Bartter Syndrome 

Bartter Syndrome – 7 Interesting Facts

1. Bartter syndrome is a rare genetic disease caused by impaired renal sodium chloride reabsorption and characterized by severe volume depletion, hypokalemia, and metabolic alkalosis due to mutations in genes encoding transporter proteins in ion channels
2. Classified by mutations into 5 types, with 2 clinical presentations (antenatal and classic)
3. Primary diagnostic tools are serum and urinary electrolyte measurements
4. Treatments include electrolyte replacement therapy and drug therapy with NSAIDs (both antenatal and classic forms), ACE inhibitors (classic form), and potassium-sparing diuretics (classic form)
5. Somatropin (recombinant hGH) is used in some patients to address short stature
6. Complications include short stature, cardiac arrhythmia (up to sudden death), gallstones, hyperuricemia, and gout
7. Prognosis is good with timely and appropriate treatment; however, some patients progress to chronic renal failure

Pitfalls

• Delayed diagnosis of antenatal Bartter syndrome can cause severe electrolyte imbalance, poor feeding, and dehydration in infants
• Quality of life may be markedly impaired in patients with severe fatigue or in those for whom medication is poorly tolerated
• When providing anesthesia to a patient with Bartter syndrome, apply special attention to ensure cardiovascular stability, manage plasma potassium level, and prevent renal damage ¹
• Advise patients and parents to be cautious and to provide adequate fluid and electrolyte replacements in hot weather, especially if engaging in strenuous exercise, because volume depletion may easily occur

Urgent Action

Patients require prompt and vigorous IV fluid replacement in situations of physiologic stress (eg, surgical procedures, trauma) where serum electrolyte levels drop rapidly

Introduction

• Bartter syndrome is a rare autosomal recessive disease caused by impaired sodium chloride reabsorption in thick ascending limb of loop of Henle ²
• Characterized by severe volume depletion, hypokalemia, metabolic alkalosis, hyperreninemia, and hyperaldosteronism caused by mutations in genes encoding transporter proteins in channels of sodium, chloride, calcium, and potassium ³

Classification

Types of Bartter Syndrome

There are 5 genetic types (Types I–V), based on the affected ion transporters:

Type	Gene Affected	Defect	Additional Features
Type I	SLC12A1	Na-K-2Cl cotransporter (NKCC2)	Severe, neonatal onset
Type II	KCNJ1	ROMK channel	Similar to Type I
Type III	CLCNKB	Cl⁻ channel	Classic Bartter (childhood onset)
Type IV	BSND (Barttin)	Cl⁻ channels + deafness	Sensorineural deafness
Type V	CASR	Ca-sensing receptor	Variable presentation

• 2 distinct presentations of Bartter syndrome (antenatal and classic) are further classified into 5 types (I-V) on the basis of renal genetic mutations
  • Antenatal Bartter syndrome: onset in utero
    • Type I ³
      • Mutation in SLC12A1 gene (solute carrier family 12 member 1)
      • Channel implicated: NKCC2 cotransporter
      • Site in renal tubule: thick ascending limb of loop of Henle
    • Type II ³
      • Mutation in KCNJ1 gene (potassium voltage-gated channel subfamily J member 1)
      • Channel implicated: renal outer medullary potassium channel
      • Site in renal tubule: thick ascending limb of loop of Henle
    • Type IV (with sensorineural deafness) ³
      • Mutation in BSND gene (barttin CLCNK type accessory β subunit) or a combination of mutations in CLCNKA and CLCNKB genes (chloride voltage-gated channels Ka and Kb)
      • Channels implicated: barttin channel and chloride voltage-gated channels Ka and Kb
      • Site in renal tubule: thick ascending limb of loop of Henle and distal convoluted tubule
    • Type V ³⁴⁵
      • 4 mutations in CASR gene (calcium-sensing receptor) account for calcium and salt wasting
      • Site in renal tubule: thick ascending limb of loop of Henle
      • Very rare and may be self-limited; defined by isolated case reports
  • Classic Bartter syndrome: onset in infancy or early childhood ⁶
    • Type III
      • Mutation in CLCNKB gene
      • Channel implicated: chloride voltage-gated channel Kb
      • Site in renal tubule: distal convoluted tubule

Diagnosis

Clinical Presentation

History

• Antenatal Bartter syndrome: patients presenting with this form of the syndrome exhibit significant symptoms from birth ³
  • Usual history of: ³
    • Polyhydramnios (from fetal polyuria) starting between 24 and 30 weeks of gestation
    • Preterm delivery
    • Rapid weight loss immediately after birth
  • Postnatal polyuria ⁶
    • Polyuria that persists for 4 to 6 weeks after birth
  • Chronic dehydration (marked by polydipsia) associated with varying degrees of: ⁷
    • Recurrent vomiting
    • Growth restriction
    • Failure to thrive in infancy
  • Poor feeding and lethargy may be noted if diagnosis is delayed
  • Fever, vomiting, and diarrhea are common symptoms that may be attributed to the stimulation of renal and systemic prostaglandin E₂ ²
• Classic Bartter syndrome: usually milder symptoms than in antenatal form ⁸
  • History of gestational complications (eg, polyhydramnios, premature delivery) is often given ⁶
  • Muscle weakness, chronic fatigue, and muscle cramping in nearly all cases ⁶⁷
    • Resulting from hypokalemia ⁷
  • Polyuria, nocturnal enuresis, and polydipsia occur and continue until late childhood or adolescence ⁷
  • Unrecognized dehydration in the early months or years of life may manifest as: ⁷
    • Vomiting
    • Feeding problems
    • Failure to thrive that persists from infancy to adolescence

