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Dietary reference values for potassium

2016; Wiley; Volume: 14; Issue: 10 Linguagem: Inglês

10.2903/j.efsa.2016.4592

1831-4732

Dominique Turck, Jean-Louis Bresson, Barbara Burlingame, Tara Dean, Susan J. Fairweather‐Tait, Marina Heinonen, Karen Ildico Hirsch‐Ernst, Inge Mangelsdorf, Harry J McArdle, Monika Neuhäuser‐Berthold, Grażyna Nowicka, Kristina Pentieva, Yolanda Sanz, Alfonso Siani, Anders Sjödin, Martin Stern, Daniel Tomé, Henk Van Loveren, Marco Vinceti, Peter Willatts, Peter Aggett, Ambroise Martin, Hildegard Przyrembel, Anja Brönstrup, J Ciok, José Ángel Gómez Ruiz, Agnès de Sesmaisons‐Lecarré, Androniki Naska,

Potassium and Related Disorders

EFSA JournalVolume 14, Issue 10 e04592 Scientific OpinionOpen Access Dietary reference values for potassium EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA), EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA)Search for more papers by this authorDominique Turck, Dominique TurckSearch for more papers by this authorJean-Louis Bresson, Jean-Louis BressonSearch for more papers by this authorBarbara Burlingame, Barbara BurlingameSearch for more papers by this authorTara Dean, Tara DeanSearch for more papers by this authorSusan Fairweather-Tait, Susan Fairweather-TaitSearch for more papers by this authorMarina Heinonen, Marina HeinonenSearch for more papers by this authorKaren Ildico Hirsch-Ernst, Karen Ildico Hirsch-ErnstSearch for more papers by this authorInge Mangelsdorf, Inge MangelsdorfSearch for more papers by this authorHarry McArdle, Harry McArdleSearch for more papers by this authorMonika Neuhäuser-Berthold, Monika Neuhäuser-BertholdSearch for more papers by this authorGrażyna Nowicka, Grażyna NowickaSearch for more papers by this authorKristina Pentieva, Kristina PentievaSearch for more papers by this authorYolanda Sanz, Yolanda SanzSearch for more papers by this authorAlfonso Siani, Alfonso SianiSearch for more papers by this authorAnders Sjödin, Anders SjödinSearch for more papers by this authorMartin Stern, Martin SternSearch for more papers by this authorDaniel Tomé, Daniel ToméSearch for more papers by this authorHenk Van Loveren, Henk Van LoverenSearch for more papers by this authorMarco Vinceti, Marco VincetiSearch for more papers by this authorPeter Willatts, Peter WillattsSearch for more papers by this authorPeter Aggett, Peter AggettSearch for more papers by this authorAmbroise Martin, Ambroise MartinSearch for more papers by this authorHildegard Przyrembel, Hildegard PrzyrembelSearch for more papers by this authorAnja Brönstrup, Anja BrönstrupSearch for more papers by this authorJanusz Ciok, Janusz CiokSearch for more papers by this authorJosé Ángel Gómez Ruiz, José Ángel Gómez RuizSearch for more papers by this authorAgnès de Sesmaisons-Lecarré, Agnès de Sesmaisons-LecarréSearch for more papers by this authorAndroniki Naska, Androniki NaskaSearch for more papers by this author EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA), EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA)Search for more papers by this authorDominique Turck, Dominique TurckSearch for more papers by this authorJean-Louis Bresson, Jean-Louis BressonSearch for more papers by this authorBarbara Burlingame, Barbara BurlingameSearch for more papers by this authorTara Dean, Tara DeanSearch for more papers by this authorSusan Fairweather-Tait, Susan Fairweather-TaitSearch for more papers by this authorMarina Heinonen, Marina HeinonenSearch for more papers by this authorKaren Ildico Hirsch-Ernst, Karen Ildico Hirsch-ErnstSearch for more papers by this authorInge Mangelsdorf, Inge MangelsdorfSearch for more papers by this authorHarry McArdle, Harry McArdleSearch for more papers by this authorMonika Neuhäuser-Berthold, Monika Neuhäuser-BertholdSearch for more papers by this authorGrażyna Nowicka, Grażyna NowickaSearch for more papers by this authorKristina Pentieva, Kristina PentievaSearch for more papers by this authorYolanda Sanz, Yolanda SanzSearch for more papers by this authorAlfonso Siani, Alfonso SianiSearch for more papers by this authorAnders Sjödin, Anders SjödinSearch for more papers by this authorMartin Stern, Martin SternSearch for more papers by this authorDaniel Tomé, Daniel ToméSearch for more papers