Low Potassium Diet Research Articles

6636 Primary Hyperaldosteronism Leading to Aldosterone Deficiency

Abstract Disclosure: N.G. Haverstick: None. J.R. Anthony: None. Primary Hyperaldosteronism is a disease process that is often missed, and under checked due to poor screening tools. The disease presents with a common problem, uncontrolled hypertension. It also presents with hypokalemia, fatigue and headaches. It can easily be masked with blood pressure medications, CKD, and pain medications. After treatment there are some rare reports of patients developing hypoaldosteronism. Some risk factors are age >50, duration of hypertension >10 years, pre-existing renal impairment and adrenal adenoma size >2 cm. The patient will present with the opposite: hyperkalemia and hypotension. This is due to the atrophy of the previously healthy gland. Usually this resolves within a year. However in our patient she has continued to require long standing mineralocorticoid replacement therapy. This case highlights the importance of early recognition of hyperaldosteronism. A 63 year-old-female with a medical history of hypertension and diabetes mellitus is being followed for 30+ years of uncontrolled hypertension. Patient has been on multiple agents and blood pressure remained elevated after trying triamterene/hctz, metoprolol, irbesartan, amlodipine. After changing her PCP, there was further investigation into the cause. Leading differentials were Primary Hyperaldosteronism vs Renal Artery Stenosis vs Primary Hypertension. She also had multiple labs with her Potassium below 3 mEq/l. Additional labs were obtained and her Aldosterone level 209 ng/dl and Renin <0.167 ng/mL/hr. The patient was referred to Endocrinology who performed a fludrocortisone suppression test, which did not suppress the levels. A CT scan of the abdomen was performed that showed a 1.3 cm right adrenal mass typical with adrenal adenoma. The patient had an adrenalectomy surgery in February 2022. The patient recovered well, however now developed hypotension off medication, and had consistent hyperkalemia with K > 5.5 mEq/l. The patient had now developed aldosterone deficiency. This was due to the long standing hyperaldosteronism that had caused her left adrenal gland to atrophy after 30 years. The patient was started on Fludrocortisone 0.1 mg daily and a low potassium diet. She has remained off any blood pressure medications since her right adrenalectomy. She has continued to require the mineralocorticoid replacement to date. The diagnostic work-up for primary aldosteronism involves screening, confirmatory testing, and localization studies to distinguish unilateral pathology which may be amenable to adrenalectomy from bilateral adrenal hyperplasia. Through literature review, one theory is that chronic suppression of renin may cause atrophy of the zona glomerulosa cells and hypoaldosteronism. Throughout the case report we emphasize on the importance of early diagnostic screening of secondary hypertension as well as the complications from adrenalectomy. Presentation: 6/2/2024

Exploring new horizons: angiotensin II, angiotensin II type 1 receptor, and renal outer medullary potassium channel interaction in distal convoluted tubule.

This study investigates angiotensin II (Ang II)'s regulatory mechanism on renal outer medullary potassium channel (ROMK) activity in the distal convoluted tubule (DCT) during low potassium intake, focusing on the Janus kinase 2 (JAK2) pathway activation mediated by the Ang II type 1 receptor (AT1R). Utilizing a low potassium diet mouse model, various methods including patch clamping, reverse transcription-quantitative polymerase chain reaction, Western blotting, and immunohistochemical staining were applied to analyze ROMK channel activity and the expression of related proteins. The findings reveal that Ang II inhibits ROMK activity in the DCT2 membrane through AT1R activation, with the JAK2 pathway playing a central role. Further, inhibiting JAK2 reverses this effect, indicating its potential in hypertension treatment. This study provides novel insights into the role of Ang II in renal potassium excretion and hypertension pathophysiology.

Regulation of ClC-K/barttin by endocytosis influences distal convoluted tubule hyperplasia.

