INTRODUCTION — Bartter and Gitelman syndromes are inherited hypokalemic salt-losing (ie, salt-wasting) tubulopathies. They are generally inherited as autosomal recessive traits due to loss-of-function mutations (table 1). Hundreds of different specific mutations in various genes have been identified that can lead to these disorders [1,2]. The mutations markedly impair or eliminate the function of one or more electrolyte transporters or channels in the kidney, which generates a renal salt wasting state.
Clinically, Bartter and Gitelman syndromes are associated with reduction of the extracellular fluid volume, hyperreninemia, secondary hyperaldosteronism, hypokalemia, and metabolic alkalosis.
The diagnosis and management of Bartter and Gitelman syndromes in adults are presented in this topic. The classification of inherited salt-wasting tubulopathies, clinical features and pathophysiology of hypokalemic salt-losing tubulopathies (including Bartter and Gitelman syndromes), and the diagnosis and treatment of these tubulopathies in children are presented separately:
When to suspect the diagnosis — Gitelman or Bartter syndrome should be suspected in any patient with unexplained hypokalemia, metabolic alkalosis, and a normal or low blood pressure. (See "Inherited hypokalemic salt-losing tubulopathies: Pathophysiology and overview of clinical manifestations", section on 'Features common to hypokalemic salt-wasting tubulopathies'.)
Initial diagnostic evaluation — Bartter and Gitelman syndromes are not common. Thus, in patients with unexplained hypokalemic metabolic alkalosis and normal or low blood pressure, it is crucial to exclude other, more common causes of these findings, in particular diuretic and/or laxative abuse and surreptitious vomiting.
The essential components of the evaluation include:
●A careful history, specifically asking about medications (especially diuretics and laxatives), psychiatric or eating disorders, excessive concern about body weight and shape, history of vomiting and/or diarrhea, and history of salt craving.
●A thorough physical examination, looking for orthostatic hypotension, salivary gland hypertrophy, dental erosions, lack of gag reflex, scarring of the dorsum of the hand, evidence of arthritis, and short stature.
●Measurement of spot urine chloride concentrations (or fractional chloride excretion), preferably in several different specimens, collected over several weeks. The spot urine chloride is usually consistently high (>20 mEq/L) in Bartter and Gitelman syndromes. It is typically consistently low (<20 mEq/L) with vomiting, and it fluctuates between low and high with intermittent (and surreptitious or denied) diuretic use.
If another explanation for the electrolyte abnormalities and clinical findings cannot be identified, then genetic testing should generally be performed to confirm the presence of mutations in one or more genes associated with Bartter syndrome or Gitelman syndrome. Genetic testing is increasingly available and can be definitive. (See 'Confirmation with genetic testing' below.)
Excluding other etiologies (differential diagnosis) — While Bartter and Gitelman syndromes are the most common Mendelian diseases that cause hypokalemic alkalosis with normal blood pressure, other rare inherited diseases may present with similar findings. More common causes of unexplained hypokalemia, metabolic alkalosis, and a normal or low blood pressure include surreptitious vomiting, surreptitious diuretic use, and, less commonly, both. In addition, several autoimmune diseases and therapeutic drugs may cause "acquired" Gitelman or Bartter syndrome.
Other genetic diseases
●Congenital chloride diarrhea – Some infants with failure to thrive and electrolyte disorders resembling Bartter syndrome have been found to have congenital chloride diarrhea, caused by mutations in a chloride bicarbonate exchanger (SLC26A3) expressed in the gastrointestinal tract [3,4]. In an infant, the watery diarrhea may be mistaken for urine saturating the diaper.
●Autosomal dominant hypocalcemia – Severe activating mutations in the calcium-sensing receptor (CASR gene) sometimes lead to hypokalemia and a Bartter-like phenotype, in addition to causing hypocalcemia. This syndrome was previously classified as Bartter syndrome type 5, but in view of the dominance of parathyroid gland dysfunction and resulting hypocalcemia, most classification schemes now define Bartter syndrome type 5 as caused by mutations in MAGED2. However, the use of the same term for two different Mendelian syndromes has engendered confusion, and some reports of patients with autosomal dominant hypocalcemia continue to describe them as having Bartter syndrome type 5.
