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Achieving the Benefits of a High-Potassium, Paleolithic Diet, Without the Toxicity

      Abstract

      The average US dietary intake of K+ is well below the current recommended nutritional requirements. This deficiency is even more striking when comparing our current intake with that of our ancestors, who consumed large amounts of dietary K+. K+ deficiency has been implicated in many diseases including cardiovascular disease, kidney stones, and osteoporosis. Importantly, dietary supplementation of K+ has favorable effects on reducing blood pressure, decreasing the risk of stroke, improving bone health, and reducing the risk of nephrolithiasis. For this comprehensive review, we scanned the literature using PubMed and MEDLINE using the following search terms: potassium intake, renal potassium excretion, and prevention of hyperkalemia. Articles were selected for inclusion if they represented primary data or review articles published between 1980 and 2015 in high-impact journals. The normal kidney has the capacity to tightly regulate K+ homoeostasis. We discuss new findings with respect to sensing mechanisms by which the kidney maintains K+ homeostasis in the gastrointestinal tract and distal tubule. There are widely prescribed hypertensive medications that cause hyperkalemia and thus require dietary K+ restriction. We conclude by discussing newly approved drugs capable of binding K+ in the gastrointestinal tract and speculate that this new pharmacology might allow diet liberalization in patients at risk for hyperkalemia, affording them the numerous benefits of a K+-rich diet.

      Abbreviations and Acronyms:

      ASDN (aldosterone-sensitive distal nephron), CKD (chronic kidney disease), DCT (distal convoluted tubule), DCT1 (proximal portion of the distal convoluted tubule), DCT2 (distal portion of the distal convoluted tubule), ENaC (epithelial Na+ channel), KS (kidney specific), NCC (NaCl cotransporter), NHANES (National Health and Nutrition Examination Survey), RAAS (renin-angiotensin-aldosterone system), ROMK (renal outer medullary K+), WNK (with no lysine family of kinases), WNK1 (WNK lysine-deficient protein kinase 1), WNK4 (WNK lysine-deficient protein kinase 4)
      Article Highlights
      • Over several million years, physiology and metabolism of humans evolved to retain Na+ and excrete K+ in response to a diet that was low in Na+ and high in K+. With the onset of agriculture and industrialization, there has been a precipitous drop in dietary K+ consumption and an equal rise in dietary salt consumption, contributing to disease onset. This is further supported by the fact that the newest Dietary Guidelines for Americans have listed K+ as a “nutrient of public health concern” because of its inadequate consumption. Low K+ intake is then implicated in various chronic diseases including hypertension, cardiovascular disease, osteoporosis, and nephrolithiasis.
      • The ability to maintain K+ homeostasis in the setting of high dietary intake is regulated by the normal kidney. In addition to the well-recognized role of aldosterone in renal K+ secretion, recent findings have identified the presence of an enteric K+ sensing mechanism that can initiate the renal secretory process upon K+ entry into the gastrointestinal tract. In addition, the distal convoluted tubule has been identified as a K+ sensor capable of initiating K+ exertion independent of mineralocorticoid activity.
      • Increased dietary K+ intake has been linked to various health benefits including decreased blood pressure, reduced risk of stroke, improved bone health, and a reduction in the risk of renal stone disease. At the same time, drugs used to treat hypertension result in increased K+ concentrations, requiring dietary restriction of K+-enriched foods.
      • A plant-based (K+-enriched) diet offers benefits that include reduced phosphorus absorption and improvement in metabolic acidosis. A limitation of such a diet can be the development of hyperkalemia in patients with impaired renal K+ excretion.
      • New drugs designed to bind K+ in the gastrointestinal tract are now available. These drugs have been shown to be effective in maintaining normokalemia in the setting of ongoing use of blockers of the renin-angiotensin-aldosterone system in patients previously intolerant of these drugs due to hyperkalemia. These drugs may allow patients to liberalize their diets so as to receive the benefits of a K+-enriched diet without development of hyperkalemia.
      Potassium is an extremely important mineral, as supported by the recent Dietary Guidelines for Americans and the Food and Drug Administration designation that K+ is a “nutrient of public health concern” because of its general underconsumption across the US population.
      • DeSalvo K.B.
      • Olson R.
      • Casavale K.O.
      Dietary Guidelines for Americans [published online ahead of print January 07, 2016].
      Underconsumption of K+ is associated with hypertension and cardiovascular diseases, 2 common adverse diet-related health outcomes in the United States.
      • DeSalvo K.B.
      • Olson R.
      • Casavale K.O.
      Dietary Guidelines for Americans [published online ahead of print January 07, 2016].
      In 2004, the Food and Nutrition Board of the Institute of Medicine

      Food and Nutrition Board, Institute of Medicine. Potassium. In: Dietary Reference Intakes for Water, Potassium, Sodium, Chloride, and Sulfate. Washington, DC: National Academies Press; 2005:186–268.