Physical examination

• Antenatal Bartter syndrome
  • Unexplained polyhydramnios is often the first presentation
    • Occurs around 24 to 30 weeks of gestation ³
    • Increased amniotic fluid is caused by fetal polyuria
    • Intrauterine growth restriction may occur
  • Presents in neonates; those affected are often born prematurely ³
    • Hyposthenuria (urine of low specific gravity) is an important finding noted after birth
    • Rapid weight loss after birth is another significant finding
    • Blood pressure is typically within reference range
    • Lethargy and poor feeding are usually noted
  • Distinctive facial features are common (eg, large eyes, triangular face, pointed ears, prominent forehead, drooping mouth/pouting expression)
  • Sensorineural deafness is present in patients with type IV ³
• Classic Bartter syndrome ⁶
  • Typically presents in infancy or early childhood (younger than 6 years); owing to the variation in genetic causes, it may rarely present in an adolescent or adult
  • Near-fatal volume depletion may be presenting condition
  • Growth restriction is commonly seen
  • Muscle weakness occurs in almost all patients
  • Compromised neurointellectual development ranging from mild to severe impairment

Causes

• Gene mutations affecting thick ascending limb of loop of Henle lead to impairment of sodium chloride reabsorption, increase in prostaglandin E₂ level, and stimulation of the renin-angiotensin-aldosterone system ³
  • Genes involved are SLC12A1, KCNJ1, BSND, CLCNKA, CASR, and CLCNKB

Risk factors and/or associations

Age ⁶

• Antenatal Bartter syndrome is seen in utero or in early infancy
• Classic Bartter syndrome usually manifests in infancy or in early childhood, typically before age 6 years; rarely, it presents in older patients (adolescents and adults) with chronic hypokalemia

Genetics

• Bartter syndrome is genetically heterogeneous ⁹
  • Based on linkage analyses in a large number of families
• Bartter syndrome is caused by mutations in the following genes:
  • SLC12A1 gene (type I) (OMIM #601678 ¹⁰)
    • Mutations in SLC12A1 (solute carrier family 12 member 1, sodium/potassium/chloride transporter) prevent NKCC2 protein from transporting ions into kidney cells
  • KCNJ1 gene (type II) (OMIM #241200 ¹¹)
    • Mutations in KCNJ1 (potassium voltage-gated channel subfamily J member 1) prevent the renal outer medullary potassium channel protein from reaching the cell membrane or alter its ability to transport potassium ions
  • CLCNKB gene (type III) (OMIM #607364 ⁹)
    • Mutations in CLCNKB (chloride voltage-gated channel Kb) inhibit NKCC2 activity, leading to intracellular chloride ion accumulation
  • BSND gene or both CLCNKA and CLCNKB genes (type IV) (OMIM #602522 ¹² and #613090 ¹³)
    • Mutations in BSND (barttin CLCNK type accessory β subunit) impair ability of protein barttin to regulate the chloride voltage-gated channels Ka and Kb, or mutations in both CLCNKA (chloride voltage-gated channel Ka) and CLCNKB (chloride voltage-gated channel Kb) impair those channels
  • CASR gene ⁴⁵³ (type V) (OMIM #300971) ¹⁴
    • 4 mutations in CASR (calcium-sensing receptor) cause autosomal dominant hypocalcemia with inappropriately low parathyroid hormone level, decreased serum calcium level, and relative hypercalciuria
  • MAGE-D2 gene is associated with a transient form of Bartter syndrome ¹⁵¹⁶ (OMIM #300971) ¹⁴
    • X-linked inheritance pattern
    • Early-onset hydramnios
    • Spontaneous disappearance of symptoms after childbirth

Diagnostic Procedures

Primary diagnostic tools

• Antenatal Bartter syndrome
  • Perform ultrasonography in all pregnant patients with possible polyhydramnios as indicated by fundal size being larger than expected for gestational age ³¹⁷
    • Polyhydramnios may also be discovered on routine prenatal ultrasonography
  • Perform amniocentesis in all pregnant patients with unexplained polyhydramnios ³
    • Evaluate electrolyte levels in amniotic fluid
      • Typical findings in Bartter syndrome include sodium and potassium levels within reference range but extremely elevated chloride level
    • Not performed if cause of polyhydramnios is apparent from prenatal ultrasonography and prenatal quad screen (maternal blood screen) for evidence of developmental anomalies (performed in second trimester)
  • Obtain neonatal urinary electrolyte levels and specific gravity in select newborns, as follows:
    • Criteria
      • Newborns whose mothers had the following during pregnancy:
        • Amniotic fluid findings consistent with Bartter syndrome
        • Polyhydramnios without testing
      • Newborns with preterm delivery, rapid weight loss, polyuria, poor feeding, lethargy, diarrhea, and vomiting
    • Interpretation of results
      • Low specific gravity is an early sign in neonates with Bartter syndrome ¹
      • Shortly after birth, extremely elevated urinary levels of calcium, sodium, and chloride are detected but potassium levels are within reference range ¹
      • Typically, urinary potassium level rises by 1 to 3 weeks after birth ¹
• Classic Bartter syndrome ¹
  • Laboratory tests are the primary diagnostic tools
    • Obtain a basic metabolic profile (with serum bicarbonate level in infants and children) and urinary electrolyte levels when Bartter syndrome is suspected
    • Obtain arterial blood gas levels for assessment of acid-base status in all adolescents and adults in whom Bartter syndrome is suspected on the basis of polydipsia, polyuria, salt craving, vomiting, constipation, and tendency toward dehydration
      • Use (venous) serum bicarbonate level (along with anion gap) to determine acid-base status in infants and children

