HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (10) Citing Articles via Google Scholar Google Scholar Articles by Jeck, N. Articles by Seyberth, H. W. Search for Related Content PubMed PubMed Citation Articles by Jeck, N. Articles by Seyberth, H. W.

INVITED REVIEW

Salt handling in the distal nephron: lessons learned from inherited human disorders

University Children's Hospital, Philipps-University, Marburg, Germany

	ABSTRACT

TOP ABSTRACT CASE REPORT FROM THE FIRST CLINICAL... MECHANISMS OF TRANSEPITHELIAL... DISORDERS OF THE LOOP... DISORDERS OF THE DISTAL... THE ENIGMATIC ROLE OF... SOLUTION OF THE CASE... GRANTS REFERENCES

 
The molecular basis of inherited salt-losing tubular disorders with secondary hypokalemia has become much clearer in the past two decades. Two distinct segments along the nephron turned out to be affected, the thick ascending limb of Henle's loop and the distal convoluted tubule, accounting for two major clinical phenotypes, hyperprostaglandin E syndrome and Bartter-Gitelman syndrome. To date, inactivating mutations have been detected in six different genes encoding for proteins involved in renal transepithelial salt transport. Careful examination of genetically defined patients ("human knockouts") allowed us to determine the individual role of a specific protein and its contribution to the overall process of renal salt reabsorption. The recent generation of several genetically engineered mouse models that are deficient in orthologous genes further enabled us to compare the human phenotype with the animal models, revealing some unexpected interspecies differences. As the first line treatment in hyperprostaglandin E syndrome includes cyclooxygenase inhibitors, we propose some hypotheses about the mysterious role of PGE₂ in the etiology of renal salt-losing disorders.

hyperprostaglandin E syndrome; Bartter syndrome; Gitelman syndrome; salt-losing tubulopathy

	CASE REPORT

TOP ABSTRACT CASE REPORT FROM THE FIRST CLINICAL... MECHANISMS OF TRANSEPITHELIAL... DISORDERS OF THE LOOP... DISORDERS OF THE DISTAL... THE ENIGMATIC ROLE OF... SOLUTION OF THE CASE... GRANTS REFERENCES

 
A child was prematurely born to consanguineous parents of Arabic origin at 28 wk of gestation. The parents had already given birth to two healthy children; another child, however, had died as a premature infant, and there were two former miscarriages. The birth weight of this child was 1,250 g (–0.3 SDS). The pregnancy was complicated by severe maternal polyhydramnios. Polyhydramnios was likely of fetal renal origin, as suggested by frequent fetal voiding determined by ultrasound, and required repeated amniocenteses during the last 6 wk of gestation. Total volume of amniotic drainage was 15 liters. Within 72 h after birth, the child was noted to have isosthenuric polyuria with urinary outputs exceeding 25 ml·kg^–1·h^–1 (normal 2–6). Consequently, the preterm infant lost nearly 20% of its birth weight. Extracellular fluid (ECF) volume depletion was accompanied by low plasma Na⁺ and Cl^– concentrations, indicating additional renal salt wasting. The child developed metabolic alkalosis, hypokalemia, and hypomagnesemia. Plasma renin activity exceeded the upper measurable limit. Intractable vomiting and abdominal distention required total parenteral nutrition.

In view of the prenatal manifestation, as well as postnatal profound saliuretic polyuria and the finding of markedly increased renal and extrarenal prostaglandin E formation, the diagnosis of a disorder of the loop of Henle, referred to as hyperprostaglandin E syndrome (also referred to as antenatal Bartter syndrome), was considered. Treatment with cyclooxygenase inhibitors was initiated 10 days after birth with beneficial effects on fluid and electrolyte balance. The infant still required supplementation of KCl, NaCl, and magnesium sulfate, albeit to a lesser extent with 15, 4, and 0.8 mmol·kg^–1·day^–1, respectively (normal 1, 3, and 0.25). Glomerular filtration was moderately impaired with calculated glomerular filtration rate (GFR; Schwartz formula) of 57 ml·min^–1·(1.73 m²)^–1 at the age of 9 mo (mean GFR at 6–12 mo being 103 ml·min^–1·(1.73 m²)^–1). In addition to renal symptoms, the child exhibited gross motor retardation and bilateral sensorineural deafness as revealed by electric response audiometry of the brain stem. Surprisingly, nephrocalcinosis, a classical feature of hyperprostaglandin E syndrome, was not detected in repeated ultrasound examinations of the patient's kidneys.

Descriptions of inherited hypochloremic alkalosis with secondary hypokalemia date back to the 1960s (95), and later, a defect in renal salt conservation as an underlying cause was hypothesized (4). In the following two decades, a plethora of data derived from perfusion studies in isolated nephron segments established the mode and stoichiometry of transepithelial ion transport (34). Specialized molecules were proposed to accomplish Na⁺-Cl^– entry from the tubular lumen into the cell and further exit through the basolateral membrane. Inhibitors of these pathways were identified. Among those were the high- ceiling diuretics and thiazides, which had already been established in clinical practice (13, 64). The functional description of ion transport proteins was a prerequisite that allowed cloning of the molecules by expression and homology-based cloning strategies. These efforts led to the identification of the cation-chloride cotransporters NCCT (28) and NKCC2 (27), the renal outer medullary K⁺ (ROMK) channel (46), and the ClC chloride channels (53). Cloning of these molecules, in turn, provided the candidate genes for the identification of inactivating mutations leading to syndromes of tubular salt wasting (47, 107–110).

A second line of research focused on a minority of patients excluded for linkage to these candidate genes. By subsequent genome-wide linkage strategy, novel proteins were discovered, and their physiological role as channel subunits or regulators was established (8, 20, 122). Heterologous expression of cloned molecules allowed for the characterization of their electrophysiological and biochemical properties and their putative interaction with accessory proteins. An additional approach to study the in vivo function by generation of genetically engineered mice deficient in the respective genes turned out to be more delicate because the phenotype of these animals did not exactly resemble the corresponding human disease (73, 100, 114). Therefore, clinicians in immediate care of the patients have the chance to complete the knowledge about the physiological role of distinct renal proteins in humans.

This review has been written by pediatricians and details their 30 years of experience in diagnosis and treatment of more than 100 patients suffering from the different forms of salt-losing tubulopathies (SLTs), with a special emphasis on its most severe form, the hyperprostaglandin E syndrome (104).

	FROM THE FIRST CLINICAL OBSERVATION TO THE MOLECULAR DECIPHERMENT OF RENAL SALT WASTING

TOP ABSTRACT CASE REPORT FROM THE FIRST CLINICAL... MECHANISMS OF TRANSEPITHELIAL... DISORDERS OF THE LOOP... DISORDERS OF THE DISTAL... THE ENIGMATIC ROLE OF... SOLUTION OF THE CASE... GRANTS REFERENCES

 
In 1957, two pediatricians described a 2-mo-old African American infant with congenital hypokalemic alkalosis, failure to thrive, dehydration, and hyposthenuria, who finally died at the age of 7.5 mo (93). Some years later, two African American patients with normotensive hyperaldosteronism, hyperplasia of the juxtaglomerular apparatus, metabolic alkalosis and severe renal K⁺ wasting were characterized by the endocrinologist Frederic Bartter (5). Other features of this syndrome included increased activity of the renin-angiotensin system and a relative vascular resistance to the pressor effect of exogeneous ANG II. After these original reports, hundreds of Bartter-like syndrome (BS) cases have been described. Although all shared the finding of hypokalemia and hypochloremic alkalosis, patients differed with regard to age of onset, severity of symptoms, degree of growth retardation, urinary concentration capacity, magnitude of urinary K⁺ and prostaglandin excretion, presence of hypomagnesemia, and extent of urinary Ca²⁺ excretion.

Gitelman and colleagues (32) pointed to the susceptibility to carpopedal spasms and tetany in three BS cases. Tetany was attributed to low plasma Mg²⁺ levels, secondary to impaired renal conservation of Mg²⁺. Further examination of these patients also revealed low urinary Ca²⁺ excretion (92). The dissociation of renal Ca²⁺ and Mg²⁺ handling was regarded to be pathognomonic for Gitelman syndrome (GS) (7). Interestingly, both patients in Bartter's original report displayed positive Chvostek's sign and carpopedal spasms. Indeed, in a recent discussion of the original Bartter paper in Milestones in Nephrology, one of the coauthors, John R. Gill, conceded that the majority of patients seen by both endocrinologists perfectly matched the later description of Gitelman (6).

Phenotypic homogeneity of BS was questioned more seriously when the pediatricians Fanconi (21) and McCredie (77) found high urinary Ca²⁺ excretion and medullary nephrocalcinosis in infants initially suspected for BS. Descriptions of this variant in the literature became more frequent in the 1980s, most likely because advances in neonatal medicine resulted in higher survival rates of extremely preterm born babies. The neonatologist Ohlsson (83) defined the antenatal history with maternal polyhydramnios, which likely predisposed to premature birth.

Immediately after birth, profound polyuria put these type of patients at high risk for life-threatening dehydration (61). Contraction of ECF volume was accompanied by markedly elevated renal and extrarenal PGE₂ production. Treatment with PG synthesis inhibitors effectively reduced polyuria, ameliorated hypokalemia, and improved growth. To emphasize the obviously critical role of PGE₂ in the pathogenesis of this distinct tubular disorder, Seyberth (102) coined the term hyperprostaglandin E syndrome (HPS).

Early reports postulated that the primary defect in "congenital hypokalemic alkalosis" was an unresponsiveness of the vascular bed to ANG II (5). In the 1970s, a defect in renal Na⁺-Cl^– conservation was suggested as the possible culprit. This assumption was largely based on studies of free water clearance and distal fractional Cl^– reabsorption and the observation that affected subjects exhibited impaired renal concentrating and diluting capacities as well as decreased distal Cl^– reabsorption (30). However, efforts to define the affected tubular segment were hampered by the fact that compensatory activation of salt-conserving mechanisms in nephron segments different from that affected by the primary genetic defect enabled partial correction of urinary salt wasting (10, 54, 80, 112). Controversial results might have also been attributed to the selection of studied patients, which, at that time, were not separated between BS (and GS) on one, and HPS on the other side. This difference became more evident when the patients' symptoms were compared with the pharmacological effects of diuretics and, subsequently, when the patients were exposed to diuretics with a well-defined action on the tubule. Patients with BS/GS syndrome displayed a thiazide-like phenotype with Mg²⁺ wasting associated with hypocalciuria and a normal increase in solute excretion upon furosemide administration (16, 113) but an impaired response upon chlorothiazide administration (86, 113). Conversely, patients with polyuric HPS were insensitive to loop diuretics such as furosemide and displayed an exaggerated salt loss with thiazides (58). These results provided clear evidence that the basic defect in BS/GS localized to the distal convoluted tubule (DCT), while HPS, the furosemide-like SLT, was due to defective salt transport in the thick ascending limb of Henle's loop (TAL). Definition of two distinct tubular sites affected in BS/GS and HPS, respectively, was essential for further selection of candidate genes and, finally, identification of inactivating mutations in the ion transport machinery of the renal tubule.

