Evaluation of the tubuloglomerular feedback system in human subjects.

It has been shown in animals that GFR decreases after administration of a carbonic anhydrase inhibitor (CAI) because of activation of the tubuloglomerular feedback. However, the magnitude of this response has never been studied in healthy subjects, nor has the possibility of inhibiting tubuloglomerular feedback with frusemide (FRU). Changes in CCr, V, CNa, CCl, CH2O, CLi were studied before and after acute administration of acetazolamide (ACZ) to 11 normal subjects or FRU to 9 normal subjects. Both ACZ and FRU increased V, CNa, CCl and CLi. Only FRU decreased CH2O. ACZ but not FRU decreased CCr, despite lesser increases of V, CLi and CH2O+CCl (rough indexes of distal delivery). The magnitude of the GFR decrease after comparable increases in distal delivery varied greatly between subjects. There was a tendency for the subjects with lower basal GFRs to show tubuloglomerular feedback responses of lesser magnitude than those with higher GFRs. These results show that it is possible to study tubuloglomerular feedback and its sensitivity in humans using CAIs. FRU blocks the tubuloglomerular feedback response. Its sensitivity appears to vary widely in normal subjects.

Urinary salt titrator stick: a useful and quick estimate of dietary sodium intake?

Repeated measures of urinary salt excretion are the best compromise between reliability and convenience for estimating dietary salt intake. In order to assess the accuracy of the Uropaper urinary salt titrator stick (giving discrete readings of 4, 6, 8, 10, 12 or 14 g/l of NaCl), 312 urine samples were analysed both with the stick and with an ion-selective electrode. There was a good stick-electrode correlation in all the 312 samples (r = 0.84). With a tolerance of +/- 1 g/l, the percentages of correct estimations dropped from 82% to 33% with increasing concentrations of NaCl in the urinary sample. For NaCl concentrations greater than 8 g/l (137 mmol/l) the error in the stick measurement consisted almost exclusively of overestimation of the electrode readings. These results were unaffected by the concentration of urinary potassium. No discrepancies were found among three different readers. This stick is easy to use and measures, with reasonable accuracy, low urinary NaCl concentrations. It could be useful for self-monitoring during low NaCl diets.

Distal nephron function in Bartter's syndrome: abnormal conductance to chloride in the cortical collecting tubule?

Five patients with the clinical patterns of Bartter's syndrome underwent a series of clearance studies in order to characterize the underlying tubule defect. Free water generation during maximal water diuresis (CH2O), expressed as percentage of the distal delivery (CH2O + CCl), was lower in the patients (72.5 +/- 3.2%) than in controls (84.4 +/- 5.5, p < 0.0001). During maximal water diuresis and furosemide administration (40 mg i.v. as bolus), NaCl reabsorption along the diluting nephron segments could be separated into 2 components, that occurring in the loop of Henle (DRNaHL) and that occurring in tubule segments beyond the macula densa (DRNaDT): DRNaHL was normal, while DRNaDT was reduced (3.1 +/- 0.8 vs. 6.2 +/- 2.5 ml/min in controls, p < 0.015). Thus, according to this furosemide protocol, our patients had normal solute reabsorption in the loop of Henle but reduced NaCl reabsorption in tubule segments beyond the macula densa. During 0.9% saline infusion (2 liters in 2 h, after stimulation of distal Na reabsorption with fludrocortisone) fractional excretion (FE) of K showed a linear rise with the increase of FECl-FEK, however, was much higher in the patients than in controls for every FECl level. In contrast, the infusion of Na2SO4, after fludrocortisone administration, induced similar FEK increases in patients and in controls. Thus, in these patients Na reabsorption in the distal nephron (possibly the cortical collecting tubule) was associated with the generation of a higher than normal electric potential gradient in the presence of Cl but not of another poorly reabsorbable anion, such as SO4(2-). These observations indicate that, in our patients, Henle's loop function is normal, while the collecting tubule function is abnormal. We suggest that NaCl wasting and enhanced tubular secretion of H+ and K in our patients might result from an abnormally low conductance to Cl in distal nephron site(s) where Na reabsorption is electrogenic, possibly the cortical collecting tubule. A larger than normal transtubular electric gradient would be generated by Na reabsorption, causing: (1) a direct stimulation of tubular secretion of K and H+ (leading to hypokalemia and alkalosis) and (2) inhibition of the reabsorption of Na ('trapped' into the tubular lumen by electric forces), with consequent extracellular volume contraction, hyperreninemia and hyperaldosteronism.

