Gitelman syndrome (GS) is a rare, inherited kidney disorder characterized by the kidneys' inability to properly reabsorb salt, leading to its loss in urine. First identified in 1966 by Dr. Hiller Gitelman, it affects approximately 1 in 40,000 people and is often diagnosed in adulthood, impacting men and women equally. GS bears a close resemblance to Bartter syndrome type 3. Those with Gitelman syndrome have to work extra hard to maintain electrolyte levels. Why? Because the genetic mutations that define the syndrome impair sodium and magnesium absorption while simultaneously boosting potassium losses.
Understanding Gitelman Syndrome
The mutations are typically in the SCL12A3 and the TRPM6 genes. The consequence of these mutations is an inability to properly absorb sodium, chloride, and magnesium in the kidneys. Alterations to these pathways lead to a variety of electrolyte disturbances. Urine is where the kidneys dispose of excess electrolytes. Specifically, those with Gitelman syndrome tend to have high levels of potassium and low levels of calcium (hypocalciuria) in the urine. Two hormonal hallmarks of Gitelman syndrome are hyperaldosteronism (high aldosterone) and hyperreninism (high renin). Over-activity of these hormones drives heavy potassium losses, often leading to hypokalemia.
Genetic Basis
Gitelman syndrome stems from changes in the SLC12A3 gene, while Bartter syndrome type 3 is linked to alterations in the CLCNKB gene. These genes play a crucial role in the distal convoluted tubule of the kidney, which filters blood and reabsorbs essential nutrients like salt and potassium. When these genes malfunction, salt and potassium are excreted in the urine instead of being reabsorbed into the bloodstream.
Inheritance Pattern
Gitelman syndrome is a genetic condition passed down through families. Individuals inherit two copies of each gene, one from each parent. Healthy individuals possess two normal copies, while carriers have one normal and one faulty copy. Carriers typically remain healthy because the normal copy compensates for the faulty one but can still pass the condition to their children. In individuals with Gitelman syndrome, neither gene copy functions correctly, causing the kidneys to leak salt into the urine. When both parents are carriers, there is a chance their child could be healthy, be a carrier, or develop Gitelman syndrome. This inheritance pattern is known as autosomal recessive inheritance.
Symptoms of Gitelman Syndrome
The symptoms of Gitelman syndrome tie directly to electrolyte disturbances. If the disturbances are mild enough, the person may be asymptomatic. Common signs and symptoms include:
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- Extreme tiredness
- Muscle cramps
- Joint pain
- Persistent thirst
- Craving for salty food
- Numbness and tingling in the hands and feet
Gitelman syndrome tends to be milder than Bartter syndrome type 3 and develops at a later age. These disorders may also be related to hypomagnesemia. Another consequence of low serum magnesium is a neuromuscular disorder called tetany. Tetany is defined by involuntary quakes, shivers, and spasms. Other symptoms of Gitelman syndrome include:
- Salt cravings and thirst in about 75% of people
- A taste for brine and citrus fruits
- Low blood pressure
- Paralysis
- A buildup of calcium crystals in the joints (chondrocalcinosis)
- Excess calcium buildup in the kidneys (nephrocalcinosis)
As you can see, the symptoms are fairly diverse. What does NCCT do? It helps absorb sodium and chloride through the tubular lumen, the interior of a tube-like structure in the kidneys. When the NCCT channel doesn’t work properly, you can’t absorb sodium and chloride. That explains the increased salt needs. But the problems with salt absorption also trigger the kidneys to release two sodium retention hormones-aldosterone and renin-that:
- Increase sodium reabsorption
- Increase potassium excretion
This explains the heavy potassium losses and resultant hypokalemia. The TRPM6 gene codes for a protein that helps magnesium flow into cells. About 1% of white people, however, are heterozygous for the SCL12A3 genetic mutation-meaning they have one mutated copy of the gene. If two heterozygous parents make a baby, the baby will have a small chance of developing Gitelman syndrome. If one of the parents is homozygous for the SCL12A3 mutation (i.e., they have Gitelman syndrome), they have a 25% chance of passing it on.
Diagnosing Gitelman Syndrome
Gitelman syndrome is usually diagnosed through blood tests revealing low levels of potassium, magnesium, and calcium. Urine tests indicate low calcium levels in Gitelman syndrome, distinguishing it from Bartter syndrome. Genetic testing can also be conducted, especially if there is a family history of Gitelman or Bartter syndrome or other kidney diseases. Gitelman syndrome can be tricky to diagnose, since many only experience subtle symptoms. The simplest way to diagnose this condition is through genetic testing. Taking certain drugs may increase electrolyte losses and cause similar symptoms to Gitelman syndrome.