Laboratory

• Amniotic fluid analysis
  • Obtain in all pregnant patients with unexplained polyhydramnios on ultrasonography ³
  • Elevated chloride level is consistent with antenatal Bartter syndrome ²
  • Reference range levels of sodium, potassium, and prostaglandin E₂ are typical ³
• Urinary electrolyte analysis
  • Obtain in all neonates whose mothers experienced polyhydramnios during pregnancy and in infants in whom antenatal Bartter syndrome is suspected on the basis of preterm delivery, rapid weight loss, polyuria, poor feeding, lethargy, diarrhea, and vomiting ³
  • Elevated urinary levels of sodium, potassium, and chloride are diagnostic of antenatal Bartter syndrome ¹⁸
  • Urine may have low specific gravity and high prostaglandin E₂ level in antenatal Bartter syndrome, although prostaglandin levels are not usually measured ³
• Serum electrolyte analysis
  • Obtain in all infants or children in whom any form of Bartter syndrome is suspected ³
  • Hypokalemia (plasma potassium levels of 3 mmol/L or less) and metabolic alkalosis are diagnostic of classic Bartter syndrome ¹⁹
  • Transient hyperkalemia may be observed in neonates with type II antenatal Bartter syndrome ³
• Arterial blood gas levels
  • Obtain for assessment of acid-base status in all adolescents and adults in whom Bartter syndrome is suspected; record as baseline at time of diagnosis

Imaging

• Ultrasonography
  • Maternal ultrasonography
    • Recommended in all pregnant patients in whom polyhydramnios is suspected (on the basis of fundal size being larger than expected for gestational age) ³
    • Polyhydramnios (amniotic fluid index greater than 24 cm) is an important diagnostic feature of antenatal Bartter syndrome, and it may indicate the need for amniocentesis, unless structural or other abnormalities provide an alternate diagnosis ⁸
  • Neonatal ultrasonography
    • Obtain in premature and ill newborns for structural evaluation and detection of congenital abnormalities
      • Obtain renal ultrasonography if urinary abnormalities are found
        • Renal ultrasonographic diagnostic findings in affected children include:
          • Normal kidney size with significant increase in echogenicity of parenchyma and loss of corticomedullary differentiation ¹⁷
          • Medullary nephrocalcinosis, indicated by diffuse, increased echogenicity of the renal pyramids without distal acoustic shadowing ¹⁷
            • Nephrocalcinosis is observed in antenatal Bartter syndrome but is absent in classic Bartter syndrome ⁶

Procedures

• Removal of 12 to 15 mL of amniotic fluid by inserting a small-gauge hollow needle through the maternal gravid abdomen ¹⁷
• Usually performed at 15 to 20 weeks of gestation ²⁰
• For diagnosis in a patient whose fetus is strongly suspected to have antenatal Bartter syndrome on the basis of polyhydramnios
• For releasing intrauterine pressure in polyhydramnios to prevent preterm labor and birth
• Absolute
  • Skin infection at planned needle insertion site
• Relative
  • Multiple gestations (owing to technical difficulty)
  • Anterior location of placenta
  • Maternal fever of unknown origin
• Miscarriage rate after amniocentesis is approximately 1.4% ²²
  • Risk factors for miscarriage include:
    • Amniocentesis before 15 weeks of gestation
    • Use of large needles
    • Multiple attempts
    • Unrecognized postprocedural chorioamnionitis
  • Risk of talipes equinovarus is elevated if amniocentesis is performed before 15 weeks of gestation
• Preterm labor
• Chorioamnionitis
• Rh sensitization of fetus
• Amniotic fluid leakage
• Fetal injury
• Biochemical analysis of amniotic fluid ³
  • Antenatal Bartter syndrome diagnosis is confirmed if chloride level is high in amniotic fluid
    • In one study, amniotic chloride levels of patients with Bartter syndrome were found to be more than 2 standard deviations above mean control values ²³
  • Sensitivity of amniotic fluid analysis to diagnose Bartter syndrome is 93%, and specificity is 100% ⁸

Differential Diagnosis

Most common

• Differentiation is based on dehydration, hypokalemia, and metabolic alkalosis
  • Pseudo-Bartter syndrome
    • Results from surreptitious use of diuretics or laxatives and/or from persistent vomiting for weight loss or due to illness
    • Similarities
      • In adolescents and adults, presentation is similar to that of later-onset Bartter syndrome, with weakness and cramping (tetany), hypokalemia, and metabolic alkalosis
    • Differentiating features
      • History of diuretic or laxative use or intentional purging (if obtainable)
      • Persistent vomiting due to illness
        • Hypokalemic metabolic alkalosis resolves with treatment of underlying disorder (eg, surgery for pyloric stenosis), but it is persistent in cases of Bartter syndrome, requiring ongoing management
    • Diagnostic tests
      • Plasma or urinary diuretic levels ²⁴
      • Urinary chloride level: high in Bartter syndrome but low in other conditions, except for diuretic abuse
  • Gitelman syndrome
    • Syndrome similar to (and historically considered a type of) Bartter syndrome; caused by mutations in SLC12A3 gene encoding sodium/chloride cotransporter (solute carrier family 12 member 3; NCCT)
    • Similarities
      • Autosomal recessive disorder characterized by hypokalemic alkalosis and salt wasting
    • Differentiating features
      • Hypocalciuria, hypomagnesemia, presentation in early adulthood, and milder symptoms compared with Bartter syndrome
      • Urinary calcium excretion is decreased in Gitelman syndrome, whereas in Bartter syndrome it is either within reference range or increased, usually with nephrocalcinosis
    • Diagnostic tests
      • To diagnose Gitelman syndrome, serum and urinary electrolyte levels are measured, and other disorders are excluded
        • Biochemical findings that differentiate Gitelman syndrome include: ¹
          • Hypomagnesemia (serum magnesium level less than 0.5 mEq/L; reference range is 0.8-1 mEq/L)
          • Hypocalciuria (urinary calcium level less than 2 mg/kg/day; reference range is 2-7 mg/kg/day)

