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Bartter and Gitelman syndromes in children: Clinical manifestations, diagnosis, and management

Bartter and Gitelman syndromes in children: Clinical manifestations, diagnosis, and management
Author:
Martin Konrad, MD
Section Editor:
Patrick Niaudet, MD
Deputy Editor:
Alison G Hoppin, MD
Literature review current through: Jan 2024.
This topic last updated: Oct 30, 2023.

INTRODUCTION — Inherited hypokalemic salt-losing tubulopathies, which include Bartter- and Gitelman-like syndromes, are disorders in which salt (ie, sodium) reabsorption is impaired, resulting in excretion of salt in excess of what is required for homeostasis (table 1). These disorders result from pathogenic variants in genes that affect proteins regulating sodium and chloride reabsorption. These proteins are located in the thick ascending limb (TAL), distal convoluted tubule (DCT), and connecting tubule/collecting duct. Clinical manifestations vary depending on the affected protein.

The clinical manifestations, diagnosis, and treatment of Bartter syndrome (BS) and Gitelman syndrome (GS) in children are presented here.

The clinical manifestations, diagnosis, and treatment of BS and GS in adults, as well as an overview that describes the classification of inherited salt-losing tubulopathies and the pathophysiology of inherited hypokalemic salt-losing tubulopathies, are discussed separately. (See "Bartter and Gitelman syndromes in adults: Diagnosis and management" and "Inherited hypokalemic salt-losing tubulopathies: Pathophysiology and overview of clinical manifestations".)

TERMINOLOGY

Tubular reabsorption is the process by which large amounts of ultrafiltrate produced by the kidney during the excretion of waste products are recovered by the kidney tubules. Water and many solutes are reabsorbed back into the bloodstream by the action of transporters, channels, and paracellular pathways along the kidney tubules, thereby maintaining homeostasis. Tubular reabsorption is energy intensive, which is why the kidneys match the heart as having the highest resting metabolic expenditure (approximately 440 kcal/kg per day).

Tubulopathy is defined as dysfunction of the kidney tubules, typically causing defects in reabsorption; these can be either inherited or acquired. The list of inherited tubulopathies is long, given the array of transported solutes [1].

Salt-losing (or salt-wasting) tubulopathies are defined as disorders in which salt (ie, sodium) reabsorption is impaired, resulting in excretion of salt in excess of what is required for homeostasis. These tubulopathies are among the most commonly encountered in clinical practice (table 1) [2].

Bartter syndrome (BS) is defined as inherited disorders caused by molecular defects that effect sodium chloride (NaCl) reabsorption in the cortical and medullary thick ascending limbs (TALs) of the loop of Henle (figure 1).

Gitelman syndrome (GS) is defined as an inherited disorder resulting in defective NaCl reabsorption in the distal convoluted tubule (DCT) (figure 2).

GENETIC CLASSIFICATION — Before the genetic defects were identified, an eponymous nomenclature was used to describe hypokalemic salt-losing tubulopathies as either BS or GS. With the discovery of the underlying genes responsible for these disorders, it became clear that mutations in the same gene can produce significant phenotypic diversity among different individuals with overlap among the two named syndromes. As a result, hypokalemic inherited tubulopathies are better described phenotypically as Bartter-like syndrome and Gitelman-like syndrome. The terms BS (types 1 through 5) and GS are used in association with specific genotypes and will be used in this topic. The terms Bartter-like and Gitelman-like syndromes are used to describe the expressed phenotype regardless of the underlying gene defect (table 1).

Bartter syndrome — BS is manifested by typical gene-specific patterns resulting from dysfunctional proteins causing impaired sodium chloride (NaCl) reabsorption in the cortical and medullary thick ascending limb (TAL) of the loop of Henle. BS is divided into several types based on the causative gene defect (figure 1 and table 2) [3]. A more detailed description of the underlying pathophysiology of these defects is presented separately. (See "Inherited hypokalemic salt-losing tubulopathies: Pathophysiology and overview of clinical manifestations", section on 'Pathophysiology'.)

BS type 1 – BS type 1 (MIM #601678) is caused by defects in SLC12A1, which encodes the Na-K-2Cl cotransporter (NKCC2). Defective NKCC2 function mimics the effects of loop diuretics, which block this pathway directly [4].

BS type 2 – BS type 2 (MIM #241200) is caused by defects in KCNJ1, which encodes the apical potassium channel KCNJ1 (also referred to as ROMK) [5]. Defective KCNJ1 function inhibits NaCl reabsorption along the TAL as potassium must recycle from cells back into the luminal fluid to maintain the action of NKCC2. This channel also participates in aldosterone-driven potassium secretion along distal segments, resulting in less severe hypokalemia for patients with BS2 compared with those with other types of BS.

Other – The following genes encode proteins that are components of chloride channel exit pathways from the TAL. Chloride reabsorbed via NKCC2 exits the cell on the basolateral side predominantly through the chloride channel ClC-Kb. Barttin is a necessary subunit for both chloride channels ClC-Kb and ClC-Ka. Pathologic variants of these genes impede chloride flow out of the cell and into the blood stream.

BS type 3 – BS type 3 (MIM #607364) is caused by defects in CLCNKB, which encodes ClC-Kb [6]. ClC-Kb also mediates basolateral chloride transport in the distal convoluted tubule (DCT), and this might explain the overlapping phenotype between patients with BS type 3 and those with Gitelman-like syndrome. (See 'Gitelman syndrome' below.)

