Search

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: 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.

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 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.

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.

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., (Copyright © 2014 American Society of Hypertension. All rights reserved.)

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.

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.

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.

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.

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.

Acute muscle weakness with severe hypokalaemia is not uncommon in adults but is rare in children. An 11-month-old girl presented with hypokalaemic paralysis following a 1-month insufficiency of dietary potassium.

Acid-base and potassium disorders occur frequently in the setting of liver disease. As the liver's metabolic function worsens, particularly in the setting of renal dysfunction, hemodynamic compromise, and hepatic encephalopathy, acid-base disorders ensue. The most common acid-base disorder is respiratory alkalosis. Metabolic acidosis alone or in combination with respiratory alkalosis also is common. Acid-base disorders in patients with liver disease are complex. The urine anion gap may help to distinguish between chronic respiratory alkalosis and hyperchloremic metabolic acidosis when a blood gas is not available. A negative urine anion gap helps to rule out chronic respiratory alkalosis. In this disorder a positive urine anion gap is expected owing to suppressed urinary acidification. Distal renal tubular acidosis occurs in autoimmune liver disease such as primary biliary cirrhosis, but often is a functional defect from impaired distal sodium delivery. Potassium disorders are often the result of the therapies used to treat advanced liver disease.

Carbonic-anhydrase inhibitors are effective in channelopathies possibly by opening the Ca2+-activated-K+ channels. However, the in vivo effects of these drugs in K+-deficient rats, the animal model of familial hypokalaemic periodic paralysis(hypokalaemic-PP), are currently unknown. Measures of insulin-responses, serum electrolytes levels and patch-clamp experiments were therefore performed in K+ -deficient rats treated in vivo with dichlorphenamide (DCP), ethoxzolamide (ETX), hydrochlorthiazide (HCT), methazolamide (MTZ), bendroflumethiazide (BFT) and acetazolamide (ACTZ). Ten days treatments of K+-deficient rats with DCP, BFT, ETX and ACTZ (5.6 mg/kg per day) restored the serum [K+] to control values and prevented the insulin-induced paralysis. In ex vivo experiments, the carbonic-anhydrase inhibitors enhanced the activity of Ca2+-activated-K+ channels with the order of efficacy: ACTZ>BFT>ETX>DCP. In contrast, HCT and MTZ failed to stimulate the Ca2+-activated-K+ channels and to prevent the hypokalaemia and paralysis. At the concentration of 1mg/kg per day, all these drugs failed to ameliorate the hypokalaemic-PP symptoms. The activation of Ca2+-activated-K+ channel in addition to the mild diuretic effect explained the efficacy of ACTZ and DCP in K+ -deficient rats and in familial hypokalaemic-PP.

Congestive heart failure (CHF) is becoming more frequent worldwide. Both potassium (K) and magnesium (Mg) deficiencies are common and can be associated with risk factors and complications of heart failure (HF). The major causes of K and Mg depletions are the effects of compensatory neuroendocrine mechanisms (activation of the renin-angiotensin-aldosterone and sympathoadrenergic systems), digoxin therapy, and administration of thiazide or loop diuretic therapy in CHF. Particular attention should be paid to K and Mg restoration in CHF, because of the consequences of both deficiencies (increased arrhythmic risk, vasoconstriction), and the co-supplementation of both ions is necessary in order to achieve K repletion. Mg and K should be employed as first-line therapy in digitalis intoxication and drug-related arrhythmias, and should be considered an important adjuvant therapy in diuretic treated patients with CHF. Another possibility to restore normal K and Mg status is usage of a K, Mg sparing diuretics.

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.

Stages of modeling of polyetiological electrolyte nephropathy in rats are described. Morphological study confirmed the presence of interstitial and tubular disorders in rat kidneys. The model is intended for studies of the mechanisms underlying the formation, development, and correction of nephrological diseases.