ClC-K/barttin channels are involved in the transepithelial transport of chloride in the kidney and inner ear. Their physiological role is crucial in humans because mutations in CLCNKB or BSND, encoding ClC-Kb and barttin, cause Bartter's syndrome types III and IV, respectively. In vitro experiments have shown that an amino acid change in a proline-tyrosine motif in the C-terminus of barttin stimulates ClC-K currents. The molecular mechanism of this enhancement and whether this potentiation has any in vivo relevance remains unknown. We performed electrophysiological and biochemical experiments in Xenopus oocytes and kidney cells co-expressing ClC-K and barttin constructs. We demonstrated that barttin possesses a YxxØ motif and, when mutated, increases ClC-K plasma membrane stability, resulting in larger currents. To address the impact of mutating this motif in kidney physiology, we generated a knock-in mouse. Comparing wild-type (WT) and knock-in mice under a standard diet, we could not observe any difference in ClC-K and barttin protein levels or localization, either in urinary or plasma parameters. However, under a high-sodium low-potassium diet, known to induce hyperplasia of distal convoluted tubules, knock-in mice exhibit reduced hyperplasia compared to WT mice. In summary, our in vitro and in vivo studies demonstrate that the previously identified PY motif is indeed an endocytic YxxØ motif in which mutations cause a gain of function of the channel. KEY POINTS: It is revealed by mutagenesis and functional experiments that a previously identified proline-tyrosine motif regulating ClC-K plasma membrane levels is indeed an endocytic YxxØ motif. Biochemical characterization of mutants in the YxxØ motif in Xenopus oocytes and human embryonic kidney cells indicates that mutants showed increased plasma membrane levels as a result of an increased stability, resulting in higher function of ClC-K channels. Mutation of this motif does not affect barttin protein expression and subcellular localization in vivo. Knock-in mice with a mutation in this motif, under conditions of a high-sodium low-potassium diet, exhibit less hyperplasia in the distal convoluted tubule than wild-type animals, indicating a gain of function of the channel in vivo.

Plant-based diet in hyperkalemic chronic kidney disease patients receiving sodium zirconium cyclosilicate: a feasibility clinical trial

BackgroundPlant-based diets (PBD) may induce hyperkalemia in chronic kidney disease (CKD) patients. ObjectivesWe explored the safety and feasibility of PBD in hyperkalemic CKD patients receiving the potassium binder sodium zirconium cyclosilicate (SZC). MethodsIn the current 6-wk trial, 26 hyperkalemic patients with CKD stage 4–5 not on dialysis received a low-protein low-potassium diet plus SZC for 3 wk and then a PBD with high potassium content delivered as a weekly food basket while continuing SZC for subsequent 3 wk. Plasma potassium was monitored weekly and SZC was titrated to achieve normokalemia. The 24-h urine excretion of potassium and sodium, 24-h food records, dietary quality, nutritional status, Bristol stool scale, Quality of life (QoL), and renal treatment satisfaction were assessed at baseline (week 0), week 3, and week 6. ResultsMean plasma potassium decreased from 5.5 to 4.4 mEq/L within 48–72 h after baseline, then rose to 4.7–5.0 mEq/L throughout the remaining study period following dose adjustments of SZC that matched the increased potassium intake of PBD from week 3 to week 6. Over the study period, 24-h urinary potassium excretion decreased from week 0 to week 3 and increased from week 3 to week 6. During the study, 58% of patients had fasting plasma potassium between 3.5 and 5.0 mEq/L and there was no episode of plasma potassium >6.5 mEq/L or <3.0 mEq/L during the study. P-carbon dioxide increased from baseline until week 6 (21 ± 2 to 23 ± 2 mEq/L; P = 0.002; mean ± SD), whereas remaining laboratory values remained unchanged. Fiber intake, dietary quality, the domain physical functioning from QoL, and 1 question of renal treatment satisfaction improved, whereas stool type and frequency did not change after starting PBD. ConclusionsPBD in hyperkalemia-prone CKD patients receiving SZC improved dietary quality and increased the intake of healthy foods, whereas plasma potassium concentration remained stable within normal values for most patients. Trial registration numberThis trial was registered at the https://clinicaltrials.gov/study/NCT04207203 as NCT04207203.

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.

