Gitelman syndrome | |
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Other names | Primary renal tubular hypokalemic hypomagnesemia with hypocalciuria |
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A model of transport mechanisms in the distal convoluted tubule. Sodium chloride (NaCl) enters the cell via the apical thiazide-sensitive NCC and leaves the cell through the basolateral Cl− channel (ClC-Kb), and the Na+/K+-ATPase. Indicated also are the recently identified magnesium channel TRPM6 in the apical membrane, and a putative Na/Mg exchanger in the basolateral membrane. These transport mechanisms play a role in familial hypokalemia-hypomagnesemia or Gitelman syndrome. | |
Specialty | Nephrology ![]() |
Causes | Mutations in SLC12A3, CLCKNB, MT-TI, MT-TF |
Gitelman syndrome (GS) is an autosomal recessive kidney tubule disorder characterized by low blood levels of potassium and magnesium, decreased excretion of calcium in the urine, and elevated blood pH. [2] It is the most frequent hereditary salt-losing tubulopathy. Gitelman syndrome is caused by disease-causing variants on both alleles of the SLC12A3 gene . The SLC12A3 gene encodes the thiazide-sensitive sodium-chloride cotransporter (also known as NCC, NCCT, or TSC), which can be found in the distal convoluted tubule of the kidney. [2] [3]
Disease-causing variants in SLC12A3 lead to a loss of NCC function, i.e., reduced transport of sodium and chloride via NCC. The effect is an electrolyte imbalance similar to that seen with thiazide diuretic therapy (which causes pharmacological inhibition of NCC activity). [4]
Gitelman syndrome was formerly considered a subset of Bartter syndrome until the distinct genetic and molecular bases of these disorders were identified.
Affected individuals may not have symptoms in some cases. [2] Symptomatic individuals present with symptoms almost identical to those of patients who are on thiazide diuretics, given that the affected transporter is the target of thiazides. [5]
Clinical signs of Gitelman syndrome include a high blood pH in combination with low levels of chloride, potassium, and magnesium in the blood and decreased calcium excretion in the urine. [2] In contrast to people with Gordon's syndrome, those affected by Gitelman syndrome generally have low or normal blood pressure. Individuals affected by Gitelman syndrome often complain of severe muscle cramps or weakness, numbness, thirst, waking up at night to urinate, salt cravings, abnormal sensations, chondrocalcinosis, or weakness expressed as extreme fatigue or irritability. [2] Though cravings for salt are most common and severe, cravings for sour foods (e.g. vinegar, lemons, and sour figs) have been noted in some persons affected. [6] More severe symptoms such as seizures, tetany, and paralysis have been reported. [2] Abnormal heart rhythms and a prolonged QT interval can be detected on electrocardiogram [2] and cases of sudden cardiac death have been reported due to low potassium levels. Quality of life is decreased in Gitelman syndrome [7]
Phenotypic variations observed among patients probably result from differences in their genetic background and may depend on which particular amino acid in the NCCT protein has been mutated. A study by Riviera-Munoz et al. identified a subset of individuals with Gitelman syndrome with a severe phenotypic expression. The clinical manifestations observed in this group were neuromuscular manifestations, growth retardation, and ventricular arrhythmias. The patients were mostly male and were found to have at least one allele of a splice defect on the SLC12A3 gene. [8]
Gitelman syndrome is caused by disease-causing variants on both alleles of the SLC12A3 gene, which encodes NCC, the sodium-chloride cotransporter. The sodium-chloride cotransporter is a protein made up of 1021 amino acids and 12 transmembrane domains. [9] A large number of disease-causing variants throughout the SLC12A3 gene have been reported, including missense, nonsense, frame-shift, splice-site and intronic variants. [10] [11] In 2012, more than 180 mutations of this transporter protein had already been described. [2]
The sodium-chloride cotransporter is a protein located in the cell membrane. It participates in the control of ion homeostasis at the distal convoluted tubule of the nephron. Thus, loss of NCC function reduces sodium and chloride reabsorption in the distal convoluted tubule. This can lead to a lower blood pressure in these patients. [12]
Loss of NCC function has several other effects. Loss of SLC12A3 has been shown to lead to a shorter distal convoluted tubule, at least in mice. [13] Therefore, other functions of the distal convoluted tubule might be perturbed as well. This is one of the possible reasons that magnesium reabsorption is reduced in patients, often leading to a low level of magnesium in the blood. [14]
Secondly, processes in the distal convoluted tubule itself are altered as well. For instance, transcellular calcium reabsorption is increased. This has been suggested to be the result of a putative basolateral Na+/Ca2+ exchanger and apical calcium channel. [15] Furthermore, continued action of the basolateral Na+/K+-ATPase might create an electrical gradient favourable for the reabsorption of divalent cations by secondary active transport. This is another mechanism that might be responsible for decreased magnesium reabsorption. [14]
