Bartter syndrome is a general term for a group of rare genetic autosomal recessive disorders of salt reabsorption resulting in extracellular fluid volume depletion with low/normal blood pressure in which there are specific defects in kidney function. It is characterized by several electrolyte abnormalities including low potassium and chloride and, in a few cases, hypomagnesemia, high renin, secondary hyperaldosteronism, metabolic alkalosis, and elevated levels of prostaglandin E2 and Acid-base manifestation. These defects impair the kidney’s ability to reabsorb salt and cause imbalances in various electrolyte and fluid concentrations in the body. The electrolytes affected are primarily mineral salts such as potassium, calcium, magnesium, sodium, and chloride. The symptoms and severity of Bartter syndrome vary from one person to another and can range from mild to severe. The age of onset of overt symptoms can range from before birth to adulthood. Bartter syndrome is caused by alterations (mutations) in one of several different genes. Treatment is aimed at correcting the electrolyte imbalances through the use of supplements and certain medications such as nonsteroidal anti-inflammatories (NSAIDs) and diuretics.
Some researchers classify these disorders based on their clinical appearance, while others classify them based on the underlying mutated gene. The different terminology and classification systems can be confusing. Bartter syndrome can be variably classified as a renal tubulopathy (because certain small tubes within the kidneys are affected), a salt-wasting disorder (because affected individuals excrete excess amounts of salt), or a salt-losing tubulopathy, and a channelopathy (because the ion channels in the kidneys are affected). Although Bartter syndrome can be broken down into subtypes based on the underlying gene or symptomatology, considerable overlap of symptoms and disease presentation exists among the subtypes, and Bartter syndrome may be best thought of as a spectrum of diseases caused by several different gene mutations. The most common classification system for these disorders is based upon the underlying genetic mutation as listed above. The term antenatal (before birth) Bartter syndrome refers to those cases that present before birth and is typically associated with types 1, 2, 4a, and 4b. These disorders were sometimes also called hyperprostaglandin E syndromes because they are associated with elevated levels of compounds known as prostaglandins, which act as signaling molecules in our body. Bartter syndrome type 3 is sometimes also referred to as classic Bartter syndrome. Gitelman syndrome, which has considerable clinical overlap with Bartter syndrome, especially type 3, is sometimes grouped with the Bartter syndromes.
Types
Impairment in the sodium-potassium-chloride cotransporter (NKCC2) or the potassium channel (ROMK) affects the transport of sodium, potassium, and chloride in the thick ascending limb of the loop of Henle (TALH). This results in increased distal delivery of these ions, where only some sodium is reabsorbed, and potassium is secreted.
Types of Bartter syndrome:
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Type I results from mutations in the sodium chloride/potassium chloride cotransporter gene (NKCC2)
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Type II results from mutations in the ROMK gene
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Type III results from mutations in the chloride channel gene (CLC-Kb)
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Type V results from mutations in extracellular calcium ion-sensing receptors and in the genes that encode the chloride channel subunits, CLC-Ka and ClC-Kb[rx]
Bartter syndrome can be secondary to aminoglycoside use. Hypokalemic metabolic alkalosis, hypomagnesemia, and hypocalcemia commonly are seen with an aminoglycoside-induced Bartter-like syndrome.[rx]
An antenatal variant of Bartter syndrome presents with severe hypokalemia, metabolic alkalosis, and profound systemic manifestations. Bartter syndrome III and V usually present later in life and have mild symptoms.
Causes
Bartter syndromes are caused by recessive mutations in the SLC12A1 gene (type 1), the KCNJ1 gene (type 2), the CLCNKB gene (type 3), and the BSND gene (type 4A), or both the CLCNKA and CLCNKB genes (type 4B). Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body. Bartter syndrome is inherited in an autosomal recessive manner, except for type 5, which is inherited in an X-linked recessive matter.
Bartter syndrome can be caused by mutations in at least five genes. Mutations in the SLC12A1 gene cause type I. Type II results from mutations in the KCNJ1 gene. Mutations in the CLCNKB gene are responsible for type III. Type IV can result from mutations in the BSND gene or from a combination of mutations in the CLCNKA and CLCNKB genes.
Most genetic diseases are determined by the status of the two copies of a gene, one received from the father and one from the mother. Recessive genetic disorders occur when an individual inherits two abnormal copies of a gene, one from each parent. If an individual inherits one normal copy and one copy of the disease, the person will be a carrier of the disease but usually will not show symptoms. The risk for two carrier parents to both pass the altered gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.
