Renal distal tubular handling of sodium in central fluid volume homoeostasis in preascitic cirrhosis.

BACKGROUND/AIMS: Patients with preascitic liver cirrhosis have an increased central plasma volume, and, for any given plasma aldosterone concentration, they excrete less sodium than healthy controls. A detailed study of the distribution of sodium reabsorption along the segments of the renal tubule, especially the distal one, is still lacking in preascitic cirrhosis. METHODS: Twelve patients with Child-Pugh class A cirrhosis and nine control subjects (both groups on a normosodic diet) were submitted to the following investigations: (a) plasma levels of active renin and aldosterone; (b) four hour renal clearance of lithium (an index of fluid delivery to the loop of Henle), creatinine, sodium, and potassium; (c) dopaminergic activity, as measured by incremental aldosterone response to intravenous metoclopramide. RESULTS: Metoclopramide induced higher incremental aldosterone responses, indicating increased dopaminergic activity in patients than controls, which is evidence of an increased central plasma volume (+30 min: 160.2 (68.8) v 83.6 (35.2) pg/ml, p<0.01; +60 min: 140.5 (80.3) v 36. 8 (36.1) pg/ml, p<0.01). Patients had increased distal fractional sodium reabsorption compared with controls (26.9 (6.7)% v 12.5 (3. 4)% of the filtered sodium load, p<0.05). In the patient group there was an inverse correlation between: (a) absolute distal sodium reabsorption and active renin (r -0.59, p<0.05); (b) fractional distal sodium reabsorption and sodium excretion (r -0.66, p<0.03). CONCLUSIONS: These data suggest that in preascitic cirrhosis the distal fractional tubular reabsorption of sodium is increased and critical in regulating both central fluid volume and sodium excretion.     

Evidence of a dynamic aldosterone-independent distal tubular control of renal sodium excretion in compensated liver cirrhosis

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).     

Renal tubular events following passage from the supine to the standing position in patients with compensated liver cirrhosis: loss of tubuloglomerular feedback

BACKGROUND AND AIMS: Patients with preascitic liver cirrhosis display significant renal sodium retention in the upright posture and an exaggerated natriuresis during recumbency. To date, intrarenal sodium handling in these patients has not been studied using lithium clearance and fractional excretion techniques during recumbency and orthostatism. METHODS: Ten patients with preascitic (Child-Pugh A) liver cirrhosis and 10 healthy subjects underwent the following measurements during recumbency and then after four hours of standing: (a) active renin and aldosterone plasma levels; and (b) renal clearance of creatinine, sodium, potassium, and lithium (an index of fluid delivery to the loop of Henle). RESULTS: Unlike the control group, in the upright posture patients had significantly lower values of lithium clearance and fractional excretion compared with recumbency (21.6 (8.6) v 30.5 (10.2) ml/min (p<0.03) and 12.8 (4.4)% v 20.8 (4.9)% (p<0.01), respectively). Our patients showed maintenance of the glomerular-tubular balance-that is, the correlation between creatinine clearance and proximal tubular reabsorption of fluid-during both recumbency and in the upright posture (r=0.96, p<0.001; r=0.97, p<0.001, respectively). In contrast, patients displayed tubuloglomerular feedback only in the supine position. This was demonstrated by the observation of a negative correlation between lithium fractional excretion (a measure of the fractional delivery of sodium to the distal nephron) and filtered sodium load only in recumbency (r=-0.73; p< 0.03) and not during standing (r=0.22; p> 0.05). CONCLUSIONS: This study suggests that both the reduction in fluid and sodium delivery to the distal nephron and loss of tubuloglomerular feedback (the mechanism increasing glomerular filtration rate when the distal tubule is reached by a reduced sodium load) contribute towards the tendency to sodium retention in compensated cirrhosis during prolonged upright posture.     

