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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 + (P K ) 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 P K is associated with nephrogenic DI (NDI), coincident with the development of altered AQP2 regulation, implicating low P K as a causal trigger of NDI. We found that P K 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 P K 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."

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.

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., (© 2017 American Society for Nutrition.)

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.

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.

Background: Potassium deficiency may cause cardiac arrhythmias culminating in syncope or sudden death., Methods: An inquiry performed among physicians caring for a total of 249 patients with inborn salt-losing tubulopathies revealed that acute cardiac complications occurred in seven children., Results: Four patients died suddenly and three had severe syncope. These episodes occurred in the context of severe chronic hypokalaemia (< or =2.5 mmol/l) or were precipitated by acute diseases, which exacerbated hypokalaemia (< or =2.0 mmol/l)., Conclusions: In conclusion, severe chronic or acute hypokalaemia is hazardous in inborn salt-losing tubulopathies.

The purpose of this study was to examine whether hypokalemia is associated with altered abundance of major renal Na+ transporters that may contribute to the development of urinary concentrating defects. We examined the changes in the abundance of the type 3 Na+/H+ exchanger (NHE3), Na+ - K+-ATPase, the bumetanide-sensitive Na+ - K+ - 2Cl- cotransporter (BSC-1), the thiazide-sensitive Na+ - Cl- cotransporter (TSC), and epithelial sodium channel (ENaC) subunits in kidneys of hypokalemic rats. Semiquantitative immunoblotting revealed that the abundance of BSC-1 (57%) and TSC (46%) were profoundly decreased in the inner stripe of the outer medulla (ISOM) and cortex/outer stripe of the outer medulla (OSOM), respectively. These findings were confirmed by immunohistochemistry. Moreover, total kidney abundance of all ENaC subunits was significantly reduced in response to the hypokalemia: alpha-subunit (61%), beta-subunit (41%), and gamma-subunit (60%), and this was confirmed by immunohistochemistry. In contrast, the renal abundance of NHE3 in hypokalemic rats was dramatically increased in cortex/OSOM (736%) and ISOM (210%). Downregulation of BSC-1, TSC, and ENaC may contribute to the urinary concentrating defect, whereas upregulation of NHE3 may be compensatory to prevent urinary Na+ loss and/or to maintain intracellular pH levels.

-Normotensive salt sensitivity, a putative precursor of hypertension, might be quite frequent in African Americans (blacks) and less frequent in Caucasian Americans (whites), but only when dietary potassium is deficient and not when maintained well within the normal range. We tested this hypothesis in 41 metabolically controlled studies of 38 healthy normotensive men (24 blacks, 14 whites) who ate a basal diet low in sodium (15 mmol/d) and marginally deficient in potassium (30 mmol/d) for 6 weeks. Throughout the last 4 weeks, NaCl was loaded (250 mmol/d); throughout the last 3, potassium was supplemented (as potassium bicarbonate) to either mid- or high-normal levels, 70 and 120 mmol/d. Salt sensitivity, defined as an increase in mean arterial blood pressure >/=3 mm Hg with salt loading, was deemed "moderate" if increasing

It is uncertain whether, in humans, potassium depletion can cause or sustain metabolic alkalosis of clinically important degree in the absence of coexisting known alkalosis-producing conditions. Previously we found, in normal humans ingesting abundant NaCl, that dietary K+ depletion alone can induce and sustain a small decrease in blood acidity and increase in plasma bicarbonate concentration; we hypothesized that more severe alkalosis was prevented by mitigating mechanisms initiated by renal retention of dietary NaCl that was induced by K+ depletion. To ascertain the acid-base response to dietary K+ depletion under conditions in which the availability of NaCl for retention is greatly limited, in the present study of six normal men we restricted dietary K+ as in the previous study except that intake of NaCl was maintained low (2 to 7 mEq/day, Low NaCl Group) instead of high (126 mEq/day, High NaCl Group). Plasma acid-base composition and renal net-acid excretion (NAE) did not differ significantly between groups during the control period. In the steady state of K+ depletion (days 11 to 15 of K+ restriction), neither plasma K+ concentration (2.9 +/- 0.9 mEq/liter vs. 3.0 +/- 0.1 mEq/liter) nor cumulative K+ deficit (399 +/- 59 mEq vs. 466 +/- 48 mEq) differed significantly between groups. During K+ restriction, persisting metabolic alkalosis developed in both groups, which was more severe in the Low NaCl Group: increment in [HCO3-]p, 7.5 +/- 1.0 mEq/liter versus 2.0 +/- 0.3 mEq/liter, P less than 0.001; decrement in [H+]p, 5.5 +/- 0.6 nEq/liter versus 2.9 +/- 0.4 nEq/liter, P less than 0.003. A significantly more severe alkalosis in the Low NaCl Group was evident at all degrees of K+ deficiency achieved during the course of the 15 days of K+ restriction, and the severity of alkalosis in the Low NaCl Group correlated with the degree of K+ deficiency. During the generation of alkalosis (days 1 to 7 of K+ restriction), NAE increased in the Low NaCl Group whereas it decreased in the High NaCl Group. During the maintenance of alkalosis (days 11 to 15), NAE stabilized in both groups after it returned to values approximating the control values. In both groups, urine Cl- excretion decreased during K+ restriction even though Cl- intake had not been changed, with the result that body Cl- content increased negligibly in the Low NaCl Group (28 +/- 6 mEq) and substantially in the High NaCl Group (355 +/- 64 mEq).(ABSTRACT TRUNCATED AT 400 WORDS)

