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Gitelman syndrome is a salt-losing tubulopathy caused by mutation of genes encoding sodium chloride (NCCT) and magnesium transporters in the thiazide-sensitive segments of the distal nephron. It is characterized by renal potassium wasting, hypokalemia, metabolic alkalosis, hypocalciuria, hypomagnesemia, and hyperreninemic hyperaldosteronism. Gitelman syndrome is also referred to as familial hypokalemia-hypomagnesemia. This activity highlights the role of the interprofessional team in managing patients with Gitelman syndrome to provide the best patient outcomes. Objectives: Review the genetic mutations in the etiology of Gitelman syndrome. Describe the pathophysiology of Gitelman syndrome. Identify the correction of electrolyte abnormalities in the treatment of Gitelman syndrome. Summarize the importance of collaboration and communication among the interprofessional team to enhance outcomes for patients affected by Gitelman syndrome. Access free multiple choice questions on this topic.

Gitelman syndrome (GS) is an autosomal recessive, salt-losing tubulopathy characterized by renal potassium wasting, hypokalemia, metabolic alkalosis, hypocalciuria, hypomagnesemia, and hyperreninemic hyperaldosteronism.[1] Gitelman syndrome is also referred to as familial hypokalemia-hypomagnesemia. GS is perhaps the most common inherited tubulopathy, with a prevalence of 1 to 10 per 40,000 and potentially more in Asia.[2] The disorder is caused by biallelic inactivating mutations.[3][4] Both hypomagnesemia and hypocalciuria are highly suggestive of the clinical diagnosis of GS; however, hypomagnesemia may be absent, and hypocalciuria is highly variable.[5][6] In some cases, it becomes difficult to use clinical and biological features to distinguish GS from other salt-losing nephropathies. Genetic testing is increasingly becoming more available for GS; however, it remains expensive. GS has been considered a benign tubulopathy for a long time, usually presenting during adolescence or adulthood. Often, the condition may remain asymptomatic or present with mild or nonspecific symptoms. However, studies have challenged this idea by emphasizing the disorder's phenotypic variation and potential severity.[7] Cruz et al. argued that GS is associated with a significantly reduced quality of life, similar to patients with congestive heart failure or diabetes.[8] Severe presentation, such as early-onset (before age six years), chondrocalcinosis, growth retardation, tetany, seizures, rhabdomyolysis, and ventricular arrhythmia, have been described.[9][10] Of note, in many cases of severe manifestation, the diagnosis of GS was made on a clinical rather than a genetic basis, potentially creating confusion with similar disorders. Many treatment options are available; however, evidence supporting the tolerability, efficacy, and safety of these management options (either as a standalone therapy or as an adjunct) in GS patients is limited.

Severe presentation, such as early-onset (before age six years), chondrocalcinosis, growth retardation, tetany, seizures, rhabdomyolysis, and ventricular arrhythmia, have been described.[9][10] Of note, in many cases of severe manifestation, the diagnosis of GS was made on a clinical rather than a genetic basis, potentially creating confusion with similar disorders. Many treatment options are available; however, evidence supporting the tolerability, efficacy, and safety of these management options (either as a standalone therapy or as an adjunct) in GS patients is limited. Information regarding the long-term outcomes of Gitelman syndrome is lacking. Long-term consequences such as chronic kidney disease, chondrocalcinosis, cardiac arrhythmias, secondary hypertension, and treatment during pregnancy need to be considered. Much insight has been gained since its genetic elucidation in 1996, yet mystery still surrounds GS. More efforts are required to substantiate issues, such as diagnostic criteria and methods, phenotypic heterogeneity, clinical workup and follow-up, clinical manifestations, nature and severity of the biochemical abnormalities, and treatment and long-term consequences of the disease.