The mechanism of improved sodium homeostasis of low-dose losartan in preascitic cirrhosis

Renal sodium retention on standing is one aspect of the abnormal renal sodium handling in preascitic, well-compensated patients with cirrhosis. Recently, it has been shown that low doses (7.5 mg) of the angiotensin II (Ang II) receptor antagonist, losartan, can reverse renal sodium retention on high, 200-mmol sodium/d diet in these patients and restore them to sodium balance. Therefore, the effect of 7.5 mg of losartan on sodium excretion, when changing from supine to erect posture for 2 hours, was examined in 10 well-compensated patients with cirrhosis and 9 age- and sex-matched controls on the same sodium diet, under strictly controlled metabolic conditions. In contrast to control subjects, in whom sodium excretion was unaffected, single 7.5-mg doses of losartan again restored the preascitic patients with cirrhosis to sodium balance. In addition, it blunted the fall in erect posture- induced renal sodium excretion by a reduction in proximal and distal tubular reabsorption of sodium. These changes occurred without any significant changes in blood volumes, systemic and renal hemodynamics, or glomerular filtration rate (GFR) and filtered sodium load compared with controls, and despite activation of the systemic renin-angiotensin-aldosterone system, which was still within normal levels. In conclusion, the beneficial natriuretic effects of low-dose losartan on erect posture - induced sodium retention in preascitic cirrhosis supports the suggestion that the pathophysiology of sodium retention in preascites is in part caused by an intrarenal tubular effect of Ang II in that posture.     

Influence of posture on haemodynamics, sodium and hormonal homeostasis in cirrhotic patients with and without ascites

BACKGROUND/AIMS: Previous studies in preascitic cirrhosis demonstrated sodium retention during upright posture and sodium hyperexcretion during bed-rest. In patients with ascites, sodium excretion and creatinine clearance decreased during upright posture. Head-down tilting (HDT) accentuated the natriuretic effect of bed-rest in short term studies. The aim of this study was to evaluate the effects of prolonged change in posture on sodium homeostasis and on haemodynamics in cirrhotic patients. METHODS: Eighteen cirrhotic patients (9 with, 9 without ascites), were studied during 12 h upright, supine and HDT position (-10 degrees). During each position, 12 h urine collections were performed and blood samples were obtained before and after change in position. Non-invasive systemic hemodynamic measurements were performed. RESULTS: There was no significant difference between HDT and supine position in both ascitic and preascitic groups for urinary volume, fractional sodium excretion, creatinine clearance, urinary and plasma hormones and hemodynamics. Urinary volume (in supine and HDT) and fractional sodium excretion (in supine) were significantly higher and urinary noradrenaline and plasma renin (in supine and HDT) significantly lower in the preascitic group compared with the ascitic patients. Cardiac output and heart rate decreased after 12 h supine and HDT, suggesting a deactivation of sympatic nervous system and catecholamines. CONCLUSION: Our results demonstrate that prolonged HDT had no advantage over normal bed-rest in both patient groups. Possibly, a short-term beneficial effect of HDT was lost after several hours.     

Abnormal sympathetic and renal response to sodium restriction in compensated cirrhosis