This is however different for the X-linked Bartter syndrome type 5, as a boy only has one X-chromosome, which he inherits from the mother. If the mother is a carrier of a mutation in MAGED2, then there is a 50% risk that she passes this on to her children. If she passes it on to a daughter, then she will be a carrier, as well, as a daughter also inherits a normal copy of MAGED2 on the X-chromosome she receives from the father. But if she passes it on to a boy, then he will be affected, as he does not have a second normal copy, for he receives the Y-chromosome from the father. Very rarely, girls who are carriers can also have disease manifestations, but it is typically much milder than in boys.
Most of the genes involved in Bartter syndrome produce (encode) proteins that are required for the proper function of the kidneys. One of the different functions of the kidney is maintaining a specific volume and composition of body fluids through the reabsorption of salts and minerals that conduct electrical impulses in the body (electrolytes). Electrolytes are necessary for various functions in the body including nerve firing, muscle contraction, energy generation, and most major biochemical reactions in the body. The kidneys maintain electrolyte balance by filtering the blood. Hair-sized structures called nephrons are the basic functional units of the kidneys and there are roughly a million of these in our kidneys. Each nephron consists of a glomerulus and a renal tubule. The glomeruli filter the blood and in an adult create a primary urine volume of about 100 ml/min (or roughly 150litres per day). This is called the glomerular filtration rate (GFR). The renal tubule then reabsorbs most of this filtrate, including electrolytes such as sodium, chloride, and potassium back into the blood to ensure that not too much is lost through the urine. The renal tubule contains four main segments known as the proximal convoluted tube, the loop of Henle, the distal convoluted tube (DCT), and the collecting duct. Bartter syndrome is primarily a disorder in the loop of Henle, but the distal convoluted tubule can also be affected in some subtypes.
The loop of Henle accounts for a significant percentage of the salt and mineral reabsorption in the body. It also plays a role in urine concentration. The DCT plays a lesser role in salt reabsorption and also has a role in functions necessary to maintain chemical balance in the body (e.g. potassium secretion). When one segment of the distal nephron does not function properly, others try to compensate. An important segment for compensation is the collecting duct, where especially the sodium that has not been reabsorbed upstream is taken up, but this occurs in exchange for potassium and acid. It is this compensation that generates the typical electrolyte abnormalities of Bartter syndrome, the low potassium, and the alkalosis (lack of acid).
Mutations in the genes involved in Bartter syndrome result in abnormal functioning of the ion channels or proteins involved in the transport of electrolytes back into the bloodstream. This abnormal functioning prevents sodium and chloride (salt) from being reabsorbed from the urine. This causes too much salt and water to be expelled from the body through the urine. In turn, either directly or indirectly, other electrolytes such as potassium, magnesium, and calcium are also affected. Thus, the proper balance of electrolytes in the body is disrupted, and it is this balance that is critical for the normal functioning of our body. These imbalances ultimately lead to the various symptoms of the Bartter syndromes.
Diagnosis
A diagnosis of one of the Bartter syndromes is based upon the identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation, and a variety of specialized tests.
Clinical Testing and Workup
Laboratory tests that are used to diagnose these disorders include blood tests to determine serum electrolyte levels, specifically potassium, chloride, bicarbonate, magnesium, renin, and aldosterone levels, and urine tests to determine the presence of prostaglandin E2 and urine electrolytes, including sodium, chloride, potassium, calcium, and magnesium.
Other abnormalities include increased serum renin and aldosterone levels with decreased magnesium and phosphate levels in a few patients. Urine electrolytes show elevated sodium, potassium, and PGE2 excretion. Elevated 24-hour urine calcium excretion helps exclude Gitelman syndrome, which is associated with low calcium excretion. Spot urine chloride concentration helps differentiate from surreptitious vomiting, where it is less than 25 meq/L. Usually, urine chloride is elevated (greater than 35 meq/L) in Bartter syndrome.
Polyhydramnios and intrauterine growth retardation are seen on ultrasound with neonatal Barrter syndrome. Amniotic fluid chloride levels may be elevated.
Abdominal radiographs, intravenous pyelograms (IVPs), renal ultrasonograms, or spiral CT scans can be done to document nephrocalcinosis. Genetic testing can be considered to rule out specific mutations.
The antenatal subtypes of Bartter syndrome can be diagnosed before birth (prenatally) when polyhydramnios is detected without the presence of associated congenital malformations, and elevated levels of chloride and aldosterone are detected in the amniotic fluid.
