Introduction

Gitelman syndrome (GS) is a rare, recessively inherited condition. It has features of salt-wasting tubulopathy characterised by hypokalemic metabolic alkalosis, hypomagnesemia and hypocalciuria. The syndrome has a prevalence rate of approximately 1-10 to 40,0000. It is the most inherited tubulopathy, with a higher frequency in the Asian population. GS is caused by biallelic inactivated mutations in the SLC12A3 gene. This encodes the thiazide-sensitive sodium-chloride cotransporter (NCC), that is present in the apical membrane of cells lining the distal convoluted tubule. Currently, throughout the SLC12A3 gene around 350 mutations have been identified in GS patients. Most of these patients are found to be heterozygous for SLC12A3 mutations. A minority of patients are found to be carrying a single SLC12A3 mutation. For a clinical diagnosis of GS, the presence of hypocalciuria and hypomagnesemia is expected, however, hypocalciuria can be variable and hypomagnesemia may be absent.¹       

This is a defect that causes impaired ability of the kidneys to reabsorb salt. This has an effect on changing various electrolyte concentrations and the contraction of extracellular fluid volume.²

Mechanism of salt wasting in gitelman syndrome

The kidneys hold an important role in electrolyte homeostasis, therefore water balance is needed. Urine is formed by the function of glomerular filtration. As the compounds (salts) are small they can fall through the glomerular filter which is then needed to be reabsorbed in the renal tubule. Seyberth and Schlingmann reviewed that the filtered salt is reabsorbed into differing parts of the renal tubule. 

• 30% is reabsorbed in the distal nephron, 
• 25% into the thick ascending limb (TAL) of Henle’s loop 
• 10% is reabsorbed in the distal convoluted tubule (DCT) and cortical collecting duct (CCD)

The role of TAL is the concentration of salt in the interstitium as essential for the countercurrent exchange of reabsorption of salt and the urinary concentration mechanism. This segment is mainly impermeable to water, as large amounts of sodium chloride are pumped from the filtrate. This generates the hypertonicity of the interstitium that drives the countercurrent exchange.        

The DCT performs a role in fine-tuning renal excretion of sodium chloride, and cations such as calcium and magnesium. The DCT is further subdivided into an early segment (DCT1), a late segment (DCT2), and the connecting tubule (CNT), connecting to the CCD.   

These subsegments are characterised by the expression of the different ion transport proteins that are responsible for salt and cation reabsorption. The reabsorption capacity of the total distal nephron can be regulated by nutritional intake and extrarenal losses of salt and water. One of the most studied checkpoints of this fine-tuning process is the macula densa (MD).    

A key player in connecting renal haemodynamics and tubular reabsorption to enable monitoring of chloride concentration in the tubular fluid. This then entails a feedback mechanism, matching glomerular filtration with tubular salt load (tubuloglomerular feedback [TGF]) 

The regulation of glomerular arterial resistance can be achieved by modulating the renin-angiotensin II system and intrarenal cyclooxygenase (COX)-2 activity. Therefore, any defects in distal tubular functions have a major impact on the clinical presentation of MD, salt-wasting tubulopathies, loop and DCT disorders.²    

Clinical manifestations of salt wasting in gitelman syndrome

Differentiating between salt-wasting nephropathies is difficult due to the clinical and biological features. For example, a phenotype in GS such as hypomagnesemia and hypocalciuria has associations with mutations in the CLCNKB gene that encodes chloride channel ClC-Kb. This mutation causes Bartter syndrome (CBS). The localisation of ClC-Kb in the DCT explains the phenotypic overlap with GS.¹       

GS is an asymptomatic condition or relatively mild/ non-specific symptoms may be associated, such as:

Cases have shown a reduction in the quality of life, and associations with diabetes and congestive heart failure. Also, severe complications have arisen in diagnosing GS, such as a diagnosis being established on a clinical ground rather than a genetic one. This has created confusion with related disorders including cBS. From a genetic point of view, phenotype variability has been documented in identical SLC12A3 mutations in patients with GS. However, there is also variability due to a combination of factors that vary across patients, for example, genotype, sex, modifier genes, environmental factors, and dietary habits.¹  

Diagnosis of salt wasting in gitelman syndrome

GS can be observed mainly in adolescents and adults. However, it can also be encountered at a younger age, as well as in the neonatal period. As GS originates from the DCT, the salt and water losses in GS patients are less pronounced in comparison to cBS patients. This is a result of the urinary concentration ability being largely intact. GS patients are usually asymptomatic or present mild symptoms, such as fatigue, thirst, and cramps, as well as spasms and tetanic episodes due to an offset of hypomagnesemia. For patients experiencing severe hypomagnesemia and hypokalemia, blood pressure is typically low. 