It has been proposed that in liver cirrhosis portal hypertension causes splanchnic vasodilation and this induces blood volume expansion to maintain blood pressure. The current study was designed to explore the homeostatic response to sodium restriction, a maneuver aiming to contract blood volume, in compensated cirrhosis. Mean blood pressure, sympathetic nervous activity, and proximal sodium reabsorption were evaluated in 16 healthy control and 21 nonazotemic cirrhotic patients (11 without ascites and 10 with ascites) under two experimental conditions: after 4 days on a free sodium diet (basal condition) and after 4 days on a restricted sodium diet (40 mmol/day). No differences were observed in basal conditions in the above parameters between control and cirrhotic patients without ascites. However, cirrhotic patients with ascites showed lower basal values of mean blood pressure and higher basal levels of both plasma norepinephrine and fractional proximal sodium reabsorption than controls. Neither control nor cirrhotic patients with ascites showed significant changes in the measured parameters after sodium restriction. In contrast, in nonascitic patients, this maneuver induced an elevation in plasma norepinephrine concentration (164.4 +/- 24.6 vs. 270.1 +/- 24.9 pg/mL; mean +/- SEM; P less than 0.005) and in fractional proximal sodium reabsorption (86.4 +/- 2.1 vs. 91.8% +/- 0.5%; P less than 0.01). In addition, the nonascitic cirrhotic patients became hypotensive compared with controls (80.9 +/- 1.6 vs. 88.5 +/- 4.8 mm Hg; P less than 0.05) when subjected to the low-sodium diet. In patients without ascites, under conditions of sodium restriction, the decrease in mean arterial pressure correlated inversely with the increase in plasma norepinephrine concentration (r = -0.713; P less than 0.05), whereas the levels of plasma norepinephrine correlated directly with fractional proximal sodium reabsorption (r = 0.893; P less than 0.01). These findings suggest that ineffective circulatory volume is detected in nonascitic cirrhotic patients only under conditions of sodium restriction, but it is always present in cirrhotic patients with ascites, irrespectively of the amount of sodium in the diet. These results are compatible with the existence of fixed arterial vasodilation in cirrhosis.     

Haemodynamic, renal sodium handling, and neurohormonal effects of acute administration of low dose losartan, an angiotensin II receptor antagonist, in preascitic cirrhosis

BACKGROUND: The renin-angiotensin system may be implicated in the subtle sodium handling abnormality in preascitic cirrhosis. AIMS: To assess the role of angiotensin II in sodium homoeostasis in preascitic cirrhosis, using losartan, its receptor antagonist. PATIENTS: Nine male, preascitic cirrhotic patients, and six age matched, healthy male controls. METHODS: A dose response study using 2.5, 5, 7.5, and 10 mg of losartan was performed on a daily 200 mmol sodium intake, followed by repeat studies with the optimal dose, 7.5 mg of losartan, to determine its effects on systemic and renal haemodynamics, renal sodium handling, and neurohumoral factors. RESULTS: Preascitic cirrhotic patients had significantly reduced baseline urinary sodium excretion compared with controls (154 (8) versus 191 (12) mmol/day, p<0.05), associated with significantly reduced systemic angiotensin II levels (6.0 (1.7) versus 39.5 (10.0) pmol/l, p=0.002). Losartan 7.5 mg normalised renal sodium handling in the preascitic cirrhotic patients (202 (12) mmol/day, p=0.05 versus baseline), without any change in systemic or renal haemodynamics, but with significantly increased systemic angiotensin II levels (7.8 (2.3) pmol/l, p=0.05 versus baseline). Losartan had no effect on renal sodium handling in controls. CONCLUSIONS: In preascitic cirrhotic patients, the subtle renal sodium retention, paradoxically associated with low systemic neurohumoral factor levels, is improved with low dose losartan, suggesting the involvement of angiotensin II via its direct action on the renal tubule.     

Pattern of sodium handling and its consequences in patients with preascitic cirrhosis

The initial abnormalities in the renal sodium handling in patients with cirrhosis before developing ascites remain unknown. The aim of this study is to further characterize sodium metabolism and the effects of sodium loading in preascitic cirrhosis. Eight male, preascitic patients with cirrhosis and 6 volunteers had their daily urinary sodium excretion level measured while on a strictly metabolically controlled diet, first consisting of 20 mmol then of 200 mmol sodium per day each for 7 days. Central blood volume, plasma norepinephrine, and atrial natriuretic factor levels were measured during each diet. Preascitic patients with cirrhosis had significantly less daily urinary sodium excretion on both diets. Volume expansion in the patients with cirrhosis was indicated by significantly greater weight gain and higher atrial natriuretic factor levels for each diet. Patients with cirrhosis had central blood volume expansion (1725 ± 54 mL/m²) compared with controls (1495 ± 81 mL/m²; P = 0.03) on a low-sodium diet. This increased significantly in the controls (1864 ± 164 mL/m²; P = 0.04) on a high-sodium diet, associated with suppression of plasma norepinephrine, but not in the patients with cirrhosis (1679 ± 107 mL/m²; P > 0.05). Failure of further central blood volume expansion in the patients with cirrhosis on high-sodium diet in the presence of significant weight gain suggests maldistribution away from the effective arterial blood volume. This study provides further reasons why preascitic patients with cirrhosis might benefit from sodium restriction.     