BS type 4a – BS type 4a (MIM #602522) is caused by defects in BSND, which encodes barttin. Defective barttin function results in a typically very severe antenatal form of BS and is associated with sensorineural deafness [7,8].

BS type 4b – BS type 4b (MIM #613090) is caused by a combination of pathologic variants of CLCNKA (encoding ClC-Ka) and CLCNKB [9].

BS type 5 – BS type 5 (MIM #300971) is caused by pathogenic variants in the MAGED2 gene that encodes MAGE-D2 (melanoma-associated antigen). These defects disrupt trafficking of NKCC2 and NCC to the apical membrane of TAL and DCT cells, although the underlying mechanism remains unclear [10,11]. Affected patients present with severe antenatal BS, which resolves after birth, at latest within two years.

Gitelman syndrome — GS (MIM #263800) is caused by dysfunctional proteins that affect NaCl reabsorption in the DCT. Classic GS is due to biallelic pathogenic variants of the SLC12A3 gene that encodes the NaCl cotransporter NCC, expressed in the apical membrane of the DCT [12] (figure 2).

Other gene variants that have been identified in individuals with Bartter- or Gitelman-like syndrome include KCNJ10 (also known as Kir4.1, encodes a glial potassium channel, and causes EAST/SESAME syndrome), CLCNKB (encodes ClC-Kb, which is found in both DCT and TAL), RRAGD (encodes the small GTPase RagD), and MT-TI or MT-TF (mitochondrial genes encoding transfer ribonucleic acids [RNAs] for isoleucine and phenylalanine).

EPIDEMIOLOGY — The exact incidence and prevalence of BS and GS are unknown.

Bartter Syndrome – The overall prevalence of all types of BS in North America and Western European countries is estimated between 1 per 40,000 to 50,000, based on data from the Framingham Heart Study that found a prevalence of 1:100,000 for BS types 1 and 2 due to SLC12A1 and KCNJ1 variants [13].

Gitelman Syndrome – The reported prevalence for GS is estimated between 1 to 10:40,000, thus, GS probably is the most frequently inherited tubular disorder [12,14]. However, given the number of incidental diagnoses of asymptomatic individuals, the prevalence is likely higher.

CLINICAL FEATURES: BARTTER SYNDROME

Overview — The term BS comprises a set of inherited salt-wasting disorders with impaired sodium chloride (NaCl) reabsorption in the thick ascending limb (TAL) of the loop of Henle that presents with hypokalemic metabolic alkalosis and normal or low blood pressure despite high renin and aldosterone levels (figure 1) (see 'Bartter syndrome' above). BS is characterized by typical gene-specific patterns, including the age of presentation based on the underlying genetic defect (table 2) [15]. (See "Inherited hypokalemic salt-losing tubulopathies: Pathophysiology and overview of clinical manifestations", section on 'Pathophysiology'.)

Clinical presentation — The following are typical symptoms seen in children with BS. The age of presentation and the presence/severity of symptoms vary depending on the underlying genetic defect (table 2) [15].

Polyhydramnios and premature delivery

Polyuria, polydipsia

Clinical signs of hypovolemia

Failure to thrive

Poor growth

Symptoms based on the timing of presentation:

Antenatal presentation – Polyhydramnios is a common finding during pregnancy presenting between 22 and 25 weeks of gestation [11]. The onset and severity of polyhydramnios varies depending on the type of BS. In fetuses with pathogenic variants in BSND or MAGED2 (BS types 4 and 5, respectively), polyhydramnios is usually observed earlier during pregnancy than BS type 1 (SLC12A1) and BS type 2 (KCNJ1). The severity of polyhydramnios is most severe for BS types 4 and 5, whereas, in BS type 3 (CLCNKB), polyhydramnios is either mild or absent.

Although fetuses with BS type 5 have the most severe form of polyhydramnios, polyuria resolves spontaneously after birth within a few weeks and, at the latest, within the first two years of life [10,11].

Neonatal presentation – All BS types except BS type 3 typically present in the neonatal period with preterm birth (median gestational age between 29 and 33 weeks) and massive polyuria (often exceeding 10 mL/kg/hour) starting at day 1 of life with rapid weight loss and evidence of hypovolemia. In contrast, individuals with BS type 3 are usually full term and do not exhibit signs of excessive urinary loss and hypovolemia during the neonatal period.

Infants with BS type 4a and 4b also have sensorineural hearing loss and fail their newborn hearing screening test [7,9].

Older infants and young children – Individuals with BS type 3 typically present after one year of age with failure to thrive and polyuria/polydipsia [16-18]. Less frequent symptoms related to hypovolemia and salt loss include constipation, persistent thirst, salt craving, unexplained fever, hypotonia, and recurrent vomiting.

Older children and adolescents – Although uncommon, BS can initially present in older children and adolescents primarily due to BS type 3. Symptoms may be similar to those seen in GS, including muscle weakness, fatigue, salt craving, thirst, nocturia, cramps, and constipation. In prepubertal children, there may be evidence of poor growth and pubertal delay. In rare cases, in this age group, BS can present with isolated nephrocalcinosis and high parathyroid hormone levels, mimicking primary hyperparathyroidism [19]. Of note, especially in BS type 1 and type 2, signs of a mild hyperparathyroidism may be detected in otherwise typical BS patients [20].