Another effect of the inactivated sodium-chloride cotransporter is the subsequent activation of the renin-angiotensin aldosterone system (RAAS). RAAS activation is a byproduct of the failure of the distal convoluted tubule in reabsorbing electrolytes, specifically sodium and chloride leading to cellular dehydration. RAAS attempts to compensate for this dehydration resulting in low serum blood potassium. [16]
Some patients have symptoms that fit with a diagnosis of Gitelman syndrome, while a genetic defect in the SLC12A3 gene cannot be found. In these cases, a different genetic defect can sometimes be identified, although some cases remain idiopathic. [17] [18]
Diagnosis of Gitelman syndrome can be confirmed after eliminating other common pathological sources of hypokalemia and metabolic alkalosis. [16] A complete metabolic panel (CMP) or basic metabolic panel (BMP) can be used to evaluate serum electrolyte levels. Electrolyte measurement and aldosterone levels can be done via urine. [16] The pathognomonic clinical markers include low serum levels of potassium, sodium, chloride, and magnesium in the blood as a result of urinary excretion. [19] Urinary fractional excretion potassium is high or inappropriately normal in the context of hypokalaemia, and high levels of urinary sodium and chloride are observed. Other clinical indicators include elevated serum renin and aldosterone in the bloodstream, and metabolic alkalosis. The symptomatic features of this syndrome are highly variable ranging from asymptomatic to mild manifestations (weakness, cramps) to severe symptoms (tetany, paralysis, rhabdomyolysis). [16] Symptom severity is multi-factorial, with phenotypic expression varying amongst individuals within the same family. Genetic testing is another measure of identifying the underlying mutations which cause the pathologic symptoms of the disease. This mode of testing is available at select laboratories. [16]
When only one pathogenic variant is found with regular diagnostics, screening of SLC12A3 introns can be considered. [11]
Work-up to exclude the differential diagnosis of the electrolyte abnormalities is key. [20] [21]
Many diseases (both genetic and non-genetic) can give symptoms which are very similar to Gitelman syndrome. The following are some examples, as well as examples of how they can differ from classic Gitelman syndrome.
To treat the symptoms related to the electrolyte abnormalities, supplementation is often needed. Dietary modification of a high salt diet incorporated with [16] potassium and magnesium supplementation to normalize blood levels is the mainstay of treatment. [2] Large doses of potassium and magnesium are often necessary to adequately replace the electrolytes lost in the urine. [2] Diarrhea is a common side effect of oral magnesium which can make replacement by mouth difficult but dividing the dose to 3-4 times a day is better tolerated. [2] Severe deficits of potassium and magnesium require intravenous replacement. Aldosterone antagonists (such as spironolactone or eplerenone) or epithelial sodium channel blockers such as amiloride have also been suggested as possible treatments, because they decrease urinary wasting of potassium. However, a consensus expert statement from 2017 warns that such drugs should only be used with caution in Gitelman syndrome because of the possible side effects (e.g., aggravated sodium depletion). [21]
Most asymptomatic individuals with Gitelman syndrome can be monitored without medical treatment. [2]
In patients with early onset of the disease such as infants and children, indomethacin is the drug of choice utilized to treat growth disturbances. [16] Indomethacin in a study by Blanchard et al. 2015 was shown to increase serum potassium levels, and decrease renin concentration. Adverse effects of indomethacin include a decrease in the glomerular filtration rate, and gastrointestinal disturbances. [24] Therefore, these drugs should also be used only with caution in Gitelman syndrome. [21]
Cardiac evaluation is promoted in the prevention of dysrhythmias and monitoring of QT interval activity. [16] Medications that extend or prolong the QT interval (macrolides, antihistamines, beta-2 agonists) should be avoided in these patients to prevent cardiac death. [3]
Estimates of the prevalence of Gitelman syndrome range from 1 in 80,000 to 1 in 500 people, depending on the population. [25] [26] The ratio of men to women affected is 1:1. This disease is encountered typically after the 1st decade of life, i.e., during adolescence or adulthood. However, it can occur in the neonatal period. Heterozygous carriers of the SLC12A3 gene mutations are 1% of the population. [16] A person with Gitelman syndrome has a low probability of passing the disease to their offspring. This chance is roughly 1 in 400, unless they are both carriers of the disease. [9]
The condition is named for Hillel Jonathan Gitelman (1932– January 12, 2015), an American nephrologist working at University of North Carolina School of Medicine. [27] [28] He first described the condition in 1966, after observing a pair of sisters with the disorder. [29] Gitelman and his colleagues later identified and isolated the gene responsible (SLC12A3) by molecular cloning. [30]
The distal convoluted tubule (DCT) is a portion of kidney nephron between the loop of Henle and the collecting tubule.