The calcium-sensing receptor is expressed in parathyroid glands and also along the thick ascending limb and distal convoluted tubule. Activation in the thick ascending limb leads to increased intracellular calcium concentrations, which inhibit cyclic adenosine monophosphate and suppress the activity of the apical sodium-potassium-chloride transporter, NKCC2. Other effects of calcium-sensing receptor stimulation along the thick ascending limb may also contribute. This syndrome is discussed in detail elsewhere. (See "Disorders of the calcium-sensing receptor: Familial hypocalciuric hypercalcemia and autosomal dominant hypocalcemia".)
●Claudin 10 mutation – Claudin 10 is a tight junction protein involved in the selectivity of paracellular ion movement in the thick ascending limb. Mutations of claudin 10 can generate a hypokalemic, salt-losing nephropathy associated with metabolic alkalosis, hypocalciuria, and hypomagnesuria. Thus, it may mimic some features of Bartter or Gitelman syndrome. However, patients with this diagnosis develop hypercalcemia and hypermagnesemia, which are not present in Bartter and Gitelman syndromes .
●EAST syndrome and hypokalemia with sensorineural deafness – A basolateral potassium channel composed of two proteins, Kir4.1 (KCNJ10) and Kir5.1 (KCNJ16), is expressed in various nephron segments (proximal tubule, distal convoluted tubule), the central nervous system, and in the ear. Mutations in KCNJ10 cause the Epilepsy, Ataxia, Sensorineural Deafness (EAST) syndrome, and mutations in KCNJ16 cause hypokalemia with sensorineural deafness and mixed acid-base features [6,7]. These disorders are distinguished clinically from Bartter and Gitelman syndromes by the presence of characteristic extrarenal findings.
●Cystic fibrosis – Patients with cystic fibrosis can lose large quantities of sodium chloride-rich sweat, especially during hot summer months. Hypokalemia and metabolic alkalosis develop in some of these patients. Although many patients who develop this complication have established cystic fibrosis, sometimes hypovolemia, hypokalemia, and metabolic alkalosis are the presenting features of the disorder. In patients with still undiagnosed cystic fibrosis, this presentation may mimic Bartter or Gitelman syndrome and, in fact, is sometimes referred to as "pseudo-Bartter" syndrome [8-16].
In general, the spot urine chloride concentration should be low in such patients, reflecting appropriate urine chloride conservation in response to reduced extracellular fluid volume, and therefore should be easy to distinguish from Bartter or Gitelman syndrome. However, some mutations responsible for cystic fibrosis may also impair renal bicarbonate excretion by reducing pendrin activity (the bicarbonate-chloride exchanger) in the distal tubule (figure 1). Although it is possible that such a defect could increase the urine chloride concentration, this has not yet been documented in humans [16-18].
●Surreptitious vomiting – The physical examination and measurement of the urine chloride concentration will usually distinguish surreptitious self-induced vomiting from Bartter or Gitelman syndromes [19-23]. Chronic surreptitious vomiting may generate characteristic physical findings such as scarring on the dorsum of the hand (from insertion into the mouth), dental erosions caused by exposure to acid gastric secretions, and parotitis.
A helpful and simple laboratory test that can help establish a diagnosis of surreptitious vomiting is the measurement of a spot urine chloride concentration. Generally, in the absence of diuretics (see below) or an inherited or acquired renal tubule salt-wasting defect, a spot urine sodium and/or chloride concentration will reflect the patient's effective arterial blood volume (effective circulating volume). Although the spot urine sodium and the spot urine chloride are both usually <20 mEq/L when effective arterial blood volume is reduced, the presence of metabolic alkalosis can raise the urine sodium. Metabolic alkalosis causes the spot urine sodium concentration to fluctuate up and down, despite a persistently reduced effective arterial blood volume. This occurs because bicarbonate is intermittently excreted into the urine as a sodium salt, and at those times, the urine sodium concentration increases. By contrast, urine chloride concentration remains consistently low (<20 mEq/L) [19,21,24]. (See "Clinical manifestations and evaluation of metabolic alkalosis" and "Evaluation of the adult patient with hypokalemia".)
