Rapid development of vasopressin resistance in dietary K+ deficiency.

The association between diabetes insipidus (DI) and chronic dietary K+ deprivation is well known, but it remains uncertain how the disorder develops and whether it is influenced by the sexual dimorphism in K+ handling. Here, we determined the plasma K+ (PK) threshold for DI in male and female mice and ascertained if DI is initiated by polydipsia or by a central or nephrogenic defect. C57BL6J mice were randomized to a control diet or to graded reductions in dietary K+ for 8 days, and kidney function and transporters involved in water balance were characterized. We found that male and female mice develop polyuria and secondary polydipsia. Altered water balance coincided with a decrease in aquaporin-2 (AQP2) phosphorylation and apical localization despite increased levels of the vasopressin surrogate marker copeptin. No change in the protein abundance of urea transporter-A1 was observed. The Na+-K+-2Cl- cotransporter decreased only in males. Desmopressin treatment failed to reverse water diuresis in K+-restricted mice. These findings indicate that even a small fall in PK is associated with nephrogenic DI (NDI), coincident with the development of altered AQP2 regulation, implicating low PK as a causal trigger of NDI. We found that PK decreased more in females, and, consequently, females were more prone to develop NDI. Together, these data indicate that AQP2 regulation is disrupted by a small decrease in PK and that the response is influenced by sexual dimorphism in K+ handling. These findings provide new insights into the mechanisms linking water and K+ balances and support defining the disorder as "potassium-dependent NDI."NEW & NOTEWORTHY This study shows that aquaporin-2 regulation is disrupted by a small fall in plasma potassium levels and the response is influenced by sexual dimorphism in renal potassium handling. The findings provided new insights into the mechanisms by which water balance is altered in dietary potassium deficiency and support defining the disorder as "potassium-dependent nephrogenic diabetes insipidus."

Potassium deficiency decreases the capacity for urea synthesis and markedly increases ammonia in rats.

Our study provides novel findings of experimental hypokalemia reducing urea cycle functionality and thereby severely increasing plasma ammonia. This is pathophysiologically interesting because plasma ammonia increases during hypokalemia by a hitherto unknown mechanism, which may be particular important in relation to the unexplained link between hypokalemia and hepatic encephalopathy. Potassium deficiency decreases gene expression, protein synthesis, and growth. The urea cycle maintains body nitrogen homeostasis including removal of toxic ammonia. Hyperammonemia is an obligatory trait of liver failure, increasing the risk for hepatic encephalopathy, and hypokalemia is reported to increase ammonia. We aimed to clarify the effects of experimental hypokalemia on the in vivo capacity of the urea cycle, on the genes of the enzymes involved, and on ammonia concentrations. Female Wistar rats were fed a potassium-free diet for 13 days. Half of the rats were then potassium repleted. Both groups were compared with pair- and free-fed controls. The following were measured: in vivo capacity of urea-nitrogen synthesis (CUNS); gene expression (mRNA) of urea cycle enzymes; plasma potassium, sodium, and ammonia; intracellular potassium, sodium, and magnesium in liver, kidney, and muscle tissues; and liver sodium/potassium pumps. Liver histology was assessed. The diet induced hypokalemia of 1.9 ± 0.4 mmol/L. Compared with pair-fed controls, the in vivo CUNS was reduced by 34% (P < 0.01), gene expression of argininosuccinate synthetase 1 (ASS1) was decreased by 33% (P < 0.05), and plasma ammonia concentrations were eightfold elevated (P < 0.001). Kidney and muscle tissue potassium contents were markedly decreased but unchanged in liver tissue. Protein expressions of liver sodium/potassium pumps were unchanged. Repletion of potassium reverted all the changes. Hypokalemia decreased the capacity for urea synthesis via gene effects. The intervention led to marked hyperammonemia, quantitatively explainable by the compromised urea cycle. Our findings motivate clinical studies of patients with liver disease.

Risk of respiratory failure among hospitalized patients with various admission serum potassium levels.