Asymptomatic patients – Incidental presentation in an asymptomatic individual is very uncommon but can occur when abnormal laboratory tests demonstrate hypokalemia metabolic alkalosis in a normotensive child, abdominal imaging demonstrates nephrocalcinosis, or after screening based on a positive family history [16-18,21].

Laboratory findings — Laboratory findings for BS include [3]:

Hypochloremic metabolic alkalosis is a common finding in children with BS (see "Inherited hypokalemic salt-losing tubulopathies: Pathophysiology and overview of clinical manifestations", section on 'Mechanisms underlying associated clinical findings'). However, neonates with BS type 2 often have transient acidosis and the degree of alkalosis is less pronounced in children with BS type 2 compared with those with other types of BS. In general, patients with BS type 3 tend to have the lowest plasma chloride levels (median 87, interquartile range 74 to 94 mEq/L [mmol/L]) followed by those with BS type 4 (median 94, interquartile range 84 to 100 mEq/L [mmol/L]) and the most pronounced alkalosis [10,16].

Hypokalemia is a characteristic diagnostic feature with potassium levels that are less than 3 mEq/L (mmol/L) in most patients [22]. However, neonates with BS type 2 often have transient hyperkalemia after birth because loss of function KCNJ1 variants initially result in impaired potassium secretion along the collecting duct [22,23]. Postnatally, hyperkalemia develops likely due to expression of alternative potassium channels that compensates for the dysfunction of KCNJ1.

Elevated renin and aldosterone levels are due to the decreased NaCl entry into macula densa cells, which stimulates renin production [24-26]. Despite the activation of the renin-angiotensin system, patients with BS have low to normal blood pressure due to chronic hypovolemia.

Low urine osmolality due to impaired concentrating ability is a key laboratory finding in BS. Patients typically have urine osmolality values equal and never greater than their plasma osmolality (isosthenuric urine) [22]. The concentrating defect is mainly due to impaired sodium transport along the TAL, leading to the loss of medullary interstitial hypertonicity and osmotic driving force for water reabsorption in the collecting duct that results in excessive amounts of dilute urine (polyuria) and volume depletion.

Urinary calcium varies based on the BS types and the underlying gene defect.

Hypercalcuria – Patients with BS type 1 and 2 have hypercalcuria (table 3). For these infants, nephrocalcinosis is often detected after one or two months of life [15].

Hypercalciuria may also be observed in neonates with BS type 5, but, due to the transient nature of the disease, it may disappear over time [10,11].

Normocalciuria – Patients with BS types 3 and 4 usually have normocalciuria, although hypercalciuria has been described in some case reports. In addition, hypocalciuria has also been reported in patients with BS type 3 as seen with patients with GS. This phenotypic overlap is best explained by impaired NaCl reabsorption in the distal convolute tubule, in which the chloride channel ClC-Kb is also expressed. Studies of affected families with BS type 3 report that calcium excretion rates may differ among family members with the same mutation [27,28].

A more detailed discussion of the underlying mechanisms that result in these laboratory findings are found separately. (See "Inherited hypokalemic salt-losing tubulopathies: Pathophysiology and overview of clinical manifestations", section on 'Bartter-like phenotype'.)

CLINICAL FEATURES: GITELMAN SYNDROME — GS is an autosomal recessive disorder that usually presents with hypokalemia, metabolic alkalosis, hypomagnesemia, hypocalciuria, and normal or slightly low blood pressure with elevated renin and aldosterone levels [12,29].

Clinical presentation — GS presents mainly in adolescents and adults with the following signs and symptoms [12]:

Muscle weakness and cramps, often after exercise, which may limit sport performance or endurance

Fatigue

Salt craving

Thirst and polydipsia

Other less common presentations include:

Younger children ‒ Although uncommon, GS can present in younger children, including neonates [22,29,30]. In addition to the above findings, growth failure with short stature and pubertal delay may be observed in prepubertal children.

Palpitations ‒ In some patients with GS, palpitations are also a presenting complaint, which is thought to be due to prolonged QT interval resulting from low serum potassium and magnesium levels [12,31]. (See 'Complications' below.)

Asymptomatic individuals ‒ GS can also be suspected after incidental laboratory testing detects hypokalemia metabolic alkalosis [12].

Laboratory findings — The following laboratory findings are characteristic of children with GS:

Chronic hypokalemic (<3.5 mEq/L) metabolic alkalosis with concomitant inappropriate urinary potassium wasting detected by a spot potassium-to-creatinine ratio >13 mEq/g creatinine (>1.5 mEq/mmol creatinine).

Elevated renin and aldosterone levels – Reduction of extracellular fluid volume due to sodium chloride (NaCl) loss stimulates renin-angiotensin-aldosterone system. Despite the elevated renin and aldosterone levels, patients with GS have low to normal blood pressure due to chronic hypovolemia.

High urinary chloride excretion – Fractional excretion of chloride >0.5 percent.

Hypomagnesemia (<1.70 mg/dL [0.7 mmol/L]) with inappropriate urinary magnesium wasting (fractional excretion of magnesium >4 percent).

Hypocalciuria – Low calcium:creatinine ratio <0.05 mg/mg [0.15 mmol/mmol] [15].