Treatment Goals

• Correct hypokalemia and metabolic alkalosis; restore plasma potassium level to the range of 3 to 3.5 mEq/L ²
• Correct dehydration
• Minimize effects of increased aldosterone and prostaglandin secretion
• Improve growth and development in children with growth restriction and compromised neurointellectual development ²⁵

Disposition

Admission criteria

If patient experiences excessive vomiting, hospitalization may be required

• Provide prompt IV fluid replacement to avoid dehydration; control vomiting
  • Patients with Bartter syndrome are at risk of dehydration and significant electrolyte imbalances owing to impairment in urine concentration during a coexisting illness (eg, gastroenteritis); therefore, they may require hospitalization for several days to receive IV fluid and electrolyte replacement

Other symptoms that may require admission:

• Pronounced muscle weakness
• Persistent hypokalemia
• Failure to thrive in infancy
• Severe regurgitation in infancy

Criteria for ICU admission

• Cardiac arrhythmia due to significant electrolyte imbalance (eg, hypokalemia, hypomagnesemia) or rhabdomyolysis
• Severe hypokalemia (potassium level of 2 mmol/L or less) requiring prompt correction and ongoing cardiac monitoring

Recommendations for specialist referral

• Refer to nephrologist or pediatric nephrologist for verification of diagnosis and assistance in management
• Consult obstetrician if amniocentesis is indicated
• For all pregnant patients with polyhydramnios due to Bartter syndrome of the fetus: refer for close follow-up by high-risk maternal-fetal medicine specialist
  • Required to guide use of NSAIDs during pregnancy and to gauge need for serial amniocentesis owing to rapidly increasing amniotic fluid volume

Treatment Options

Treatment of Bartter syndrome requires lifelong management and consists of 2 strategies: replacement therapy and drug therapy ¹

• Replacement therapy overview ¹
  • Goal is correction of fluid and electrolyte imbalance in both classic and antenatal Bartter syndrome
  • Antenatal Bartter syndrome
    • Saline IV infusion is used, especially in the first few weeks of life ¹
    • Oral replacement therapy with potassium chloride and sodium chloride (15% solution) follows initial IV saline therapy ¹
      • Used to treat postnatal hypokalemic alkalosis in antenatal Bartter syndrome
      • Potassium replacement is typically not needed in the first 2 to 3 weeks of life, owing to low urinary potassium loss during that period in antenatal Bartter syndrome
  • Classic Bartter syndrome
    • Potassium chloride supplementation ¹
      • Used to treat hypokalemic alkalosis ¹
      • Titrate dose on the basis of individual patient needs and the amount lost by the kidneys ¹
    • Magnesium supplementation ¹
      • Administered concomitantly to treat hypomagnesemia that occasionally presents in classic Bartter syndrome
• Drug therapy overview
  • NSAIDs inhibit prostaglandin-endoperoxide synthases (cyclooxygenases), reducing synthesis of prostaglandins. They are used as part of standard therapy in addition to electrolyte replacement therapy in both classic and antenatal Bartter syndrome ¹²⁶
    • Indomethacin: Most commonly used NSAID for treatment of both classic and antenatal Bartter syndrome ³
      • Helps reduce polyuria, salt wasting, hypokalemia, and systemic symptoms of hyperprostaglandinism (eg, fever, vomiting, diarrhea) ⁶
      • Improves growth rates ⁶
      • Antenatal Bartter syndrome ⁶
        • Administered after oral replacement therapy has begun ¹
        • Delay use for 4 to 6 weeks after birth in premature infants, owing to reversible decreases of GFR that occur with use ¹
      • Classic Bartter syndrome
        • Administered in conjunction with potassium supplementation ⁶
    • Ibuprofen is another NSAID for treatment of classic Bartter syndrome ²
      • Helps improve growth rates in children
      • Reduces symptoms of hypokalemia
  • ACE inhibitors (eg, enalapril, captopril) are used to improve hypokalemia and reduce aldosterone level in classic Bartter syndrome ⁶
    • Used in addition to NSAID treatment, mainly in adults, with mixed results ¹
    • Use with caution in children, owing to risk of development of symptomatic hypotension ¹
  • Potassium-sparing diuretics (eg, spironolactone, triamterene eplerenone, amiloride) have an antialdosterone effect and help correct the total body potassium balance in classic Bartter syndrome ¹¹⁵
    • Therapeutic effect when combined with oral potassium supplementation ¹
    • Initially useful in treatment of hypokalemia, but effect is transient ³
    • Not recommended for use in antenatal Bartter syndrome owing to risk of hypercalciuria and subsequent nephrocalcinosis ¹
  • Somatropin (recombinant hGH) accompanied by potassium supplementation has been used successfully to improve growth in short children with Bartter syndrome ²⁷
    • Use in patients taking other conventional therapies (eg, potassium supplements, spironolactone, indomethacin) whose growth remains poor ²⁷
    • Also restores serum magnesium levels to reference range ²⁷
• Bilateral nephrectomy combined with kidney transplant may be considered in cases that are poorly controlled by drug therapy or for patients who are nonadherent to therapy ²⁸
  • Best offered before development of end-stage renal disease
• In pregnant patients with polyhydramnios due to Bartter syndrome of the fetus: refer for close follow-up by a high-risk maternal-fetal medicine specialist to guide use of NSAIDs during pregnancy and to gauge the need for serial amniocenteses owing to rapidly increasing amniotic fluid volume ³
  • Fetal monitoring by ultrasonography is important to ascertain patency of the ductus arteriosus, which may constrict in response to NSAID therapy

