Bartter/Gitelman syndrome

What is Bartter/Gitelman syndromes?

These diseases are syndromes where congenital renal tubular dysfunction causes hypokalemia and metabolic alkalosis, as well as their associated clinical symptoms.
Bartter syndrome usually occurs from the neonatal period to infancy, whereas Gitelman syndrome usually occurs from infancy to school age, but some patients remain asymptomatic for life.

Symptoms of Bartter/Gitelman syndromes

Kidney tubules reabsorb water and electrolytes essential for the body from the primary urine, which is the source of the urine. In Bartter/Gitelman syndromes, congenital dysfunction of the kidney tubules cause a decrease in blood electrolytes, and symptoms, including a feeling of weakness, muscular symptoms, and/or polydipsia/polyuria, appear, especially due to hypokalemia. Growth disorders such as short stature may also occur. Furthermore, some patients progress to end-stage kidney disease. Hearing loss is also observed in some types.
Other than the above, so-called unidentified clinical symptoms (fatigue, headache, dizziness, and marked fatigue especially when suffering from a cold) are present in many patients, but some patients are not aware that these symptoms are due to the disease.

Treatment for Bartter/Gitelman syndromes

Currently, there is no specific treatment. Treatment is mainly symptomatic such as electrolyte supplementation. However, nonsteroidal anti-inflammatory agents are sometimes effective, and so these medicines are recommended when electrolyte supplementation alone does not improve symptoms.

Q&A

1) What is the approximate number of these diseases?

According to a large-scale survey on the number of patients receiving medical care in Japan, the estimated number of patients as of 2017 was 550. However, given that this disease cannot be diagnosed without a blood test, the potential number of undiagnosed patients seems to be large.

2) Is the cause of these diseases known?

Bartter syndrome and Gitelman syndromes are both known to be caused by genetic abnormalities.

3) Are these diseases hereditary?

The mode of inheritance for these diseases is mostly autosomal recessive. This means that if, by chance, parents are both asymptomatic carriers of a genetic abnormality, each child has a 1 in 4 chance of developing the disease. It is rare that a patient passes the disease on to his/her children.

4) What is the clinical course of these diseases?

Some patients with Bartter syndrome progress to end-stage kidney disease. In some patients of these diseases, growth disorder such as short stature and hearing loss are also present.
Gitelman syndrome is milder in severity than Bartter syndrome, and has a favorable kidney prognosis.
However, as described above, both diseases may be associated with unidentified clinical symptoms such as fatigue, which affect everyday life

To patients with Gitelman syndrome

Gitelman syndrome is described below with details.
The function of the kidneys

The kidney is an organ that excretes excess water and unnecessary waste in the blood into the urine. By this function, the blood in the body is always kept clean, and water volume and electrolyte levels in the body are regulated to be constant. This may sound easy when described in words, but the process involves very complicated tasks as below:
1. A large volume of blood is perfused to the kidneys via the arteries (Figure 1).
2. Excess water and unnecessary waste in the blood are discharged from the kidney glomerulus into kidney tubules (Figure 2).
3. To balance the electrolytes in the blood, electrolyte exchange is performed between the urine in the kidney tubules and the blood in the capillary blood vessels (Figure 2).
4. Then, the urine flows from the kidney tubules into the ureters and bladder (Figure 1).
5. The purified, clean blood flows into the veins (Figure 1).

Cause of Gitelman syndrome

This disease is caused by mutations in the gene that encodes the transporter that transports the electrolytes, sodium and chloride from the urine into the capillary blood vessels in kidney tubules described above. Because of the transporter dysfunction, a large amount of sodium leaks into the urine. To stop sodium necessary for the body from continuing to leak into the urine, potassium and magnesium, which are both cations like sodium, also leak into the urine in large quantities. Consequently, blood potassium and magnesium decrease, leading to hypokalemia and hypomagnesemia.