A more detailed discussion of the underlying mechanisms that result in these laboratory findings is found separately. (See "Inherited hypokalemic salt-losing tubulopathies: Pathophysiology and overview of clinical manifestations", section on 'Gitelman-like phenotype'.)

DIAGNOSIS — The diagnosis of either BS or GS is clinically suspected uon recognition of their characteristic features but requires genetic testing for confirmation. Genetic testing will also differentiate among the various types of BS, although the different types of BS and GS can often be clinically distinguished (table 2).

Antenatal diagnosis: Bartter syndrome — Polyhydramnios detected at the beginning of the second trimester of gestation raises the clinical suspicion of BS [3]. There are two possible options to confirm the diagnosis: prenatal genetic testing and biochemical analysis of amniotic fluid. However, both measures are invasive and carry the risk of procedure-related complications, including fetal loss. As a result, we do not routinely perform these tests and we await postnatal genetic testing for confirmation of the diagnosis.

There may be clinical situations where the establishment of a confirmed diagnosis of BS is helpful for counseling of the couple and discussion of possible therapeutic measures. Whenever there is a need for prenatal diagnosis, genetic testing is the most reliable method. If genetic testing is unavailable or not informative, the biochemical measurement of the concentration of total protein and alpha-fetoprotein in the amniotic fluid can be used to calculate the Bartter index (total protein × alpha-fetoprotein), which has been reported to be useful in predicting the diagnosis of BS (sensitivity of 86 percent and specificity of 84 percent) [32,33]. In contrast, other biochemical components of the amniotic fluid such as electrolytes (high chloride) and/or aldosterone have not been shown to be useful in distinguishing BS from other causes of polyhydramnios [33,34].

Postnatal diagnosis

When to suspect either Bartter or Gitelman syndrome — The two inherited hypokalemic salt-wasting tubulopathies BS and GS are clinically suspected in individuals who present with hypokalemic hypochloremic metabolic alkalosis, high urinary chloride excretion, and normal to low blood pressure despite elevated renin and aldosterone levels. (See 'Clinical features: Bartter syndrome' above and 'Clinical features: Gitelman syndrome' above and "Inherited hypokalemic salt-losing tubulopathies: Pathophysiology and overview of clinical manifestations", section on 'Features common to hypokalemic salt-wasting tubulopathies'.)

The following clinical features distinguish between the two disorders [3,12]:

Neonatal presentation with evidence of hypovolemia due to massive polyuria is consistent with a clinical diagnosis of BS types 1, 2, 4a, and 4b but not GS or BS type 3. In particular, urinary concentrating ability is impaired in BS but fully preserved in GS.

Reduced urinary calcium excretion is observed in GS, whereas high or normal urinary calcium excretion is seen in most subtypes of BS. In particular, hypercalciuria occurs in patients with BS types 1 and 2, which may result in nephrocalcinosis by 1 or 2 months of age.

Renal magnesium wasting with hypomagnesemia is a prominent feature in GS but rarely occurs in BS, except patients with BS type 3 who also have a tendency towards low serum magnesium levels.

Genetic testing — The detection of pathogenic variants in one or more of the genes responsible for BS or GS confirms the clinical diagnosis (table 1) [3,12]. For affected neonates, early genetic testing can differentiate among the different types of BS. This information would allow for avoidance of aggressive treatment for individuals with transient BS type 5, which typically resolves soon after birth, and identify infants with BS type 4a/b who also have sensorineural hearing loss in addition to renal salt-wasting.

Because of the number of causative genes, we suggest that next-generation sequencing (NGS) testing be performed using gene panels that should include at least SLC12A1, KCNJ1, BSND, CLCNKA, CLCNKB, MAGED2, and SLC12A3. In children, the clinical sensitivity of NGS testing using this panel is approximately 75 percent and specificity is approximately 90 to 100 percent [35]. Of note, sensitivity decreases in adults due to the rise of secondary causes of hypokalemic metabolic alkalosis (eg, chronic use of diuretics and laxatives) [36]. Although large rearrangements (deletions or duplications) can be detected by NGS testing, a second independent method (eg, multiplex ligation-dependent probe amplification or quantitative polymerase chain reaction) should be used for confirmation. Large rearrangements are particularly frequent in the CLCNKB but have also been described in KCNJ1, BSND, and MAGED2 [7,11,37].

In cases where the differential diagnosis is expanded, the gene panel can be extended to include genes responsible for congenital chloride diarrhea (SLC26A3), HELIX syndrome (CLDN10), EAST/SeSAME syndrome (KCNJ10), hypokalemic tubulopathy and deafness (KCNJ16), kidney tubulopathy with cardiomyopathy (RRAGD), mitochondrial Gitelman-like syndrome (MT-TI, MT-TF), autosomal dominant hypocalcemia (CASR), and type 1 pseudohypoaldosteronism (SCNN1A, SCNN1B, SCNN1G, NR3C2). (See 'Differential diagnosis' below.)

Genetic counselling should be offered to any patient with BS and to parents with an affected child and can help guide testing of other family members. Testing relatives is particularly useful to identify heterozygous female carriers in families with an index case carrying a MAGED2 mutation [10].

Prenatal diagnosis and preimplantation genetic testing are feasible and may be considered on an individual basis with reliable genetic counselling, according to national ethical and legal standards.

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of BS and GS depends on clinical manifestations, including age of presentation.