by this authorHenk Van Loveren, Henk Van LoverenSearch for more papers by this authorMarco Vinceti, Marco VincetiSearch for more papers by this authorPeter Willatts, Peter WillattsSearch for more papers by this authorPeter Aggett, Peter AggettSearch for more papers by this authorAmbroise Martin, Ambroise MartinSearch for more papers by this authorHildegard Przyrembel, Hildegard PrzyrembelSearch for more papers by this authorAnja Brönstrup, Anja BrönstrupSearch for more papers by this authorJanusz Ciok, Janusz CiokSearch for more papers by this authorJosé Ángel Gómez Ruiz, José Ángel Gómez RuizSearch for more papers by this authorAgnès de Sesmaisons-Lecarré, Agnès de Sesmaisons-LecarréSearch for more papers by this authorAndroniki Naska, Androniki NaskaSearch for more papers by this author First published: 25 October 2016 https://doi.org/10.2903/j.efsa.2016.4592Citations: 37 Correspondence: nda@efsa.europa.eu Requestor: European Commission Question number: EFSA-Q-2011-01221 Panel members: Jean-Louis Bresson, Barbara Burlingame, Tara Dean, Susan Fairweather-Tait, Marina Heinonen, Karen Ildico Hirsch-Ernst, Inge Mangelsdorf, Harry McArdle, Androniki Naska, Monika Neuhäuser-Berthold, Grażyna Nowicka, Kristina Pentieva, Yolanda Sanz, Alfonso Siani, Anders Sjödin, Martin Stern, Daniel Tomé, Dominique Turck, Henk Van Loveren, Marco Vinceti and Peter Willatts Acknowledgements: The Panel wishes to thank the EFSA staff members: Sofia Ioannidou and Olga Vidal Pariente for the support provided to this scientific opinion Adopted: 22 September 2016 This publication is linked to the following EFSA Supporting Publications article: http://onlinelibrary.wiley.com/wol1/doi/10.2903/sp.efsa.2016.EN-1095/abstract AboutSectionsPDF ToolsExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Abstract Following a request from the European Commission, the EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA) derives dietary reference values (DRVs) for potassium. The Panel decides to set DRVs on the basis of the relationships between potassium intake and blood pressure and stroke. The Panel considers that randomised controlled trials and an observational cohort study carried out in a European adult population provide evidence that a potassium intake of 3,500 mg (90 mmol)/day has beneficial effects on blood pressure in adults. Furthermore, there is consistent evidence from observational cohort studies that potassium intakes below 3,500 mg/day are associated with a higher risk of stroke. Available data cannot be used to determine the average requirement of potassium but can be used as a basis for deriving an adequate intake (AI). A potassium intake of 3,500 mg/day is considered adequate for the adult population and an AI of 3,500 mg/day for adult men and women is proposed. For infants and children, the AIs are extrapolated from the AI for adults by isometric scaling and including a growth factor. An AI of 750 mg (19 mmol)/day is set for infants aged 7–11 months. For children, AIs from 800 mg (20 mmol)/day (1–3 years old) to 3,500 mg/day (15–17 years old) are set. Considering that the daily accretion rate of potassium in fetal and maternal tissues can be met by the adaptive changes which maintain potassium homeostasis during pregnancy, the AI set for adults applies to pregnant women. For lactating women, the amount of potassium needed to compensate for the losses of potassium through breast milk is estimated and an AI of 4,000 mg (102 mmol)/day is proposed. Summary Following a request from the European Commission, the EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA) was asked to deliver a Scientific Opinion on Dietary Reference Values (DRVs) for the European population, including potassium. Potassium is an essential mineral in the human diet. It is the predominant osmotically active element inside cells. It plays a major role in the distribution of water inside and outside cells, assists in the regulation of the acid–base balance, and contributes to establishing a membrane potential which supports electrical activity in nerve fibres and muscle cells. Potassium has a role in cell metabolism, participating in energy transduction, hormone secretion, and the regulation of protein and glycogen synthesis. Potassium is present in all natural foods, in