergic tone (12). Thus, both changes in blood pressure and in renal sympathetic activity may be expected to influence renal function. The second aspect of taurine metabolism potentially related to hydrosaline homeostasis is that the major determinant of taurine concentration in the whole body is the degree of renal excretion (29). In contrast to most aminoacids, which are avidly reabsorbed by the renal tubule, taurine can be either reabsorbed or secreted, due to the extraordinary adaptive response of the renal cortex to variations in plasma concentration of the aminoacid (10). Thus, diets deprived of taurine cause an enhancement of tubular reabsorption, while excessive dietary taurine causes massive taurinuria. Studies on the transepithelial movements across the renal tubule have shown that taurine enters the tubular cell via an active, ouabain sensitive, Na-coupled trasport system, against a concentration gradient. For example, in the flounder renal tubule (30) taurine is concentrated up to 500 times the plasma concentration. Similar findings have been detected in the mammalian kidney as well (31). After the accumulation in the tubular cell, taurine moves into the lumen down a concentration gradint. The nature of the latter downhill movement is uncertain, but has been proposed to be an electrogenic Na-dependent cotransport. The urinay excretion of taurine is, at least partially, under hormonal control. In humans, the adrenal steroids cause an increase in urinary taurine excretion (32) and, in the rat, adrenalectomy is followed by its decrease (33). In addition, the overall tubular excretion oftaurine is modulated by factors such as the environmental "salinity": a decrease in "salinity", for example, causes net efflux oftaurine from the cells and incresed rate of tubular secretion. It is noteworthy that these unique adaptive responses to osmotic changes form the basis of the osmoprotective role of taurine at the cellular level (26). The peculiarity of taurine metabolism in the kidney suggests that abrupt changes in plasma taurine concentration which may be obtained by the intravenous administration of the aminoacid may have some inpact on renal sodium excretion, particularly in conditions associated with excessive Na reabsorption, such as liver cirrhosis. The third aspect of taurine metabolism which needs to be taken into con sideration here is the importance of heart taurine in the inotropic regulation of the myocardium, as evidenced by many recent studies both in animals and humans. Myocardial taurine concentration decreases in congestive heart failure (34) and oral taurine is efficacious in the treatment of this condition in man(35). Taurine administration significantly improved cardiac output in rabbits under betablockers or experimental aortic regurgitation (11). A dilated cardiomyopathy associated withs low plasma taurine has been demonstrated in cats and shown to be reversed by taurine feeding (36). And, finally, Dlouha & McBroom (13) have demontrated that taurine feeding to hamsters with

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hereditary cardiomyopathy is followed by an increase in both diuresis and natriuresis, possibly through the release and/or activation of atrial natriuretic factor. For all the above reasons, and since administration of up to 6 grams of taurine per day in humans has been shown to be safend well tolerated (28), we thought it would be of interest to investigate the acute effects of intravenous taurine infusion in patients with ascitic cirrhosis. The most important findings of this study are that a) an intravenouse taurine infusion enhancing the plasma levels to the pharmacological range, is followed by a prompt, although transient, increase in both diuresis and natriuresis and that b) this is associated with a significant decrease of PRA an PA concentration, but c) no changes in blood pressure nor in the apparent cardiac activity are detectable. Since the study was not designed to define the exact mechanism of action oftaurine, it is not possible to offer a precise pathophysiological explanation to these results. However, in light of the above consideration, we interpret our findings as the consequence of the antiadrenergic activity of taurine. It is well known that the sympathoadrenergic tone is increased in decompensated liver cirrhosis (37). Despite plasma norepinephrine was not mesured in this study, the observed reduction of PRA may well be due to the inhibitory action of taurine on the symphatetic control of its release (28). Accordingly, the decrease in PA may follow the inhibition of the renin-angiotensin system. It is noteworthy, in this respect, that a specific antagonizing effect of taurine on the intrinsic renin-like activity of the brain has been recently demonstrated (38). Alternative or additional possibilities include a direct effect of taurine at the renal tubular level, through an osmotic diuresis due to massive taurinuria, Unfortunately, we were unable to measure urinary taurine in these patients. However, the slight, althoughtnot significant, increase in urinary osmolality observed after taurine load does not allow to exclude the latter hypothesis. Finally, a possible contributory role of an improved myocardial activity cannot be ruled out, althought it was not clinically evident. In conclusion, we have shown that intravenous taurine infusion in patients with decompensated cirrhosis promotes transient diuresis and natriuresis, apparently through the inhibition of the renin-aldosterone system. Further studies are necessary to define the precise mechanisms underlying these findings and to assess their possible clinical relevance.

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