Gitelman syndrome is an autosomal recessive tubular disorder caused by mutations of some of the genes encoding the sodium, chloride, and magnesium carriers in the apical membrane of the distal convoluted tubule, which is responsible for 7% to 10% of tubular absorption of electrolyte. Magnesium channels are also down-regulated in the duodenal cells. The mutations involve: SLC12A3 gene which encodes the thiazide-sensitive sodium chloride cotransporter (NCCT).[11] TRPM6 (cation channels subfamily 6 of the protein Claudin 16) gene handles the distal tubular magnesium transport.[12][13] The disease is a manifestation of a biallelic inactivating mutation in the SLC12A3 gene that encodes the thiazide-sensitive sodium chloride cotransporter (NCC) present in the apical membrane of cells on the distal convoluted tubule.[14] More than 350 mutations in SLC12A3 have been identified in these patients.[3][4] The majority of patients are heterozygous for SLC12A3 mutations, but many GS patients are found to have only a single SLC12A3 mutation. A GS-like phenotype, including hypocalciuria and hypomagnesemia, has also been seen with mutations in the CLCNKB gene, which encodes the chloride channel ClC-Kb. This is the cause of classic Bartter syndrome (cBS). The presence of ClC-Kb in the distal convoluted tubule explains the phenotypic overlap with GS.[15][16] Phenotypic variability is also seen in genetically confirmed GS patients, such as patients with identical SLC12A3 mutations.[17] A combination of modifier genes, sex, genotype, compensatory mechanisms, environmental factors, and dietary habits could be involved in such variability.[18]

Gitelman syndrome is a rare disorder, and its prevalence is estimated at 25 cases per one million population. However, the prevalence of heterozygous persons is approximately 1% in the white population.[19] Though rare, Gitelman syndrome is the most common inherited salt-losing renal tubulopathy.[20]

The handling of sodium, chloride, magnesium, calcium, and potassium ions by the kidney is a complex process and depends on the molecular activity of various renal tubular channels. The distal convoluted tubular channels play an important role in handling the ions. Alterations in the activity of these channels result in a variable degree of electrolyte abnormalities. There is also significant phenotypic variability in the affected members of the family with identical genetic defects.[20] SLC12A3 encodes the NCCT channel in the apical membrane of the first part of the DCT. NCCT helps absorb sodium and chloride ions from the tubular lumen. Mutations in the SLC12A3 gene result in loss of function of NCCT, which in turn results in increased sodium and chloride delivery to the collecting tubule and volume contraction. This leads to increased renin and aldosterone secretion. Through its effect on the epithelial sodium channels (ENaC) in the collecting tubule, aldosterone increases sodium reabsorption along with increased excretion of potassium and hydrogen ions. These effects cause hypokalemia and metabolic alkalosis. A minority of Gitelman syndrome patients do not have a mutation in SLC12A3 but have a mutation in the CLCNKB gene that encodes the chloride channel in the basolateral membrane (CLC-kb).[19] The relationship between calcium and magnesium is complex and still not well defined. TRPM6 magnesium-permeable channels are located at the apical domain of the distal convoluted tubules and brush border of the duodenal magnesium-transporter cells. In Gitelman syndrome, there is a reduced expression of TRPM6 channels. Downregulation of these channels in the distal tubule and duodenum results in urinary and intestinal magnesium wasting, leading to hypomagnesemia in Gitelman syndrome.[20]

The relationship between calcium and magnesium is complex and still not well defined. TRPM6 magnesium-permeable channels are located at the apical domain of the distal convoluted tubules and brush border of the duodenal magnesium-transporter cells. In Gitelman syndrome, there is a reduced expression of TRPM6 channels. Downregulation of these channels in the distal tubule and duodenum results in urinary and intestinal magnesium wasting, leading to hypomagnesemia in Gitelman syndrome.[20] Hypomagnesemia can also impair the function of calcitropic hormones, and there is an inverse association between ionized calcium, parathyroid hormone (PTH), and calcitriol. This is down-regulated in these patients and reduces skeletal sensitivity to PTH and impaired intestinal calcium transport despite normal calcitriol levels. This blunted response possibly also explains the lack of hypercalcemic response to hypocalciuria in these patients. Calcium pool studies show hypomagnesemia-induced lower intestinal and skeletal sensitivity to the calcitropic hormones. Compared to thiazide-treated subjects, the Gitelman syndrome patients do not show changes in bone mineral content related to hypocalciuria. The normal serum phosphate and fractional phosphate excretion in these patients suggest a lack of parathyroid hyperfunction. In addition, metabolic alkalosis plays a vital role in calcium abnormalities in these patients.[21] Hypomagnesemia may also reduce pyrophosphatase activity, which could promote pyrophosphate crystallization in joints, causing joint pains and chondrocalcinosis.[22] The increased sodium chloride load in the collecting duct stimulates the aldosterone-driving transcellular sodium across the epithelial sodium channels of the principal cell luminal membrane. This tubular sodium transport generates an electronegative transmembrane voltage that is neutralized either by chloride-transmembrane diffusion across the paracellular pathway or by a coupled potassium ion and hydrogen ion cellular secretion, eventually resulting in metabolic alkalosis and hypokalemia. In addition, the low effective extracellular volume activates the renin-angiotensin-aldosterone system and the effect of aldosterone results in potassium secretion through apical potassium channels.[23]