Antenatal – The differential diagnosis for BS types that present with polyhydramnios include (see "Polyhydramnios: Etiology, diagnosis, and management in singleton gestations", section on 'Conditions associated with polyhydramnios'):

Congenital chloride diarrhea due to fetal secretory diarrhea resulting in excessive amniotic fluid.

Fetal conditions that result in decreased fetal swallowing, including esophageal and gastrointestinal obstruction, which can be primary (esophageal or duodenal atresia) or secondary (eg, diaphragmatic hernia), and neuromuscular disorders (eg, trisomy 18). These disorders can often be distinguished from BS by fetal ultrasound or abnormal karyotype.

Although prenatal genetic testing and amniotic fluid biochemistry can be used to differentiate BS from other disorders associated with polyhydramnios, they are not recommended, due to significant adverse effects, including fetal loss. As a result, differentiating between BS and these conditions may need to be done after delivery. (See 'Antenatal diagnosis: Bartter syndrome' above.)

Neonates – The differential diagnosis for neonates with BS is based on the most common finding of significant hypovolemia associated with metabolic alkalosis.

Pseudohypoaldosteronism type 1 is differentiated from BS as it is associated with hyperkalemia and metabolic acidosis, whereas BS typically is characterized by hypokalemic metabolic alkalosis. Important to note that patients with BS type 2 (KCNJ1) may mimic pseudohypoaldosteronism type 1 during the first weeks of life due to transient hyperkalemia.

Congenital chloride diarrhea, which also presents with hypokalemic metabolic alkalosis, can be differentiated from BS as it is associated with low urinary chloride excretion, whereas BS is characterized by high urinary chloride excretion.

Older infants and children – Beyond the neonatal period, the differential diagnosis for BS and GS can be challenging and depends on the presenting clinical finding.

Nephrocalcinosis/urolithiasis is commonly observed in the following disorders as well as BS types 1 and 2.

-Distal renal tubular acidosis is distinguished from BS by laboratory testing demonstrating metabolic acidosis rather than metabolic alkalosis.

-Apparent mineralocorticoid excess is associated with hypokalemic hypochloremic alkalosis. However, apparent mineralocorticoid excess is characterized by hypervolemia and hypertension with low renin and aldosterone, findings that differentiate it from BS, which is characterized by hypovolemia, low/normal blood pressure, and high renin and aldosterone levels.

Hypovolemia associated with hypokalemic alkalosis is observed in patients with BS and GS as well as a subset of patients with cystic fibrosis (referred to as pseudo-BS) [15], surreptitious vomiting, and chronic use of laxatives [3,12]. A high chloride excretion rate distinguishes BS and GS from these other disorders, which are characterized by a low urinary chloride excretion [3].

The differential diagnosis also includes chronic or surreptitious use of diuretics, which may have variable levels of urinary chloride excretion. However, this is unusual in children but, if present, it is difficult to be distinguished from GS and BS type 3.

The following rare renal tubular disorders exhibit metabolic alkalosis and are differentiated from BS and GS by their characteristic clinical findings and confirmation by genetic testing [3,12,38]:

-EAST/SESAME syndrome (MIM #612780; KCNJ10) [39]

-HNF1B nephropathy [40]

-HELIX syndrome (MIM #617671; CLDN10) [41,42]

-Mitochondrial Gitelman-like syndrome (MT-TI, MT-TF) [43]

-Hypokalemic tubulopathy and deafness (MIM #619406; KCNJ16) [38]

-Kidney tubulopathy with cardiomyopathy (MIM #620152; RRAGD) [44]

-Autosomal dominant hypocalcemia (MIM #601198; CASR) [45]

Hypokalemia is a finding that occurs in a wide range of disorders, and the diagnostic evaluation to determine the underlying cause is discussed separately (see "Hypokalemia in children", section on 'Evaluation to determine underlying etiology'). BS and GS is typically differentiated from other causes of hypokalemia by their characteristic findings of persistent urinary potassium loss (urine potassium to creatinine ratio >15 mg/g, creatinine [1.5 mEq/mmol], or fractional excretion rates >15 percent), normal to low blood pressure, metabolic alkalosis, and high chloride excretion rate (algorithm 1).

MANAGEMENT/THERAPY

Prenatal therapy — Although there are a few successful case reports of the use of serial amniocentesis and maternal administration of nonsteroidal antiinflammatory drugs (NSAIDs) to treat polyhydramnios due to BS, it remains uncertain whether this approach provides sufficient benefit to outweigh potential adverse effects, including fetal loss [3]. The management of severe polyhydramnios due to BS is provided by a multidisciplinary team and is discussed in greater detail separately. (See "Polyhydramnios: Etiology, diagnosis, and management in singleton gestations", section on 'Additional issues in patients with severe polyhydramnios'.)

Postnatal therapy — Postnatal therapy consists of initial repletion and maintenance therapy of fluid, sodium chloride (NaCl), and potassium. Because urinary losses are continuous for both NaCl and potassium, supplements should be administered in frequent doses throughout the day. For infants receiving continuous tube feeding, supplements can be added to the feed. In more severe cases, the use of NSAIDs may be needed.

Sodium chloride — Adequate daily NaCl consumption to account for tubular loss is one of the mainstays of managing BS and GS. (See "Inherited hypokalemic salt-losing tubulopathies: Pathophysiology and overview of clinical manifestations", section on 'Pathophysiology'.)