High plasma cardiac natriuretic peptides associated with enhanced cyclic guanosine monophosphate production in preascitic cirrhosis

BACKGROUND/AIMS: The initial abnormalities of renal sodium handling in cirrhosis remain unclear. The aim of this study was to characterize sodium metabolism in preascitic cirrhosis. METHODS: Ten patients with preascitic cirrhosis and ten controls were studied. All subjects ate a diet providing 120 mmol sodium during an equilibration period lasting 5 days and the study day. On the study day, after remaining in bed, plasma levels of atrial natriuretic peptide, brain natriuretic peptide, renin activity, aldosterone, noradrenaline, and cyclic guanosine monophosphate were measured at 7 am. Thereafter, they were instructed to maintain an upright posture until dinner and the measurements were repeated at 9 am and 6 pm. After having dinner, all subjects were asked to remain in bed and the measurements were repeated at 11 pm. To measure renal sodium and cyclic guanosine monophosphate excretion, 24-h urine collections were performed, starting from 7 pm on the day before the experimental day. RESULTS: Plasma levels of atrial natriuretic peptide, brain natriuretic peptide and cyclic guanosine monophosphate in patients with preascitic cirrhosis were significantly elevated compared with those in controls at every sampling time (p=0.03 or less, p= 0.04 or less, and p=0.01 or less). In contrast, plasma renin activities at every sampling time were significantly lower in patients than in controls (p= 0.04 or less). Plasma aldosterone and noradrenaline levels were not significantly different at every sampling time in the two groups. No significant differences in daily renal sodium excretion were found. However, urinary cyclic guanosine monophosphate excretion was significantly higher in patients than in controls (p<0.01). CONCLUSIONS: The initial abnormalities of sodium metabolism in cirrhosis might be characterized by blunted renal responsiveness to natriuretic peptides. The results of the study also provide indirect evidence that the impairment is mainly located at postreceptor levels of signal transduction pathway to the peptides, if the activation of antinatriuretic factors other than renin-angiotensin or sympathoadrenergic systems does not play a role.     

Renal tubular reabsorption of calcium in familial hypocalciuric hypercalcaemia

To investigate the nephron site of the enhanced tubular calcium reabsorption in familial hypocalciuric hypercalcaemia (FHH), the renal plasma clearance of lithium and calcium and the glomerular filtration rate were determined simultaneously after an overnight fast in nine FHH patients and ten healthy controls. As the renal plasma clearance of lithium equals the rate of the proximal tubular fluid delivered into the thin descending loop of Henle's loop, the reabsorption of calcium in the proximal and distal tubule, respectively, could be calculated. We found that the FHH patients had a significantly higher fractional calcium reabsorption in the proximal tubule (77.6 +/- 4.7 (%) vs 73.3 +/- 3.1, P less than 0.05). The same held true for the absolute proximal calcium reabsorption (1.49 +/- 0.12 (mmol/l) vs 1.07 +/- 0.05, P less than 0.001). There was a significant linear correlation between the increased tubular capacity for calcium reabsorption and the absolute proximal calcium reabsorption (r = 0.70, P less than 0.05). The distal tubular calcium reabsorption did not differ in the two groups. Our results therefore suggest that the enhanced tubular calcium reabsorption in FHH takes place exclusively in the proximal renal tubule.     

