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Response to Furosemide

Journal of Pediatrics
Volume 129 � Number 4 � October 1996
Copyright � 1996 Mosby-Year Book, Inc.

Impaired response to furosemide in Hyperprostaglandin E syndrome: Evidence for a tubular defect in the loop of Henle

Arnold Kockerling MD
Stephan C. Reinalter
Hannsjorg W. Seyberth MD
From the Department of Pediatrics, Philipps University,
Marburg, Germany


In hyperprostaglandin E syndrome (HPS) renal wasting of electrolytes and water is consistently associated with enhanced synthesis of prostaglandin E2 . In contrast to Bartter or Gitelman syndrome (BS/GS), HPS is characterized by its severe prenatal manifestation, leading to fetal polyuria, development of polyhydramnios, and premature birth. This disorder mimics furosemide treatment with hypokalemic alkalosis, hypochloremia, isosthenuria, and impaired renal conservation of both calcium and magnesium. Therefore the thick ascending limb of the loop of Henle seems to be involved in HPS. To characterize the tubular defect we investigated the response to furosemide (2 mg/kg) in HPS (n = 8) and BS/GS (n = 3) 1 week after discontinuation of long-term indomethacin treatment. Sensitivity to furosemide was completely maintained in patients with BS/GS. The diuretic, saluretic, and hormonal responses were similar to those of a control group of healthy children (n = 13), indicating an intact function of the thick ascending limb of the loop of Henle in BS/GS. In contrast, patients with HPS had a marked resistance to this loop diuretic. Furosemide treatment increased urine output by 7.5 � 0.7 ml/kg per hour in healthy control subjects but only by 4.4 � 1.2 ml/kg per hour ( p <0.5) in children with HPS. In parallel, the latter also had a markedly impaired saluretic response (DeltaClurine 0.14 � 0.04 mmol/kg per hour vs 0.85 � 0.09 mmol/kg per hour, p <0.001; DeltaNaurine 0.23 � 0.06 mmol/kg per hour vs 0.77 � 0.09 mmol/kg per hour, p <0.001). Furosemide therapy further enhanced prostaglandin E2 excretion in patients with HPS (54 � 17 to 107 � 28 ng/hr per 1.73 m2 , p <0.05), whereas no significant effect was observed in healthy children (20 � 3 to 12 � 3 ng/hr per 1.73 m2 ). We conclude that a defect of electrolyte reabsorption in the thick ascending limb of the loop of Henle plays a major role in HPS.

1996;129:519-28
BS Bartter syndrome
GS Gitelman syndrome
HPS Hyperprostaglandin E syndrome
PGE2
Prostaglandin E2
PGE-M
7alpha-5,11-Diketo-tetranorprosta-1,16-dioic acid
TALH
Thick ascending limb of the loop of Henle
Supported by grant No. Se 263/11-1 from the Deutsche Forschungsgemeinschaft.

Presented in part at the International Congress of Nephrology, Madrid, Spain, July 2-6, 1995.

Submitted for publication Jan. 29, 1996; accepted May 23, 1996.
Copyright � 1996 by Mosby-Year Book, Inc.

9/21/75366

Renal tubular disorders associated with hypokalemic metabolic alkalosis are often compiled as ``Bartter syndrome'' but probably represent a number of variants resulting from different pathophysiologic events. [1] [2] Clinically postnatal forms including classic Bartter syndrome [3] and hypomagnesemic Gitelman syndrome [4] must be distinguished from prenatal hyperprostaglandin E syndrome. The latter is characterized by polyhydramnios leading to premature delivery, a marked hypercalciuria resulting in nephrocalcinosis, and isosthenuria or even hyposthenuria. [5] [6] [7] To date no consensus has been achieved regarding the sites of tubular dysfunction in these disorders. Results derived from various clearance studies in patients with BS suggest impaired electrolyte reabsorption in the proximal tubule, [8] the loop of Henle, [9] [10] the distal tubule, [11] [12] [13] or the cortical collecting duct. [14] In a comparison of two clearance methods, Boer et al. [8] emphasized the problems in interpreting clearance data as a result of the compensatory mechanisms modulating urinary electrolyte excretion in more distal tubular segments. Therefore exposure to diuretics with a well-defined action on tubular transport mechanisms seems to be a more promising approach. Normal increase in solute excretion after furosemide treatment [13] [14] but impaired response to chlorothiazide [13] [15] provide strong evidence that the primary defect in the postnatal variants is located in the distal convoluted tubule rather than in the loop of Henle.

