The Dietary Approach to the Treatment of the Rare Genetic Tubulopathies Gitelman's and Bartter's Syndromes.

Gitelman's (GS) and Bartter's (BS) syndromes are rare, inherited autosomal recessive tubulopathies characterized by hypokalemia, metabolic alkalosis, renal sodium, chloride, and potassium and magnesium-wasting. While the treatment based on potassium, sodium, chloride, and magnesium supplementation in addition to other pharmacologic options are widely established, recommendations about the dietary approach to GS and BS still remain generic. In this review we focus on the dietary strategies to increase sodium, potassium, and magnesium intake in GS and BS patients. Potassium and magnesium-rich foods and supplements are considered together with those that may reduce through different mechanisms the potassium and magnesium plasma level. Magnesium supplementation is often poorly tolerated, causing abdominal pain and diarrhea in most patients. New formulations using liposome and, in particular, sucrosomial technology have been recently proposed for magnesium supplementation in order to increase magnesium supplement tolerability and intestinal absorption. The dietary approach to GS and BS may be very important in the therapeutic approach to these syndromes. Due to the relevance of the dietary approach to these syndromes, a nutritional counseling should always be recommended and the nutritionist should join nephrologists in the follow-up of GS and BS patient care.

Hypocalcaemia and hyponatraemia masquerading the diagnosis of Gitelman syndrome.

Gitelman syndrome is the most common renal tubulopathy, recently exhibiting a dramatic rise of incidence in Asia.A 50-year-old woman presented with vomiting, fatigue and quadriparesis. Physical examination revealed a positive Trousseau sign , hypotonia and areflexia.Suspecting hypocalcaemia, she was given intravenous 10% calcium gluconate (10 mL administered slowly over 10 min) but her manifestations persisted. An exhaustive laboratory work up revealed the diagnosis of Gitelman syndrome.The peculiarity of this case however, is entailed in its coexistence with hypocalcaemia and hyponatraemia. In addition, the age of primary presentation being 50 years further culminates its atypicality.Multiple electrolyte imbalances were corrected by oral and intravenous supplementation and a high sodium-potassium diet was advocated. Administration of spironolactone imposed a pitfall in the management of our patient due to exacerbation of pre-existing hyponatraemia.On follow-up, her electrolyte profile was stable and corresponding symptoms were alleviated.

Potassium Intake, Bioavailability, Hypertension, and Glucose Control.

Potassium is an essential nutrient. It is the most abundant cation in intracellular fluid where it plays a key role in maintaining cell function. The gradient of potassium across the cell membrane determines cellular membrane potential, which is maintained in large part by the ubiquitous ion channel the sodium-potassium (Na+-K+) ATPase pump. Approximately 90% of potassium consumed (60-100 mEq) is lost in the urine, with the other 10% excreted in the stool, and a very small amount lost in sweat. Little is known about the bioavailability of potassium, especially from dietary sources. Less is understood on how bioavailability may affect health outcomes. Hypertension (HTN) is the leading cause of cardiovascular disease (CVD) and a major financial burden ($50.6 billion) to the US public health system, and has a significant impact on all-cause morbidity and mortality worldwide. The relationship between increased potassium supplementation and a decrease in HTN is relatively well understood, but the effect of increased potassium intake from dietary sources on blood pressure overall is less clear. In addition, treatment options for hypertensive individuals (e.g., thiazide diuretics) may further compound chronic disease risk via impairments in potassium utilization and glucose control. Understanding potassium bioavailability from various sources may help to reveal how specific compounds and tissues influence potassium movement, and further the understanding of its role in health.

Effects of potassium supplementation on markers of osmoregulation and volume regulation: results of a fully controlled dietary intervention study.