Dietary Management of Gitelman Syndrome
Treatment for Gitelman syndrome primarily involves managing salt levels through dietary adjustments and supplements. While normalizing salt levels completely may not be possible, increasing them can significantly alleviate symptoms. People with Gitelman syndrome are likely to be advised to follow a special diet that is high in salt, potassium and magnesium. This should only be undertaken with advice and monitoring by a specialist kidney dietitian.
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General Dietary Recommendations
While the treatment based on potassium, sodium, chloride, and magnesium supplementation in addition to other pharmacologic options are widely established, recommendations about the dietary approach to GS and BS still remain generic. The dietary approach to BS and GS can be done through sodium, potassium, and magnesium-rich foods and/or supplements containing these minerals. Some foods and beverages can contribute to reducing plasma potassium and magnesium levels and therefore these patients or their parents, in the case of children with these syndromes, should know them and moderate the use of these beverages and foods. GS patients should consider that some foods may cause a loss of potassium and/or magnesium.
Sodium and Chloride Intake
The dietary approach recommended to counteract the sodium and chloride losses is an ad libitum salt diet supplemented with sodium chloride tablets. Slow-release sodium tablets could be used at the dose of 2.4-4.8 g per day in four divided doses. The clinical picture of BS, although much more severe, presents clinical characteristics virtually indistinguishable from GS and its dietary treatment largely shares the same interventions. Post-natal treatment supplementation with sodium chloride represents the main treatment to restore extracellular volume and improve electrolyte abnormalities. In late childhood patients, the increase of dietary salt intake due to salt craving is important. Salt supplementation must be avoided in BS type 1 and type 2 patients with secondary forms of nephrogenic diabetes insipidus. The solute load, due to the high salt intake, in fact, could worsen polyuria and induce hypernatriemic dehydration. When you can’t absorb sodium properly, you need to consume more of it. As a baseline, most folks need about 2-3 teaspoons of salt per day. (That’s around 4-6 grams of sodium.) Those with Gitelman syndrome will need more. Getting to 4-6 grams sodium and beyond requires aggressive salt shaking-more aggressive than most can manage through diet alone.
Potassium Intake
Hypokalemia is one the more frequent and crucial manifestations of GS. A recent consensus on GS suggested that a reasonable target for potassium may be 3.0 mmol/L. There are some differences between meats, fruits, and vegetables as sources of potassium. Meat increases the acid load due to the high content of organic sulfur in its proteins, while fruit and vegetable intake is associated to a net base production due to their content of organic acid anions. Moreover, the carbohydrate content of fruits and vegetables stimulates insulin secretion, favoring intracellular entry of potassium. It should also be considered that potassium losses from cooking of high potassium-rich foods can be significant. The main preparation method that loses potassium from many foods is through boiling in water. However, if the cooking water is consumed, all the potassium is introduced. Steaming vegetables could be used instead of boiling as steamed foods retain potassium, which is not lost in the cooking water.
When potassium replacement is administered as oral supplement, it should be given in the form of chloride, which is the main anion lost in the urine of GS patients, contributing to alkalosis. However, other formulations are also available. Potassium supplementation may cause serious side effects including vomiting, diarrhea, and gastric ulcers. To minimize these side effects, potassium supplements must be taken on a full stomach and slow-release formulation should be preferred. A recent consensus suggests a starting dose of ≥40 mmol KCl (1-2 mmol/kg in children) in divided doses throughout the day, with 3.0 mmol/L as the target for the potassium plasma level.
When patients do not tolerate oral potassium or when the target cannot be reached, intravenous KCl should be administered. The concentration of potassium for intravenous administration via a peripheral vein should not exceed 40 mmol/L at a maximum rate of 10 mmol/h, as higher concentrations can cause phlebitis and pain. In severe cases of hypokalemia, KCl solution up to 80 mmol/L at a maximum rate of 20 mmol/h should be given via a central venous route. Recommendations about dietary potassium reported for GS patients should be applied also for BS patients. Although the optimal plasma potassium level is not exactly known, 3.0 mmol/L is recommended as a reasonable target level. With the potassium assumption, urinary losses shortly increase, causing a fast reduction of the plasma potassium level. Therefore, supplements of potassium chloride should be taken several times a day and not on an empty stomach due to the risk of gastric damage. Similarly to GS patients, a potassium rich diet is recommended also for BS patients.
