**2. Renal tubular handling of potassium**

## **2.1 Glomerular filtration and proximal tubule**

Glomerular filtration produces >160 L of filtrate per day in a healthy adult, and 99% of this volume and majority of filtered solutes are reabsorbed along the nephron. The filtrate is identical to that of plasma with respect to water and solutes of low molecular weight, such as glucose, chloride, sodium, phosphate, urea, uric acid, creatinine and potassium.

The proximal convoluted tubule is responsible for reabsorption of glucose, amino acids, phosphate, sodium and low-molecular weight proteins. Around 65% of filtered sodium is reabsorbed in the proximal tubule. Potassium reabsorption is closely coupled to sodium transport (driven passively by the electrical gradient) and around 75% of filtered potassium is reabsorbed by the proximal convoluted tubule. The proximal straight tubule may secrete some potassium into the urine, and this secretion can be upregulated significantly in

Renal Potassium Handling and Associated Inherited Tubulopathies Leading to Hypokalemia 91

The connecting tubules, initial collecting tubule and the cortical collecting duct, are major sites of regulated potassium secretion. Indeed, potassium secretion in these nephron segments may be upregulated to exceed the filtered load of potassium. In addition, if potassium reabsorption is required, this part of the nephron and regions of the medullary collecting duct may reabsorb potassium. In the cortical collecting duct two important cell

In principal cells, sodium entry occurs via selective sodium channels (ENaCs), located on apical membrane. Potassium secretion in these cells occurs by a transcellular movement of potassium, mediated by a basolateral Na+K+ATPase pump and apical ROMK potassium

The distribution of ENaC channels within the apical membrane is regulated by effects of aldosterone on the mineralocorticoid receptor. The ENaC channel has three subunits: alpha, beta and gamma encoded by genes *SCNN1A*, *SCNN1B* and *SCNN1C.* Alpha-intercalated cells in the cortical collecting duct mediate potassium reabsorption. An apical H+K+ATPase pump allows potassium reabsorption coupled to proton excretion, whilst an apical proton pump transports hydrogen ions into the lumen. In states of potassium depletion, there is

**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

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

types mediate potassium transport: principal cells and intercalated cells.

channels. Potassium secretion is directly linked to sodium entry via ENaC.

upregulation of the apical H+K+ATPase pump in alpha intercalated cells.

spherocytosis secondary to AE1 mutations (Norgett, et al., 2011).

**2.5 The collecting ducts** 

patients with chronic kidney disease. Generalized defects in proximal tubule handling of solutes result in Fanconi syndrome syndrome. Specific proximal tubular handling defects leading to hypokalemia include proximal renal tubular acidosis, and have been recently reviewed elsewhere (Fry &Karet, 2007).