The dysrhythmia that happens after open-heart surgery has at times been attributed to potassium depletion. Therefore, in some centers, patients scheduled for open-heart surgery are routinely given potassium supplements. We have assessed the potassium status of 32 patients prior to cardiac surgery (1) by measurements of plasma, red cell, and leukocyte potassium levels and total body potassium before and after administration of potassium supplements (144 mmoles daily for 3 days) and (2) by the changes in urine potassium during the supplementation. On admission none of the patients showed evidence of a large potassium deficit, and none of them retained much of the supplemental potassium. The observations that have previously been taken as evidence of potassium depletion in such patients are discussed, and alternative explanations are suggested for all these observations.

Chronic potassium deficiency results in progressive tubulointerstitial injury, associated with augmented renal ammoniagenesis. We investigated the role of elevated renal ammonia levels and the interaction of ammonia with the complement system in this injury. Potassium deficiency was induced in rats by feeding a low potassium diet. Experimental animals received 150 mM NaHCO3 or equimolar NaCl, as drinking water. After 3 wk, NaHCO3 supplemented rats demonstrated decreased ammonia production, less renal hypertrophy, less histologic evidence of injury, and less proteinuria. In in vitro studies on normal cortical tubular fragments, the addition of ammonia to serum in concentrations comparable to renal cortical levels in potassium-deficient animals significantly increased tubular deposition of C3 as quantitated by a radiolabeled antibody binding technique. Thus, alkali supplementation reduced chronic tubulointerstitial disease in a rat model of hypokalemic nephropathy. We propose that increased cortical ammonia levels contribute to hypokalemic nephropathy through ammonia-mediated activation of the alternative complement pathway.

We demonstrated that potassium depletion significantly increased gentamicin nephrotoxicity in Sprague-Dawley rats (100 mg X kg-1 X day-1). To determine whether this enhanced toxicity was mediated by renin secretion, we evaluated the effect of a converting enzyme inhibitor in this model. When we administered the combination of captopril (100 mg X kg-1 X day-1) and gentamicin in potassium-depleted rats, we observed a surprising and significant adverse effect of this combination on the clearances of inulin (CIn) and PAH (CPAH) and renal blood flow (RBF). Pretreatment with indomethacin significantly improved CIn and CPAH, and potassium repletion abolished this effect entirely. In potassium-depleted animals that received both gentamicin and captopril, the intra-arterial administration of imidazole, a thromboxane synthetase inhibitor, significantly reduced urinary TXB2 excretion and significantly improved RBF and CIn in vivo. In the same group of animals, administration of the kallikrein antagonist aprotinin also significantly increased both RBF and CIn. To measure total renal thromboxane B2 production (TXB2), we perfused kidneys ex vivo with cell-free perfusate. Three groups of animals were studied: potassium-repleted control animals, potassium-depleted control animals, and potassium-depleted animals treated with gentamicin alone, captopril alone, or the combination of gentamicin and captopril. We measured TXB2 in renal venous effluent by radioimmunoassay. Ex vivo perfused kidneys from potassium-depleted control animals produced significantly more TXB2 than potassium-repleted controls. Kidneys from potassium-depleted animals that received both gentamicin and captopril produced significantly greater amounts of TXB2 than did kidneys from potassium-depleted animals treated with captopril alone, gentamicin alone, or control potassium-depleted kidneys. The administration of imidazole ex vivo at a rate equivalent to in vivo administration (10 microM/min) reduced TXB2 production by potassium-depleted kidneys that received the combination of gentamicin and captopril to that of potassium-repleted control kidneys. These results suggest that the deleterious effect of captopril in potassium-depleted rats that received gentamicin is due at least in part to kinin-stimulated renal TXB2 production.