Carbonic-anhydrase (CA) inhibitors are used in the treatment of hypokalaemic periodic paralysis (hypoPP) and related channelopathies but their mechanism of action is unknown. Patch-clamp experiments and molecular modeling investigations were performed to evaluate the mechanism of actions of CA inhibitors on skeletal muscle Ca2+-activated-K+ (BK) channel of K+-deficient rats used as animal model of hypoPP. CA inhibitors showing different degree of CA inhibition such as acetazolamide (ACTZ), dichlorphenamide (DCP), hydrochlorthiazide (HCT), etoxzolamide (ETX), methazolamide (MTZ), and bendroflumethiazide (BFT), which lacks inhibitory effects on CA enzymes, were tested in vitro on BK channels. The application of ACTZ, BFT, ETX, and DCP to excised patches activated the BK channel with potency: ACTZ(DE50=7.3x10(-6)M)>BFT(DE50=5.93x10(-5)M)>ETX(DE50=1.17x10(-4)M)>>DCP. In contrast, MTZ and HCT failed to activate the BK channel. Molecular modeling studies showed that the capability of CA inhibitors to open the BK channel was related to the presence in their structures of an intra-molecular hydrogen bond with calculated inter-atomic distances ranging between 1.82 A degrees and 3.01 A degrees and of an aromatic ring poor of electrons. ACTZ, BFT, ETX, and DCP showed these pharmacofores, while MTZ and HCT did not. Our data indicate that the activation of BK channel is a property of CA inhibitors that interact with the channel subunit/s and that this effect is not related to their capability to inhibit the CA enzymes.

Objective: This study determined relationship between total body potassium (TBK) and morbidity and mortality of patients with end stage renal disease (ESRD). DESIGN, PATIENTS, SETTING: Long term observational study of 15 ESRD patients receiving chronic hemodialysis in an academically affiliated Veterans Affairs Medical Center Hospital. METHODOLOGY AND OUTCOME MEASURE: TBK by whole-body counting of 40K, dialysis potassium losses, and patient demographic characteristics were determined. Survival was evaluated retrospectively after seven years of follow-up., Results: Six of 15 patients (40%) had TBK depletion. All patients who were TBK depleted, expired by study end. In contrast, only 4 of 9 patients with normal K+ stores had died during the same time period (P<0.02). Median survival time of subjects with normal TBK was 100 vs 55 months for the depleted group (chi2=4.6, P<0.05). Patients with normal TBK were younger (41.9 vs 62.5 years, P<0.02) and predominantly black (78%). The ESRD group with normal TBK received more hours of hemodialysis (HD) per week (11.2 hours vs 9.7, P<0.02) and had greater K+ removal than the depleted patients (70.5 mmol/treatment vs 43.8). Urea reduction ratio was not statistically different between groups. Serum albumin, interdialytic increases in BUN and weight, and body mass index were not different between normal and TBK depleted groups., Conclusions: TBK depletion occurs in a significant proportion of HD patients and is associated with increased mortality. It is prudent to customize HD and dietary prescriptions to maintain normal levels of TBK in ESRD patients.

Potassium depletion prevails among the healthy population of north-east Thailand, as well as among patients with certain metabolic disorders such as upper urinary tract stones, the sudden unexplained death syndrome, distal renal tubular acidosis and hypokalaemic periodic paralysis. However, definite proof of the relationship of potassium depletion and these metabolic disorders is lacking. We prospectively studied muscle and kidney potassium content including renal tissue pathology in three groups of healthy adult Thai subjects who died of vehicular accidents. Group 1 (n = 24) were Bangkok city dwellers; groups 2 (n = 10) and 3 (n = 22) lived in north-eastern Thailand in the metropolitan area and in the villages, respectively. The muscle potassium content of group 1 (338.5 +/- 9.6 mEq/kg dry weight (DW)) were similar to group 2 (307.9 +/- 11.9 mEq/kg DW), but was greater than group 3 (295.4 +/- 9.1 mEq/kg DW; P < 0.01). The kidney potassium content of group 1 (208.6 +/- 7.8 mEq/kg DW) was significantly higher than group 3 (175.9 +/- 6.3 mEq/kg DW, P < 0.05). In group 3, the muscle potassium correlated linearly with the kidney potassium (r = 0.455, P = 0.33). None of the group 3 patients had renal histopathological change compatible with a diagnosis of focal or diffuse interstitial nephritis. This study confirms that potassium depletion is common among healthy rural dwellers in north-east Thailand. This deficit was probably chronic. However, there was minimal renal tubulo-interstitial change.