particular starchy roots or tubers, vegetables, fruits, whole grains, dairy products and coffee. Based on the data from 13 dietary surveys in nine countries of the European Union, average potassium intakes ranged between 821 and 1,535 mg (21 and 39 mmol)/day in infants (< 1 year), between 1,516 and 2,005 mg (39 and 51 mmol)/day in children aged 1 to < 3 years, between 1,668 and 2,750 mg (43 and 70 mmol)/day in children aged 3 to < 10 years, between 2,093 and 3,712 mg (54 and 95 mmol)/day in children aged 10 to < 18 years, and between 2,463 and 3,991 mg (63 and 102 mmol)/day in adults (≥ 18 years). Potassium deficiency, presenting as hypokalaemia, is defined as a serum potassium concentration lower than 3.5 mmol/L and is usually caused by increased potassium losses (e.g. via diarrhoea, vomiting or excessive renal losses) or intracellular shift of potassium (e.g. during alkalosis). Hypokalaemia resulting from insufficient dietary intake is rare and may be associated with severe hypocaloric diets, or with a relative insufficiency caused by an increased requirement of potassium for the synthesis of tissue during recovery from malnutrition. About 90% of dietary potassium is absorbed, mainly in the small intestine. Body potassium content is regulated by the balance between dietary intake and renal excretion. Urine is the major route of potassium excretion, while the remaining part is eliminated in the faeces and, to a lesser extent, in the sweat. Urinary potassium excretion, based on 24-h urine collection, is regarded as a reliable biomarker of dietary intake in adults on a population basis. Most of body potassium is located in the muscle, with lower amounts present in the bone, liver, skin and red blood cells. Because of tight homeostatic mechanisms, blood potassium concentrations and total body potassium content are only minimally affected by variations in dietary potassium intake. The Panel therefore considers that there is no suitable biomarker of potassium status which can be used for setting DRVs for potassium in the general population. Potassium intake has been reported to be associated with several health outcomes, particularly cardiovascular endpoints. Overall, the Panel considers that randomised controlled trials and an observational cohort study carried out in a European adult population provide evidence that a potassium intake of 3,500 mg (90 mmol)/day has beneficial effects on blood pressure in adults. Furthermore, there is consistent evidence from observational cohort studies that potassium intakes below 3,500 mg (90 mmol)/day are associated with a higher risk of stroke. Evidence on the association between potassium intake and coronary heart disease is unclear and inconsistent. Evidence in relation to diabetes mellitus type 2, kidney stones and bone health were also reviewed but the available data could not be used to derive DRVs for potassium. The Panel decides to set DRVs for potassium based on the relationship between potassium intake and blood pressure and stroke. Currently, available data cannot be used to determine the average requirement of potassium but can be used as a basis for deriving an adequate intake (AI). A potassium intake of 3,500 mg (90 mmol)/day can be considered adequate for the adult population and an AI of 3,500 mg (90 mmol)/day for adult men and women is proposed. No data are available on which to base an average potassium requirement for infants and children. The Panel derives AIs extrapolated from the AI for adults, taking into account differences in reference body weight (isometric scaling) and including a growth factor to take into account requirements for growth. The AI set for infants aged 7–11 months is 750 mg (19 mmol)/day. For children, AIs range from 800 mg (20 mmol)/day (1–3 years old) to 3,500 mg (90 mmol)/day (15–17 years old). The Panel considers that the requirement for the daily accretion rate of potassium in fetal and maternal tissues can be met by the adaptive changes which maintain potassium homeostasis during pregnancy. The AI for pregnant women is set at 3,500 mg (90 mmol)/day, the same as for non-pregnant women. Considering evidence which indicates that total body potassium content decreases in lactating women, a conservative approach is taken and the amount of potassium