Introductory Chapter: Potassium in Human Health

3.1 Cell structure and function

Potassium is an important intracellular ion critical in the maintenance of cellular osmolarity and function. The resting cell membrane potential is a crucial component of cellular function especially for excitable cells, such as muscles and nerves. It is created and maintained by the movement of sodium and potassium through corresponding channels and transporters in the cell membrane, specifically, the Na-K-ATPase and K-selective outward ion channels. Disturbances in extracellular potassium concentration can affect membrane potential and alter cellular function [5].

Potassium is also important for several intracellular processes including ribosome structure and function. Rozov et al. (2019) examined the role of potassium in ribosomal protein synthesis at the three-dimensional level using long-wavelength X-ray crystallography [6]. They found that potassium stabilized main functional ligands such as messenger RNA and transfer RNAs, as well as ribosomal RNAs and ribosomal proteins, through direct interactions with nitrogen and oxygen atoms of nucleotide bases and polypeptide or sugar-phosphate residues. Potassium helped preserve ribosome structural and functional integrities, by coordinating the conformational rearrangements in the decoding center upon binding of aminoacyl-tRNA, allowing tighter binding of mRNA.

In the mitochondria, several potassium channels have been described in the inner mitochondrial membrane: ATP-regulated potassium channel, Ca²⁺-activated potassium channel, the voltage-gated Kv1.3 potassium channel, and the two-pore domain TASK-3 potassium channel [7]. They help preserve mitochondrial membrane potential, oxidative phosphorylation coupling, and matrix volume, and regulate several key mitochondrial metabolic actions [8, 9].

3.2 Blood pressure (BP)

Hypertension is a leading cause of heart attacks, strokes, and other end-organ damage. The antihypertensive effect of increased potassium intake is likely multifactorial. Blood pressure is in part determined by body salt and fluid status; potassium is an essential ion for salt and fluid volume regulation. Potassium intake can modulate the activity of sodium-chloride cotransporter (NCC), a key channel for renal salt reabsorption located at distal nephron, and a special potassium channel, Kir4.1, located in the basolateral side of distal convoluted tubule [10]. Kir4.1 plays a key role in sensing plasma potassium. Low potassium intake (LKI) activates Kir4.1, hyperpolarizes cells at the distal convoluted tubule which, in turn, increases the abundance of NCC channel at the luminal side and ultimately leads to salt retention and higher blood pressure [10]. Increased potassium intake increases urinary salt excretion, thereby reducing blood pressure. In addition, higher potassium intake can directly lower the blood pressure by vasodilation due to vascular endothelium-dependent smooth muscle cell hyperpolarization [11]. Finally, potassium intake can also modulate baroreceptor sensitivity, and reduce vascular sensitivity to catecholamines [12].

Large epidemiologic studies have consistently appear significant but inverse associations between potassium intake and BP, independent of dietary salt intake [13, 14, 15]. Controlled interventional trials of vegetarian diets (typically higher in potassium content) in both normotensive and hypertensive populations also demonstrated a BP-lowering effect [16, 17]. According to the seminal Dietary Approaches to Stop Hypertension (DASH) trial, a diet rich in fruits, vegetables, and reduced saturated and total fat (potassium content: 2776 vs. 1447 mg/day in the control group) substantially lowered blood pressure [18]. Unfortunately, prospective clinical trials examining the independent BP effect from oral potassium supplementation have yielded conflicting results [19, 20, 21]. The effect size from potassium intake alone may be small; therefore, a larger number of study participants and a longer duration of follow-up are needed. To address these concerns, several meta-analyses were conducted and again confirmed the BP reduction effect from potassium supplementation [22, 23, 24]. A meta-analysis of 33 randomized controlled trials involving 2609 participants in whom potassium supplementation was the only difference between the intervention and control conditions, showed that potassium supplementation was associated with a significant reduction in mean (95% confidence interval) systolic BP (SBP) and diastolic BP (DBP) of −3.11 mm Hg (−1.91 to −4.31 mm Hg) and − 1.97 mm Hg (−0.52 to −3.42 mm Hg), respectively [22]. However, a small meta-analysis (n = 483) with a short duration of follow-up failed to show statistically significant BP reduction by potassium supplementation. Despite the lack of statistical significance in this meta-analysis, both SBP and DBP were reduced with potassium supplementation (mean difference in SBP: −11.2, 95% CI: −25.2 to 2.7; mean difference in DBP: −5.0, 95% CI: −12.5 to 2.4) [25].

