Low Dietary Potassium Intake Research Articles

Associations between dietary potassium intake and urinary potassium excretion: a protocol for systematic review and meta-analysis

BackgroundWhile numerous studies have reported associations between low dietary potassium intake and adverse clinical outcomes, methods to estimate potassium intake, mainly self-reported dietary measures and urinary potassium excretion, entail certain limitations. Self-reported measures are subject to underreporting and overreporting. Urinary potassium excretion is affected by multiple factors including renal function. Revealing the degree of bias inherent in these measures would help accurately assess potassium intake and its association with disease risk. We aim to summarize evidence on the strength of the associations between potassium intake estimated from 24-h urinary potassium excretion and potassium intake estimated from self-reported dietary measures or objective quantification methods in populations with different kidney function levels and age groups. We also aim to identify factors that affect the association strength.MethodsWe will search for potentially eligible studies that examined associations between self-reported potassium intake, 24-h urinary potassium excretion, and objectively quantified potassium intake, using MEDLINE (PubMed), Embase, Web of Science, and Scopus. Studies on children, adolescents, adults, and the elderly are eligible. Studies of patients on dialysis will be excluded. Collective study results, including a meta-analysis, will be synthesized if an adequate number of studies examining similar dietary potassium intake estimation methods are found. Analyses will be performed separately according to age groups and renal function. For the meta-analysis, fixed-effects or random-effect models will be employed depending on the degree of study heterogeneity to combine across studies the correlation coefficient, ratio, or standardized mean difference for potassium intake, comparing dietary potassium intake based on self-reported or objectively quantified methods and intake based on 24-h urinary potassium excretion. The degree of heterogeneity among included studies will be examined by calculating I2 statistics. To investigate sources of study heterogeneity, random-effects meta-regression analyses will be performed.DiscussionRevealing the strength of the association between dietary and urinary measures in populations with different levels of kidney function and age groups will enhance researchers’ and clinicians’ ability to interpret studies that utilize these measures and help establish a more solid evidence base for the role of potassium intake in changing chronic disease risk. Identifying factors that modify the associations between these measures may aid in developing predictive models to estimate actual potassium intake.Systematic review registrationPROSPERO CRD42022357847.

Dietary Sodium and Potassium Intakes and Kidney Stone Prevalence: The National Health and Nutrition Examination Survey 2011-2018.

The associations between dietary sodium intake (DSI), dietary potassium intake (DPI), and kidney stone disease (KSD) are not clear. We examined The National Health and Nutrition Examination Survey 2011-2018 to determine the independent associations between daily DSI, DPI, DSI/DPI, and KSD prevalence. In total, 19,405 participants were included for analysis, of which 1,895 had KSD. Higher DSI was not associated with increased odds of KSD in regression analysis when DSI was modeled as a continuous variable (OR = 0.99, 95% CI: 0.99-1.00, p = 0.2), or when comparing highest quartile of DSI to lowest quartile (OR = 0.84, 95% CI: 0.68-1.04, p = 0.1). Unlike DSI, higher DPI was strongly associated with reduced odds of KSD in regression analysis when DPI was modeled as a continuous variable (OR = 0.99, 95% CI: 0.99-0.99, p = 0.02), or when comparing highest quartile of DPI to lowest quartile (OR = 0.75, 95% CI: 0.60-0.94, p = 0.01). Lastly, higher DSI/DPI was also strongly associated with increased odds of KSD in regression analysis when DSI/DPI was modeled as a continuous variable (OR = 1.1, 95% CI: 1.01-1.20, p = 0.03), or when comparing highest quartile of DPI to lowest quartile (OR = 1.30, 95% CI: 1.10-1.70, p = 0.008). All the observed relationships were independent of total calorie intake. In conclusion, both lower DPI and higher DSI/DPI are associated with an increased risk of KSD. Future prospective studies are needed to clarify these causal relationships.

Abstract P338: ASSOCIATION OF HYPERTENSION AND FOOD INSECURITY WITH DIETARY SODIUM AND POTASSIUM IN ADULTS

Food insecurity (FIS), the lack of consistent access to nutritious food is a risk factor for HTN and leads to poorer health outcomes. Although studies show a higher prevalence of HTN in patients living with FIS, there is limited data exploring the underlying mechanism. Using dietary recall data, we sought to evaluate the relationship between HTN and FIS. We performed a cross-sectional analysis of 16,703 adults aged between 18 and 65 years who participated in the National Health and Nutrition Examination Survey between 2011 and 2018. We excluded pregnant participants. We examined the association between FIS, HTN, and dietary sodium and potassium levels using univariate and multivariate analysis. Adults who reported FIS were more likely to have HTN (aOR=1.22, 95% CI: 1.02-1.46, p=0.029). Non-Hispanic Blacks participants were more likely to have HTN than Non-Hispanic Whites (aOR=1.74, 95% CI: 1.54-1.96, p<0.001) while Hispanic participants were more likely to have lower BP (aOR=0.82, 95% CI: 0.71-0.94, p=0.007). The prevalence of FIS was higher among Non-Hispanic Black (28.8%) (aOR= 1.28, 95% CI= 1.02-1.61, p<0.01) and Hispanic participants (33.5%) (aOR= 1.67, 95% CI= 1.33-2.09, p<0.01) compared to Non-Hispanic White. Individuals living in food-insecure households had a higher prevalence of obesity (23.7%) compared to adults who lived in food secure households. (18.4% for normal weight and 17.9% for overweight; p < 0.01). The prevalence of hypertension increased with age, peaking in the 60-65 age group (p<0.001). Individuals who reported FIS had a significantly lower mean intake of sodium (3.57 ± 0.04 gm) and potassium (2.5 ± 0.03 gm) compared to individuals living in food secure households (3.69 ± 0.02 gm and 2.74 ± 0.02 gm, respectively; p < 0.01 for both). We found that for every 1 gm increase in dietary sodium, the odds of HTN increased by 1% (p<0.01). For every 1 gm increase in dietary potassium the odds of HTN decreased by 9% and the odds of living in a food insecure household decreased by 16%. Adults with a lower dietary potassium intake were more likely to report FIS and have HTN. Increasing assess to healthy foods, particularly foods rich in sources of potassium, for individuals living with FIS, may reduce the prevalence of HTN and lead to better cardiovascular outcomes.