The urine chloride concentration is consistently low (<20 mEq/L) in patients with chronic vomiting as a result of hypovolemia and hypochloremia. By contrast, because of their underlying genetic defect in renal sodium and chloride reabsorption, patients with Bartter or Gitelman syndrome will typically have much higher urine chloride concentration (usually greater than 40 mEq/L), despite a relatively reduced effective arterial blood volume. In the steady state, patients with Bartter or Gitelman syndrome excrete the amount of sodium and chloride they ingest each day .
●Surreptitious diuretic use – Surreptitious loop and/or thiazide diuretic use (also called diuretic abuse) must always be considered in any patient with unexplained hypokalemia and metabolic alkalosis [21,25,26]. This is also true of children who may be secretly given diuretics by their parents or caregivers . In past years, secretly searching an inpatient's room for hidden drugs could lead to a definitive diagnosis, but legal concerns have largely ended this practice [28,29].
When loop and/or thiazide diuretics act on the renal tubules, the urine chloride concentration and fractional chloride excretion are generally high (ie, urine chloride >20 mEq/L). Then, when the diuretic effect ceases, the urine chloride concentration and fractional excretion fall sharply (ie, urine chloride <20 mEq/L), reflecting the patient's reduce extracellular fluid volume.
Thus, obtaining multiple urine specimens over several days and at different times of the day (because the diuretic effect will usually wax and wane) may provide strong evidence of surreptitious diuretic use. If the urine chloride is relatively high (>20 mEq/L) in some specimens but relatively low (<20 mEq/L) at other times, intermittent diuretic use is likely. Although urine assays for diuretics can be sent for confirmation, there have been no blinded studies of the reliability of these assays.
By contrast, the daily urine chloride excretion is equal to intake, and the spot chloride concentration is usually persistently >40 mEq/L in Bartter and Gitelman syndromes.
●Autoimmune disease – A phenotype resembling Gitelman syndrome can result from autoimmune diseases, most commonly in patients with Sjögren's disease–associated interstitial nephritis [30-34]. Renal tubular acidosis (RTA) has been reported in as many as 25 percent of cases of Sjögren's disease, often associated with hypokalemia and nephrocalcinosis. (See "Kidney disease in primary Sjögren's disease".)
However, some patients with Sjögren's disease and interstitial nephritis have hypokalemia and alkalosis without nephrocalcinosis, differentiating it from immune-mediated distal RTA [35,36]. Such patients may also have hypomagnesemia and hypocalciuria, thereby mimicking Gitelman syndrome. Two patients identified with this presentation were heterozygous for Gitelman syndrome-causing mutations in SLCA3, suggesting a combined etiology [37,38].
Other autoimmune diseases, such as systemic lupus erythematosus and scleroderma, may produce a similar phenotype [39,40].
●Side effects of drugs – An iatrogenic Bartter- or Gitelman-like phenotype may result from various drugs, most commonly antibiotics and antineoplastic agents. Hypokalemic alkalosis with hypomagnesemia and hypocalciuria has been described following cisplatin treatment , and the electrolyte abnormalities may persist following cessation of therapy. (See "Cisplatin nephrotoxicity".)
Aminoglycoside antibiotics, such as gentamicin, and colistin, which is often used to treat multidrug-resistant gram-negative infections, can also lead to hypokalemia and alkalosis . (See "Pathogenesis and prevention of aminoglycoside nephrotoxicity and ototoxicity" and "Manifestations of and risk factors for aminoglycoside nephrotoxicity".)