Drug therapy

• NSAIDs ⁶
  • Standard therapy for both antenatal and classic Bartter syndrome
    • Monitor for adverse effects: necrotizing enterocolitis, nephrotoxicity, and gastrointestinal toxicity (all potentially fatal)
  • Not effective in preventing nephrocalcinosis in antenatal Bartter syndrome
  • Indomethacin
    • Most widely used NSAID for both antenatal and classic Bartter syndrome
    • Well tolerated by children and causes reinstitution of weight gain ¹
    • Indomethacin oral suspension; Neonates (older than 4-6 weeks if premature) and infants: 1.5 to 2.5 mg/kg/day in 2 divided doses. ⁶
    • Indomethacin Oral suspension; Children and Adolescents 3 years to 14 years: 1 to 2 mg/kg/day PO in divided doses initially. May increase to Max of 3 to 4 mg/kg/day or 150 to 200 mg/day PO, whichever is less.
    • Indomethacin Oral suspension; Adolescents 15 to 17 years: 25 mg PO 2 to 3 times/day initially. May increase by 25 to 50 mg/day at weekly intervals (Max:150 to 200 mg/day).
    • Indomethacin Oral capsule; Adults: 25 mg PO 2 to 3 times/day may increase dose by 25 mg/day PO every 7 days up to 200 mg/day.
  • Ibuprofen ³
    • Ibuprofen Oral suspension; Infants and Children 6 months and older (6 months to 17 years): 30 to 40 mg/kg/day PO in 3 to 4 divided doses. Doses not to exceed adult dosing. ³
    • Ibuprofen Oral tablet; Adults: 400 to 800 mg PO 3 times daily with meals.
• Potassium-sparing diuretics ³
  • Often added to NSAID therapy in treatment of classic Bartter syndrome
  • Effect is transient
  • Use increases growth rates in children
  • Unsafe in situations of gross salt and water wasting and circulatory volume contraction
  • Spironolactone ²⁹
    • Spironolactone Oral tablet; Infants†, Children†, and Adolescents†: 1 to 3.3 mg/kg/day PO given in 1 to 2 divided doses (Max: 100 mg/day PO).
    • Spironolactone Oral tablet; Adults: 25 to 100 mg PO once daily or in divided doses.
  • Triamterene
    • Triamterene Oral capsule; Children† and Adolescents†: 1 to 4 mg/kg/day PO in 2 divided doses. Max: 300 mg/day.
    • Triamterene Oral capsule; Adults: 100 mg PO twice daily. Use lower initial dose when used in combination with another diuretic or antihypertensive agent. Max: 300 mg/day PO.
  • Eplerenone ³⁰
    • Eplerenone Oral tablet; Adults: 50 mg PO once daily. For inadequate response after 4 weeks, may increase dosage to 50 mg PO twice daily. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Doses up to 150 mg/day have been used. ³⁰
  • Amiloride ³⁰³¹
    • Amiloride Hydrochloride Oral tablet; Children† and Adolescents†: 0.4 to 0.625 mg/kg/dose PO once daily. Max: 20 mg/day.
    • Amiloride Hydrochloride Oral tablet; Adults: Initially, 5 to 10 mg/day PO. Titrate the dosage to achieve clinical goals. Max: 20 mg/day.
• Recombinant hGH
  • For treatment of short children in Bartter syndrome: considered safe therapy and superior to indomethacin in assisting growth ³²
    • Growth measured at less than 2 standard deviations from the mean or growth falling off from an established growth rate defines growth restriction ³²
  • Somatropin
    • Somatropin (recombinant hGH) Solution for injection; Infants and Children: 0.2 mg/kg/week subcutaneously has been used. ³³
• ACE inhibitors ⁶
  • These drugs provide significant improvement in electrolyte balance and symptomatic relief ³⁴
  • Monitor blood pressure closely during first few hours of therapy for severe (but transient) hypotension
  • Activation of renin-angiotensin-aldosterone axis drives both urinary potassium wasting and stimulation of prostaglandin production
  • Limitations of this therapy are renal failure and hypotension owing to physiologic dependence on angiotensin II for blood pressure maintenance
  • Enalapril ⁶
    • Enalapril Maleate Oral solution; Infants, Children, and Adolescents 16 years and younger: 0.08 mg/kg/dose PO once daily (Max: 5 mg) initially; adjust dosage based on clinical response up to 0.6 mg/kg/day PO given in 1 to 2 divided doses (Max: 40 mg/day).
    • Enalapril Maleate Oral solution; Adolescents 17 years: 2.5 to 5 mg PO once daily initially. The usual dosage range is 10 to 40 mg/day PO given in 1 to 2 divided doses.
    • Enalapril Maleate Oral tablet; Adults: 5 mg PO once daily, initially. May increase dose if further control is needed. Usual dose range: 5 to 40 mg/day PO in 1 to 2 divided doses.
  • Captopril ⁶
    • Captopril Oral tablet; Neonates†: 0.01 to 0.1 mg/kg/dose PO 1 to 3 times daily, initially. Titrate up to 0.5 mg/kg/dose PO 1 to 4 times daily based on clinical response.
    • Captopril Oral tablet; Infants†: 0.05 mg/kg/dose PO 1 to 4 times daily, initially; titrate to clinical response (Max: 6 mg/kg/day).
    • Captopril Oral tablet; Children† and Adolescents†: 0.5 mg/kg/dose (Initial Max: 25 mg/dose) PO 3 times daily, initially. Titrate to clinical response (Max: 6 mg/kg/day [Max: 450 mg/day]).
    • Captopril Oral tablet; Adults: 25 mg PO 2 to 3 times daily, initially. May increase dose to 50 mg PO 3 times daily after 1 to 2 weeks or 24 hours or less under continuous medical supervision, followed by 100 mg PO 2 to 3 times daily and 150 mg PO 2 to 3 times daily if further control is needed. Usual dose range: 12.5 to 150 mg/day in 2 to 3 divided doses. Max: 450 mg/day.