Enhanced vasodilatation to endothelin antagonism in patients with compensated cirrhosis and the role of nitric oxide

BACKGROUND AND AIMS: Patients with advanced cirrhosis have systemic vasodilatation and increased nitric oxide (NO) production despite activated vasopressor systems, including the endothelin system. The aims of this study were to assess the contribution of endogenous endothelin 1 (ET-1) and NO to the maintenance of basal forearm vascular tone in patients with preascitic cirrhosis (n=7) and in age and sex matched healthy controls (n=7). METHODS: Using venous occlusion plethysmography, forearm blood flow (FBF) responses to subsystemic locally active intra-arterial infusion of BQ-123 (a selective endothelin type A receptor (ET(A)) receptor antagonist; 10 nmol/min) were measured before and during application of an "NO clamp": a balanced co-infusion of L-N(G)-monomethyl-arginine (a selective NO synthase inhibitor) and sodium nitroprusside (an exogenous NO donor) to block endogenous NO production and restore NO mediated basal FBF, respectively. RESULTS: L-NMMA infusion produced a reduction in FBF (p<0.001) which was similar in both groups. Before applying the "NO clamp", BQ-123 caused an increase in FBF in both groups (p<0.001) that was greater in patients with cirrhosis (p<0.01). During the "NO clamp", BQ-123 induced vasodilatation was abolished in controls and attenuated in patients (p<0.001) but remained significantly greater in patients with cirrhosis (p<0.01). CONCLUSIONS: These findings indicate a greater ET(A) mediated contribution of endogenous ET-1 to the maintenance of basal forearm vascular tone in patients with preascitic cirrhosis. In addition, enhanced vasodilatation to ET(A) receptor antagonism in cirrhosis cannot be entirely attributed to NO release but is likely to be related to reversal of direct ET-1 mediated tone.     

Role of angiotensin II in regulation of basal and sympathetically stimulated vascular tone in early and advanced cirrhosis

BACKGROUND & AIMS: The renin-angiotensin and sympathetic nervous systems are activated in cirrhosis. This study aimed to establish the role of angiotensin II (ANG II) in the regulation of basal and sympathetically stimulated vascular tone in preascitic cirrhotic patients and patients with diuretic-refractory ascites compared with age- and sex-matched healthy controls. METHODS: Forearm blood flow (FBF) responses to lower body negative pressure (LBNP) and to subsystemic, intrabrachial infusions of losartan, an angiotensin II type 1 (AT(1)) receptor antagonist, norepinephrine, and ANG II were measured using venous occlusion plethysmography. RESULTS: In all groups, ANG II and norepinephrine caused dose-dependent reductions in FBF (P < 0.001); responses to norepinephrine were similar across the 3 groups but those to ANG II were less in both cirrhotic groups than in controls (P < 0.01). Losartan caused a dose-dependent increase in FBF only in patients with refractory ascites (P < 0.01). LBNP caused less reduction in FBF in refractory ascites patients than in both preascitic patients and controls (P < 0.01). CONCLUSIONS: Despite hyporesponsiveness to exogenous ANG II in both early and advanced cirrhosis, endogenous ANG II contributes to the maintenance of basal vascular tone only in advanced cirrhosis. These findings suggest a role of ANG II in the pathogenesis of ascites. Attenuated LBNP responses occurred only in advanced cirrhosis, without apparent interaction with endogenous ANG II.     

Loss of Tubuloglomerular Feedback in Decompensated Liver Cirrhosis: Physiopathological Implications