Multiplatform analysis of DCT-specific mechanisms during low dietary potassium intake

Western diets are typically high in sodium, widely regarded to increase blood pressure (BP). They are also characterised by a relatively low potassium (K) intake, also linked to higher BP. Previous studies have shown that the ability of low dietary K to increase BP is almost fully accounted for by an increase in the abundance and activity of the thiazide-sensitive sodium-chloride transporter (NCC) in the kidney distal convoluted tubule (DCT). This study aims to increase our understanding of the specific effects of low K intake on the molecular landscape of the DCT. Hypothesis: During low dietary K intake unique DCT specific mechanisms account both for the higher NCC abundance and underlie the DCT remodelling processes leading to DCT hypertrophy. Methods: Due to the relatively low abundance of DCT cells vs. whole kidney, many DCT-specific changes are undetectable when analysing whole kidney or cortex samples. To uncover DCT-specific mechanisms, Parvalbumin-GFP+ mice (GFP expressed only in DCT) were fed control (1% K) or a low K (0.2%K, n=7) diet for 4 days. Kidneys were collected on day 5, a single cell suspension prepared and GFP- and GFP+ cells separated using FACs. Cells were prepared for both bulk RNAseq and protein mass spectrometry. In parallel, kidney samples were embedded in paraffin, tubules were isolated using a laser microdissection system (LMD) and a protocol optimized to analyse these samples with mass spectrometry. Results: Compared to control diets, mice on 0.2%K intake had increased NCC (+44%) and phosphorylated NCC (+51%), and decreased expression of α-ENaC (-20%) and cleaved γ-ENaC (-10%). Mice on 0.2%K also had higher BP by tail cuff plethysmography (SBP 121.4 ± 2.1 vs. 110.8 ± 1.1 mmHg), reduced urine volume and reduced urinary K excretion (5.5-fold). Plasma K was slightly decreased compared to control diets (4.06 vs. 4.35mmol/l). FACs of living GFP+ cells was optimized to 95±2% purity and enrichment of DCT cells confirmed at protein and RNA level for DCT specific genes of interest. RNAseq and mass spectrometry studies of these samples are ongoing. For LMD samples, mass spectrometry detected ~1400 proteins from ~40 tubules. Samples from specific segments were enriched for proteins known to be expressed in these regions. Ongoing studies are addressing the proteomes of proximal tubule, DCT and collecting duct cells subsequent to 0.2% K+ intake. Perspectives: Understanding the mechanisms of K handling and their effects on BP may offer new targets for prevention or treatment of hypertension, both through drug and dietary intervention. We have developed a multiplatform approach to study DCT cells by proteomics, transcriptomics and coupled it to functional studies. We have also developed a protocol for processing LMD samples that allows for a good recovery of proteins from a low number of tubules, opening up the possibilities to process a large number of already existing samples from a range of different studies. Novo Nordisk Foundation (NNF21OC0067647), Leducq Foundation (17CVD05). This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

