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.     

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.     

Abnormal renal responses to calcium entry blockade in normotensive offspring of hypertensive parents

In nine young normotensive subjects with no family history of hypertension and nine age-matched normotensive subjects with one parent with essential hypertension, effective renal plasma flow (p-aminohippuric acid clearance), glomerular filtration rate (inulin clearance), and excretion of sodium and exogenously administered lithium were measured for 90 minutes before and after administration of a single 20-mg oral dose of the calcium entry blocker nifedipine. Segmental tubular handling of fluid and sodium was estimated using lithium clearance as a marker of proximal tubular reabsorption. Nifedipine did not cause any change in subjects with no family history of hypertension, but in those with one hypertensive parent there was a marked increase in effective renal plasma flow (from 644 +/- 39 to 847 +/- 42 [SEM] ml/min x 1.73 m2; p less than 0.001) and a decrease in filtration fraction (from 17.6 +/- 1.0 to 12.6 +/- 0.4%; p less than 0.001), while the glomerular filtration rate was unchanged, thus suggesting a prevailing efferent vasodilation. Sodium excretion rate (p less than 0.02) and fractional sodium excretion (p less than 0.025) increased slightly but significantly in subjects with one hypertensive parent, but not in normotensive subjects with no family history of hypertension. Lithium clearance also rose (from 29.0 +/- 2.0 to 32.8 +/- 1.9 ml/min, p less than 0.001), and the derived value of fractional proximal reabsorption diminished (from 75.8 +/- 1.0 to 71.3 +/- 1.2%, p less than 0.001). Estimated distal delivery of sodium and absolute distal sodium reabsorption both increased significantly (p less than 0.005), while fractional distal sodium reabsorption was unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)     

A comparison of the action of atriopeptin III on renal function in normal and DOCA-salt hypertensive rats

Administration of atriopeptin III (125, 250 and 500 ng/kg, intravenously) into pentobarbitone anaesthetized normotensive and DOCA-salt hypertensive rats had no effect on blood pressure or renal haemodynamics. Urine flow and absolute and fractional sodium excretion were increased by 48-90% from the lowest to the highest dose of atriopeptin III in the normotensive group, but were increased by over twice these amounts in the DOCA-salt hypertensive rats. Fractional lithium excretion and calculated proximal tubular fluid reabsorption were unaffected by the peptide in the normotensive rats, but in the hypertensive group atriopeptide III increased fractional lithium excretion by 25-50% and decreased proximal tubular reabsorption to a similar extent. Beyond the proximal tubule there were similar increases in fractional and absolute fluid handling in both groups of rats. These results demonstrated that in DOCA-salt hypertension there was increased sensitivity to the natriuretic activity of atriopeptin III which appeared to result from an increased responsiveness of the proximal tubule.     

Lithium infusion to study sodium handling in unanesthetized hypertensive rats

To investigate renal tubular handling of sodium in various types of experimental hypertension, sodium, lithium, and inulin clearances were measured simultaneously in unanesthetized rats. Fractional excretion of lithium was used as an index of proximal sodium reabsorption. Eight groups of animals, all of the Wistar-Kyoto strain, were studied. Three were hypertensive: spontaneously hypertensive rats (SHR), rats with two-kidney, one clip renal hypertension, and uninephrectomized rats with deoxycorticosterone-salt hypertension. The five normotensive control groups included animals given normal, low, or high dietary sodium loads and rats with reduced renal mass. Fractional excretion of lithium was not influenced by moderate changes of glomerular filtration rate, but was sharply enhanced by sodium loading. Increased blood pressure was associated with enhanced urinary sodium excretion in uninephrectomized deoxycorticosterone-salt hypertensive and two-kidney, one clip hypertensive rats, as a result of decreased distal tubular reabsorption ("pressure natriuresis"). In contrast, SHR showed reduced sodium excretion and decreased fractional excretion of lithium, which suggests that increased sodium reabsorption in the proximal tubule may contribute significantly to the maintenance of hypertension.     