#2481 Reduction in ultra-processed food by providing medically tailored healthy food baskets to patients with CKD: the HELPFUL trial

Abstract Background and Aims Over the past decade, there has been a growing interest in classifying foods based on the extent and purpose of industrial processing according to the NOVA system, which outlines four main food categories: unprocessed and minimally processed foods, processed culinary ingredients, processed foods, and ultra-processed foods (UPFs). The latter is characterized by industrial formulations with an elevated content of additives, sugar, unhealthy fat, and sodium. Increased consumption of UPFs can worsen metabolic derangements that develop as kidney function decreases in patients with chronic kidney disease (CKD). We evaluated food intake according to the NOVA food classification system before and after a medically tailored meal intervention with plant-based food baskets for patients with CKD who had hyperkalemia at inclusion and received sodium zirconium cyclosilicate (SZC) to normalize plasma potassium. Additionally, we aimed to assess the diets’ environmental impact by evaluating the greenhouse gas emissions (GHGE) associated with these dietary changes. Method Data were based on a six-week feasibility one-arm clinical study, the HELPFUL trial (identifier: NCT04207203), that enrolled 26 adult patients with CKD stages 4 and 5, not on dialysis and with plasma potassium 5.1-6.5 mmol/L at inclusion. In the first 3 weeks, patients were guided to adhere to a low-protein and low-potassium diet with concomitant use of SZC. The following 3 weeks, patients received food baskets containing fruits, vegetables, legumes, nuts, and either white meat, fish or egg to provide a healthy low-protein high-potassium diet. To assess dietary changes, 24-hour food recalls were collected at weeks 0, 3 and 6 and subsequently classified according to the NOVA classification. The mean adequacy ratio to the dietary recommended intake (DRI) of 11 nutrients (MAR-11 score) was calculated to assess dietary quality. Furthermore, the 24-hour food recalls were linked to GHGE estimations for analysis of environmental impact using the RISE food climate database which is representative of Swedish food consumption. Statistical analyses using Friedman's test or ANOVA for repeated measures were employed to identify significant differences before and after the plant-based food basket intervention. This study was funded by Astra Zeneca. Results The plasma potassium (mmol/L) normalized after the use of SZC (week 0: 5.52 ± 0.3; week 3: 4.72 ± 0.4; week 6: 4.8 ± 0.4; P &amp;lt; 0.01). Figure 1 shows changes in energy intake according to the NOVA classification. A significant reduction in UPF consumption (P = 0.024) was observed. In the post-hoc analysis, the change between week 3 and 6 was borderline significant (P = 0.052) while that between week 0 and 6 was statistically significant (P = 0.008). The healthy food basket diet led to a significant increase in dietary fibers (P = 0.002) and servings of fruits (P &amp;lt; 0.01), vegetables (P = 0.04), nuts (P &amp;lt; 0.01), poultry (P = 0.02), and fish (P &amp;lt; 0.001) and reduced servings of red meat (P = 0.03). As a result, the MAR-11 score increased significantly (P = 0.021). The GHGE analysis of carbon dioxide equivalents revealed no differences between emissions (median and interquartile range) in week 0 [1.79 (1.24; 3.13)], week 3 [1.79 (1.47; 2.74)] and week 6 [1.87 (1.51; 2.61)]. Conclusion Delivering medically tailored healthy food baskets to patients with CKD with concomitant use of SZC led to increased dietary quality and decreased UPF intake. However, these beneficial changes were not aligned with a decrease in GHGE, highlighting the complex relationship between dietary choices and environmental impact.

24-h urinary sodium and potassium excretions, plasma metabolomic profiles, and cardiometabolic biomarkers in the United States adults: a cross-sectional study