The BP-lowering effect by potassium appears to be modified by race, with individuals who identified as being Black, appearing to be particularly sensitive to the BP-lowering effect of potassium. According to a randomized, double-blind clinical trial, the reduction in SBP reached a mean of 19 mmHg compared to the 3.4 mmHg reduction in the overall study population [26]. Since there is a physiologic interdependency of sodium and potassium, the BP-lowering effect of potassium also appears to be modified by salt intake. Clinical studies have demonstrated that dietary potassium intake did not affect BP after salt restriction [21, 27]. However, higher potassium intake blunted the rising in BP after salt loading [28]. These were consistent with the epidemiologic studies showing that the BP-lowering effect of potassium was more discernible in participants who had a high sodium intake [22, 29]. As a result, a dietary sodium-to-potassium ratio is now being accepted as a better metric for cardiovascular risk as compared to the separate dietary sodium or potassium values alone [30]. A 1:1 molar ratio of sodium to potassium is considered beneficial for health [31].

3.3 Insulin resistance and diabetes

Diabetes is a global epidemic affecting over 34 million Americans and 422 million people worldwide [32]. Studies examining the association between dietary potassium intake and diabetes risk have been mixed and mostly unrevealing. This could be due to the lack of standardized measures of dietary potassium intake, and possibly a small effect size from dietary potassium manipulation alone. Total body potassium depletion has been linked to an increased risk for insulin resistance and diabetes. Medically-induced hypokalemia has been associated with reduced pancreatic β-cell sensitivity and insulin release in response to hyperglycemia. Potassium supplementation corrected the defective insulin response to glucose, further implicating hypokalemia as the direct cause of glucose intolerance [33, 34]. Adding to the existing evidence, observational studies showed a significant inverse association between serum potassium levels and risk of incident diabetes [35, 36]. Genetic studies also demonstrated that mutations in genes coding for potassium channels on pancreatic β-cells affect insulin secretion. The KCNJ11 gene encodes for the ATP-sensitive potassium channel in the pancreatic beta-cell and mutations in this gene have been linked to neonatal diabetes [37], with single nucleotide polymorphisms associated with increased susceptibility to type II diabetes [38]. Another potassium channel gene, KCNQ1, is also involved in insulin secretion and its polymorphisms have been associated with an increased risk for type II diabetes in Asian women [39].

3.4 Cardiovascular disease and survival

Physiologic increases in potassium concentration can inhibit superoxide anion formation by endothelial cells and monocytes/macrophages, leading to a reduction in oxidative stress and inflammation [40]. Higher physiological potassium concentrations can reduce vascular smooth muscle cell proliferation and inhibit vascular thrombosis, leading to a reduction in ischemic events [41]. Oral potassium supplementation can also significantly improve endothelial function as measured by brachial artery flow-mediated dilatation, increase arterial compliance as assessed by carotid-femoral pulse wave velocity, decrease left ventricular mass, and improve left ventricular diastolic function [42]. More importantly, since hypertension and diabetes are the two strongest risk factors for cardiovascular disease (CVD) and CVD mortality, higher potassium intake can theoretically reduce the risk of CVD and improve survival by lowering BP and improving insulin sensitivity. Indeed, the protective effect of potassium on CVD and survival is supported by a large randomized controlled trial of 1981 Chinese veterans, in whom the use of potassium-enriched salt led to a significant reduction in CVD mortality (age-adjusted hazard ratio: 0.59; 95% CI: 0.37–0.95) [43]. A meta-analysis of 11 studies that included 247,510 adult participants (follow-up 5–19 years) showed that higher potassium intake (by 1.64 g per day), was associated with a 21% lower risk of stroke (risk ratio (RR): 0.79; 95% CI: 0.68–0.90; p = 0.0007), and trended toward lower risk of CVD including coronary heart disease, which was statistically significant after the exclusion of a single cohort, based on sensitivity analysis (RR: 0.74; 95% CI: 0.60–0.91; p = 0.0037) [44]. In this meta-analysis, potassium intake was assessed either by 24-h dietary recall, food frequency questionnaire, or 24-h urinary excretion. Another meta-analysis of nine cohort studies also detected a protective effect of higher potassium intake on the risk of incident stroke (RR 0.76, 95% CI: 0.66–0.89). However, potassium intake had a non-significant relation with incident cardiovascular disease (RR 0.88, 95% CI: 0.70–1.10) and coronary heart disease (RR 0.96, 95% CI: 0.78–1.19). Mortality analyses were not performed in this meta-analysis due to missing data [45].