BACKGROUND: The objective of this study was to assess the relationship between admission serum potassium and the risk of respiratory failure requiring mechanical ventilation in all hospitalized patients. METHODS: All non-dialysis and non-mechanically ventilated patients who had serum potassium measurement at admission from 2011 to 2013 were studied. Serum potassium levels were stratified into five groups; ≤3.4, 3.5 to 3.9, 4.0 to 4.4, 4.5 to 4.9, 5.0 to 5.4, and ≥5.5 mEq/L. The outcome of interest was the respiratory failure requiring mechanical ventilation during hospitalization. Logistic regression analysis was performed to assess the independent risk of in-hospital respiratory failure requiring mechanical ventilation based on various admission serum potassium, using serum potassium of 4.0 to 4.4 mEq/L as the reference group. RESULTS: Of 67,034 eligible patients, with the mean admission serum potassium of 4.2 ± 0.5 mEq/L, 2,886 (4.3%) patients developed respiratory failure requiring mechanical ventilation during hospitalization. As demonstrated by U-shaped association, increased risk of in-hospital respiratory failure was significantly associated with low admission serum potassium ≤ 3.4 mEq/L (odds ratio 1.36, p-value <0.001) and high admission serum potassium ≥5.5 mEq/L (odds ratio 1.37, p-value = 0.01). CONCLUSION: Increased risk of in-hospital respiratory failure requiring mechanical ventilation was noted when serum potassium was below 3.5 mEq/L or above 5.4 mEq/L at the time of hospital admission. Patients with either hypokalemia or hyperkalemia are at risk of respiratory failure requiring mechanical ventilation.

Effects of potassium supplements on glucose metabolism in African Americans with prediabetes: a pilot trial.

Background: Low potassium has been identified both as a risk factor for type 2 diabetes and as a mediator of the racial disparity in diabetes risk. Low potassium could be a potentially modifiable risk factor, particularly for African Americans.Objective: We sought to determine the effects of potassium chloride (KCl) supplements, at a commonly prescribed dose, on measures of potassium and glucose metabolism.Design: Among African-American adults with prediabetes, we conducted a double-blinded pilot randomized controlled trial that compared the effects of 40 mEq K/d as KCl supplements with a matching placebo, taken for 3 mo, on measures of potassium and glucose metabolism, with measures collected from frequently sampled oral-glucose-tolerance tests (OGTTs).Results: Twenty-seven of 29 recruited participants completed the trial. Participants had high adherence to the study medication (92% by pill count). Participants in both groups gained weight, with an overall mean ± SD weight gain of 1.24 ± 2.03 kg. In comparison with participants who received placebo, urine potassium but not serum potassium increased significantly among participants randomly assigned to receive KCl (P = 0.005 and 0.258, respectively). At the end of the study, participants taking KCl had stable or improved fasting glucose, with a mean ± SD change in fasting glucose of -1.1 ± 8.4 mg/dL compared with an increase of 6.1 ± 7.6 mg/dL in those who received placebo (P = 0.03 for comparison between arms). There were no significant differences in glucose or insulin measures during the OGTT between the 2 groups, but there was a trend for improved insulin sensitivity in potassium-treated participants.Conclusions: In this pilot trial, KCl at a dose of 40 mEq/d did not increase serum potassium significantly. However, despite weight gain, KCl prevented worsening of fasting glucose. Further studies in larger sample sizes, as well as with interventions to increase serum potassium more than was achieved with our intervention, are indicated to definitively test this potentially safe and inexpensive approach to reducing diabetes risk. This trial was registered at clinicaltrials.gov as NCT02236598.

Does Potassium Deficiency Contribute to Hypertension in Children and Adolescents?

The increasing prevalence of cardiovascular risk factors in children and adolescents has been largely, but not entirely, related to the childhood obesity epidemic. Among the noted risk factors detectable in children is elevated blood pressure. Emerging findings indicate that in addition to overweight and obesity, sodium intake is associated with elevated blood pressure in youth. Moreover, dietary sodium intake is quite high and well above recommended levels throughout childhood. In adults, the relationship of sodium consumption with hypertension is well established, and there is evidence from both population and clinical studies that potassium intake is also associated with blood pressure. Higher potassium intake is associated with lower blood pressure; and potassium deficit leads to an increase in blood pressure. Findings on relationships of potassium intake with blood pressure in childhood are sparse. There are some reports that provide evidence that a dietary pattern that includes potassium-rich foods is associated with lower blood pressure and may also lower blood pressure in adolescents with elevated blood pressure. Considering the secular changes in dietary patterns throughout childhood, it is prudent to encourage a diet for children that is high in potassium-rich foods.