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.

Hypokalemia is a common electrolyte abnormality encountered in clinical practice. It can be identified in an asymptomatic patient undergoing routine electrolyte screening or can manifest itself as part of a number of functional abnormalities in a variety of organs and systems. Among the most commonly recognized complications are profound effects on the cardiovascular and neuromuscular systems, together with abnormalities in acid-base regulation. In humans, hypokalemia contributes to the development of hypertension and predisposes patients to a variety of ventricular arrhythmias, including ventricular fibrillation. Commonly recognized neuromuscular complications include weakness, cramping, and myalgia. Hypokalemia also affects systemic acid-base homeostasis by interfering with multiple components of the renal acid-base regulation and is a frequent cause of metabolic alkalosis. Less known, however, is the role of potassium deficiency in causing progressive renal failure. In animals, potassium deficiency stimulates renal enlargement because of cellular hypertrophy and hyperplasia. If potassium deficiency persists, interstitial infiltrates appear in the renal interstitial compartment, and eventually tubulointerstitial fibrosis develops. In humans, longstanding hypokalemia is associated with the development of renal cysts, chronic interstitial nephritis, and progressive loss of renal function, the so-called hypokalemic nephropathy. This review focuses on the potential mechanisms involved in the development of the hypokalemic nephropathy with emphasis on the role of ammonia and growth factors in its pathogenesis., (Copyright 2002 by the National Kidney Foundation, Inc.)

Skeletal muscles surgically obtained from the stone-former group (external oblique muscle; n = 202, 82 males & 120 females), control group I (external oblique muscle; n = 5, all males), control group II (rectus abdominis muscle; n = 23, all females) and control group III (quadriceps femoris muscle; n = 11, all males) were analyzed for potassium (K), sodium (Na) and magnesium (Mg) contents. Muscle samples were digested with 65 per cent HNO3 and determined for K, Na and Mg by an atomic absorption spectrophotometer. The results of analysis showed the mean K, Na and Mg (+/- S.D.) contents in mumol per one gram of fresh tissue of the stone-former group, control groups I, II and III were 73.5 +/- 16.6, 51.3 +/- 13.4 and 6.6 +/- 1.3, 77.5 +/- 3.9, 43.9 +/- 9.9 and 7.2 +/- 0.5, 83.8 +/- 27.5, 49.4 +/- 24.1 and 6.7 +/- 1.8 and 85.0 +/- 17.1, 48.5 +/- 12.1 and 6.8 +/- 1.3. Among these variables, only the K content of control group III was higher significantly (p < 0.05) than that of the stone-former group. In the stone-former group, regression analysis showed significant correlations between K and Mg contents (r = 0.856, p < 0.001) and K and Na contents (r = -0.325, p < 0.001). Due to no available data of the external oblique, we made a comparison of our results to the soleus type of skeletal muscle of normal subjects reported by Dorup et al and found that the external oblique muscle had lower mean contents of K and Mg but a higher Na content than those of the soleus. Our results were similar to the K and Mg depleted muscles obtained from the patients receiving long-term treatment with diuretic drugs. The results suggest that most of our subjects in both the stone-former and the 3 control groups were in a state of K and Mg depletion. The causes may be multifactorial, for instance low intake, high sweat loss and the existence of environmental inhibitor (s) for K transport like vanadium.

