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Bartter's Syndrome – Causes, Symptoms, Diagnosis, Treatment and Ongoing care
Basics
Bartter’s syndrome and Bartter’s-like syndrome are a group of rare autosomal, recessive, salt-wasting nephropathies characterized by polyuria, hypokalemia, metabolic alkalosis, and normotension with hyperreninemic-hyperaldosteronism (1).
Traditionally they have been divided into two main disorders according to where the defect is located in the renal tubule, but since genetic classification has been available there are more subtypes (2).
Bartter (Furosemide type) with 5 subtypes and Gitelman (Thiazide type) with 2 subtypes and combinations of the two.
Description
Bartter’s disorders have diverse genetic origins, with a common pathological mechanism of a severe reduction in salt reabsorption by the thick ascending limb of Henle (TAL) and/or the distal convoluted tubule (DCT).
Epidemiology
Prevalence
Gitelman’s prevalence is calculated at 1:40000. Heterozygote state in Caucasians: 1% (3)
Risk Factors
Consanguinity
Genetics
Autosomic recessive
Pathophysiology
Bartter type is caused by inactivating mutations in one of several genes encoding membrane proteins in charge of transporting Na, Cl, K, and sometimes Ca in the loop of Henle where 25% of the filtered solute load is reabsorbed. This causes large urinary losses of Na, Cl, K, Mg, and Ca. It resembles the effect of large doses of furosemide, which results in hypovolemia with activation of the renin aldosterone system without any hypertension. According to which transporter is compromised, the disease will be more or less severe and it will start sooner or later. When it starts in utero it causes polyhydramnios because of fetal polyuria. There is also secondary stimulation of prostaglandin E2 (PGE2) production with worsening of salt losses (2).
In the Gitelman type the inactivating mutations are in the distal convoluted tube where 5% of the filtered Na is reabsorbed. It resembles the effect of thiazides and causes urinary losses of Na, Cl, K, and Mg, but not Ca. It is clinically less severe (2).
Etiology
The inactivating mutations in Bartter syndrome are in type I. The Na+-K-2Cl- cotransporter (SLC12A1 encoding NKCC2), in type II the apical inward-rectifying potassium channel (KCNJ1 encoding ROMK), in type III the basolateral chloride channel (ClCNK encoding ClC-Kb), and in type IV the BSND, a protein that acts as an essential activator β-subunit for ClC-Ka and ClC-Kb chloride channels. Type V is a gain-of-function mutations in the extracellular calcium ion-sensing receptor (CaSR) that cause a variant with hypocalcemia (12).
In Gitelman the inactivating mutations are in the SLC12A3 gene encoding the thiazide sensitive Na-Cl cotransporter, or NCCT (23).
Commonly Associated Conditions
Polyhydramnios, prematurity
Nephrocalcinosis, rickets, growth retardation
Hyperprostaglandin levels
Sensoneural deafness, mental retardation in type IV
Cardiac problems (4)
Gallstones (5)
Constipation
Diagnosis
History
Polyuria and polydipsia are always present. History of episodes of dehydration.
In types I, II, IV, and V the presentation is usually prenatal with polyhydramnios, prematurity, and postnatally there is failure to thrive, dehydration, muscle weakness, seizures, tetany, and paresthesias. This type has been called Neonatal Bartter of In Bartter there is always hypercalciuria with normomagnesemia. Nephrocalcinosis is present in type I and II. Type II can show hyperkalemia at birth and less hypokalemia than the other subtypes.
Type III is variable and can present later in early childhood with no nephrocalcinosis.
Gitelman usually presents later with muscle weakness and hypokalemia, hypomagnesemia, and hypocalciuria.
Physical Exam
Premature AGE, normotension, and failure to thrive later on
Dysmorphic features, including triangular facies, protruding ears, large eyes, and drooping mouth.
Tetany, hypotonia.
Diagnostic Tests & Interpretation
Lab
Hypokalemia of <2.5 mEq/L with metabolic alkalosis is almost universal. Only in type II hypokalemia may not be as severe and it may even have hyperkalemia in the newborn period.