In contrast, HPS, the prenatal variant of BS, resembles clinical and biochemical characteristics also found in infants exposed to long-term furosemide treatment such as hypokalemic alkalosis, normotension despite hyperreninemia and hyperaldosteronism, isosthenuria, and hypercalciuria with nephrocalcinosis. [7] Additionally a reduction of tubular Tamm-Horsfall protein synthesis and excretion has been observed in HPS but not in BS. [16] This indicates involvement of the thick ascending limb of the loop of Henle only in HPS. Consequently the aim of our study was to investigate the response to the loop diuretic furosemide in children with HPS and thereby to localize the tubular segment affected in this disorder.

METHODS
Patients.
Eleven patients with urinary salt loss and hypokalemic alkalosis were enrolled in the study, among them eight children with HPS (median age 10.5 years, range 84 to 11.8 years), two girls with GS (8.7 and 9.3 years), and one boy with classic BS (14.4 years). Classification into these distinct disorders was made according to the history, clinical, and biochemical characteristics as depicted in Table I . Children with HPS were hypercalciuric, and nephrocalcinosis was present in each of them as shown by renal ultrasonography. All patients had been treated with indomethacin (patients with HPS: 2.9 � 0.8 mg/kg per day; patients with GS/BS: 3, 1.9, and 3.1 mg/kg per day) for several years; two patients also were treated with additional potassium supplementation (one patient with HPS: 1.7 mmol/kg per day; one patient with GS: 3.5 mmol/kg per day). Because of the very low serum levels of potassium this supplementation was continued during the entire study period. No other medication was taken by any of the subjects.

Long-term indomethacin treatment was discontinued 1 week before the children were exposed to furosemide to prevent any drug interaction and to study the tubular dysfunction in a ``native'' state. Blood samples and 24-hour urine collections were obtained before and 6 days after withdrawal of indomethacin, respectively. During this time patients were allowed to be on a self-demand dietary schedule required by the individual losses of electrolytes and free water. Withdrawal of indomethacin resulted in recurrence of the clinical picture and laboratory characteristics of the disorder within a few days (Tables II and III) .

Control groups.
Thirteen age-matched healthy children (median age 10.2 years, range 6.4 to 15.1 years) volunteered as control subjects during furosemide administration. In 10 of these children separate 24-hour urine collections were obtained under basal conditions. For ethical reasons, however, no blood samples were collected in this group. In addition three unaffected siblings (aged 8.8, 15.3, and 15.5 years) of patients with either HPS or BS were studied under the same protocol as their diseased family members. The protocol was approved by the university ethics committee. Informed parental consent and oral assent of the children was obtained before enrollment in the study.

Furosemide test.
The study was performed on two succeeding days according to the schedule shown in Fig. 1 . Urine was collected for a 3-hour-period subsequent to voiding at 9:30 am. The first day served as the control period. On the second day a single oral dose of furosemide (2 mg/kg as Lasix Liquidum) was administered. Fluid intake and composition of breakfast were the same during the test periods on both days. Blood samples were taken in the middle of each observation period.

