Evidence for a tubular defect in the loop of Henle

Hyperprostaglandin E syndrome.
Long-term indomethacin treatment (serum levels 4 hours after dosing: 1168 ? 320 ng/ml) suppressed urinary excretion of PGE2 and PGE-M to subnormal levels. Subsequently hyperreninemia, hyperaldosteronism, hyperkaliuria, metabolic alkalosis, and serum chloride and potassium levels were corrected sufficiently. However, some pathognomonic features of HPS could be influenced only moderately or even remained unchanged. Isosthenuria continued despite a serum osmolality of 293 ? 3 mOsm/kg. No significant change in urinary loss of sodium or chloride was observed, and a considerable amount of hypercalciuria and hypermagnesiuria persisted during indomethacin treatment. Biochemical data obtained before and 6 days after discontinuation of the drug, respectively, are summarized in Tables II and III .

There was a marked resistance to furosemide in patients with HPS, although urinary drug excretion rates (132 ? 17 mug/kg per hour) were not different from those of healthy children (106 ? 11 mug/kg per hour) or siblings (86, 118, and 80 mug/kg per hour) (Tables IV and V) . Furosemide-induced diuresis (DeltaVfuro ) was 77 ? 9 ml/mg in the control group but reached only 39 ? 13 ml/mg in patients with HPS (Fig. 2) . In parallel, furosemide had only a poor effect on chloride and sodium excretion in children with HPS when compared with healthy control subjects (DeltaClfuro 1.1 ? 0.3 vs 8.4 ? 0.8 mmol/mg; DeltaNafuro , 2.0 ? 0.6 vs 7.7 ? 1.0 mmol/mg) (Fig. 3) . Similar differences were observed with regard to changes in calciuria and magnesiuria. However, the increase in potassium excretion did not differ from that of healthy control subjects (Table IV) . Considerable differences also were found in the pattern of hormonal reactions. Administration of furosemide was associated with a doubling of PGE2 excretion in patients with HPS, whereas no significant effect was observed in the group of healthy children (Table V) . In contrast, hyperreninemia and hyperaldosteronism developed in siblings and further increased in patients with GS/BS but remained at preexisting high levels in the HPS group (Table V) .

Bartter and Gitelman syndromes.
The increase in urinary PGE2 after indomethacin withdrawal was less pronounced in GS compared with HPS or BS. However, one patient with GS excreted large amounts of PGE-M. Polyuria was absent during indomethacin (serum levels 623, 1454, and 823 ng/ml) and recurred only moderately after the treatment was discontinued. In contrast to the group with HPS, none of the patients with BS/GS was hyposthenuric or isosthenuric, even in the untreated state. Inhibition of PGE2 synthesis was associated with a decrease of potassium excretion in GS and BS, whereas renal loss of sodium and chloride was reduced in GS only. Renal handling of magnesium and calcium remained unaffected (Tables II and III) .

Similar to healthy control subjects and siblings, patients with GS or BS showed a marked diuretic and saluretic response to furosemide (drug excretion rates 69, 82, and 181 mug/kg per hour) (Table IV) . Neither the extent of furosemide-induced polyuria and electrolyte excretion nor the hormonal response differed from those observed in the control groups (Figs. 2 and 3 , Tables IV and V) .

Since the first description of Bartter syndrome, a number of pathogenic mechanisms have been considered to play a major role in this disease and its variants. Either inappropriate release of prostaglandins [22] [23] [24] [25] or defects in tubular transport mechanisms [8] [9] [10] [11] [12] [13] [14] [15] [16] may be the primary event causing renal salt wasting and loss of water. Recently an angiotensin II receptor gene abnormality has been reported. [26] One reason for these inconsistent findings may be the heterogeneity of this syndrome. Stein [1] and later Clive [2] emphasized that “Bartter syndrome” must be divided at least into three distinct disorders. Thus classification of tubular disorders associated with hypokalemic alkalosis into Bartter, Gitelman, and hyperprostaglandin E syndrome was a basic requirement in this study.

The use of clearance studies to examine the involvement of the loop of in these disorders may be of limited value because of the modulatory mechanisms in more distal tubular segments. [8] [11] However, exposure to loop diuretics seemed to be a helpful tool to detect the tubular source of salt wasting,

Figure 4. Correlation between furosemide excretion and renal chloride loss in healthy subjects (a) and patients with HPS (b). Solid squares represent individual values of health control subjects (n = 13); x’s represent healthy siblings (n = 3), and solid triangles represent patients with HPS (n = 8).because clinical and biochemical findings in HPS almost completely resemble the effects of chronic furosemide treatment. [7] [27] [28] Moreover, the pharmacologic action of furosemide is well characterized as a dose-dependent inhibition of active chloride reabsorption in the thick ascending limb by blocking the luminal Na+ -2Cl- -K+ -cotransporter. [29]

In this study a correlation between furosemide excretion and renal electrolyte loss was observed only in healthy subjects but not in those with HPS (Fig. 4) . Our data demonstrate a markedly impaired sensitivity to furosemide in children with HPS regarding the diuretic and saluretic response and the effect on the renin-angiotensin-aldosterone system. Because patients with HPS differed from the other groups by having substantial hypercalciuria, this feature could be supposed to interfere with the tubular effect of furosemide.