In healthy subjects, arterial pressure reduction or renal ischemia produces renal artery dilatation through autoregulation and tubuloglomerular feedback (TuGF). Patients with decompensated cirrhosis have reduced kidney perfusion pressure but show renal vasoconstriction instead of autoregulation-mediated vasodilation. This study investigates the consequences of kidney autoregulation loss on renal perfusion, glomerular filtration rate, and tubular handling of electrolytes in both compensated and ascitic nonazotemic cirrhotic patients. Forty-two consecutive patients with diuretic-free liver cirrhosis (32 with preascitic and 10 with ascitic disease) and 10 controls were submitted to the following determinations: (a) basal plasma renin activity and aldosterone levels; (b) endogenous dopaminergic activity measured as incremental aldosterone responses during metoclopramide administration; and (c) renal clearances of sodium, potassium, inulin, para-aminohippurate and lithium. Compared with the other groups, ascitic patients showed lower renal plasma flow (P < 0.01) and lithium clearance (P < 0.05), a higher filtration fraction (P < 0.01), and secondary aldosteronism. Controls and preascitic patients displayed tubuloglomerular feedback (the mechanism increasing the glomerular filtration rate when a reduced sodium load reaches the distal tubule), as demonstrated by negative correlations between fractional excretion of lithium (an expression of fractional delivery of sodium to the distal nephron) and glomerular filtration rate (respectively, r = –0.73, P < 0.03, and r = –0.48, P < 0.01). Conversely, patients with ascites showed a positive correlation between lithium fractional excretion and glomerular filtration rate (r = 0.64, P < 0.05). Reduction in renal perfusion, increased filtration fraction, and TuGF derangement, as found in decompensated patients, are indicative of prevalent postglomerular arteriolar vasoconstriction, with ensuing stimulation of proximal tubular sodium reabsorption.     

Cardiovascular effects of canrenone in patients with preascitic cirrhosis

In patients with cirrhosis and portal hypertension, standing induces a reduction in cardiac index (CI) and an increase in systemic vascular resistance index. Our previous studies indicate that this abnormal hemodynamic response to standing is due to an altered myocardial function, because cirrhotic patients are unable to compensate for the reduced preload with an increase in left ventricular (LV) ejection fraction (EF) and stroke volume. To evaluate whether the cardiac dysfunction in cirrhosis is influenced by canrenone, an aldosterone antagonist, 8 patients with preascitic, nonalcoholic cirrhosis, and portal hypertension underwent echocardiographic assessment of LV function and systemic hemodynamics and determinations of plasma volume, urinary sodium excretion, and plasma renin activity (PRA), aldosterone (PAC), and norepinephrine (PNE) when on a 150-mmol/d-sodium diet (baseline), after 1 month on canrenone (100 mg/d) plus a 40-mmol/d-sodium diet and after 1 month on canrenone plus a 150-mmol/d-sodium diet. Echocardiographic evaluation was performed with the patient in the supine position and during active standing. At baseline, patients had high plasma volume and normal renal function, PRA, PAC, and PNE. CI, LVEF, and stroke volume index were also normal. Standing caused a significant reduction in CI and LVEF. After canrenone and either sodium diet, CI significantly decreased, and PRA and PNE increased in the supine position. On standing, LVEF and CI did not decrease further. Plasma volume significantly decreased only after low-sodium diet plus canrenone. In conclusion, canrenone normalizes the cardiac response to the postural challenge in patients with preascitic cirrhosis.     

Renal tubular reabsorption of calcium and sodium in primary hyperparathyroidism

Nine patients with primary hyperparathyroidism were studied to investigate the renal tubular reabsorption of calcium and sodium. Fasting serum and urine samples were analysed, and the glomerular filtration rate and the renal plasma clearance of lithium were determined simultaneously. Comparison was made with 9 age- and sex-matched normocalcemic controls. In the proximal tubule, there was a significantly higher absolute reabsorption of calcium in patients than in controls, whereas the fractional reabsorption rate of calcium did not differ between the two groups. In the distal tubule, the absolute calcium reabsorption rate was significantly higher in the patients, whereas the fractional reabsorption rate of calcium was significantly lower than in controls. In the patient group there was a significantly positive linear correlation between the increased tubular capacity for calcium reabsorption and the absolute proximal calcium reabsorption rate, but not between the increased capacity and the absolute distal calcium reabsorption rate. No significant differences were found in the renal tubular handling of sodium between patients and controls. Our results suggest that the increased capacity for tubular calcium reabsorption in primary hyperparathyroidism mainly is localized in the proximal tubule, and that the renal tubular handling of calcium and sodium in this disease differs from that in familial hypocalciuric hypercalcemia.     