Nondrug and supportive care

Saline infusion: antenatal Bartter syndrome ¹

• In neonates with excessive fluid loss, especially in the first few weeks of life, provide IV saline, which is usually needed in large amounts
  • Urinary loss of sodium and chloride right after birth may be in the range of 115 to 120 mEq/L; fluid requirements in the first few days of life are approximately 1000 mL/kg of body weight, and this amount may increase in the early weeks, tapering to approximately 400 mL/kg after age 6 weeks ²³
  • Saline infusion helps prevent weight loss and dehydration by maintaining levels of sodium and chloride within reference range
• After the first 2 to 3 weeks of life, provide oral replacement therapy with sodium chloride and potassium chloride combined in 15% solution
  • Divide doses and give 3 to 4 times a day; titrate per patient needs

Oral potassium supplementation: provide potassium chloride, which is usually needed in large amounts ²⁵

• Mainstay of treatment
• Up to 10 mEq/kg/day in children and 500 mEq/day in adults
• Adults maintaining blood potassium levels above 3 mmol/L may not need supplementation ⁷
• Monotherapy alone is not very effective; use in conjunction with NSAIDs
  • Large amounts of exogenous potassium increase renal potassium loss by further stimulating aldosterone synthesis

Dietary adaptation

• Recommend nutritional counseling ²⁵
• In mild forms of Bartter syndrome, advise patients or parents to reduce rather than increase dietary salt ⁷
  • Salt balance is maintained even with low intake, resulting in good control of blood potassium levels
  • Increase in salt intake results in enhanced urinary potassium excretion
• Daily fluid intake should be 4 quarts (3.79 L) in growing children (as compared to a reference range benchmark of 2 quarts [1.89 L] in developing children) ³⁵

Magnesium supplementation ¹

• Magnesium deficiency may aggravate potassium wasting
• Addition of magnesium salts may be appropriate when hypomagnesemia is present. ³⁶
  • Initial daily dose is 4 to 5 mg/kg/day, divided into 3 to 4 doses to avoid diarrhea ³⁶
• Magnesium supplementation may be poorly tolerated, so encourage dietary sources ²⁵

Procedures

Nephrectomy with renal transplant ²⁸

General explanation

• Surgical removal of 1 or both kidneys, followed by renal transplant
• Has been used to successfully treat antenatal Bartter syndrome

Indication

• Life-threatening dehydration and electrolyte imbalance due to Bartter syndrome, refractory to medical control
• Growth restriction or failure to thrive (infants) secondary to Bartter syndrome

Contraindications

• Uncontrolled coagulopathy

Complications

• Renal rejection (graft-versus-host disease)
• Infection
• Anastomotic leakage

Special populations

• Pregnant patients ³⁷
  • Although rarely encountered, Bartter syndrome in a pregnant patient is managed largely with potassium supplementation; avoid NSAIDs, ACE inhibitors, and potassium-sparing diuretics (eg, spironolactone) owing to their teratogenicity
  • Restoration of serum potassium level to reference range is difficult to achieve in these patients, and levels of 2.5 to 3 mEq/L have been shown to be sufficient to support pregnancy, with normal outcomes reported
• Patients receiving anesthesia ¹
  • Give special attention to patients with Bartter syndrome who are receiving anesthesia; ensure cardiovascular stability, control of serum potassium level, and avoidance of renal damage

Monitoring

• Adequacy of treatment can be determined by measurement of serum electrolyte levels, but absolute normalization of these levels may be difficult to achieve
• Schedule regular, frequent follow-up appointments to monitor symptoms and assess treatment, with frequency determined by severity of disease
  • As growth is occurring and medications are stable, frequency of appointments may decrease
• Monitor serum electrolyte levels, renal function (by basic metabolic panel), and hydration status
• Monitor growth and development in infants, children, and adolescents
  • Document monthly measurements of height and weight on a growth curve