CIRCADIAN BLOOD PRESSURE PROFILE IN PEDIATRIC PATIENTS WITH PRIMARY HYPERTENSION

Objective: Disturbed circadian blood pressure (BP) profile is a risk factor for cardiovascular complications in adults. The study aimed to evaluate factors affecting circadian BP profile and its association with hypertension-mediated organ damage (HMOD) in pediatric patients with primary hypertension (PH). Design and method: The study included 112 children (79 boys, 33 girls, 14.7 ± 2.7 years) with untreated PH. Circadian BP profile was assessed by 24-hour ABPM. Disturbed circadian BP profile (non-dipping) was defined as a nocturnal drop in systolic or diastolic BP (SBP, DBP) < 10%. A nocturnal drop in SBP or DBP > 20% was defined as extreme dipping. Patients were evaluated for central BP, HMOD (left ventricular mass index - LVMI, aortic pulse wave velocity, augmentation index (AIx75HR), intima-media thickness, albuminuria), and clinical and biochemical parameters, including sodium-potassium balance. Results: In the study group, the mean nocturnal drop in SBP was 10.9 ± 5.9 [%] and in DBP - 16.2 ± 8.5 [%]. Non-dipping was found in 50 (44.6%) children and extreme-dipping in 29 (25.9%) patients. The nocturnal drop in SBP correlated negatively with Z-scores of body weight (r = -0.191, p = 0.043) and BMI (r = -0.242, p = 0.010) and with LVMI [g/m2.7] (r = -0.395, p = 0.006). The nocturnal drop in SBP and DBP correlated positively with urinary potassium excretion [mmol/kg/24 h] (r = 0.656, p = 0.001 and r = 0.540, p = 0.011, respectively). Patients with disturbed circadian blood pressure profile were characterized by higher LVMI (44.5 ± 12.5 vs. 36.8 ± 8.8 [g/m2.7]) and albuminuria (median: 10.8, IQR: 5.3–53.3 vs. median: 8.1, IQR: 5.5–16.4 [mg/24 h], p = 0.043) and lower urinary potassium excretion (0.6 ± 0.2 vs. 1.1 ± 0.3 [mmol/kg/24 h]). Extreme-dipping patients had a higher AIx75HR than the other patients (median: + 3.3, IQR: -6.3- + 17.7 vs. -4.6, IQR: -17.3- + 4.0 [%], p = 0.048). Conclusions: 1. Disturbed circadian BP profile is common in children with PH and should not be considered a marker of secondary hypertension. 2. Disturbed circadian BP profile may be associated with higher body weight and lower dietary potassium intake. 3. Pediatric patients with PH and disturbed BP profile are at risk for HMOD: left ventricular hypertrophy and microalbuminuria. 4. Extreme-dipping may be associated with increased arterial stiffness in children with PH.

Hypokalemia in peritoneal dialysis patients in Thailand: the pivotal role of low potassium intake.

Hypokalemia is highly prevalent in chronic peritoneal dialysis (PD) patients worldwide, particularly in Thailand. This study aims to investigate the major determinants of hypokalemia in Thai PD patients. A cross-sectional study was performed in chronic PD patients at 4 PD centers in Bangkok, Thailand. Hypokalemia was defined if the average serum potassium level during the last 3 consecutive visits was < 3.5mEq/L. Patients and/or their caregivers were asked to perform a 3-day dietary food record and take pre- and post-meal pictures following the instructed protocol. Daily dietary nutrients, including potassium, were estimated by a single dietician using INMUCAL-N software. Total potassium excretion was determined by 24-h PD effluents and urine collection. Intracellular and extracellular water values (ICW and ECW, respectively) were measured by electrical bioimpedance assay (BIA) to indirectly explore the role of intracellular potassium shift in hypokalemia. Among 60 eligible PD patients, 19 (31%) had hypokalemia. Hypokalemic patients had significantly lower dietary potassium intake (24.4 ± 11.1 vs. 30.5 ± 9.4mEq/day, p = 0.031) and lower total potassium excretion (28.5 ± 8.4 vs. 36.7 ± 11.2mEq/day, p = 0.006) compared to normokalemic patients. Both groups had comparable values of ICW and ECW. On logistic regression, there was no significant correlation between hypokalemia and daily PD exchange volume, total Kt/Vurea, residual renal function, concurrent medications (insulin, diuretics, renin-angiotensin-aldosterone inhibitor, and beta-blockers) or ICW. Low dietary potassium was an independent risk factor for hypokalemia. Low dietary potassium intake, rather than increased potassium excretion or intracellular shift, is the major contributing factor of hypokalemia in Thai chronic PD patients. Dietary intervention or potassium supplement protocol should be implemented.

Dietary Potassium Intake and Mortality in a Prospective Hemodialysis Cohort

Among hemodialysis patients, clinical practice guidelines recommend dietary potassium restriction given concerns about potential hyperkalemia leading to malignant arrhythmias and mortality. However, there are sparse data informing recommendations for dietary potassium intake in this population. We thus sought to examine the relationship between dietary potassium intake and death risk in a prospective cohort of hemodialysis patients. Among 415 hemodialysis patients from the prospective "Malnutrition, Diet, and Racial Disparities in Chronic Kidney Disease" cohort recruited across 16 outpatient dialysis clinics, information regarding dietary potassium intake was obtained using Food Frequency Questionnaires administered over October 2011 to March 2015. We first examined associations of baseline dietary potassium intake categorized as tertiles with mortality risk using Cox regression. We then examined clinical characteristics associated with low dietary potassium intake (defined as the lowest tertile) using logistic regression. In expanded case-mix Cox analyses, patients whose dietary potassium intake was in the lowest tertile had higher mortality (ref: highest tertile) (adjusted hazard ratio 1.74, 95% confidence interval 1.14-2.66). These associations had even greater magnitude of risk following adjustment for laboratory and nutritional covariates (adjusted hazard ratio 2.65, 95% confidence interval 1.40-5.04). In expanded case-mix restricted cubic spline analyses, there was a monotonic increase in mortality risk with incrementally lower dietary potassium intake. In expanded case-mix logistic regression models, female sex; higher serum bicarbonate; and lower dietary energy, protein, and fiber intake were associated with low dietary potassium intake. In a prospective cohort of hemodialysis patients, lower dietary potassium intake was associated with higher mortality risk. These findings suggest that excessive dietary potassium restriction may be deleterious in hemodialysis patients, and further studies are needed to determine the optimal dietary potassium intake in this population.