BS – For most patients with BS, NaCl supplementation of at least 5 to 10 mEq/kg/day (mmol/kg/day) is needed to compensate for urinary losses.

However, salt supplementation should be avoided in the uncommon setting of patients with BS types 1 and 2 who have secondary nephrogenic diabetes insipidus, who typically present with hypernatremia and hyposthenuric urine [46]. In these children with secondary nephrogenic diabetes insipidus, salt supplementation may lead to worsening polyuria and more severe hypernatremia.

GS ‒ For GS, increased dietary salt consumption is usually sufficient to compensate for the tubular loss of salt.

Potassium supplementation — Hypokalemia is a characteristic finding for both BS and GS. In both disorders, symptoms due to hypokalemia are common and, in some cases, hypokalemia can lead to significant complications (eg, muscle weakness and paralysis, prolonged QT interval, and cardiac arrhythmias) [3,12]. However, the intake of large amounts of potassium is also associated with serious side effects including gastric ulcers, vomiting, and diarrhea. As a result, the goal of therapy is not to normalize potassium levels but to achieve a target of ≥3 mEq/L (mmol/L), which should alleviate symptoms associated with hypokalemia.

Potassium supplements should be given as potassium chloride because chloride is the main anion lost in the urine [3,12]. Potassium citrate and potassium acetate should be avoided as they could aggravate the alkalosis associated with these disorders. In our center, oral potassium chloride supplementation is administered at an initial dose of 1 to 2 mEq/kg/day (mmol/kg/day) in divided doses throughout the day administered in water, as a syrup, or as a slow-release formulation, based on patient preference. The dose is then modified with a target of maintaining a target potassium level ≥3 mEq/L (mmol/L). However, it has to be noted that this target level may not be reached in all patients. Potassium-rich foods are recommended; however, some of these foods contain high amounts of carbohydrates and calories. Similar to NaCl supplementation, potassium supplementation should be divided into as many doses as possible.

Magnesium supplementation — Hypomagnesemia (<1.70 mg/dL [0.7 mmol/L]) is a common feature of GS as well as BS type 3 and may aggravate the complaints/complications associated with hypokalemia [12]. In affected individuals, oral magnesium supplementation may be needed to reach a targeted goal of 1.46 mg/dL (0.6 mmol/L).

For patients needing magnesium supplements, oral organic magnesium salts are recommended (eg, aspartate, citrate, lactate) because of their higher bioavailability as compared with magnesium oxide or hydroxide [47]. Treatment of hypomagnesemia may also facilitate potassium supplementation because hypomagnesemia may worsen hypokalemia and render it refractory to potassium. Doses of magnesium need individual adjustment, but a reasonable starting daily dose of elemental magnesium in children is 5 mg/kg (0.2 mmol/kg) divided into three to four doses. A slow-release formulation is used whenever possible. Of note, gastrointestinal side effects are common (especially diarrhea), which often requires dose reduction.

Nonsteroidal antiinflammatory drugs — Treatment with NSAIDs for BS is based on the observation of increased production of prostaglandin E2, which contributes to high urinary NaCl losses [48]. Based on the available observational evidence demonstrating beneficial effects of NSAIDs, we suggest NSAIDs be given to symptomatic patients (eg, poor growth or recurrent bouts of hypovolemia) with BS who fail to adequately respond to salt supplementation and fluid therapy.

Choice and administration of NSAIDs ‒ There are no data showing that one specific NSAID is more effective than another in the management of BS. Commonly used NSAIDs for BS include indomethacin (daily dose of 1 to 3 mg/kg/day divided into two or four doses), ibuprofen (daily dose 15 to 30 mg/kg divided into three doses), and the selective cyclooxygenase (COX)-2 inhibitor celecoxib (daily dose 2 to 10 mg/kg divided into two doses).

In our center, we use indomethacin for infants and small children and celecoxib in older children (>5 years of age) and adolescents. For preterm and neonates, we begin with a low dose of 0.1 mg/kg/day indomethacin with a stepwise increase to 1.5 to 2 mg/kg/day according to changes in urinary output and aldosterone levels. For older infants and young children, higher doses may be needed (up to 3 mg/kg/day) to maintain euvolemia and adequate levels of electrolytes and fluid.

Before starting NSAIDs, it is important to establish euvolemia with adequate replacement of salt and fluid losses because of the significant risk of acute renal failure.

Indications ‒ In our center, the main indications for NSAIDs are excessive polyuria that cannot be managed by replacement therapy alone, failure to thrive, growth retardation, and potentially dangerous electrolyte disturbances despite maximal supplementation.

Efficacy data ‒ Supporting evidence for the use of NSAIDs to manage BS is based on observational studies and case series that report that NSAIDs decrease urinary prostaglandin E excretion [49-52], normalize renin and aldosterone levels [49-53], and result in the following clinical benefits:

Decreased NaCl and potassium supplementation due to a reduction in urinary excretion of NaCl and potassium [49,52-55]

Decreased urine volume

Decreased hypercalciuria [56,57]

Improved weight gain and growth [53,55,58-61]

Adverse effects of NSAIDs

Gastrointestinal complications ‒ The use of nonselective COX inhibitors (indomethacin or ibuprofen) is associated with gastrointestinal complications including gastritis and gastric ulcer disease [15,55]. If a nonselective COX inhibitor is used, gastric acid inhibitors should be prescribed to reduce the risk of gastrointestinal complications [3]. The potential risk of serious gastrointestinal complications (eg, ulcers, perforation) due to NSAIDs, especially in preterm and term neonates, need to be weighed against the beneficial effects on renal salt loss in BS and avoiding the complications associated with significant hypovolemia.