needed to compensate for the losses of potassium through breast milk is added to the AI for adult. Thus, an AI of 4,000 mg (102 mmol)/day is proposed for lactating women. Background as provided by the European Commission The scientific advice on nutrient intakes is important as the basis of Community action in the field of nutrition, for example such advice has in the past been used as the basis of nutrition labelling. The Scientific Committee for Food (SCF) report on nutrient and energy intakes for the European Community dates from 1993. There is a need to review and, if necessary, to update these earlier recommendations to ensure that the Community action in the area of nutrition is underpinned by the latest scientific advice. In 1993, the SCF adopted an opinion on the nutrient and energy intakes for the European Community.1 The report provided Reference Intakes for energy, certain macronutrients and micronutrients, but it did not include certain substances of physiological importance, for example dietary fibre. Since then new scientific data have become available for some of the nutrients, and scientific advisory bodies in many European Union (EU) Member States and in the United States have reported on recommended dietary intakes. For a number of nutrients, these newly established (national) recommendations differ from the reference intakes in the SCF (1993) report. Although there is considerable consensus between these newly derived (national) recommendations, differing opinions remain on some of the recommendations. Therefore, there is a need to review the existing EU Reference Intakes in the light of new scientific evidence, and taking into account the more recently reported national recommendations. There is also a need to include dietary components that were not covered in the SCF opinion of 1993, such as dietary fibre, and to consider whether it might be appropriate to establish reference intakes for other (essential) substances with a physiological effect. In this context, the European Food Safety Authority (EFSA) is requested to consider the existing population reference intakes (PRIs) for energy, micro- and macronutrients and certain other dietary components, to review and complete the SCF recommendations, in the light of new evidence, and in addition advise on a PRI for dietary fibre. For communication of nutrition and healthy eating messages to the public, it is generally more appropriate to express recommendations for the intake of individual nutrients or substances in food-based terms. In this context, EFSA is asked to provide assistance on the translation of nutrient-based recommendations for a healthy diet into food based recommendations intended for the population as a whole. Terms of reference as provided by the European Commission In accordance with Article 29 (1)(a) and Article 31 of Regulation No 178/20022, the Commission requests EFSA to review the existing advice of the Scientific Committee for Food on PRIs for energy, nutrients and other substances with a nutritional or physiological effect in the context of a balanced diet which, when part of an overall healthy lifestyle, contribute to good health through optimal nutrition. In the first instance, EFSA is asked to provide advice on energy, macronutrients and dietary fibre. Specifically advice is requested on the following dietary components: carbohydrates, including sugars; fats, including saturated fatty acids, polyunsaturated fatty acids and monounsaturated fatty acids, trans fatty acids; protein; dietary fibre. Following on from the first part of the task, EFSA is asked to advise on PRIs of micronutrients in the diet and, if considered appropriate, other essential substances with a nutritional or physiological effect in the context of a balanced diet which, when part of an overall healthy lifestyle, contribute to good health through optimal nutrition. Finally, EFSA is asked to provide guidance on the translation of nutrient-based dietary advice into guidance, intended for the European population as a whole, on the contribution of different foods or categories of foods to an overall diet that would help to maintain good health through optimal nutrition (food-based dietary guidelines). Assessment 1 Introduction In 1993, the Scientific Committee for Food (SCF) adopted an opinion on nutrient and energy intakes for the European Community. For potassium, the SCF proposed a population reference intake (PRI) of 3,100 mg (80 mmol)/day for adults, including pregnancy and lactation, and a Lower Threshold Intake of 1,600 mg (40 mmol)/day, which was accepted as the intake needed to avoid low plasma potassium concentrations (SCF, 1993). 