It is often said that the introduction of insulin into clinical medicine made a 'dramatic' difference to the mortality resulting from diabetic coma. This is true in the sense that before 1922 it was almost uniformly fatal, but until the 1950s the mortality in many large hospitals was as high as 30-50%. Often autopsy did not establish a cause of death. Many may have been a result of hypokalaemia, a complication which was not recognized until 1946; in that year in the Journal of the American Medical Association, Jacob Holler described a patient who developed respiratory paralysis 12h into treatment that, after several hours in an iron lung, was cured by potassium infusion. In the 5 years after Holler's paper there were many reports of deaths resulting from hypokalaemia, as well as several 'near misses', but clinicians were extremely cautious about early replacement probably, as an editorialist in The Lancet suggested, because 'the frightening effects of intravenous injections of potassium made clinicians reluctant to believe in a lack of potassium as a cause of trouble, except in very rare conditions such as familial periodic paralysis'. It had been known since 1923 that insulin lowered serum potassium, but this was not of great interest because the symptoms of hypokalaemia were not known. Also, potassium was not an electrolyte with which clinicians were familiar. Until the introduction of flame photometry in 1950, it was only measured in research studies as chemical methods took several hours to complete.

Distal renal tubular acidosis is a common health problem in northeastern Thailand, with the population background of the low potassium intake, low urine citrate, and decreased red blood cell Na-K adenosine triphosphatase (ATPase) activity and the environment of the high soil vanadium. The disease is usually seen in the people with low socioeconomic status in summer. The patients have decreased gastric acidity and low urine potassium. There are varying degrees of renal function from normal to impairment. Gastric hypoacidity is an important clue. Defects in H-K ATPase and anion exchange (AE2) mechanism are considered. The urine vanadium is higher in the patients than that of normal rural northeastern villagers. Inhibition of H-K ATPase by vanadium seems possible and requires more supporting evidence. AE1 gene mutation is noted in few patients. The cause of dRTA is not apparent. The AE2 gene and H-K ATPase gene remain to be studied. Both environmental and genetic factors could contribute to the pathogenesis of the disease.

-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

Animals with cardiac disease can have a variety of nutritional alterations for which interventional nutrition can be beneficial. Deviation from optimal body weight, both obesity and cachexia, is a common problem in cardiac patients and adversely affects the animal. Methods for maintaining optimal weight are important for good quality of life in dogs and cats with cardiac disease. Providing proper diets to prevent excess intake of sodium and chloride also is important, but severe salt restriction may not be necessary until later stages of disease. Certain nutrient deficiencies may play a role in the pathogenesis or complications of cardiac disease, but nutrients also may have effects on cardiac disease which are above and beyond their nutritional effects (nutritional pharmacology). Supplementation of nutrients such as taurine, carnitine, coenzyme Q10, and omega-3 polyunsaturated fatty acids may have benefits in dogs or cats with cardiac disease through a number of different mechanisms. By addressing each of these areas maintaining optimal weight, avoiding nutritional deficiencies and excesses, and providing the benefits of nutritional pharmacology, optimal patient management can be achieved.

(1) Dietary deficiencies of Zn, Mg and K lead to a rapid drop in serum concentrations, with no change (Zn) or a slow decline (Mg and K) in the concentrations in skeletal muscle. (2) These deficiencies all lead to inhibition of growth and protein synthesis in muscle. (3) The inhibition of protein synthesis is faster in onset than the loss of Zn, Mg and K from muscle and therefore unlikely to result from cellular mineral deficiency. (4) The deficiencies are likely to be detected by the early drop in serum concentration, but the mechanism is unknown. (5) Possible mediators of growth inhibition are anorexia, GH and IGF-I. (6) Early detection of mineral deficiencies allows the organism to minimize wasteful protein synthesis and the formation of functionally inadequate tissues.

Normal Mg metabolism has been reviewed. The most expeditious method of identifying disorders of Mg deficiency or excess is to order a serum Mg determination. In our opinion, routine serum Mg would significantly enhance the clinician's ability to identify disorders of Mg metabolism. Refractory K repletion can be avoided by identifying co-existing hypomagnesemia in hypokalemic patients; as a result, prompting the clinician to institute simultaneous repletion of Mg as well as K. While oral Mg is the preferred route of repletion in critically ill patients, intravenous administration of Mg is recommended. Refractory hypotension, mental obtundation, and respiratory arrest occur with significant hypermagnesemia. Hemodialysis is recommended for treatment of symptomatic hypermagnesemia.