A complication of GS includes chondrocalcinosis and sclerochoroidal calcifications. Magnesium ions increase the solubility of calcium pyrophosphate crystals and are vital in activating tissue-nonspecific alkaline phosphatase. This hydrolyses pyrophosphates (PPi) into inorganic phosphate (Pi), which is why hypomagnesemia may contribute to the formation of calcium pyrophosphate crystals (in joints and sclera). Additionally, GS patients have a higher bone mineral density due to an increased renal calcium reabsorption contributing to calcium deposition.  

Growth retardation may also be presented, alongside short stature and pubertal delay. This reflects a possible alteration in the growth hormone, insulin-like growth factor.¹ A pleiotropic effect is a result of biochemical disturbance.  

Ultrasound and X-ray examinations can confirm suggestions of chondrocalcinosis. An ophthalmology examination can be performed where sclerochoroidal calcifications are indicated. Genetic testing has become increasingly available for the condition due to a widespread number of patients with GS but remains expensive.  

An increased risk of ventricular tachycardia and sudden death in GS patients has been reported. Depleted potassium and magnesium levels prolong the duration of action potential in cardiomyocytes, resulting in a longer QT interval in around 50% of GS patients, increasing the risk of ventricular arrhythmias. It is recommended that an electrocardiogram (ECG) be performed in resting phases to assess rhythm and the QT phase.   

Chronic hypokalemia may lead to kidney disease in GS patients. This has an association with various other mechanisms causing renal damage and fibrosis. These include tubulointerstitial nephritis, tubule vacuolisation, volume depletion, cystic changes as well as an increased renin angiotensin-aldosterone. Many patients have also reported abdominal pain which may be caused by intestinal paresis because of hypokalemia. Another explanation is to intolerability of potassium and magnesium supplements.¹

Summary

GS is a familial benign tubulopathy, which is commonly detected in adolescence or adulthood. It is the most frequent hereditary salt-wasting tubulopathy. Symptoms vary amongst individuals due to the severity of GS, from everyday difficulties, salt cravings, and low blood pressure to long-term consequences such as paralysis and seizures. 

GS can be managed by salt intake as well as oral magnesium and potassium supplementation. Individuals with GS are recommended potassium-sparing diuretics, renin-angiotensin system, and receptor blockers, as well as angiotensin-converting-enzyme inhibitors. Non-steroidal anti-inflammatory drugs may also be advised. However, data supporting tolerability, efficacy, and safer treatment options are limited. Information in regards to long-term outcomes in GS is insufficient and further research is required. These long-term consequences are chondrocalcinosis, hypertension, kidney disease, cardiac arrhythmias as well as managing the condition during pregnancy. Limited knowledge has been challenged by the emphasis on phenotypic variability and the potential severity of GS.  

FAQs

What is salt wasting in gitelman syndrome?

Gitelman syndrome (GS) is a familial autosomal recessive tubule disorder of the kidneys. It has distinct features of low levels of potassium and magnesium in blood and an increased blood pH. Low levels of calcium in the urine are excreted.

When was gitelman syndrome first discovered?

GS was initially described in 1966. 

What is the genetic disorder of salt wasting?

GS is commonly caused by mutations in the SLC12A3 gene but can also be caused by mutations in the CLCNKB gene. The proteins that are produced from these genes have an involvement in the kidneys’ mechanism, reabsorbing salt from the urine back into the bloodstream.  

Is gitelman syndrome life-threatening?

Some individuals with GS experience mild symptoms, however, the spectrum of the GS varies drastically and some symptoms may be severe, resulting in life-threatening consequences. 

Is there a cure for gitelman syndrome?

As GS is a hereditary condition, there are no curative treatment options. Currently, GS can only be managed by therapies and potassium-sparing diuretics.