A Renal Potassium‐Switch Prioritizes Dietary Potassium Over Sodium, Driving Salt‐Sensitive Hypertension

Reducing dietary salt (NaCl) is well appreciated to lower blood pressure (BP), but a growing body of evidence indicates that increasing dietary potassium (K+) intake plays an equally important role. A ‘renal potassium switch’ that turns on the thiazide‐sensitive NaCl cotransporter (NCC) in the distal convoluted tubule (DCT) in response to low dietary potassium intake and off in response to high potassium intake has been implicated.Here we test the idea in genetically engineered mice, containing a DCT1‐specific, conditionally active SPAK (CA‐SPAK mice) which phospho‐activates NCC, and locks the switch “on.” BP responses to small, physiologic changes in plasma [K+] (P[K+]) in CA‐SPAK mice were compared to control mice. Dietary potassium content was varied to acutely titrate P[K+] over a physiologic range (3.7mM (LK), 4.4mM (MK), and 5.1mM (HK)). Blood pressure was monitored by telemetry at each P[K+] level in mice consuming control or high salt diet (HNa). At the end of each dietary treatment, the BP response to hydrochlorothiazide (HCTZ) was measured to assess the contribution of NCC to BP.BP decreased by ~10 mmHg when P[K+] increased from 3.7 to 5.1 mM in control mice, coincident with inactivation of NCC. When the switch was on (LK and MK groups), HNa significantly elevated BP but had no effect when the switch was inactivated by HK. HCTZ significantly reduced BP in the LK/HNa and MK/HNa groups but had no effect on BP in the HK/HNa group, further supporting the idea that low potassium‐dependent activation NCC exacerbates the effects of sodium. Studies in CA‐SPAK mice reveal a causal relationship between switch activation and BP responses to sodium and potassium. In contrast to control mice, increasing P[K+] in CA‐SPAK mice had no effect on BP under control salt conditions and failed to blunt the significant hypertensive effects of HNa. HCTZ significantly decreased BP in all CA‐SPAK groups to near control levels, consistent with NCC‐driven salt reabsorption. Thus, locking on the potassium switch prevents the anti‐hypertensive effects of HK. No sex differences were found.In summary, low K+ consumption, common in modern diets, presses the switch pathway to turn on to conserve K+ at the expense of increasing sodium retention, even in the face of high dietary sodium, and this elevates BP. Thus, switch activation can drive salt‐sensitive hypertension.Support or Funding InformationNIH

WNK-SPAK/OSR1 signaling: lessons learned from an insect renal epithelium.

WNK [with no lysine (K)] kinases regulate renal epithelial ion transport to maintain homeostasis of electrolyte concentrations, extracellular volume, and blood pressure. The SLC12 cation-chloride cotransporters, including the sodium-potassium-2-chloride (NKCC) and sodium chloride cotransporters (NCC), are targets of WNK regulation via the intermediary kinases SPAK (Ste20-related proline/alanine-rich kinase) and OSR1 (oxidative stress response). The pathway is activated by low dietary potassium intake, resulting in increased phosphorylation and activity of NCC. Chloride regulates WNK kinases in vitro by binding to the active site and inhibiting autophosphorylation and has been proposed to modulate WNK activity in the distal convoluted tubule in response to low dietary potassium. WNK-SPAK/OSR1 regulation of NKCC-dependent ion transport is evolutionarily ancient, and it occurs in the Drosophila Malpighian (renal) tubule. Here, we review recent studies from the Drosophila tubule demonstrating cooperative roles for chloride and the scaffold protein Mo25 (mouse protein-25, also known as calcium-binding protein-39) in the regulation of WNK-SPAK/OSR1 signaling in a transporting renal epithelium. Insights gained from this genetically manipulable and physiologically accessible epithelium shed light on molecular mechanisms of regulation of the WNK-SPAK/OSR1 pathway, which is important in human health and disease.

Urinary potassium excretion, renal ammoniagenesis, and risk of graft failure and mortality in renal transplant recipients

Background: Renal transplant recipients (RTRs) have commonly been urged to limit their potassium intake during renal insufficiency and may adhere to this principle after transplantation. Importantly, in experimental animal models, low dietary potassium intake induces kidney injury through stimulation of ammoniagenesis. In humans, low potassium intake is an established risk factor for high blood pressure.Objective: We hypothesized that low 24-h urinary potassium excretion [UKV; urinary potassium concentration × volume], the gold standard for assessment of dietary potassium intake, represents a risk factor for graft failure and mortality in RTRs. In secondary analyses, we aimed to investigate whether these associations could be explained by ammoniagenesis, plasma potassium, or blood pressure.Design: In a prospective cohort of 705 RTRs, we assessed dietary potassium intake by a single 24-h UKV and food-frequency questionnaires. Cox regression analyses were used to investigate prospective associations with outcome.Results: We included 705 stable RTRs (mean ± SD age: 53 ± 13 y; 57% men) at 5.4 y (IQR: 1.9–12.0 y) after transplantation and 253 kidney donors. Mean ± SD UKV was 73 ± 24 mmol/24 h in RTRs compared with 85 ± 25 mmol/24 h in kidney donors. During follow-up for 3.1 y (IQR: 2.7–3.9 y), 45 RTRs developed graft failure and 83 died. RTRs in the lowest sex-specific tertile of UKV (women, <55 mmol/24 h; men, <65 mmol/24 h) had an increased risk of graft failure (HR: 3.70; 95% CI: 1.64, 8.34) and risk of mortality (HR; 2.66; 95% CI: 1.53, 4.61), independent of potential confounders. In causal path analyses, 24-h urinary ammonia excretion, plasma potassium, and blood pressure did not affect these associations.Conclusions: Our results indicate that low UKV is associated with a higher risk of graft failure and mortality in RTRs. Specific attention for adequate potassium intake after transplantation seems warranted. This trial was registered at clinicaltrials.gov as NCT02811835.