OBJECTIVE: Lifestyle measures including dietary sodium restriction and increased potassium intake are recognized to lower blood pressure (BP). Potassium was found to be effective in reducing BP at higher levels of sodium intake, but to have little effect when sodium intake is restricted. The humoral mechanisms underlying these sodium intake dependent effects of potassium are unknown. We investigated the effects of potassium supplementation on top of a fully controlled sodium-restricted diet on markers of osmoregulation and volume regulation. METHODS: In this post-hoc analysis, we included 35 (pre)hypertensive individuals participating in a randomized, double-blind, placebo-controlled crossover trial. Individuals received capsules containing sodium [3.0 g (130 mmol)/day], potassium [2.8 g (72  mmol)/day], or placebo for three four-week periods. Linear mixed-effect models were used to estimate the effects of potassium supplementation compared with placebo. Skewed data were ln-transformed before analysis. RESULTS: Increased potassium intake was associated with a significant decrease in 24-h BP (-3.6/-1.6 mmHg). Furthermore, we found a significant decrease in ln MR-proANP [-0.08 (95% confidence interval -0.15, -0.01) pmol/l, P = 0.03] and significant increases in 24-h heart rate [2.5 (0.9, 4.0) bpm, P = 0.002], ln plasma copeptin [0.11 (0.01, 0.20) pmol/l, P = 0.02], ln renin [0.34 (0.08, 0.60) µIU/ml, P = 0.01], and ln aldosterone [0.14 (0.07, 0.22) nmol/l, P < 0.001] compared with placebo. CONCLUSIONS: We found that potassium has BP-lowering effects during sodium restriction. These BP-lowering effects, however, seem mitigated by several counter regulatory mechanisms (i.e. increased secretion of vasopressin, stimulation of RAAS, and increased heart rate) that were activated to maintain volume homeostasis and counterbalance the decrease in BP.

Dietary acid load in early life and bone health in childhood: the Generation R Study.

BACKGROUND: Dietary contribution to acid-base balance in early life may influence subsequent bone mineralization. Previous studies reported inconsistent results regarding the associations between dietary acid load and bone mass. OBJECTIVE: We examined the associations of dietary acid load in early life with bone health in childhood. DESIGN: In a prospective, multiethnic, population-based cohort study of 2850 children, we estimated dietary acid load as dietary potential renal acid load (dPRAL), based on dietary intakes of calcium, magnesium, phosphorus, potassium, and protein, and as a protein intake to potassium intake ratio (Pro:K) at 1 y of age and in a subgroup at 2 y of age : Bone mineral density, bone mineral content (BMC), area-adjusted BMC, and bone area were assessed by dual-energy X-ray absorptiometry at the median age of 6 y. Data were analyzed by using multivariable linear regression models. RESULTS: After adjusting for relevant maternal and child factors, dietary acid load estimated as either dPRAL or Pro:K ratio was not consistently associated with childhood bone health. Associations did not differ by sex, ethnicity, weight status, or vitamin D supplementation. Only in those children with high protein intake in our population (i.e., >42 g/d), a 1-unit increase in dPRAL (mEq/d) was inversely associated with BMC (difference: -0.32 g; 95% CI: -0.64, -0.01 g). CONCLUSIONS: Dietary acid load in early life was not consistently associated with bone health in childhood. Further research is needed to explore the extent to which dietary acid load in later childhood may affect current and future bone health.

Clinical perspectives on the rationale for potassium supplementation.

Hypokalemia is a common electrolyte disturbance, observed in > 20% of hospitalized patients. Hypokalemia, although not formally defined, is generally considered to be when serum potassium levels fall below the normal value of 3.6 mmol/L. In contrast to other electrolytes, potassium is primarily an intracellular ion: only 2% of all potassium in the body is present in the extracellular fluid, so a small decrease in serum potassium may represent a significant decrease in intracellular potassium. Individuals with mildly decreased potassium levels (3.0-3.5 mmol/L) may be asymptomatic, but patients with more pronounced decreases may report symptoms including muscle weakness, fatigue, and constipation. Very low serum potassium levels (≤ 2.5 mmol/L) can lead to muscle necrosis, paralysis, cardiac arrhythmias, and impaired respiration, which can be life-threatening. Absent comprehensive and robust treatment guidelines, strategies for the prevention or treatment of hypokalemia, such as how to diagnose hypokalemia, when to treat patients, what dosage regimen of potassium supplementation to use and for how long, are often based on the experience of the physician and empirical evidence. However, proper evaluation and treatment of hypokalemia in patients is essential because of associated morbidities. Because small potassium deficits in serum represent large body losses, potassium repletion requires substantial and prolonged supplementation. For patients with known risk factors for hypokalemia (e.g. hypertension, heart failure, or diabetes), careful monitoring is crucial to avoid the adverse sequelae associated with potassium deficits and to ensure that adequate and timely preventive measures can be taken. In this review, we provide practical insights into the etiology, differential diagnosis, and treatment of hypokalemia, including treatment strategies for patients with known risk factors.