However, in children with idiopathic hypercalciuria a normal saluretic response to furosemide could be demonstrated. [30] It also may be argued that the resistance to loop diuretics in patients with HPS was caused by previous volume depletion. [31] This possibility can be ruled out because the loss in body weight before furosemide administration (6 days after withdrawal of indomethacin) was similar in children with GS/BS (4.1%, 3.0%, and 5.3%) and those with HPS (3.4% ? 0.8%). Patients with GS/BS had normal sensitivity to furosemide, whereas a subnormal response was observed in the HPS group only. Moreover, children with HPS show a complete loss of concentrating ability, [17] [32] a feature that is typical for a lack of diluting capability in the TALH. [33] Impaired electrogenic chloride transport in the TALH also inhibits the voltage-driven paracellular reabsorption of calcium and magnesium. [29] This is in accordance with our data regarding the weak effect of furosemide on renal excretion of both sodium chloride and divalent cations in HPS (Table IV) . Interestingly, a distinction between the excretion of monovalent ions and divalent cations was observed in the HPS group. Although these patients had substantial hypercalciuria and hypermagnesiuria, sodium and chloride excretion before the use of furosemide was similar to that of healthy control subjects (Table IV) . The latter finding is probably related to compensatory reabsorptive mechanisms in the more distal segments of the nephron. The coincidence of hypercalciuria and normal or even high levels of serum calcium indicates extrarenal mechanisms in maintaining calcium wasting in the TALH. These mechanisms may be elevated bone resorption as a result of systemic PGE2 formation [34] and increased intestinal calcium absorption. [32] Similar observations were made in rats that received furosemide. Hypercalciuria, hypermagnesiuria, and enhanced intestinal absorption of divalent cations developed. [35] These secondary effects of furosemide persisted after the initial natriuresis decreased. [35]

In summary, our observations indicate that a tubular defect in the TALH may be the primary event in HPS. This hypothesis is further supported by a recent study demonstrating a marked reduction of Tamm-Horsfall protein synthesis in these patients. [17] Further investigations should elucidate the molecular mechanisms underlying the tubular defect in HPS, because active chloride transport in the TALH depends on a number of cellular components including luminal Na+ -2Cl- -K+ -cotransporter, potassium recycling via luminal K+ channels, and opening of basolateral Cl- channels by increased cyclic adenosine monophosphate. [29]

Prostaglandin E2 is known to inhibit chloride reabsorption in this segment by decreasing intracellular cyclic adenosine monophosphate. [36] [37] Therefore inadequate increase of PGE2 synthesis also must be discussed as a very proximal event mimicking chronic furosemide treatment in HPS. However, suppression of PGE2 formation with indomethacin failed to restore urinary concentrating capacity. It had a poor effect on sodium chloride excretion and improved hypercalciuria and hypermagnesiuria only moderately (Table III) . These observations provide strong evidence that the primary defect causing impaired electrolyte reabsorption in the TALH is largely independent of PGE2 .

Enhanced formation of PGE2 in HPS is probably a separate event or even a phenomenon secondary to the tubular defect. Other causes of chronic volume contraction such as cyclic vomiting [38] or profuse diarrhea [39] also are associated with enhanced PGE2 synthesis. Controversial findings regarding PGE2 release after acute furosemide administration have been reported. [40] [41] [42] This may be explained by different experimental conditions. Gerber and Nies [43] demonstrated that loop diuretics stimulate an indomethacin-sensitive increase of renal blood flow only in states of salt depletion and dehydration. This may explain the divergent effect of furosemide on prostaglandin excretion in healthy control subjects and children with HPS. In the latter, however, enhanced formation of PGE2 independent of volume contraction cannot be ruled out completely, because administration of furosemide failed to increase PGE2 excretion in patients with either GS or BS who were dehydrated to the same extent.

Interestingly, indomethacin is of crucial therapeutic benefit in patients with HPS, although the primary tubular defect remains unchanged. This can be explained as follows. (1) In untreated patients with HPS impaired electrolyte reabsorption in the TALH leads to renal salt wasting and chronic volume contraction. The subsequent decrease in the glomerular filtration rate and renal blood flow is counterbalanced by the release of vasodilatory PGE2 . [25] [44] [45] Under this condition indomethacin decreases glomerular filtration rate, [34] thereby reducing delivery of sodium chloride to the defective TALH. (2) Both the tubuloglomerular feedback and direct stimulation by PGE2 activate the renin-angiotensin-aldosterone system to prevent severe hypotension and hyponatremia. [1] [44] [46] The secondary hyperaldosteronism seems to be responsible for hyperkaliuria and reduced renal sodium loss in HPS, because antialdosterone treatment has been shown to correct hypokalemia and to cause hyponatremia without affecting concentrating ability and hypercalciuria. [5] [6] Indomethacin is also effective in preventing secondary hyperaldosteronism and consequently hypokalemia (Table II) . (3) The excessive PGE2 release further aggravates polyuria and salt loss by antagonizing vasopressin-dependent water flow in the collecting duct and inhibiting sodium reabsorption in both the distal tubule and collecting duct. [44] [47] [48] Consequently indomethacin treatment changes hyposthenuria to isosthenuria (Table III) .

In contrast to HPS, a normal sensitivity to furosemide was found in both GS and BS. Diuretic and saluretic effects and the hormonal response were similar to those observed in healthy control subjects. Apparently, reabsorption capacity in the TALH is completely maintained in GS and BS. This assumption is confirmed by either low or normal calcium excretion and a urine osmolality reaching more than 600 mOsm/kg even after withdrawal of indomethacin (Table III) . [12]

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