Distinguishing Bartter syndrome type 3 from Gitelman syndrome — Bartter syndrome type 3 and Gitelman syndrome usually present in adolescence or early adulthood. All of the other forms of Bartter syndrome present before birth, soon after birth, or in very early childhood.
Bartter syndrome type 3 and Gitelman syndrome are now usually identified and distinguished with genetic testing. (See 'Confirmation with genetic testing' below.)
Many of the biochemical and clinical features of Bartter syndrome type 3 and Gitelman syndrome overlap, and in the absence of genetic confirmation, it can be difficult to differentiate these disorders . Nonetheless, certain features are characteristic of one disorder or the other.
Measurement of urine calcium and magnesium excretion (with either a 24-hour urine collection or spot calcium/creatinine and magnesium/creatinine ratios) can help differentiate between Bartter syndrome type 3 and Gitelman syndrome. Urine calcium excretion is high-normal or elevated in Bartter syndrome type 3 but reduced with Gitelman syndrome (analogous to the effects of loop diuretics and thiazide diuretics on calcium excretion). Renal magnesium wasting and hypomagnesemia are present in Gitelman syndrome but are usually not seen with Bartter syndrome type 3. However, the range of normal values for these measurements is wide and varies with age and body weight. In addition, the urine calcium/creatinine ratio in a given individual can vary with the urine osmolality and, for unclear reasons, with both the urine and serum concentrations of magnesium [44,45].
In healthy adults, the upper limit for 24-hour urinary calcium excretion is approximately 275 mg (6.9 mmol) in females and 300 mg (7.5 mmol) in males. The upper range for the urine calcium/creatinine ratio in healthy adults is approximately 200 mg/g of creatinine (565 mmol/mol). The lower limit of normal for calcium excretion is unclear, and adult data are scarce. In one series of 29 adults with genetically confirmed Gitelman syndrome, a spot urine calcium/creatinine ratio of less than 44 mg/g had a sensitivity of 80 percent . A spot urine calcium/creatinine ratio of less than 70 mg/g (0.2 mmol/mmol) has been proposed to define hypocalciuria in adults when Gitelman syndrome is suspected .
The urine electrolyte response (for example the change in spot urine chloride concentration or fractional chloride excretion) to loop or thiazide diuretics has also been utilized as a diagnostic test in the past. Patients with Barter syndrome type 3 would be expected to exhibit a blunted response to loop diuretics and an enhanced response to thiazide diuretics. Patients with Gitelman syndrome should exhibit the opposite pattern of response [47-50]. However, a brisk diuretic response to these drugs can be dangerous in hypovolemic patients. For that reason, and because genetic testing is now readily available, diuretic response tests are generally no longer utilized.
The abnormal luminal membrane transporters in Gitelman syndrome (the sodium chloride cotransporter [NCC]) are shed into the urine in nanovesicles called urine exosomes. Reduced NCC activity in urine exosomes has been described in patients with Gitelman syndrome, and this may be utilized in the future as a diagnostic test .
Confirmation with genetic testing — Patients with unexplained hypokalemia, metabolic alkalosis, normal or low blood pressure, and persistently elevated urine chloride who have had other more common etiologies excluded have a presumed clinical diagnosis of Bartter or Gitelman syndrome. Such patients should be offered genetic testing to confirm the diagnosis [46,52].
Genetic analysis for many of the gene mutations leading to Bartter and Gitelman syndromes are commercially available. The National Center for Biotechnology Information (NCBI), a division of the National Institutes of Health, maintains a list of laboratories that offer genetic testing. Although the practicality of genetic testing had been limited by the large size of the involved genes, the multitude of recognized mutations, an absence of "hot spots" along the gene, intrafamilial heterogeneity, and high cost, most of these barriers have been overcome.