There is an increased requirement for nutrients in normal pregnancy, not only due to increased demand, but also increased loss. There is also an increased insulin-resistant state during pregnancy mediated by the placental anti-insulin hormones estrogen, progesterone, human somatomammotropin; the pituitary hormone prolactin; and the adrenal hormone, cortisol. If the maternal pancreas cannot increase production of insulin of sustain normoglycemia despite these anti-insulin hormones, gestational diabetes occurs. Gestational diabetes is associated with excessive nutrient losses due to glycosuria. Specific nutrient deficiencies of chromium, magnesium, potassium and pyridoxine may potentiate the tendency towards hyperglycemia in gestational diabetic women because each of these four deficiencies causes impairment of pancreatic insulin production. This review describes the pathophysiology of the hyperglycemia and the nutrient loss in gestational diabetes and further postulates the mechanism whereby vitamin/mineral supplementation may be useful to prevent or ameliorate pregnancy-related glucose intolerance.

Weanling male inbred Dahl rats (Jr salt-sensitive (S) and salt-resistant (R) strains) were placed on high (4%, HK) and low (0.2%, LK) potassium diets for 4 weeks. Both diets contained 8% sodium chloride, 2.5% calcium, 0.8% magnesium, and 2.0% phosphorous. Balance studies were carried out during the final week on the diets. Mean arterial blood pressure was determined, and dietary intake and urinary output of water, sodium, chloride, potassium, calcium, magnesium, and phosphate were monitored daily during this period. The data show that blood pressures of S rats were significantly higher than those of R rats on both HK and LK diets; however, reduced dietary potassium was associated with increased blood pressure in both strains. Urinary excretions of calcium and magnesium were higher, and urinary phosphate excretion was lower, in S compared to R rats. Decreased potassium intake was associated with increased excretion of calcium, magnesium and phosphate in both strains. The changes in calcium and magnesium excretion were significantly correlated to blood pressure across strains and diets. We conclude that the effects of a high salt diet on increasing blood pressure can be potentiated by lack of potassium, even in previously salt-resistant rats. Increased blood pressure is associated with increased divalent cation excretion. It is not yet known whether this is a cause-and-effect relationship.

Hypokalemia and potassium depletion are frequent complications of amphotericin B therapy. Both ischemic and gentamicin-induced renal failure is potentiated by potassium depletion; it is, therefore, possible that amphotericin B nephrotoxicity is similarly influenced. This study evaluated whether the acute nephrotoxic response to amphotericin B is potassium sensitive. Potassium-depleted and control rats were subjected to an acute intravenous infusion of either amphotericin B (AmB-K; AmB, n = 10 in each) or its vehicle (V-K, V; n = 6 in each). Potassium-depleted rats had both lower urinary daily excretion and lower plasma levels of potassium than control animals (0.1 +/- 0.0 vs. 2.1 +/- 0.2 mEq/day, p < 0.001, and 3.8 +/- 0.2 vs. 1.9 +/- 0.1 mEq/l, p < 0.001, respectively). In AmB and AmB-K groups, there were equivalent falls in glomerular filtration rate and renal blood flow, and a rise in renal vascular resistance, compared with V and V-K. In contrast, the AmB-K group showed a higher urinary excretion of sodium (AmB-K vs. AmB: 2.9 +/- 0.7 vs. 1.1 +/- 0.3 microEq/min; p < 0.05) and fractional excretion of Na (AmB-K vs. AmB: 1.6 +/- 0.4 vs. 0.6 +/- 0.1%; p < 0.05) in comparison to the AmB group. Neither of these parameters changed in either amphotericin B or vehicle-treated groups. These results suggest that potassium depletion does not influence the acute renovascular effects of amphotericin B but potentiates its tubular toxicity. This may have clinical implications since hypokalemia and potassium depletion are frequent complications of amphotericin B therapy.