Complications and Prognosis

Complications

• Short stature and growth restriction ³⁸
  • Seen in almost all patients
  • Treat with indomethacin (NSAID) and potassium supplementation; use somatropin if those are not effective
• Cardiac arrhythmia (up to sudden death)
  • May result from electrolyte imbalance
• Gallstones ³⁹
  • Occur in patients with antenatal Bartter syndrome; may be caused by:
    • Long-term administration of loop diuretics, which is common in patients born prematurely
    • Altered function of either NKCC2 cotransporter (from SLC12A1 mutation) or renal outer medullary potassium channel (from KCNJ1 mutation) within hepatobiliary system
• Hyperuricemia and gout ⁴⁰
  • Hyperuricemia is seen in about 50% of patients, whereas about 20% of patients have acute gouty arthritis
  • Both gout and hyperuricemia may be due to metabolic alkalosis, a feature of Bartter syndrome that decreases clearance of uric acid
• Chronic tubulointerstitial nephropathy causing gradual reduction in GFR and chronic renal failure
  • Results from hypercalciuria, hypokalemia, and nephrocalcinosis
• Renal failure ³⁸
  • Most likely in patients with BSND mutations (type IV Bartter syndrome)
• Renal abnormalities
  • Long-term salt and water loss causes volume depletion and stimulation of the renin-angiotensin-aldosterone system, resulting in juxtaglomerular hyperplasia and increased renin production with subsequent potassium wasting and impedance of water reabsorption ³
    • Despite high renin and angiotensin levels, blood pressure remains within reference range owing to nonresponse of blood vessels to angiotensins

Prognosis

• Dehydration, electrolyte imbalance, and intercurrent infections may occur in untreated patients with antenatal Bartter syndrome, which may ultimately result in death ³
• Almost all patients with antenatal Bartter syndrome experience growth restriction ³
• Growth and neurointellectual development are improved with early diagnosis and timely treatment ²⁰
  • Mental development and puberty (long-term outcomes) are typically normal in treated antenatal Bartter syndrome
  • Patients with classic Bartter syndrome have neurointellectual impairment, ranging from mild to severe; many attend school
• Severe fatigue or poor medication tolerance may markedly impair the quality of life for some patients
• Long-term prognosis is unclear. Although some patients stay well, some undergo a slow progression to chronic renal failure due to interstitial fibrosis
  • In one study, patients with type I and type II Bartter syndrome showed satisfactory prognosis after median follow-up of more than 10 years ³⁹
  • Spontaneous recovery from antenatal Bartter syndrome after a period of therapy has been reported ^2 20

Screening and Prevention

Screening

At-risk populations ⁷

• Classic Bartter syndrome (type III) has a highly variable phenotype, ranging from the highly symptomatic neonatal form to the asymptomatic or mildly symptomatic later-onset form diagnosed during adolescence or adulthood
  • Screening both parents of an affected child for a mild form of the syndrome is recommended
  • If either parent is affected, the chance of transmitting the genotype in a future pregnancy is 50%

Screening tests ⁷

• Plasma potassium level

References

1.Amirlak I et al: Bartter syndrome: an overview. QJM. 93(4):207-15, 2000

View In Article|Cross Reference

2.Gómez de la F CL et al: Bartter syndrome: an infrequent tubulopathy of prenatal onset. Rev Chil Pediatr. 90(4):437-42, 2019

View In Article|Cross Reference

3.Bhat YR et al: Antenatal Bartter syndrome: a review. Int J Pediatr. 2012;857136, 2012

View In Article|Cross Reference

4.Vezzoli G et al: Autosomal dominant hypocalcemia with mild type 5 Bartter syndrome. J Nephrol. 19(4):525-8, 2006

View In Article|Cross Reference

5.Letz S et al: Amino alcohol- (NPS-2143) and quinazolinone-derived calcilytics (ATF936 and AXT914) differentially mitigate excessive signalling of calcium-sensing receptor mutants causing Bartter syndrome type 5 and autosomal dominant hypocalcemia. PLoS One. 9(12):e115178, 2014

View In Article|Cross Reference

6.Shaer AJ: Inherited primary renal tubular hypokalemic alkalosis: a review of Gitelman and Bartter syndromes. Am J Med Sci. 322(6):316-32, 2001

View In Article|Cross Reference

7.Colussi G: Bartter syndrome. Orphanet website. Updated March 2005. Accessed October 11, 2021. https://www.orpha.net/data/patho/GB/uk-Bartter.pdf

View In Article|Cross Reference

8.Garnier A et al: Bartter syndrome prenatal diagnosis based on amniotic fluid biochemical analysis. Pediatr Res. 67(3):300-3, 2010

View In Article|Cross Reference

9.Bartter Syndrome, Type 3; BARTS3. Online Mendelian Inheritance in Man. OMIM website. Johns Hopkins University. Edited September 25, 2019. Accessed October 11, 2021. http://www.omim.org/entry/607364

View In Article|Cross Reference

10.Bartter Syndrome, Type 1, Antenatal; BARTS1. Online Mendelian Inheritance in Man. OMIM website. Johns Hopkins University. Edited July 12, 2018. October 11, 2021. http://www.omim.org/entry/601678

View In Article|Cross Reference

11.Bartter Syndrome, Type 2, Antenatal; BARTS2. Online Mendelian Inheritance in Man. OMIM website. Johns Hopkins University. Edited May 22, 2019. Accessed October 11, 2021. http://www.omim.org/entry/241200

View In Article|Cross Reference

12.Bartter Syndrome, Type 4A, Neonatal, With Sensorineural Deafness; BARTS4A. Online Mendelian Inheritance in Man. OMIM website. Johns Hopkins University. Edited May 12, 2016. Accessed October 11, 2021. http://www.omim.org/entry/602522

View In Article|Cross Reference

13.Bartter Syndrome, Type 4B, Neonatal, With Sensorineural Deafness; BARTS4B. Online Mendelian Inheritance in Man. OMIM website. Johns Hopkins University. Edited May 12, 2016. Accessed October 11, 2019. http://www.omim.org/entry/613090