H,K-ATPase type 2 contributes to salt-sensitive hypertension induced by K(+) restriction.

In industrialized countries, a large part of the population is daily exposed to low K(+) intake, a situation correlated with the development of salt-sensitive hypertension. Among many processes, adaptation to K(+)-restriction involves the stimulation of H,K-ATPase type 2 (HKA2) in the kidney and colon and, in this study, we have investigated whether HKA2 also contributes to the determination of blood pressure (BP). By using wild-type (WT) and HKA2-null mice (HKA2 KO), we showed that after 4 days of K(+) restriction, WT remain normokalemic and normotensive (112 ± 3 mmHg) whereas HKA2 KO mice exhibit hypokalemia and hypotension (104 ± 2 mmHg). The decrease of BP in HKA2 KO is due to the absence of NaCl-cotransporter (NCC) stimulation, leading to renal loss of salt and decreased extracellular volume (by 20 %). These effects are likely related to the renal resistance to vasopressin observed in HKA2 KO that may be explained, in part by the increased production of prostaglandin E2 (PGE2). In WT, the stimulation of NCC induced by K(+)-restriction is responsible for the elevation in BP when salt intake increases, an effect blunted in HKA2-null mice. The presence of an activated HKA2 is therefore required to limit the decrease in plasma [K(+)] but also contributes to the development of salt-sensitive hypertension.

Osteoporosis y complicaciones en implantes auditivos. Análisis de 2 casos / Osteoporosis and complications in hearing implants. Analysis of two cases

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Sodium surfeit and potassium deficit: keys to the pathogenesis of hypertension.

The pathogenic role of Na(+) in primary hypertension is widely recognized but that of K(+) remains unappreciated. Yet, extensive evidence indicates that together, the body's dominant cations constitute the chief environmental factor in the pathogenesis of hypertension and its cardiovascular sequelae. In this Review, we provide a synthesis of the determinants of Na(+) retention and K(+) loss developing in the body as the Na(+)-rich and K(+)-poor modern diet interacts with kidneys intrinsically poised to conserve Na(+) and excrete K(+); and the molecular pathways utilized by these disturbances in the central nervous system and the periphery to increase sympathetic tone and vascular resistance, and establish hypertension. These fresh insights point to new directions for targeted pharmacotherapy of hypertension. The interdependency of Na(+) and K(+) in the pathogenesis of hypertension indicates that Na(+) restriction and increased K(+) intake are important strategies for the primary prevention and treatment of hypertension and its cardiovascular consequences.

[Hypomagnesaemia severe in patients with high flow ileostomy]. / Hipomagnesemia severa en paciente con ileostomía de alto débito.

The need to create a stoma is frequent in the daily clinical practice. Usually ileostomies work well within the first 24 hours. However, many times they are associated with important morbidity up to 76%. Although the complications derived from this technique may be surgical, metabolic complications, which are preceded by large losses through the stoma, are the ones going undetected. It is not rare to see patients carrying an ileostomy that come repeatedly to the hospital with severe metabolic impairments and in whom the underlying cause remains untreated. The case reported herein is just one of a series published in this journal making us aware of the need for a multidisciplinary approach of the ileostomies and the prevention of major complications derived from their poor functioning.

Guideline: potassium intake for adults and children / Sur l'apport en potassium chez l'adulte et chez l'enfant / Ingesta de potasio en adultos y niños

This guideline provides the first global, evidence-informed recommendations on the consumption of potassium to reduce NCDs in most adults and children which WHO had developed. The recommendations in this guideline can be used by policy-makers, technical and programme planners in the government and various organizations involved in the design, implementation and scaling-up of nutrition actions for public health and prevention of NCDs, to assess current potassium intake levels relative to a benchmark and develop measures to increase potassium intake, where necessary, through public health interventions including, but not limited to, food and product labelling, consumer education, and the establishment of food-based dietary guidelines (FBDG). The guideline should be should be used in conjunction with sodium and other nutrient guidelines to develop and guide national policies and public health nutrition programmes.