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However, many potassium-rich foods contain large amounts of carbohydrates (fruit juices, potatoes, sweet potatoes, bananas, dried apricots, etc.). These foods should be eaten with moderation as they can induce an important insulin secretion with the consequent migration of potassium into the cells and a further reduction of the plasma potassium level. To start, those with Gitelman syndrome should eat plenty of potassium-rich foods like oranges, bananas, green leafy vegetables, salmon, lentils, avocados, and tomatoes. This will help prevent hypokalemia. Large doses of supplemental potassium may also be helpful. These drugs should be used cautiously because they can cause hypotension (low blood pressure).
Magnesium Intake
The exact mechanisms of hypomagnesemia as well as hypocalciuria in GS, is still uncertain. Hypomagnesemia in GS is assumed to be a consequence of the inactivation of NCC in the distal convoluted tubule (DCT) with a mechanism similar to thiazides. However, data suggest that magnesium-wasting is the primary abnormality. Renal alterations in magnesium and calcium reabsorption could result from a functional or structural defect in the DCT caused by the loss of NCC activity rather than as a consequence of hypokalemia or alkalosis. In turn, magnesium depletion promotes urinary potassium excretion, favoring hypokalemia. Conversely, in BS, in which hypomagnesemia is mild or absent, the upregulation of the TRPM6 expression is a compensatory mechanism in order to restore the reduced reabsorption of Mg2+ in the thick ascending limb (TAL).
The exact target for plasma magnesium in GS and BS patients is uncertain. Dietary magnesium is present in vegetal and animal foods. Legumes, nuts, green leafy vegetables, seeds, bananas, whole grains, dark chocolate, and fish and are good sources of this mineral. Magnesium supplementation is often poorly tolerated due to abdominal pain and diarrhea induced by high doses of magnesium salts. Few data are available on the bioavailability of different magnesium supplementation salts. Animal studies showed that organic salts (e.g., aspartate, citrate, fumarate, gluconate, and lactate) are more bioavailable than inorganic forms (e.g., oxide, hydroxide, and chloride) and, among organic salts, magnesium gluconate exhibits the highest bioavailability. It is recommended to start magnesium supplementation with a dose of 300 mg/day (12.24 mmol) of elemental magnesium (5 mg/kg in children, i.e., 0.2 mmol/kg) using, if possible, slow-release tablets. Along with potassium, those with Gitelman syndrome should also get their magnesium in check. Both forms are poorly absorbed and can cause diarrhea. A good plan is to take 300 to 500 mg magnesium malate in divided doses throughout the day.
To increase magnesium bioavailability, liposomes have been employed both for drug and nutrients delivery. Liposomes, vesicles consisting of one or more phospholipid bilayers surrounding an aqueous solution core, are able to cross the cell membrane, carrying their contents inside the cells. In the field of nutrient supplementation, liposomes are employed for vitamin and mineral delivery. Recently, a new delivery system consisting of phospholipids covered by a sucrester matrix has been proposed both for iron and magnesium supplementation. Sucrester is a surfactant derived from the esterification of fatty acids with sucrose (sucrose esters) that has been shown to act as an absorption enhancer due to its ability to reduce intestinal barrier resistance. Sucrosomial magnesium has demonstrated a higher bioavailability both in vitro and in human studies compared to others magnesium forms.
A commercial preparation of sucrosomial magnesium was compared to other forms of magnesium dietary supplements. Ex vivo evaluation showed that sucrosomial magnesium was absorbed faster and in larger amounts in respect to magnesium oxide, while in healthy subjects, surosomial preparation induced higher magnesium concentrations than citrate, oxide, and bisglycinate forms in plasma, urine, and red blood cells. Magnesium ions encapsulated within a sucrosomial membrane pass through the intestine without direct interaction with the mucosa and lumen content, and then are absorbed via passive paracellular mechanisms that account for about 90% of the whole intestinal uptake. In the sucrosomial form, magnesium is protected from the interaction with other substances that may limit its adsorption. Due to this mechanism, the amount of magnesium not absorbed in the intestine is lower and the absorbed magnesium protected by sucrosome exerts a low osmotic effect, reducing the risk of diarrhea. However, until now, clinical studies concerning the effectiveness of sucrosomial magnesium in restoring its plasma levels are lacking. Preliminary data from our laboratory shows in a cohort of hypomagnesemic renal transplanted patients, a higher effectiveness and tolerability of sucrosomial magnesium (ULTRAMAG® PharmaNutra S.p.A, Pisa, Italy) compared to magnesium pidolate (Innico et al. As mentioned above, a similar technology has been used for iron supplementation, evidencing that sucrosomial iron was more tolerated and more effective compared to other forms of magnesium. When oral supplementations are not able to improve hypomagnesemia or in the case of severe muscle cramps, weekly intravenous magnesium sulfate may be used. In GS patients with hypomagnesemia, vitamin D levels should also be evaluated. Magnesium, in fact, plays a central role in several steps of the vitamin D metabolism and in particular in the enzymatic conversion of 25(OH)D3 to the active form 1,25(OH)D3, which is a magnesium-dependent process.
