Special thanks to: 

Reviewer: Prof. Dr. med. Hannsjörg W. Seyberth, Center of Pediatrics and Adolescent Medicine at Philipps University Marburg, Marburg, Germany

Writer: Robert Tomaino, Managing Editor, RareShare

The exact prevalence of the Bartter syndromes is unknown, although these disorders are estimated to affect one per one million people worldwide. Gitelman syndrome is estimated to affect approximately 1 in 40,000 people. These disorders can be diagnosed in all age groups equally. Gitelman syndrome is diagnosed more often in adulthood than during childhood. These syndromes affect males and females in equal numbers. 

Several different gene mutations are known to cause loop and DCT disorders. Mutations in the SLC12A1 gene cause Bartter syndrome type 1 (loop disorder type 1). Mutations in the KCNJ1 gene cause Bartter syndrome type 2 (loop disorder type 2). Mutations in the CLCNKB gene cause Bartter syndrome type 3 (DCT disorder type 2). Mutations in the BSND gene cause type 4a (loop-DCT disorder type 2). A combination of mutations in the CLCNKA and CLCNKB genes cause type 4b (loop-DCT disorder type 1). Mutations in the SLC12A3 gene cause Gitelman syndrome (DCT disorder type 1).

These genes produce proteins that play important roles in the transport and reabsorption of salt in the kidneys. The alternations impair the kidneys’ ability to reabsorb salt in the form of sodium and chloride, leading to the excessive loss of salt through the urine (salt wasting). These proteins may also affect the reabsorption, secretion, or handling of other electrolytes including potassium, calcium, and magnesium. The kidneys attempt to compensate for the loss of salt and water (volume depletion) by producing excess amounts of the hormone aldosterone and the enzyme renin. This overproduction further contributes to the chemical and fluid imbalances within the body.  

The protein products of the SLC12A1 (NKCC2), the KCNJ1 (ROMK) and CLCNKA (chloride channel C1C-Ka) genes are primarily active in the loop of Henle. The protein product (NCC) of the SLC12A3 gene is exclusively active in the DCT. The protein product of the CLCNKB gene, the chloride channel ClC-Kb, is present in both parts; however, this channel is only essential in DCT as the product of the CLCNKA gene, the chloride channel ClC-Ka, can take over at least in part the function of the ClC-Kb in the loop of Henle. The protein product barttin of the BSND gene is essential as a beta-subunit for normal function of both chloride channels. That’s why the loop-DCT disorder type 2 - like the loop-DCT disorder type 1 - is the most severe form of salt-losing tubulopathies.   

Most forms of Bartter syndrome are inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.²

The severity of these disorders is highly variable. Some people have severe symptoms that are present at or shortly after birth. Others may have mild symptoms and the disorder can remain undiagnosed until adulthood. Generally, the antenatal forms of the disorder (Bartter syndromes 1, 2, 4a, and 4b, i.e. loop and combined loop/DCT disorders) are more severe and sometimes life threatening while Bartter syndrome type 3 and Gitelman syndrome (DCT disorders) are milder. 

The antenatal forms generally cause noticeable symptoms before birth, causing an abnormal fluid buildup around the developing fetus (polyhydramnios) due to excess production of urine (polyuria) of the affected fetus. Birth occurs prematurely, particularly when the size of the polyhydramnios reaches more than several liters. In the newborn period, these infants can lose significant amounts of salt and fluids through excess polyuria. If these losses are not replaced, complications such as severe contraction of the blood and the extracellular fluid volume (ECF) and eventually a complete collapse of the systemic circulation (shock) can develop. As a consequence of the impaired salt reabsorption in the loop of Henle the production of prostaglandin E2 (PGE2) is elevated, which leads to even more salt and water wasting. In addition, PGE2 is a potent pro-inflammatory mediator that can lead to fever, vomiting, diarrhea, and failure to thrive.  Furthermore, most infants with increased calcium excretion in the urine will consequently develop thinning of the bone mass (osteopenia) and nephrocalcinosis, a condition in which too much calcium is deposited or accumulated in the kidneys. 

In addition to the symptoms seen in other antenatal forms, infants with combined loop-DCT disorders (Bartter syndromes type 4a and 4b) cannot hear from birth due to an inability of the auditory nerves to transmit sensory input to the brain (sensorineural hearing loss). These infants and children may also develop poor functioning of the kidneys (renal insufficiency). 

The classic form of the disorder (Bartter syndrome type 3 or DCT disorder type 2) often develops later than the antenatal forms often during infancy or early childhood, although some individuals may remain undiagnosed until later in life even adulthood. The specific symptoms associated with classic Bartter syndrome are highly variable from one person to another. In a minority of patients signs and symptoms can be observed that resemble those in patients with loop disorders such as somewhat reduced capability to produce a highly concentrated urine, quite variable urinary calcium excretion rates, and polyhydramnios, which, however, is much less pronounced and is rarely associated with premature birth. Consequently, classic Bartter syndrome much less frequently causes polyuria, polydipsia, and the need to urinate at night (nocturia) than the antenatal loop disorders.

