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• W1513779513 abstract "Background and aim. In preascitic cirrhosis increased sodium retention occurs in kidney distal tubule in spite of normal aldosterone plasma levels. No clearance technique can dissect the respective contribution to sodium retention exerted by Henle's loop, distal convoluted tubule and collecting duct, so we evaluated proximal and distal tubular sodium handling in preascites during two manoeuvres that temporarily increase aldosterone secretion. Methods. Ten patients with compensated cirrhosis and nine controls were studied in recumbency, during standing and after dopamine receptor blockade with metoclopramide through: 4 h renal clearances of sodium, potassium, lithium and creatinine; plasma levels of active renin and aldosterone. Results. Whilst comparable in recumbency, aldosterone levels significantly rose during standing and after metoclopramide in both groups. In patients, dopaminergic blockade caused a fall of distal sodium delivery (P < 0.01) but urinary sodium excretion was unchanged because the reabsorbed fraction of distal sodium delivery also fell (P < 0.03). Cirrhotic patients showed the same findings in the passage from recumbency to standing. Conclusions. In preascitic cirrhosis, the distal tubular segments of the nephron are able to cope with decreases in tubular flow by reducing reabsorption at an aldosterone-independent site (possibly the loop of Henle). Studies in experimental cirrhosis have shown that sodium retention precedes ascites formation [1-3]. Seemingly, preascitic cirrhotic patients demonstrate renal sodium handling abnormalities. In preascites, increase in circulating and central plasma volume occurs, as demonstrated by several findings: increased distribution volume of 131I-labelled albumin and 51Cr-labelled erythrocytes [4]; increased central blood volume measured through radionuclide angiography [5]; increased end-diastolic left ventricular diameters on two-dimensional echocardiography [6]. In addition, an increased total blood volume in preascitic cirrhosis is reflected by the depression of the renin-angiotensin-aldosterone system (RAAS) [7-9], by high levels of plasma atrial natriuretic peptide [10] and by increased endogenous dopaminergic activity [11]. Regarding the mechanisms of sodium and water retention in preascites, this occurs despite normal or increased glomerular filtration rate (GFR) [12, 13], indicative of inappropriately elevated tubular electrolyte and fluid retention [14, 15]. In human preascitic cirrhosis tubular sodium retention has been shown to be related to erect posture as bed-rest-induced hypernatriuresis has actually been described at this disease stage [9, 16]. Excessive production of angiotensin II in the erect posture could induce increased proximal renal tubular reabsorption of sodium, whilst increased aldosterone production in the same posture might be responsible for an increase in distal renal tubular reabsorption of this electrolyte. Actually, when the RAAS was evaluated in compensated cirrhotic patients, a near normal haemodynamic and endocrine profile in the upright position, with insignificant elevations of serum aldosterone levels, was found [16-19]. Instead, it has been suggested that the erect posture might induce exclusively intrarenal exaggerated production of angiotensin II with subtle increase in proximal tubular reabsorption of sodium [17, 18]. As a matter of fact, a low dose of an angiotensin II-receptor antagonist, losartan, was able to abolish the erect posture-induced sodium retention in compensated cirrhosis, without interfering with systemic haemodynamics [17]. Most data on tubular sodium handling in cirrhosis have been obtained through the lithium clearance (C-Li) and fractional excretion technique. Since lithium clearance approximates the delivery of fluid from the proximal convoluted tubule to the descending limb of Henle's loop, this method directly measures proximal tubular handling of sodium and water. In addition, it also provides indirect measurement of sodium handling in the ‘distal nephron’, which therefore includes, according to this technique, Henle's loop, distal convoluted tubule and collecting duct [20-22]. Using the above technique, Wong et al. [14] described in supine compensated cirrhotic patients, following an intravenous sodium load, decreased lithium fractional excretion, a measure of the fraction of filtered sodium load that escapes proximal tubular reabsorption. Furthermore, in compensated cirrhotic patients whilst reclining, significant retention of sodium by the distal nephron has been detected, either isolated [23] or associated with proximal tubular sodium retention [14] but always in the presence of moderately depressed or actually suppressed systemic RAAS function [7-9, 14, 23]. Therefore, if renal tubules (both proximal and distal) retain sodium