View In Article|Cross Reference

14.Bartter Syndrome, Type 5, Antenatal, Transient; BARTS5. Online Mendelian Inheritance in Man. OMIM website. Johns Hopkins University. Edited April 3, 2020. Accessed October 11, 2021. http://www.omim.org/entry/300971

View In Article|Cross Reference

15.Cunha TDS et al: Bartter syndrome: causes, diagnosis, and treatment. Int J Nephrol Renovasc Dis. 11:291-301, 2018

View In Article|Cross Reference

16.Takemori S et al: Prenatal diagnosis of MAGED2 gene mutation causing transient antenatal Bartter syndrome. Eur J Med Genet. 64(10):104308, 2021

View In Article|Cross Reference

17.Adam MJ et al: Performance of diagnostic ultrasound to identify causes of hydramnios. Prenat Diagn. 41(1):111-22, 2021

View In Article|Cross Reference

18.Gupta MR et al: Neonatal Bartter syndrome. Indian J Clin Pract. 25(5):471-3, 2014

View In Article|Cross Reference

19.Bettinelli A et al: Use of calcium excretion values to distinguish two forms of primary renal tubular hypokalemic alkalosis: Bartter and Gitelman syndromes. J Pediatr. 20:38-43, 1992

View In Article|Cross Reference

20.Mrad FCC et al: Bartter’s syndrome: clinical findings, genetic causes and therapeutic approach. World J Pediatr. 17(1):31-9, 2021

View In Article|Cross Reference

21.Smith RP: Amniocentesis. In: Smith RP et al, eds: Netter’s Obstetrics and Gynecology. 3rd ed. Elsevier; 2018:517-8

View In Article|Cross Reference

22.Tabor A et al: Fetal loss rate after chorionic villus sampling and amniocentesis: an 11-year national registry study. Ultrasound Obstet Gynecol. 34(1):19-24, 2009

View In Article|Cross Reference

23.Massa G et al: Electrolyte composition of the amniotic fluid in Bartter syndrome. Eur J Obstet Gynecol Reprod Biol. 24(4):335-40, 1987

View In Article|Cross Reference

24.Reimann D et al: Chronic, diagnosis-resistant hypokalaemia. Nephrol Dial Transplant. 14(12):2957-61, 1999

View In Article|Cross Reference

25.Francini F et al: The dietary approach to the treatment of the rare genetic tubulopathies Gitelman’s and Bartter’s syndromes. Nutrients. 13(9), 2021

View In Article|Cross Reference

26.Gasongo G et al: Effect of nonsteroidal anti-inflammatory drugs in children with Bartter syndrome. Pediatr Nephrol. 34(4):679-84, 2019

View In Article|Cross Reference

27.Ko CW et al: Recombinant human growth hormone and Gitelman’s syndrome. Am J Kidney Dis. 33:778-81, 1999

View In Article|Cross Reference

28.Chaudhuri A et al: Option of pre-emptive nephrectomy and renal transplantation for Bartter’s syndrome. Pediatr Transplant. 10(2):266-70, 2006

View In Article|Cross Reference

29.Tavakkoli F: Review of the role of spironolactone in the therapy of children. 18th Expert Committee on the selection and use of essential medicines. WHO website. Updated March 2011. Accessed July 3, 2019. https://www.who.int/selection_medicines/committees/expert/18/applications/spironolactone/en/

View In Article|Cross Reference

30.Blanchard A et al: Indomethacin, amiloride, or eplerenone for treating hypokalemia in Gitelman syndrome. J Am Soc Nephrol. 26(2):468-75, 2015

View In Article|Cross Reference

31.Griffing GT et al: Amiloride in Bartter’s syndrome. Clin Pharmacol Ther. 31(6):713-8, 1982

View In Article|Cross Reference

32.Gil-Peña H et al: Longitudinal growth in chronic hypokalemic disorders. Pediatr Nephrol. 25(4):733-7, 2010

View In Article|Cross Reference

33.Buyukcelik M et al: Bartter syndrome and growth hormone deficiency: three cases. Pediatr Nephrol. 27(11):2145-8, 2012

View In Article|Cross Reference

34.Guay-Woodford LM: Bartter syndrome: unraveling the pathophysiologic enigma. Am J Med. 105:151-61, 1998

View In Article|Cross Reference

35.Hansen B: Bartter’s syndrome. Adv Nurse Pract. 14(7):59-62, 2006

View In Article|Cross Reference

36.Al Shibli A et al: Bartter and Gitelman syndromes: spectrum of clinical manifestations caused by different mutations. World J Methodol. 5(2):55-61, 2015

View In Article|Cross Reference

37.Luqman A et al: Bartter’s syndrome in pregnancy: review of potassium homeostasis in gestation. Am J Med Sci. 338(6):500-4, 2009

View In Article|Cross Reference

38.Walsh PR et al: Clinical and diagnostic features of Bartter and Gitelman syndromes. Clin Kidney J. 11(3):302-9, 2018

View In Article|Cross Reference

39.Puricelli E et al: Long-term follow-up of patients with Bartter syndrome type I and II. Nephrol Dial Transplant. 25(9):2976-81, 2010

View In Article|Cross Reference

40.Meyer WJ 3rd et al: Gout as a complication of Bartter’s syndrome. A possible role for alkalosis in the decreased clearance of uric acid. Ann Intern Med. 83(1):56-9, 1975

View In Article|Cross Reference