Foods and Beverages to Avoid or Limit
GS patients should consider that some foods may cause a loss of potassium and/or magnesium. Licorice root contains glycyrrhizinic acid, an inhibitor of the enzyme 11β-hydroxysteroid dehydrogenase type 2 that converts cortisol into cortisone. Cortisol, unlike cortisone, exerts mineralocorticoid activity, inducing sodium retention and increasing potassium excretion. A prolonged use of products containing glycyrrhizinic acid (above 50 mg daily), including herbal preparations, dietary supplements, candies, and liqueurs, may cause hypokaliemia, sodium and water retention (with or without hypertension), and rhabdomyolysis. Usually, rhabdomyolysis can occur when potassium levels fall below 2.0 mEq/L. GS patients should avoid excessive use of alcoholic beverages. Indeed, alcohol abuse may result in electrolyte disorders including hypomagnesemia and hypokalemia. These abnormalities are mainly due to tubular dysfunctions. Some beverages, such as fruit juice, citrate, and bicarbonate-rich beverages, as well as almond-based beverages, favor metabolic alkalosis and induce a further fall in plasma potassium levels. Fruit juices may cause alkalosis due to the presence of organic acids, mainly citrate and malate. These organic acids are an intermediate of the Krebs cycle and once adsorbed are mostly oxidized. Bicarbonate and bicarbonate-rich beverages, such as sparkling waters, may have a strong alkalinizing effect. GS and BS patients should limit fruit juice intake considering both their organic acids and sugar content. As an alternative, a moderate amount (<500 g/d) of fresh fruit which has a higher content of potassium and less carbohydrates is preferable.
Other Dietary Considerations
Low carb and ketogenic approaches to diet are likely not the best options for folks with Gitelman Syndrome, since these diets increase our tendency to lose both sodium and potassium.
Pharmacological Interventions
High doses of potassium and/or magnesium supplements may be needed, which can be difficult to digest and can cause side effects such as abdominal pain and diarrhea. Liquid supplements tend to cause fewer side effects than tablets. During periods when the body is under stress, such as during illness or after surgical procedures, salt levels can change very quickly. This may result in the need for intravenous (IV) therapy in hospital to quickly top up salt levels. Non-steroidal medications such as indomethacin may also be prescribed, especially for Bartter syndrome, to help the kidneys hold on to the potassium and magnesium that the body needs. Potassium sparing diuretics may also be prescribed. These medications increase the amount of fluid that leaves the body in the urine, while retaining the potassium that would normally also be lost.
Novel Therapeutic Approaches
Previously the only available therapies for the hypokalemia and hypomagnesemia associated with Gitelman’s Syndrome were high dose oral potassium and magnesium supplements. The need for oral potassium replacement being negated with a simultaneous blockade of both the renin and mineralocorticoid receptor as well as the need for oral magnesium being minimized through the utilization of the SGLT-2 receptor blocker canagliflozin.
Initial therapy for hypokalemia was with the combination of the renin receptor blocker aliskiren and the aldosterone receptor blocker spironolactone. This resulted in normokalemia and negated the need for potassium supplements. The success of correcting the hypokalemia was tempered by the inability to increase her serum magnesium level. Based on reports that SGLT-2 inhibitors increased serum magnesium levels through increased renal absorption and since she had prediabetes she was started on ertugliflozin at 15 mg daily which was later increased to 30 mg daily due to a lack of efficacy. However, when ertugliflozin was discontinued and canagliflozin therapy was initiated at 100 mg daily and later at 300 mg daily her serum magnesium level rose.
In patients with Gitelman’s Syndrome, blockade of the renin and mineralocorticoid receptors may negate the need for potassium supplementation. Furthermore, the need for magnesium supplementation may be negated or reduced utilizing an SGLT-2 inhibitor. Reducing or eliminating the need for potassium and/or magnesium supplementation will result in a reduction or elimination in the gastrointestinal symptoms associated with the excess intake of potassium and magnesium supplements in addition to an improvement of the quality of life which is decreased with both high dose potassium and/or magnesium supplementation.
Long-Term Management
Gitelman syndrome requires lifelong monitoring and treatment. The amounts of supplements and medications prescribed are likely to change over time. Without treatment, potassium and magnesium levels in the blood could become very low, which can cause heart rhythm problems. Although Gitelman syndrome affects how well the kidneys work, it doesn’t affect their actual structure. Dialysis or a kidney transplant are therefore rarely needed.
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