Characterization of the human genes encoding the tubular solute transporters and subsequent identification of loss-of-function mutations was the outstanding contribution of Simon and Lifton (107–110) from Yale University. Remarkably, their initial interest was directed toward the identification of genes relevant for monogenic forms of hypertension. Increased salt reabsorption in the renal tubule due to overactive epithelial Na⁺ channel (ENaC) was previously identified in Liddle's syndrome by the same group (41, 42). Although within the next two years, no further genes could be associated with inherited forms of hypertension, Simon and collaborators could establish four genes of the tubular apparatus responsible for the opposite phenotype of renal salt wasting, thereby deciphering the molecular pathogenesis of BS/GS and HPS (107–110). Other groups corroborated their results and elaborated a correlation between the genotypes and phenotypes (Table 1; 47, 62, 65, 75, 118).

	MECHANISMS OF TRANSEPITHELIAL SALT REABSORPTION IN THE DISTAL NEPHRON

TOP ABSTRACT CASE REPORT FROM THE FIRST CLINICAL... MECHANISMS OF TRANSEPITHELIAL... DISORDERS OF THE LOOP... DISORDERS OF THE DISTAL... THE ENIGMATIC ROLE OF... SOLUTION OF THE CASE... GRANTS REFERENCES

Approximately 25% of the filtered solute load is reabsorbed in the TAL. Transmembrane transport of Na⁺, K⁺, and Cl^– from the lumen into the epithelial cell is mediated by the Na⁺-K⁺-2Cl^– symporter type 2 (NKCC2) (Fig. 1A). NKCC2 is driven by the steep electrochemical gradient for Na⁺ established by the basolateral ATP-dependent Na⁺ pump. This Na⁺ gradient provides the energy for "uphill" transport of K⁺ and Cl^– into the cell. K⁺ channels (ROMK) in the luminal membrane allow for apical K⁺ recycling, whereas two highly homologous Cl^– channels (ClC-K) act in parallel as basolateral exit mechanisms for Cl^–. Operation of both Cl^– channels is dependent on an additional protein, the -subunit barttin. Furosemide acts via a direct inhibition of the Na⁺-K⁺-2Cl^– symporter, probably by attachment to its central hydrophobic domain (117).

View larger version (47K): [in this window] [in a new window]   Fig. 1. Modules of transcellular Na+-Cl– reabsorption in the thick ascending limb of Henle's loop (TAL; A), distal convoluted tubule (DCT; B) and cortical collecting duct (C), and site of action of the classic diuretic agents: chlorothiazide and furosemide. , ClC-K Cl– channel subunit barttin; NCCT, Na+-Cl– cotransporter; ClC-Ka and ClC-Kb, renal Cl– channel Ka and Kb, respectively; ENaC, epithelial Na+ channel; ROMK, renal outer medullary K+ channel, NKCC2, Na+-K+-2Cl– symporter type 2.

It is important to note that in contrast to the proximal tubule or collecting duct, in the TAL and DCT segments, transcellular Na⁺ reabsorption is directly coupled to Cl^– reabsorption. Therefore, disorders of salt reabsorption in the TAL and DCT affect both Na⁺ and Cl^– homeostasis. With the exception of Na⁺-K⁺-ATPase, mutations in all proteins, which have been mentioned here, were identified to cause SLTs with secondary hypokalemia. Despite this genetic heterogeneity, the historical separation into two major phenotypes still holds true, with disorders of the TAL, the furosemide-like SLTs, on the one side and disorders of the DCT, the thiazide-like SLTs, on the other. Because ion transport mechanisms are tightly coupled to each other, loss-of-function mutations affecting one module lead to the breakdown of the complete transport process in the respective tubular segment. Nevertheless, careful clinical evaluation revealed some distinctive features (Fig. 2), which are restricted to the defect of distinct proteins, and will be discussed in the following section in more detail.

View larger version (27K): [in this window] [in a new window]   Fig. 2. Genotype-phenotype correlation in untreated salt-losing tubulopathies. A: age of gestation at birth (GA). B: maximal urine osmolality in random morning urine samples. C: minimal plasma Cl– concentration. D: maximal urinary Ca2+ excretion (dashed line indicates the upper normal limit of about 4 mg·kg–1·day–1) and percentage of medullary nephrocalcinosis (NC). E: minimal plasma Mg2+ concentration (dashed line indicates the lower normal limit of 0.65 mM). Horizontal lines indicate the median; the open symbol in the Barttin group indicates the digenic ClC-Ka/ClC-Kb disorder.

	DISORDERS OF THE LOOP OF HENLE, THE FUROSEMIDE-LIKE SLTS

TOP ABSTRACT CASE REPORT FROM THE FIRST CLINICAL... MECHANISMS OF TRANSEPITHELIAL... DISORDERS OF THE LOOP... DISORDERS OF THE DISTAL... THE ENIGMATIC ROLE OF... SOLUTION OF THE CASE... GRANTS REFERENCES

Furosemide-sensitive Na⁺-K⁺-2Cl^– Cotransporter Type 2

Disruption of Na⁺-Cl^– reabsorption in the TAL due to inactivating mutations in NKCC2 causes a severe disorder with antenatal onset. Within the 2nd trimenon, fetal polyuria leads to increasing maternal polyhydramnios. Cl^– concentration in the amniotic fluid is elevated up to 118 mM (74, 85). Untreated, premature delivery occurs around 32 wk of gestation. The most striking abnormality of the newborns is profound polyuria. With adequate fluid replacement, daily urinary outputs can easily exceed half of the body weight of the newborn (>20 ml·kg^–1·h^–1). Despite both ECF volume depletion and presence of high vasopressin levels, the urine still has an osmolality hardly approaching that of plasma, indicating a virtually complete concentrating defect (103) (Fig. 2).

A gross deficit in the ability to concentrate urine is not unexpected in view of the unique location of the NKCC2 protein at the luminal surface of the TAL cells. Absence of the transcellular Na⁺-Cl^– transport via NKCC2 is also expected to abolish the lumen-positive transepithelial voltage that enables paracellular reabsorption of Na⁺. The combined absence of transcellular and paracellular transport of salt across the TAL cells prevents the establishment of the cortico-medullary osmotic gradient necessary for urine concentration. In turn, as salt reabsorption in the TAL segment is also critical for urine dilution, patients' urine osmolality typically did not decrease below 160 mosmol/kgH₂O. Moderately preserved ability to dilute urine might be explained by an adaptive increase of DCT salt reabsorption, which functions as the most distal portion of the diluting segment (87). This moderate hyposthenuria clearly separates NKCC2-deficient patients from polyuric patients with nephrogenic diabetes insipidus, who often display urine osmolalities below 100 mosmol/kgH₂O.

In addition to iso- or hyposthenuric polyuria, newborns lose large amounts of Na⁺-Cl^– through the urine, causing hyponatremia (120 mM) and hypochloremia (90 mM). Within days or a few weeks, urinary Na⁺ is decreasing and urinary K⁺ is increasing ("Na⁺-K⁺ switch") (88). Increased Na⁺ delivery to the distal tubule, particularly when combined with activation of renin-angiotensin-aldosterone system (RAAS), enhances excretion of K⁺ and H⁺, causing hypokalemic alkalosis. Interestingly, RAAS activation is present both prenatally and postnatally. Therefore, increased aldosterone levels in the amniotic fluid had been proposed as a diagnostic marker for the disorder (106).

Control of renin secretion is closely dependent on the function of salt-reabsorbing molecules. Macula densa (MD) cells possess the same solute transporter equipment as TAL epithelial cells. NKCC2 mediates Cl^– entry and, by this, provides a sensing mechanism for Cl^– concentration in the fluid of the adjacent lumen. When NKCC2 is defective, MD cells transduce a signal falsely indicating a very low amount of Cl^– in the lumen and activate, via MAP-kinases and cyclooxygenase (COX-2), renin release from juxtaglomerular cells (90, 127). An impaired MD chloride-sensing mechanism also disrupts tubuloglomerular feedback (TGF). Pharmacological inhibition of NKCC2 is known to prevent luminal Na⁺-Cl^– from affecting glomerular vascular tone (125). The absence of compensatory TGF-mediated decrease of GFR aggravates tubular salt and fluid wasting.

Within the first months of life, nearly all patients develop medullary nephrocalcinosis in parallel with persistently high urinary Ca²⁺ excretion. In the normal TAL, apical K⁺ secretion, together with basolateral secretion of Cl^– results in a transepithelial, lumen positive voltage difference of 10 mV (33, 34). This voltage gradient provides an important driving force for the paracellular flux of Na⁺, Ca²⁺, and Mg²⁺ into the interstitial space. In turn, impaired electrogenic Cl^– transport in the TAL inhibits paracellular transport of Ca²⁺, resulting in hypercalciuria. Remaining high Na⁺-Cl^– concentrations in the tubular lumen lead to an adaptive increase in Na⁺-Cl^– transport in segments downstream from TAL (1, 80). This will inhibit Ca²⁺ absorption in these more distal segments and further exacerbate urinary Ca²⁺ wasting (19). It is puzzling that conservation of Mg²⁺ is not affected to a similar extent, as NKCC2-deficient patients do not commonly have hypomagnesemia. This is even more surprising because loss-of-function mutations in paracellin-1, which ensures transport of divalent cations through the tight junctions of the TAL epithelia, invariably cause both hypercalciuria and hypermagnesiuria. Plasma Mg²⁺ levels in paracellin-1-deficient patients are often found to be below 0.4 mM (124). The difference between both disorders with respect to Mg²⁺ handling might be explained by an indissoluble upregulation of both Na⁺-Cl^– and Mg²⁺ reabsorption pathways in DCT cells in case of a NKCC2 defect (55).

Cardinal symptoms of NKCC2 deficiency displayed by humans, such as polyuria, hypercalciuria, PGE₂ overproduction, and failure to thrive, similarly were observed in the mouse knockout model. With respect to K⁺ handling and acid-base balance, however, NKCC2-deficient mice display a clearly different phenotype with metabolic acidosis and hyperkalemia (Table 2). Plasma Na⁺ and Cl^– concentrations are markedly elevated, suggesting that water diuresis exceeds renal salt loss. This discrepancy is likely attributable to profound congenital hydronephrosis of NKCC2-deficient mice, probably in response to the back pressure produced by polyuria (114). Similar morphological changes were also observed in polyuric mice lacking functional aquaporin-2 or V2 vasopressin receptor (126, 128). Therefore, these mouse models harbor a substantial risk that secondary structural damages conceal the consequences of the primary tubular dysfunction.

Operation of the NKCC2 symporter in TAL and MD cells requires continuous K⁺ supply from the cell into the tubular lumen (36). K⁺ recycling is enabled by the apical K⁺ channel ROMK (Fig. 1A). Because of this close functional coupling, ROMK-deficient patients share many tubular disabilities with patients defective for NKCC2. Retrospective genotyping of the HPS patients from Seyberth's original description (103) revealed patients 2–4 to be affected by NKCC2 mutations, and patient 5 to be affected by ROMK mutations.