3.5 Acid-base regulation

Tight blood pH control within a narrow range is essential for proper cellular and organ function.

The kidney plays a key role in bicarbonate reabsorption and generation, as well as proton excretion, to maintain acid-base homeostasis. This is achieved by ammoniagenesis in the proximal tubule, where glutamine is transported internally and metabolized into ammonia, bicarbonate, and glucose [46]. This process can be dramatically upregulated in response to metabolic acidosis.

In animals under dietary potassium deprivation, protein expression of the glutamine transporter (system N transporter, SN1) in the proximal tubule was stimulated, along with an upregulation of key enzymes in glutamine catabolism including glutaminase, glutamate dehydrogenase, and phosphoenolpyruvate carboxykinase, leading to an enhanced ammoniagenesis. The increase in urinary ammonia formation and excretion is observed within 2 days of potassium deprivation while the blood potassium level is still maintained within normal limits. The observed effect was independent of systemic metabolic acidosis or changes in volume status [47]. In a human study where participants had moderate potassium depletion acutely induced by dietary potassium restriction (with sodium substitution), a significant increase in urine ammonia excretion was observed along with a rise in plasma bicarbonate and a reduction in blood acidity. None of the participants had increases in mineralocorticoid levels or evidence of chloride depletion [48]. In another study of human volunteers, acute potassium depletion was induced by dietary restriction alone or with additional use of potassium binding resin. There were increases in urinary excretions of both net acid and ammonium [49]. Similar findings were observed in patients with chronic potassium depletion. In a study of eight patients with chronic potassium depletion and 20 healthy controls, potassium depletion was associated with an almost two-fold higher ammoniagenesis measured by the amount of ammonia excreted in the urine plus the amount added to the venous blood. There was also an increased urinary ammonia excretion and an enhanced renal extraction of glutamine (56.6 ± 5.9 mumol/min/1.73 m² vs. 34.6 ± 3.1 in controls). Total ammonia production was inversely correlated with serum potassium and directly correlated with urine flow. Stepwise multiple regression analysis again showed that serum potassium was the predominant factor affecting renal ammonia production [50].

While hypokalemia stimulates ammoniagenesis, hyperkalemia suppresses renal ammonia production in the proximal tubule and potentiates the development of hyperchloremic metabolic acidosis. In an experiment using renal tissue from animals, treatment with a higher potassium bath (7–25 vs. 4–5 meq/L) resulted in significantly less ammonia production and suppression of the catabolic pathway of glutamine [51]. In an animal study, chronic potassium loading leading to hyperkalemia resulted in a 40% reduction in urinary ammonium excretion and a 50% reduction in whole kidney ammonium production. These animals also developed metabolic acidosis [52]. Similar findings were observed in a genetic animal model of hyperkalemia (DCT-CA-SPAK mice), who developed co-existing metabolic acidosis and reduced ammonia excretion [53]. These mice were found to have reduced proximal tubule expressions of key enzymes in ammoniagenesis and reduced ammonia transporter expression in the distal nephron. Treatment with hydrochlorothiazide corrected the hyperkalemia and metabolic acidosis, increased ammonia excretion, and normalized both enzyme levels in ammoniagenesis and distal nephron ammonia transporter expression [53].