      recommended intake levels of 4700 mg/d. Despite these recommendations, data from the National Health and Nutrition Examination Survey (NHANES) 2007 to 2008 estimated mean intakes in the United States to be 2290 mg/d for women and 3026 mg/d for men, substantially lower than the suggested values.
      • Cogswell M.
      • Zhang Z.
      • Carriquiry A.
      • et al.
      Sodium and potassium intakes among US adults: NHANES 2003-2008.
      This relative “deficiency” of dietary K+ is even more noteworthy when one considers that the K+ intake of prehistoric humans was estimated to be 15,000 mg/d, which actually exceeds the NHANES recommendations by a factor greater than 4.
      • Eaton S.B.
      • Konner M.
      Paleolithic nutrition: a consideration of its nature and current implications.
      • Sebastian A.
      • Frassetto L.A.
      • Sellmeyer D.E.
      • Morris Jr., R.C.
      The evolution-informed optimal dietary potassium intake of human beings greatly exceeds current and recommended intakes.
      Not only are diets of Western industrialized societies lower in K+ intake, but they also differ from prehistoric cultures with respect to Na+ intake. The daily intake of salt in Western industrialized societies is about 3 times higher than the daily intake of K+ on a molar basis, whereas salt intake in primitive cultures is approximately 7 times lower than K+ intake.
      • Young D.B.
      • Lin H.
      • McCabe R.D.
      Potassium's cardiovascular protective mechanisms.
      The changes in K+ and Na+ intake over time reflect a shift from traditional plant-based diets high in K+ and low in Na+ (characterized by fruits, leafy greens, roots, and tubers) to processed foods high in Na+ and low in K+. The transition to processed foods began approximately 10,000 years ago with the onset of agriculture. This time period is short in comparison to the preceding several million-year period dating from the Stone Age to the onset of agriculture. Inadequate consumption of K+ combined with excessive intake of Na+ contributes to the pathophysiology of various chronic diseases such as obesity, hypertension, diabetes, kidney stones, and bone disease.
      One prevailing hypothesis is that our current diet represents a mismatch between what our body has the capability to metabolize and what we are actually consuming. The normal kidney has the capacity to maintain K+ homeostasis in the setting of high dietary intake. As an example, serum K+ levels are maintained in the normal range even when dietary K+ intake is increased to approximately 15 g/d for 20 days.
      • Rabelink T.J.
      • Koomans H.A.
      • Hené R.J.
      • Dorhout Mees E.J.
      Early and late adjustment to potassium loading in humans.
      • Hené R.J.
      • Koomans H.A.
      • Boer P.
      • Dorhout Mees E.J.
      Adaptation to chronic potassium loading in normal man.
      This ability to maintain a normal serum K+ concentration when challenged with large intake over a prolonged period of time suggests that humans are able to consume and excrete high K+ loads (Table 1). The mechanism by which the kidney is able to maintain K+ homeostasis in the setting of high intake is discussed below.
      Table 1Health Benefits of a High-K+ Diet
      • Decreased blood pressure
        • Effect greater in blacks and in the setting of high-Na+ intake
        • Mechanism
          • Increased urinary Na+ excretion
          • Decreased adrenergic outflow
          • Direct effect of K+ on vascular tone
      • Decreased risk of stroke
        • Related to improved blood pressure
        • Blood pressure–independent effects
      • Favorable effect on bone health
        • Alkali load in a diet
        • Direct effect of K+
      • Decreased risk of nephrolithiasis
        • Alkali load
        • Effect of K+ in the distal convoluted tubule to decrease urinary Ca2+ excretion
      • Benefits in patients with chronic kidney disease
        • Decreased gastrointestinal absorption of phosphate with plant protein compared with animal protein
        • Better control of metabolic acidosis

      Overview of Renal K+ Handling

      K+ is freely filtered by the glomerulus, and then mostly reabsorbed in the proximal tubule and thick ascending limb such that only a small amount reaches the distal nephron. Reabsorption in the proximal tubule is primarily through the paracellular pathway and is in rough proportion to Na+ and water. The apical membrane Na+-K+-2Cl cotransporter mediates transcellular K+ transport in the thick ascending limb of Henle. In the early distal convoluted tubule (DCT), K+ secretion begins and progressively increases in magnitude into the cortical collecting duct. As recently reviewed, the secretory component of K+ handling is that which varies and is regulated according to physiological needs.
      • Palmer B.F.
      Regulation of potassium homeostasis.
      The major K+secretory mechanism in the distal nephron is electrogenic secretion through the ROMK (renal outer medullary K+) channel. A second channel (maxi-K+ or BK channel) also mediates K+ secretion under conditions of increased flow. In addition to stimulating maxi-K+ channels, tubular flow augments electrogenic K+ secretion by diluting luminal K+ concentration and stimulating Na+ reabsorption through the epithelial Na+ channel (ENaC). In part, this stimulatory effect can be traced to a mechanosensitive property by which shear stress increases the open probability of the ENaC.
      • Morimoto T.
      • Liu W.
      • Woda C.
      • et al.
      Mechanism underlying flow stimulation of sodium absorption in the mammalian collecting duct.
      The biomechanical characteristics of Na+ and K+ transport in the distal nephron are ideally suited to buffer any increase in extracellular K+ concentration following a K+-rich diet. A protein-enriched meal high in K+ content, typical of early humans, would lead to an increase in glomerular filtration rate and tubular flow.
      • Satlin L.M.
      • Carattino M.D.
      • Liu W.
      • Kleyman T.R.
      Regulation of cation transport in the distal nephron by mechanical forces.
      Increased flow through the distal nephron increases distal Na+ delivery and dilutes luminal K+ concentration, both of which augment electrogenic K+ secretion through the ROMK channel. Along with the flow-mediated activation of maxi-K+ channels, these events enhance renal K+ secretion, thus providing a defense against development of hyperkalemia.
      The renal response to a high-K+, low-Na+ diet has been studied in experimental rats.
      • Halperin M.L.
      • Cheema-Dhadli S.
      • Lin S.H.
      • Kamel K.S.
      Control of potassium excretion: a Paleolithic perspective.
      • Cheema-Dhadli S.
      • Lin S.H.
      • Keong-Chong C.
      • Kamel K.S.
      • Halperin M.L.
      Requirements for a high rate of potassium excretion in rats consuming a low electrolyte diet.
      Animals were fed a diet high in K+ and low in Na+ for several days and given exogenous deoxycorticosterone to ensure a steady-state level of mineralocorticoid activity. Renal K+ handling was then examined after an acute KCl load. In the initial 2 hours following the intraperitoneal injection of KCl, there was a large increase in renal K+ excretion, primarily due to increased secretion into the collecting duct. This increased K+ secretory capacity is likely due to increased density of both ROMK and maxi-K+ channels, which are both known to increase under conditions of high-K+ intake.
      • Najjar F.
      • Zhou H.
      • Morimoto T.
      • et al.
      Dietary K+ regulates apical membrane expression of maxi-K channels in rabbit cortical collecting duct.
      Over the next 4 hours, renal K+ excretion continued to be high, but kaliuresis was mostly due to high flow through the collecting duct. The timing of the 2 phases is important because the effect of high flow to simulate renal K+ secretion would be maximal only when K+ channels are maximally expressed.
      Increased medullary recycling and accumulation of K+ in the interstitium of the kidney decreases Na+ reabsorption both in the thick ascending limb and in the proximal tubule, thus providing a mechanism for high K+ intake to increase tubular flow.
      • Stokes J.B.
      Consequences of potassium recycling in the renal medulla: effects of ion transport by the medullary thick ascending limb of Henle's loop.
      • Sufit C.R.
      • Jamison R.L.
      Effect of acute potassium load on reabsorption in Henle's loop in the rat.
      • Brandis M.
      • Keyes J.
      • Windhager E.E.
      Potassium-induced inhibition of proximal tubular fluid reabsorption in rats.
      • McCormick J.A.
      • Ellison D.H.
      Distal convoluted tubule.
      Given the high capacity of the proximal tubule and thick ascending limb to reabsorb Na+, more recent studies have focused on how K+ intake modulates transport in the low-capacity early DCT as a way to adjust tubular flow to K+ secretory sites. In the setting of a high-K+, low-Na+ diet, inhibiting transport in high-capacity upstream segments might lack the precision necessary to ensure that the delivery of Na+ is appropriate to maximally stimulate K+ secretion and at the same time not be excessive, predisposing to volume depletion.