ROMK-deficient patients share a history of maternal polyhydramnios, prematurity with median age of gestation of 33 wk, DDAVP-insensitive polyuria, isosthenuria, and hypercalciuria with secondary nephrocalcinosis, a condition clearly reflecting complete disruption of Na⁺-Cl^– reabsorption in the TAL. For renal physiologists, this finding might be surprising in view of the fact that microperfusion studies in the isolated TAL formerly demonstrated at least two distinct apical K⁺ channels, one with low (35 pS) and one with intermediate (70 pS) conductance (9). Because of its high open probability and larger single-channel conductance, it was assumed that the 70 pS channel contributes to two-thirds of the apical K⁺ conductance in the TAL. Functional characterization of cloned ROMK was compatible with the native 35 pS K⁺ channel. In contrast, cloning efforts of the 70 pS K⁺ channel were not successful in the past. Clinical data derived from ROMK-deficient patients now strongly suggest that the TAL 70 pS K⁺ channel is composed of ROMK and an accessory protein, which modifies the biophysical properties of the assembled complex. This is also in accordance with very recent observations in ROMK-deficient mice, which express neither the 70 pS nor the 35 pS K⁺ channels in TAL cells on either normal or high-K⁺ diets (72). Within the Kir family of inwardly rectifying K⁺ channels, which also contains the ROMK channel, interactions with other membrane proteins, such as ABC-binding cassette transporters, are not uncommon (18, 78, 115).

The mechanism of RAAS activation is virtually identical to that proposed for NKCC2-deficient patients. However, despite the presence of high plasma aldosterone levels, ROMK-deficient patients exhibit transient hyperkalemia in the first days of life (48). Hyperkalemia and coexistent hyponatremia together resemble the clinical picture of pseudohypoaldosteronism type 1 (PHA1). Indeed, several published cases of PHA1 turned out to be misdiagnosed since subsequent mutation analysis identified ROMK mutations as the underlying defect (2, 23, 106). The severity of initial hyperkalemia decreases with gestational age (84). Hyperkalemia is attributed to the additional role of ROMK in the cortical collecting duct (CCD) where it participates in the process of K⁺ secretion (Fig. 1C). Although less pronounced compared with defective NKCC2, most ROMK-deficient patients develop hypokalemia in the course of the disease (48). The only transient nature of hyperkalemia in our patients must be explained by an alternative K⁺ secretion pathway in the CCD. As correction of hyperkalemia does not occur right from the beginning, this alternative pathway might possibly be subject to maturation. One attractive candidate for the alternative route is the large-conductance (>100 pS) K⁺-channel identified in the apical membrane of CCD principal cells (25, 96). Because of its low open probability, the large-conductance K⁺ channel provides no significant apical K⁺ release under physiological conditions. Experimental data, however, suggest that its activity increases with enhanced fluid and solute delivery to the CCD (116, 121).

A tendency toward hyperkalemia is also observed in genetically engineered mice lacking ROMK, which might suggest the predominant role of ROMK for net K⁺ secretion in mice (71, 73). Drawing conclusions from the mouse model, however, again is hampered by concomitant congenital hydronephrosis. Total GFR of ROMK-deficient mice was only 15% of the wild-type, likely due to a reduced number of functioning nephrons (71). Renal insufficiency accounts for metabolic acidosis, which further aggravates hyperkalemia. Untreated, only a small percentage of ROMK-deficient mice survived to weaning. Remarkably, surviving mice preserve their ability to concentrate urine to about twice of the plasma osmolality. This is in contrast to NKCC2-deficient mice and is also not observed in the human phenotype (Fig. 2). Because Na⁺-Cl^– reabsorption in the TAL is an essential determinant of urinary concentration capacity, surviving ROMK-deficient mice may harbor compensatory mechanisms to overcome complete inhibition of TAL salt reabsorption. This was confirmed by micropuncture studies, which found Cl^– reabsorption between late proximal and early distal tubular sites to be reduced by 40%, but not completely blunted (71).

Chloride Channel -Subunit Barttin

The most recently identified molecule in the salt transport machinery of TAL epithelial cells is the renal Cl^– channel -subunit barttin. Discovery of barttin was initiated by chromosomal linkage of a very rare variant of tubular salt wasting associated with sensorineural deafness. Eight affected families have been reported so far, two of whom are treated in our hospital (50). By a positional cloning strategy, a novel gene, BSND, was identified, and inactivating mutations were found in affected individuals (8). Because the gene product, barttin, had no homology to any known protein, its physiological function remained unclear until two groups independently described the role of barttin as an essential -subunit of the ClC-K Cl^– channels (20, 122).

Two Cl^–1 channels of the ClC family are highly expressed along the distal nephron, with ClC-Ka being exclusively expressed in the thin ascending limb (tAL), and its homolog ClC-Kb predominantly expressed in the distal tubule. Colocalization of both Cl^– channels was observed in rat TAL segments (122). Previous efforts to express functional human ClC-K channels were unsuccessful. Only coexpression of ClC-K with the newly identified protein barttin reconstituted ClC-K-specific Cl^– currents. The function of barttin was defined as to facilitate the transport of ClC-K channels to the cell surface and to modulate biophysical properties of the assembled channel.

In affected individuals, the barttin defect implies a disruption of Cl^– exit across the basolateral membrane in TAL, as well as DCT cells. As a consequence, patients display the most severe phenotype among SLTs. The phenotype is in several features indistinguishable from the clinical picture attributed to a defect of the solute transporters in the apical TAL membrane, which proves the cross-talk between Na⁺-Cl^– apical entry and basolateral exit mechanisms.

The first symptom of the disorder is maternal polyhydramnios due to fetal polyuria beginning at 22 wk of gestation. Again, as in the NKCC2 or ROMK defect, polyhydramnios accounts for preterm labor and extreme prematurity. Postnatally, patients are at high risk of dehydration. Plasma Cl^– levels decrease to 80 mM; a further decrease usually can be avoided by close laboratory monitoring and rapid intervention in neonatal intensive care units. Polyuria again is resistant to DDAVP and urine osmolalities range between 200 and 400 mosmol/kgH₂O.

Unlike patients with loss-of-function mutations in ROMK and NKCC2, barttin-deficient patients exhibited only transitory hypercalciuria (50, 105). Medullary nephrocalcinosis was absent; instead, kidney biopsies showed pronounced tissue damage (glomerular sclerosis, tubular atrophy, and mononuclear infiltration). In contrast to classical HPS, progressive renal failure is common, two reported patients underwent renal transplantation (50), and one expired from acute renal failure (unpublished observation). Lack of hypercalciuria can be explained by the additional role of ClC-K-mediated Cl^– transport in the DCT. As chronic pharmacological inhibition of Na⁺-Cl^– transport in DCT by thiazides leads to hypocalciuria, the net effect of a combined defect in Na⁺-Cl^– transport in TAL and DCT might be neutral with respect to urinary Ca²⁺ excretion. In contrast, renal Mg²⁺ conservation is severely impaired, leading to a progressive decline of plasma Mg²⁺ concentration which is possibly the result of the disruption of both Mg²⁺ reabsorption pathways, the paracellular one in the TAL and the transcellular one in DCT, respectively. Likewise, the concerted action of furosemide and thiazides is associated with a greater risk to develop clinically relevant Mg²⁺ deficiency (57).

The barttin defect is invariably associated with sensorineural deafness. Clarification of the pathogenesis of this rare disorder has provided a deeper insight into the mechanisms of endolymph secretion in the inner ear: Marginal cells of the stria vascularis contribute to the endolymph composition by establishment of a high K⁺ gradient. Transcellular K⁺ passage is mediated by the furosemide-sensitive Na⁺-K⁺-2Cl^– symporter type 1 (NKCC1) ensuring K⁺ entry into the marginal cells. Voltage-dependent K⁺ channels mediate K⁺ secretion into the endolymph. Functional operation of NKCC1 requires Cl^– recycling from the cell into the interstitium. The barttin-deficient phenotype demonstrated for the first time that this recycling is provided by the ClC-K/barttin complex. Disruption of ion movement either by mutations in barttin or the apical K⁺ channels abolishes K⁺ secretion into the endolymph and causes inner ear deafness (111). Ototoxicity of furosemide which, next to NKCC2, also blocks the NKCC1 symporter, is also related to this pathway.

Renal Chloride Channels ClC-Ka and ClC-Kb (Digenic Disorder)

The concept of the physiological role of barttin as a common -subunit of ClC-K channels was substantiated by the very recent description of an individual harboring inactivating mutations in both the ClC-Ka and ClC-Kb Cl^– channel, respectively (97). The patient's phenotype is indistinguishable from barttin-deficient patients (Fig. 2) (39). This observation not only proves the concept of the functional interaction of barttin with both ClC-K isoforms but also excludes other important functions of barttin, not related to ClC-K channel interaction.

	DISORDERS OF THE DISTAL TUBULE, THE THIAZIDE-LIKE SLTs

TOP ABSTRACT CASE REPORT FROM THE FIRST CLINICAL... MECHANISMS OF TRANSEPITHELIAL... DISORDERS OF THE LOOP... DISORDERS OF THE DISTAL... THE ENIGMATIC ROLE OF... SOLUTION OF THE CASE... GRANTS REFERENCES

 
Renal Chloride Channel ClC-Kb (Monogenic Disorder)

Given a normal ClC-Ka function, an isolated defect of the ClC-Kb gene leads to a more variable phenotype. Several studies have indicated that the clinical variability is not related to a certain kind of mutation (62, 130). Even the most deleterious mutation, which implies the absence of the complete coding region of the ClC-Kb gene and which affects nearly 50% of this patient cohort, can cause varying degrees of disease severity. Features of tubular dysfunction distal from the TAL predominate (Fig. 2), suggesting a major role of ClC-Kb in the thiazide-sensitive tubular segment. Although TAL salt transport can be impaired to a variable extent, its function is never completely blunted. Obviously, other routes of basolateral Cl^– exit can be recruited in the TAL segment, most likely via ClC-Ka.

The neonatal period in ClC-Kb-deficient patients is usually uneventful. Only one of four patients had a history of mild maternal polyhydramnios. Median duration of pregnancy is 38.4 wk in our patient cohort. More than half of the patients are diagnosed within the first year of life. Symptoms at initial presentation include failure to thrive, dehydration, muscular hypotonia, and lethargy. Laboratory examination reveals plasma Cl^– concentration as low as 60 mM, plasma Na⁺ concentration of 120 mM, and severe hypokalemic alkalosis ([K⁺]_Plasma frequently below 2 mM). At first presentation, electrolyte derangement is usually more pronounced compared with the other groups, because renal salt wasting progresses slowly and is virtually not accompanied by polyuria, which delays medical consultation. Plasma renin activity is markedly increased, whereas plasma aldosterone concentration is only slightly elevated. This discrepancy might be attributed to inhibition of aldosterone secretion by hypokalemia and alkalosis. Therefore, normal or slightly elevated aldosterone levels under conditions of profound hypokalemic alkalosis are, in fact, inappropriately high.

Urinary concentration ability is preserved at least to a certain extent. Several patients achieved urinary osmolalities above 700 mosmol/kgH₂O in morning urine samples (Fig. 2). Because medullary hypertonicity critically depends on Na⁺-Cl^– reabsorption in the TAL, the ability to concentrate urine above 700 mosmol/kgH₂O indicates intact TAL function despite ClC-Kb deficiency. The integrity of TAL function is also reflected by the finding that hypercalciuria is present in only half of the patients and exists only temporarily. Indeed, the majority of patients exhibit normal or even low urinary Ca²⁺ in the follow-up examinations. Medullary nephrocalcinosis is rare. Plasma Mg²⁺ concentration gradually decreases over time because of impaired renal conservation (49). The molecular mechanisms for transcellular Mg²⁺ reabsorption in DCT will be discussed below. So far, it appears that transcellular Mg²⁺ transport closely depends on the function of Cl^– transport through DCT cells. Several ClC-Kb-deficient patients exhibit both hypomagnesemia and hypocalciuria, a condition that was thought to be pathognomonic for Gitelman's variant of Bartter syndrome (49, 101, 130). At present, a mouse ClC-Kb knockout is not available.