Gitelman syndrome and Bartter syndrome type 3 are autosomal recessive diseases, and it is likely that more than 1 percent of the general population are heterozygous for one of these disorders [53-56]; mutations that usually generate Gitelman syndrome are much more common than mutations generating Bartter syndrome type 3. These are recessive disorders, and heterozygotes are either normal or very subtly affected (eg, their average blood pressure and serum potassium levels are slightly lower than a well-matched control group) [54-57].
However, 15 to 20 percent of patients with clinically overt Gitelman syndrome have only one mutation that can be identified with contemporary available genetic techniques . This anomaly may be explained by the inability of the techniques to identify less common and/or occult mutations or genomic rearrangements of the of the SLC12A3 gene. Also, some mutations located in noncoding regulatory regions or in introns may not be identified yet may have pathogenicity. In one large cohort of such individuals, a substantial fraction of patients were found to have large genomic rearrangements in the other apparently "unaffected" allele . Thus, some apparently "heterozygous" patients may actually represent individuals with compound biallelic mutations, including one mutation that can be identified and one that cannot with available technology.
As genetic testing becomes more sophisticated, more patients with compound biallelic mutations may be identified. As an example, two thirds of patients in one study who had only one mutation identified using older methodology were found to have apparently pathogenic intron variations or previously unrecognized exon mutations using newer testing methods .
Alternatively, patients with Gitelman-like syndrome may have a mutation that does not involve the SLC12A3 gene. In one study, for example, several mutations of mitochondrial DNA were identified in 13 different families with Gitelman-like syndrome .
Goals of treatment — Medical therapy, which generally must be lifelong, is aimed at correcting or minimizing electrolyte abnormalities and extracellular volume depletion. The tubule transport defects that exist in patients with Bartter syndrome type 3 or Gitelman syndrome cannot be corrected except by kidney transplantation. However, kidney transplantation is not performed unless the patient develops severe chronic kidney disease. (See 'Kidney transplantation' below.)
Approach to therapy — Most patients with Bartter syndrome type 3 and Gitelman syndrome require a combination of treatments aimed at correcting their electrolyte and mineral abnormalities and hypovolemia. First-line therapy is always oral supplementation with generous doses of sodium chloride, potassium chloride, and when magnesium levels are reduced, magnesium salts.
Sodium and potassium supplements — Patients with Bartter and Gitelman syndromes and other sodium-wasting disorders often crave salt, and generous sodium chloride intake should be encouraged. Potassium chloride supplementation is also almost always necessary.
The typical required doses are:
●Sodium chloride tablets, 1 to 3 g two to four times daily (each 1 g tablet contains approximately 17 mEq of sodium chloride)
●Potassium chloride tablets, 20 to 40 mEq two to four times daily
Lower doses of sodium and potassium are generally needed in patients with impaired kidney function.
Magnesium supplementation — Severe hypomagnesemia may occur, usually in patients with Gitelman syndrome. In such patients, the resulting symptoms often dominate the clinical picture. Magnesium depletion and hypomagnesemia also worsen renal potassium wasting . (See "Hypomagnesemia: Clinical manifestations of magnesium depletion".)
Thus, magnesium supplementation is of critical importance for hypomagnesemic patients:
●When severe magnesium depletion exists (ie, serum magnesium less than or equal to 1 mg/dL [0.4 mmol/L or 0.8 mEq/L]), parenteral infusion with magnesium sulfate is generally required. Magnesium sulfate 4 to 8 grams (16 to 32 mmol of magnesium) is dissolved in 500 mL of either 5 percent dextrose in water or normal saline and infused over 8 to 12 hours. Some patients with persistent, severe hypomagnesaemia undergo placement of a central venous access for intermittent parenteral supplementation; however, longstanding indwelling central venous catheters may lead to venous stenosis and sepsis, and we believe that patients can generally be managed effectively without them. (See "Hypomagnesemia: Evaluation and treatment".)
