Introduction

Gitelman syndrome (familial hypokalemia–hypomagnesemia) is the most common inherited tubular disease resulting from mutations of the SLC12A3 gene encoding the thiazide-sensitive sodium–chloride cotransporter (NCC), which is responsible for NaCl reabsorption in the early distal convoluted tubules. The syndrome is transmitted as an autosomal recessive trait and is characterized by hypokalemic metabolic alkalosis in combination with hypomagnesemia and hypocalciuria (Table 1) [1,2,3].

Table 1 Gitelman syndrome: main laboratory findings
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Aim of this review is the presentation of the underlying pathophysiologic mechanisms of acid–base and electrolyte abnormalities observed in patients with Gitelman syndrome (Table 1).

Hypokalemia and kaliuria

Hypokalemia (serum potassium concentration <3.5 mEq/L) owing to renal potassium wasting (potassium to creatinine ratio in a random urine specimen >18 mEq/g creatinine) is a cardinal manifestation of Gitelman syndrome. The underlying mechanisms of kaliuria include (Fig. 1):

Fig. 1
figure 1

Gitelman syndrome: Pathophysiology of the associated acid–base and electrolyte abnormalities. TRMP6 epithelial magnesium channel transient receptor potential cation channel subfamily M member 6, FE fractional excretion, ENaC epithelial sodium channel, ROMK renal outcome medullary potassium channel

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  1. 1.

    Increased distal flow rate as a result of the decreased sodium chloride reabsorption in the early distal convoluted tubules leads to increased potassium secretion due to diffusion gradient through enhanced “big” or “maxi” potassium channels activity [4,5,6].

  2. 2.

    Volume depletion-induced increased aldosterone levels lead to increased potassium secretion through the renal outer medullary potassium (ROMK) channels. Additionally, the aldosterone-induced increased sodium reabsorption in the late distal convoluted and cortical collecting tubules by the epithelial sodium channel [ENaC] is associated with increased potassium excretion through an increased electronegativity of the lumen resulting in an elevated electrical gradient favoring potassium secretion [4,5,6,7,8].

  3. 3.

    Hypomagnesemia is also associated with inappropriate kaliuresis and can contribute to the development of hypokalemia [9, 10].

Increased excretion of chloride

The decreased sodium and chloride reabsorption in the early distal convoluted leads to increased fractional excretion of chloride. Indeed, a fractional excretion of chloride >0.5% is among the diagnostic criteria proposed for the diagnosis of Gitelman syndrome [1]. However, increased chloride excretion is also observed in other genetic tubulopathies (such as Bartter syndrome) or diuretics surreptitious intake [11, 12]. It has been proposed that a thiazide test can be useful for the diagnosis of the Gitelman genotype in patients with normotensive hypokalemic alkalosis. Thus, in cases of Gitelman syndrome 3 h after the administration of 50 mg of hydrochlorothiazide fractional chloride clearance increases by less than 2.3% [13].

Metabolic alkalosis

Hypokalemia is commonly associated with metabolic alkalosis. The underlying mechanisms of metabolic alkalosis are shown in Fig. 2. Hypokalemia is associated with redistribution of potassium out of the cells resulting in entry of H+ into cells. This intracellular acidosis in the renal tubular cells is associated with increased H+ secretion in both proximal and distal tubules along with increased bicarbonate reabsorption. Furthermore, increased potassium depletion-associated ammoniogenesis in the proximal renal tubules may also play a role in the development of alkalosis. Finally, hypokalemia is also associated with induction of the H+–K+–ATPase in the a-intercalated tubular cells in the collecting tubules resulting in increased excretion of H+, which can also contribute to the development of metabolic alkalosis [14].

Fig. 2
figure 2

Mechanisms of metabolic alkalosis in patients with Gitelman syndrome

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Hypocalciuria

Hypocalciuria, defined as a spot urine calcium to creatinine ratio <0.07 mg/mg (0.2 mmol/mmol) in adults, is a common finding in patients with Gitelman syndrome [1]. It has been reported that the decreased calcium excretion is related to the extracellular volume contraction-mediated compensatory increase in sodium reabsorption in the proximal renal tubules leading to an increased passive calcium paracellular transport through an increase in the electrochemical gradient [15,16,17]. In fact, it is well known that in the proximal renal tubules calcium reabsorption is coupled tightly to sodium chloride reabsorption [15]. It has been proposed that increased calcium reabsorption at the thiazide-sensitive site in the distal convoluted tubules may contribute to the hypocalciuria [7, 18] though this mechanism has not been confirmed [16]. In fact, in the distal tubules the reduced NCC expression is associated with reduced intracellular sodium levels leading to increased calcium exit across the basolateral membrane through the Na+–Ca2+ exchanger 1. The resulting low intracellular calcium leads to increased apical calcium entry into the cells through the transient receptor potential cation channel subfamily V member 5 (TRPV5) channels. Alternatively, the decreased magnesium reabsorption in the distal convoluted tubules results in reduced intracellular magnesium concentration leading to increased TRPV5-mediated calcium reabsorption [18].

