| Abstract|| |
The inherited hypokalemic tubular disorders are frequently summarized under the heading "Bartter syndrome" since they shareseveral clinical and biochemical findings such as renal salt wasting, hypokalemic metabolic alkalosis, normal blood pressure despite hypereninemic hyperaldosteronism and hyperplasia of the juxtaglomerular apparatus. However, careful characterization of the clinical phenotype and the correlation with the underlying molecular basis justifies the differentiation into at least four distinct disease entities: (i) the hyperprostaglandin E syndrome or antenatal variant of Bartter syndrome (HPS/aBS), which is caused by mutations in either the Na-K-2Cl cotransporter or the potassium channel of the medullary thick ascending limb of Henle's loop; (ii) the HPS/aBS with sensorineural deafness which results from inactivating mutations in the Barttin betasubunit of the renal chloride channels; (iii) the classic Bartter syndrome caused by mutations in the chloride channel of the distal nephron; and (iv) Gitelman's variant of Bartter syndrome which is caused by mutations of the Na-Cl cotransporter of the distal convoluted tubule. This review will summarize the clinical characteristics of these diseases and the progress recently made in the identification of the underlying molecular defects that will hopefully add to the current knowledge of the pathogenesis of these diseases.
Keywords: Bartter syndrome, hyperprostaglandin E syndrome, Gitelman syndrome, Electrolyte transport
|How to cite this article:|
Peters M, Konrad M, Seyberth HW. Hereditary Hypokalemic Salt-losing Tubular Disorders. Saudi J Kidney Dis Transpl 2003;14:386-97
|How to cite this URL:|
Peters M, Konrad M, Seyberth HW. Hereditary Hypokalemic Salt-losing Tubular Disorders. Saudi J Kidney Dis Transpl [serial online] 2003 [cited 2019 Jul 15];14:386-97. Available from: http://www.sjkdt.org/text.asp?2003/14/3/386/33018
| Introduction|| |
In 1957, two pediatricians first reported a two months old dystrophic patient with persistent hypokalemic alkalosis despite marked dehydration caused by gastrointestinal losses and impaired renal concentrating capacity.  Five years later, Bartter and colleagues described their two index patients with hypokalemic metabolic alkalosis and tetanic spells, associated with normotensive hypereninemic hyperaldosteronism, and hyperplasia of the juxtaglomerular apparatus.  Later, Gitelman et al described a hypocalciuric variant of Bartter syndrome (BS) with the additional finding of hypomagnesemia as the cause of intermittent episodes of muscle weakness and/or tetany.  This hypocalciuric and hypomagnesemic variant of BS was subsequently described as "Gitelman syndrome" (GS).
The first description of a neonatal variant of BS was in 1971. It included a salt losing tubulopathy (SLT) with severe polyhydramnios and consecutive premature delivery, severe hyposthenuric polyuria, marked renal salt loss and hypercalciuria leading to nephrocalcinosis. , As this phenotypic entity was a SLT clearly distinct from BS and as it was found to be associated with highly increased prostaglandin E2(PGE2) excretion, the term "hyperprostaglandin E syndrome" (HPS) was introduced by our group. , Later, this antenatal variant was also described as "antenatal Bartter syndrome" (aBS), thus the term HPS/aBS has been introduced to describe this entity.
In 1995, Landau et al  described another variant of HPS/aBS with characteristic symptoms including polyhydramnios with premature delivery, postnatal polyuria, severe potassium depletion and normotensive hyperreninemic hyperaldosteronism. However, this disease is additionally characterized by inner ear deafness and a substantial proportion of affected individuals develop chronic renal failure. ,
Following the clinical observations and pathophysiological studies, it is reasonable to distinguish between at least four entities of hereditary hypokalemic salt-losing tubular disorders: the HPS/aBS, HPS/aBS with inner ear deafness, the classic BS, and the GS.