BackgroundHigh-sodium and low-potassium intakes are associated with a higher risk of hypertension and cardiovascular disease, but there are limited data on the circulating metabolomics profiles of 24-h urinary sodium and potassium excretions in free-living individuals. ObjectivesWe aimed to characterize the metabolomics signatures of a high-sodium and low-potassium diet in a cross-sectional study. MethodsIn 1028 healthy older adults from the Women’s and Men’s Lifestyle Validation Studies, we investigated the association of habitual sodium and potassium intakes measured by 2 to 4 24-h urine samples with plasma metabolites (quantified using liquid chromatography-tandem mass spectrometry) and metabolomic pathways. Our primary exposures were energy-adjusted 24-h urinary sodium excretion, potassium excretion, and sodium-to-potassium ratio, calculated based on energy expenditure derived from the doubly labeled water method. We then assessed the partial correlations of their metabolomics scores, derived from elastic net regressions, with cardiometabolic biomarkers. ResultsHigher sodium excretion was associated with 38 metabolites including higher piperine, phosphatidylethanolamine, and C5:1 carnitine. In pathway analysis, higher sodium excretion was associated with enhanced biotin and propanoate metabolism and enhanced degradation of lysine and branched-chain amino acids (BCAAs). Metabolites associated with higher potassium and lower sodium-to-potassium ratio included quinic acid and proline-betaine. After adjusting for confounding factors, the metabolomics score for sodium-to-potassium ratio positively correlated with fasting insulin (Spearman’s rank correlation coefficient ρ = 0.27), C-peptide (ρ = 0.30), and triglyceride (ρ = 0.46), and negatively with adiponectin (ρ = −0.40), and high-density lipoprotein cholesterol (ρ = −0.42). ConclusionsWe discovered metabolites and metabolomics pathways associated with a high-sodium diet, including metabolites related to biotin, propanoate, lysine, and BCAA pathways. The metabolomics signature for a higher sodium low-potassium diet is associated with multiple components of elevated cardiometabolic risk.

Dietary potassium effects on renal calcium transport at single nucleus resolution

Calcium homeostasis is maintained by the coordination of the intestines, bones, and kidneys. Dietary calcium is absorbed in the intestines, enters the bloodstream, and eventually finds its place in the bone reservoir or undergoes filtration by the glomerulus before being reabsorbed throughout the nephron. The late distal convoluted tubule (DCT2) and connecting tubule (CNT) determine the final rate of urinary calcium excretion, since no calcium reabsorption takes place beyond the connecting tubule (CNT). When excess calcium is excreted in the urine, also known as hypercalciuria, it contributes to the development of osteoporosis and the formation of kidney stones. High dietary potassium intake is strongly associated with a lower risk of kidney stone formation. Yet, the precise mechanism by which potassium intake modulates calcium excretion is not clear. To examine the transcriptional changes linking high dietary potassium intake and calcium transport, we applied single-nucleus RNA-sequencing (snRNA-Seq) in enriched distal nephron cells. To achieve the enrichment, we crossed a Calbindin 1 (Calb1)-driven Cre mouse line with the INTACT (for Isolation of Nuclei TAgged in Specific Cell Types) reporter line, which allows the GFP reporter to be expressed at the nuclear envelope of all calbindin 1-expressing cells. As the Calb1-Cre is constitutively expressed, all cells that have calbindin 1 expression at any time point during development will express the reporter. We examined the GFP expression by immunofluorescence, and found that it is expressed along the entire distal nephron from the distal convoluted tubule (DCT), CNT, to the collecting duct (CD). Male Calb1-Cre-INTACT mice were provided either a normal (NK, 1.05%) or a high (HK, 2%) potassium diet for 4 days and kidneys were snap-frozen for targeted snRNA-Seq using 10X Chromium (n=3 mice per group, targeting 10,000 nuclei per mouse). Our snRNA-seq dataset showed 6 major clusters, including DCT (DCT1 and DCT2), CNT (3 subclusters), CD principal cells (3 subclusters), ɑ-intercalated cells (2 subclusters), β-intercalated cells (2 subclusters), and proliferating cells. We curated a calcium score from the expression of known calciotropic genes ( Slc8a1, Vdr, Trpv5, Calb1, S100g, Ryr2, Trpv6) and used it as an index of calcium handling capacity. The calcium score is the highest in DCT2 and CNT along the distal nephron. In all CNT subclusters of the HK-treated animals, the calcium score is higher compared to the NK-treated animals, suggesting more calcium transport in CNT. Given that HK stimulates aldosterone and causes CNT hypertrophy, we compared the results with mice subjected to low dietary potassium (LK) treatment and metolazone (thiazide) treatment. The aim was to delineate the effects of dietary potassium and aldosterone A comprehensive summary of plasma potassium levels, urinary calcium excretion, aldosterone levels, calcium scores, and CNT morphology has been presented in the table below. Notably, the comparative analysis reveals a significant correlation between aldosterone levels and CNT size, both of which exhibit an inverse relationship with urinary calcium excretion: [Formula: see text] Our results suggest that DCT2 and CNT are the major sites for calcium transport. Yet, CNT exhibit more heightened adaptability in response to physiological or pharmacological perturbations at both transcriptional and morphological levels. Calcium homeostasis coincides with the regulation of aldosterone levels and CNT remodeling. DK51496 and DK133220 to DHE; K01DK121737 and AHA 20CDA35320169 to JWN. This is the full abstract presented at the American Physiology Summit 2024 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.