Typical for all salt losing tubular disorder, patients may crave salt and in the state of dehydration they may experience constipation. Eventually they can get into a critical situation when they experience additional fluid losses through diarrhea, vomiting or excessive sweating. However, most important and characteristic for all Batter- and Gitelman-like disorders, chronic renal salt wasting with ECF contraction leads to high renin activity and aldosterone levels that is called secondary hyperaldosteronism. The consequence of high aldosterone levels is that sodium reabsorption is increased in the aldosterone-sensitive portion of the distal nephron in an attempt to reduce the renal sodium wastage. However, for reason of electroneutrality this compensatory mechanism leads to increased tubular secretion of potassium and hydrogen and consequently to hypokalemia and metabolic alkalosis. 

Despite the fact that there might be some similarities in the clinical features of patients with classic Bartter syndrome to those of patients having loop disorders, it is of note that in the majority of patients the key symptoms and signs are very similar to the clinical presentation of patients with Gitelman syndrome (DCT disorder type 1). In some people the symptoms of these two disorders may be virtually indistinguishable. The explanation for this great similarity is that in the majority of patients the chloride channel ClC-Ka has taken over the function of the failing ClC-Kb channel in the loop of Henle but not in the DCT.

Gitelman syndrome and thus also classical Bartter syndrome can be characterized by episodes of tetany, which can be accompanied by gastrointestinal symptoms such as abdominal pain and vomiting. Affected individuals may experience sudden, painful involuntary muscle contractions of the hands and feet (carpopedal spasms). A burning or prickling sensation, particularly affecting the face (paresthesia), may also occur. Some individuals develop swelling and tenderness of joints due to the accumulation of calcium and chronic hypomagnesemia in the joints (pseudogout or chondrocalcinosis). In some individuals, seizures, cardiac arrhythmias, and, in extremely rare instances, the rapid breakdown of damaged skeletal muscles (rhabdomyolysis) have also occurred in individuals with Gitelman syndrome. Almost all these symptoms are causally related to low magnesium levels (hypomagnesemia) that are due to renal magnesium wasting in DCT disorders. 

Although a rare occurrence, the cardiac arrhythmias associated with DCT disorders can progress to cause a prolonged QT interval, which indicates that the heart muscle is taking longer to recharge between beats than normal. A prolonged QT interval can potentially cause cardiac arrest and sudden death. 

Loop and DCT disorders are usually diagnosed after a combination of blood and urine tests are performed on an individual with the signs and symptoms of the condition. An extremely diluted urine with a daily volume of more than several liters, excessive thirst and fluid intake (polydipsia), and the need to urinate several times at night (nocturia) associated with high urinary calcium levels and nephrocalcinosis are very strong indicators for a loop disorder, while symptoms of tetany associated with hypomagnesemia and very low urinary levels of calcium is very characteristic symptom of DCT disorder. A thorough examination of an individual’s medical history is important in individuals suspected of having one of these disorders. Through specific blood and urine examination and a detailed patient history it is possible to properly diagnose an individual who has a loop or DCT disorder and begin the appropriate treatment

It is possible through molecular genetic testing can be used to confirm a diagnosis by identifying one of the specific gene mutations known to cause these disorders. However, these tests are usually not performed because they are only available at specialized medical laboratories, are extremely expensive, and are rarely necessary to obtain a diagnosis.  

Blood tests can reveal low blood potassium levels (with normal blood pressure). High levels of aldosterone and renin in the blood also support the diagnosis of a loop or DCT disorder. Other than blood tests, urine osmolality, urinary calcium excretion, and the levels of magnesium in the plasma are the most informative and easily accessible clinical parameters to differentiate between loop and DCT disorders. Urine osmolality measures the concentration of particles in the urine and can determine whether the balance of electrolytes is normal. Urine analysis can demonstrate high levels of sodium, chloride, and potassium. 

When these laboratory data are complemented by an accurate and comprehensive case history, an almost definitive diagnosis can be made, particularly when either a maternal medical history of a pregnancy complicated by development of a massive polyhydramnios exists that has led to premature birth, or clinical signs of symptomatic hypomagnesemia have been reported, such as a positive Chvostek’s sign and carpopedal spasm. Chvostek’s sign is a diagnostic test in which certain muscles around the mouth involuntary twitch or spasm when the facial nerve is lightly tapped. 

One common therapeutic approach in both loop and DCT disorders is to replace as much of the urinary losses as possible. The goal should be to replenish the electrolyte and mineral total body pool and the extracellular fluid volume, the most effective way to treat metabolic alkalosis and secondary hyperaldosteronism. This involves ensuring individuals receive sufficient fluids and take supplements of the substances that are lost through excess urination such as sodium, chloride in form of salt, potassium and magnesium.