The diuretic, saluretic, and hormonal changes observed between day 1 and day 2 were considered to be induced by furosemide administration. Because loop diuretics act from the luminal side of the tubule, their efficiency completely depends on urinary drug levels. Thus furosemide-induced inhibition of chloride reabsorption (DeltaClfuro ) can be calculated by the formula DeltaClfuro = DeltaClurine /Furourine , where DeltaClurine is the change in chloride excretion observed after furosemide administration and Furourine is the urinary excretion rate of furosemide. By analogy furosemide-induced sodium excretion and diuresis can be expressed as DeltaNafuro = DeltaNa urine /Furourine , and DeltaVfuro = DeltaVurine /Furourine , respectively.

Analytic methods.
Urinary and serum electrolyte concentrations, osmolality, and creatinine concentrations were measured by conventional laboratory methods. Plasma renin activity and aldosterone were assayed by radioimmunologic methods; upper normal limits in our laboratory are 5 ng/ml per hour and 15 ng/dl, respectively. Serum levels of indomethacin [17] and urinary levels of furosemide [18] were determined by high-performance liquid chromatography. To quantify the biosynthesis of prostaglandin E2 , urinary excretion of PGE2 and its major metabolite 7alpha5,11-diketo-tetranorprosta-1,16-dioic acid were measured by gas chromatography-mass spectrometry as described by Schweer et al. [19] Excretion of PGE-M is regarded to reflect predominantly the extent of systemic PGE2 production, whereas urinary PGE2 represents renal biosynthesis. [20] [21]

Data are reported as means � SEM in the control group and in the HPS group. The Student t test for related or unrelated samples was used to determine statistical difference. Values of p <0.05 were considered significant. Data of the three patients with either BS or GS and of the three healthy siblings are given as single values.

RESULTS
Control groups.
Oral administration of 2 mg/kg furosemide in healthy children not related to the patients induced isosthenuria and a sixfold increase in urine output (Table IV , Fig. 2) . The saluretic response was based mainly on the inhibition of chloride and sodium reabsorption (Fig. 3) , whereas potassium excretion was elevated only moderately. As is typical of loop diuretics, furosemide caused marked calciuria and magnesiuria (Table IV) . Urinary excretion of PGE2 and PGE-M decreased slightly but not significantly (Table V) . Normal sensitivity to furosemide also was found in the patients' siblings. The renal loss of water and electrolytes equaled that observed in unrelated healthy control subjects (Table IV , Figs. 2 and 3) and was accompanied by hyperreninemia and hyperaldosteronism (Table V) . However, PGE-M but not PGE2 release was slightly increased in each of the three siblings (Table V) .

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) .

DISCUSSION
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]

Early clearance studies suggested a defect in chloride transport in the TALH to be the proximal event in BS. [9] [10] In later studies, however, the combined use of clearance methods and diuretics revealed an impaired thiazide-sensitive salt reabsorption, suggesting that the distal convoluted tubule is the segment primarily affected in GS [13] and BS. [12] [15] Recently mutations in the thiazide-sensitive NaCl-cotransporter gene were detected in patients with GS. [49] Chaimovitz et al. [50] described a boy with ``Bartter syndrome'' who had a normal response to thiazides. This observation was probably the result of an incomplete characterization of the patient, who had typical features of HPS such as isosthenuria and severe failure to thrive. [50] Unfortunately no data referring to calcium and magnesium excretion were given in this case. Two of our children with HPS did show a normal response to hydrochlorothiazide (l mg/kg per day) during a treatment period of 1 week (unpublished observations).

In summary the classification of inborn hypokalemic tubular disorders into distinct entities could be confirmed by the use of furosemide administration. In HPS the markedly impaired response to furosemide revealed a tubular defect in the TALH. The beneficial effect of indomethacin treatment underscores the important pathophysiologic role of concomitant PGE2 overproduction in HPS. In contrast, patients with BS or GS had normal sensitivity to furosemide, indicating an intact function of the TALH in these disorders.

We thank Dr. Klaus Ehlenz for performing plasma renin activity and aldosterone assays, Dr. Horst Schweer for mass spectrometric analysis of urinary prostaglandins, and Bernhard Watzer for measuring the drug levels. We thank the nursing staff for their assistance in urine collections.

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