●Less severe hypomagnesemia can be treated with oral supplementation. The oral dose of magnesium required by most adults with Gitelman syndrome ranges from 15 to 125 mol/day (table 2) . One study suggested that magnesium lactate was better tolerated and more effective than other oral magnesium salts . However, attaining adequate oral magnesium replacement can be difficult, because the large doses required almost invariably result in diarrhea and other gastrointestinal complaints. (See "Hypomagnesemia: Evaluation and treatment".)
An ongoing problem with all forms of magnesium supplementation is the fact that renal excretion increases markedly as the serum levels are increased.
Patients with insufficient response to supplementation — Patients with Bartter syndrome type 3 or Gitelman syndrome often have an inadequate response to oral sodium chloride, potassium chloride, and magnesium salt supplementation (ie, hypovolemia, hypokalemia, and/or hypomagnesemia).
In such patients, a number of other therapeutic options can be used:
●Potassium-sparing diuretics – Drugs that block distal sodium-potassium exchange (figure 2), such as spironolactone, eplerenone, or amiloride, are generally the next line of therapy when supplementation alone is insufficient. These drugs raise serum potassium and can partially correct metabolic alkalosis and hypomagnesemia [62-64]. They are generally prescribed in addition to, rather than instead of, supplementation. The antihypertensive effects of these medications may be limiting, particularly in patients with Bartter syndrome type 3 or Gitelman syndrome who often have low or low-normal blood pressure.
Spironolactone may be started at 100 mg daily and is often titrated, as needed, to doses of 300 mg daily. Alternatively, eplerenone, which has fewer endocrine-related side effects than spironolactone, may be started at 50 mg daily and can be titrated to levels of 150 mg daily. Another option for blocking distal tubule potassium loss is amiloride. This can be started at 10 mg daily and then titrated up to levels of 20 to 30 mg daily.
In a randomized crossover trial of 30 adult patients with Gitelman syndrome, addition of either eplerenone (150 mg daily) or amiloride (20 mg daily) to baseline electrolyte supplementation increased serum potassium by a mean of 0.15 and 0.19 mEq/L, respectively, and normalized potassium concentrations in 10 percent .
●Nonsteroidal antiinflammatory drugs (NSAIDs) – NSAIDs may be helpful in patients with Bartter syndrome type 3 and Gitelman syndrome; indomethacin is the NSAID typically used in such patients [62,64]. However, these drugs have significant gastrointestinal side effects and can reduce kidney function and even precipitate severe kidney injury. Thus, we add them when the combination of supplementation and a potassium-sparing diuretic produce insufficient results.
Systemic levels and urinary excretion of prostaglandins, especially prostaglandin E2 (PGE2), are generally very high in the Bartter syndrome subtypes that present before, or soon after, birth (types 1, 2, 4a, and 4b). Inhibitors of prostaglandin synthesis are a cornerstone of therapy for patients with these disorders. (See "Bartter and Gitelman syndromes in children: Clinical manifestations, diagnosis, and management", section on 'Management/therapy'.)
By contrast, systemic and urine prostaglandin levels are only slightly elevated, or not elevated at all, in patients with Bartter syndrome 3 and Gitelman syndrome. Nonetheless, NSAIDs may sometimes be helpful in patients with these disorders .
In the crossover trial mentioned above , indomethacin (75 mg daily) increased serum potassium by a mean of 0.38 mEq/L and normalized potassium concentrations in 20 percent of patients. However, glomerular filtration rate declined when taking indomethacin, and 20 percent of patients had to discontinue therapy due to gastrointestinal side effects .
●Angiotensin-converting enzyme (ACE) inhibitors – ACE inhibitors reduce the generation of angiotensin II, the major stimulus for the adrenal secretion of aldosterone. Thus, these drugs reduce aldosterone levels and therefore renal potassium loss. However, ACE inhibitors also reduce blood pressure, and this can be problematic for these patients who already have low or low-normal blood pressure. These classes of drugs should generally be added only after the other therapeutic efforts outlined above have been proven to be inadequate. If they are used, it is important to start with low doses and understand that the benefits may require several weeks to become apparent. Angiotensin receptor blockers (ARBs) should have similar efficacy but have not been well studied in these patients.