2 Definition/category 2.1 Chemistry Potassium (K) is an abundant and highly reactive alkali metal which makes up 2.4 mass% of the Earth's crust. It has an atomic mass of 39.1 Da. Potassium is present in only one oxidation state (+ 1). It is a powerful reducing agent that is easily oxidised. Because of its high reactivity, potassium is not found free in nature but only as salts. Potassium compounds have good water solubility. Naturally occurring potassium is composed of three isotopes, namely the stable isotopes 39K (natural abundance 93.3%) and 41K (6.7%), and the radioactive isotope 40K (0.01%), which has a very long half-life (1.251 × 109 years). The latter is responsible for most of the naturally occurring radioactivity in the body (Kee et al., 2010; Crook, 2012). 2.2 Function of potassium 2.2.1 Biochemical functions Potassium is an essential mineral in the human diet. Potassium is the predominant osmotically active element inside cells. Together with sodium and chloride, which are characteristic of the extracellular fluid, potassium contributes to osmolarity and plays a major role in the distribution of fluids inside and outside cells. In addition, potassium participates in the regulation of the acid–base balance. Differences in potassium and sodium concentrations across cell membranes are maintained by the specific permeability of membranes to each of these ions and by Na+/K+-ATPase activity, which pumps sodium out of and potassium into the cells (Bailey et al., 2014; Gumz et al., 2015). The enzyme Na+/K+-ATPase plays an important role in the strict homeostatic control of plasma potassium concentrations. As a result, the intracellular potassium concentration is about 30 times higher than that of plasma and interstitial fluid. This concentration gradient (largely responsible for driving the membrane potential) is important for the transmission of electrical activity in nerve fibres and muscle cells. Small changes in the ratio of extracellular to intracellular potassium concentration have large effects on neural transmission, muscle contraction and vascular tone (Bailey et al., 2014; Gumz et al., 2015). Potassium transport across the membranes of the endothelial and vascular smooth muscle cells has important effects on their contractile state, which can, in turn, influence endothelial function, blood flow and blood pressure (Haddy et al., 2006). The concentration of potassium in cells of the collecting duct system of the kidney is important for the excretion of sodium. Maintenance of the transmembrane gradient is the key element for electrolytes and fluid homeostasis, a critical factor in blood pressure regulation (Bailey et al., 2014; Gumz et al., 2015). Passive transport of potassium occurs via intracellular and paracellular pathways. The intracellular transport mechanism involves potassium channels. Channels have 'gates' which open or close in response to specific stimuli, such as voltage, ATP, ionic calcium concentration, hormones and neurotransmitters. Various stimuli sometimes act together on a channel. Potassium channels exhibit great diversity and may be divided into four main groups: voltage-gated (Kv) channels; calcium-activated (KCa) channels, covering big conductance (BK), intermediate conductance (IK), and small conductance (SK) channels; inwardly rectifying (Kir) channels, and two-pore domain (K2P) channels (Heitzmann and Warth, 2008; Horn et al., 2014). Different types of potassium channels have been implicated in functions such as salivary secretion, bile and gastric acid secretion, protein digestion and absorption, insulin secretion, carbohydrate digestion and absorption, and taste transduction. Potassium has a role in cell metabolism, participating in energy transduction, hormone secretion and the regulation of protein and glycogen synthesis. Potassium is a cofactor for a number of enzymes including glycerol dehydrogenase, mitochondrial pyruvate carboxylase, pyruvate kinase, l-threonine dehydratase, ATPases and aminoacyl transferase (Page and Di Cera, 2006; Toraya et al., 2010). 