It has been also reported that increased sodium chloride transport in the thick ascending loop of Henle (TAL) through the K+–Na+–2Cl− cotransporter is observed in these patients as a result of tubular adaptation to renal sodium loss [19, 20]. This process is associated with an increase in transepithelial voltage along the TAL leading to paracellular calcium reabsorption along this segment [19]. It has recently been reported that the thiazide-sensitive NCC gene inactivation in experimental animals is associated with increased duodenal calcium absorption as well as osteoblast differentiation and bone calcium storage [21]. These findings may explain the higher bone mineral density observed in patients with Gitelman syndrome but also in thiazide-treated patients [22].

Hypomagnesemia

Hypomagnesemia (serum magnesium <1.2 mEq/L) associated with inappropriate magnesiuria (fractional magnesium excretion >4%) [23] is a characteristic feature of patients with Gitelman syndrome [1]. In these patients, the underlying mechanisms of magnesiuria are not well delineated. However, it has been suggested that hypomagnesemia is related to downregulation of the epithelial magnesium channel transient receptor potential cation channel subfamily M member 6 (TRMP6), which is expressed along the apical membrane of the distal convoluted tubules and is responsible for the active transcellular transport of magnesium [15, 24]. The underlying mechanisms of this downregulation are not clear, but atrophy of the early distal convoluted cells observed in mice not expressing the NCC in the apical membrane of the distal convoluted cells may be responsible [16]. Additionally, increased aldosterone levels observed in these patients have been shown to be related to magnesiuria possibly through downregulation of TRMP6 channels. Thus, spironolactone is useful in these patients since it can reduce urinary magnesium excretion and increase magnesium levels 1 [25]. Finally, hypokalemia may also play a role in the development of hypomagnesemia since it is also associated with renal magnesium wasting [9]. It should be mentioned that hypomagnesemia in combination with hypokalemia can lead to a prolonged QT interval and cardiac arrhythmias [26, 27]. Thus, patients with these electrolyte derangements should avoid drugs prolonging the QT interval.

Hypophosphatemia

Hypophosphatemia due to renal phosphate wasting has been occasionally reported in patients with Gitelman syndrome. The underlying mechanisms are not clear though hypophosphatemia may be due to increased aldosterone levels or to the coexistent metabolic derangements (hypokalemia and metabolic alkalosis) [28, 29].

Hyponatremia

Hyponatremia is rarely reported in patients with Gitelman syndrome [30]. A NCC blockage-induced syndrome of inappropriate antidiuretic hormone secretion (SIADH) has been proposed, especially in case of an impaired renal tubular dilutional capacity owing to inability to decrease distal tubular Na+ and Cl− concentration, similar to thiazide-induced hyponatremia mechanism [31]. Additionally, extracellular volume contraction seen in patients with Gitelman syndrome due to urinary Na+ loss may increase antidiuretic hormone release. Patients with Gitelman syndrome exhibit decreased free water clearance [19], a factor that increases the risk of hyponatremia if other contributing factors ensue, such as a substantial increase in free water intake [30, 32], renal tubular salt wasting [32] or pneumonia-induced antidiuretic hormone inappropriate secretion [33].

Mechanisms of blood pressure control and carbohydrate metabolism abnormalities

Even though these patients exhibit hypovolemia-induced elevated angiotensin II and aldosterone levels, their blood pressure tends to be normal or even low. The absence of hypertension is related to renal sodium wasting but also to the increased concentration of angiotensin-converting enzyme 2 (ACE-2), which converts angiotensinogen to angiotensin_1-7 that possess vasodilatory effects. However, hypertension in adulthood is common in patients with Gitelman syndrome possibly due to the chronic elevated levels of angiotensin II and aldosterone [34,35,36].

Both increased and decreased insulin resistance have been described in patients with Gitelman syndrome. Glucose intolerance and insulin resistance are possibly related to chronic hypokalemia/hypomagnesemia [36]. Additionally, impaired insulin secretion compared with healthy subjects has been reported in Gitelman patients [37]. However, increased insulin sensitivity along with reduced oxidative stress as well as improved endothelial function possibly due to reduced angiotensin II signaling have also been found [38,39,40].

Conclusions

Gitelman syndrome is usually characterized by hypokalemic metabolic alkalosis in combination with hypomagnesemia and hypocalciuria, but increased chloride excretion and renin/aldosterone levels, hypophosphatemia (occasionally), hyponatremia (rarely) and glucose intolerance/insulin resistance can be also observed. The knowledge of the associated pathophysiologic mechanisms is useful for the treatment of patients with Gitelman syndrome as well as for the understanding of clinical and laboratory manifestations of other tubular diseases.