L'objectif ici poursuivi est de fournir des recommandations sur la consommation de potassium afin de réduire les MNT chez la plupart des adultes et des enfants. Ces recommandations pourront être utiles aux personnes qui sont chargées d'élaborer des programmes et des politiques visant à évaluer les apports en potassium par rapport à une valeur de référence. Elles pourront servir également, si nécessaire, à élaborer des mesures en vue d'augmenter l'apport en potassium au moyen d'interventions de santé publique telles que l'étiquetage des produits et denrées alimentaires, la sensibilisation des consommateurs et l'application de principes diététiques.

El objetivo de estas directrices es formular una serie de recomendaciones relativas al consumo de potasio a fin de reducir las ENT entre los adultos y los menores. Las recomendaciones pueden servir, a la hora de elaborar programas y políticas, como referencia para cuantificar el consumo actual de potasio y, en caso necesario, para diseñar medidas destinadas a aumentar el consumo mediante intervenciones de saludpública, como el etiquetado de alimentos y otros productos, la educación del consumidor y el establecimiento de directrices dietéticas basadas en los alimentos.

Sodio, potasio e hipertensión arterial / Sodium, potassium and hypertension

La hipertensión arterial tiene una prevalencia cercana al 30 por ciento en la población adulta chilena y es la mayor causa de muerte en el mundo. La hipertensión primaria resulta de la interacción de distintos factores tanto genéticos, como funcionales renales y en particular un estilo de vida poco saludable. En este artículo se describe la influencia del exceso de sodio y el déficit de potasio, característicos de nuestra alimentación, en el desarrollo de hipertensión. Se revisan los estudios observacionales más importantes, los mecanismos fisiopatológicos para explicar el rol dañino del exceso de sodio y el déficit de potasio y finalmente se hacen recomendaciones para adecuar su consumo con el fin de prevenir hipertensión y sus complicaciones.

Arterial hypertension has a prevalence of about 30 percent in the adult Chilean population and it is the major cause of mortality worldwide. Primary hypertension results from the interaction of genetic factors, functional renal impairment and particularly from an altered life style. This article describes the impact of the excess of sodium and the deficit of potassium of our usual alimentation in the development of hypertension. In this setting, some important observational studies and physiopathological mechanisms were discussed, and finally some recommendations to reduce sodium and to increase potassium intake to prevent hypertension and vascular complications, were made.

Effect of potassium depletion on urinary stone risk factors in Wistar rats.

Various studies have suggested that potassium depletion leads to acidosis and hypocitraturia. In Northeastern Thailand, for example, mild hypokalemia and mild hyperoxaluria are observed in most stone formers. However, there are limited reports about the direct link between potassium depletion and the formation of urinary stones, most of which are calcium oxalate stones. Therefore, we studied the direct effect of potassium depletion on the risk factors for calcium oxalate stone formation. Seventy-two rats were fed a control diet or a potassium-deficient diet for 1, 2, or 3 weeks (n = 12 per group). Twenty-four-hour urine collection was done for the measurement of potassium, calcium, oxalate, glycolate, citrate, phosphorus, and magnesium. Lactate dehydrogenase activity was also measured in order to assess renal tubular damage, and kidneys were harvested for histological examination. Furthermore, urinary supersaturation of calcium oxalate was calculated. With potassium depletion, the urinary concentrations of potassium, citrate, magnesium, and phosphorus decreased rapidly. There was no detectable renal damage, renal calcium deposition, and no significant increase of urinary oxalate or calcium. However, the urinary supersaturation index of calcium oxalate increased significantly in rats with potassium depletion. These findings indicate that potassium deficiency may increase the risk of stone formation through enhanced supersaturation.

Acetazolamide prevents vacuolar myopathy in skeletal muscle of K(+) -depleted rats.