Twelve patients with congestive heart failure receiving maintenance therapy with digoxin and potent diuretics were followed closely during development of hypokalemia and potassium loss. Cardiac arrhythmias compatible with digoxtin toxicity developed in 6 patients in the presence of stable, normal serum digoxin concentrations. The mechanisms involved in the development of the rhythm disturbances are discussed with regard to hypokalaemia, intracellular potassium loss, intra-/extracellular potassium gradients and digoxin, and the significance of maintaining a normal potassium balance in this setting is stressed.

The total body potassium (TBK) and potassium retention were measured during the early stages of recovery of malnourished children on three levels of potassium intake. A potassium intake of 2 mEq/kg/day resulted in significantly greater potassium retention than one of 3 mEq/kg/day. A higher level of intake (15 mEq/kg/day) did not result in an absolute increase in potassium retention and is not recommended because of its theoretical dangers, although it may have stimulated an increase in potassium capacity.

The serum immunoreactive insulin (IRI) concentrations, and glucose dissappearance rate-constants after intravenous glucose administration were measured on admission and during recovery in children suffering from protein-energy malnutrition (PEM). 2. A high potassium intake resulted in a considerable increase in the serum IRI levels early in the treatment period. There was a definite relationship between potassium depletion and many measurements of insulin secretion. 3. The results are consistent with the hypothesis that impaired insulin release in children suffering from PEM is partly the result of potassium depletion.

The effect of potassium ion (K+) depletion on postmyocardial infarction ventricular arrhythmias was investigated in 32 dogs: 12 control animals, 10 animals that ate a diet extremely low in K+ for 15 days, and 10 others that, in addition to dietary K+ deprivation, received 50 mg of hydrochlorothiazide four times. The experimental myocardial infarction was created by proximal left anterior descending coronary artery ligation. In a subgroup of 24 animals selected for relatively uniform size of myocardial infarction (14% to 22% of left ventricular mass), eight animals with mean cumulative K+ balance of -4.01 +/- 2.19 meq/kg developed spontaneous ventricular fibrillation within 4 to 17 min of coronary ligation, whereas 16 animals with a mean cumulative K+ balance of -0.11 +/- 1.82 meq/kg didn't. By univariate analysis cumulative K+ deficit (p = .001) and plasma K+ concentration (p = .039) correlated significantly with spontaneous ventricular fibrillation. Multivariate analysis of the entire population of 32 animals identified cumulative K+ deficit and size of myocardial infarction as the only independent predictors of ventricular fibrillation. Cumulative K+ deficit was also an independent predictor of ventricular fibrillation induced by programmed cardiac stimulation in the conscious state 1 day after myocardial infarction.

A father and son are described with a condition characterized by benign hypertension, potassium deficiency, increased aldosterone secretion rate (ASR), raised plasma volume and suppressed plasma renin activity (PRA). There were intermittent elevations of urine 17-ketosteroids and 17-hydroxycorticoids (17-OHCS) but no increase in urine THS, normal circadian rhythm of plasma 17-OHCS, and normal urine 17-OHCS response to dexamethasone and intravenous ACTH. Plasma ACTH and corticosterone secretion were not elevated. Pregnanetriol excretion was normal but urine pregnanediol was increased. At operation on the father no adrenal tumour was found; the excised left adrenal weighed 7 g. and showed nodular cortical hyperplasia; juxtaglomerular cells showed only occasional granules. Following operation hypertension persisted and ASR was half the preoperative value. All abnormalities in father and son were relieved by dexamethasone (DM) 2 mg. daily. The condition recurred following cessation of DM but was relieved by a second course of treatment. No such response to DM was seen in a normal subject or in a patient with Conn's syndrome. For a number of reasons it is suggested that patients with hypertension, increased ASR and low PRA be given a trial of dexamethasone treatment before undergoing adrenal surgery.

A study of the effect of additional oral potassium on the low body potassium of seven patients with severe valvular heart disease showed that the potassium supplements were retained. After one month's treatment the exchangeable potassium was significantly increased, but the predicted value was not reached in any of the patients. There was no significant change in plasma potassium. These results suggest that it is of benefit to increase the dose of oral potassium for at least one month preoperatively in patients undergoing cardiac surgery.