Effects of insulin and lipid emulsion on renal haemodynamics and renal sodium handling in IDDM patients

Summary To evaluate the role of insulin and hypertriglyceridaemia in the regulation of renal haemodynamics and sodium handling in insulin-dependent diabetes mellitus (IDDM), 11 IDDM patients without microalbuminuria and 13 weight-, age-, protein intake- and sex-matched healthy control subjects were studied. Clearances of inulin (C_in), para-amino-hippuric acid (C_PAH), sodium (C_Na), and lithium (C_Li) were measured in four 60-min clearance periods (periods I, II, III and IV) during isoinsulinaemia with lipid emulsion infusion (study 1), a hyperinsulinaemic isoglycaemic clamp with Intralipid infusion (study 2), and during time-controlled isoinsulinaemia (study 3). We found that C_in, C_PAH and filtration fraction were comparable in IDDM and control subjects, whereas C_Na was decreased in diabetic subjects (2.01±1.11 vs 3.03±1.32 ml/min; p<0.05) due to elevations of proximal tubular fractional and absolute reabsorptions of sodium (p<0.05). Insulin infusion did not affect C_in, increased C_PAH (p<0.05) and, consequently, lowered the filtration fraction (p<0.01) in both groups. While acute hyperinsulinaemia resulted in increases in distal tubular fractional and absolute reabsorptions of sodium (p<0.01) contributing to a fall in C_Na (p<0.01) in control subjects, in diabetic subjects the sodium-retaining effect of insulin was not significant. The lipid emulsion did not alter any of the estimated parameters. We conclude that IDDM without microalbuminuria is associated with a tendency to sodium retention which is not aggravated by insulin when compared to control subjects. Acutely induced hypertriglyceridaemia does not alter renal haemodynamics or renal sodium handling.Abbreviations IDDM Insulin-dependent diabetes mellitus - GFR glomerular filtration rate - RPF renal plasma flow - C_in clearance of inulin - C_PAH clearance of para-amino-hippuric acid - C_Na clearance of sodium - C_Li clearance of lithium - APR_Na absolute proximal tubular reabsorption of sodium - FPR_Na fractional proximal tubular reabsorption of sodium - ADR_Na absolute distal tubular reabsorption of sodium - FDR_Na fractional distal tubular reabsorption of sodium - FIRI free plasma immunoreactive insulin - TG serum triglycerides - NEFA serum non-esterified fatty acids - MCR metabolic clearance rate of glucose - FF filtration fraction - ANOVA analysis of variance     

Natriuretic and aquaretic effects of intravenously infused calcium in preascitic human cirrhosis: physiopathological and clinical implications

BACKGROUND: Preascitic cirrhosis is characterised by subtle renal sodium retention. Calcium inhibits Na(+)-K(+)-2Cl(-) cotransport in the Henle's loop and could potentially correct sodium-handling abnormalities at that site. AIM: To investigate the effects of calcium infusion on sodium handling in 10 patients with preascitic cirrhosis and nine healthy controls after 1 week of sodium loading of 200 mmol sodium/day. METHODS: All patients underwent a 3 h supine determination of inulin, para-aminohippurate, lithium and free-water clearances, absolute and fractional excretions of sodium, potassium and calcium and plasma concentrations of renin, aldosterone, norepinephrine and vasopressin. The same were repeated over a further 3 h supine period including 60 min intravenous infusion of 33 mg/min calcium gluconate. RESULTS: After sodium loading, the 24 h urinary sodium excretion in patients with cirrhosis was lower than that in controls (p<0.03). Calcium infusion significantly decreased plasma norepinephrine levels (p<0.03), and induced greater increases in fractional delivery of sodium to the Henle's loop (p<0.5) in those with cirrhosis than in controls. This was associated with a decreased fractional reabsorption of sodium beyond the proximal tubule (p<0.03), resulting in greater urinary volume, sodium excretion and free-water clearance in those with cirrhosis than in controls (all with p<0.05). Because the aldosterone-driven potassium secretion, as assessed by the computation of tubular-capillary gradient of [K(+)] in the collecting duct, was similar in the two groups and unaffected by calcium, sodium retention must have occurred in the Henle's loop in those with cirrhosis. CONCLUSION: Calcium is natriuretic in patients with preascitic cirrhosis; it also decreases norepinephrine release, which could be responsible for decreased reabsorption of sodium in the Henle's loop.     