without stimulation of systemic RAAS, further sodium-retentive mechanisms will remain to be uncovered. The unanswered question is: could an aldosterone-insensitive part of the ‘distal’ nephron (according to lithium clearance technique), for instance the Loop of Henle, be involved in the sodium retention of human preascitic cirrhosis? As no clearance technique is able to dissect the contributions to distal sodium retention exerted by Henle's loop and anatomical distal convoluted tubule and collecting ducts, we evaluated in patients with preascitic liver cirrhosis the renal proximal and distal tubular sodium handling and contemporary hormonal status in the course of two manoeuvres specifically aimed at temporarily increasing aldosterone plasma concentrations and, in turn, tubular sodium retention in the aldosterone-dependent nephron segments. Ten patients (five men, five women; age range 37–71 years) with biopsy-proven liver cirrhosis belonging to the functional stage A according to the Child-Pugh classification [24] were studied. Patients with previous variceal bleeding or evidence of ascites, diuretic consumption, heart failure, intrinsic renal disease, arterial hypertension, diabetes mellitus requiring drug therapy or endocrine disease were excluded. No steroids, prostaglandin synthesis inhibitors, amines or antihypertensive drugs were administered for at least 1 month prior to the study. Nine healthy subjects of age comparable with patients (five men, four women; age range 30–68 years) were also studied as controls. Alcohol consumption had been stopped in the patients at least 3 months previously and in controls was discontinued during the last week before the study. This study, which was performed in compliance with the 1975 Declaration of Helsinki ethical guidelines, was approved by the University of Turin ethics committee. All patients gave informed consent before participation in the study. Before the study, controls and patients underwent an equilibration period of 5 days, during which they received a diet providing 220 mEq of sodium and 60 mEq of potassium daily. The same diet was followed during the whole study. Patients and controls were submitted to three study days, which were patterned on two different protocols of clinical determinations, in order to get their renal function evaluated whilst reclining, during the upright posture and during a dopaminergic DA2 receptor block with i.v. metoclopramide (MTC). First protocol. In phase 1, at 22:00 h of the day before the study, 600 mg lithium carbonate was administered orally. After an overnight fast spent supine, on the following morning a urine collection period started at 08:00 h. Urine was collected by spontaneous voiding. Blood samples were taken at the beginning and at the end of the urine collection period which lasted 4 h (until 12:00 h). Water intake was fixed at 1 L in the course of the 4-h period and the subjects were kept supine throughout this period. Blood samples at the beginning and at 12:00 h were analysed for sodium (P-Na), potassium (P-K), lithium (P-Li) and creatinine (P-Cr) plasma concentrations. Blood samples at the beginning of the clearance period were also analysed for plasma active renin (AR) and aldosterone (A) concentrations. Urine samples were analysed for lithium (U-Li), sodium (U-Na), potassium (U-K) and creatinine (U-Cr) concentrations. At 22:00 h of the same day there was a second oral administration of 600 mg lithium carbonate. In phase 2, the following day, a further 4-h clearance period was started at 08:00 h and the same blood and urine samples were taken, as described in phase 1, except for the determinations of the plasma levels of AR and A, which were assessed at 12:00 h. In this phase both patients and controls were asked to have a water intake of 1 L and to keep the standing position for the whole 4 h period (slow walking and brief periods in sitting position were allowed). Second protocol. At 22:00 h of the second study day, 600 mg of lithium carbonate was administered orally. On the following morning (third study day), whilst supine, a further 4-h urine collection started at 08:00 h, when blood samples were taken in order to measure P-Na, P-K, P-Li, P-Cr and plasma concentrations of AR and A. Immediately after this blood withdrawal a bolus of MTC (10 mg i.v.; Plasil, Lepetit, Milan, Italy) was injected and blood was collected 30 and 60 min after this injection for measurements of aldosterone plasma concentrations. The magnitude of incremental aldosterone responses 30 min after the dopaminergic blockade was considered a measure of endogenous dopaminergic activity, due to the tonic inhibitory effect of endogenous dopamine on mineralocorticoid secretion, as currently stated in endocrinological literature [25, 26]. At 12:00 h blood samples were withdrawn in order to measure P-Na, P-K, P-Li, P-Cr. Urine samples were analysed for