Prenatal testing of amniotic fluid may be diagnostic (6).
Initial lab tests
Na, K, Cl, tCO2, Ca, and Mg in serum and in urine. There will be hypokalemia with elevated tCO2 and normomagnesemia with hyperkaluria, hyperchloruria, and hypercalciuria in Bartter, while in Gitelman there will be hypomagnesemia and decreased urinary calcium.
Renin and aldosterone will always be elevated and Prostaglandin E2 will be elevated in Bartter but not in Gitelman.
Follow-Up & Special Considerations
Electrolytes need to be followed very frequently until they stabilize and then monthly. Urinary random Ca/Cr should be followed at least twice a year.
Creatinine and BUN should be followed because there can be renal failure mainly from nephrocalcinosis (7).
Cardiac studies are indicated (4).
Imaging
Renal ultrasound is indicated always in Bartter because of the presence of nephrocalcinosis. It should be done about every 2 years.
Pathological Findings
Renal biopsy shows hyperplasia of the juxtaglomerular apparatus.
Differential Diagnosis
Chronic diuretic abuse
Chronic vomiting
Treatment
The main goal in the neonatal period is to keep patients hydrated with correction of hypokalemia.
In Gitelman, correction of hypomagnesemia is also important.
Medication
Non-steroidal antiinflammatory drugs (NSAIDs) should be used in Bartter’s (8).
First Line
Bartter: NSAIDs, potassium and sodium supplementation, spironolactone
Gitelman: Potassium and magnesium supplementation. NSAIDs are not useful.
Second Line
H2 blockers or proton-pump inhibitors when using NSAIDs
Ongoing Care
Diet
High in salt, potassium, and water
Prognosis
Good in general. With adequate management patients can grow normally (8).
Complications
Nephrocalcinosis, gastric ulcers, chronic kidney disease (1)
References
1. Chadha V, Alon US et al. Hereditary renal tubular disorders. Semin Nephrol. 2009;29:399–411.
2. Seyberth HW et al. An improved terminology and classification of Bartter-like syndromes. Nature clinical practice. Nephrology. 2008;4:560–7.
3. Knoers NV, Levtchenko EN et al. Gitelman syndrome. Orphanet J Rare Dis. 2008;3:22.
4. Scognamiglio R, Calò LA, Negut C et al. Myocardial perfusion defects in Bartter and Gitelman syndromes. Eur J Clin Invest. 2008;38:888–95.
5. Shin JI, Lee JS et al. Comment on: Bartter syndrome and cholelithiasis in an infant: is this a mere coincidence? (Eur J Pediatr 2008;167(1):109–110). Eur J Pediatr. 2009;168.
6. Garnier A, Dreux S, Vargas-Poussou R et al. Bartter syndrome prenatal diagnosis based on amniotic fluid biochemical analysis. Pediatr Res. 2010;67:300–3.
7. Lin CM, Tsai JD, Lo YF et al. Chronic renal failure in a boy with classic Bartter’s syndrome due to a novel mutation in CLCNKB coding for the chloride channel. Eur J Pediatr. 2009;168:1129–33.
8. Puricelli E, Bettinelli A, Borsa N et al. Long-term follow-up of patients with Bartter syndrome type I and II. Nephrol Dial Transplant. 2010;25:2976–81.
Additional Reading
Brochard K, Boyer O, Blanchard A et al. Phenotype-genotype correlation in antenatal and neonatal variants of Bartter syndrome. Nephrol Dial Transplant. 2009;24:1455–64.
Nozu K, Iijima K, Kanda K et al. The pharmacological characteristics of molecular-based inherited salt-losing tubulopathies. J Clin Endocrinol Metabol. 2010.
Codes
ICD9
255.13 Bartter’s syndrome
Snomed
71275003 pseudoprimary aldosteronism (disorder)
Clinical Pearls
Bartter’s and Bartter’s-like syndromes are autosomic recessive hypokalemic salt-losing nephropathies that mimic diuretic effects.
