**3. When hypokalemia may be the presentation of an inherited tubulopathy?**

Physiological serum potassium levels are usually tightly maintained between 3.5-5.0 mmol/L. Hypokalemia represents a deviation from this regulation and may be defined as mild, moderate or severe. Mild hypokalemia (Serum K+ 3.0-3.5 mmol/L) is usually asymptomatic whilst moderate hypokalemia (Serum K+ 2.5-3.0 mmol/L) may present with muscle weakness, myalgia, arrhythmias, cramps and constipation. With severe hypokalemia, (K+ <2mmol/L), hyporeflexia, flaccid paralysis and occasionally rhabdomyolysis occur. There are many causes of hypokalemia to be considered before a renal tubulopathy is suspected. These can be divided into an assessment of potassium intake, potassium distribution within tissues and potassium excretion (see Table 1). In order to assess this, a careful history including history of drugs and over the counter medications, and the presence of Gastrointestinal (GI) disturbance (vomiting or diarrhoea) should be sought. Clinical examination (including blood pressure (BP) and orthostatic changes in BP)) is also necessary. This, combined with serum and urine biochemistry (including osmolality) will help to assess the causes of hypokalemia. Occasionally, a high WBC count may be associated with a spurious low serum potassium level. Pseudohypokalemia has recently been reported in 2 patients with hereditary spherocytosis secondary to AE1 mutations (Norgett, et al., 2011).

Potassium is present in a wide variety of foods (citrus fruits, vegetables, meat). Therefore, examples of inadequate intake are limited to anorexia, bulimia, alcoholism and starvation. Certain factors may affect the distribution of potassium from extracellular to intracellular compartments, leading to hypokalemia. Endogenous or administered insulin, catecholamines, beta-agonists and metabolic alkalosis will all promote cellular uptake of potassium. Excretion of potassium may be grouped into extra renal loss and renal loss. Extra renal loss of potassium is mainly via the gastrointestinal tract (GI) and may occur with diarrhoea, GI fistulas, and laxative abuse. Renal loss of potassium may be associated with a variety of acquired and inherited tubular disorders and drugs. Amphotericin B, aminoglycosides and cisplatin all increase renal potassium losses. Many diuretics, apart

Renal Potassium Handling and Associated Inherited Tubulopathies Leading to Hypokalemia 93

careful drug and dietary histories are taken, together with urine electrolytes and serum

Bartter's syndrome is an autosomal recessive renal disorder described by Bartter et al. in 1962 (Bartter, et al., 1962). It has estimated incidence of 1.2 per million (Rudin, 1988). Impaired salt (sodium chloride) reabsorption in the thick ascending loop of Henle (TAL) leads to renal salt wasting and a hypokalemic metabolic alkalosis. The majority of cases present in the early neonatal period with salt-losing crises. An antenatal diagnosis can also be suspected if a pregnancy is complicated by polyhydramnios or premature birth (Sieck &Ohlsson, 1984). Bartter's syndrome is also associated with short stature, growth retardation in infancy, muscle weakness, polyuria and polydipsia. Some children have characteristic facies that are triangular-shaped with a prominent forehead, large eyes, protruding ears and a drooping mouth. Blood pressure is normal. Bartter's syndrome should be suspected in patient presenting with the above symptoms and signs and the following laboratory findings: hypokalemic alkalosis, high urinary chloride and urinary potassium levels and normal or raised urinary calcium level. Serum magnesium levels are

The biochemical abnormalities are a consequence of renal salt wasting in the TAL. This stimulates the renin-angiotensin II-aldosterone system (RAAS) and causes hyperplasia of juxtaglomerular apparatus, a feature originally noted by Bartter (Bartter, et al., 1962). Raised RAAS increases sodium reabsorption in the distal nephron (via ENaC) in exchange for K+ and H+, which leads to hypokalemic alkalosis. Increases in prostaglandin E2 synthesis aggravate the salt wasting by its effect on ROMK1 and NKCC2. Despite raised RAAS, leading to hyperreninemia and hyperaldosteronism, patients with Bartter's syndrome remain normotensive. The various phenotypes of Bartter's syndrome are now more simply

