**4.3 Gitelman's syndrome**

Gitelman's syndrome refers to an autosomal recessive congenital condition, which is characterized by a hypokalemic alkalosis with hypocalciuria and often hypomagnesaemia (Gitelman, et al., 1966). Gitelman's syndrome has incidence of 1:40,000, which makes it one of the commonest inherited tubulopathies. The electrolyte disturbance mimics that of chronic thiazide diuretic use. Patients with this syndrome have genetic defect in the *SLC12A3* gene encoding the thiazide-sensitive sodium-chloride cotransporter (NCCT) (Simon, et al., 1996a). This cotransporter is located in the apical membrane of distal convoluted tubular (DCT) cells. Defects in NCCT result in reduced sodium reabsorption in the DCT, leading to increased delivery of sodium to the CCD. This leads to increased absorption of sodium via ENaC, coupled with K excretion, leading to hypokalemia. Subsequent stimulation of K reabsorption via H+K+ATPase in intercalated cells results in a metabolic alkalosis. Within the DCT, transcellular absorption of magnesium (via the apical magnesium channel TRPM6 and a putative basolateral Na+/Mg2+ exchanger) is also reduced. The exact mechanism of hypocalciuria has been the subject of speculation for some time. Evidence from studying thiazide treatment in murine models now suggests that as result of volume contraction enhanced proximal tubular sodium reabsorption occurs, and with it, an increase in proximal tubular paracellular absorption of calcium (Nijenhuis, et al., 2005).

Gitelman's syndrome is often asymptomatic into adult life, presenting with weakness, paraesthesia, fatigue and tetany. Salt craving may be a feature. Typically the patients are normotensive and may have polyarthritis and chondrocalcinosis secondary to severe and longstanding hypomagnesaemia (Cobeta-Garcia, et al., 1998). Clinical diagnostic features for Gitelman's syndrome include a low urinary calcium:creatinine ratio (typically <0.2), low serum magnesium (<0.65 mmol/L) and a hypokalemic metabolic alkalosis, once thiazide use is ruled out. Surreptitious ingestion of thiazide may be ruled out by screening the urine. Cisplastin nephrotoxicity may resemble Gitelman's syndrome as may some of the magnesium wasting tubulopathies (Knoers et al., 2003) discussed below. Treatment is with lifelong potassium and magnesium supplements and diet rich in sodium and potassium. Amiloride and spironolactone may also be useful treatments to ensure maintained serum potassium levels. Occasionally, a severe childhood onset phenotype

Renal Potassium Handling and Associated Inherited Tubulopathies Leading to Hypokalemia 97

of salts in a similar manner to NCCT defects, leading to secondary activation of the renin-

Recent molecular genetic studies have identified the basis of Gordon syndrome, also known as pseudohypoaldosteronism type II or chloride shunt syndrome, an autosomal dominant form of hypertension. It is noteworthy and mentioned here given that the diagnostic features resemble a mirror image of Gitelman's syndrome. This includes hyperkalemia, hypertension and hyperchloraemic metabolic acidosis. It can present in early neonatal period with hyperkalemic acidosis or later in life with hypertension. Additional clinical features include short stature, muscle weakness, intellectual impairment and dental abnormalities. Laboratory findings include low fractional excretion of sodium, low renin and aldosterone levels and normal renal function. This syndrome is caused by mutations in the gene encoding WNK4 (Lalioti, et al., 2006), which is a member of serine-threonine protein kinases. In humans, WNK4 is present exclusively in kidney. WNK4 acts as an inhibitor of thiazide-sensitive sodium-chloride co-transporter (NCCT). Mutations in WNK4 relieve this inhibition causing excess sodium retention and subsequent hypertension. Hyperkalemia is explained by inhibition of potassium ROMK channels. Treatment of Gordon syndrome is with low potassium diet and use of thiazide diuretics. Sodium loading

Liddle's syndrome, also called pseudoaldosteronism, is an autosomal dominant disorder which is characterized by early onset severe hypertension, suppressed renin and aldosterone levels and hypokalaemic metabolic alkalosis (Liddle, et al., 1963). This syndrome is a familial renal disorder simulating primary aldosteronism but with negligible aldosterone secretion and is caused by up regulation of epithelial Na channel (ENaC) located in the collecting duct. Up regulation leaves the ENaC in 'open' state which enhances sodium reabsorption and causes hypertension. ENaC is a heterotrimeric protein, its three subunits named alpha, beta and gamma. Mutations in the beta and gamma subunits can cause constitutive channel opening (Hansson, et al., 1995a, Hansson, et al., 1995b). The beta and gamma subunits of ENaC are encoded by *SCNN1B* and *SCNN1G* genes, respectively. A key regulator of ENaC is NEDD4L, which is able to ubiquitinate ENaC leading to its removal from the luminal cell membrane in the renal collecting ducts. It has been postulated that loss of function defects in NEDD4L or alternative splicing of NEDD4L may also lead to hypertension (Dunn, et al., 2002). Patients with Liddle's syndrome are often asymptomatic and they are usually investigated after incidental finding of hypertension. Affected children may have symptomatic polyuria and polydipsia and faltering growth. A strong family history of premature stroke may prompt investigations. Liddle's syndrome should be suspected in a young person with high blood pressure, a family history of hypertension and low serum potassium together with a metabolic alkalosis. However, Liddle's syndrome may mimic essential hypertension as hypokalemia may not always be present (Rossi, et al., 2011). Indeed, genetic variants in ENaC genes may be found in patients with presumed essential hypertension (Hannila-Handelberg, et al., 2005). In Liddle's syndrome, there is a high variability of penetration which appears to be dependent on environmental factors such as dietary salt intake. Because serum and urine aldosterone levels are low, differential diagnosis should include certain forms of congenital adrenal hyperplasia, syndrome of apparent mineralocorticoid

angiotensin-aldosterone axis.

**4.5 Liddle's syndrome** 

should be avoided as it may worsen hypertension.

may occur, mimicking Bartter's syndrome in terms of severity. Early replacement of electrolytes is important and in common with Bartter's syndrome, NSAIDs have been used to good effect to promote growth in these children (Liaw, et al., 1999). Patients with Gitelman's syndrome have very good long term prognosis, however sudden cardiac deaths associated with prolonged QT intervals and cardiac arrhythmias have been reported (Cortesi, et al., 2010). In keeping with this less than benign phenotype, Gitelman's patients may have severe symptoms which are debilitating. For example, weakness, tetany and cramps are often so severe that emergency admissions to hospitals are required for intravenous potassium and magnesium replacement. Indeed, following quality of life questionnaires, Gitelman's patients' scores were comparable to patients with congestive heart failure (Cruz, et al., 2001). As discussed previously, mutations in *CLCNKB* encoding the basolateral chloride channel can also cause a Gitelman's phenotype. CLC-KB is expressed in the DCT as well as the TAL, accounting for this phenotypic overlap. Indeed, patients within the same family with identical *CLCNKB* mutation may present with a spectrum of phenotypes including both Bartter's and Gitelman's syndrome (Zelikovic, et al., 2003). In a recent large cohort of 448 Gitelman's patients, *CLCNKB* mutations accounted for just 3% of cases (Vargas-Poussou, et al., 2011).