Hypokalemia is a low level of potassium (K+) in the blood serum. Mild low potassium does not typically cause symptoms. Symptoms may include feeling tired, leg cramps, weakness, and constipation. Low potassium also increases the risk of an abnormal heart rhythm, which is often too slow and can cause cardiac arrest.
Loop diuretics are pharmacological agents that primarily inhibit the Na-K-Cl cotransporter located on the luminal membrane of cells along the thick ascending limb of the loop of Henle. They are often used for the treatment of hypertension and edema secondary to congestive heart failure, liver cirrhosis, or chronic kidney disease. While thiazide diuretics are more effective in patients with normal kidney function, loop diuretics are more effective in patients with impaired kidney function.
The syndrome of inappropriate antidiuretic hormone secretion (SIADH), also known as the syndrome of inappropriate antidiuresis (SIAD), is characterized by a physiologically inappropriate release of antidiuretic hormone (ADH) either from the posterior pituitary gland, or an abnormal non-pituitary source. Unsuppressed ADH causes a physiologically inappropriate increase in solute-free water being reabsorbed by the tubules of the kidney to the venous circulation leading to hypotonic hyponatremia.
Amiloride, sold under the trade name Midamor among others, is a medication typically used with other medications to treat high blood pressure or swelling due to heart failure or cirrhosis of the liver. Amiloride is classified as a potassium-sparing diuretic. Amiloride is often used together with another diuretic, such as a thiazide or loop diuretic. It is taken by mouth. Onset of action is about two hours and it lasts for about a day.
Chlortalidone, also known as chlorthalidone, is a thiazide-like diuretic drug used to treat high blood pressure, swelling, diabetes insipidus, and renal tubular acidosis. Because chlortalidone is effective in most patients with high blood pressure, it is considered a preferred initial treatment. It is also used to prevent calcium-based kidney stones. It is taken by mouth. Effects generally begin within three hours and last for up to three days. Long-term treatment with chlortalidone is more effective than hydrochlorothiazide for prevention of heart attack or stroke.
Thiazide refers to both a class of sulfur-containing organic molecules and a class of diuretics based on the chemical structure of benzothiadiazine. The thiazide drug class was discovered and developed at Merck and Co. in the 1950s. The first approved drug of this class, chlorothiazide, was marketed under the trade name Diuril beginning in 1958. In most countries, thiazides are the least expensive antihypertensive drugs available.
Magnesium deficiency is an electrolyte disturbance in which there is a low level of magnesium in the body. It can result in multiple symptoms. Symptoms include tremor, poor coordination, muscle spasms, loss of appetite, personality changes, and nystagmus. Complications may include seizures or cardiac arrest such as from torsade de pointes. Those with low magnesium often have low potassium.
Metabolic alkalosis is an acid-base disorder in which the pH of tissue is elevated beyond the normal range (7.35–7.45). This is the result of decreased hydrogen ion concentration, leading to increased bicarbonate, or alternatively a direct result of increased bicarbonate concentrations. The condition typically cannot last long if the kidneys are functioning properly.