Cardinal symptoms of Gitelman syndrome

Due to hypomagnesemia and hypokalemia, symptoms such as getting tired easily, numbness in limbs, cramps in limbs, muscular pain, and headache appear. In addition, because sodium leaks into the urine in large quantities, as described above, urine osmotic pressure increases, and as a result, a lot of water also leaks into the urine. Because of this, patients with this disease typically drink a lot and urinate a lot (polydipsia, polyuria). In particular, although urinary output should normally decrease during the night, patients with Gitelman syndrome frequently urinate also during the night and may have nocturnal enuresis or wake up to go to the toilet once or twice during the night. Furthermore, patients get exhausted to an unusual extent when suffering from a common cold and may even require transfusion and/or hospitalization. As another feature of this disease, patients are often short-statured. On the other hand, some patients remain asymptomatic for life.
Patients with this disease typically prefer sodium-rich meals to supplement sodium, which leaks into the urine in large quantities. During childhood, many some patients may drink soy sauce or lick salt. This is not absolutely recommended, but sodium-rich foods need to be provided to some extent. As a very rare complication, long QT syndrome, which may lead to sudden death due to arrhythmia, has been reported, but this arrhythmia disappears in most cases by appropriately supplementing electrolytes.
To improve all symptoms, treatment is necessary to maintain potassium and magnesium levels at a certain level or higher.

Treatment for Gitelman syndrome

The most important treatment is the supplementation of potassium and magnesium. By this, blood potassium and magnesium levels increase. However, even after this treatment, various symptoms may remain. Also, this treatment is not effective for bedwetting and polyuria at all. If these symptoms are present to the extent that everyday life is affected, oral nonsteroidal anti-inflammatory agents (brand name: Infree, Inteban, etc. Inteban is not on the market in Japan as of 2019) are used. Currently, these drugs are considered most effective, but as long-term use may cause kidney side effects, caution should be taken. Patients can visit a pediatric or internal medicine clinic, but as Gitelman syndrome is relatively rare, most physicians have no clinical experience of treating this disease. Therefore, even if the patient complains of symptoms associated with Gitelman syndrome, the physician may not able to make the correct diagnosis or judgment sometimes.

Clinical course of Gitelman syndrome

Gitelman syndrome is typically considered a mild disease, but symptoms, including getting tired easily, become obvious with age and may affect everyday life; for example, it may be difficult to continue working because of these symptoms. Oral use of above-mentioned nonsteroidal anti-inflammatory agents may mitigate the symptoms to some extent, and so patients are advised to consult with a doctor.
In some patients, kidney function may slowly deteriorate, and there have also been reports of patients requiring dialysis. Furthermore, as described above, if the potassium level is not controlled, long QT syndrome may cause arrhythmia and sudden death, although this is very rare.

Considerations to be made in school life

Most symptoms associated with Gitelman syndrome are unidentified clinical symptoms, which are often observed in adolescence (e.g., feeling weary, having a headache, and getting tired easily). Therefore, these symptoms may be considered by others to be just a “matter of feeling,” and so more understanding is necessary about this. In addition, there are some patients who are deeply troubled because, in spite of being in adolescence, they have bedwetting episodes every night. General medicines for nocturnal enuresis have little effect. People around patients need to understand about this problem. Furthermore, when suffering from a cold (e.g., influenza), patients with this syndrome typically get exhausted and feel their symptoms more severe to an extent that appears exaggerated. Therefore, when they have a cold, please try to understand their condition and let them have a good rest.

Considerations to be made in adults

As patients with Gitelman syndrome often present with so-called unidentified clinical symptoms, including fatigue, dizziness, and muscle weakness, their condition is sometimes mistaken for a psychiatric disease. On top of the fatigue patients usually have, they experience more severe fatigue and a reduced activity when they have a cold. Common symptoms in adult patients with Gitelman syndrome and their frequencies are as follows: salt craving (liking salty foods, 90%), myospasm (cramp, 84%), fatigue (82%), dizziness (80%), night pollakisuria (80%), thirst (76%), and muscle weakness (70%) (cited from Cruz et al., KidneyInt 2001). Most of these symptoms are considered to be associated with the disease. It is necessary to create an environment to help both patients and people around them have a deeper understanding of the symptoms of Gitelman syndrome.

