World Journal Of Pediatrics-articles

Author Affiliations: Tufts University School of Medicine; The Barbara Bush Children's Hospital, Maine Medical Center, Portland, Maine, USA (Fremont OT, Chan JCM)

Corresponding Author: James C. M. Chan, M.D., Professor of Pediatrics, Tufts University School of Medicine; Director of Research, The Barbara Bush Children's Hospital, Maine Medical Center, 22 Bramhall Street, Portland, Maine 04102-3175, USA (Tel: 207-662-2439; Fax: 207-662-6272; Email: cmchanj@comcast.net)

Background: We aim to review the clinical features of two renal tubular disorders characterized by sodium and potassium wasting: Bartter syndrome and Gitelman syndrome.

Data sources: Selected key references concerning these syndromes were analyzed, together with a PubMed search of the literature from 2000 to 2011.

Results: The clinical features common to both conditions and those which are distinct to each syndrome were presented. The new findings on the genetics of the five types of Bartter syndrome and the discrete mutations in Gitelman syndrome were reviewed, together with the diagnostic workup and treatment for each condition.

Conclusions: Patients with Bartter syndrome types 1, 2 and 4 present at a younger age than classic Bartter syndrome type 3. They present with sypmtoms, often quite severe in the neonatal period. Patients with classic Bartter syndrome type 3 present later in life and may be sporadically asymptomatic or mildly symptomatic. The severe, steady-state hypokalemia in Bartter syndrome and Gitelman syndrome may abruptly become life-threatening under certain aggravating conditions. Clinicians need to be cognizant of such renal tubular disorders, and promptly treat at-risk patients.

Key words: Bartter syndrome; blood pressure control; Gitelman syndrome; NCCT; NKCC2; potassium; sodium

Bartter syndrome^[1,2] and Gitelman syndrome,^[3] both result from congenital defects in renal tubular handling of sodium, potassium and chloride.^[4,5] We shall highlight the clinical characteristics of each condition^[5,6] and comment on the molecular defects^[7-10] before discussing diagnostic tests.^[11-13] Finally we shall review the impact and limitations of treatment.^[14,15] Key references concerning Bartter syndrome and Gitelman syndrome were evaluated in concert with a PubMed literature search from 2001 to 2011. The most current and relevant information from the literature pertaining to these two syndromes were reviewed.

Patients with Bartter syndrome and Gitelman syndrome present with complaints of constipation, muscle cramps and weakness, secondary to chronic hypokalemia.^[16,17] Patients with either syndrome may also present with non-specific dizziness and fatigue. The biochemical features of both syndromes include hypokalemic, hypochloremic metabolic alkalosis associated with high plasma renin activity and high aldosterone concentration.^[16-18]

Although the chronic hypokalemia can be mildly symptomatic, it can be aggravated by diarrhea or vomiting, precipitating prolonged QT interval, increased risk of rhabdomyolysis, cardiac arrhythmia, syncope, and sudden death.^[19] Alcohol abuse, cocaine or other drug abuse can also precipitate life-threatening arrhythmia.^[19] Prompt electrolyte and fluid repair, oral potassium supplementation, potassium sparing diuretics, cyclo-oxygenase inhibitors, and renin-angiotensin blockers become life-saving in such emergencies.^[19]

Finally, in familial cases, both conditions are conveyed by autosomal recessive transmission.^[18,20]

The site of defect in Bartter syndrome^[1,5] is at the thick ascending limb (TAL) of the loop of Henle, whereas in Gitelman syndrome,^[3] the defect resides at the distal convoluted tubule (DCT). Patients with Bartter syndrome present in early childhood and the failure to thrive is more severe and with a great deal of growth retardation.^[16,17] Gitelman syndrome is associated with less severe failure to thrive and the growth retardation is milder. Gitelman symptoms are similar to thiazide diuretic-abusers with salt wasting.^[21,22]

Sensorineural deafness is a feature of Bartter syndrome type 4, arising from BSND mutation in Bartter syndrome type 4 and digenic mutation of CLCNKA and CLCNKB in Bartter syndrome type 4.^[23,24] Hearing defect is absent in Gitelman syndrome, as well as in Bartter syndrome types 1, 2 and 3.

Indeed, Gitelman patients are mostly thought to be asymptomatic. They often present for workup of isolated, asymptomatic hypokalemia,^[21] but on closer questioning 80% of Gitelman patients complain of dizziness and fatigue; 70% of the patients complain of muscle weakness and cramps and 50% with nocturia and polyuria, in whom 90% are subsequently found to be salt wasters.