| Clinical Characterization|| |
The SLTs described above are all characterized by an autosomal recessive mode of inheritance. During the course of the disease, most patients show pronounced hypokalemia (mean values <3 mmol/l) due to increased renal potassium excretion and elevated sodium and chloride excretion rates, which are often more pronounced in the neonatal period with NaCl excretion rates up to 50 mmol/kg/d. During follow-up at older ages, the salt loss may be less severe manifesting mostly as volume contraction without remarkable changes in the serum concentration of sodium and chloride. More reliable parameters for the renal salt loss are the plasma renin and aldosterone levels, which are elevated in all SLTpatients. However, all patients are normotensive. In addition to these changes, the patients have metabolic alkalosis with a mean serum bicarbonate level >30 mmol/l and corresponding positive base excess >5 mmol/l.
Hyperprostaglandin E syndrome/ antenatal Bartter syndrome (HPS/aBS)
Typically, this disorder manifests in the 2nd gestational trimester with the development of marked polyhydramnios due to fetal polyuria that result in premature delivery. The preterm infants are at high risk for dehydration as polyuria continues postnatally. Hyponatremia is a very early laboratory finding and may be accompanied by hyperkalemia that may lead to the misdiagnosis of pseudohypoaldosteronism type I. 0 During follow-up, most patients with HPS/aBS develop hypokalemia and typical metabolic alkalosis. Another hallmark of the disease is the markedly increased calcium excretion (up to 15 mg/ kg/d), leading uniformly to medullary nephrocalcinosis, often within the first weeks of life. In addition, elevation of renal PGE 2 and systemic PGE-M prostaglandin formation is found in all patients, which aggravates renal salt and water loss and may be responsible for the extrarenal symptoms such as fever, vomiting, diarrhea, failure to thrive, osteopenia and growth retardation.
| HPS/aBS with Sensorineural Deafness|| |
Landau et al described a subtype of HPS/ aBS with inner ear deafness in a large Bedouin family.  The renal phenotype is even more severe than in HPS/aBS with massive salt and water loss that often requires long-term parenteral fluid supply. Hypercalciuria and nephrocalcinosis are uncommon, and indomethacin at a conventional dose (2 mg/kg/d) is not effective. In addition, many patients develop chronic renal failure of unknown origin. 
| Classic Bartter Syndrome (cBS)|| |
The cBS patients typically present with hypokalemic alkalosis and failure to thrive during the first two years of life. Some patients are severely affected during the neonatal period with severe salt and water loss, while others are incidentally diagnosed after the detection of electrolyte imbalances, especially hypokalemia and/or hyponatremia. cBS patients show a tendency to hypomagnesemia during their clinical course. Urinary calcium excretion varies widely ranging from hypocalciuria to hypercalciuria but most patients have normal calcium excretion rates. Only few patients develop medullary nephro-calcinosis. Without further evaluations and mutational analysis, it is sometimes difficult to differrentiate cBS from the Gitelman variant. ,,
| Gitelman's Variant of Bartter Syndrome (GS)|| |
Characteristic biochemical features of GS include hypocalciuria and hypomagnesemia, which is claimed to be responsible for most of the clinical symptoms such as muscle weakness, carpopedal spasms or tetany.  As clinical symptoms are not consistently present and sometimes only mild, GS is often diagnosed late during childhood or even in adult life. Asymptomatic hypokalemia is a rather common incidental finding in these patients, diagnosed during preoperative serum electrolyte measurements or in the context of family surveys due to an affected sibling. Beside the clinical symptoms mentioned above, few patients may complain of joint pain provoked by chondrocalcinosis or may present with marked growth retardation. 
GS is often described as the mildest variant of the salt-losing tubular disorders. However, in a retrospective analysis of 50 GS patients, Cruz et al demonstrated that none of their patients were truly asymptomatic.  The most frequent clinical findings were salt craving, nocturia and paresthesia. These authors could also demonstrate that GS affects quality-of-life to the same degree as hypertension or diabetes mellitus for example.