The increased sodium chloride load in the collecting duct stimulates the aldosterone-driving transcellular sodium across the epithelial sodium channels of the principal cell luminal membrane. This tubular sodium transport generates an electronegative transmembrane voltage that is neutralized either by chloride-transmembrane diffusion across the paracellular pathway or by a coupled potassium ion and hydrogen ion cellular secretion, eventually resulting in metabolic alkalosis and hypokalemia. In addition, the low effective extracellular volume activates the renin-angiotensin-aldosterone system and the effect of aldosterone results in potassium secretion through apical potassium channels.[23] Both the overstimulation of the renin-angiotensin system in response to increased delivery of distal tubular sodium at the macular zone and the stimulation of baroreceptors from hypovolemia may result in polydipsia.[24] In Gitelman syndrome, there is increased passive calcium reabsorption in the proximal convoluted tubule, which is likely a reason for hypocalciuria.

The clinical manifestations of Gitelman syndrome are highly variable and depend on the age at presentation, the severity of symptoms, and biochemical abnormalities. Patients often are asymptomatic and noted to have hypokalemia on routine laboratory testing or may have nonspecific symptoms of fatigue and generalized malaise. Some patients may experience muscle cramps. Many patients have low blood pressure. Tetany and hypokalemic paralysis have been reported, the latter being more common in Asian populations. In addition to hypokalemia, metabolic alkalosis and hypocalciuria are common. Hypomagnesemia can be seen in many but not in all cases. The biochemical findings are similar to an individual taking a thiazide diuretic.[25] GS generally presents in adolescents and adults but may also be found in children, even in the neonatal period.[10][26] The main clinical features and manifestations indicating a diagnosis of GS include the following: Salt craving (i.e., preference for salty food or a salted treat during childhood) Muscle weakness, fatigue, limited sports performance or endurance Episodes of fainting, cramps, tetany, paresthesia, carpopedal spasms Growth retardation, pubertal delay, short stature Thirst or abnormal drinking behavior Episodes of abdominal pain Dizziness, vertigo, polyuria, nocturia, joint pain, palpitations, and visual problems may be reported in adults. Increased thirst and salt cravings were noted in three-fourths of patients. Many patients prefer pickle brine, salted cucumbers, oranges, and lemons. Some patients may have joint pains. Also, some cases of chondrocalcinosis and nephrocalcinosis have been reported.[27] Cardiac arrhythmias are common, with palpitations in about 60% of patients and prolonged QTc in about 50%, but sudden death is rare. The classic electrocardiographic manifestations of hypokalemia and hypomagnesemia (U wave greater than 1 mm, ST depression greater than 0.5 mm, flattened T waves) were not observed in patients with Gitelman syndrome.[28]