Dietary sodium and potassium intake were associated with hypertension, kidney damage and adverse perinatal outcome in pregnant women with preeclampsia

ABSTRACTObjectives: In this study, we hypothesized that dietary salt and potassium intake may be related with blood pressure, kidney damage and perinatal outcome in pregnants with preeclampsia (PE). Methods: In total, 200 women (50 control women with healthy pregnancy, 150 women with PE) were recruited for the study. Daily salt and potassium intake was estimated based on calculation of 24-hour urinary sodium U[Na+] and potassium U[K+] excretion. U[Na+]/[K+] was calculated by dividing U[Na+] by U[K+]. At the end of the measurements, the pregnant women with PE (n=150) were divided into tertiles according to U[Na+]/[K+]: low Na/K group (n=50, mean U[Na+]/[K+]: 1,04±0,32), medium Na/K group (n=50, mean U[Na+]/[K+]: 2,49± 0,54), high Na/K group (n=50, mean U[Na+]/[K+]: 6,62±3,41). Results: The mean SBP and DBP levels were significantly lower in low Na/K group compared with medium or high Na/K groups (p=0.024, p=0.0002; respectively). Serum creatinine was significantly lower in low Na/K group than high Na/K group (p=0.025). Frequency of severe preeclampsia is lower in low Na/K group than medium or high Na/K groups (p=0.002, p=0.0001; respectively). Birth weight and gestational age at birth were higher in low Na/K group compared with high Na/K group (p=0.045, p=0.0002; respectively). After adjusting for covariates, SBP and DBP and creatinine levels were independently associated with 24 hours urinary [Na+]/[K+] Conclusion: These findings suggest that pregnant with PE with high dietary salt and low potassium intake may have greater maternal and neonatal morbidity risk than pregnant with PE under low dietary salt and high potassium intake.

The role of dietary potassium in hypertension and diabetes.

Potassium is an essential mineral which plays major roles for the resting membrane potential and the intracellular osmolarity. In addition, for several years, it has been known that potassium also affects endothelial and vascular smooth muscle functions and it has been repeatedly shown that an increase in potassium intake shifts blood pressure to a more preferable level. Meanwhile, the blood pressure lowering effects of potassium were presented in several intervention trials and summarized in a handful of meta-analyses. Furthermore, accumulating epidemiological evidence from, especially, the last decade relates low dietary potassium intake or serum potassium levels to an increased risk for insulin resistance or diabetes. However, intervention trials are required to confirm this association. So, in addition to reduction of sodium intake, increasing dietary potassium intake may positively affect blood pressure and possibly also glucose metabolism in many populations. This concise review not only summarizes the studies linking potassium to blood pressure and diabetes but also discusses potential mechanisms involved, like vascular smooth muscle relaxation and endothelium-dependent vasodilation or stimulation of insulin secretion in pancreatic β-cells, respectively.

Low dietary potassium intake stimulates NCC to cause sodium retention (892.16)

Low dietary K+ stimulates the renal sodium chloride cotransporter (NCC), whereas high salt intake inhibits it. As most people in the world consume a diet that is both low in K+ and high in salt, we investigated how NCC responds to conflicting Na+ and K+ signals. High salt (HS)/ low K+ (LK) intake increased NCC and pNCC compared with HS/normal K+ (NK) and redistributed SPAK, OSR1, and WNK4 to cytoplasmic punctae. These effects were preserved in both SPAK‐/‐ and AT1aR‐/‐ mice. A HS/LK diet also decreased urinary Na+, compared with a HS/NK diet. This anti‐natriuretic effect, however was absent in NCC‐/‐ mice. As mineralocorticoids have been reported to stimulate NCC, we confirmed that fludrocortisone (F) increases NCC and phosphorylated NCC (pNCC) in mice. A high K+ diet, which normalized plasma K+, prevented the effects of F on pNCC. F also caused substantially more hypokalemia in NCC‐/‐ mice, than in wild type mice, suggesting that NCC is essential to preserve plasma K+. Amiloride, which caused hyperkalemia and volume contraction, decreased NCC and pNCC, suggesting K+ was determining NCC status. Mice treated with both F and A had plasma K+ and both NCC and pNCC levels equal to A alone. In HEK293 cells, low K+ medium increased pNCC and pSPAK/pOSR1, an effect that was dependent on WNK kinases as shown through siRNA studies. Transfection with mutant KCNJ10 channels that depolarize cells, including multiple EAST sydrome mutants, reduced pNCC compared with wild type KCNJ10. Treatment with barium also reduced pNCC. The results suggest that low plasma K+ stimulates NCC directly, independent of any intermediating signaling hormones; this effect likely requires WNK‐SPAK/OSR1. Our data suggest that the DCT responds to plasma K+ and predominantly modulates renal K+ excretion.Grant Funding Source: Supported by NIDDK, the Department of Veterans Affairs, and the American Heart Association