3.6 Kidney stones

Kidney stone disease is common in the general population with an estimated prevalence of around 10–15% in males and 3–5% in females [54]. Calcium-based kidney stones are the most common type (>80%), with high urine calcium excretion being a strong risk factor for stone formation [55]. Potassium is a key regulator of urinary calcium excretion at the thick ascending limb of the loop of Henle. The Na/K/2Cl cotransporter (NKCC) reabsorbs sodium and potassium with potassium returning to the lumen via the renal outer medullary K channel (ROMK). This, in turn, results in a more positively charged milieu that promotes the reabsorptions of calcium through paracellular routes. Loss-of-function mutations in KCNJ1 coding for ROMK results in Bartter syndrome, with increased urinary calcium loss [56]. Body stores of potassium can affect potassium intraluminal availability, and therefore play a role in this intricate regulation of calcium excretion. Furthermore, potassium deficiency has been shown to increase phosphorus excretion, which may lead to an increase in vitamin D and subsequent modulation of calcium homeostasis [57]. According to a study in adult volunteers, potassium administration increases, and potassium deprivation reduces urinary calcium excretion [58]. In this study, dietary potassium deprivation with a mean intake of 67 ± 8 mmol/day led to a significant increase in daily urinary Ca excretion (+1.31 ± 0.25 mmol/day, p < 0.005), which was later normalized after the administrations of either potassium chloride or potassium bicarbonate (90 mmol/day). An independent association between dietary potassium intake and incident kidney risk was demonstrated in a large epidemiologic study [59]. Taylor et al. (2016) prospectively examined potassium intake and risk of incident kidney stones in the Health Professionals Follow-Up Study (n = 42,919), the Nurses’ Health Study I (n = 60,128), and the Nurses’ Health Study II (n = 90,629). After multivariable adjustment, there was a strong inverse association between potassium intake and risk of incident stones with a HR of 0.44 (95% CI: 0.36–0.53) for the HPFS, 0.57 (95% CI: 0.45–0.72) for the NHS I, and 0.67 (95% CI: 0.57–0.78) for the NHS II (all P values for trend <0.001) [59].

3.7 Bone health

Bone health is determined by body calcium stores and acid-base balance with both calcium depletion and acidosis being among the strongest risk factors for bone mineral loss [60]. As mentioned earlier, potassium is a key regulator of both calcium homeostasis and acid-base balance. Potassium depletion can lead to renal calcium loss and stimulation of ammoniagenesis whereas potassium supplementation will preserve body calcium storage and may inhibit ammoniagenesis, if hyperkalemia is present. Therefore, potassium has long been thought to play an important role in bone health and osteoporosis prevention. The DASH diet, typically high in potassium, was also found to associate with improved biomarker profile for bone turnover [61]. However, epidemiologic studies using fruits and vegetables as a marker of potassium intake have reported conflicting results [62, 63, 64]. This could be due to differences in various other dietary nutrients (such as acid, protein, calcium, phosphorus, and vitamins), which may be confounding the association between potassium and bone turnover. Indeed, findings from studies focusing on specific dietary potassium have been rather consistent [65, 66, 67, 68]. In an analysis of the Framingham Heart Study, higher potassium intake was significantly associated with greater bone mineral density (BMD) and less decline in BMD in both men and women [65]. According to a large Korean population survey, dietary potassium intake was associated with improved bone mineral density in both older men (age > 50) and postmenopausal women [66]. Overall, participants in the highest tertile of potassium intake had a significantly higher total hip and femur neck BMD as compared to those in the lower tertile groups (p = 0.014, and 0.012 for total hip and femur neck respectively). Among postmenopausal women, those in the highest tertile of potassium intake also had significantly higher lumbar, total hip, and femur neck BMD as compared to those in lower potassium intake tertile groups (p = 0.029, 0.002, and 0.002 for lumbar spine, total hip, and femur neck respectively). Currently, there are only a few small clinical trials that have used potassium supplements to examine their effect on bone health. In a trial of 201 healthy older adults (age ≥ 65), daily supplementation with 60 mmol potassium citrate resulted in significantly increased bone mineral density at the lumbar spine and improved bone microarchitecture compared to placebo [69]. Similar findings were observed in another randomized, placebo-controlled trial of 233 older adults aged 50 years and older. Supplemental potassium bicarbonate at 1–1.5 mmol/kg daily for 3 months led to a significantly reduced biochemical markers of bone turnover and urinary calcium excretion [70]. However, an earlier randomized controlled trial of 276 postmenopausal women (age 55–65), supplementation with potassium citrate at either 18.5 or 55.5 mEq/day for 2 years did not reduce bone turnover or increase BMD at the hip or lumbar spine compared with placebo [71]. The differences in the study population may be the reason for the different study findings. Thus far, there is no conclusive evidence proving an independent effect of potassium intake on bone health and turnover. Future large-scale randomized trials are needed.