U-Li, U-Na, U-K and U-Cr in the whole 4-h clearance period. P-Na, U-Na, P-Li, U-Li, P-K, U-K were measured by a flame photometer (Instrumentation Laboratory model 143, Paderno Dugnano, MI, Italy). P-Cr and U-Cr were determined colorimetrically. The determination of human AR has been performed on EDTA plasma. AR was determined by a two-site immunoradiometric assay for the measurement of AR protein (Nichols Institute Diagnostics, San Clemente, CA, USA). Plasma AR values are given in μU mL−1. The normal range from our laboratory is 5–47 μU mL−1 in supine subjects and 7–76 μU mL−1 in upright posture. Plasma A concentrations were evaluated by radioimmunoassay, using a kit from Sorin Biomedica (Saluggia, VC, Italy) supplying solid-phase antibody-coated tubes. Intra-assay variability was 7.4%. Plasma A values are given in pg mL−1. The normal range from our laboratory is 10–150 pg mL−1 in supine and 35–300 pg mL−1 in upright posture. Assuming that lithium is reabsorbed in the proximal tubule in parallel with sodium and water and that it is neither secreted nor reabsorbed beyond the proximal tubule, from C-Li, U-Na × V, C-Na and C-Cr the following parameters were derived according to current literature [21, 27]: Finally it should be noted that, throughout the study, the expression ‘distal tubule’ indicates all the segments of renal tubule beyond the proximal one. The results are expressed as mean ± SD. Comparisons between measurements obtained in different experimental conditions or body positions are carried out by Wilcoxon signed rank test. Comparisons between patients and controls are carried out by Wilcoxon rank sum test. Correlation coefficients were derived using Spearman's rank correlation. Significance is accepted at the 5% probability level. The incremental aldosterone response at 30 and 60 min after MTC is expressed as the mean ± SD of the individual incremental aldosterone responses. The main baseline clinical and laboratory findings of cirrhotic patients are reported in Table 1. Hormones (Table 2). Whilst reclining, AR and A plasma levels did not differ significantly between healthy controls and patients, with slightly depressed values of both hormones in the cirrhotic group. Renal function (Table 3). UNaV and sodium fractional excretion (FENa) were significantly lower in cirrhotic patients than in controls. Conversely, GFR and FlNa were quite close in the two groups. In reclining cirrhotic patients, the values of lithium clearance (i.e. distal tubular fluid delivery) were significantly lower and DFRNa significantly higher than in controls, so determining the above increased value of FENa. Correlations. In the group of patients, aldosterone was slightly correlated with the values of DRNa, but without reaching levels of significance (r = 0.49, P > 0.05). We found significant correlations between plasma aldosterone and urinary sodium excretion values neither in patients nor in controls (respectively, r = −0.07; P > 0.05 and r = −0.44; P > 0.05). Hormones (Table 2). After the 4-h standing period, plasma AR and A levels did not differ significantly between controls and patients, although A values were slightly increased in the cirrhotic group. With the assumption of the standing position A and AR plasma levels increased significantly in both controls and patients, with an incremental value of plasma A (Δ increase) significantly higher in the group of patients with respect to controls (118.5 ± 15.01 pg mL−1 vs. 72.3 ± 28.01 pg mL−1; P < 0.05). Renal function (Table 3). Compared with controls, during standing the cirrhotic patients showed significantly lower values of UNaV, FENa, DDNa, FELi (the latter being expression of the fraction of filtered sodium load that escapes proximal tubular reabsorption) than controls. Surprisingly, DFRNa turned out to be significantly lower in patients than in controls. In effect, with the assumption of the standing position the cirrhotic patients showed a marked reduction of C-Li (Fig. 1) and of FELi. In spite of this, FENa did not worsen due to an apparently compensatory decrease of DFRNa, i.e. the fraction of distal sodium delivery that is reabsorbed by the ‘distal nephron’ (Henle's loop, distal anatomical tubule and collecting duct) (Fig. 2). After taking the upright posture a significant increase of FEK was not observed in the cirrhotic group. None of the studied parameters changed significantly in the control group as a consequence of the passage from recumbency to the upright posture. Lithium clearance values (C-Li) in controls and cirrhotic patients in basal condition (recumbency), during dopaminergic blockade and in the erect posture. Distal fractional sodium reabsorption (DFRNa) in controls and cirrhotic patients in basal condition (recumbency), during dopaminergic blockade and in the erect posture. Correlations. Plasma aldosterone correlated with the values of UNaV, DRNa or DFRNa neither in