The ClC-Kb disorder largely parallels the features of Bartter's original description. The ethnic origin of Bartter's first patients supports this idea. Both were African Americans, and among this racial group, only ClC-Kb mutations have been found so far (101). African Americans were also suggested to be affected by BS more frequently (40) and to express a more severe course of the disease (123). In a recent study in five African American patients with ClC-Kb mutations, two of them had a history of polyhydramnios, which accounted for extreme prematurity (101). Postnatal polyuria and metabolic derangement led to a diagnosis in the neonatal period. The incidence of chronic renal failure tends to be higher among African American BS patients compared with other ethnic groups (3, 101).

Thus the phenotypic variability displayed by ClC-Kb-deficient patients might, in part, be explained by ethnic differences. It is tempting to speculate that usage of ion transport pathways is subject to evolutionary changes. The basolateral membrane of TAL epithelial cells is, in particular, suitable for more complex regulation, as at least two distinct Cl^– exit pathways exist. ClC-Ka and ClC-Kb orthologs were found to be coexpressed in the TAL segment in rats (122). An isolated defect of the ClC-Ka protein, as demonstrated by a ClC-Ka-deficient mouse model, induces a mild diabetes insipidus-like phenotype without major disturbances of renal salt homeostasis (76).

It was also suggested that Cl^– may pass across the basolateral membrane via K⁺-Cl^– cotransporters, which also reside in the TAL segment (17, 35), although knockout mice deficient for K⁺-Cl^– cotransporters do not suffer from renal salt wasting (11, 12). Again, physiological variations between different mammalian species have to be considered. In humans, the barttin- and combined ClC-Ka/b-deficient phenotypes suggest that the ClC-K channels predominantly mediate basolateral Cl^– efflux in the TAL segment. The relative contribution to this process can change between both channels, for example, by confounding genetic factors. Very recently, we described a frequent genetic variant of ClC-Kb, T481S, which causes pronounced channel activation (51). This polymorphism turned out to be more frequent in Western Africa and is associated with essential hypertension (52). Therefore, we hypothesize that genetic confounders, which are unequally distributed among different ethnicities, might also influence the ability to recruit ClC-Ka for compensation of ClC-Kb deficiency in the TAL, accounting for the more variable manifestation of the ClC-Kb disorder.

Thiazide-Sensitive Na⁺-Cl^– Cotransporter

Because the NCCT cotransporter is specifically expressed in DCT, the human phenotype deficient for NCCT serves as a valuable tool to assess the specific contribution of this segment to renal salt and fluid conservation. DCT epithelia contain two cell types (82): DCT1 cells that express the NCCT as its predominant apical Na⁺ entry pathway, and further distal residing DCT2 cells that express the epithelial Na⁺ channel as an additional pathway for apical Na⁺ reabsorption (Fig. 3) (70). Both Na⁺ entry pathways are inducible by aldosterone. DCT1 and DCT2 cells probably also differ in divalent cation transport.

View larger version (30K): [in this window] [in a new window]   Fig. 3. Division of DCT in type 1 and type 2 cells and main distribution of transport molecules for cation reabsorption (70, 120). DCT1 cells reabsorb Na+ and Mg2+ via the Na+-Cl– cotransporter and TRPM6, respectively, whereas DCT2 cells predominantly express the epithelial Na+ and the epithelial Ca2+ channels for apical entry. Preponderance of DCT1 cell function in hyperprostaglandin E syndrome (HPS), and preponderance of DCT2 cell function in Gitelman syndrome (GS) and to a lesser extent in Bartter syndrome could explain the hypercalciuric, normomagnesemic phenotype in HPS and the hypocalciuric, hypomagnesemic phenotype in GS.

Yet, the pathophysiology that compromises distal Mg²⁺ reabsorption and favors reabsorption of Ca²⁺ has not been identified conclusively. However, two observations in our and other patient studies provide some insights: 1) The occasional coexistence of hypomagnesemia and hypocalciuria in ClC-Kb-deficient patients indicates that the dissociation of renal Ca²⁺ and Mg²⁺ handling is not restricted to NCCT defects but rather a consequence of impaired transcellular Na⁺-Cl^– reabsorption in the DCT segment; and 2) 70% of the filtered load of Mg²⁺ and 30% of filtered Ca²⁺ are reabsorbed in the TAL via the paracellular route. Disruption of the paracellular route due to mutations of the tight-junction protein paracellin-1 causes severe hypomagnesemia and hypercalciuria. NKCC2 and ROMK patients with defective TAL Na⁺-Cl^– reabsorption also display hypercalciuria but do not develop severe hypomagnesemia. Different from the paracellin-1 disorder, defective salt reabsorption in the TAL increases the Na⁺-Cl^– load in the distal tubule and induces an upregulation of NCCT/ClC-Kb and ENaC (1, 80). Because loss-of-function of NCCT and ClC-Kb is associated with hypermagnesuria, one might safely predict that upregulation of NCCT/ClC-Kb will increase distal Mg²⁺ reabsorption. A significant influence of ENaC on distal Mg²⁺ uptake appears less likely as neither activating nor inactivating mutations cause major disturbances in renal Mg²⁺ handling.

Recently, the genetic analysis of a rare Mg²⁺-wasting disorder, hypomagnesemia with secondary hypocalcemia, identified TRPM6, a new member of the transient receptor potential (TRP) family of cation channels, as the first component of active transcellular Mg²⁺ reabsorption in the DCT (98). TRPM6 colocalizes with the NCCT protein, and is thought to participate in the formation of the apical Mg²⁺-permeable ion channel in DCT1 cells (Fig. 3) (120). Yet, a direct link between active Na⁺-Cl^– absorption and uptake of Mg²⁺ in DCT1 cells is still missing. However, indirect evidence is provided by the laboratory condition found in NCCT (and ClC-Kb)-deficient patients, as well as by morphological studies upon pharmacological inhibition of NCCT in rats. Long-term administration of thiazides reduced DCT cell mass in rat kidney, probably by inducing apoptosis (69). This observation was also confirmed by morphometric analyses of distal convolutions in NCCT-deficient mice (100). Laboratory examination further confirmed the dissociation of renal Ca²⁺ and Mg²⁺ handling as previously described for GS patients, although these mice did not exhibit metabolic alkalosis and hypokalemia. Whereas NCCT (and TRPM6)-containing DCT1 cells undergo apoptosis, the DCT2 cells that predominantly express ENaC can proliferate. Because DCT2 cells also express the epithelial Ca²⁺ channel ECaC (Fig. 3) (70), subsequent increase of the absorption capacity for Ca²⁺ could explain low urinary Ca²⁺ in Bartter/Gitelman syndrome, as well as the hypocalciuric effect of long-term administration of thiazides.

	THE ENIGMATIC ROLE OF PROSTAGLANDIN E2 IN SLT

TOP ABSTRACT CASE REPORT FROM THE FIRST CLINICAL... MECHANISMS OF TRANSEPITHELIAL... DISORDERS OF THE LOOP... DISORDERS OF THE DISTAL... THE ENIGMATIC ROLE OF... SOLUTION OF THE CASE... GRANTS REFERENCES

 
The involvement of prostaglandins in the pathogenesis of SLTs has been recognized early by several investigators (22, 31, 119). Bartter hypothesized PGE₂ hyperactivity being a phenomenon secondary to hypokalemia. However, this hypothesis is not supported by several more recent experimental and clinical studies. In SLT patients, PGE₂ excretion did not correlate with the degree of hypokalemia. For example, ROMK-deficient patients who exert only modest hypokalemia, if at all, displayed much higher urinary PGE₂ concentrations compared with BS/GS patients with more severe hypokalemia (Table 4).

First, indomethacin reduces polyuria by reducing GFR. Although COX inhibition is associated with a moderate decrease of GFR by an average of 22% in these studies, this does not completely explain the correction of saluresis by about 50% (range 34 to 65%) and a rise in urinary osmolality from a median of 155 to 187 mosmol/kgH₂O (99) (236 to 270 mosmol/kgH₂O, more recent unpublished data) in furosemide-like SLTs (31, 67, 81, 89, 90, 99, 103).

Second, indomethacin reduces polyuria by inhibiting the diuretic effects of PGE₂. Single nephron perfusion studies from the late 1980s have shown that coadministration of furosemide and indomethacin reduces the diuretic effect observed with furosemide only in the loop of Henle by 50% (37). Add-back experiments with various prostaglandins have shown that only PGE₂ restores the diuretic effect of furosemide when coadministered with indomethacin (56). This finding indicates that the diuretic action of furosemide requires induction and action of PGE₂. PGE₂ exerts its biological effects through interaction with various tubular G protein coupling receptors, named EP-receptors. In rabbit isolated perfused collecting ducts, activation of EP1 inhibits Na⁺ and water reabsorption via a Ca²⁺-coupled mechanism (38). EP3 inhibits cAMP formation by coupling to pertussis-sensitive inhibitory G-protein. Activation of EP3 has been shown to inhibit AVP stimulated salt and water absorption in the thick ascending limb and the collecting duct, respectively (45). The notion that PGE₂ has direct tubular effects is in keeping with the observation that indomethacin reduces polyuria to a greater extent than GFR in SLT patients (90).

Finally, excessive PGE₂ formation may result in an enhanced renal medullary perfusion (94), resulting in a washout of the osmotic gradient and may thus further compromise renal concentrating ability in patients affected by hypokalemic SLT.

Presently unresolved is the issue about the precise molecular mechanisms that activate COX-2 and microsomal PGE₂ synthase in the salt-wasting state, as well as the precise molecular targets of PGE₂. Nevertheless, unspecific COX inhibitors, as well as COX-2-specific inhibitors, are presently the major pharmacotherapeutic option we can offer to our patients with SLTs. They are of unsurpassed benefit, particularly during life-threatening situations in the perinatal period and early infancy due to renal salt and water wasting and the deleterious effects of extrarenal PGE₂ hyperactivity like vomiting, diarrhea, and fever. Treatment of SLT patients with COX-2 inhibitors such as rofecoxib compared with classical nonsteroidal anti-inflammatory drugs (NSAIDs) such as indomethacin may be superior in terms of gastrointestinal side effects and specificity. However, recent studies suggest that long-term exposure to rofecoxib may carry a higher cardiovascular risk compared with nonselective inhibitors such as naproxen (24). Therefore, treatment of SLT patients should be initiated with classical NSAIDs such as indomethacin.