Sodium homeostasis with chronic sodium loading in preascitic cirrhosis

BACKGROUND: Preascitic cirrhotic patients receiving 200 mmol of sodium daily for seven days remain in positive sodium balance. Thereafter, sodium handling is unknown. AIM: To assess renal sodium handling in preascitic cirrhosis on a high sodium diet for five weeks. METHODS: Sixteen biopsy proven preascitic cirrhotics were assessed at weekly intervals for five weeks on a diet of 200 mmol sodium/day using a daily weight diary and weekly 24 hour urinary sodium estimations. Fasting supine neurohormone levels were measured at baseline and weekly for five weeks while haemodynamics were measured at baseline and at five weeks. RESULTS: The daily diet of 200 mmol of sodium resulted in weight gain and a positive sodium balance for three weeks, associated with significant suppression of plasma renin activity and aldosterone levels, and a significant rise in plasma atrial natriuretic peptide levels (p<0.05). Patients' weights plateaued during week 4, associated with complete sodium balance and significant suppression of plasma noradrenaline levels (p<0.05). This was followed by a negative sodium balance and weight loss, and finally complete sodium balance, again despite a mean net gain of 2.3 (0.3) kg, associated with a return of plasma renin activity and aldosterone levels to within normal ranges. The lack of increase in central blood volume in addition to the persistent increase in plasma atrial natriuretic peptide levels indicated that residual volume expansion, consequent to persistent weight gain, was distributed on the venous side of the circulation. No free fluid was seen on repeat abdominal ultrasound after five weeks. CONCLUSION: Preascitic cirrhotics have a natriuretic "escape" after three weeks on high sodium dietary intake, associated with elevated plasma atrial natriuretic peptide levels and suppression of the renin-angiotensin-aldosterone system. With continued suppressed sympathetic activity, preascitics re-establish complete sodium balance but with a net weight gain and presumed increased intravascular volume, but without ascites. This further elucidates the compensated sodium retaining abnormality that characterises preascitic cirrhosis.     

The effect of posture on central blood volume in patients with preascitic cirrhosis on a sodium-restricted diet

The status of the central blood volume in cirrhosis is controversial. A combination of sodium restriction and upright posture, which redistributes intravascular volume to dependent parts of the body should further aggravate a contracted central blood volume reduction. The aim of this study was to determine the effect of upright posture and sodium restriction on central blood volume (CBV) in preascitic cirrhotic patients, compared with controls. Eight male, preascitic, alcoholic cirrhotic subjects and eight healthy male controls were studied while on a 20-mmol/d sodium diet. Measurements of CBV by radionuclide angiography, and neurohumoral factors were performed on day 7 in both supine and erect positions and cardiac output and systemic vascular resistance (SVR) was calculated. Sodium restriction resulted in less weight loss in the cirrhotic patients (P = .03), with significantly lower plasma renin activity (P = .001). Similar central blood volumes and systemic hemodynamics were observed in both groups in the supine posture. In contrast to the cirrhotic patients, in the control subjects, upright posture resulted in a significant reduction in cardiac output (P = .002) and increase in SVR (P = .005), associated with a decrease in all blood volumes which were significantly less than in the cirrhotic patients. Mean arterial pressure was maintained in both groups in both postures. In conclusion, with sodium restriction, preascitic cirrhotic patients have less intravascular volume contraction than control patients. Erect posture results in redistribution of this relatively expanded intravascular volume to the CBV. Therefore, a low-sodium diet can be safely administered in preascitic cirrhotic patients. (Hepatology 1996 May;23(5):1141-7)     

Sodium handling in patients with well compensated cirrhosis is dependent on the severity of liver disease and portal pressure

