What are the diagnostic criteria and management options for a patient presenting with hypokalemia, metabolic alkalosis, and hypercalciuria, suspected of having Bartter's syndrome?

Diagnosis of Bartter's Syndrome

Diagnose Bartter syndrome clinically based on the triad of hypokalemic metabolic alkalosis, renal salt wasting with elevated fractional chloride excretion (>0.5%), and elevated renin-aldosterone, then confirm with genetic testing using a multi-gene panel. 1

Clinical Presentation by Age

Prenatal/Neonatal Period:

• Severe polyhydramnios from excessive fetal polyuria is virtually pathognomonic for Bartter syndrome (no other inherited tubular disorder causes this) 1
• Premature birth, typically 29-35 weeks gestational age 1
• Postnatal presentation includes renal salt wasting, severe polyuria, rapid weight loss, and dehydration 1

Beyond Neonatal Period:

• Failure to thrive, recurrent vomiting, repeated fever 1
• Hypochloremic and hypokalemic metabolic alkalosis 1
• Nephrocalcinosis (particularly Types 1 and 2) 1
• Salt craving, muscle weakness, low blood pressure, pubertal delay 1
• Rare presentations include hypokalemic paralysis (even in middle age) or severe hypocalcemia with altered sensorium 2, 3

Essential Diagnostic Workup

Medical History Assessment: 1

• Polyhydramnios during pregnancy
• Premature birth
• Growth failure and developmental milestones
• Family history (autosomal recessive inheritance pattern)

Biochemical Parameters (Serum): 1, 2

• Electrolytes: sodium, chloride (critical), potassium, calcium (ionized preferred), magnesium
• Acid-base status (expect hypochloremic metabolic alkalosis)
• Renin and aldosterone levels (hyperreninemic hyperaldosteronism)
• Creatinine (assess for AKI from volume depletion)

Urine Studies: 1, 2

• Fractional excretion of chloride (>0.5% indicates renal salt wasting) - this distinguishes renal from extrarenal losses
• Urinary calcium-creatinine ratio (hypercalciuria in Types 1 and 2; normocalciuria or hypocalciuria in Type 3)
• Urinary potassium (elevated despite hypokalemia)

Imaging: 1

• Renal ultrasound to detect medullary nephrocalcinosis and/or kidney stones
• Avoid CT scanning unless there is direct therapeutic consequence (e.g., obstructive uropathy) due to radiation burden

Genetic Confirmation

Genetic testing with a multi-gene panel is recommended for all patients with clinical suspicion of Bartter syndrome. 1

Genes to Include in Panel: 1

• SLC12A1 (Type 1 - NKCC2 defect)
• KCNJ1 (Type 2 - ROMK defect)
• CLCNKB (Type 3 - ClC-Kb defect)
• BSND (Type 4 - Barttin defect)
• MAGED2 (Type 5 - transient form)

Genetic Testing Considerations: 1

• Analytical sensitivity: 90-100%
• Clinical sensitivity: ~75% in children, only 12.5% in adults (due to broader differential diagnosis including diuretic/laxative abuse)
• Large rearrangements are particularly frequent in CLCNKB and should be confirmed by multiplex ligation-dependent probe amplification
• Early genetic diagnosis helps identify overlapping phenotypes and guides management (e.g., screening for deafness in Type 4, avoiding aggressive treatment in transient Type 5)

Genetic counseling should be offered to all affected families, including cascade screening of relatives. 1

Distinguishing Features by Type

Type	Age at Onset	Polyhydramnios	Calciuria	Key Features
Type 1 (SLC12A1)	Prenatal	Severe	High	Nephrocalcinosis after 1-2 months [1]
Type 2 (KCNJ1)	Prenatal	Severe	High	Nephrocalcinosis after 1-2 months [1]
Type 3 (CLCNKB)	0-5 years	Absent/mild	Variable (can be low, mimicking Gitelman)	Later presentation [1]
Type 4 (BSND)	Prenatal	Very severe	Variable	Deafness, risk for CKD/ESRD [1]
Type 5 (MAGED2)	Prenatal	Present	High	Transient disease [1]

Critical Differential Diagnoses

Exclude These Acquired Causes First: 1, 2, 4

• Diuretic abuse (loop or thiazide diuretics)
• Laxative abuse
• Vomiting (surreptitious)

Distinguish from Gitelman Syndrome: 2, 4

• Gitelman presents later (typically adolescence/adulthood, after age 6)
• Hypocalciuria (not hypercalciuria) is the critical distinguishing feature
• Hypomagnesemia is more prominent
• Milder symptoms overall

Other Considerations: 1

• Congenital chloride diarrhea (watery diarrhea with hypokalemic, hypochloremic metabolic alkalosis)
• Pseudo-Bartter syndrome in cystic fibrosis (salt loss in sweat)
• Pseudohypoaldosteronism type I (though polyhydramnios cases have been shown to harbor KCNJ1 mutations)

Critical Pitfalls to Avoid

Do NOT perform tubular function tests with furosemide or thiazides - these are obsolete and carry risk of severe volume depletion, especially in infants. 1, 5 Genetic testing has surpassed functional testing.

Do NOT assume AKI requires standard management - this is volume depletion from salt wasting requiring salt supplementation, not restriction. 2

Do NOT overlook magnesium levels - severe hypomagnesemia can present as "hypocalcemia" by impairing PTH secretion and must be corrected for calcium to normalize. 2

Do NOT use potassium citrate - use only potassium chloride for replacement, as non-chloride salts worsen the metabolic alkalosis. 2

Do NOT miss the diagnosis in adults - Bartter syndrome can present in middle age with hypokalemic paralysis or be discovered incidentally. 6, 3, 7