      Distal Tubule as a K+ Sensor

      The DCT is composed of a proximal portion (DCT1) in which salt transport is driven exclusively by the thiazide-sensitive NaCl cotransporter (NCC) (Figure 1). In the distal portion of the DCT (DCT2), electroneutral NaCl transport coexists with electrogenic Na+ and K+ transport pathways.
      • McCormick J.A.
      • Ellison D.H.
      Distal convoluted tubule.
      • Ellison D.H.
      • Terker A.S.
      Why your mother was right: how potassium intake reduces blood pressure.
      Aldosterone sensitivity begins in the DCT2 and extends to the collecting duct. Changes in transport in the early DCT control the delivery of NaCl to the downstream connecting tubule and collecting duct in which the ENaC mediates electrogenic Na+ reabsorption and in which K+ is secreted. In this regard, cells of the early DCT play a substantial, albeit indirect, role in K+ secretion.
      Figure thumbnail gr1
      Figure 1Older studies suggest that high dietary K+ intake inhibits Na+ reabsorption in the proximal nephron and thick ascending limb of Henle, causing increased flow and delivery of Na+ to the aldosterone-sensitive distal nephron, resulting in increased K+ excretion. More recent studies suggest that this process is more regionalized to the distal nephron and implicates the distal convoluted tubule (DCT) as a renal K+ sensor. The proximal portion of the DCT (DCT1) reabsorbs NaCl in an electroneutral fashion via the Na+-Cl cotransporter (NCC). High dietary intake achieved through changes in plasma K+ concentration leads to an inhibitory effect on NCC activity. As a result, Na+ delivery and flow are increased to the aldosterone-sensitive K+ secretory segments located in the later portions of the DCT (DCT2) and collecting duct (CD). Increased plasma K+ concentration stimulates aldosterone release from the adrenal gland, which, in turn, facilitates electrogenic K+ secretion through the renal outer medullary K+ (ROMK) channel. Both increased flow and aldosterone stimulate K+ secretion through the maxi-K channel. Increased K+ secretion may begin upon K+ entry into the gastrointestinal tract before any change in plasma K+ concentration through an enteric sensing mechanism, which leads to an inhibitory effect on NCC activity. ENaC = epithelial Na+ channel.
      The low-capacity nature of the DCT and its location immediately upstream from the aldosterone-sensitive distal nephron (ASDN) makes this segment a more likely site for changes in dietary K+ intake to modulate Na+ transport and ensure that the downstream delivery of Na+ is precisely the amount needed to ensure maintenance of K+ homeostasis without causing unwanted effects on volume.
      Increased dietary K+ intake leads to an inhibitory effect on Na+ transport in this segment and does so through effects on members of the with no lysine family of kinases (WNK).
      • Cheng C.J.
      • Truong T.
      • Baum M.
      • Huang C.L.
      Kidney-specific WNK1 inhibits sodium reabsorption in the cortical thick ascending limb.
      • Liu Z.
      • Xie J.
      • Wu T.
      • Truong T.
      • Auchus R.J.
      • Huang C.L.
      Downregulation of NCC and NKCC2 cotransporters by kidney-specific WNK1 revealed by gene disruption and transgenic mouse models.
      WNK lysine-deficient protein kinase 1 (WNK1) and its shorter spliced variant kidney specific (KS)-WNK1 are highly expressed in the DCT and connecting duct. KS-WNK1 functions as a physiological antagonist to the actions of long WNK1. Changes in the ratio of KS-WNK1 and long WNK1 in response to dietary K+ contribute to the physiological regulation of renal K+ excretion.
      • O'Reilly M.
      • Marshall E.
      • Macgillivray T.
      • et al.
      Dietary electrolyte-driven responses in the renal WNK kinase pathway in vivo.
      • Wade J.B.
      • Fang L.
      • Liu J.
      • et al.
      WNK1 kinase isoform switch regulates renal potassium excretion.
      • Lazrak A.
      • Liu Z.
      • Huang C.L.
      Antagonistic regulation of ROMK by long and kidney-specific WNK1 isoforms.
      • Cope G.
      • Murthy M.
      • Golbang A.P.
      • et al.
      WNK1 affects surface expression of the ROMK potassium channel independent of WNK4.
      Under normal circumstances, long WNK1 prevents the ability of WNK4 (another member of the WNK family) to inhibit the activity of the Na+-Cl cotransporter in the DCT. Thus, increased activity of long WNK1 leads to a net increase in NaCl reabsorption. Dietary K+ loading increases the abundance of KS-WNK1, which has the effect to block the inhibitory effect of long WNK1 on WNK4. The net effect is inhibition of Na+-Cl cotransport in the DCT and increased Na+ delivery to more distal portions of the tubule. The increase in KS-WNK1 in response to high K+ intake also antagonizes the effect of long WNK1 to stimulate endocytosis of ROMK. In addition, KS-WNK1 exerts a stimulatory effect on the ENaC. In total, increases in KS-WNK1 in response to dietary K+ loading facilitates K+ secretion through the combined effects of increased Na+ delivery through the down-regulation of Na+-Cl cotransport in the early DCT, increased electrogenic Na+ reabsorption via the ENaC, and greater abundance of ROMK. These effects can occur independently of any change in mineralocorticoid activity, suggesting an intrinsic sensing capability of this segment to changes in dietary K+.
      • Ellison D.H.
      • Terker A.S.
      Why your mother was right: how potassium intake reduces blood pressure.
      Recent studies
      • Terker A.S.
      • Zhang C.
      • Erspamer K.
      • Gamba G.
      • Yang C.L.
      • Ellison D.H.
      Unique chloride-sensing properties of WNK4 permit the distal nephron to modulate potassium homeostasis.
      • Terker A.S.
      • Zhang C.
      • McCormick J.A.
      • et al.
      Potassium modulates electrolyte balance and blood pressure through effects on distal cell voltage and chloride.
      suggest that extracellular K+ modulates the WNK axis by altering membrane voltage and changing intracellular chloride concentration. An increased plasma K+ concentration as with increased dietary intake would depolarize cells in the DCT1, resulting in increased intracellular Cl concentration. This increase alters WNK4 activity in such a way that activity of NCC is decreased. The unique sensitivity of WNK4 to Cl is consistent with this model.
      High K+ intake also has a stimulatory effect on the release of aldosterone at the level of the adrenal gland. Increased aldosterone compliments the effect of KS-WNK1 in the DCT.
      • Ring A.M.
      • Leng Q.
      • Rinehart J.
      • et al.
      An SGK1 site in WNK4 regulates Na+ channel and K+ channel activity and has implications for aldosterone signaling and K+ homeostasis.
      • Náray-Fejes-Tóth A.
      • Snyder P.M.
      • Fejes-Tóth G.
      The kidney-specific WNK1 isoform is induced by aldosterone and stimulates epithelial sodium channel-mediated Na+ transport.
      Aldosterone up-regulates serum- and glucocorticoid-dependent protein kinase 1, which, in turn, phosphorylates WNK4. This modification prevents WNK4 from inhibiting the ROMK channel and the ENaC.
      • Ring A.M.
      • Leng Q.
      • Rinehart J.
      • et al.
      An SGK1 site in WNK4 regulates Na+ channel and K+ channel activity and has implications for aldosterone signaling and K+ homeostasis.
      • Lin D.H.
      • Yue P.
      • Rinehart J.
      • et al.
      Protein phosphatase 1 modulates the inhibitory effect of with-no-lysine kinase 4 on ROMK channels.
      Serum- and glucocorticoid-dependent protein kinase 1 also increases ENaC expression and activity through effects on the ubiquitin-protein ligase Nedd4-2.
      • Palmer B.F.
      • Alpern R.J.
      Liddle's syndrome.
      It should be emphasized that the absence of angiotensin II is a critical factor in the ability of high K+ intake to bring about the changes necessary to facilitate K+ secretion without excessive Na+ reabsorption, a phenomenon referred to as the aldosterone paradox.
      K+-rich foods, such as fruits and vegetables, are also rich in precursors to bicarbonate ions. The alkali present in such a diet directly affects the determinants of K+ transport in the DCT so as to facilitate the renal excretion of the co-ingested K+ load.
      • Aronson P.S.
      • Giebisch G.
      Effects of pH on potassium: new explanations for old observations.
      • Cornelius R.J.
      • Wen D.
      • Hatcher L.I.
      • Sansom S.C.
      Bicarbonate promotes BK-α/β4-mediated K excretion in the renal distal nephron.
      For example, ENaC abundance is increased when luminal or basolateral HCO3 and pH are elevated. In addition, increased intracellular pH increases the activity of ENaC, ROMK, and maxi-K+ channels. These effects of an alkaline pH provide an additional mechanism to facilitate K+ excretion after the ingestion of such foods.