 In infants with a full-blown, life-threatening loop disorder (antenatal Bartter syndromes), the very first step is adequate replacement of salt and water (via a central vein catheter). However, excessive fluid replacement aggravates polyuria, indicating the need to include antidiuretic therapy with a drug that prevents the production of prostaglandin E2 (i.e. an inhibitor of PGE2 synthesis), preferably indomethacin. 

In contrast to this acute postnatal management, older children and adults with a slowly developing and often accidently diagnosed DCT disorder (classic Bartter syndrome or Gitelman syndrome), a salt- and potassium-rich diet is the basis of short- and long-term treatment. However, it should be noted that early treatment with magnesium supplementation is imperative for effective treatment and prevention of complicating hypokalemia. The general use of inhibitors and blockers of the renin-aldosterone-angiotensin system (RAAS) and the potassium-sparing diuretics such as eplerenone and amiloride, respectively, is not recommended for the first-line pharmacotherapy. These medicines are not very efficacious for treating hypokalemia. Moreover, they might be even counterproductive as they aggravate renal sodium wasting and cause a further raise of the aldosterone plasma level that is of concern from a cardiovascular and renal point of view.

Broad prognostic statements for loop and DCT disorders are not possible because of the lack of international registries, which are databases that collect data and information about people with a specific diagnosis. Such registries are important for rare disorders and allow physicians to make much clearer statements about prognosis. 

Some individuals with DCT disorders experience an aggravation of symptoms upon adulthood, requiring an increase in therapeutic efforts. Conversely, individuals with loop disorders usually experience their most severe symptoms during infancy and improve as they grow older, often allowing for a tapering of treatment efforts. 

Some medications used to treat loop and DCT disorders carry the risk of side effects. Prolonged use of prostaglandin inhibitors in loop disorders has been associated with gastrointestinal intolerance and even toxicity. Indomethacin, which is generally well tolerated and efficacious in children, remains the treatment of choice of this class of drug. Sometimes, medications that control gastric acid levels such as proton pump inhibitors (PiPs) and protect the integrity of the mucous membranes lining the stomach (gastric mucosa) such as prostaglandin analogues may be indicated. 

There is a risk in some individuals of developing secondary kidney failure during chronic volume contraction (decrease in the volume of body fluid), particularly in individuals with excessive urination (polyuria) who do not take their medication and the appropriate daily salt and fluid intake as directed by their physicians (noncompliance). The long-term prognosis of combined loop/DCT disorders (Bartter syndromes type 4a and 4b), which are prone to kidney failure, is not fully known. Some of them needed kidney transplantation.

Because of the risk of cardiac arrhythmias and a prolonged QT interval, individuals with DCT disorders should avoid medications that are known to prolong the QT interval. A list of such medications is available at: https://crediblemeds.org/index.php. Patients with DCT disorders, who are prone to developing hypomagnesemia, should be treated as far as possible with PIPs, but not for longer periods as these medicines can cause hypomagnesemia on their own. 

There are reports of some individuals with loop disorder type 2 (Bartter syndrome type 2) developing high blood pressure (arterial hypertension) and high protein levels in the urine (proteinuria). Proteinuria is a finding that can be associated with kidney damage. The significance of these findings is not understood. 

Genetic counseling may be beneficial to patients and their families. With respect of the overall diagnostic and therapeutic management patients and their families are advised to see for consultation physicians in a nephrologic clinic that has (broad) experiences in the field of inherited tubular disorders.

Blanchard A, Vargas-Poussou R, Vallet M, et al. Indomethacin, amiloride, or eplerenone for treating hypokalemia in Gitelman syndrome. Am Soc Nephrol. 2015;26(2):468-475. 

Colussi G. Bartter Syndrome. Orphanet website. Available at: http://www.orpha.net/consor/cgi-bin/OC_Exp.php?Expert=112  Updated: September 2014. Accessed: July 27, 2015.

Ellison DH. Adaptation in Gitelman syndrome: “we just want to pump you up.” Clin J Am Soc Nephrol. 2012;7(3):379-382. http://cjasn.asnjournals.org/content/7/3/379.full Accessed November 12, 2015

Emmett M. Bartter and Gitelman Syndromes. UpToDate, Inc. Available at: http://www.uptodate.com/contents/bartter-and-gitelman-syndromes  Updated: February 24, 2015. Accessed: July 27, 2015. 

Favre GA, Nau V, Kolb, et al. Localization of tubular adaptation to renal sodium loss in Gitelman syndrome. Clin J Am Soc Nephrol. 2012;7(3):472-478. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3302678/ Accessed November 12, 2015.

Seyberth HW. Pathophysiology and clinical presentation of salt-losing tubulopathies. Pediatr Nephrol. 2015;[Epub ahead of print].

Seyberth HW, Schlingmann KP. Bartter- and Gitelman-like syndromes: salt-losing tubulopathies with loop or DCT defects. Pediatr Nephrol. 2011;26(10):1789-1802. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3163795/ Accessed November 12, 2015.