For a better differentiation, some important clinical and biochemical features of these SLTs are summarized in [Table - 1].
| Pathophysiology|| |
The hereditary SLTs described above comprise a wide spectrum of tubular disorders with overlapping clinical symptoms, which lead to confusion about the underlying pathomechanisms. The phenotype of GS patients resembles the long-term administration of thiazides whereas the phenotype of HPS/ aBS patients resembles the long-term administration of furosemide. This behavior denoted the defects in the Na-Cl contransporter (NCCT) located in the distal convoluted tubule (DCT) for the GS and the Na-K-2Clcotransporter (NKCC2) in the thick ascending (TAL) limb of Henle's loop for HPS/aBS. ,
Recent studies of renal transporters and ion channels involved in the transepithelial transport of sodium chloride have identified loss-of-function mutations in six different genes [Table - 2],[Figure - 1]: the SLC12A1 gene that encodes the NKCC2, expressed in the TAL, , the KCNJ1 gene that encodes the renal outer medullary potassium channel (ROMK), expressed in the apical membrane of the TAL and cortical collecting duct (CCD), , the BSND gene that encodesBarttin, expressed in the basolateral membrane along the distal nephron, ,, the CLCNKB gene that encodes the basolateral chloride channel ClC-Kb with wide distribution along the human nephron, ,. and the SLC12A3 gene that encodes the thiazidesensitive NCCT in the distal convoluted tubule. 
Recently, a phenotype reminiscent of Bartter syndrome has been reported in individuals carrying a heterozygous activating mutation of the calcium-sensing receptor (CaSR), which is expressed in the basolateral membrane of the distal nephron. , Initially, these patients presented with autosomal dominant hypocalcemia. During follow-up, the patients developed renal salt and water loss associated with hypokalemic alkalosis. Activation of the CaSR under normal serum calcium concentrations appears to induce significant loss of NaCl via inhibition of salt reabsorption in the TAL and the DCT.
In healthy adults, approximately 30% of the filtered chloride and 12% of the filtered sodium is reabsorbed in the TAL via NKCC2; this reabsorption is essential to generate the medullary hypertonicity and renal concentrating capacity.  Proper functioning of NKCC2 depends on potassium recycling via ROMK see [Figure - 1]. The apical outward current of potassium also leads to a lumenpositive potential difference that drives the reabsorption of calcium and magnesium.  Sodium that enters the TAL cell is transported across the basolateral membrane by the NaK-ATPase, whereas chloride is thought to leave the cell either via the basolateral chloride channel ClC-Kb and/or the basolateral KCl-cotransporter.
In the DCT, about 7% of the filtered sodium chloride is reabsorbed via the NCCT. As in TAL, the Na-K-ATPase generates a sodium gradient which enables the sodium transport across the apical membrane via NCCT. Chloride is transported into the blood by ClC-Kb.
| Molecular Genetics|| |
| Hyperprostaglandin E Syndrome/ antenatal Bartter syndrome (HPS/aBS)|| |
The symptoms of HPS/aBS patients are comparable with the pharmacological effects of a long-term administration of furosemide. In 1994, a furosemide-sensitive cotransporter NKCC2 was cloned in rodents. , Two years later, the human gene SLC12A1 was cloned and mapped to chromosome 15q15q21.  The encoded membrane protein consists of 26 exons and predicts a cotransporter of 1,099 amino acid residues with 12 potential membrane-spanning helices flanked by intracellular N- and C-termini [Figure - 2]. In recent years, mutations in this gene were identified in a subset of HPS/aBS-patients. ,,
As not all HPS/aBS families showed linkage to the NKCC2 gene locus, the involvement of a further gene was assumed. It was already known that proper functioning of NKCC2 is dependent on permanent potassium recycling via the potassium channel ROMK. Therefore, for the remaining HPS/aBS families, ROMK seemed to be a promising candidate gene, which had been cloned previously from rat and human kidneys. , The encoding gene, KCNJ1, is located on chromosome 11q24 and contains five exons, which produce five distinct transcripts predicting three ROMK proteins (ROMK1-3) with a variable length from 372-391 amino acids. 