Manajemen Diet Rendah Kalium pada Pasien dengan Diangnosa Medis Chronic Kidney Disease (CKD) E. C Hiieperkalemia di Ruangan Matahari RSUD dr. TC. HILERS Maumere

Chronic Kidney Disease (CKD) with et causa Hyperkalemia is one of the highest causes of death in Indonesia as well as in Sikka district. Based on data obtained in 2022, there were 300 cases of the largest CKD in 25 sub-districts, based on data in the Matahari room there were 22 cases recorded. The aim of this research is to enable prospective nurses to apply professional practices and manage a low potassium diet in hyperkalemia patients to reduce potassium levels in the Matahari Room at RSUD dr. T.C. HILERS Maumere. This research is a case study research using the case study method which begins with identifying previous nursing care reports or via the internet The results of the study showed that there was a decrease in potassium levels in the participants as evidenced by the results of potassium examinations from 6.5 mmol/L down to 5.0 mmol/L. From the research results it can be concluded that low potassium diet management is very influential in helping to reduce potassium levels in the blood. Suggestions for relevant agencies are that low-chlorium diet management can be used as a nursing care option for patients with Chronic Kidney Disease. It is hoped that by knowing the effect of a low potassium diet on hyperkalemia sufferers, it is hoped that this can be an input for improving the quality of services in further nursing care.

KS-WNK1 is required for the renal response to extreme changes in potassium intake.

Kidney-specific with-no-lysine kinase 1 (KS-WNK1) is an isoform of WNK1 kinase that is predominantly found in the distal convoluted tubule of the kidney. The precise physiological function of KS-WNK1 remains unclear. Some studies have suggested that it could play a role in regulating potassium renal excretion by modulating the activity of the Na+-Cl- cotransporter (NCC). However, changes in the potassium diet from normal to high failed to reveal a role for KS-WNK1, but under a normal-potassium diet, the expression of KS-WNK1 is negligible. It is only detectable when mice are exposed to a low-potassium diet. In this study, we investigated the role of KS-WNK1 in regulating potassium excretion under extreme changes in potassium intake. After following a zero-potassium diet (0KD) for 10 days, KS-WNK1-/- mice had lower plasma levels of K+ and Cl- while exhibiting higher urinary excretion of Na+, Cl-, and K+ compared with KS-WNK1+/+ mice. After 10 days of 0KD or normal-potassium diet (NKD), all mice were challenged with a high-potassium diet (HKD). Plasma K+ levels markedly increased after the HKD challenge only in mice previously fed with 0KD, regardless of genotype. KSWNK1+/+ mice adapt better to HKD challenge than KS-WNK1-/- mice after a potassium-retaining state. The difference in the phosphorylated NCC-to-NCC ratio between KS-WNK1+/+ and KS-WNK1-/- mice after 0KD and HKD indicates a role for KS-WNK1 in both NCC phosphorylation and dephosphorylation. These observations show that KS-WNK1 helps the distal convoluted tubule to respond to extreme changes in potassium intake, such as those occurring in wildlife.NEW & NOTEWORTHY The findings of this study demonstrate that kidney-specific with-no-lysine kinase 1 plays a role in regulating urinary electrolyte excretion during extreme changes in potassium intake, such as those occurring in wildlife. .

Kinase Scaffold Cab39 Is Necessary for Phospho-Activation of the Thiazide-Sensitive NCC.