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.     

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.     

Effects of insulin on renal haemodynamics and the proximal and distal tubular sodium handling in healthy subjects

Summary The effects of insulin on renal haemodynamics and renal sodium handling were studied in 10 healthy males. Using the euglycaemic insulin clamp technique, insulin was infused on separate days resulting in two levels of hyperinsulinaemia (41 ± 3 and 90 ± 7 mU/1, respectively). Renal haemodynamics and the proximal and distal tubular sodium handling were studied using inulin, para-amino-hippuric acid, sodium and lithium clearances. Low- and high-dose insulin infusions were followed by a fall in sodium clearance from 1.6 ± 0.1 ml/min to 1.2 ± 0.1 and 1.0 ± 0.1 ml/min, respectively. Both levels of hyperinsulinaemia resulted in increased distal tubular sodium reabsorption. The distal antinatriuretic effect of insulin was associated with dose- and time-dependent decline in proximal tubular sodium reabsorption. The changes in proximal tubular sodium handling occurred without any significant changes in natriuretic factors, such as renal dopamine and plasma atrial natriuretic peptide levels. However, hyperinsulinaemia resulted in time- and dose-dependent increases in renal plasma flow, and renal vasodilatation could, possibly via changes in renal interstitial pressure, have contributed to the fall in the proximal tubular sodium reabsorption. The results also suggest that decreased proximal sodium reabsorption may be a compensatory mechanism counteracting the insulin-induced sodium retention.     

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 lithium reabsorption in man: physiologic and pharmacologic determinants.

In order to evaluate the premise that renal lithium reabsorption may reflect proximal tubular sodium reabsorption, the fractional excretion of lithium (FELi) was measured, during a variety of experimental maneuvers known to affect renal cation reabsorption, in normal volunteers who had been pre-loaded with lithium. Furosemide increased FELi, as well as sodium, calcium, and magnesium excretion, during the first hour following diuretic administration. Subsequently, sodium, calcium, and magnesium excretion continued to remain elevated after furosemide, despite progressive volume depletion, but FELi values usually declined at least to pretreatment levels. Oral glucose ingestion increased lithium, calcium, and magnesium excretion while sodium and potassium excretion decreased concomitantly. Increases in FELi during volume expansion with saline were correlated with changes in fractional flow (V/GFR) in natriuretic subjects. Parathyroid extract (PTE) increased both FELi and fractional phosphate excretion (FEphos). FELi and FEphos were correlated significantly in the studies with furosemide and PTE, but not after saline volume expansion. In persons who previously had undergone unilateral nephrectomy, FELi was not increased over values in normal subjects. These results indicate that changes in lithium reabsorption may be dissociated from the reabsorption of other cations. They are consistent with the hypothesis that FELi may reflect proximal tubular sodium rejection, but do not exclude other more distal sites of lithium reabsorption.     

Differential effect of salt loading on sodium and lithium excretion in Dahl salt-resistant and -sensitive rats

Fractional excretion of lithium, as a marker for proximal sodium reabsorption, was determined in normotensive Dahl S rats (susceptible to NaCl hypertension) and Dahl R rats (resistant to NaCl hypertension) before and following an acute sodium load. Baseline mean arterial pressures, inulin clearances, sodium excretion rates, and fractional lithium clearances were not different between the R and S rats. Following the salt loading and despite similar mean arterial pressures and degree of volume expansion, the glomerular filtration rate, urinary flow rates, and absolute sodium excretion rates were greater in R than S rats. The fractional excretion of lithium was also greater in R than S rats. These data demonstrate that, at equal mean arterial pressures, Dahl S rats have a reduced capacity for sodium excretion, and that this defect is present prior to the development of hypertension. Furthermore, the observation that these animals also have a lower fractional lithium excretion during volume expansion suggests that salt loading reduces proximal tubule reabsorption to a lesser extent in Dahl S than R rats. These data suggest that the subnormal sodium and water excretion observed after sodium loading in S rats may be partially due to an abnormality in proximal tubule sodium handling.     