Chronic kidney disease (CKD) ‒ Individuals with BS appear to be at risk for CKD; however, it remains uncertain whether NSAIDs play a significant contributing role as there are additional risk factors for CKD, including prematurity and repeated bouts of hypovolemia [3]. (See 'Complications' below.)

Other management considerations

Nutritional support ‒ Poor weight gain and growth are common complications of BS. Nutritional support is focused on maximal caloric intake. In infants and small children, tube feeding may be helpful to provide optimal caloric intake as well as administration of salt and fluid supplements [3]. In older children and adolescents, foods rich in potassium and magnesium (table 4A-B) should be encouraged as additional sources for electrolyte supply [62].

Growth hormone – Persistent growth failure despite adequate therapy of metabolic disturbances has been repeatedly reported in BS, especially in BS type 3 [15,17,63]. It remains unclear whether poor growth is due to acid/base or electrolyte disturbances in BS or whether it is an intrinsic part of the disorder. Although recombinant growth hormone has been used, poor response has been reported in patients with poor metabolic control [15]. Requirements before consideration of recombinant growth hormone therapy consist of an adequately maintained biochemical and fluid status and evaluation of the growth hormone axis in collaboration with a pediatric endocrinologist or other clinicians with expertise in poor growth. (See "Treatment of growth hormone deficiency in children".)

Potassium-sparing diuretics, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers have been considered in both BS and GS cases with persistent, symptomatic hypokalemia when supplements are not sufficient despite adherence or when side effects are unacceptable or both [3,12]. However, these agents may exacerbate renal salt wasting and increased polyuria resulting in critical hypovolemia, especially in patients with BS. As a result, we suggest that these drugs should not be used routinely and only be considered in individual cases for patients with severe symptoms due to hypokalemia despite maximization of routine treatment with NaCl and potassium supplementation, and NSAIDs for BS. These agents should only be prescribed by clinicians with expertise in caring for patients with BS.

Follow-up care — The follow-up care for patients with BS and GS is based on the age of the patient, severity of symptoms, and therapeutic interventions (table 5). Care is provided by specialized centers with expertise in renal tubular disorders in conjunction with the individual's primary care provider.

RESOURCES FOR PATIENTS — It is imperative that individuals and family/caregivers are provided information regarding their underlying disease. This information can be accessed through a variety of means including patient led-forums and web-based resources. There is no evidence suggesting that participation in sports is deleterious, but children and their caregivers should be aware of the risk of volume depletion and receive education on preventive measures to avoid hypovolemia.

National Organization for Rare Disorders: BS

National Organization for Rare Disorders: GS

UK Kidney Association: BS

UK Kidney Association: GS and type 3 BS

COMPLICATIONS

Poor weight gain and growth impairment – These are common in patients with BS. As noted above, salt and electrolyte supplementation, use of nonsteroidal antiinflammatory drugs (NSAIDs), and optimal nutrition are used to improve weight gain and growth. Body weight and height should be measured at every pediatric follow-up visit. (See 'Management/therapy' above.)

Hypokalemia – Complications due to hypokalemia may be life-threatening and include prolongation of the QT interval, which increases the risk of ventricular arrhythmias and sudden cardiac death [3,12]. For patients with persistent hypokalemia, an electrocardiogram is performed to assess QT interval and rhythm. Further cardiac workup is performed for patients with palpitations or syncope, which may include Holter monitoring and stress test. (See "Hypokalemia in children", section on 'Cardiac findings'.)

The use of drugs that slow sinus rhythm or cause additional prolongation of the QT interval should be considered on an individual basis. These include negative chronotropic drugs (eg, beta blockers), or drugs that may induce or exacerbate hypomagnesemia (which aggravates hypokalemia) [12], such as proton pump inhibitors, macrolides, fluoroquinolones, gentamicin, or antiviral drugs.

For patients who require anesthesia, hypokalemia and hypomagnesemia can potentiate the effects of anesthetic agents [3,12].

Chronic kidney disease (CKD) – CKD (ie, proteinuria and decreased glomerular function) is reported in patients with BS, especially those with types 1, 4a, and 4b [15,16,64,65]. This is likely the result of multiple factors (preterm birth, repeated bouts of severe dehydration, chronic use of NSAIDs, nephrocalcinosis), and it is uncertain what role the underlying genetic defect plays in the development of CKD [3,15]. Some patients progress to kidney failure. In the few reported cases of kidney transplantation, all of the electrolyte and urinary concentrating abnormalities were corrected and there was no evidence of recurrent disease.

SUMMARY AND RECOMMENDATIONS

Definitions ‒ Bartter syndrome (BS) and Gitelman syndrome (GS) are inherited hypokalemic salt-losing tubulopathies with impaired salt (ie, sodium) reabsorption resulting in excretion of salt in excess of what is required for homeostasis (table 1). (See 'Terminology' above and "Inherited hypokalemic salt-losing tubulopathies: Pathophysiology and overview of clinical manifestations".)

