BASICS
- Bartter syndrome and Bartter-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. However, more subtypes have been described with genetic classification (2).
- Bartter (furosemide type) has 5 subtypes, and Gitelman (thiazide type) has 3 subtypes; there are 3 combinations of the 2 (3).
DESCRIPTION
Bartter disorders have diverse genetic origins, with a common pathologic 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 prevalence is calculated at 1:40,000. Heterozygote state in Caucasians: 1%.
ETIOLOGY AND 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).
- 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 mutation in the extracellular calcium ion-sensing receptor (CaSR) that causes a variant with hypocalcemia (1,2).
- In Gitelman, the inactivating mutations are in the SLC12A3 gene encoding the thiazide-sensitive Na-Cl cotransporter or NCCT (2,4).
Genetics
Autosomal recessive
RISK FACTORS
Consanguinity
COMMONLY ASSOCIATED CONDITIONS
- Polyhydramnios, prematurity
- Nephrocalcinosis, rickets, growth retardation
- Hyperprostaglandin levels in Bartter syndrome (5)
- Sensorineural deafness, mental retardation in type IV
- Cardiac problems
- Gallstones
- Constipation
- Hypertension later in life
- Chondrocalcinosis in Gitelman syndrome due to hypomagnesemia (5)
DIAGNOSIS
HISTORY
- Polyuria and polydipsia are always present, and there is a history of episodes of dehydration.
- In types I (pure furosemide), II, IV (furosemide-thiazide), and V, the presentation is usually prenatal with polyhydramnios, prematurity; postnatally, there is failure to thrive, dehydration, muscle weakness, seizures, tetany, and paresthesias. This type has been called neonatal Bartter. In Bartter, there is hypercalciuria with normomagnesemia. Nephrocalcinosis is present in types I and II. Type II can show hyperkalemia at birth and less hypokalemia than the other subtypes (furosemide-amiloride type) (3).
- Type III (mixed thiazide-furosemide) is variable and can present later in early childhood with no nephrocalcinosis and hypomagnesemia.
- Gitelman (pure thiazide) 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
DIFFERENTIAL DIAGNOSIS
- Chronic diuretic and laxative abuse
- Chronic vomiting
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.
Initial Tests (lab, imaging)
- Na, K, Cl, CO2, Ca, and Mg in serum and in urine; serum renin, aldosterone, and PGE2
- Bartter: hypokalemia with elevated total CO2 and normomagnesemia with hyperkaluria, hyperchloruria, and hypercalciuria
- Gitelman: hypomagnesemia and decreased urinary Ca
- Renin, aldosterone, and PGE2 will be elevated in Bartter but not in Gitelman.
- Renal ultrasound is always indicated in Bartter because of the presence of nephrocalcinosis. It should be done about every 2 years.
- Electrolytes need to be followed 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 and possibly hyperaldosteronism.
- Cardiac studies are indicated.
- Hypertension can occur later in Gitelman (6).
Test Interpretation
Renal biopsy shows hyperplasia of the juxtaglomerular apparatus.
TREATMENT
- The main goal in the neonatal period is to keep up with severe fluid and sodium losses as well as correcting hypokalemia (7).
- In Gitelman, correction of hypomagnesemia is also important.
MEDICATION
NSAIDs should be used in Bartter (furosemide type).
First Line
- Bartter: NSAIDs, K and Na supplementation, spironolactone
- Gitelman (thiazide type): K and Mg supplementation. NSAIDs are not useful.
Second Line
- H2 blockers or proton pump inhibitors when using NSAIDs
- Avoidance of medications that prolong the QT
ONGOING CARE
DIET
High in salt, potassium, and water
PROGNOSIS
Good in general. With adequate management, patients can grow normally.
COMPLICATIONS
Nephrocalcinosis, gastric ulcers, chronic kidney disease
REFERENCES
11 Chadha V, Alon US. Hereditary renal tubular disorders. Semin Nephrol. 2009;29(4):399-411.22 Seyberth HW. An improved terminology and classification of Bartter-like syndromes. Nat Clin Pract Nephrol. 2008;4(10):560-567.33 Seyberth HW, Schlingmann KP. Bartter- and Gitelman-like syndromes: salt-losing tubulopathies with loop or DCT defects. Pediatr Nephrol. 2011;26(10):1789-1802.44 Knoers NV, Levtchenko EN. Gitelman syndrome. Orphanet J Rare Dis. 2008;3:22.55 Jain G, Ong S, Warnock DG. Genetic disorders of potassium homeostasis. Semin Nephrol. 2013;33(3):300-309.66 Berry MR, Robinson C, Karet Frankl FE. Unexpected clinical sequelae of Gitelman syndrome: hypertension in adulthood is common and females have higher potassium requirements. Nephrol Dial Transplant. 2013;28(6):1533-1542.77 Azzi A, Chehade H, Desch ªnes G. Neonates with Bartter syndrome have enormous fluid and sodium requirements. Acta Paediatrica 2015 Jul;104(7):e294-e299.
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(5):1455-1464.
- Nozu K, Iijima K, Kanda K, et al. The pharmacological characteristics of molecular-based inherited salt-losing tubulopathies. J Clin Endocrinol Metab. 2010;95(12):E511-E518.
- Walsh SB, Unwin E, Vargas-Poussou R, et al. Does hypokalaemia cause nephropathy? An observational study of renal function in patients with Bartter or Gitelman syndrome. QJM. 2011;104(11):939-944.
CODES
ICD10
E26.81 Bartter's syndrome
ICD9
255.13 Bartter's syndrome
SNOMED
- Bartter's syndrome with hypercalciuria and nephrocalcinosis (disorder)
- Bartter syndrome antenatal type 1 (disorder)
- Bartter syndrome antenatal type 2 (disorder)
- Bartter syndrome type 3 (disorder)
- Bartter syndrome type 4 (disorder)
CLINICAL PEARLS
Bartter and Bartter-like syndromes are autosomal recessive, hypokalemic, salt-losing nephropathies that mimic diuretic effects.