2.2.2 Health consequences of deficiency and excess 2.2.2.1 Deficiency Potassium deficiency, presenting as hypokalaemia, is defined as a serum potassium concentration lower than 3.5 mmol/L (Pepin and Shields, 2012). In general, deficiency may be caused by increased potassium losses via diarrhoea, vomiting, burns or excessive renal losses (owing, for example, to renal tubular acidosis, high secretion of mineralocorticoids, some diuretics) leading to low total body potassium (Crop et al., 2007; Rodenburg et al., 2014). Hypokalaemia can also occur when total body potassium is normal in case of an intracellular shift of potassium (Rastegar, 1990). The most important causes of an intracellular shift include alkalosis, insulin excess, catecholamine excess and familial periodic paralysis (i.e. a genetic disease related to malfunction in the ion channels in skeletal muscle cell membranes) (Gumz et al., 2015). Hypokalaemia resulting from insufficient dietary intake is rare and may be associated with severe hypocaloric diets or occur as the result of an increased requirement needed for the synthesis of new tissue (e.g. muscle) during recovery from malnutrition. Hypokalaemia is generally associated with increased morbidity and mortality, especially from cardiac arrhythmias or sudden cardiac death. When serum potassium concentration is < 3 mmol/L, the prevalence of malignant ventricular arrhythmia has been observed to increase twofold in patients on diuretic treatment (Byatt et al., 1990). The risk of atrial fibrillation is higher in hypokalaemic subjects compared to the general population (Krijthe et al., 2013). Other adverse consequences of hypokalaemia include polyuria, muscle weakness, decreased peristalsis possibly leading to intestinal ileus, mental depression and respiratory paralysis in severe cases (Rodenburg et al., 2014). 2.2.2.2 Excess Hyperkalaemia is commonly defined as a serum potassium concentration greater than approximately 5.5 mmol/L in adults (Pepin and Shields, 2012; Michel et al., 2015). Hyperkalaemia is often asymptomatic and diagnosed because of conduction abnormalities on the electrocardiogram (Lehnhardt and Kemper, 2011). Clinical manifestations of mild to moderate hyperkalaemia are usually non-specific and may include generalised weakness, paralysis, nausea, vomiting and diarrhoea (Pepin and Shields, 2012). Severe hyperkalaemia may lead to life-threatening cardiac arrhythmias (Paice et al., 1983; Lehnhardt and Kemper, 2011). Hyperkalaemia is rare in the general population. The majority of cases occur from impaired renal function (Lehnhardt and Kemper, 2011; Crook, 2012). Non-renal causes include inappropriately high intakes of oral potassium supplements or parenteral potassium administration and a potassium shift from cells (for instance in the case of metabolic acidosis, hypoxia, severe tissue damage). Hyperkalaemia following excessive dietary intake of potassium is rare because of the effective homeostasis mediated by increased cellular uptake of potassium from the bloodstream by various organs and increased urinary excretion (Lehnhardt and Kemper, 2011). No tolerable upper intake level (UL) has been set for potassium by EFSA due to insufficient data (EFSA, 2005). The Panel considered that the risk of adverse effects from potassium intake from food sources (up to 5,000–6,000 mg (129–154 mmol)/day in adults) is low for the general healthy population. It also stated that long-term intakes of about 3,000 mg (77 mmol) potassium/day as potassium chloride supplements, in addition to intake from food, have been shown not to have adverse effects in healthy adults (Cappuccio et al., 2016). A few case studies have reported that supplemental potassium in doses of 5,000–7,000 mg (128–179 mmol)/day can cause adverse effects on heart function in apparently healthy adults. Gastrointestinal symptoms have been observed in healthy subjects taking some forms of potassium supplements (e.g. slow release, wax-matrix formulations) with potassium doses ranging from about 1,000 to 5,000 mg (26–128 mmol)/day, but incidence and severity seem to depend more on the formulation than on the dose (EFSA, 2005). 