Serum potassium level is associated with metabolic syndrome: A population-based study

Evidence has suggested that low serum potassium concentration or low dietary potassium intake can result in many metabolic disorders. Our objective was to evaluate the association between serum potassium level and risk of prevalent metabolic syndrome. We conducted a cross-sectional study in 10,341 participants aged 40 years or older. Metabolic syndrome was defined according to guidelines from the National Cholesterol Education Program with modification. The prevalence rate of metabolic syndrome was 51.7% in participants with hypokalemia and 37.7% in those with normokalemia. With the reduction of serum potassium quartiles, participants were tended to have higher level of triglycerides and uric acid, lower level of high-density lipoprotein cholesterol (HDL-C), larger waist circumference and more severe insulin resistance. Serum potassium level significantly decreased with the increasing number of metabolic syndrome components. Compared with subjects in the highest quartile of serum potassium level, multivariate adjusted odds ratios for prevalent metabolic syndrome in the lowest quartile was 1.48 (95% confidence interval, 1.16-1.87). Moreover, compared with subjects without central obesity, hypertriglyceridemia, low HDL-C and elevated fasting plasma glucose, those with each of these metabolic syndrome components have lower level of serum potassium after adjusted for age and sex. Low serum potassium level significantly associated with prevalence of metabolic syndrome in middle-aged and elderly Chinese.

Low serum potassium level is associated with nonalcoholic fatty liver disease and its related metabolic disorders

Subjects with nonalcoholic fatty liver disease (NAFLD) have a high risk of developing type 2 diabetes and cardiovascular diseases. Low serum potassium concentration or low dietary potassium intake can result in metabolic disorders. Our objective was to evaluate the association between low serum potassium level and prevalence of NAFLD in a Chinese population. A population-based cross-sectional study. We conducted a community-based study in 8592 subjects to investigate the association of serum potassium with the risk of prevalent NAFLD. NAFLD was diagnosed by hepatic ultrasonography. The prevalence rate of NAFLD was 30·3% in this population and gradually decreased across serum potassium quartiles. With the reduction in serum potassium level, participants have larger waist circumference (WC) and more severe insulin resistance. The correlations hold also in multivariate linear regression analysis. In logistic regression analysis, compared with subjects in the highest quartile of serum potassium level, the adjusted odds ratios (ORs) in the lowest quartile was 1·33 [95% confidence interval (CI), 1·11-1·60] for NAFLD, 1·81 (95% CI, 1·49-2·19) for insulin resistance and 1·58 (95% CI, 1·30-1·93) for central obesity. In subgroup analysis after multiple adjustments, significant relation between serum potassium level and prevalent NAFLD was detected in women, younger subjects, those with insulin resistance and those with central obesity, respectively. Low serum potassium level significantly associated with prevalence of NAFLD in middle-aged and elderly Chinese.

Serum and Dietary Potassium and Risk of Incident Type 2 Diabetes Mellitus

Serum potassium levels affect insulin secretion by pancreatic β-cells, and hypokalemia associated with diuretic use has been associated with dysglycemia. We hypothesized that adults with lower serum potassium levels and lower dietary potassium intake are at higher risk for incident diabetes mellitus (DM), independent of diuretic use. We analyzed data from 12 209 participants from the Atherosclerosis Risk in Communities (ARIC) Study, an ongoing prospective cohort study, beginning in 1986, with 9 years of in-person follow-up and 17 years of telephone follow-up. Using multivariate Cox proportional hazard models, we estimated the hazard ratio (HR) of incident DM associated with baseline serum potassium levels. During 9 years of in-person follow-up, 1475 participants developed incident DM. In multivariate analyses, we found an inverse association between serum potassium and risk of incident DM. Compared with those with a high-normal serum potassium level (5.0-5.5 mEq/L), adults with serum potassium levels lower than 4.0 mEq/L, 4.0 to lower than 4.5 mEq/L, and 4.5 to lower than 5.0 mEq/L had an adjusted HR (95% confidence interval [CI]) of incident DM of 1.64 (95% CI, 1.29-2.08), 1.64 (95% CI, 1.34-2.01), and 1.39 (95% CI, 1.14-1.71), respectively. An increased risk persisted during an additional 8 years of telephone follow-up based on self-report with HRs of 1.2 to 1.3 for those with a serum potassium level lower than 5.0 mEq/L. Dietary potassium intake was significantly associated with risk of incident DM in unadjusted models but not in multivariate models. Serum potassium level is an independent predictor of incident DM in this cohort. Further study is needed to determine if modification of serum potassium could reduce the subsequent risk of DM.