Beside homozygous deletions of exons 1+2, presumably affecting the transcription and/ or translation of ROMK, numerous missense mutations, frameshifts and stop codons have been detected, ,,,, [Figure - 3].
| HPS/aBS with Sensorineural Deafness|| |
By homozygosity mapping using the large Bedouin family from the original report, Brennan et al could map a gene for HPS/ aBS with deafness to chromosome 1p31.  Four years later, a novel gene (BSND) encoding a protein, which was named Barttin was identified by positional cloning and presumable loss of function mutation were characterized in the affected patients.  This protein has no similarity to any other known protein. Consistent with the phenotypic presentation, Barttin was found to be expressed not only in the kidney tubules but also in the stria vascularis of the inner ear. Functional expression revealed that Barttin acts as a beta-subunit of the renal chloride channels ClC-Ka and ClC-Kb. ,
| Classic Bartter Syndrome (cBS)|| |
In 1997, the cBS phenotype was linked to the gene CLCNKB on chromosome 1p36, encoding the chloride channel ClC-Kb  which is predominantly expressed in the basolateral membranes of the distal parts of the nephron.  ClC-Kb consists of 19 exons with 13 hydrophobic helical domains with 11 domains integrated in the plasma membrane.
Numerous missense, splice-site and frameshift mutations have been found in CLCNKB ,, [Figure - 4]. Interestingly, deletions of the entire gene have been detected in almost 50% of cBS patients probably resulting from the close vicinity of the almost identical CLCNKA gene, which predisposes to inhomologous recombination.
| Gitelman's Variant of Bartter Syndrome (GS)|| |
Thiazide-sensitive sodium-chloride cotransport in the DCT has been identified.  The corresponding absorptive thiazide-sensitive NCCT was cloned from the rat kidney and flounder. , In 1996, the human gene SLC12A3 encoding hNCCT on chromosome 16q13 was identified, encoding a protein of 26 exons with 1021 amino acids and 12 putative transmembrane domains,  [Figure - 5]. NCCT is exclusively expressed in the DCT. To date, numerous mutations have been described, in particular in the Cterminus of NCCT, leading to single amino acid exchanges, small deletions, insertions and splice-site mutations. ,,,, Functional studies have found an underlying trafficking defect due to these mutations. ,
| Therapy|| |
Since we are not able to cure the primary genetic defects of the SLTs, therapy is still restricted to relief of symptoms. Adequate fluid and electrolyte substitution, especially in the sensitive neonatal period of the HPS/ aBS patients is important. Careful monitoring of fluid balance is absolutely necessary to prevent acute hypovolemic renal failure, fever or cerebral convulsions. Potassium supplementation has to be started upon the development of hypokalemic alkalosis.  Symptoms of the HPS/aBS patients such as fever, vomiting, diarrhea, and failure to thrive have been attributed to enhanced systemic prostaglandin E formation and are usually treated with cyclooxygenase inhibitors such as indomethacin (doses range from 0.2 mg/ kg/d in preterm infants up to 3 (-5) mg/kg/d). This treatment generally results in approximately 50% reduction of the saluretic polyuria, normalization of the hyperprostaglandinuria, amelioration of the clinical symptoms and induction of a rapid catch-up growth.  In order to assess the success of the indomethacin therapy serum potassium, plasma renin, and the urinary excretion of calcium, potassium and pro-staglandins should be followed up at regular intervals. The benefit of long-term indo-methacin therapy outweighs the adverse effects such as gastrointestinal complaints or a reversible decline of the glomerular filtration rate.  Nowadays, more selective cyclooxygenase inhibitors, which have proven successful in the treatment of these diseases, are available.  However, recent studies have shown an impaired glomerulogenesis and renal cortical development in rodents after administration of COX-2 selective inhibitors during pregnancy.  Therefore, caution should be exercised during the long-term therapy with these inhibitors.
