From the Guidelines
Gitelman syndrome leads to hypomagnesemia primarily through increased renal magnesium wasting, resulting from mutations in the SLC12A3 gene that encodes the thiazide-sensitive sodium-chloride cotransporter (NCC) in the distal convoluted tubule (DCT) of the kidney. This genetic disorder affects the normal functioning of the NCC, leading to decreased sodium reabsorption in the DCT, which in turn causes volume contraction and activation of the renin-angiotensin-aldosterone system 1. The activation of this system results in increased sodium reabsorption in the collecting duct in exchange for potassium and hydrogen ions, further contributing to the development of hypomagnesemia.
The reduced sodium reabsorption in the DCT also creates a less positive luminal voltage, which decreases the driving force for magnesium reabsorption through TRPM6 channels, as noted in studies on electrolyte balance and renal function 1. Additionally, the chronic hypokalemia that occurs in Gitelman syndrome may downregulate TRPM6 expression, further impairing magnesium reabsorption. The compensatory increase in sodium reabsorption in the connecting tubule and collecting duct cannot make up for the magnesium loss since these segments have minimal capacity for magnesium reabsorption.
This results in persistent urinary magnesium wasting and hypomagnesemia, which is a characteristic feature of Gitelman syndrome alongside hypokalemia, metabolic alkalosis, and hypocalciuria. It is essential to monitor and manage electrolyte imbalances, including magnesium levels, in patients with Gitelman syndrome to prevent complications and improve quality of life, as emphasized in guidelines on clinical nutrition in hospitalized patients with acute or chronic kidney disease 1. Therefore, it is crucial to prioritize the management of hypomagnesemia in Gitelman syndrome through careful monitoring and supplementation of magnesium, as well as addressing the underlying causes of electrolyte imbalances.
From the Research
Mechanism of Hypomagnesemia in Gitelman Syndrome
- Gitelman syndrome is characterized by hypomagnesemia, hypokalemia, and hypocalciuria, resulting from inactivating mutations in the gene encoding the thiazide-sensitive sodium-chloride cotransporter (NCC) in the distal convoluted tubule 2, 3, 4, 5, 6.
- The NCC plays a crucial role in reabsorbing sodium, chloride, and magnesium ions from the distal convoluted tubule 2, 3, 4, 5, 6.
- Mutations in the SLC12A3 gene, which encodes the NCC, lead to impaired reabsorption of magnesium ions, resulting in hypomagnesemia 3, 5, 6.
- The mechanism of hypomagnesemia in Gitelman syndrome is similar to that seen with thiazide diuretics, which also inhibit the NCC and lead to increased excretion of magnesium ions 2.
Clinical Characteristics and Diagnosis
- Gitelman syndrome is typically diagnosed during adolescence or adulthood, often with mild and nonspecific symptoms such as muscle weakness, salt craving, and tetany 3, 5, 6.
- Diagnosis is based on clinical symptoms, biochemical abnormalities (hypokalemia, metabolic alkalosis, hypomagnesemia, and hypocalciuria), and genetic testing 3, 5, 6.
- Genetic diagnosis is recommended for all patients, and the diagnosis is confirmed when biallelic inactivating SLC12A3 mutations are identified 5.
Treatment and Management
- Treatment of Gitelman syndrome includes magnesium and potassium supplements, as well as a liberal salt intake 3, 5, 6.
- Other medications, such as aldosterone receptor antagonists, angiotensin-converting-enzyme inhibitors, and prostaglandin synthetase inhibitors, may be used to manage hypokalemia, but their side effects should be carefully considered 5.
- Regular follow-up and monitoring by a nephrologist are recommended to manage the disease and prevent complications 5, 6.