      Enteric Sensing of K+ Intake

      A number of enteric solute sensors capable of responding to dietary Na+, K+, and phosphate have been identified that signal the kidney to rapidly alter ion excretion or reabsorption.
      • Thomas L.
      • Kumar R.
      Control of renal solute excretion by enteric signals and mediators.
      • Michell A.R.
      • Debnam E.S.
      • Unwin R.J.
      Regulation of renal function by the gastrointestinal tract: potential role of gut-derived peptides and hormones.
      • Lee F.N.
      • Oh G.
      • McDonough A.A.
      • Youn J.H.
      Evidence for gut factors in K+ homeostasis.
      In this regard, the ability to sense K+ within the gastrointestinal tract may have evolved as a way to rapidly initiate the kaliuretic response, thereby facilitating maintenance of K+ homeostasis in the setting of high K+ intake. For example, the kaliuretic response to a K+ load is greater when given as a meal compared with an intravenous infusion even in a setting in which plasma K+ concentration is identical.
      • Oh K.S.
      • Oh Y.T.
      • Kim S.W.
      • Kita T.
      • Kang I.
      • Youn J.H.
      Gut sensing of dietary K+ intake increases renal K+ excretion.
      Gastric delivery of K+ leads to an almost complete dephosphorylation of the Na+-Cl cotransporter in the early DCT, causing decreased activity of the transporter, thus enhancing the delivery of Na+ to the ASDN.
      • Youn J.H.
      Gut sensing of potassium intake and its role in potassium homeostasis.
      • Sorensen M.V.
      • Grossmann S.
      • Roesinger M.
      • et al.
      Rapid dephosphorylation of the renal sodium chloride cotransporter in response to oral potassium intake in mice.
      • McDonough A.A.
      • Youn J.H.
      Need to quickly excrete K+? Turn off NCC.
      The downstream shift in Na+ reabsorption from the DCT to the ENaC in the ASDN as well as increased K+ secretion in the maxi-K channel due to increased flow account for the increase in renal K+ excretion. This rapid natriuretic response to increases in dietary K+ intake is consistent with the blood pressure–lowering effect of K+-rich diets discussed further below. These data suggest that splanchnic sensing of K+ can initiate the renal excretory response independent of change in plasma K+ concentration or mineralocorticoid activity.
      The great facility and prodigious capacity of the healthy (normal) kidney to excrete K+ suggests and substantiates metabolic benefits associated with the consumption of a high-K+ diet. These health benefits are discussed below (see Table 1).