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.     

Response of superficial proximal convoluted tubule to decreased and increased renal perfusion pressure. In vivo microperfusion study in rats

Although urinary sodium excretion is positively influenced by acute changes in renal perfusion pressure, micropuncture studies show highly conflicting results concerning the response of superficial proximal tubule sodium reabsorption to changes in renal perfusion pressure. In the present study, the changes of superficial proximal reabsorption to decreased and increased renal perfusion pressure were determined in rats by an in vivo microperfusion method. In vivo microperfusion was selected as the method to determine the proximal sodium reabsorption because this method made it possible to deliver a constant fluid and electrolyte load to the proximal tubule without the influence of possible changes of glomerular filtration rate. Renal perfusion pressure was decreased from normal pressure by inflating a suprarenal aortic cuff and was increased from the normal level by the occlusion of celiac and mesenteric arteries and the infrarenal aorta. Although fractional excretion of sodium (FENa) in the urine was decreased from 1.24 +/- 0.23% to 0.45 +/- 0.11% (n = 7, p less than 0.01) when renal perfusion pressure was decreased from 125 +/- 6 to 99 +/- 3 mm Hg, absolute tubular reabsorption by the superficial proximal convoluted tubules was not increased (from 4.4 +/- 0.5 to 4.2 +/- 0.3 nl/min/mm, n = 22). When the renal perfusion pressure was elevated from 126 +/- 4 to 149 +/- 4 mm Hg, tubular reabsorption by the superficial proximal tubules was decreased from 4.1 +/- 0.3 to 2.5 +/- 0.3 nl/min/mm (n = 36, p less than 0.01) with an accompanying increase in FENa (from 1.28 +/- 0.24% to 2.29 +/- 0.37%, n = 9, p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Normal renal tubular response to changes of sodium intake in hypertensive man

In a comparative study the influence of changes in dietary sodium intake on blood pressure, renal function, extracellular fluid volume, the renin-angiotensin-aldosterone system and plasma concentrations of arginine vasopressin, atrial natriuretic factor and cyclic guanosine monophosphate (GMP) was investigated in 12 patients with essential hypertension and in 10 normotensive controls. The subjects were studied after 4 days on a low (50 mmol/day), medium (180 mmol/day) or high (380 mmol/day) sodium intake. Renal sodium handling was assessed by simultaneous measurements of 51Cr-ethylenediaminetetraacetic acid (EDTA), lithium and sodium clearances. Identical values for the extracellular fluid volume, glomerular filtration rate and proximal and distal tubular resorption rates of sodium and water were found in the hypertensive patients and the controls at all three levels of sodium intake. In both groups, raising the sodium intake from low to high significantly increased 51Cr-EDTA and lithium clearance (an indirect measure of end-proximal fluid delivery), with intermediate values for the medium-sodium diet. The estimated values of fractional proximal and distal sodium resorption decreased when sodium intake was raised; the absolute proximal sodium resorption rate did not change, whereas the absolute distal sodium resorption rate as well as the extracellular fluid volume and sodium clearance increased. Blood pressure and the heart rate were unaffected by sodium intake. In both hypertensives and controls, plasma concentrations of active renin, angiotensin II and aldosterone decreased with increasing sodium intake, arginine vasopressin did not change, and atrial natriuretic factor and cyclic GMP increased.(ABSTRACT TRUNCATED AT 250 WORDS)     

Exaggerated natriuresis and lithium clearance in spontaneously hypertensive rats

Since hypertension is associated with changes in the handling of various cations (including sodium and lithium) across the cell membrane, the present study investigated the validity of the lithium clearance method in hypertension by comparing two measures of proximal reabsorption. Thus, fractional lithium excretion and transit time (TT)-occlusion time (OT; e-TT/T) were determined successively in the same spontaneously hypertensive rat (SHR, Okamoto strain). The rats were examined both before and after an acute saline load. The results show that the lithium clearance method can be used for the determination of proximal reabsorption in SHR. Utilizing the lithium clearance method, the changes in renal sodium handling underlying the exaggerated natriuresis were investigated in unanaesthetized catheterized rats. It was found that the exaggerated natriuresis was associated with an increased output from the proximal tubule, whereas no difference in distal sodium handling could be detected between SHR and normotensive Wistar-Kyoto rats (WKY).     