Metolazone is a thiazide-like diuretic marketed under the brand names Zytanix, Metoz, Zaroxolyn, and Mykrox. It is primarily used to treat congestive heart failure and high blood pressure. Metolazone indirectly decreases the amount of water reabsorbed into the bloodstream by the kidney, so that blood volume decreases and urine volume increases. This lowers blood pressure and prevents excess fluid accumulation in heart failure. Metolazone is sometimes used together with loop diuretics such as furosemide or bumetanide, but these highly effective combinations can lead to dehydration and electrolyte abnormalities.
Bartter syndrome (BS) is a rare inherited disease characterised by a defect in the thick ascending limb of the loop of Henle, which results in low potassium levels (hypokalemia), increased blood pH (alkalosis), and normal to low blood pressure. There are two types of Bartter syndrome: neonatal and classic. A closely associated disorder, Gitelman syndrome, is milder than both subtypes of Bartter syndrome.
Pseudohypoaldosteronism (PHA) is a condition that mimics hypoaldosteronism. Two major types of primary pseudohypoaldosteronism are recognized.
The sodium-chloride symporter (also known as Na+-Cl− cotransporter, NCC or NCCT, or as the thiazide-sensitive Na+-Cl− cotransporter or TSC) is a cotransporter in the kidney which has the function of reabsorbing sodium and chloride ions from the tubular fluid into the cells of the distal convoluted tubule of the nephron. It is a member of the SLC12 cotransporter family of electroneutral cation-coupled chloride cotransporters. In humans, it is encoded by the SLC12A3 gene (solute carrier family 12 member 3) located in 16q13.
Within the nephron of the kidney, the ascending limb of the loop of Henle is a segment of the heterogenous loop of Henle downstream of the descending limb, after the sharp bend of the loop. This part of the renal tubule is divided into a thin and thick ascending limb; the thick portion is also known as the distal straight tubule, in contrast with the distal convoluted tubule downstream.
Dent's disease is a rare X-linked recessive inherited condition that affects the proximal renal tubules of the kidney. It is one cause of Fanconi syndrome, and is characterized by tubular proteinuria, excess calcium in the urine, formation of calcium kidney stones, nephrocalcinosis, and chronic kidney failure.
WNK , also known as WNK1, is an enzyme that is encoded by the WNK1 gene. WNK1 is serine-threonine protein kinase and part of the "with no lysine/K" kinase WNK family. The predominant role of WNK1 is the regulation of cation-Cl− cotransporters (CCCs) such as the sodium chloride cotransporter (NCC), basolateral Na-K-Cl symporter (NKCC1), and potassium chloride cotransporter (KCC1) located within the kidney. CCCs mediate ion homeostasis and modulate blood pressure by transporting ions in and out of the cell. WNK1 mutations as a result have been implicated in blood pressure disorders/diseases; a prime example being familial hyperkalemic hypertension (FHHt).
Serine/threonine protein kinase WNK4 also known as WNK lysine deficient protein kinase 4 or WNK4, is an enzyme that in humans is encoded by the WNK4 gene. Missense mutations cause a genetic form of pseudohypoaldosteronism type 2, also called Gordon syndrome.
EAST syndrome is a syndrome consisting of epilepsy, ataxia, sensorineural deafness and salt-wasting renal tubulopathy. The tubulopathy in this condition predispose to hypokalemic metabolic alkalosis with normal blood pressure. Hypomagnesemia may also be present.
A diuretic is any substance that promotes diuresis, the increased production of urine. This includes forced diuresis. A diuretic tablet is sometimes colloquially called a water tablet. There are several categories of diuretics. All diuretics increase the excretion of water from the body, through the kidneys. There exist several classes of diuretic, and each works in a distinct way. Alternatively, an antidiuretic, such as vasopressin, is an agent or drug which reduces the excretion of water in urine.
Idiopathic hypercalcinuria (IH) is a condition including an excessive urinary calcium level with a normal blood calcium level resulting from no underlying cause. IH has become the most common cause of hypercalciuria and is the most serious metabolic risk factor for developing nephrolithiasis. IH can predispose individuals to osteopenia or osteoporosis, and affects the entire body. IH arises due to faulty calcium homeostasis, a closely monitored process, where slight deviations in calcium transport in the intestines, blood, and bone can lead to excessive calcium excretion, bone mineral density loss, or kidney stone formation. 50%-60% of nephrolithiasis patients suffer from IH and have 5%-15% lower bone density than those who do not.