	SOLUTION OF THE CASE REPORT

TOP ABSTRACT CASE REPORT FROM THE FIRST CLINICAL... MECHANISMS OF TRANSEPITHELIAL... DISORDERS OF THE LOOP... DISORDERS OF THE DISTAL... THE ENIGMATIC ROLE OF... SOLUTION OF THE CASE... GRANTS REFERENCES

 
When treatment with indomethacin was initiated, initially, hyperprostaglandin E syndrome was suspected. However, the demonstration of sensorineural deafness, as well as the absence of medullary nephrocalcinosis, which was established shortly thereafter, rather suggested a barttin defect. Surprisingly, neither the haplotype data nor the direct sequencing of the barttin gene could confirm this assumption. A novel explanation was a digenic disorder that affects both ClC-K Cl^– channels. Indeed, this hypothesis turned out to be true when we identified for the first time a homozygous point mutation in the ClC-Ka channel, together with a complete deletion of the ClC-Kb channel gene (97). Thus the patient's unique clinical picture with severe salt-wasting, sensorineural deafness, and absence of nephrocalcinosis together with the knowledge about the function of ClC-Ka and ClC-Kb previously defined in barttin-deficient patients, led to the identification of the underlying genetic defect. Without this premise, the detection of an extremely rare digenic defect affecting two Cl^– channel genes probably would not have been possible.

Perspectives

Although careful clinical examination of patients suffering from inherited salt-losing kidney disorders taught us a lot about the role of the affected transport proteins in the process of renal tubular salt reabsorption, there still remain several open questions: How do we identify regulators of compensatory activation of Na⁺-Cl^– conserving mechanisms in response to pharmacological or inherited blockage of a single solute transporter? How can we explain the dramatic effect of cyclooxygenase inhibitors on renal tubular salt handling? And what are the reasons for the phenotypic differences between the human diseases and the animal models? We hope that with this review, we have clearly pointed out that to answer these questions, we depend on the close interaction between basic science and clinical medicine.

	GRANTS

TOP ABSTRACT CASE REPORT FROM THE FIRST CLINICAL... MECHANISMS OF TRANSEPITHELIAL... DISORDERS OF THE LOOP... DISORDERS OF THE DISTAL... THE ENIGMATIC ROLE OF... SOLUTION OF THE CASE... GRANTS REFERENCES

 
This work was supported by the Deutsche Forschungsgemeinschaft (Ko1480-3/3, Wa1088/3-2, and Se263/17-2).

	ACKNOWLEDGMENTS

 
We thank M. L. Halperin in Toronto and D. Puliyanda in Los Angeles for critical reading of the manuscript.

	FOOTNOTES

 

Address for reprint requests and other correspondence: Hannsjörg W. Seyberth, MD, Univ. Children's Hospital, Philipps-Univ., Deutschhausstrasse 12, D-35037 Marburg, Germany (E-mail:seyberth{at}staff.uni-marburg.de)

	REFERENCES

TOP ABSTRACT CASE REPORT FROM THE FIRST CLINICAL... MECHANISMS OF TRANSEPITHELIAL... DISORDERS OF THE LOOP... DISORDERS OF THE DISTAL... THE ENIGMATIC ROLE OF... SOLUTION OF THE CASE... GRANTS REFERENCES

 