Renal sodium handling in acute and chronic salt loading/depletion protocols: the confounding influence of acute water loading

OBJECTIVES: Renal tubular sodium handling was measured in healthy subjects submitted to acute and chronic salt-repletion/salt-depletion protocols. The goal was to compare the changes in proximal and distal sodium handling induced by the two procedures using the lithium clearance technique. METHODS: In nine subjects, acute salt loading was obtained with a 2 h infusion of isotonic saline, and salt depletion was induced with a low-salt diet and furosemide. In the chronic protocol, 15 subjects randomly received a low-, a regular- and a high-sodium diet for 1 week. In both protocols, renal and systemic haemodynamics and urinary electrolyte excretion were measured after an acute water load. In the chronic study, sodium handling was also determined, based on 12 h day- and night-time urine collections. RESULTS: The acute and chronic protocols induced comparable changes in sodium excretion, renal haemodynamics and hormonal responses. Yet, the relative contribution of the proximal and distal nephrons to sodium excretion in response to salt loading and depletion differed in the two protocols. Acutely, subjects appeared to regulate sodium balance mainly by the distal nephron, with little contribution of the proximal tubule. In contrast, in the chronic protocol, changes in sodium reabsorption could be measured both in the proximal and distal nephrons. Acute water loading was an important confounding factor which increased sodium excretion by reducing proximal sodium reabsorption. This interference of water was particularly marked in salt-depleted subjects. CONCLUSION: Acute and chronic salt loading/salt depletion protocols investigate different renal mechanisms of control of sodium balance. The endogenous lithium clearance technique is a reliable method to assess proximal sodium reabsorption in humans. However, to investigate sodium handling in diseases such as hypertension, lithium should be measured preferably on 24 h or overnight urine collections to avoid the confounding influence of water.     

Association between arterial properties and renal sodium handling in a general population

Mean arterial pressure drives pressure-natriuresis and determines arterial structure and function. In a population sample, we investigated the relation between arterial characteristics and renal sodium handling as assessed by the clearance of endogenous lithium. We ultrasonographically measured diameter, cross-sectional compliance (CC) and distensibility (DC) of the carotid, brachial, and femoral arteries in 1069 untreated subjects (mean age: 41.6 years; 50.1% women; 18.8% hypertensive subjects). While accounting for covariates and standardizing for the sodium excretion rate in both sexes, CC and DC of the femoral artery increased with higher fractional distal sodium reabsorption. Differences associated with a 1-SD change in fractional distal reabsorption of sodium were 51.7 mm(2)/kPax10(-3) (95% CI: 23.9 to 79.5; P=0.0002) and 0.56x10(-3)/kPa (95% CI: 0.17 to 0.94; P=0.004) for femoral CC and DC, respectively. In women as well as in men, a 1-SD increment in fractional proximal sodium reabsorption was associated with decreases in femoral and brachial diameter, amounting to 111.6 mum (95% CI: 38.2 to 185.1; P=0.003) and 52.5 mum (95% CI: 10.0 to 94.9; P=0.016), respectively. There was no consistent association between the properties of the elastic carotid artery and renal sodium handling. In conclusion, higher fractional sodium reabsorption in the distal nephron is associated with higher femoral CC and DC, and higher proximal sodium reabsorption is associated with decreased brachial and femoral diameters. These findings demonstrate that there might be an influence of renal sodium handling on arterial properties or vice versa or that common mechanisms might influence both arterial and renal function.     

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.