Dietary Sodium Reduction

In the years between 1960 and 1991, the prevalence of hypertension in the United States decreased from 29.7% to 20.4%. The recognition of hypertension as the Bsilent killer[ and the work of the National High Blood Pressure Education Program contributed to this public health success. In recent years, however, hypertension has reemerged as a major public health problem. The prevalence of hypertension in US adults has steadily increased and now hovers between 29% and 30%. This increase is due in part to aging demographics as well as the epidemic of overweight and obesity. It is now estimated that nearly 75 million or 1 in every 3 adults has hypertension. Hypertension constitutes a significant risk factor for myocardial infarction, stroke, heart failure, and renal failure. Cardiovascular clinicians have an enormous armamentarium of pharmacological agents that, particularly when used in combination, have the potential to control most cases of hypertension; indeed, control rates have risen over time, according to an article published inThe Journal of the American Medical Association in May 2010. In an accompanying editorial, Aram Chobanian, Boston University Medical Center, and first author of the Joint National Committee on the Prevention Detection and Treatment of Hypertension (JNC 7) guidelines, commented that although the progress in treatment is encouraging, rates of high blood pressure will continue to rise as the population ages unless steps are taken to change some of its underlying causes. Ford and colleagues, in a recent article, calculated the percentage of Americans considered Blow risk[ for CVD. The trend from the period 1999 to 2004 was unfavorable, demonstrating that only 7.5% (down from 10.5% in the period 1988Y1994) would be considered low risk. One factor contributing to this negative trend was the decrease in the percentage of normotensive patients. Recently, the Institute of Medicine (IOM), in its report entitled BA Population-Based Policy and Systems Change Approach to PreventandControlHypertension,[ published in February 2010, declared high blood pressure a Bneglected disease.[ In its report, the IOM called for population-based strategies designed to impact large numbers of people and improve population health status. The IOM further championed behavioral and lifestyle interventions that target risk factors that contribute to hypertension, identifying the following: unhealthy diets, excess salt consumption and low dietary potassium intake, overweight/obesity, and sedentary lifestyles. In April 2010, the IOM released a second report related to the hypertension document, BStrategies to Reduce Sodium Intake in the United States,[ focusing on a population approach to dietary sodium reduction. In 2008, Congress actually petitioned the IOM for recommendations on strategies to reduce dietary sodium intake. The average intake of sodium for American adults is approximately 3400 mg daily, fully 50% more than the current upper limit recommendation of no more than 2300 mg daily. (Actually, for at least 70% of adults in the United StatesVthose with hypertension, African Americans, and those older than 40 yearsVthe daily consumption of sodium should not exceed 1500 mg.) Typically, when clinicians open a dialogue with hypertensive or heart failure patients regarding reducing dietary sodium intake, patients often reply that Bthe salt shaker is not even on the table,[ unaware that only about 6% of dietary sodium comes from salt added at the table. Approximately 75% of dietary sodium comes from processed food. Voluntary efforts to reduce sodium intake have been unsuccessful. The

The Future of Antihypertensive Treatment

Despite progress in recent years in the prevention, detection, and treatment of high blood pressure (BP), hypertension remains an important public health challenge. Hypertension affects approximately 1 billion individuals worldwide. High BP is associated with an increased risk of mortality and morbidity from stroke, coronary heart disease, congestive heart failure, and end-stage renal disease; it also has a negative impact on the quality of life. Hypertension cannot be eliminated because there are no vaccines to prevent the development of hypertension, but, its incidence can be decreased by reducing the risk factors for its development, which include obesity, high dietary intake of fat and sodium and low intake of potassium, physical inactivity, smoking, and excessive alcohol intake. For established hypertension, efforts are to be directed to control BP by lifestyle modification (LSM). However, if BP cannot be adequately controlled with LSM, then pharmacotherapy can be instituted along with LSM. Normalization of BP reduces cardiovascular risk (for cardiovascular death, myocardial infarction, and cardiac arrest), provides renoprotection (prevention of the onset or slowing of proteinuria and progression of renal dysfunction to end-stage renal disease in patients with hypertension, diabetes mellitus types 1 and 2, and chronic renal disease), and decreases the risk of cerebrovascular events (stroke and cognition impairment), as has been amply demonstrated by a large number of randomized clinical trials. In spite of the availability of more than 75 antihypertensive agents in 9 classes, BP control in the general population is at best inadequate. Therefore, antihypertensive therapy in the future or near future should be directed toward improving BP control in treated hypertensive patients with the available drugs by using the right combinations at optimum doses, individually tailored gene-polymorphism directed therapy, or development of new modalities such as gene therapy and vaccines. Several studies have shown that BP can be reduced by lifestyle/behavior modification. Although, the reductions appear to be trivial, even small reductions in systolic BP (for example, 3-5 mm Hg) produce dramatic reduction in adverse cardiac events and stroke. On the basis of the results of clinical and clinical/observational studies, it has been recommended that more emphasis be placed on lifestyle/behavior modification (obesity, high dietary intake of fat and sodium, physical inactivity, smoking, excessive alcohol intake, low dietary potassium intake) to control BP and also to improve the efficacy of pharmacologic treatment of high BP. New classes of antihypertensive drugs and new compounds in the established drug classes are likely to widen the armamentarium available to combat hypertension. These include the aldosterone receptor blockers, vasodilator beta-blockers, renin inhibitors, endothelin receptor antagonists, and dual endopeptidase inhibitors. The use of fixed-dose combination drug therapy is likely to increase. There is a conceptual possibility that gene therapy may yield long-lasting antihypertensive effects by influencing the genes associated with hypertension. But, the treatment of human essential hypertension requires sustained over-expression of genes. Some of the challenging tasks for successful gene therapy that need to be mastered include identification of target genes, ideal gene transfer vector, precise delivery of genes into the required site (target), efficient transfer of genes into the cells of the target, and prompt assessment of gene expression over time. Targeting the RAS by antisense gene therapy appears to be a viable strategy for the long-term control of hypertension. Several problems that are encountered in the delivery of gene therapy include 1) low efficiency for gene transfer into vascular cells; 2) a lack of selectivity; 3) problem in determining how to prolong and control transgene expression or antisense inhibition; and 4) difficulty in minimizing the adverse effects of viral or nonviral vectors. In spite of the hurdles that face gene therapy administration in humans, studies in animals indicate that gene therapy may be feasible in treating human hypertension, albeit not in the near future. DNA testing for genetic polymorphism and determining the genotype of a patient may predict response to a certain class of antihypertensive agent and thus optimize therapy in individual patients. In this regard, there are some studies that report the effectiveness of antihypertensive therapy based upon the genotype of selected patients. Treatment of human hypertension with vaccines is feasible but is not likely to be available in the near future.