      Clinical Benefits of K+ Supplementation

      Hypertension

      Epidemiological studies
      • Appel L.J.
      • Brands M.W.
      • Daniels S.R.
      • Karanja N.
      • Elmer P.J.
      • Sacks F.M.
      American Heart Association
      Dietary approaches to prevent and treat hypertension: a scientific statement from the American Heart Association.
      have established that K+ intake is inversely related to the prevalence of hypertension. In addition, K+ supplements and avoidance of hypokalemia, lower blood pressure in people with hypertension, whereas blood pressure increases in people with hypertension placed on a low-K+ diet. This increase in blood pressure is associated with increased renal Na+ reabsorption.
      • Krishna G.G.
      • Kapoor S.C.
      Potassium depletion exacerbates essential hypertension.
      A total of 17,000 adults participated in the NHANES III, and data obtained from this study
      • Hajjar I.M.
      • Grim C.E.
      • George V.
      • Kotchen T.A.
      Impact of diet on blood pressure and age-related changes in blood pressure in the US population: analysis of NHANES III.
      suggested that increased dietary K+ intakes were associated with lower blood pressures. Another study
      • Appel L.J.
      • Moore T.J.
      • Obarzanek E.
      • et al.
      DASH Collaborative Research Group
      A clinical trial of the effects of dietary patterns on blood pressure.
      called Dietary Approaches to Stop Hypertension trial also found beneficial effects of a K+-rich diet on blood pressure. The study compared diets that consisted of 3.5 servings/d of fruits and vegetables and 1700 mg/d of K+ with the diet of the Dietary Approaches to Stop Hypertension trial, which included 8.5 servings/d of fruits and vegetables and 4100 mg/d of K+. These findings specifically indicated that the high-K+ diet was associated with lower blood pressure by an average of 2.8/1.1 mm Hg in all participants and by an average of 7.2/2.8 mm Hg in those with hypertension. In addition, an increased K+ intake of 2300 to 3900 mg/d substantially reduced blood pressure by an average of 1.8/1.0 mm Hg in people with normal blood pressure and 4.4/2.5 mm Hg in people with hypertension, as reported in a meta-analysis of 33 randomized controlled trials including 2609 individuals.
      • Whelton P.K.
      • He J.
      • Cutler J.A.
      • et al.
      Effects of oral potassium on blood pressure. Meta-analysis of randomized controlled clinical trials.
      Blood pressure lowering was affected by race, as the effect was more pronounced in black individuals, as well as in those who consumed larger amounts of Na+. Lastly, another meta-analysis
      • Aburto N.J.
      • Hanson S.
      • Gutierrez H.
      • Hooper L.
      • Elliott P.
      • Cappuccio F.P.
      Effect of increased potassium intake on cardiovascular risk factors and disease: systematic review and meta-analyses.
      of 21 randomized controlled trials reported that higher K+ consumption resulted in lower blood pressure and this was more pronounced in patients with hypertension or those consuming a high-Na+ diet.
      It has long been appreciated that K+ has natriuretic and diuretic effects. As discussed previously, dietary K+ intake leads to changes in KS-WNK1 and long WNK1, which affect Na+ handling. These effects may be important in the observed relationship between dietary K+ intake and hypertension. A diet deficient in K+ increases the ratio of long WNK1 to KS-WNK1. This response can be viewed as physiological because long WNK1 increases retrieval of ROMK and therefore limits secretion under conditions of low K+ intake. However, long WNK1 also leads to a stimulatory effect on ENaC activity as well as alters WNK4 so that NaCl cotransport is increased in the early DCT.
      • Vallon V.
      • Wulff P.
      • Huang D.Y.
      • et al.
      Role of Sgk1 in salt and potassium homeostasis.
      • Rozansky D.J.
      The role of aldosterone in renal sodium transport.
      • Xu B.E.
      • Stippec S.
      • Chu P.Y.
      • et al.
      WNK1 activates SGK1 to regulate the epithelial sodium channel.
      These effects suggest that a K+-deficient diet will reduce K+ secretion at the expense of increased Na+ retention, thus potentially contributing to increased blood pressure (Figure 2).
      Figure thumbnail gr2
      Figure 2Effect of decreased dietary K+ on Na+ transport in the distal tubule. Decreased dietary K+ achieved through a decrease in plasma K+ concentration hyperpolarizes cells in the proximal portion of the distal convoluted tubule (DCT1), leading to decreased intracellular Cl concentration, which, in turn, activates WNK lysine-deficient protein kinase 4 (WNK4). K+ deficiency is associated with increases in the ratio of long WNK lysine-deficient protein kinase 1 (WNK1) to kidney specific (KS)-WNK1. An increase in this ratio (L-WNK1/KS-WNK1) leads to an increased retrieval of renal outer medullary K+ (ROMK) from the apical membrane, thereby minimizing K+ secretion, which would be an appropriate response to the K+-deficient diet. Increased L-WNK1/KS-WNK1 also alters WNK4 activity such that activity of the thiazide-sensitive Na+-Cl cotransporter (NCC) is increased. In addition, increased L-WNK1 leads to an increased activity of the epithelial Na+ channel (ENaC). These last 2 effects lead to salt retention and thus could explain the genesis of salt-sensitive hypertension in patients ingesting K+-deficient diets.
      Under conditions of dietary K+ deficiency, renal conservation of K+ and Na+ may have evolved as an adaptation during development because typically dietary K+ and Na+ deficiency likely occurred together.
      • Eaton S.B.
      The ancestral human diets: what was it and should it be a paradigm for contemporary nutrition?.
      Importantly, this adaptation is potentially deleterious in our present setting of consumption of low-K+, high-Na+ foods. The effects of an increased ratio of long WNK1 to KS-WNK1 in the kidney under conditions of modern-day high-Na+, low-K+ diet could be central to the pathogenesis of salt-sensitive hypertension.
      • Huang C.L.
      • Kuo E.
      Mechanisms of disease: WNK-ing at the mechanism of salt-sensitive hypertension.
      In addition to effects leading to renal salt retention, low K+ intake may contribute to increased sympathetic tone as a mechanism causing hypertension. As recently reviewed, Na+ excess and K+ deficiency can alter the electrolyte and hormonal composition of the cerebral spinal fluid, activating sensors, which through the hypothalamus leads to neurohumoral activation.
      • Adrogué H.J.
      • Madias N.E.
      Sodium surfeit and potassium deficit: keys to the pathogenesis of hypertension.
      In addition, Na+ retention and K+ depletion have been linked to direct vascular effects, eventuating in increased vascular tone.

      Stroke

      Several large epidemiological studies have suggested that increased K+ intake is associated with a decreased risk of stroke. A prospective study
      • Ascherio A.
      • Rimm E.B.
      • Hernán M.A.
      • et al.
      Intake of potassium, magnesium, calcium, and fiber and risk of stroke among US men.
      of more than 43,000 men followed for 8 years found that men in the top quintile of dietary K+ intake (median intake, 4300 mg/d) were significantly less likely (62%) to have a stroke than those in the lowest quintile of K+ intake (median intake, 2400 mg/d). This inverse association was especially strong in men with hypertension. Furthermore, an analysis of 11 cohort studies with a total of 127,038 participants reported that K+ intake in the range of 90 to 120 mmol/d was associated with a decreased risk of stroke (relative risk, 0.79; 95% CI, 0.68-0.93).
      • Aburto N.J.
      • Hanson S.
      • Gutierrez H.
      • Hooper L.
      • Elliott P.
      • Cappuccio F.P.
      Effect of increased potassium intake on cardiovascular risk factors and disease: systematic review and meta-analyses.
      Ingestion of a low-K+ diet (<34.6 mmol/d) in 9805 men and women followed for an average of 19 years experienced a 28% higher risk of stroke.
      • Bazzano L.A.
      • He J.
      • Ogden L.G.
      • et al.
      Dietary potassium intake and risk of stroke in US men and women: National Health and Nutrition Examination Survey I epidemiologic follow-up study.
      In 90,137 postmenopausal women aged 50 to 79 years followed prospectively for an average of 11 years, higher K+ intake was associated with a lower risk of all strokes and ischemic stroke.
      • Seth A.
      • Mossavar-Rahmani Y.
      • Kamensky V.
      • et al.
      Potassium intake and risk of stroke in women with hypertension and nonhypertension in the Women's Health Initiative.
      Taken together, these epidemiological data suggest that a modest increase in fruits and vegetable intake (rich sources of dietary K+), especially in those with hypertension and/or relatively low-K+ intakes, could significantly reduce the risk of stroke.
      • Aaron K.J.
      • Sanders P.W.
      Role of dietary salt and potassium intake in cardiovascular health and disease: a review of the evidence.
      Although much of the ability of increased K+ consumption to lower the risk of stroke is through its effects to lower blood pressure, studies in experimental animals support additional mechanisms for stroke prevention primarily related to the inhibition of atherosclerotic lesion formation and progression. Increased extracellular K+ concentration achieved through increased intake has been found to decrease vascular smooth muscle cell proliferation and migration, free radical formation, and platelet aggregation.
      • Rigsby C.S.
      • Pollock D.M.
      • Dorrance A.M.
      Dietary potassium supplementation improves vascular structure and ameliorates the damage caused by cerebral ischemia in normotensive rats.