Multiple case reports and small series have found that captopril or enalapril does raise serum potassium in adult patients with a Bartter-like or Gitelman-like phenotype [65-68]. In one report, for example, seven such patients were treated with enalapril for three months; the mean serum potassium rose from 2.4 to 3.9 mEq/L, and hypomagnesemia and serum bicarbonate also improved in all patients .
Follow-up care and patient education — The follow-up care for patients with Bartter syndrome type 3 and Gitelman syndrome is based upon the severity of symptoms and which therapeutic interventions are being used. Once an adequate treatment strategy is established, most patients can be monitored every three to four months. Care should ideally be provided by specialized centers with expertise in renal tubular disorders in conjunction with the individual's primary care provider.
Patients with Bartter syndrome type 3 and Gitelman syndrome are occasionally diagnosed during childhood or adolescence. Transition to care by an adult nephrologist and internist presents a set of unique challenges. Patient education and communication and coordination between the pediatric and adult caregivers is imperative [69,70].
Patients should be provided with information regarding their underlying disease. This information can be accessed through a variety of means, including patient-led forums and web-based resources:
Pregnancy considerations — Most patients with Gitelman syndrome who become pregnant have successful pregnancies and deliver healthy infants, although their requirement for potassium and magnesium replacement usually increases during pregnancy [71-75]. NSAIDs are discouraged during pregnancy, and drugs that block the renin-angiotensin system (eg, ACE inhibitors and ARBs) are contraindicated. Thus, these agents should be discontinued in patients who are pregnant or attempting pregnancy.
Although there are no large-scale studies, smaller reports suggest that spironolactone, eplerenone, and/or amiloride can be safely used during pregnancy [73-75]. Thus, these agents should be used instead of NSAIDs, ACE inhibitors, and ARBs.
Kidney transplantation — Kidney transplantation corrects the transport abnormalities in Gitelman and Bartter syndromes, and recurrent disease after transplantation has not been described. It is typically only performed in patients with Bartter or Gitelman syndrome who develop end-stage kidney disease (ESKD), which may occur as a result of chronic volume depletion, electrolyte abnormalities, drug-related side effects, nephrocalcinosis, or a coexisting kidney disease [76-79].
Kidney transplantation is generally not performed to treat symptoms of Bartter or Gitelman syndrome. However, two cases have been described of preemptive bilateral nephrectomy and kidney transplantation for severe neonatal Bartter syndrome characterized by life-threatening episodes of hypokalemia and hypovolemia .
Experimental therapies — Many mutations generate disease because they cause sequestration of transporters or channels within intracellular compartments, so that they fail to correctly insert into the appropriate cell membrane. Molecular chaperones can sometimes improve the cellular transit of these proteins so they are successfully inserted into cell membranes, where they are at least partially functional.
The use of molecular chaperones, such as 4-phenylbutyrate, can improve the delivery and insertion of these fully or partially functional proteins into the cell membrane and partially rescue sodium chloride reabsorption in experimental models [80-82]. However, trials of such therapies in human patients are lacking.
GENETIC COUNSELING — Since the Gitelman syndrome mutation has a prevalence in the population of approximately 1 percent, there is a 1 in 100 chance that an unaffected (ie, "healthy") biological parent is a carrier (ie, heterozygote); if so, 50 percent of their children receive the mutated allele (this is a 0.5 percent or 1 in 200 chance). If the other biological parent has Gitelman syndrome (which is autosomal recessive), then each offspring has a 0.5 percent or 1 in 200 chance of also having Gitelman syndrome. Of course, approximately 50 percent of the offspring of an affected biological parent will be heterozygous for the mutation; although heterozygous individuals may have slightly lower blood pressure and potassium levels, they are not generally symptomatic.