controls, nor in patients. Hormones (Table 2). Both in patients and controls aldosterone plasma levels significantly increased after MTC administration. Incremental plasma aldosterone responses were significantly greater in patients than in control subjects both 30 and 60 min after i.v. MTC administration (Table 2), showing higher values of endogenous dopaminergic activity in the cirrhotic group [25, 26]. Renal function (Table 3). In the cirrhotic group, MTC administration caused a significant reduction of lithium clearance, indicative of drug-induced stimulation of proximal tubular sodium and fluid retention (Fig. 1). Once again, FENa did not worsen due to an apparently compensatory decrease of DFRNa to subnormal levels (Fig. 2). These same parameters of renal tubular sodium handling remained unaffected by MTC administration in the control group. Correlations. During dopaminergic blockade plasma aldosterone correlated with the values of UNaV, DRNa or DFRNa neither in controls, nor in patients. A definite explanation is still needed for the pathophysiology of fluid homeostasis in patients with cirrhosis in the preascitic stage. In previous literature, several findings seemed to support a major role for the RAAS in this context. Basically, the temporal relationship between increase in urinary aldosterone excretion and sodium retention in cirrhotic rats and the reversal of this process by spironolactone [3], the development of sodium retention in compensated cirrhotic patients almost exclusively whilst standing [16] and the plasma volume decrease obtained through spironolactone administration [28] are findings that point to aldosterone as a major cause of sodium retention in preascites [29]. In addition, at least whilst preascitic patients are supine, significantly higher sodium reabsorption has been found in the distal nephron. However, the latest observation was made in patients with lower-than-normal plasma values of aldosterone and without any correlation between aldosterone levels and renal sodium excretion or distal tubular sodium reabsorption [23]. This last finding could be hardly interpreted assuming a hyperbolic relationship between aldosterone levels and sodium retention [29]. Even when compensated patients are studied whilst standing, the observation that low doses of the angiotensin II-antagonist losartan reversed sodium retention without interfering with blood volumes and hormonal status [17] seems to point to a role for proximal convoluted tubule in the sodium retention of preascites as angiotensin II directly causes sodium reabsorption in this nephron segment [30, 31]. In the present study, when taking the upright posture, compensated cirrhotic patients displayed a marked decrease in distal tubular fluid (Fig. 1) and sodium delivery (expressed as C-Li and DDNa respectively) without any change in GFR, indicative of a posture-induced enhancement of proximal tubular reabsorption (Table 3). Even when dopaminergic function was blocked by MTC, the net effect was an increased proximal tubular reabsoprtion of sodium (Table 3). This did not come unexpected as dopaminergic doses of dopamine, acting on the renal cortical DA1 and DA2 receptors, inhibit Na+-K+-ATPase activity in proximal tubule segments, and increase sodium delivery to the distal nephron [32-34]. As both prolonged upright posture and dopaminergic blockade did cause only a slight decrease in urinary sodium excretion, our patients’ distal nephron (which includes, on the basis of lithium clearance technique, Henle's loop, macula densa, distal convoluted tubule and collecting duct) showed the capacity to reduce at least transiently in a quasi-compensatory manner its sodium avidity, as demonstrated by the prompt fall of DRNa and DFRNa (Table 3). The standing- and MTC-associated reductions of DFRNa (i.e. the fraction of distal sodium delivery that is reabsorbed by the distal nephron) (Fig. 2) indicate that the decline of DRNa was not a mere mechanical process, simply due to the fall of the amount of sodium that reaches this tubular segment, but an active one. This compensatory mechanism should be effective along the loop of Henle and not in an aldosterone-dependent site (distal convoluted tubule and collecting duct) by reason of the simultaneous increase in aldosterone secretion following both prolonged upright posture and MTC administration (Table 2). A qualitatively similar decrease in distal delivery of sodium, with ensuing reduction of distal tubular reabsorption of this electrolyte, was already observed by this group when primarily documenting the derangement of tubuloglomerular feedback in the erect posture [18] and the dependence of proximal tubular sodium handling on the degree of endogenous dopaminergic function in preascites [35]. Apart from the two studies just mentioned, the only further published paper dealing with lithium clearance determinations in