      Osteoporosis

      K+-rich foods, such as fruits and vegetables, are rich in precursors to bicarbonate ions, which buffer acids in the body. The modern Western diet tends to be relatively low in sources of alkali (fruits and vegetables) and high in sources of acid (fish, meats, and cheeses). When the quantity of bicarbonate ions is insufficient to maintain normal pH, the body mobilizes alkaline calcium salts from the bone to neutralize the acids consumed in the diet and generated by metabolism. Increased consumption of fruits and vegetables reduces the net acid content of the diet and may preserve calcium in bones, which might otherwise be mobilized to maintain normal pH. In addition to providing a more alkaline diet, the larger amount of K+ in fruits and vegetables may exert an anion-independent effect on bone metabolism. Addition of KCl to K+-depleted mouse calvariae reduces bone resorption and net calcium efflux and increases bone collagen synthesis.
      • Bushinsky D.A.
      • Riordon D.R.
      • Chan J.S.
      • Krieger N.S.
      Decreased potassium stimulates bone resorption.
      In a study
      • Sebastian A.
      • Harris S.T.
      • Ottaway J.H.
      • Todd K.M.
      • Morris Jr., R.C.
      Improved mineral balance and skeletal metabolism in postmenopausal women treated with potassium bicarbonate.
      of 18 postmenopausal women, potassium bicarbonate supplementation decreased urinary acid and calcium excretion, resulting in increased biomarkers of bone formation and decreased biomarkers of bone resorption. In a study
      • Zhu K.
      • Devine A.
      • Prince R.L.
      The effects of high potassium consumption on bone mineral density in a prospective cohort study of elderly postmenopausal women.
      of 266 elderly postmenopausal women, increased dietary K+ as determined from 24-hour urine collections was associated with significantly higher hip (at 1 and 5 years) and total body (at 5 years) bone mineral densities as compared with those with lower amounts of K+ intake. Increased fruits and vegetable intake accompanied by higher levels of K+ consumption have been found to exert similar beneficial effects on bone mineral density, including biomarkers of bone formation in premenopausal and postmenopausal women and elderly men.
      • Tucker K.L.
      • Hannan M.T.
      • Chen H.
      • Cupples L.A.
      • Wilson P.W.
      • Kiel D.P.
      Potassium, magnesium, and fruit and vegetable intakes are associated with greater bone mineral density in elderly men and women.
      Overall, ingestion of K+-rich fruits and vegetables may help lower the risk of osteoporosis.

      Nephrolithiasis

      Abnormally high urinary calcium (hypercalciuria) and low urinary citrate concentrations increase the risk of developing kidney stones. In individuals with a history of developing calcium-containing kidney stones, increased dietary acid loads are significantly associated with increased urinary calcium excretion and decreased urinary citrate. K+ deprivation has also been found to increase urinary calcium excretion as well as reduce urinary citrate.
      • Morris Jr., R.C.
      • Schmidlin O.
      • Tanaka M.
      • Forman A.
      • Frassetto L.
      • Sebastian A.
      Differing effects of supplemental KCl and KHCO3: pathophysiological and clinical implications.
      • Lemann Jr., J.
      • Pleuss J.A.
      • Gray R.W.
      Potassium causes calcium retention in healthy adults.
      Increasing dietary K+ (and thereby increasing the alkali content) facilitated by increasing fruit and vegetable consumption, or by taking potassium bicarbonate supplements, has been found to decrease urinary calcium and increase urinary citrate and lower urinary urate. As discussed earlier, increasing plasma K+ concentration will lead to a decreased activity of NCC in the DCT1. Urinary calcium decreases in a manner similar to that which occurs with thiazide diuretic–induced inhibition of NCC. Increased dietary K+ intake derived from K+-rich foods, such as fruits and vegetables, in prospective trials
      • Curhan G.C.
      • Willett W.C.
      • Speizer F.E.
      • Spiegelman D.
      • Stampfer M.J.
      Comparison of dietary calcium with supplemental calcium and other nutrients as factors affecting the risk for kidney stones in women.
      • Curhan G.C.
      • Willett W.C.
      • Rimm E.B.
      • Stampfer M.J.
      A prospective study of dietary calcium and other nutrients and the risk of symptomatic kidney stones.
      has been shown to significantly reduce the risk of kidney stones in both men and women as compared with those with low K+ intake.

      Use of K+-Enriched Diet in Chronic Kidney Disease

      Although ingestion of a K+-enriched diet can safely provide the aforementioned benefits to patients with normal renal function, development of life-threatening hyperkalemia may limit the ability to use such a diet in patients with chronic kidney disease (CKD). This toxicity creates a therapeutic dilemma because a diet rich in fruits and vegetables may offer benefits that are unique to patients with CKD. These benefits are discussed below.

      Phosphorus Control

      Two important aspects of nutritional management in patients with CKD are maintenance of adequate protein intake and prevention of phosphate overload and hyperphosphatemia. This can be problematic because organic phosphorus is bound to protein and the amount of protein eaten will predictably determine phosphorus intake. Organic phosphorus from plant protein has a lower absorption rate than does phosphorus from animal protein, ranging from 40% to 50%, because phosphorus from plants is in the form of phytates and mammals lack phytases. Phosphorus in animal protein is in the form of organic phosphate, which is readily hydrolyzed and absorbed.
      • Kalantar-Zadeh K.
      • Gutekunst L.
      • Mehrotra R.
      • et al.
      Understanding sources of dietary phosphorus in the treatment of patients with chronic kidney disease.
      In a model of progressive CKD, rats were fed either a casein-based or a grain-based protein diet, both of which had equivalent total phosphorus content. Despite maintaining the same serum phosphorous concentration, the casein-fed animals had increased urinary phosphorus excretion and increased serum fibroblast growth factor 23 levels as compared with the grain-fed rats, which was consistent with increased gastrointestinal absorption with the casein-based diet.
      • Moe S.M.
      • Chen N.X.
      • Seifert M.F.
      • et al.
      A rat model of chronic kidney disease-mineral bone disorder.
      Phosphate homeostasis was examined in a crossover trial
      • Moe S.M.
      • Zidehsarai M.P.
      • Chambers M.A.
      • et al.
      Vegetarian compared with meat dietary protein source and phosphorus homeostasis in chronic kidney disease.
      of 9 patients with CKD comparing a diet rich in animal or vegetable protein for 7 days. Despite equivalent protein and phosphorus concentrations in the diet, ingestion of the vegetarian diet had lower serum phosphorus levels and significantly reduced fibroblast growth factor 23 levels, which was again consistent with the reduced gastrointestinal absorption of phosphate. These data suggest that ingestion of a diet rich in plant protein could be a viable strategy to maintain adequate protein intake with less tendency to cause phosphorus overload.