2.3 Physiology and metabolism 2.3.1 Intestinal absorption About 90% of dietary potassium is absorbed, mainly in the small intestine, mostly through passive mechanisms in response to electrochemical gradients (Agarwal et al., 1994; Bailey et al., 2014). In the proximal small intestine, water absorption provides a driving force for the movement (solute drag) of potassium across the intestinal mucosa. In the ileum, the transepithelial electrical potential difference strongly influences its movement. It has been hypothesised that potassium may also be actively absorbed in the small intestine due to the presence of an H+/K+-ATPase in the apical membrane (Heitzmann and Warth, 2008). In surface cells of the distal colon, potassium is excreted through apical potassium channels in exchange for sodium which is reabsorbed through epithelial sodium channels. Potassium may also be reabsorbed in the colon through the action of luminal H+/K+-ATPases (colonic type), which can be of importance during potassium deprivation (Meneton et al., 1998). 2.3.2 Transport in blood In healthy individuals, serum potassium concentrations range between 3.5 and 5.5 mmol/L, whereas plasma concentrations are lower by about 0.3–0.4 mmol/L. This difference is due to a release of potassium during clot formation (Nijsten et al., 1991; Sevastos et al., 2008). Homeostatic mechanisms act to maintain blood potassium concentration within a narrow range, even in the presence of wide variations in dietary potassium intake (Giebisch, 1998, 2004; Palmer, 2014; Gumz et al., 2015) (Section 2.3.3). In plasma, most potassium is present as free ions and 10–20% is bound to proteins (Ifudu et al., 1992). 2.3.3 Distribution to tissues Around 98% of systemic potassium is within the cells, making potassium the major intracellular cation. Most of body potassium is located in the muscle (70%), with lower amounts present in the bone, liver, skin and red blood cells (Weiner et al., 2010). Most of the body potassium (about 85%) is rapidly exchangeable (half time of less than 7 h), while exchanges with red blood cells and brain pools are slower (Jasani and Edmonds, 1971). Intra- and extracellular concentrations of potassium are maintained within narrow limits. After a meal, potassium is absorbed and rapidly enters the extracellular fluid. The subsequent rise in plasma potassium concentration is quickly attenuated by cellular uptake (Giebisch, 1998; Palmer, 2014). Na+/K+-ATPase is responsible for the active transport of potassium into the cells and for the maintenance of the extra- and intracellular sodium and potassium concentrations against electrochemical gradients. This ATPase is found in the cytoplasmic membrane of virtually all cells (McDonough and Nguyen, 2012). Potassium is also actively transported into some gastrointestinal cells and renal tubules by H+/K+-ATPase (Sections 2.3.1 and 2.3.5.1). Various Na+-K+-Cl− cotransporters, which carry Na+, K+ and Cl− into the cell and are driven by the force of ion gradients, have been identified in the salivary glands, gastrointestinal tract and renal tubules (Sections 2.3.1 and 2.3.5.1). The K+-Cl− cotransporter plays an important role for erythrocytes to maintain a specific shape and mediates potassium efflux (Lote, 2007). Potassium transfer between the extra- and intracellular milieus is influenced by a variety of endogenous and exogenous factors (Gumz et al., 2015). Cellular potassium uptake by the muscle, liver, bone and red blood cells is promoted by the increase in plasma potassium concentration, by insulin, epinephrine and aldosterone, by metabolic alkalosis, and by drugs activating β-2 adrenergic receptors. Conversely, a decrease in plasma potassium concentration, metabolic acidosis, hyperosmolarity of the extracellular fluid, and α-antagonist drugs induce potassium transport from cells to the extracellular fluid. Hyperkalaemia stimulates the secretion of insulin, aldosterone and epinephrine, while hypokalaemia has the opposite effect (Giebisch, 2004; Grossman et al., 2013). The mechanisms of fetoplacental potassium transfer have not been fully elucidated. Animal studies indicate that potassium is actively transported across the placenta and that the developing fetus is efficient in maintaining consta