Potassium regulates the WNK (with no lysine kinase)-SPAK (STE20/SPS1-related proline/alanine-rich kinase) signaling axis, which in turn controls the phosphorylation and activation of the distal convoluted tubule thiazide-sensitive NCC (sodium-chloride cotransporter) for sodium-potassium balance. Although their roles in the kidney have not been investigated, it has been postulated that Cab39 (calcium-binding protein 39) or Cab39l (Cab39-like) is required for SPAK/OSR1 (oxidative stress response 1) activation. This study demonstrates how they control the WNK-SPAK/OSR1-NCC pathway. We created a global knockout of Cab39l and a tamoxifen-inducible, NCC-driven, Cab39 knockout. The 2 lines were crossed to generate Cab39-DKO (Cab39 double knockout) animals. Mice were studied under control and low-potassium diet, which activates WNK-SPAK/OSR1-NCC phosphorylation. Western blots were used to assess the expression and phosphorylation of proteins. Blood and urine electrolytes were measured to test for compromised NCC function. Immunofluorescence studies were conducted to localize SPAK and OSR1. Both Cab39l and Cab39 are expressed in distal convoluted tubule, and only the elimination of both leads to a striking absence of NCC phosphorylation. Cab39-DKO mice exhibited a loss-of-NCC function, like in Gitelman syndrome. In contrast to the apical membrane colocalization of SPAK with NCC in wild-type mice, SPAK and OSR1 become confined to intracellular puncta in the Cab39-DKO mice. In the absence of Cab39 proteins, NCC cannot be phosphorylated, resulting in a Gitelman-like phenotype. Cab39 proteins function to localize SPAK at the apical membrane with NCC, reminiscent of the Cab39 yeast homolog function, translocating kinases during cytokinesis.

Dietary potassium stimulates Ppp1Ca-Ppp1r1a dephosphorylation of kidney NaCl cotransporter and reduces blood pressure.

Consumption of low dietary potassium, common with ultraprocessed foods, activates the thiazide-sensitive sodium chloride cotransporter (NCC) via the with no (K) lysine kinase/STE20/SPS1-related proline-alanine-rich protein kinase (WNK/SPAK) pathway to induce salt retention and elevate blood pressure (BP). However, it remains unclear how high-potassium "DASH-like" diets (dietary approaches to stop hypertension) inactivate the cotransporter and whether this decreases BP. A transcriptomics screen identified Ppp1Ca, encoding PP1A, as a potassium-upregulated gene, and its negative regulator Ppp1r1a, as a potassium-suppressed gene in the kidney. PP1A directly binds to and dephosphorylates NCC when extracellular potassium is elevated. Using mice genetically engineered to constitutively activate the NCC-regulatory kinase SPAK and thereby eliminate the effects of the WNK/SPAK kinase cascade, we confirmed that PP1A dephosphorylated NCC directly in a potassium-regulated manner. Prior adaptation to a high-potassium diet was required to maximally dephosphorylate NCC and lower BP in constitutively active SPAK mice, and this was associated with potassium-dependent suppression of Ppp1r1a and dephosphorylation of its cognate protein, inhibitory subunit 1 (I1). In conclusion, potassium-dependent activation of PP1A and inhibition of I1 drove NCC dephosphorylation, providing a mechanism to explain how high dietary K+ lowers BP. Shifting signaling of PP1A in favor of activation of WNK/SPAK may provide an improved therapeutic approach for treating salt-sensitive hypertension.

Dietary Potassium and Clinical Outcomes among Patients on Peritoneal Dialysis.

The association between dietary potassium and clinical prognosis is unclear in patients with chronic kidney disease (CKD). Here, we explored the association between dietary potassium intake and all-cause and cardiovascular (CV) mortality in peritoneal dialysis (PD) patients. Here, we present a retrospective analysis of a prospective study. Patients that began incident PD in our center between 1 October 2002 and 31 August 2014 were screened. We recorded all demographic and clinical data at baseline. Repeated measurements were recorded at regular intervals to calculate time-averaged values. Spline regression analysis and Cox proportional regression models were used to evaluate the relationship between dietary potassium and mortality. We followed 881 PD patients for 45.0 (21.5, 80.0) months; 467 patients died, of which 189 (40.5%) died of CV death and 93 were still on PD treatment. Compared with those who had baseline dietary potassium ≥1200 mg/d, the majority of patients with lower dietary potassium were female, older, or poorly educated. They were prone to have poorer nutritional status, CV disease, and diabetes mellitus (p < 0.05). In the unadjusted analysis, both baseline and time-averaged dietary potassium <1200 mg/d predicted higher all-cause and CV mortality (p < 0.001~0.01). After adjusting for demographic and laboratory data, the association between potassium intake and all-cause and CV mortality weakened, which even disappeared after additional adjustment for dietary fiber, protein, and energy intake. Dietary potassium in PD patients was not independently associated with all-cause and CV mortality.