      Control of Metabolic Acidosis

      The reduction in renal mass in CKD leads to decreased capacity for net acid excretion, resulting in the development of chronic metabolic acidosis. Current guidelines suggest that metabolic acidosis should be treated with the goal of maintaining the serum bicarbonate concentration in the normal range (23-29 mEq/L) to avoid complications of chronic acidosis, including protein-energy wasting, insulin resistance, bone demineralization, and progression of renal disease.
      • Chen W.
      • Abramowitz M.K.
      Metabolic acidosis and the progression of chronic kidney disease.
      • Vallet M.
      • Metzger M.
      • Haymann J.P.
      • et al.
      NephroTest Cohort Study
      Urinary ammonia and long-term outcomes in chronic kidney disease.
      The usual therapy is oral NaHCO3, but this approach is associated with increased Na+ intake and can exacerbate the volume expansion and hypertension commonly present in CKD. In addition some patients are intolerant because of complications of bloating. Because the modern Western diet leads to increased net acid production, an alternative approach is to increase the consumption of fruits and vegetables, which is associated with alkali precursors and is not accompanied by a salt load.
      • Sebastian A.
      • Frassetto L.A.
      • Sellmeyer D.E.
      • Merriam R.L.
      • Morris Jr., R.C.
      Estimation of the net acid load of the diet of ancestral preagricultural Homo sapiens and their hominid ancestors.
      • Ströhle A.
      • Hahn A.
      • Sebastian A.
      Estimation of the diet-dependent net acid load in 229 worldwide historically studied hunter-gatherer societies.
      This strategy was tested in a group of patients with stage 2 CKD due to hypertensive nephrosclerosis. Urine indices of renal injury were measured and compared after 30 days of increased fruit and vegetable consumption vs oral NaHCO3 therapy. Reduction in urinary albumin and N-acetyl β-d-glucosaminidase was similar between the 2 groups. In addition, the fruit and vegetable diet (which is rich in K+, as discussed previously) resulted in a significantly greater reduction in systolic blood pressure.
      • Goraya N.
      • Simoni J.
      • Jo C.
      • Wesson D.E.
      Dietary acid reduction with fruits and vegetables or bicarbonate attenuates kidney injury in patients with a moderately reduced glomerular filtration rate due to hypertensive nephropathy.
      In a similar study,
      • Goraya N.
      • Simoni J.
      • Jo C.H.
      • Wesson D.E.
      A comparison of treating metabolic acidosis in CKD stage 4 hypertensive kidney disease with fruits and vegetables or sodium bicarbonate.
      71 patients with stage 4 CKD and serum bicarbonate level less than 22 mEq/L were randomized to 1 year of sodium bicarbonate at 1.0 mEq/kg per day or increased fruits and vegetables to reduce dietary acid by half. Serum bicarbonate levels increased with the dietary intervention, although less than in the bicarbonate group, whose alkali dose would be expected to almost completely neutralize the dietary acid load. The aforementioned markers of kidney injury declined similarly in the 2 groups. These findings suggest that the alkali load afforded by a diet rich in fruits and vegetables can slow the progression of CKD through correction of metabolic acidosis. In addition to avoiding the salt load and potential volume overload that can complicate NaHCO3 therapy, the diet is associated with reduction in blood pressure, possibly related to increased K+ intake. Importantly, there were no complications due to hyperkalemia, but only patients with plasma K+ levels 4.6 mEq/L or less were enrolled in the study.