Brochure about Gitelman syndrome
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Diagnosis and treatment guidelines
(For healthcare providers)

○　 Overview

Overview
Bartter/Gitelman syndromes are diseases where congenital renal tubular dysfunction causes hypokalemia and metabolic alkalosis, as well as their associated clinical symptoms. Furthermore, the absence of secondary causes, including regular use of laxatives or diuretics and extreme thinness, is the essential condition for making the diagnosis of these diseases.
Cause
Due to an abnormality in the gene encoding the channels and transporters localized from the thick Henle’s loop to the distal kidney tubule, sodium is lost in the urine, and consequently potassium, which is also a cation, is lost in the urine as well, leading to hypokalemia. Bartter syndrome is categorized into Types 1 to 5 based on the causative gene (Table 1).

Symptoms
The cardinal symptoms include a feeling of weakness, muscular symptoms, and polydipsia/polyuria associated with hypokalemia. In some disease types, the condition progresses to end-stage kidney disease. Growth disorders such as short stature may also occur. Hearing loss is also observed in some disease types. In addition, an overseas survey on clinical symptoms in patients with Gitelman syndrome reported the following symptoms: preference for salt (liking salty foods, 90%), myospasm (cramp, 84%), fatigue (82%), dizziness (80%), night pollakisuria (80%), thirst (76%), and muscle weakness (70%) (cited from Cruz et al., KidneyInt 2001). Therefore, health care providers should be aware that these symptoms are associated with the disease.

1） Type 1 Bartter syndrome
An abnormality in the SLC12A1 gene encoding NKCC2, the cotransporters of Na⁺-K⁺-2Cl^–, where furosemide acts, is responsible for the onset of this disease. Type 1 is the neonatal type; in most cases, polyhydramnios is present before birth, and the baby is born with premature delivery and low birth weight. After that, growth disorder is likely to occur, and symptoms such as polydipsia/polyuria, fever, vomiting, and dehydration appear. Hypercalciuria and nephrocalcinosis are also observed. Some patients progress to end-stage kidney disease.

2） Type 2 Bartter syndrome
An abnormality in the KCNJ1 gene encoding ROMK, a potassium (K) channel, is responsible for the onset of this disease. Polyhydramnios, premature delivery, and low birth weight are observed. Type 2 is categorized into the neonatal type like Type 1. However, in Type 2, hyperkalemia, metabolic acidosis, and polyuria are present for a while after birth, and so it is very difficult to make a diagnosis of Type 2 Bartter syndrome immediately after birth. The serum potassium level begins to decrease several months after birth, but the decrease in potassium level is slower compared with Type 1, and the level may be maintained around the lower limit of normal. Hypercalciuria and nephrocalcinosis are observed in all patients. Some patients progress to end-stage kidney disease.

3） Type 3 Bartter syndrome
An abnormality in the CLCNKB gene encoding ClC-Kb, a chloride channel, is responsible for the onset of this disease. Type 3 is generally categorized into the classic type and is found in infancy through polydipsia/polyuria or growth disorder. Nephrocalcinosis is absent, and progression to end-stage kidney disease is considered rare.
Urine calcium output is also normal or mildly increased in most patients. It is also reported that there are some patients with hypocalciuria and some with hypomagnesemia, and in these patients, differential diagnosis with Gitelman syndrome may be very difficult to make.

4） Type 4 Bartter syndrome, Type 4b Bartter syndrome
Type 4 is the neonatal type and is associated with sensorineural hearing loss. In typical cases, it is the most severe type among all types of Bartter syndrome. It has been reported that Type 4 Bartter syndrome follows a severe clinical course, where polyhydramnios, low birth weight, prominent polyuria, growth disorder, and motor development disorder occur, and patients respond poorly to nonsteroidal anti-inflammatory drugs (NSAIDs), develop renal dysfunction in early childhood, and progress to end-stage kidney disease. Subsequently, the responsible gene and protein, BSND and Barttin, respectively, were cloned. Furthermore, it was discovered that Barttin is expressed in the kidneys and inner ear and acts as the common β subunit for Clc-Ka and Clc-Kb in the kidney tubules.
Recently,digenic mutations in both the CLCNKA and CLCNKB genes have been reported to lead to a clinical course similar to that of Type 4 Bartter syndrome. These cases support the role of Barttin and are categorized into Type 4b Bartter syndrome.