Mitogen-Activated Protein Kinases Inhibit the ROMK (Kir 1.1)-Like Small Conductance K Channels in the Cortical Collecting Duct

It was demonstrated previously that low dietary potassium (K) intake stimulates Src family protein tyrosine kinase (PTK) expression via a superoxide-dependent signaling. This study explored the role of mitogen-activated protein kinase (MAPK) in mediating the effect of superoxide anions on PTK expression and ROMK (Kir 1.1) channel activity. Western blot analysis demonstrated that low K intake significantly increased the phosphorylation of P38 MAPK (P38) and extracellular signal-regulated kinase (ERK) but had no effect on phosphorylation of c-JUN N-terminus kinase in renal cortex and outer medulla. The stimulatory effect of low K intake on P38 and ERK was abolished by treatment of rats with tempol. The possibility that increases in superoxide and related products that are induced by low K intake were responsible for stimulating phosphorylation of P38 and ERK also was supported by the finding that application of H(2)O(2) increased the phosphorylation of ERK and P38 in the cultured mouse collecting duct cells. Simultaneous blocking of ERK and P38 completely abolished the effect of H(2)O(2) on c-Src expression in mouse collecting duct cells. For determination of the role of P38 and ERK in the regulation of ROMK-like small-conductance K (SK) channels, the patch-clamp technique was used to study the effect of inhibiting P38 and ERK on SK channels in the cortical collecting duct from rats that were on a control K diet (1.1%) and on a K-deficient diet for 1 d. Inhibition of ERK, c-JUN N-terminus kinase, or P38 alone had no effect on SK channels. In contrast, simultaneous inhibition of P38 and ERK significantly increased channel activity. The effect of inhibiting MAPK on SK channels was not affected in the presence of herbimycin A, a PTK inhibitor, and was larger in rats that were on a K-deficient diet than in rats that were on a normal-K diet. However, the stimulatory effect of inhibiting ERK and P38 on SK was absent in the cortical collecting duct that was treated with colchicine. It is concluded that low K intake-induced increases in superoxide levels are responsible for stimulation of P38 and ERK and that MAPK inhibit the SK channels by stimulating PTK expression and via a PTK-independent mechanism.

Serum potassium level and dietary potassium intake as risk factors for stroke.

Numerous studies have found that low potassium intake and low serum potassium are associated with increased stroke mortality, but data regarding stroke incidence have been limited. Serum potassium levels, dietary potassium intake, and diuretic use in relation to risk for stroke in a prospectively studied cohort were investigated. The study comprised 5,600 men and women older than 65 years who were free of stroke at enrollment. Baseline data included serum potassium level, dietary potassium intake, and diuretic use. Participants were followed for 4 to 8 years, and the incidence and types of strokes were recorded. Low serum potassium was defined as less than 4.1 mEq/L, and low potassium intake as less than 2.4 g/d. Among diuretic users, there was an increased risk for stroke associated with lower serum potassium (relative risk [RR]: 2.5, p < 0.0001). Among individuals not taking diuretics, there was an increased risk for stroke associated with low dietary potassium intake (RR: 1.5, p < 0.005). The small number of diuretic users with lower serum potassium and atrial fibrillation had a 10-fold greater risk for stroke compared with those with higher serum potassium and normal sinus rhythm. A lower serum potassium level in diuretic users, and low potassium intake in those not taking diuretics were associated with increased stroke incidence among older individuals. Lower serum potassium was associated with a particularly high risk for stroke in the small number of diuretic users with atrial fibrillation. Further study is required to determine if modification of these factors would prevent strokes.