Genetic classification and epidemiology ‒ (See 'Genetic classification' above and 'Epidemiology' above.)

BS is divided into several types based on the underlying gene defect that impacts presentation. The overall prevalence of all types of BS in North America and Western European countries is estimated between 1 per 40,000 to 50,000 (table 2). (See 'Bartter syndrome' above.)

GS is caused by dysfunctional proteins that affect sodium chloride (NaCl) reabsorption in the distal convoluted tubule (DCT). Classic GS is due to biallelic pathogenic variants of the SLC12A3 gene that encodes the NaCl cotransporter NCC expressed in the apical membrane of the DCT (figure 2). Other genes variants that have been identified in individuals with Gitelman-like syndromes. (See 'Gitelman syndrome' above.)

Clinical features of BS

Presentation – Presenting features of BS and the age of presentation vary depending on the underlying genetic defect. Manifestations include polyhydramnios, preterm delivery, polyuria, polydipsia, signs of hypovolemia, failure to thrive, and poor growth (table 2). (See 'Clinical presentation' above.)

Laboratory findings – Laboratory features include (see 'Laboratory findings' above):

-Hypochloremic metabolic alkalosis

-Hypokalemia

-Elevated renin and aldosterone but with normal or low blood pressure

-Isosthenuric urine – Urine osmolality values equal but never greater than plasma osmolality

Clinical features of GS ‒ (See 'Clinical features: Gitelman syndrome' above.)

Presentation – GS presents mainly in adolescents and adults, with muscle weakness and cramps, fatigue, salt craving, thirst, and polydipsia.

Laboratory findings – Laboratory features include hypokalemia, elevated renin and aldosterone with low to normal blood pressure, high urinary chloride excretion, hypocalciuria, and hypomagnesemia.

Diagnosis – The diagnosis of either BS or GS is clinically suspected upon recognition of their characteristic features but requires genetic testing for confirmation. (See 'Diagnosis' above.)

Differential diagnosis – The differential diagnosis of BS and GS depends on clinical manifestations, including age of presentation. (See 'Differential diagnosis' above.)

Antenatal management – Serial amniocentesis and maternal administration of nonsteroidal antiinflammatory drugs (NSAIDs) are not used to routinely manage polyhydramnios due to BS, as the available evidence is insufficient to show that the benefit outweighs potential adverse effects, including fetal loss. The management of polyhydramnios is discussed separately. (See "Polyhydramnios: Etiology, diagnosis, and management in singleton gestations", section on 'Additional issues in patients with severe polyhydramnios'.)

Postnatal management

Repletion and maintenance of fluid, NaCl, and potassium ‒ (See 'Postnatal therapy' above.)

-For patients with BS, NaCl supplementation of at least 5 to 10 mEq/kg/day (mmol/kg/day) and potassium chloride supplementation at an initial dose of 1 to 2 mEq/day are required to compensate for urinary losses. Because urinary losses are continuous, supplements should be administered in frequent doses throughout the day.

-For patients with GS, increased dietary salt consumption is usually sufficient to compensate for the tubular loss of sodium. However, potassium supplementation may be needed to maintain target potassium level ≥3 mEq/L (mmol/L).

If supplements are provided, they should be administered in frequent doses throughout the day as urinary losses are continuous. For patients with potassium supplementation, the target potassium goal is ≥3 mEq/L (mmol/L), which should alleviate symptoms associated with hypokalemia. (See 'Postnatal therapy' above.)

NSAIDs – In more severe symptomatic cases of BS that fail to respond adequately to salt supplementation and fluid therapy, we suggest administrating NSAIDs in addition to routine supportive care (Grade 2C). (See 'Nonsteroidal antiinflammatory drugs' above.)

Nutrition – Maximal caloric intake, which may include tube feeding, is required to reduce the risk of poor weight gain and poor growth that is commonly seen in patients with BS. (See 'Other management considerations' above.)

Follow-up care – Care is provided by specialized centers with expertise in renal tubular disorders in conjunction with the individual's primary care provider. The frequency of follow-up visits depends on the age of the patient, severity of symptoms, and therapeutic interventions (table 5). (See 'Follow-up care' above.)

Patient education – Education of patient and family/caregivers is provided by care providers, including access to information through patient led-forums and web-based resources. (See 'Resources for patients' above.)

Complications ‒ (See 'Complications' above.)

Hypokalemia – For both patients with BS and GS, complications due to hypokalemia may be life-threatening and include increased risk of ventricular arrhythmias and sudden cardiac death. Adequate potassium chloride supplementation that increases potassium ≥3 mEq/L (mmol/L) reduces this risk.

Growth failure – Poor weight gain and growth impairment are common findings for children with BS who do not receive or respond adequately to medical therapy. Growth depends on optimizing medical therapy by providing adequate fluid and electrolyte supplementation and caloric intake and, in some cases, NSAIDs. For children who continue to have poor growth despite adequate medical therapy, growth hormone therapy may be considered. (See 'Other management considerations' above.)

Chronic kidney disease (CKD) – Proteinuria and decreased glomerular function have been observed in patients with BS especially those with types 1, 4a, and 4b. However, CKD is likely the result of multiple factors (preterm birth, repeated bouts of severe dehydration, chronic use of NSAIDs, nephrocalcinosis) and it is uncertain what role the underlying genetic defect plays in the development of CKD.

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Topic 131435 Version 8.0

References

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