1. Abdallah JG, Schrier RW, Edelstein C, Jennings SD, Wyse B, and Ellison DH. Loop diuretic infusion increases thiazide-sensitive Na(+)/Cl(-)-cotransporter abundance: role of aldosterone. J Am Soc Nephrol 12: 1335–1341, 2001.[Abstract/Free Full Text]
2. Abramson O, Zmora E, Mazor M, and Shinwell ES. Pseudohypoaldosteronism in a preterm infant: intrauterine presentation as hydramnios. J Pediatr 120: 129–132, 1992.[CrossRef][Web of Science][Medline]
3. Arant BS, Brackett NC Jr, Young RB, and Still WJ. Case studies of siblings with juxtaglomerular hyperplasia and secondary aldosteronism associated with severe azotemia and renal rickets—Bartter's syndrome or disease? Pediatrics 46: 344–361, 1970.[Abstract/Free Full Text]
4. Bartter FC. On the pathogenesis of Bartter's syndrome. Miner Electrolyte Metab 3: 61–65, 1980.
5. Bartter FC, Pronove P, Gill JR Jr, MacCardle RC, and Diller E. Hyperplasia of the juxtaglomerular complex with hyperaldosteronism and hypokalemic alkalosis. A new syndrome. Am J Med 33: 811–828, 1962.[CrossRef][Web of Science][Medline]
6. Bartter FC, Pronove P, Gill JR Jr, MacCardle RC, and Lifton RP. Hyperplasia of the juxtaglomerular complex with hyperaldosteronism and hypokalemic alkalosis. A new syndrome 1962. J Am Soc Nephrol 9: 516–528, 1998.[Abstract]
7. Bettinelli A, Bianchetti MG, Girardin E, Caringella A, Cecconi M, Appiani AC, Pavanello L, Gastaldi R, Isimbaldi C, Lama G, Marchesoni C, Matteuchi C, Patriarca P, Di Natale B, Setzu C, and Vitucci P. Use of calcium excretion values to distinguish two forms of primary renal tubular hypokalemic alkalosis: Bartter and Gitelman syndromes. J Pediatr 120: 38–43, 1992.[CrossRef][Web of Science][Medline]
8. Birkenhager R, Otto E, Schurmann MJ, Vollmer M, Ruf EM, Maier-Lutz I, Beekmann F, Fekete A, Omran H, Feldmann D, Milford DV, Jeck N, Konrad M, Landau D, Knoers NV, Antignac C, Sudbrak R, Kispert A, and Hildebrandt F. Mutation of BSND causes Bartter syndrome with sensorineural deafness and kidney failure. Nat Genet 29: 310–314, 2001.[CrossRef][Web of Science][Medline]
9. Bleich M, Schlatter E, and Greger R. The luminal K+ channel of the thick ascending limb of Henle's loop. Pflügers Arch 415: 449–460, 1990.[CrossRef][Web of Science][Medline]
10. Boer WH, Hene RJ, Koomans HA,. and Dorhout Mees E. J. Discrepancy between lithium and free water clearance in patients with Bartter's syndrome. Nephron 67: 82–87, 1994.[Web of Science][Medline]
11. Boettger T, Hubner CA, Maier H, Rust MB, Beck FX, and Jentsch TJ. Deafness and renal tubular acidosis in mice lacking the K-Cl co-transporter Kcc4. Nature 416: 874–878, 2002.[CrossRef][Medline]
12. Boettger T, Rust MB, Maier H, Seidenbecher T, Schweizer M, Keating DJ, Faulhaber J, Ehmke H, Pfeffer C, Scheel O, Lemcke B, Horst J, Leuwer R, Pape HC, Volkl H, Hubner CA, and Jentsch TJ. Loss of K-Cl co-transporter KCC3 causes deafness, neurodegeneration and reduced seizure threshold. EMBO J 22: 5422–5434, 2003.[CrossRef][Web of Science][Medline]
13. Burg M, Stoner J, Cardinal N, and Green N. Furosemide effect on isolated perfused tubules. Am J Physiol 225: 119–124, 1973.[Free Full Text]
14. Cheng HF, Wang JL, Zhang MZ, McKanna JA, and Harris RC. Role of p38 in the regulation of renal cortical cyclooxygenase-2 expression by extracellular chloride. J Clin Invest 106: 681–688, 2000.[Web of Science][Medline]
15. Ciabattoni G, Pugliese F, Cinotti GA, Stirati G, Ronci R, Castrucci G, Pierucci A, and Patrono C. Characterization of furosemide-induced activation of the renal prostaglandin system. Eur J Pharmacol 60: 181–187, 1979.[CrossRef][Web of Science][Medline]
16. Colussi G, Rombola G, Verde G, Airaghi C, Loli P, and Minetti L. Distal nephron function in Bartter's syndrome: abnormal conductance to chloride in the cortical collecting tubule? Am J Nephrol 12: 229–239, 1992.[Web of Science][Medline]
17. Di Stefano A, Jounier S, and Wittner M. Evidence supporting a role for KCl cotransporter in the thick ascending limb of Henle's loop. Kidney Int 60: 1809–1823, 2001.[CrossRef][Web of Science][Medline]
18. Dong K, Xu J, Vanoye CG, Welch R, MacGregor GG, Giebisch G, and Hebert SC. An amino acid triplet in the NH2 terminus of rat ROMK1 determines interaction with SUR2B. J Biol Chem 276: 44347–44353, 2001.[Abstract/Free Full Text]
19. Ellison DH. Divalent cation transport by the distal nephron: insights from Bartter's and Gitelman's syndromes. Am J Physiol Renal Physiol 279: F616–F625, 2000.[Abstract/Free Full Text]
20. Estevez R, Boettger T, Stein V, Birkenhager R, Otto E, Hildebrandt F, and Jentsch TJ. Barttin is a Cl- channel -subunit crucial for renal Cl- reabsorption and inner ear K+ secretion. Nature 414: 558–561, 2001.[CrossRef][Medline]
21. Fanconi A, Schachenmann G, Nüssli R, and Prader A. Chronic hypokalaemia with growth retardation, normotensive hyperrenin-hyperaldosteronism ("Bartter's syndrome"), and hypercalciuria. Report of two cases with emphasis on natural history and on catch-up growth during treatment. Helv Paediat Acta 2: 144–163, 1971.
22. Fichman MP, Telfer N, Zia P, Speckart P, Golub M, and Rude R. Role of prostaglandins in the pathogenesis of Bartter's syndrome. Am J Med 60: 785–797, 1976.[CrossRef][Web of Science][Medline]
23. Finer G, Shalev H, Birk OS, Galron D, Jeck N, Sinai-Treiman L, and Landau D. Transient neonatal hyperkalemia in the antenatal (ROMK defective) Bartter syndrome. J Pediatr 142: 318–323, 2003.[CrossRef][Web of Science][Medline]
24. FitzGerald GA. Cardiovascular pharmacology of nonselective nonsteroidal anti-inflammatory drugs and coxibs: clinical considerations. Am J Cardiol 89: 26D–32D, 2002.[CrossRef][Web of Science][Medline]
25. Frindt G and Palmer LG. Ca-activated K channels in apical membrane of mammalian CCT, and their role in K secretion. Am J Physiol Renal Fluid Electrolyte Physiol 252: F458–F467, 1987.[Abstract/Free Full Text]
26. Fuson AL, Komlosi P, Unlap TM, Bell PD,. and Peti-Peterdi J. Immunolocalization of a microsomal prostaglandin E synthase in rabbit kidney. Am J Physiol Renal Physiol 285: F558–F564, 2003.[Abstract/Free Full Text]
27. Gamba G, Miyanoshita A, Lombardi M, Lytton J, Lee WS, Hediger MA, and Hebert SC. Molecular cloning, primary structure, and characterization of two members of the mammalian electroneutral sodium-(potassium)-chloride cotransporter family expressed in kidney. J Biol Chem 269: 17713–17722, 1994.[Abstract/Free Full Text]
28. Gamba G, Saltzberg SN, Lombardi M, Miyanoshita A, Lytton J, Hediger MA, Brenner BM, and Hebert SC. Primary structure and functional expression of a cDNA encoding the thiazide-sensitive, electroneutral sodium-chloride cotransporter. Proc Natl Acad Sci USA 90: 2749–2753, 1993.[Abstract/Free Full Text]
29. Gascon A, Cobeta-Garcia JC, and Iglesias E. Hypomagnesemia and chondrocalcinosis in Gitelman syndrome. Am J Med 107: 301–302, 1999.[CrossRef][Web of Science][Medline]
30. Gill JR Jr and Bartter FC. Evidence for a prostaglandin-independent defect in chloride reabsorption in the loop of Henle as a proximal cause of Bartter's syncrome. Am J Med 65: 766–772, 1978.[CrossRef][Web of Science][Medline]
31. Gill JR Jr, Frolich JC, Bowden RE, Taylor AA, Keiser HR, Seyberth HW, Oates JA, and Bartter FC. Bartter's syndrome: a disorder characterized by high urinary prostaglandins and a dependence of hyperreninemia on prostaglandin synthesis. Am J Med 61: 43–51, 1976.[CrossRef][Web of Science][Medline]
32. Gitelman HJ, Graham JB, and Welt LG. A new familial disorder characterized by hypokalemia and hypomagnesemia. Trans Assoc Am Physicians 79: 221–223, 1966.[Medline]
33. Good DW, Knepper MA, and Burg MB. Ammonia and bicarbonate transport by thick ascending limb of rat kidney. Am J Physiol Renal Fluid Electrolyte Physiol 247: F35–F44, 1984.[Abstract/Free Full Text]
34. Greger R. Ion transport mechanisms in thick ascending limb of Henle's loop of mammalian nephron. Physiol Rev 65: 760–797, 1985.[Free Full Text]
35. Greger R and Schlatter E. Properties of the basolateral membrane of the cortical thick ascending limb of Henle's loop of rabbit kidney. A model for secondary active chloride transport. Pflügers Arch 396: 325–334, 1983.[CrossRef][Web of Science][Medline]
36. Greger R and Schlatter E. Presence of luminal K+, a prerequisite for active NaCl transport in the cortical thick ascending limb of Henle's loop of rabbit kidney. Pflügers Arch 392: 92–94, 1981.[CrossRef][Web of Science][Medline]
37. Greven J and Farjam A. Effect of inhibitors of prostaglandin synthesis on the furosemide action in the loop Henle of rat kidney. Pflügers Arch 411: 579–583, 1988.[CrossRef][Web of Science][Medline]
38. Guan Y, Zhang Y, Breyer RM, Fowler B, Davis L, Hebert RL, and Breyer MD. Prostaglandin E2 inhibits renal collecting duct Na+ absorption by activating the EP1 receptor. J Clin Invest 102: 194–201, 1998.[Web of Science][Medline]
39. Haas NA, Nossal R, Schneider CH, Lewin MA, Ocker V, Holder M, and Uhlemann F. Successful management of an extreme example of neonatal hyperprostaglandin-E syndrome (Bartter's syndrome) with the new cyclooxygenase-2 inhibitor rofecoxib. Pediatr Crit Care Med 4: 249–251, 2003.[CrossRef][Medline]
40. Hall BD. Preponderance of Bartter syndrome among blacks. N Engl J Med 285: 581, 1971.[Web of Science][Medline]
41. Hansson JH, Schild L, Lu Y, Wilson TA, Gautschi I, Shimkets R, Nelson-Williams C, Rossier BC, and Lifton RP. A de novo missense mutation of the subunit of the epithelial sodium channel causes hypertension and Liddle syndrome, identifying a proline-rich segment critical for regulation of channel activity. Proc Natl Acad Sci USA 92: 11495–11499, 1995.[Abstract/Free Full Text]
42. Hansson JH, Nelson-Williams C, Suzuki H, Schild L, Shimkets R, Lu Y, Canessa C, Iwasaki T, Rossier B, and Lifton RP. Hypertension caused by a truncated epithelial sodium channel subunit: genetic heterogeneity of Liddle syndrome. Nat Genet 11: 76–82, 1995.[CrossRef][Web of Science][Medline]
43. Harding P, Sigmon DH, Alfie ME, Huang PL, Fishman MC, Beierwaltes WH, and Carretero OA. Cyclooxygenase-2 mediates increased renal renin content induced by low-sodium diet. Hypertension 29: 297–302, 1997.[Abstract/Free Full Text]
44. Harris RC, McKanna JA, Akai Y, Jacobson HR, Dubois RN, and Breyer MD. Cyclooxygenase-2 is associated with the macula densa of rat kidney and increases with salt restriction. J Clin Invest 94: 2504–2510, 1994.[Web of Science][Medline]
45. Hebert RL, Jacobson HR, Fredin D, and Breyer MD. Evidence that separate PGE2 receptors modulate water and sodium transport in rabbit cortical collecting duct. Am J Physiol Renal Fluid Electrolyte Physiol 265: F643–F650, 1993.[Abstract/Free Full Text]
46. Ho K, Nichols CG, Lederer WJ, Lytton J, Vassilev PM, Kanazirska MV, and Hebert SC. Cloning and expression of an inwardly rectifying ATP-regulated potassium channel. Nature 362: 31–38, 1993.[CrossRef][Medline]
47. International Study Group for Bartter-like syndromes, Károlyi L, Konrad M, Kockerling A, Ziegler A, Zimmermann DK, Roth B, Wieg C, Grzeschik KH, Koch MC, Seyberth HW, Vargas R, Forestier L, Jean G, Deschaux M, Rizzoni GF, Niaudet P, Antignac C, Feldmann D, Lorridon F, Cougoureux E, Laroze F, Alessandri JL, David L, Saunier P, Deschenes G, Hildebrandt F, Vollmer M, Proesmans W, Brandis M, Van Den Heuvel LP, Lemmink HH, Nillesen W, Monnens LAH, Knoers NV, Guay-Woodford LM, Wright CJ, Madrigal G, and Hebert SC. Mutations in the gene encoding the inwardly-rectifying renal potassium channel, ROMK, cause the antenatal variant of Bartter syndrome: evidence for genetic heterogeneity. Hum Mol Genet 6: 17–26, 1997.[Medline]
48. Jeck N, Derst C, Wischmeyer E, Ott H, Weber S, Rudin C, Seyberth HW, Daut J, Karschin A, and Konrad M. Functional heterogeneity of ROMK mutations linked to hyperprostaglandin E syndrome. Kidney Int 59: 1803–1811, 2001.[CrossRef][Web of Science][Medline]
49. Jeck N, Konrad M, Peters M, Weber S, Bonzel KE, and Seyberth HW. Mutations in the chloride channel gene, CLCNKB, leading to a mixed Bartter-Gitelman phenotype. Pediatr Res 48: 754–758, 2000.[Web of Science][Medline]
50. Jeck N, Reinalter SC, Henne T, Marg W, Mallmann R, Pasel K, Vollmer M, Klaus G, Leonhardt A, Seyberth HW, and Konrad M. Hypokalemic salt-losing tubulopathy with chronic renal failure and sensorineural deafness. Pediatrics 108: E5, 2001.[CrossRef][Medline]
51. Jeck N, Waldegger P, Doroszewicz J, Seyberth H, and Waldegger S. A common sequence variation of the CLCNKB gene strongly activates ClC-Kb chloride channel activity. Kidney Int 65: 190–197, 2004.[CrossRef][Web of Science][Medline]
52. Jeck N, Waldegger S, Lampert A, Boehmer C, Waldegger P, Lang PA, Wissinger B, Friedrich B, Risler T, Moehle R, Lang UE, Zill P, Bondy B, Schaeffeler E, Asante-Poku S, Seyberth H, Schwab M, and Lang F. Activating mutation of the renal epithelial chloride channel ClC-Kb predisposing to hypertension. Hypertension 43: 1175–1181, 2004.[Abstract/Free Full Text]
53. Jentsch TJ, Steinmeyer K, and Schwarz G. Primary structure of Torpedo marmorata chloride channel isolated by expression cloning in Xenopus oocytes. Nature 348: 510–514, 1990.[CrossRef][Medline]
54. Kaissling B, Bachmann S, and Kriz W. Structural adaptation of the distal convoluted tubule to prolonged furosemide treatment. Am J Physiol Renal Fluid Electrolyte Physiol 248: F374–F381, 1985.[Abstract/Free Full Text]
55. Kamel KS, Oh MS, and Halperin ML. Bartter's, Gitelman's, and Gordon's syndromes. From physiology to molecular biology and back, yet still some unanswered questions. Nephron 92, Suppl 1: 18–27, 2002.[CrossRef][Web of Science][Medline]
56. Kirchner KA, Martin CJ, and Bower JD. Prostaglandin E2 but not I2 restores furosemide response in indomethacin-treated rats. Am J Physiol Renal Fluid Electrolyte Physiol 250: F980–F985, 1986.[Abstract/Free Full Text]
57. Knauf H and Mutschler E. Diuretic effectiveness of hydrochlorothiazide and furosemide alone and in combination in chronic renal failure. J Cardiovasc Pharmacol 26: 394–400, 1995.[Web of Science][Medline]
58. Kockerling A, Reinalter SC, and Seyberth HW. Impaired response to furosemide in hyperprostaglandin E syndrome: evidence for a tubular defect in the loop of Henle. J Pediatr 129: 519–528, 1996.[CrossRef][Web of Science][Medline]
59. Komhoff M, Jeck ND, Seyberth HW, Grone HJ, Nusing RM, and Breyer MD. Cyclooxygenase-2 expression is associated with the renal macula densa of patients with Bartter-like syndrome. Kidney Int 58: 2420–2424, 2000.[CrossRef][Web of Science][Medline]
60. Komhoff M, Reinalter SC, Grone HJ, and Seyberth HW. Induction of microsomal prostaglandin E2 synthase in the macula densa in children with hypokalemic salt-losing tubulopathies. Pediatr Res 19: 19, 2003.
61. Konrad M, Leonhardt A, Hensen P, Seyberth HW, and Kockerling A. Prenatal and postnatal management of hyperprostaglandin E syndrome after genetic diagnosis from amniocytes. Pediatrics 103: 678–683, 1999.[Abstract/Free Full Text]
62. Konrad M, Vollmer M, Lemmink HH, van den Heuvel LP, Jeck N, Vargas-Poussou R, Lakings A, Ruf R, Deschenes G, Antignac C, Guay-Woodford L, Knoers NV, Seyberth HW, Feldmann D, and Hildebrandt F. Mutations in the chloride channel gene CLCNKB as a cause of classic Bartter syndrome. J Am Soc Nephrol 11: 1449–1459, 2000.[Abstract/Free Full Text]
63. Kramer BK, Kammerl MC, and Komhoff M. Renal cyclooxygenase-2 (Cox-2). Physiological, pathophysiological, and clinical implications. Kidney Blood Press Res 27: 43–62, 2004.[CrossRef][Web of Science][Medline]
64. Kunau RT Jr, Weller DR, and Webb HL. Clarification of the site of action of chlorothiazide in the rat nephron. J Clin Invest 56: 401–407, 1975.[Web of Science][Medline]
65. Lemmink HH, Knoers NV, Karolyi L, van Dijk H, Niaudet P, Antignac C, Guay-Woodford LM, Goodyer PR, Carel JC, Hermes A, Seyberth HW, Monnens LA, and van den Heuvel LP. Novel mutations in the thiazide-sensitive NaCl cotransporter gene in patients with Gitelman syndrome with predominant localization to the C-terminal domain. Kidney Int 54: 720–730, 1998.[CrossRef][Web of Science][Medline]