Pseudo-Bartter's syndrome from surreptitious diuretic intake: differential diagnosis with true Bartter's syndrome.

Five patients with pseudo-Bartter's syndrome from surreptitious diuretic abuse were compared with six patients with true Bartter's syndrome, diagnosed as a normotensive, hyperreninaemic, hypokalaemic metabolic alkalosis with normal urine chloride excretion, low CH2O/(CH2O+CCl) ratio during maximal water diuresis and negative urine screen for diuretics. The latter was positive for frusemide in four and for hydrochlorothiazide in the remaining pseudo-Bartter's patients. The two groups of patients did not differ as for plasma Na+, Cl-, K+, HCO3-, renin, and aldosterone, while uric acid and Mg2+ were greater in pseudo-Bartter's patients. Daily and fasting urine Na+, Cl- and K+ excretion were less in pseudo-Bartter's patients; however, there was substantial overlap of values between the two groups. Fractional distal solute reabsorption during maximal water diuresis was low in the six patients with Bartter's syndrome and in two pseudo-Bartter's patients; thus, this parameter could not be taken as a specific diagnostic marker of Bartter's syndrome. Frusemide administration, 40 mg i.v., induced a brisk increase of urine flow (11.7-21.8 ml/min), UOsm (148-186 mOsm/kg H2O) and FENa (14.6-24%) in Bartter's syndrome, but not pseudo-Bartter's patients; in all pseudo-Bartter's patients frusemide-induced changes of UOsm (13-97) and FENa (-0.5 to 10.2) were markedly less than in Bartter's syndrome patients. Frusemide resistance in pseudo-Bartter's patients was most probably related to diuretic-induced ECF volume contraction and increased proximal tubule solute reabsorption; in fact fractional lithium clearance (FELi, a marker of post-proximal solute delivery) was low in pseudo-Bartter's, but not in Bartter's syndrome patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of acute administration of acetazolamide and frusemide on lithium clearance in humans.

To investigate the mechanism(s) of acute frusemide-induced increases in FELi, the effects of frusemide and acetazolamide, the carbonic anhydrase inhibiting agent, were evaluated in 19 healthy subjects either before or after pretreatment with acetazolamide or frusemide (11 subjects and eight subjects respectively). Acetazolamide pretreatment did not modify frusemide-induced increases in FELi (delta FLi 12.8 +/- 4.1% compared to 14.6 +/- 7.3%, P = NS); similarly, frusemide pretreatment did not modify acetazolamide-induced increases in FELi (delta FLi: 11.3 +/- 5.9% compared to 9.8 +/- 3.8%, P = NS). Acetazolamide-induced changes of FELi were correlated significantly with acetazolamide-induced increases of FEHCO3 (r = 0.61, P less than 0.05), FENa (r = 0.46, P less than 0.05) but not of FECl (r = 0.25, P = NS). On the other hand, frusemide-induced changes of FELi were correlated significantly with frusemide-induced increases of FENa (r = 0.62, P less than 0.005), FEC1 (r = 0.52, P less than 0.025) but not of FEHCO3 (r = 0.3, P = NS). Thus, frusemide effects on tubular lithium reabsorption are not related to carbonic anhydrase inhibition; furthermore, it appears that frusemide and acetazolamide affect lithium reabsorption by different and independent mechanism(s), possibly acting at different nephron site(s).