BACKGROUND AND AIMS: To test the contribution of portal pressure gradient (PPG) and neurohumoral factors to sodium handling in cirrhotic patients without ascites, by comparing preascitic cirrhotic patients with patients with transjugular intrahepatic portosystemic stent shunt (TIPSS) and previous ascites. PATIENTS: Ten patients with TIPSS and 10 preascitic cirrhotic patients. METHODS: Changes in glomerular filtration, renal plasma flow, urinary sodium excretion (U(Na)V), and neurohumoral factors were measured before and for two hours after infusion of one litre of 0. 9% saline over one hour. RESULTS: Glomerular filtration rate and renal plasma flow were significantly higher in patients with TIPSS compared with preascitic cirrhotic patients. Following saline infusion both parameters increased significantly; this increase was significantly greater in patients with TIPSS. U(Na)V increased significantly in both groups following saline infusion. The increase in U(Na)V was significantly greater in the TIPSS group. Plasma renin activity and angiotensin II decreased significantly in both groups. Basal U(Na)V was independently correlated with angiotensin II concentration and PPG and the change in U(Na)V correlated with the PPG. CONCLUSIONS: Results suggest that patients with advanced liver disease and low portal pressure handle sodium as well as patients with compensated liver disease and high portal pressure. These results are consistent with the notion that in addition to peripheral vasodilatation and severity of liver disease, the severity of portal hypertension contributes to the abnormalities of sodium retention in cirrhosis.     

Glomerular and tubular antinatriuretic actions of low-dose angiotensin II infusion in man.

OBJECTIVE: The aim was to study the physiological effects of angiotensin II upon the glomerular and tubular handling of sodium. DESIGN: Healthy volunteers were examined before and during infusion with either low-dose angiotensin II (n = 11) or placebo (n = 13). METHODS: Lithium clearance was used to estimate the segmental tubular reabsorption of sodium. RESULTS: During infusion with angiotensin II a sustained and marked fall in renal plasma flow was observed. The glomerular filtration rate (GFR) decreased to a minor extent so that the filtration fraction increased during angiotensin II infusion. Angiotensin II caused an extensive and instantaneous fall in both urinary flow and urinary sodium excretion. Proximal absolute reabsorption of sodium was unchanged despite the fall in GFR, showing that proximal fractional reabsorption was enhanced by angiotensin II. Distal absolute reabsorption was decreased during the entire period of angiotensin II infusion. However, when the distal reabsorption was related to the delivery of sodium from the proximal tubules, distal fractional reabsorption in fact increased after 30 min angiotensin II infusion. None of the measured parameters changed during infusion with placebo. A significant increase in plasma aldosterone was observed 30 min after the start of the angiotensin II infusion. Plasma atrial natriuretic peptide did not change during infusion with either angiotensin II or placebo. CONCLUSIONS: We conclude that physiological increments in angiotensin II affect glomerular haemodynamics and cause a marked antinatriuresis in man. The antinatriuretic effect of angiotensin II is caused initially by a combination of a decrease in the GFR and an increase in proximal fractional sodium reabsorption, and later by the enhanced distal fractional reabsorption of sodium.     

A lithium clearance study of sodium reabsorption at the proximal tubule in liver cirrhosis with ascites

Since the reabsorption of lithium occurs almost exclusively in the proximal tubule and is associated with that of sodium, the fractional excretion of lithium (FELit) ws examined in 18 patients with cirrhosis in order to examine the reabsorption rate of sodium at the proximal tubule. As expected, the fractional excretion of sodium (FENa) was significantly lower in cirrhotic patients with ascites (0.43 +/- 0.10%, mean +/- SEM) than in cirrhotic patients without ascites (0.75 +/- 0.14%, P less than 0.05) and healthy controls (0.82 +/- 0.17%, P less than 0.05). By contrast, there was no significant difference in FELit among cirrhotic patients with ascites (16.7 +/- 2.0%), cirrhotic patients without ascites (15.4 +/- 2.0%) and controls (17.4 +/- 1.5%). It is unlikely, therefore, that in cirrhotic patients with ascites, the impaired sodium excretion is solely caused by the abnormal sodium reabsorption capacity of the proximal tubule.