Bartter’s Syndrome – Causes, Symptoms, Diagnosis, Treatment and Ongoing care
- 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.
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).
Gitelman’s prevalence is calculated at 1:40000. Heterozygote state in Caucasians: 1% (3)
- 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).
- 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)
- 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.
- 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
- 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).
Renal ultrasound is indicated always in Bartter because of the presence of nephrocalcinosis. It should be done about every 2 years.
Renal biopsy shows hyperplasia of the juxtaglomerular apparatus.
- Chronic diuretic abuse
- Chronic vomiting
- The main goal in the neonatal period is to keep patients hydrated with correction of hypokalemia.
- In Gitelman, correction of hypomagnesemia is also important.
Non-steroidal antiinflammatory drugs (NSAIDs) should be used in Bartter’s (8).
- Bartter: NSAIDs, potassium and sodium supplementation, spironolactone
- Gitelman: Potassium and magnesium supplementation. NSAIDs are not useful.
H2 blockers or proton-pump inhibitors when using NSAIDs
High in salt, potassium, and water
Good in general. With adequate management patients can grow normally (8).
Nephrocalcinosis, gastric ulcers, chronic kidney disease (1)
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.
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.
255.13 Bartter’s syndrome
71275003 pseudoprimary aldosteronism (disorder)
Bartter’s and Bartter’s-like syndromes are autosomic recessive hypokalemic salt-losing nephropathies that mimic diuretic effects.