      Management of Hyperkalemia

      Although there are clear benefits of ingestion of K+, the development of hyperkalemia (defined by serum K+ levels >5.0 mEq/L) can be a limiting factor in implementing such a diet because of the risk of cardiac arrhythmias and increased mortality.
      • Palmer B.F.
      • Clegg D.J.
      Hyperkalemia.
      The risk of hyperkalemia is particularly high in patients with CKD and in the setting of drugs that interfere with K+ homeostasis, such as renin-angiotensin-aldosterone system (RAAS) blockers. The initial approach to managing hyperkalemia is eliminating other sources of K+ such as supplements (including those found in salt substitutes and some herbal medications), discontinuing prescribed or over-the-counter drugs known to interfere with renal K+ excretion (nonsteroidal anti-inflammatory drugs), and ensuring effective diuretic therapy (Table 2).
      • Palmer B.F.
      • Clegg D.J.
      Electrolyte and acid-base disturbances in patients with diabetes mellitus.
      Table 2Approach to Minimize Risk of Hyperkalemia When Ingesting High-K+ Diet
      • Accurately assess level of renal function to better define risk
      • Discontinue drugs that interfere with renal K+ secretion, inquire about herbal preparations, and discontinue nonsteroidal anti-inflammatory drugs to include the selective cyclooxygenase 2 inhibitors
      • Inquire about K+-containing salt substitutes
      • Thiazide or loop diuretics (loop diuretics necessary when estimated glomerular filtration rate is <30 mL/min)
      • Sodium bicarbonate to correct metabolic acidosis in patients with chronic kidney disease
      • Initiate therapy with low-dose ACE inhibitor or angiotensin receptor blocker
        • Measure K+ 1 wk after the initiation of therapy or after increasing the dose of the drug
        • For increases in K+ concentration up to 5.5 mEq/L, decrease the dose of the drug; if taking some combination of ACE inhibitor, angiotensin receptor blocker, and aldosterone receptor blocker, discontinue one and recheck K+ concentration
        • The dose of spironolactone should not exceed 25 mg/d when used with an ACE inhibitor or angiotensin receptor blocker; this combination of drugs should be avoided with a glomerular filtration rate of <30 mL/min
        • For K+ concentration ≥5.6 mEq/L despite above steps, discontinue drugs
      • Consider long-term use of new K+-binding drugs (patiromer or sodium zirconium cyclosilicate)
      ACE = angiotensin-converting enzyme.
      Pharmacological management of hyperkalemia has relied for more than 50 years on the chronic use of sodium polystyrene sulfonate (Kayexalate), which binds K+ in the gastrointestinal tract; however, this is poorly tolerated and has been linked to gastrointestinal toxicity. Moreover, long-term administration is linked to serious adverse effects such as rare cases of intestinal necrosis, resulting in a blackbox warning by the Food and Drug Administration. Recently, there are new oral compounds—patiromer (Veltassa) and sodium zirconium cyclosilicate—that are K+-binding drugs shown to be effective in preventing development of hyperkalemia. Patiromer is approved for clinical use, and sodium zirconium cyclosilicate is pending approval. Both agents exhibit good tolerability and are not associated with serious adverse effects. Recently, clinical trials found that these compounds lower the risk of incident hyperkalemia associated with RAAS blockade in people with diabetes, those with heart failure, and/or those who have CKD. Patiromer is a nonabsorbed polymer that binds K+ in the gastrointestinal tract, predominately in the colon. Patiromer effectively decreases serum K+ concentrations in high-risk patients taking RAAS blockers, including those with heart failure, those with CKD, and those with diabetic nephropathy.
      • Weir M.R.
      • Bakris G.L.
      • Bushinsky D.A.
      • et al.
      OPAL-HK Investigators
      Patiromer in patients with kidney disease and hyperkalemia receiving RAAS inhibitors.
      In a study of more than 300 patients with diabetic nephropathy with either mild to moderate hyperkalemia, the drug lowered the serum K+ concentration in a dose-dependent manner, with the greatest reduction in those with higher starting values. The drug remained effective in controlling plasma K+ concentration over a 44-week maintenance phase despite ongoing administration of RAAS inhibitors.
      • Bakris G.L.
      • Pitt B.
      • Weir M.R.
      • et al.
      AMETHYST-DN Investigators
      Effect of patiromer on serum potassium level in patients with hyperkalemia and diabetic kidney disease: the AMETHYST-DN randomized clinical trial.
      The drug was well tolerated, with the main adverse events being constipation (infrequent and self-limiting) and hypomagnesemia, which required magnesium replacement in a small number of participants.
      Sodium zirconium cyclosilicate is a nonabsorbed microporous compound that binds K+ throughout the gastrointestinal tract. The pore size renders it highly selective for the K+ ion as compared with calcium or magnesium ions. Like patiromer, this drug has also been shown effective in lowering plasma K+ concentration in a dose-dependent manner, with a greater reduction in those with the highest levels.
      • Kosiborod M.
      • Rasmussen H.S.
      • Lavin P.
      • et al.
      Effect of sodium zirconium cyclosilicate on potassium lowering for 28 days among outpatients with hyperkalemia: the HARMONIZE randomized clinical trial.
      • Packham D.K.
      • Rasmussen H.S.
      • Lavin P.T.
      • et al.
      Sodium zirconium cyclosilicate in hyperkalemia.
      However, despite being well tolerated, there are reports of edema at higher doses.
      Importantly, dietary K+ intake was not specifically controlled in the clinical trials with patiromer and sodium zirconium cyclosilicate. Although the effectiveness of these drugs in patients purposely ingesting a K+-enriched diet has not been studied, their ability to control plasma K+ concentration in those patients with a history of hyperkalemia despite ongoing use of RAAS blockers suggests that these agents could prove useful in allowing patients at risk for hyperkalemia to liberalize their diets to include K+-rich sources such as fruits and vegetables. In addition to improving the quality of life through liberalization of diets, these high-risk patients could enjoy the cardiovascular and metabolic benefits afforded by such a dietary change.

      Implementation of K+-Enriched Diets in Patients at Risk for Hyperkalemia

      In a recent observational study
      • Araki S.
      • Haneda M.
      • Koya D.
      • et al.
      Urinary potassium excretion and renal and cardiovascular complications in patients with type 2 diabetes and normal renal function.
      of patients with type 2 diabetes, higher urinary K+ excretion was associated with lower cardiovascular complications and a slower decline of renal function, further supporting the association between increased K+ intake and cardiovascular benefits. Importantly, participants in this trial had normal baseline renal function. There are no long-term studies examining the benefits of a K+-enriched diet in patients with CKD because of the concern for development of life-threatening hyperkalemia. In addition to the potential benefits of better phosphate control and amelioration of metabolic acidosis discussed previously, one speculation arises whether liberalization of dietary K+ in patients with CKD may provide long-term cardiovascular benefits. Management of patients with CKD typically involves some degree of K+ restriction, which is further reinforced as patients transition to end-stage renal disease and ultimately dialysis. With the advent of novel K+-binding agents, it is interesting to speculate whether clinical trials focusing on liberalization of the diet to include sources of K+ might provide cardiovascular benefits in this patient population. Although not specifically tested as an approach to prevent diet-induced hyperkalemia, these new compounds are well tolerated and could be used to study whether patients with CKD would benefit from liberalization of dietary K+, potentially contributing to a better quality of life.

      Conclusion

      There are abundant data suggesting that ingestion of K+-rich foods is beneficial and may reduce the incidence of stroke, hypertension, nephrolithiasis, and osteoporosis. The data on dietary consumption indicate that Western diets are high in processed foods, high in Na+ content, and low in K+. The kidney is designed to handle significantly higher K+ loads than are currently consumed in our diet. Furthermore, patients who could most benefit from increasing their intake of K+-rich foods are the very same patients who are unable to do so because of reductions in renal function. Specifically, cardiovascular disease is prevalent in patients with reduced renal function, and therefore one would argue that this patient population would benefit the most from ingesting diets enriched in K+. Currently, the standard treatment for hypertension in these patients is the use of RAAS blockers, pharmacology that results in hyperkalemia, necessitating the use of a low-K+ diet. There are 2 new therapeutic options to chronically treat hyperkalemia, affording the speculation that these drugs may allow for liberalization of dietary K+ so as to maximize cardiovascular benefits.
      It is important to rethink the role of K+ in the diet, especially when it is recognized that Western diets result in overconsumption of Na+ and underconsumption of K+, leading to increased disease prevalence. People are actively seeking dietary changes and are embracing diets such as the Paleolithic diet that tout their benefits of reduced consumption of processed foods (and thereby Na+) and increased consumption of fruits and vegetables (and thereby K+). We conclude by restating that K+, an often underappreciated cation/mineral, may be directly related to health benefits.

      Supplemental Online Material

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