5）Gitelman syndrome
An abnormality in the SLC12A3 gene encoding the Na⁺-Cl^–transporter NCCT is responsible for the onset of this disease. In typical cases, Gitelman syndrome is obviously milder than Bartter syndrome. This syndrome may be identified at school age or later or in adulthood through polydipsia/polyuria, general malaise, or numbness in limbs due to hypokalemia and hypomagnesemia, and many patients are also diagnosed by a casual blood test. In addition, there are cases identified in infancy through dehydration associated with a cold and those diagnosed by short stature. Because Gitelman syndrome presents with hypocalciuria and hypomagnesemia, it is considered differentiable from Bartter syndrome, and thus until recently, the two diseases have been differentiated based on the differences in these laboratory values. However, as described above, some cases of Type 3 Bartter syndrome are difficult to differentiate from Gitelman syndrome based on clinical features and laboratory results alone. Moreover, in recent years, it has been reported that there are some patients with an abnormality in the SLC12A3 gene who do not have hypocalciuria or hypomagnesemia. Consequently, there are many patients for whom a definitive diagnosis can be made only by genetic diagnosis.
Treatment
There is no specific treatment. Treatment is mainly symptomatic such as electrolyte supplementation. The priority is to treat hypokalemia. Potassium preparations are given. If hypomagnesemia is observed, magnesium should also be supplemented. Salt intake should not be restricted but allowed to some extent.
In refractory cases, most clinical symptoms can be reduced by adding nonsteroidal anti-inflammatory agents (e.g., Indometacin and Infree), but these medicines should be used with caution because they may cause deterioration of kidney function.

＜Diagnostic criteria (provisional)＞

Diagnostic criteria for Bartter syndrome/Gitelman syndrome
(developed by research group)

Essential criteria
1. Hypokalemia (serum potassium: ≤ 3.5 mEq/L)
2. Metabolic alkalosis (blood gas analysis [HCO3-]: ≥ 25 mEq/L)

Referential criteria
1. Increase in plasma renin activity
2. Increase in plasma aldosterone level
3. Normal blood pressure or hypotension
4. Polyhydramnios, premature delivery, low birth weight, nephrocalcinosis, and hypercalciuria (Type 1 or Type 2 Bartter syndrome is strongly suspected)
5. Polyhydramnios, premature delivery, low birth weight, and hearing loss (Type 4 Bartter syndrome is strongly suspected)
6. Either hypomagnesemia or hypocalciuria alone or both (Type 3 Bartter syndrome or Gitelman syndrome is strongly suspected)
* If criteria 4 to 6 above are not met, the possibility of Type 3 Bartter syndrome should be considered.

Differential diagnosis
The following diseases are excluded:
１．Secondary causes: use of diuretics/laxatives, severe hyperemesis gravidarum, anorexia nervosa, habitual vomiting, excessive dieting, and alcoholic intoxication may cause so-called pseudo-Bartter/Gitelman syndromes.
２．Other hereditary diseases: hypoplastic kidney, nephronophthisis, Dent disease, mitochondrial disease, congenital renal tubular diseases such as autosomal dominant hypocalcemia (ADH), cystic fibrosis, and congenital chloridorrhea. In these diseases, the clinical condition may be similar to that of Bartter syndrome, and in such a case, it can be very difficult to make the differential diagnosis from Bartter syndrome. In particular, it has been reported that the onset of ADH due to an activating mutation of the calcium-sensing receptor (CaSR) gene (CASR) leads to a clinical condition similar to that of Bartter syndrome, and this condition is sometimes categorized into Type 5 Bartter syndrome. However, even if there is a mutation in the CASR gene, Bartter syndrome-like symptoms rarely appear, and so this condition is not considered to be a subtype of Bartter syndrome in the diagnostic criteria.

Genetic testing
Genetic diagnosis is made with reference to Table 1. Recently, all disease types can be exhaustively analyzed by an analysis using a next-generation sequencer.

＜Diagnosis＞

Cases with a “definite” diagnosis as defined below.
Definite: Both essential criteria are met, all differential diagnoses are excluded, and the causative genetic mutation is identified by genetic diagnosis.
Probable: Both essential criteria are met, all differential diagnoses are excluded, and although the causative genetic mutation is not identified by genetic diagnosis (genetic diagnosis has not been performed or has been performed without identifying the causative genetic mutation), three of the referential criteria are met.