KLHL3-dependent WNK4 degradation affected by potassium through the neddylation and autophagy pathway

BackgroundStudies reported that kelch-like protein 3 (KLHL3)-Cullin3(CUL3) E3 ligase ubiquitinated with-no-lysine kinase 4 (WNK4). Impaired WNK4 ubiquitination plays a key role in Familial hyperkalemic hypertension (FHHt, also called pseudohypoaldosteronism type II) which results from overaction of thiazide-sensitive sodium chloride cotransport (NCC). In addition, researchers have also found that dietary potassium deficiency activates NCC along the renal distal convoluted tubule (DCT). However, the underlying mechanism remains unclear about the relationship between potassium and WNK4.MethodsIn the present study, we conducted in vitro and in vivo experiments to confirm that KLHL3-dependent WNK4 degradation is affected by potassium through the neddylation and autophagy pathway. In vitro, the WNK4 and KLHL3 plasmids were cotransfected into HEK293 cell lines by lipofectamine 2000, and then incubated with different potassium concentrations (1mmol/L and 10mmol/L) for 24 h, and further treated with MLN4924 or the autophagy inhibitor or both of MLN4924 and the autophagy inhibitor for another 24 h respectively. In vivo, we created mice that were fed with low or high potassium diets and then were injected MLN4924 in the experimental groups. The expression of WNK4, pWNK4, KLHL3, NEDD8, LC3 ,and P62 was detected by western blotting in vitro and vivo experiments.ResultsWe found that the abundance and phosphorylation of WNK4 increase when neddylation is inhibited both in vitro and vivo. Furthermore, the abundance of pWNK4, WNK4, NEDD8, and KLHL3 was increased in the low potassium (LK) group. Inhibiting autophagy can ameliorate the effect of potassium on the abundance and activity of WNK4 to some extent.ConclusionThese findings suggest a complex regulation of potassium in the degradation of WNK4. Low potassium can activate WNK4, which may be related to neddylation and autophagy, but the mechanism needs to be further studied.

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.

High sodium intake does not worsen low potassium-induced kidney damage.

High sodium and low potassium intake have both been linked to poor cardiovascular health outcomes and increased mortality rates. A combination of the two is thought to be particularly detrimental. While mechanisms are multiple, the kidney is an important target of harmful effects and low potassium influences on both proximal and distal nephron segments are especially potent. We recently reported that a combined high sodium/low potassium diet causes kidney injury and that low potassium in isolation can have similar effects. However, how sodium intake alters this process is not well-understood. Here we tested the hypothesis that a high sodium intake amplifies effects of low dietary potassium on kidney injury. We observed adding high sodium to low potassium caused an expected increase in blood pressure, but did not worsen markers of kidney injury, inflammation, and fibrosis. It also did not increase abundance or phosphorylation of the sodium chloride cotransporter or its regulatory kinases, SPAK and OxSR1, known renal targets of low potassium. Findings support the claim that dietary potassium deficiency, and not high sodium, is a dominant factor affecting kidney injury in animal models of high sodium/low potassium intake. This suggests further investigation is required to identify optimal ranges of sodium and potassium intake in both healthy populations and in those with kidney disease.

Randomized Trial on the Effect of Oral Potassium Chloride Supplementation on the Thiazide-Sensitive Sodium Chloride Cotransporter in Healthy Adults