66. Leonhardt A, Busch C, Schweer H, and Seyberth HW. Reference intervals and developmental changes in urinary prostanoid excretion in healthy newborns, infants and children. Acta Paediatr 81: 191–196, 1992.[Web of Science][Medline]
67. Leonhardt A, Timmermanns G, Roth B, and Seyberth HW. Calcium homeostasis and hypercalciuria in hyperprostaglandin E syndrome. J Pediatr 120: 546–554, 1992.[CrossRef][Web of Science][Medline]
68. Lin SH, Cheng NL, Hsu YJ, and Halperin ML. Intrafamilial phenotype variability in patients with Gitelman syndrome having the same mutations in their thiazide-sensitive sodium/chloride cotransporter. Am J Kidney Dis 43: 304–312, 2004.[CrossRef][Web of Science][Medline]
69. Loffing J, Loffing-Cueni D, Hegyi I, Kaplan MR, Hebert SC, Le Hir M, and Kaissling B. Thiazide treatment of rats provokes apoptosis in distal tubule cells. Kidney Int 50: 1180–1190, 1996.[Web of Science][Medline]
70. Loffing J, Loffing-Cueni D, Valderrabano V, Klausli L, Hebert SC, Rossier BC, Hoenderop JG, Bindels RJ, and Kaissling B. Distribution of transcellular calcium and sodium transport pathways along mouse distal nephron. Am J Physiol Renal Physiol 281: F1021–F1027, 2001.[Abstract/Free Full Text]
71. Lorenz JN, Baird NR, Judd LM, Noonan WT, Andringa A, Doetschman T, Manning PA, Liu LH, Miller ML, and Shull GE. Impaired renal NaCl absorption in mice lacking the ROMK potassium channel, a model for type II Bartter's syndrome. J Biol Chem 277: 37871–37880, 2002.[Abstract/Free Full Text]
72. Lu M, Wang T, Yan Q, Wang W, Giebisch G, and Hebert SC. ROMK is required for expression of the 70-pS K channel in the thick ascending limb. Am J Physiol Renal Physiol 286: F490–F495, 2004.[Abstract/Free Full Text]
73. Lu M, Wang T, Yan Q, Yang X, Dong K, Knepper MA, Wang W, Giebisch G, Shull GE, and Hebert SC. Absence of small conductance K+ channel (SK) activity in apical membranes of thick ascending limb and cortical collecting duct in ROMK (Bartter's) knockout mice. J Biol Chem 277: 37881–37887, 2002.[Abstract/Free Full Text]
74. Massa G, Proesmans W, Devlieger H, Vandenberghe K, Van Assche A, and Eggermont E. Electrolyte composition of the amniotic fluid in Bartter syndrome. Eur J Obstet Gynecol Reprod Biol 24: 335–340, 1987.[CrossRef][Web of Science][Medline]
75. Mastroianni N, De Fusco M, Zollo M, Arrigo G, Zuffardi O, Bettinelli A, Ballabio A, and Casari G. Molecular cloning, expression pattern, and chromosomal localization of the human NaCl thiazide-sensitive cotransporter (SLC12A3). Genomics 35: 486–493, 1996.[CrossRef][Web of Science][Medline]
76. Matsumura Y, Uchida S, Kondo Y, Miyazaki H, Ko SB, Hayama A, Morimoto T, Liu W, Arisawa M, Sasaki S, and Marumo F. Overt nephrogenic diabetes insipidus in mice lacking the ClC-K1 chloride channel. Nat Genet 21: 95–98, 1999.[CrossRef][Web of Science][Medline]
77. McCredie DA, Blair-West JR, Scoggins BA, and Shipman R. Potassium-losing nephropathy of childhood. Med J Aust 1: 129–135, 1971.[Web of Science][Medline]
78. McNicholas CM, Guggino WB, Schwiebert EM, Hebert SC, Giebisch G, and Egan ME. Sensitivity of a renal K+ channel (ROMK2) to the inhibitory sulfonylurea compound glibenclamide is enhanced by coexpression with the ATP-binding cassette transporter cystic fibrosis transmembrane regulator. Proc Natl Acad Sci USA 93: 8083–8088, 1996.[Abstract/Free Full Text]
79. Moreno E, Tovar-Palacio C, de los Heros P, Guzman B, Bobadilla NA, Vazquez N, Riccardi D, Poch E, and Gamba G. A single nucleotide polymorphism alters the activity of the renal Na+:Cl- cotransporter and reveals a role for transmembrane segment 4 in chloride and thiazide affinity. J Biol Chem 279: 16553–16560, 2004.[Abstract/Free Full Text]
80. Na KY, Oh YK, Han JS, Joo KW, Lee JS, Earm JH, Knepper MA, and Kim GH. Upregulation of Na+ transporter abundances in response to chronic thiazide or loop diuretic treatment in rats. Am J Physiol Renal Physiol 284: F133–F143, 2003.[Abstract/Free Full Text]
81. Nusing RM, Reinalter SC, Peters M, Komhoff M, and Seyberth HW. Pathogenetic role of cyclooxygenase-2 in hyperprostaglandin E syndrome/antenatal Bartter syndrome: therapeutic use of the cyclooxygenase-2 inhibitor nimesulide. Clin Pharmacol Ther 70: 384–390, 2001.[CrossRef][Web of Science][Medline]
82. Obermuller N, Bernstein P, Velasquez H, Reilly R, Moser D, Ellison DH, and Bachmann S. Expression of the thiazide-sensitive NaCl-cotransporter in rat and human kidney. Am J Physiol Renal Fluid Electrolyte Physiol 269: F900–F910, 1995.[Abstract/Free Full Text]
83. Ohlsson A, Sieck U, Cumming W, Akhtar M, and Serenius F. A variant of Bartter's syndrome. Bartter's syndrome associated with hydramnios, prematurity, hypercalciuria and nephrocalcinosis. Acta Paediatr Scand 73: 868–874, 1984.[Web of Science][Medline]
84. Peters M, Jeck N, Reinalter S, Leonhardt A, Tonshoff B, Klaus GG, Konrad M, and Seyberth HW. Clinical presentation of genetically defined patients with hypokalemic salt-losing tubulopathies. Am J Med 112: 183–190, 2002.[CrossRef][Web of Science][Medline]
85. Proesmans W, Massa G, Vandenberghe K, and Van Assche A. Prenatal diagnosis of Bartter syndrome. Lancet 1: 394, 1987.[CrossRef][Web of Science][Medline]
86. Puschett JB, Greenberg A, Mitro R, Piraino B, and Wallia R. Variant of Bartter's syndrome with a distal tubular rather than loop of Henle defect. Nephron 50: 205–211, 1988.[Web of Science][Medline]
87. Reilly RF and Ellison DH. Mammalian distal tubule: physiology, pathophysiology, and molecular anatomy. Physiol Rev 80: 277–313, 2000.[Abstract/Free Full Text]
88. Reinalter S, Devlieger H, and Proesmans W. Neonatal Bartter syndrome: spontaneous resolution of all signs and symptoms. Pediatr Nephrol 12: 186–188, 1998.[CrossRef][Web of Science][Medline]
89. Reinalter SC, Grone HJ, Konrad M, Seyberth HW, and Klaus G. Evaluation of long-term treatment with indomethacin in hereditary hypokalemic salt-losing tubulopathies. J Pediatr 139: 398–406, 2001.[CrossRef][Web of Science][Medline]
90. Reinalter SC, Jeck N, Brochhausen C, Watzer B, Nusing RM, Seyberth HW, and Komhoff M. Role of cyclooxygenase-2 in hyperprostaglandin E syndrome/antenatal Bartter syndrome. Kidney Int 62: 253–260, 2002.[CrossRef][Web of Science][Medline]
91. Ring T, Knoers N, Oh MS, and Halperin ML. Reevaluation of the criteria for the clinical diagnosis of Gitelman syndrome. Pediatr Nephrol 17: 612–616, 2002.[CrossRef][Web of Science][Medline]
92. Rodriguez-Soriano J, Vallo A, and Garcia-Fuentes M. Hypomagnesaemia of hereditary renal origin. Pediatr Nephrol 1: 465–472, 1987.[CrossRef][Web of Science][Medline]
93. Rosenbaum P and Hughes M. Persistent, probably congenital, hypokalemic metabolic alkalosis with hyaline degeneration of renal tubules and normal urinary aldosterone (Abstract). Am J Dis Child 94: 560, 1957.
94. Rossat J, Maillard M, Nussberger J, Brunner HR, and Burnier M. Renal effects of selective cyclooxygenase-2 inhibition in normotensive salt-depleted subjects. Clin Pharmacol Ther 66: 76–84, 1999.[CrossRef][Web of Science][Medline]
95. Royer P, Delaitre R, Mathieu H, Gabilan JC, Raynaud C, Pasqualini JR, Debris P, Gerbeaux S, and Habib R. L'hypokaliémie chronique idiopathique avec hyperkaliurie de l'enfant. Rev Franc Etudes Clin et Biol IX: 61–87, 1964.
96. Schlatter E, Frobe U, and Greger R. Ion conductances of isolated cortical collecting duct cells. Pflügers Arch 421: 381–387, 1992.[CrossRef][Web of Science][Medline]
97. Schlingmann KP, Konrad M, Jeck N, Waldegger P, Reinalter SC, Holder M, Seyberth HW, and Waldegger S. Salt wasting and deafness resulting from mutations in two chloride channels. N Engl J Med 350: 1314–1319, 2004.[Free Full Text]
98. Schlingmann KP, Weber S, Peters M, Niemann Nejsum L, Vitzthum H, Klingel K, Kratz M, Haddad E, Ristoff E, Dinour D, Syrrou M, Nielsen S, Sassen M, Waldegger S, Seyberth HW, and Konrad M. Hypomagnesemia with secondary hypocalcemia is caused by mutations in TRPM6, a new member of the TRPM gene family. Nat Genet 31: 166–170, 2002.[CrossRef][Web of Science][Medline]
99. Schroter J, Timmermans G, Seyberth HW, Greven J, and Bachmann S. Marked reduction of Tamm-Horsfall protein synthesis in hyperprostaglandin E-syndrome. Kidney Int 44: 401–410, 1993.[Web of Science][Medline]
100. Schultheis PJ, Lorenz JN, Meneton P, Nieman ML, Riddle TM, Flagella M, Duffy JJ, Doetschman T, Miller ML, and Shull GE. Phenotype resembling Gitelman's syndrome in mice lacking the apical Na+-Cl- cotransporter of the distal convoluted tubule. J Biol Chem 273: 29150–29155, 1998.[Abstract/Free Full Text]
101. Schurman SJ, Perlman SA, Sutphen R, Campos A, Garin EH, Cruz DN, and Shoemaker LR. Genotype/phenotype observations in African Americans with Bartter syndrome. J Pediatr 139: 105–110, 2001.[CrossRef][Web of Science][Medline]
102. Seyberth HW, Koniger SJ, Rascher W, Kuhl PG, and Schweer H. Role of prostaglandins in hyperprostaglandin E syndrome and in selected renal tubular disorders. Pediatr Nephrol 1: 491–497, 1987.[CrossRef][Web of Science][Medline]
103. Seyberth HW, Rascher W, Schweer H, Kuhl PG, Mehls O, and Scharer K. Congenital hypokalemia with hypercalciuria in preterm infants: a hyperprostaglandinuric tubular syndrome different from Bartter syndrome. J Pediatr 107: 694–701, 1985.[CrossRef][Web of Science][Medline]
104. Seyberth HW, Soergel M, and Kockerling A. Hypokalemic tubular disorders: the hyperprostaglandin E syndrome and the Bartter-Gitelman syndrome. In: Oxford Textbook of Clinical Nephrology, edited by Davidson AM, Cameron JS, and Grünfeld JP. Oxford: Oxford Medical Publications, 1998, p. 1085–1094.
105. Shalev H, Ohali M, Kachko L, and Landau D. The neonatal variant of Bartter syndrome and deafness: preservation of renal function. Pediatrics 112: 628–633, 2003.[Abstract/Free Full Text]
106. Shalev H, Ohaly M, Meizner I, and Carmi R. Prenatal diagnosis of Bartter syndrome. Prenat Diagn 14: 996–998, 1994.[Web of Science][Medline]
107. Simon DB, Karet FE, Hamdan JM, DiPietro A, Sanjad SA, and Lifton RP. Bartter's syndrome, hypokalaemic alkalosis with hypercalciuria, is caused by mutations in the Na-K-2Cl cotransporter NKCC2. Nat Genet 13: 183–188, 1996.[CrossRef][Web of Science][Medline]
108. Simon DB, Karet FE, Rodriguez-Soriano J, Hamdan JH, DiPietro A, Trachtman H, Sanjad SA, and Lifton RP. Genetic heterogeneity of Bartter's syndrome revealed by mutations in the K+ channel, ROMK. Nat Genet 14: 152–156, 1996.[CrossRef][Web of Science][Medline]
109. Simon DB, Bindra RS, Mansfield TA, Nelson-Williams C, Mendonca E, Stone R, Schurman S, Nayir A, Alpay H, Bakkaloglu A, Rodriguez-Soriano J, Morales JM, Sanjad SA, Taylor CM, Pilz D, Brem A, Trachtman H, Griswold W, Richard GA, John E, and Lifton RP. Mutations in the chloride channel gene, CLCNKB, cause Bartter's syndrome type III. Nat Genet 17: 171–178, 1997.[CrossRef][Web of Science][Medline]
110. Simon DB, Nelson-Williams C, Bia MJ, Ellison D, Karet FE, Molina AM, Vaara I, Iwata F, Cushner HM, Koolen M, Gainza FJ, Gitleman HJ, and Lifton RP. Gitelman's variant of Bartter's syndrome, inherited hypokalaemic alkalosis, is caused by mutations in the thiazide-sensitive Na-Cl cotransporter. Nat Genet 12: 24–30, 1996.[CrossRef][Web of Science][Medline]
111. Splawski I, Timothy KW, Vincent GM, Atkinson DL, and Keating MT. Molecular basis of the long-QT syndrome associated with deafness. N Engl J Med 336: 1562–1567, 1997.[Free Full Text]
112. Stanton BA and Kaissling B. Regulation of renal ion transport and cell growth by sodium. Am J Physiol Renal Fluid Electrolyte Physiol 257: F1–F10, 1989.[Abstract/Free Full Text]
113. Sutton RA, Mavichak V, Halabe A, and Wilkins GE. Bartter's syndrome: evidence suggesting a distal tubular defect in a hypocalciuric variant of the syndrome. Miner Electrolyte Metab 18: 43–51, 1992.[Web of Science][Medline]
114. Takahashi N, Chernavvsky DR, Gomez RA, Igarashi P, Gitelman HJ, and Smithies O. Uncompensated polyuria in a mouse model of Bartter's syndrome. Proc Natl Acad Sci USA 97: 5434–5439, 2000.[Abstract/Free Full Text]
115. Tanemoto M, Vanoye CG, Dong K, Welch R, Abe T, Hebert SC, and Xu JZ. Rat homolog of sulfonylurea receptor 2B determines glibenclamide sensitivity of ROMK2 in Xenopus laevis oocyte. Am J Physiol Renal Physiol 278: F659–F666, 2000.[Abstract/Free Full Text]
116. Taniguchi J and Imai M. Flow-dependent activation of maxi K+ channels in apical membrane of rabbit connecting tubule. J Membr Biol 164: 35–45, 1998.[CrossRef][Web of Science][Medline]
117. Tovar-Palacio C, Bobadilla NA, Cortes P, Plata C, De Los Heros P, Vazquez N, and Gamba G. Ion and diuretic specificity of chimeric proteins between apical Na⁺-K⁺-2Cl^– and Na+-Cl^– cotransporters. Am J Physiol Renal Physiol 287: F570–F577, 2004.[Abstract/Free Full Text]
118. Vargas-Poussou R, Feldmann D, Vollmer M, Konrad M, Kelly L, van den Heuvel LP, Tebourbi L, Brandis M, Karolyi L, Hebert SC, Lemmink HH, Deschenes G, Hildebrandt F, Seyberth HW, Guay-Woodford LM, Knoers NV, and Antignac C. Novel molecular variants of the Na-K-2Cl cotransporter gene are responsible for antenatal Bartter syndrome. Am J Hum Genet 62: 1332–1340, 1998.[CrossRef][Web of Science][Medline]
119. Verberckmoes R, van Damme BB, Clement J, Amery A, and Michielsen P. Bartter's syndrome with hyperplasia of renomedullary cells: successful treatment with indomethacin. Kidney Int 9: 302–307, 1976.[Web of Science][Medline]
120. Voets T, Nilius B, Hoefs S, van der Kemp AW, Droogmans G, Bindels RJ, and Hoenderop JG. TRPM6 forms the Mg2+ influx channel involved in intestinal and renal Mg2+ absorption. J Biol Chem 279: 19–25, 2004.[Abstract/Free Full Text]
121. Wade JB. Distribution of transporters along the mouse distal nephron: something old, something borrowed, something new. Am J Physiol Renal Physiol 281: F1019–F1020, 2001.[Free Full Text]
122. Waldegger S, Jeck N, Barth P, Peters M, Vitzthum H, Wolf K, Kurtz A, Konrad M, and Seyberth HW. Barttin increases surface expression and changes current properties of ClC-K channels. Pflügers Arch 444: 411–418, 2002.[CrossRef][Web of Science][Medline]
123. Walker SH. Severe Bartter syndrome in blacks. N Engl J Med 285: 1150, 1971.[Web of Science][Medline]
124. Weber S, Schneider L, Peters M, Misselwitz J, Ronnefarth G, Boswald M, Bonzel KE, Seeman T, Sulakova T, Kuwertz-Broking E, Gregoric A, Palcoux JB, Tasic V, Manz F, Scharer K, Seyberth HW, and Konrad M. Novel paracellin-1 mutations in 25 families with familial hypomagnesemia with hypercalciuria and nephrocalcinosis. J Am Soc Nephrol 12: 1872–1881, 2001.[Abstract/Free Full Text]
125. Wright FS and Schnermann J. Interference with feedback control of glomerular filtration rate by furosemide, triflocin, and cyanide. J Clin Invest 53: 1695–1708, 1974.[Web of Science][Medline]
126. Yang B, Gillespie A, Carlson EJ, Epstein CJ, and Verkman AS. Neonatal mortality in an aquaporin-2 knock-in mouse model of recessive nephrogenic diabetes insipidus. J Biol Chem 276: 2775–2779, 2001.[Abstract/Free Full Text]
127. Yang T, Park JM, Arend L, Huang Y, Topaloglu R, Pasumarthy A, Praetorius H, Spring K, Briggs JP, and Schnermann J. Low chloride stimulation of prostaglandin E2 release and cyclooxygenase-2 expression in a mouse macula densa cell line. J Biol Chem 275: 37922–37929, 2000.[Abstract/Free Full Text]
128. Yun J, Schoneberg T, Liu J, Schulz A, Ecelbarger CA, Promeneur D, Nielsen S, Sheng H, Grinberg A, Deng C, and Wess J. Generation and phenotype of mice harboring a nonsense mutation in the V2 vasopressin receptor gene. J Clin Invest 106: 1361–1371, 2000.[Web of Science][Medline]
129. Zelikovic I. Hypokalaemic salt-losing tubulopathies: an evolving story. Nephrol Dial Transplant 18: 1696–1700, 2003.[Free Full Text]
130. Zelikovic I, Szargel R, Hawash A, Labay V, Hatib I, Cohen N, and Nakhoul F. A novel mutation in the chloride channel gene, CLCNKB, as a cause of Gitelman and Bartter syndromes. Kidney Int 63: 24–32, 2003.[CrossRef][Web of Science][Medline]