SUMMARY AND RECOMMENDATIONS
●General – Bartter and Gitelman syndromes are inherited hypokalemic salt-losing (ie, salt-wasting) tubulopathies. They are generally inherited as autosomal recessive traits due to loss-of-function mutations (table 1). (See 'Introduction' above.)
●Diagnosis – Bartter or Gitelman syndrome should be suspected in any patient with unexplained hypokalemia, metabolic alkalosis, and a normal or low blood pressure. In such patients, it is crucial to exclude other more common causes of these findings, in particular diuretic and/or laxative abuse and surreptitious vomiting. In addition to a careful history and examination, measurement of spot urine chloride concentrations (or fractional chloride excretion) should be collected, preferably in several different specimens, over several weeks. The spot urine chloride is usually consistently high (>20 mEq/L) in Bartter and Gitelman syndromes. It is typically consistently low (<20 mEq/L) with vomiting, and it fluctuates between low and high with intermittent (and surreptitious or denied) diuretic use. If another explanation for the electrolyte abnormalities and clinical findings cannot be identified, then genetic testing should generally be performed to confirm the presence of mutations in one or more genes associated with Bartter syndrome or Gitelman syndrome. (See 'Diagnosis' above and 'Confirmation with genetic testing' above.)
●Distinguishing Bartter syndrome type 3 from Gitelman syndrome – Bartter syndrome type 3 and Gitelman syndrome usually present in adolescence or early adulthood. All of the other forms of Bartter syndrome present before birth, soon after birth, or in very early childhood. Bartter syndrome type 3 and Gitelman syndrome are now usually identified and distinguished with genetic testing. Nonetheless, certain features are characteristic of one disorder or the other: Urine calcium excretion is high-normal or elevated in Bartter syndrome type 3 but reduced with Gitelman syndrome (analogous to the effects of loop diuretics and thiazide diuretics on calcium excretion), and renal magnesium wasting and hypomagnesemia are present in Gitelman syndrome but are usually not seen with Bartter syndrome type 3. (See 'Distinguishing Bartter syndrome type 3 from Gitelman syndrome' above.)
●Management – Medical therapy, which generally must be lifelong, is aimed at correcting or minimizing electrolyte abnormalities and extracellular volume depletion. Most patients will need a combination of treatments. (See 'Management' above.)
•Sodium and potassium supplements (first line) – Patients with Bartter syndrome type 3 or Gitelman syndrome require oral supplementation with generous doses of sodium chloride, potassium chloride, and when magnesium levels are reduced, magnesium salts. Electrolyte supplementation is first-line therapy. The typical required doses are sodium chloride tablets, 1 to 3 g two to four times daily; potassium chloride tablets, 20 to 40 mEq two to four times daily; and, if magnesium supplementation is needed, 15 to 125 mmol/day (table 2).
•Potassium-sparing diuretics (second line) – Patients who have an inadequate response to oral sodium chloride, potassium chloride, and if needed, magnesium salt supplementation, we suggest adding an agent that inhibits distal sodium-potassium exchange (figure 2), such as spironolactone, eplerenone, or amiloride, rather than other secondary options such as nonsteroidal antiinflammatory drugs (NSAIDs) or angiotensin-converting enzyme (ACE) inhibitors (Grade 2C). Spironolactone may be started at 100 mg daily and is often titrated, as needed, to doses of 300 mg daily. Eplerenone may be started at 50 mg daily and can be titrated to levels of 150 mg daily. Amiloride can be started at 10 mg daily and then titrated up to 20 to 30 mg daily.
•Third-line options – In patients who have an inadequate response to the combination of electrolyte supplementation and a potassium-sparing diuretic, options for additional therapy include NSAIDs and ACE inhibitors. The choice should be individualized. NSAIDs have significant gastrointestinal side effects and can reduce kidney function and even precipitate severe kidney injury. ACE inhibitors reduce blood pressure, and this can be problematic for these patients who already have low or low-normal blood pressure.
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