Antenatal Bartter's syndrome (Type 1) is caused by homozygous or compound heterozygous mutation in the *SLC12A1* gene, encoding NKCC2 (Simon, et al., 1996a). NKCC2 is kidney specific, electroneutral transporter protein, located at the apical membrane

Type 1 is a severe form of Bartter's syndrome which may present in utero with marked polyhydramnios and premature birth. Amniocentesis shows high chloride (and aldosterone) levels. Analysis of a pregnant mother's urine may also suggest the diagnosis, demonstrating low Na+, Cl- and Ca2+ (Matsushita, et al., 1999). A definitive diagnosis may be made using

Prenatal diagnosis is important as indomethacin may be a useful treatment for polyhydramnios (Smith et al., 1990). and early neonatal treatment may be life saving. Neonates typically present with severe salt-wasting crises, hypokalemic alkalosis, vomiting and diarrhoea. The latter two symptoms are due to renal activation of prostaglandin synthesis, as a consequence of hypokalemia. A feature that distinguishes this type from others is marked hypercalciuria, which causes nephrocalcinosis and osteopenia in infancy. Treatment is with potassium supplements, often combined with potassium-sparing diuretics (such as spironolactone and amiloride) and inhibitors of

mutational analysis of DNA from amniocytes (Konrad, et al., 1999).

**4. Inherited tubulopathies leading to hypokalemic alkalosis** 

biochemistry.

**4.1 Bartter's syndrome** 

typically normal or mildly low.

of the TAL (Simon, et al., 1996a).

classified by their underlying genetic mutation.

from potassium-sparing ones, cause increased urinary losses of potassium. Magnesium depletion may also lead to renal potassium wasting. A 24 h urine collection can be used to assess renal potassium excretion in a hypokalemia patient. This should be < 15 mmol/24 h if there is extra renal potassium wasting. In a similar way, a spot urine for a potassium/creatinine ratio should be less than 1 in the presence of extra renal potassium wasting. Calculations of transtubular potassium gradient will give similar information. Urinary chloride will also be low in cases of significant GI volume losses (vomiting, diarrhoea, laxative abuse). If renal K wasting is suspected and confirmed then further thought regarding the blood pressure and acid base status of the patient aids the diagnosis of hypokalemia**.** 



Reasons to suspect an inherited tubulopathy may include evidence for a persistent electrolyte disturbance, the presence of renal impairment, nephrocalcinosis and renal stone formation (Sayer &Pearce, 2001). A detailed and extensive family history is necessary. In paediatric cases, faltering growth, abnormal growth patterns, developmental delay and deafness may all be clues to an inherited tubulopathy. Neonates may present with a saltwasting crisis and are particularly sensitive to severe hypovolemia and electrolyte disturbance due to immature tubular physiology and low-salt intakes in standard feeds. With nephron maturation, the propensity to present with salt-wasting crises decreases. Individual tubular diseases can be differentiated by their serum and urine biochemical profiles (discussed below). Hypokalemia may be the only presenting feature of a tubulopathy and it is important to follow the diagnostic 'lead' to differentiate the many causes. Nephrocalcinosis should be thoroughly investigated and differential diagnosis such as hyperparathyroidism, vitamin D intoxication and sarcoidosis first excluded. Renal tubular disorders associated with nephrocalcinosis include Bartter's syndrome, Dent's disease, hypomagnesemic hypercalciuric nephrolithiasis, idiopathic hypercalciuria and distal renal tubular acidosis.

Renal tubulopathies are best investigated by urine pH and 24-hour urine collection for potassium, calcium, magnesium, citrate and phosphate along with serum biochemistry. Nevertheless, renal tubulopathies are rare and they should be considered only after careful drug and dietary histories are taken, together with urine electrolytes and serum biochemistry.