Normal blood pressure in patients with Bartter syndrome^[16,17] is a feature thought to be different from the occasional hypotension of Gitelman syndrome. However, there is much overlap in this feature, so that the blood pressure levels cannot be a consistent feature to distinguish between the two syndromes.

Focal segmental glomerulosclerosis^[25] has been described in Bartter syndrome. In contrast, Gitelman patients often complain of nocturia and polyuria. Persistent hypokalemia may give rise to interstitial nephritis, signaled by urinary anomalies. Medical non-compliance to potassium chloride supplementation and other therapy is an important issue in long-term follow-up of Bartter and Gitelman patients.

Urinary calcium excretion is important because it distinguishes the two syndromes.^[18] In contrast to the hypocalciuria of Gitelman syndrome, Bartter patients are often documented to have hypercalciuria. Patients with antenatal Bartter syndrome (type 1 and type 2) fail to establish an adequate transepithelial voltage gradient to drive calcium and magnesium absorption, giving rise to hypercalciuria and hypermagnesiuria, which increase predisposition to nephrocalcinosis. Patients with type 3 (classic) Bartter syndrome generally do not show nephrocalcinosis and nephrolithiasis.^[26,27] In addition, focal segmental glomerulosclerosis was described in the index cases of Bartter syndrome^[1] and in the subsequent reports on the performance of kidney biopsies. But, no study of the prevalence of focal segmental glomerulosclerosis in Bartter syndrome has been conducted. Kidney biopsies were not performed in the index cases of Gitelman syndrome.^[3] Earlier reports on Bartter syndrome have documented the juxtaglomerular hyperplasia that is thought to be essential to adequately characterize Bartter syndrome.^[28] But, more recent reports have not used kidney biopsies to confirm the diagnosis, relying on renal functional tests for that purpose.

The molecular defects of chloride reabsorption in Bartter syndrome^[7-9] and Gitelman syndrome^[10]originate at different sites of the nephron. The transport defects for Bartter syndrome are at the TAL of the loop of Henle and for Gitelman syndrome, at the DCT, respectively. Table 1 shows a summary of the gene mutations and gene products in Bartter syndrome and Gitelman syndrome.

Accordingly, Bartter syndrome has been classified into five types (Table).^[16-18,29] On the luminal (urinary) side of the TAL cell, the following transport proteins are defective:

Type 1: Na-K-Cl co-transporter protein, previously referred to as antenatal Bartter syndrome or hyperprostaglandin E syndrome.

Type 2: renal outer medullary potassium (ROMK) channel defect often referred to as neonatal Bartter syndrome with transient hyperkalemic metabolic acidosis or as antenatal Bartter syndrome or hyperprostaglandin E syndrome.

On the basal lateral (blood) side of the TAL cell, the following defective transport channels and molecules are seen:

Type 3: mutation in the CLCNKB gene, giving rise to a defective chloride channel Kb (ClC-Kb). Currently the type is referred to as classic Bartter syndrome.

Type 4: BSND gene mutation gives rise to defective function of Barttin, β-subunit of chloride channel Ka (ClC-Ka) and ClC-Kb, required for membrane localization. Digenic inheritance in type 4 Bartter syndrome is outside of the scope of Mendelian inheritance.^[23] Type 4 Bartter syndrome has been previously referred to as antenatal Bartter syndrome with sensorineural deafness.

Patients with types 1, 2 and 4 Bartter syndrome have previously been grouped indiscriminately into "hyperprostaglandin E syndrome". Type 5 Bartter syndrome:^[29] calcium sensing receptor (CASR) mutation gives rise to a condition characterized by hypocalcemia, suppressed parathyroid hormone function with Bartter-like syndrome. The gene defect occurs on chromosome band 16q13 and the inheritance is autosomal dominant.

Forewarning of Bartter syndrome types 1 and 2 is apparent even during pregnancy with polyhydramnios and becomes more pressing in the neonate with marked polyuria and significant dehydration episodes.^[14] Hypercalciuria of types 1 and 2 Bartter syndrome patients leads to nephrocalcinosis, which is not present generally in type 3 or type 4 Bartter syndrome patients. The initial, neonatal presentation of Bartter syndrome type 2 is hyperkalemic, metabolic acidosis.^[30] Such symptoms overlap those of pseudohypoaldosteronism, and type 4 Bartter syndrome patients have often been misdiagnosed as having pseudohypoaldosteronism. Steadily, as ROMK and other potassium channels or transporters recompense, these neonates become hypokalemic and show metabolic alkalosis. Once these more typical Bartter-like features come to the fore, the physician usually will arrive at the correct diagnosis.