Clinically, most patients have unremarkable physical examinations or have subtle clinical findings. Patients have normal or low blood pressure. There could be a bunch of lab findings. The serum potassium is low (hypokalemia). Serum magnesium may be low (hypomagnesemia) or normal. The serum bicarbonate is usually high in keeping with (metabolic alkalosis). Plasma renin and aldosterone are high (hyper-reninemic hyperaldosteronism). The urinary calcium excretion is low (hypocalciuria).[29][30] The lab findings may mimic thiazide diuretic use, and a urinary diuretic screen may be helpful in difficult cases in the absence of family history. Increased urinary sodium and chloride excretion in response to thiazide diuretics help distinguish Gitelman syndrome patients with a blunted chloride fractional excretion.[31] Laxative abuse is another differential diagnosis to consider in patients with hypokalemia. However, there can be metabolic acidosis with a urine potassium/creatinine ratio of less than 1.5.[32] The proposed biochemical criteria for suspecting Gitelman syndrome in a patient include the following: Documented chronic hypokalemia (2.0 mmol/mmol [>18 mmol/g]) in the absence of potassium-lowering drugs Metabolic alkalosis Hypomagnesemia (4%)[33] Hypocalciuria (spot urine, calcium-creatinine ratio 0.5% Normal or low blood pressure Normal renal ultrasound with the absence of nephrocalcinosis or renal abnormalities If plasma electrolytes are within normal ranges or near normal in a patient taking magnesium or potassium supplements or both, these should be stopped at least 48 hours before to unmask the abnormalities. Concomitantly, plasma and urine samples should be obtained. No evidence suggests the need for 24-hour urine collection. Usually, spot urine samples are sufficient to establish the diagnosis. Arguments that go against the diagnosis of GS include the following: Family history of renal malformations or any kidney disease dominantly transmitted A history of polyhydramnios or hyperechogenic fetal kidneys The presence of a renal malformation, such as unilateral kidneys or polycystic kidneys A long history of hypertension Chronic use of diuretics or laxatives Lack of hypokalemia or inconsistent hypokalemia in the absence of substitutive therapy Presentation before age three years Manifestations of increased extracellular fluid volume

A history of polyhydramnios or hyperechogenic fetal kidneys The presence of a renal malformation, such as unilateral kidneys or polycystic kidneys A long history of hypertension Chronic use of diuretics or laxatives Lack of hypokalemia or inconsistent hypokalemia in the absence of substitutive therapy Presentation before age three years Manifestations of increased extracellular fluid volume Of note, arterial hypertension does not rule out the diagnosis of GS in adults.[34][35] The definite diagnosis of GS rests on genetic testing and is proven by identifying biallelic inactivating mutations in the SLC12A3 gene. As genetic testing has rapidly progressed, hydrochlorothiazide testing is no longer considered a diagnostic tool in GS due to the related risks, such as when used to distinguish from Bartter syndrome, there can be acute volume depletion in patients with the loop of Henle defect. Another such limitation is in children or patients on medications that affect tubular transport processes. Generally, hydrochlorothiazide may also cause acute interstitial nephritis and hypersensitivity reactions. A renal biopsy is generally not needed unless there is a significant complication, such as heavy proteinuria.

Treatment is symptomatic, which is supplementation with potassium and magnesium. Correction of hypokalemia may require large doses of potassium chloride. It is crucial to use potassium chloride and not other salts linked with anions, such as gluconate or aspartate, as these may worsen the associated metabolic alkalosis. The poor gastric tolerability of potassium chloride (KCL) is often the primary issue.[20] It is best to avoid taking potassium supplements on an empty stomach to avoid gastric issues. KCl supplements can be administered as syrup, in water, or in a slow-release formulation, according to the patient’s preference. The dose will be titrated individually, knowing the maintenance dose may be high. A reasonable target for potassium is 3.0 mmol/l. Intravenous KCl may be necessary for certain situations, such as when the patient cannot take oral drugs or when the potassium deficit is severe, leading to cardiac arrhythmias, respiratory failure, quadriplegia, or rhabdomyolysis.[36] In cases of persistent or symptomatic hypokalemia, despite supplementation or when adverse effects are unacceptable, renin-angiotensin system blockers, potassium-sparing diuretics, or nonsteroidal anti-inflammatory drugs (NSAIDs), such as indomethacin, or a combination of these have been recommended. Magnesium replacement by magnesium sulfate or oxide may result in diarrhea. Magnesium chloride is better tolerated than sulfate or oxide. It can be given at a daily dosage of 4 mg/kg to 5 mg/kg per day, divided into four to six doses to avoid diarrhea.[37][38] In the presence of hypomagnesemia, magnesium replacement should be considered first because the repletion of magnesium will facilitate potassium repletion, reducing the risk of tetany and other such complications.[39] A target magnesium level of 0.6 mmol/l (1.46 mg/dl) is recommended. Oral administration of magnesium supplements is preferred. All magnesium salts are effective; however, their bioavailability is highly variable, causing osmotic diarrhea at higher doses.[40]