The putative "renal-K switch" mechanism links dietary potassium intake with sodium retention and involves activation of the sodium chloride (NaCl) cotransporter (NCC) in the distal convoluted tubule in response to low potassium intake, and suppression in response to high potassium intake. This study examined NCC abundance and phosphorylation (phosphorylated NCC [pNCC]) in urinary extracellular vesicles (uEVs) isolated from healthy adults on a high sodium diet to determine tubular responses to alteration in potassium chloride (KCl) intake. Healthy adults maintained on a high sodium (∼4.5 g [200 mmol]/d) low potassium (∼2.3 g [60 mmol]/d) diet underwent a 5-day run-in period followed by a crossover study, with 5-day supplementary KCl (active phase, Span-K 3 tablets (potassium 24 mmol) thrice daily) or 5-day placebo administrated in random order and separated by 2-day washout. Ambulatory blood pressure (BP) and biochemistries were assessed, and uEVs were analyzed by western blotting. Among the 18 participants who met analysis criteria, supplementary KCl administration (vs. placebo) was associated with markedly higher levels of plasma potassium and 24-hour urine excretion of potassium, chloride, and aldosterone. KCl supplementation was associated with lower uEV levels of NCC (median fold change (KCl/Placebo)= 0.74 [0.30-1.69], P< 0.01) and pNCC (fold change (KCl/Placebo)= 0.81 [0.19-1.75], P< 0.05). Plasma potassium inversely correlated with uEV NCC (R2= 0.11, P= 0.05). The lower NCC and pNCC in uEVs in response to oral KCl supplementation provide evidence to support the hypothesis of a functional "renal-K switch" in healthy human subjects.

Excess Dietary Lysine Increases Skeletal Muscle and Plasma Trimethyllysine in Rats

Trimethyllysine, a carnitine precursor, is a cation. This study was designed to determine whether dietary potassium and lysine concentration or oral lysine supplementation affects tissue carnitine and trimethyllysine concentration in rats. In Experiment 1, rats were fed a control diet, a low or high potassium diet, or a high lysine diet. In Experiment 2, rats were given by gavage a solution containing either L-proline (control) or L-lysine. In Experiment 1, rats fed the high lysine diet had significantly lower plasma total carnitine concentration than controls. Rats fed the high lysine diets had significantly higher concentrations of free trimethyllysine in skeletal muscle and plasma relative to control rats and rats fed the high potassium diet. Rats fed the low potassium diet had a similar increase in skeletal muscle free trimethyllysine. In Experiment 2, rats given lysine had significantly lower plasma total carnitine concentration, and significantly greater skeletal muscle and plasma trimethyllysine concentration relative to controls. We conclude that dietary potassium and lysine, and oral lysine, have a significant effect upon the distribution of carnitine and trimethyllysine in rats. The distributional changes caused by lysine, however, seem to be due to effects other than exchange of lysine for carnitine or trimethyllysine in tissues.

Dietary calcium intake was related to the onset of pre-eclampsia: The TMM BirThree Cohort Study.

This study aimed to explore the relationship between dietary electrolyte intake and the prevalence of hypertensive disorders of pregnancy (HDP) subtypes. Our analysis included 19914 pregnant women from the Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study. A food frequency questionnaire was used to estimate dietary calcium, potassium, sodium, and magnesium intakes. HDP was determined based on the medical records during regular antenatal care. Logistic regression analysis assessed the relationship between dietary electrolytes intake quintiles, and HDP subtypes with adjustment for basic characteristics. Dietary electrolyte intakes were applied for the prediction model. Of the cohort, 547 participants delivered with pre-eclampsia (PE), 278 with superimposed PE (SP), and 896 with gestational hypertension (GH). PE was associated with low crude calcium intake (odds ratio of the first quintile [<251mg/day] to the fifth quintile [>623mg/day] and 95% confidence interval, 1.31 [1.00-1.70]) and P for trend was .02. SP was not associated with any nutritional intake; however, the combined outcome of PE and SP was related to low crude calcium and potassium and energy-adjusted calcium, potassium, and magnesium intakes (P for trend, .01, .048, .02, .04, and .02, respectively). The same tendency was observed for GH. A prediction model that included crude calcium and potassium intakes performed better than a model without them. In conclusion, low dietary calcium, potassium, and magnesium were associated with higher HDP subtypes prevalence. The prediction model implied that crude calcium and potassium intakes might play a critical role in PE and SP pathogenesis.

Chloride-sensitive signaling turns the potassium switch on

The potassium switch refers to plasma potassium regulation of the sodium-chloride cotransporter (NCC), which controls distal sodium delivery and therefore potassium secretion. Low extracellular potassium activates NCC by relieving chloride inhibition of With-No-Lysine 4 (WNK4). A new mouse model carrying a chloride-insensitive WNK4 mutant still shows NCC activation on low potassium diet. These effects are mediated by WNK4 activation and kelch-like 3 (KLHL3) inhibition and reveal additional chloride-sensitive pathways for NCC activation.