This article has been cited by other articles:

				A. B. Weder, L. Gleiberman, and A. Sachdeva Whites Excrete a Water Load More Rapidly Than Blacks Hypertension, April 1, 2009; 53(4): 715 - 718. [Abstract] [Full Text] [PDF]

				D. Bockenhauer, M. Cruwys, R. Kleta, L.F. Halperin, P. Wildgoose, T. Souma, N. Nukiwa, S. Cheema-Dhadli, C.K. Chong, K.S. Kamel, et al. Antenatal Bartter's syndrome: why is this not a lethal condition? QJM, December 1, 2008; 101(12): 927 - 942. [Abstract] [Full Text] [PDF]

				Q. Yan, X. Yang, A. Cantone, G. Giebisch, S. Hebert, and T. Wang Female ROMK null mice manifest more severe Bartter II phenotype on renal function and higher PGE2 production Am J Physiol Regulatory Integrative Comp Physiol, September 1, 2008; 295(3): R997 - R1004. [Abstract] [Full Text] [PDF]

				C. A. Wagner, D. Loffing-Cueni, Q. Yan, N. Schulz, P. Fakitsas, M. Carrel, T. Wang, F. Verrey, J. P. Geibel, G. Giebisch, et al. Mouse model of type II Bartter's syndrome. II. Altered expression of renal sodium- and water-transporting proteins Am J Physiol Renal Physiol, June 1, 2008; 294(6): F1373 - F1380. [Abstract] [Full Text] [PDF]

				M. Sakai, K. Tamura, Y. Tsurumi, Y. Tanaka, Y. Koide, M. Matsuda, T. Ishigami, M. Yabana, Y. Tokita, Y. Hiroi, et al. Expression of MAK-V/Hunk in renal distal tubules and its possible involvement in proliferative suppression Am J Physiol Renal Physiol, May 1, 2007; 292(5): F1526 - F1536. [Abstract] [Full Text] [PDF]

				C. A. Pressler, J. Heinzinger, N. Jeck, P. Waldegger, U. Pechmann, S. Reinalter, M. Konrad, R. Beetz, H. W. Seyberth, and S. Waldegger Late-Onset Manifestation of Antenatal Bartter Syndrome as a Result of Residual Function of the Mutated Renal Na+-K+-2Cl- Co-Transporter J. Am. Soc. Nephrol., August 1, 2006; 17(8): 2136 - 2142. [Abstract] [Full Text] [PDF]

				T. M. Fujiwara and D. G. Bichet Molecular Biology of Hereditary Diabetes Insipidus J. Am. Soc. Nephrol., October 1, 2005; 16(10): 2836 - 2846. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (10) Citing Articles via Google Scholar Google Scholar Articles by Jeck, N. Articles by Seyberth, H. W. Search for Related Content PubMed PubMed Citation Articles by Jeck, N. Articles by Seyberth, H. W.