BACKGROUND AND PURPOSE: Acetazolamide and dichlorphenamide are carbonic anhydrase (CA) inhibitors effective in the clinical condition of hypokalemic periodic paralysis (hypoPP). Whether these drugs prevent vacuolar myopathy, which is a pathogenic factor in hypoPP, is unknown. The effects of these drugs on the efflux of lactate from skeletal muscle were also investigated. EXPERIMENTAL APPROACH: For 10 days, K(+)-depleted rats, a model of hypoPP, were administered 5.6 mg kg(-1) day(-1) of acetazolamide, dichlorphenamide or bendroflumethiazide (the last is not an inhibitor of CA). Histological analysis of vacuolar myopathy and in vitro lactate efflux measurements were performed in skeletal muscles from treated and untreated K(+)-depleted rats, and also from normokalemic rats. KEY RESULTS: About three times as many vacuoles were found in the type II fibres of tibialis anterioris muscle sections from K(+)-depleted rats as were found in the same muscle from normokalemic rats. In ex vivo experiments, a higher efflux of lactate on in vitro incubation was found in muscles of K(+)-depleted rats compared with that found in muscles from normokalemic rats. After treatment of K(+)-depleted rats with acetazolamide, the numbers of vacuoles in tibialis anterioris muscle decreased to near normal values. Incubation with acetazolamide in vitro inhibited efflux of lactate from muscles of K(+)-depleted rats. In contrast, bendroflumethiazide and dichlorphenamide failed to prevent vacuolar myopathy after treatment in vivo and failed to inhibit lactate efflux in vitro. CONCLUSIONS AND IMPLICATIONS: Acetazolamide prevents vacuolar myopathy in K(+)-depleted rats. This effect was associated with inhibition of lactate transport, rather than inhibition of CA.

WNK kinases and essential hypertension.

PURPOSE OF REVIEW: The present review summarizes recent literature and discusses the potential roles of WNKs in the pathogenesis of essential hypertension. RECENT FINDINGS: WNKs (with-no-lysine [K]) are a recently discovered family of serine-threonine protein kinases with unusual protein kinase domains. The role of WNK kinases in the control of blood pressure was first revealed by the findings that mutations of two members, WNK1 and WNK4, cause Gordon's syndrome. Laboratory studies have revealed that WNK kinases play important roles in the regulation of sodium and potassium transport. Animal models have been created to unravel the pathophysiology of sodium transport disorders caused by mutations of the WNK4 gene. Potassium deficiency causes sodium retention and increases hypertension prevalence. The expression of WNK1 is upregulated by potassium deficiency, raising the possibility that WNK1 may contribute to salt-sensitive essential hypertension associated with potassium deficiency. Associations of polymorphisms of WNK genes with essential hypertension in the general population have been reported. SUMMARY: Mutations of WNK1 and WNK4 cause hypertension at least partly by increasing renal sodium retention. The role of WNK kinases in salt-sensitive hypertension within general hypertension is suggested, but future work is required to firmly establish the connection.

[Recent progress on the searchs of pathogenesis of thyrotoxic periodic paralysis].

In Japan, more than 60% of hypokalemic periodic paralysis is thyrotoxic instead of familial type frequently experienced in Caucasian countries. The pathogenesis of familial hypokalemic periodic paralysis (FHPP) has been elucidated to be due to the mutation of one of the genes in either Ca(CACN1AS), Na(SCN4A) or K channel(KCNE3). Clinical features of thyrotoxic periodic paralysis (TPP) is very similar to that of FHPP and rigorous attempts have been devoted to the search of the gene mutation of ion channels in TPP. To date, however, no such an attempt has been successful except for the findings of SNiPs in those ion channel genes or in the vicinity of TRE of CACN1AS. Those SNiPs may provide a risk to the attack of TPP. In TPP, we and others reported that the serum insulin level tremendously elevated prior to the attack of paralysis. There were clinical evidences indicating that hypokalemic periodic paralysis is caused by the depolarization block of muscle cell membrane instead of hyperpolarization block once assumed previously. Otsuka reported that insulin can induce depolarization block of muscle membrane in low K concentration by increasing membrane permeability to Na. We have reported that K deficiency and thyroid hormone excess increased NaK-ATPase and may sensitize the muscle membrane to the effect of insulin to cause depolarization in an animal model. In fact, in Japan, incidence of TPP of male decreased from 8.6% in 1958 to 4.3% in 1998. During this 40 years, intake of K was increased from 43 to 65 mEq per day per person as described by the National Survey of Nutrition. The SNiPs of ion channel genes, together with K deficiency or thyroid hormone excess, may provide a risk to the occurrence of TPP.