The management is generally more difficult with advancing age. In addition to rather high indomethacin doses, continuous potassium supplementation is required in almost all patients; some patients also require oral sodium chloride and/or magnesium supplementation. Nevertheless, it remains often difficult to achieve normal serum concentrations of these electrolytes. For GS patients, indomethacin has only minor therapeutic benefit as urinary prostaglandin levels are close to normal ranges. Therefore, substitution of fluid and electrolytes is of major importance. The pronounced hypokalemia has sometimes to be treated with drugs that antagonize aldosterone activity or block the sodium channel in the distal nephron, such as amiloride or spironolactone. Furthermore, GS patients with additional growth hormone (GH) deficiency may also benefit from GH replacement therapy. 
| Genotype-Phenotype Correlation|| |
Mutations of both ROMK and NKCC2 lead to the phenotype of HPS/ aBS characterized by impaired renal concentrating capacity, saluretic polyuria, and hypercalciuria that result in the characteristic clinical triad of polyhydramnios, hypo- or isosthenuria, and nephrocalcinosis. This triad clearly distinguishes these patients from those with ClC-Kb or NCCT defects. In contrast to patients with defect of NKCC2, the majority of patients with ROMK defect show transient neonatal hyperkalemia with metabolic acidosis, resembling the phenotype of pseudohypoaldosteronism type I. , During follow-up, almost all ROMK patients develop hypokalemia to some degree although the renal potassium loss is less pronounced than NKCC2 patients reflected by higher serum potassium levels and lower requirement for potassium supplementation.  The higher serum potassium levels in ROMK patients might be explained by the expression of ROMK in the cortical collecting duct, where it is thought to participate in the net potassium secretion. 
In contrast, ClC-Kb patients present with a variable phenotype but most patients present as cBS. They usually develop well in utero and are born at term, but fail to thrive during the first two years of life. During follow-up, the clinical course may be very similar to GS. , Only few patients are diagnosed early due to preterm delivery and saluretic polyuria. ,
All mutations in NCCT reported so far result in the GS phenotype. Patients are usually born at term and are often diagnosed incidentally in early childhood due to asymptomatic hypokalemia. In addition to the metabolic alkalosis, predominant biochemical findings include hypocalciuria and hypomagnesemia, which are found in almost all GS patients. In some patients, growth retardation is a leading clinical presentation, while other patients present with carpopedal spasms and/or tetany.
We conclude that in contrast to the uniform clinical picture of ROMK/NKCC2 and NCCT patients, the initial presentation and clinical course of ClC-Kb patients is much more variable, possibly reflecting the wider expression of ClC-Kb along the nephron and additional compensatory chloride channels and transporter such as the basolateral KClcotransporter.
| Prognosis/Perspective|| |
Before the introduction of neonatal intensive care and the therapeutic intervention with indomethacin, only few HPS/aBS patients survived the first few weeks of life due to their extreme prematurity and the excessive postnatal salt and water loss. Patients who survive the critical neonatal period seem to have a good long-term prognosis. However, since the oldest patients treated with indomethacin are not older than about 25-30 years, a definitive prognosis concerning the long-term outcome is rather difficult.
Hopefully, a more specific therapeutic approach with selective COX-2 inhibitors may lead to a similar therapeutic success with less negative side effects, such as gastrointestinal complaints. However, further studies in children are necessary to prove the efficacy and safety of these drugs for pediatric patients before long-term use might be considered.
A more causative therapy is directed at the restoration of the mutated protein, as demonstrated for specific CFTR mutations in cystic fibrosis. In this disorder, a rescue of certain stop mutations was achieved by applying aminoglycoside antibiotics which overcome the stop codon with consecutive production of 10-20% full-length CFTR. , Beside stop mutations, the trafficking mutations were rescued by the application of butyrates or glycerol. They act as chemical chaperones which promote proper folding and trafficking to the cell membrane. similar therapeutic interventions aiming at the repair of the mutated protein might also be successful in these SLTs. , However, exact analysis of the underlying pathomechanisms has to be evaluated first for establishing future therapeutic approaches.
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Hannsjorg W Seyberth
Department of Pediatrics, Philipps-University Marburg, Deutschhaustrasse 12, D-35037 Marburg
[Figure - 1], [Figure - 2], [Figure - 3], [Figure - 4], [Figure - 5]
[Table - 1], [Table - 2]