Type 3 Bartter syndrome patients have the mildest presentation, presumably although CLCNKB is mutated in type 3 Bartter syndrome, CLCNKA chloride permeability is preserved.^[30] In view of the fact that CLCNKA is also present in the DCT, the symptoms of Bartter syndrome and Gitelman syndrome overlap.

The presentation of type 4 Bartter syndrome is more severe, because both CLCNKA and CLCNKB channels are affected.^[30] Type 4 Bartter syndrome has an altered subunit protein, barttin, which is needed for potassium chloride membrane localization. Different mutations of CLCNKA lead to different functional deficits in barttin, resulting in different severity of type 4 Bartter syndrome.^[23]

Hypocalcemia with Bartter-like syndrome (alias type 5 Bartter syndrome) results from autosomal dominant, L125P mutations of an extracellular basolateral CASR, giving rise to hypocalcemic hypercalciuria and suppressed parathyroid hormone activity.^[29,30] Bartter syndrome type 5 is the only TAL salt-losing defect, which is inherited by autosomal dominant transmission. All other types of Bartter syndrome are autosomal recessive.

Gitelman syndrome^[31] is due to defective NaCl-cotransporter (NCCT) at the DCT, encoded by the SLC12A3 gene.

Significantly, the abnormal mutation of the NCCT protein in DCT is also expressed in blood mononuclear cells,^[31] which are easily accessible. Thus, the confirmation of NCCT protein mutation in the blood mononuclear cells becomes a useful tool in diagnosis of Gitelman syndrome.

Aside from providing diagnostic tools and better classification of Bartter-like syndromes,^[4] how does research into the molecular mechanisms of these rare, congenital tubular diseases translate to the patient? Recent reports on the SPAK and OSRI molecules in Bartter syndrome, Gitelman syndrome and pseudohypoaldosteronism type II (PHA II) stimulate a lot of interest.^[32,33] SPAK stands for [STE20/SPS1-related proline/alanine-rich kinase]. It is activated by WNK1/4, which can in turn phosphorylate and activate NCCT/NKCC1/2. Oxidative stress-responsive kinase-1 is abbreviated to OSR1. There is enormous interest concerning how these two kinases^[33] enter blood pressure control, in these rare, congenital renal diseases―not only in gaining insight into basic mechanism of blood pressure regulation, but exciting potentials in finding a significant, new class of anti-hypertensive medication.

The molecular mechanism of childhood deafness has everything to do with potassium and chloride pumps.^[34] Cochlear hearing function relies on a number of molecular processes. Hearing requires inflow of potassium into hair cells of the cochlear. Potassium is driven into hair cells by electro-chemical forces and recycled via KCNQ4 channels or enters Deiter's cells (via KCC3, KCC4). Potassium chloride from hair cells passes through connexins, returns or secrets into endolymph at the cochlear.^[34] Disturbances in transport, return or secretion of potassium chloride are the molecular basis of childhood deafness, and likely apply to the sensorineural deafness in type 4 Bartter syndrome.

The differential diagnosis of hypokalemic, metabolic alkalosis include vomiting in young infants, especially that related to pyloric stenosis, chloride-losing diarrhea, cystic fibrosis, and diuretic abuse. Ongoing vomiting or diarrhea is usually clear from the history. Measurement of urinary chloride excretion can help distinguish between renal and non-renal causes of chloride loss.^[13] It can be difficult to distinguish between diuretic abuse and Bartter or Gitelman syndromes without directly evaluating the urine for presence of diuretics.

Distinguishing between Bartter and Gitelman syndromes is not always straightforward due to phenotypic variance. Genetic diagnosis is now possible, but there are several limitations including lack of general availability, cost, and absence of "hot spot" mutations along the gene. As mentioned, Bartter syndrome is typically associated with hypercalciuria and Gitelman syndrome with hypocalciuria, although some patients with type 3 Bartter syndrome have normal urinary calcium excretion.