Molecular genetic testing can confirm a diagnosis. Molecular genetic testing can detect mutations in specific genes known to cause the Bartter syndromes but is only available as a diagnostic service at specialized laboratories.
Treatment
The treatment of the Bartter syndromes is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians or general internists, kidney specialists (nephrologists or pediatric nephrologists), and other healthcare professionals may need to systematically and comprehensively plan an affected child’s treatment. Genetic counseling is recommended for affected individuals and their families. Psychosocial support for the entire family is essential as well.
A saline infusion may be needed in the neonatal period. The target is to normalize potassium levels in serum which can be achieved with oral potassium supplementation such as KCL 25 to 100 mmol/day. ACE inhibitors and angiotensin receptor blockers (ARB) help decrease elevated angiotensin II and aldosterone levels, limit proteinuria, and increase serum potassium in some cases. Other options include amiloride 5 to 40 mg/day, spironolactone, and NSAID (indomethacin 1-3 mg/kg/24 hours) to antagonize increased urine PGE2 levels. Magnesium supplementation should be considered, as hypomagnesemia may aggravate potassium wasting.Medically supervised sodium, chloride and potassium supplementation is necessary, and spironolactone can be also used to reduce potassium loss.[rx]
There is no cure for these disorders, which requires lifelong administration of certain supplements and medications. The mainstay of treatment is restoring the proper balance of fluids and electrolytes in the body. This typically includes sodium and potassium chloride supplementation to help correct electrolyte imbalances. Potassium chloride supplementation is preferred to other forms of potassium salts because of the corresponding chloride deficiencies. Some infants with severe, life-threatening loop disorders (antenatal Bartter syndromes) may require intravenous salt and water replacement. Because the elevated levels of prostaglandins aggravate the polyuria and electrolyte abnormalities, treatment typically includes a drug that decreases the production of these such as indomethacin, ibuprofen, or celecoxib. These drugs are also called nonsteroidal anti-inflammatory drugs (NSAIDs). Indomethacin has generally been used and shown to be effective in individuals with Bartter syndromes, but can have severe side effects, especially in premature babies with regards to perforation in the intestinal tract, especially the stomach. If used, it is recommended to do so in combination with a stomach acid blocker. Newer forms of NSAID, such as celecoxib (also called “COX2 inhibitors”) have a much lower risk of these intestinal side effects and have also been shown to be effective in Bartter syndrome, but there is less experienced in their use. With increasing age, Bartter syndrome tends to get easier to manage and control. The most difficult period is usually the first year(s) of life. As there is also concern that long-term use of NSIAD may affect kidney function, these medications often get reduced or weaned off over the years.
Some affected individuals may receive medications known as potassium-sparing diuretics such as spironolactone or amiloride. These drugs increase the excretion of sodium in the urine but retain potassium and acid thereby improving low potassium levels in the blood (hypokalemia) and alkalosis. Yet, because they worsen the loss of sodium, they risk low blood pressure and potentially even collapse (hypovolemic shock) and it is usually recommended to take these together with adequate sodium chloride supplementation.
Drugs that inhibit or block the renin-aldosterone-angiotensin system (RAAS inhibitors) have been used to treat individuals with Bartter syndromes in addition to other therapies (adjunct therapy). RAAS inhibitors include aldosterone antagonists, angiotensin II receptor blockers, and angiotensin-converting enzyme (ACE) inhibitors. These drugs can prevent the secretion of aldosterone from the adrenal glands and counteract the effects of renin on the kidneys, thereby reducing potassium and acid loss. But, like the potassium-sparing diuretics, they may dangerously lower blood pressure, which may already be low in individuals with Bartter syndromes, and can potentially impact kidney and cardiovascular function. Thus, their use should be carefully considered and monitored and the drugs must be stopped, if the patient has additional salt losses, e.g. from diarrhea and/or vomiting.
Successful use of growth hormone therapy has been reported in some cases for the treatment of growth retardation and short stature potentially associated with Bartter syndrome.
Especially in Bartter syndrome type 3, magnesium supplementation may be used to treat muscle spasms or tetany. Adequate salt and water intake are necessary. Affected individuals typically have a large appetite for salt due to salt cravings and should be encouraged to indulge in salty foods. Affected individuals may also be encouraged to eat foods that are high in potassium. Cochlear implants can be used to treat deafness associated with Bartter syndromes type 4A and 4B.
In stressful situations, blood electrolytes can change rapidly, and require prompt intravenous treatment. Stressful situations can include surgical procedures, trauma, and the presence of another type of disease or infection (intercurrent disease).
References
Bartonellosis