Magnesium replacement by magnesium sulfate or oxide may result in diarrhea. Magnesium chloride is better tolerated than sulfate or oxide. It can be given at a daily dosage of 4 mg/kg to 5 mg/kg per day, divided into four to six doses to avoid diarrhea.[37][38] In the presence of hypomagnesemia, magnesium replacement should be considered first because the repletion of magnesium will facilitate potassium repletion, reducing the risk of tetany and other such complications.[39] A target magnesium level of 0.6 mmol/l (1.46 mg/dl) is recommended. Oral administration of magnesium supplements is preferred. All magnesium salts are effective; however, their bioavailability is highly variable, causing osmotic diarrhea at higher doses.[40] Organic salts, such as aspartate, citrate, and lactate, have a higher bioavailability than magnesium oxide and hydroxide.[40] Magnesium chloride (MgCl2) will also compensate for the urinary loss of chloride. The starting dose is usually 300 mg/day (12.24 mmol) of elemental magnesium. For children, this dose is 5 mg/kg (0.2 mmol/kg) in slow-release tablets whenever possible. Intravenous infusion of magnesium should be reserved for the following situations: Patients with acute or severe complications of hypomagnesemia, such as tetany or cardiac arrhythmias Digestive intolerance to oral supplements In cases of acute tetany, intravenous administration of 20% MgCl2 (0.1 mmol Mg/kg per dose) is recommended and can be repeated every 6 hours. If tolerated, consider aldosterone antagonists, potassium-sparing diuretics like amiloride (5 mg to 10 mg per day), and spironolactone (200 mg to 300 mg per day), as well as inhibitors of the renin-angiotensin system. However, these agents may not be well-tolerated in patients with low blood pressure and should be administered with caution.[41] Because GS is due to a primary pathology in a sodium chloride cotransporter, NaCl intake should be strongly advised. Patients should also be encouraged to follow their salt cravings. The potential advantage of pharmacological NaCl supplementation, in addition to liberal salt intake, has not been tested.

The differential diagnosis of Gitelman syndrome includes various disorders and salt-losing tubulopathies. The important conditions to be considered are: Bartter syndrome Pseudo Bartter-Gitelman syndrome Surreptitious vomiting[42] Laxative abuse Licorice Congenital chloride diarrhea Labs are essential in differentiating the disorders. Both serum and urine electrolytes should be carefully examined.

In the near future, whole-exome and whole-genome sequencing, followed by targeted analysis, are more likely to become the genetic tests of preference. Genetic counseling and informed consent should always precede these genetic screening tests.[43] With the increasing availability of functional studies and new-population–based genetic data, the classification of variants may be changing. The perception about previous disease-associated genetic variants may change, their pathogenicity could be challenged, and, conversely, variants with unknown significance may be confirmed as pathogenic.[44]

The prognosis of patients with Gitelman syndrome is excellent, except a few patients may be at risk for cardiac arrhythmias.[45] However, the severity of fatigue could seriously affect some patients in their daily activities. Worsening of this condition and progression to renal insufficiency is excessively rare in GS.

Following are some of the rare but significant complications that could potentially occur in patients with Gitelman syndrome: Seizures Tetany Ventricular tachycardia Rhabdomyolysis Blurred vision Pseudotumor cerebri Sclerochoroidal calcifications

Genetic counseling should be offered to patients with Gitelman syndrome and also to parents having a child with GS. This counseling should also include testing of parents, partners, and siblings. Prenatal diagnosis is technically feasible when two pathogenic SLC12A3 mutations are identified. Generally, these tests are not done because of the good prognosis in most GS patients. In severe cases, the potential use of these predictive tests may be potentially discussed.

Diuretic abuse and surreptitious vomiting are important conditions to consider in the differential diagnosis of patients presenting with hypokalemia.[42] The risk of transmitting the disease genetically to offspring is 25%.[46]

Gitelman syndrome is a rare genetic disorder and is best managed by an interprofessional team that includes a nephrologist, cardiologist, internist, primary care physician, and mid-level providers (NP and PA). The treatment is based on symptoms, and most patients require correction of hypokalemia. The nurse and pharmacist should educate the patient on compliance with therapy; otherwise, there is a risk of developing arrhythmias. The prognosis for most patients is excellent.[47][48]