A thiazide test has recently been described to help distinguish between the two conditions.^[11] It involves oral administration of hydrochlorothiazide (1 mg/kg up to 50 mg), after a 7-day "washout" period, during which therapies aside from potassium and magnesium supplements are held. In patients with Gitelman syndrome, where the defect is in the thiazide-sensitive NCCT, this results in very little change (<2.3%) in the fractional excretion of chloride from baseline. In patients with Bartter syndrome, however, this blunted response is not seen.^[11,12] This test is not recommended for infants or children at age of less than 7 years, with suspected Bartter syndrome because of a higher risk of volume depletion.

Acute therapy in settings such as dehydration in a young patient with neonatal Bartter syndrome, cardiac arrhythmia, or rhabdomyolysis due to hypokalemia^[19] is beyond the scope of this review. The focus of chronic therapy in patients with Bartter syndrome and Gitelman syndrome includes electrolyte replacement as well as inhibition of secondary increases in prostaglandin production and/or the renin-angiotensin-aldosterone axis, which exacerbate the urinary electrolyte losses.

Bartter syndrome is typically treated with indomethacin and potassium chloride. The dose of indomethacin can be as high as 2-3 mg/kg per day (mean: 2.1 mg/kg per day in one study).^[15] Indomethacin can lead to improvement in laboratory parameters as well as the failure to thrive typically seen in patients with Bartter syndrome. Indomethacin should be used with caution in premature infants because of the increased risk for gastrointestinal perforation or necrotizing enterocolitis.^[35,36] Long-term gastrointestinal side effects of indomethacin including chronic gastritis and gastric ulcers can be dose limited, and cyclooxygenase-2 selective inhibitors might be considered as an alternative.^[37]

Sodium chloride supplementation may be needed early in life, but high dietary salt intake is often sufficient in older children. Other medications to consider, depending on clinical and laboratory parameters, include ACE inhibitors, potassium-sparing diuretics (particularly spironolactone), and magnesium supplementation. Thiazide diuretic should not be used to treat hypercalciuria and nephrocalcinosis in Bartter syndrome patients because further inhibition of salt reabsorption in the DCT removes the kidneys' ability to compensate, while increasing the risk of significant dehydration.

Because patients with Gitelman syndrome do not typically show the increased prostaglandin production seen in patients with Bartter syndrome,^[37] the same response to indomethacin is not seen. Hypomagnesemia is a more prominent component of Gitelman syndrome, so magnesium supplementation is routinely required. Otherwise management of Gitelman syndrome is similar to that of Bartter syndrome.

Long-term outcome study of over 10 years in type 1 and type 2 Bartter syndrome patients showed a glomerular filtration rate of less than 90 mL/min per 1.73 m² in 25% of the patients.^[14] This is likely the result of the prevalent nephrocalcinosis. In addition, interstitial nephritis from life-long hypokalemia or non-steroidal anti-inflammatory medications may be compounding factors. The use of indomethacin at an average dose of 0.9 mg/kg body weight per day for over 10 years is unrelated to any lesions on kidney biopsies in patients with type 1 and type 2 Bartter syndrome.^[14] Finally, almost 9% of patients with these two types of Bartter syndrome are found to have gallstone.^[14] Predisposing factors include prematurity, chronic use of loop diuretics and dysfunction of hepatobiliary ROMK.

Some experts regard hypocalcemia with Bartter-like syndrome from CASR (OMIM 601199) as type 5 Bartter syndrome.^[29] Others list antenatal Bartter syndrome from CLCNKA and CLCNKB mutations as type 5 Bartter syndrome.^[4] Out of such confusion, a proposal has been made of a new classification,^[4] utilizing the advances in our understanding of the syndrome.

Chronic hypokalemia in patients with Bartter syndrome and Gitelman syndrome can be aggravated by diarrhea or vomiting into life-threatening rhabdomyolysis, cardiac arrhythmia, and syncope. Clinicians need to be cognizant with these congenital, renal tubular disorders, and promptly treat such patients. Finally, these syndromes of normal (or low) blood pressure, despite hyperreninemia and hyperaldosteronism, may provide insight into molecular control of blood pressure and lead to new antihypertensives.

Funding: This study was supported by grants RO1 DK31370, RO1 DK32431, RO1 DK50419, T32 DK07526, T32 DK07761 from the National Institutes of Health, Bethesda, MD, USA.

Competing interest: No benefits in any form have been received or will be received from any commercial party related directly or indirectly to the subject of this article.

Contributors: Chan JCM proposed the study and wrote the first draft. Fremont OT analyzed the data. Both authors contributed to the design and interpretation of the study and to further drafts. Chan JCM is the guarantor.

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