different bodily positions identified the proximal tubule as the segment where a substantial increase of sodium retention occurred in standing compensated cirrhotic patients [17]. The surprinsing lack of aldosterone-dependent increase in distal tubular retention of sodium in upright posture and during dopaminergic blockade we observed is also supported by the observation that under those two stimuli no increase in potassium fractional excretion occurred (Table 3). How can we explain these data? First, it must be reminded that an effective aldosterone-driven increase in sodium reabsorption by distal anatomic tubule and collecting duct (i.e. aldosterone-dependent tubular segments) might have been masked by a simultaneous decrease in sodium reabsorption along the Henle's loop. Secondly, the occurrence of abnormal constitutive activation of the epithelial sodium channel, which could reabsorb sodium independently from any activation of the mineralocorticoid receptor (as occurs in Liddle's syndrome) [36, 37] must be ruled out. Lastly, a rapid review of the mechanisms of regulation of tubular sodium handling after changes in fluid delivery between different nephron segments could throw new light on this intriguing process. A physiopathological context of unexpected Liddle-like syndrome is easily ruled out observing the large increase of aldosterone secretion after the passage from reclining to standing in patients. Liddle's syndrome, in effect, is characterized by low or absent aldosterone increase in the passage from reclining to standing, as a consequence of chronically expanded extracellular fluid volume [36, 37]. Regarding the mechanisms of transitory depression of sodium reabsorption by the distal nephron when the latter is reached by reduced tubular loads of electrolyte, the following interpretation can be put forward. Kidney adapts to any tendency towards urinary loss of sodium and water (such as in uncontrolled diabetes mellitus) through up-regulation of the epithelial sodium channel (ENaC) in the thick ascending limb of Henle's loop [38]. The opposite occurs when the Henle's loop is reached by reduced fluid loads. In short, reduced distal tubular delivery of sodium and water (as observed in these study patients during upright posture and after dopamine receptor blockade) causes down-regulation of Na-K-2Cl cotransporters in the thick ascending limb of the Henle's loop, with the consequence that the more this tubular segment retains sodium in basal conditions, the more its reabsorptive function is down-regulated when the proximal tubule sodium retention is avid [39]. In effect, it has been recently proposed that the Henle's loop may primarily retain abnormally high amount of sodium in rat models of preascitic cirrhosis, as hypertrophy of this tubular segment and increased sensitivity to the effects of furosemide have been shown [40, 41]. Moreover, epithelial amiloride-sensitive Na+ absorption in collecting ducts is inhibited by extracellular nucleotides such as ATP through stimulation of purinergic P2-receptors [42]. If distal delivery of fluid is reduced tissue ATP concentration will increase due to reduced reabsorptive trafficking at the level of Henle's loop and macula densa [43]. In turn, this extracellular surplus of ATP may determine purinergic inhibition of ENaC in the inner medullary collecting ducts. Finally, the distal ‘permissive’ adaptation to reduced delivery of tubular fluid in upright cirrhotic patients could reflect a yet unsubstantiated but proposed posture-dependent decrease in kidney perfusion [44], which in turn could lessen Henle's loop reabsorptive function. In effect, the thick ascending limb of Henle's loop is the nephron segment most sensitive to ischaemic functional injury [45]. According to the hitherto published literature evaluating renal tubular function in both supine and erect postures in compensated cirrhosis [17, 18], we observed that the core of tubular sodium retention in standing patients (as well as during dopamine receptor blockade) is strictly located in the proximal renal tubule and not in the aldosterone-dependent distal nephron. The paradoxically reduced sodium reabsorption in the distal nephron during the exertion of these stimuli uncovers a remarkable mechanism of compensation at least operating at this stage of disease and likely occurring at an aldosterone-independent distal tubular site, namely the loop of Henle. No conflict of interest was declared. This work was supported by grants from the Ministry of University and Scientific Research (60%), 2000, and from the Italian Society of Gastroenterology (SIGE), 2000." @default.
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• W1513779513 title "Evidence of a dynamic aldosterone-independent distal tubular control of renal sodium excretion in compensated liver cirrhosis*" @default.
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