Effect of dried California Mission figs on mineral status and food replacement.

OBJECTIVE: Figs are a rich source of several different minerals and fibres. We studied the effect of the consumption of dried California Mission figs on mineral and nutrient levels, as well as the effect of the addition of figs to a self-selected habitual diet on dietary patterns. DESIGN: A crossover randomized controlled trial study design in which participants with a mean of age of approximately 56 years were randomly assigned to eat either their usual diet for 5 weeks or to add dried California Mission figs (120 g/d) to their usual diet for 5 weeks, after which they crossed over to the other group for an additional 5 weeks. Six 24 h dietary recalls and four blood samples were obtained from each participant. SETTING: Loma Linda University School of Public Health, USA. SUBJECTS: A follow-up study using data collected from eighty-eight American males and females from September to December 2008. RESULTS: Diets reported in the 24 h dietary recall during the fig-supplemented diet period were significantly higher in Ca and K in the dietary and total phase (P value<0·05). Nevertheless, data on mineral levels in the body gathered by means of biochemical analyses from blood samples were nearly the same for both the figs-added and the participants' standard diet. The estimated displacement suggests that eating figs resulted in the elimination of 4% of desserts, 5% of vegetables, 10% of dairy products, 23% of grain products and 168% of beverages from other sources that participants would otherwise consume. CONCLUSIONS: Based on 24 h dietary recalls, the daily consumption of figs may increase the intake of several different minerals. However, mineral levels in blood samples were not altered significantly.

Parálisis periódica hipopotasémica tirotóxica: a propósito de un caso / Thyrotoxic hypokalemic periodic paralysis. A case report

La parálisis periódica hipopotasémica tirotóxica (PPT) es una rara complicación de la tirotoxicosis caracterizada por la aparición de episodios de debilidad muscular asociados a hipopotasemia en pacientes con hipertiroidismo, más frecuentemente con enfermedad de Graves-Basedow. El tratamiento con antitiroideos y suplementos de potasio revierte la sintomatología de debilidad muscular y evita la reaparición de estos síntomas (AU)

Thyrotoxic hypokalemic periodic paralysis is an uncommon complication of thyrotoxicosis, characterized by attacks of generalized muscular weakness associated with hypokalemia in patients with hyperthyroidism, most frequently with Graves-Basedow disease. Treatment with antithyroid drugs and potassium supplements reversed the symptoms and the episodes of acute muscular weakness did not reappear (AU)

Hypokalemia: a potent risk for QTc prolongation in clarithromycin treated rats.

Clarithromycin belongs to macrolide group of antibiotics commonly known for their proarrhythmic potency. Besides agents interfering with CYP 3A, electrolyte imbalance might influence repolarization problems of clarithromycin. The proarrhythmic tendency of clarithromycin particularly in association with hypokalemia manifested a change in QT interval in rat electrocardiogram (ECG). Varying degree of hypokalemia was induced by intraperitoneal injection of furosemide (50, 30, and 10 mg/kg, for seven days). The serum electrolyte levels confirmed that hypokalemia was established in the groups receiving furosemide. Simultaneously, clarithromycin was orally administered in the doses of 100 and 80 mg/kg for seven days. ECG was measured for 5 min in anaesthetised rat before and after 2 h of treatment. The QT interval was corrected for heart rate and reported as corrected QT (QTc). Distinct QTc interval prolongation was observed in groups receiving furosemide (50 and 30 mg/kg) alone and in all the groups receiving clarithromycin alongside furosemide. Neither, clarithromycin (80 mg/kg) nor furosemide (10 mg/kg) exhibited any significant change in the QTc interval but in combination these drugs led to a significant increase in the QTc interval. Most interestingly, potassium supplementation was found to reduce QTc interval in the group presenting with maximum QTc prolongation. These results suggest that hypokalemic condition potentiates the clarithromycin induced QTc prolongation, thereby indicating the importance of monitoring serum electrolyte during clarithromycin therapy. Although, selection of rat for examination of proarrhythmic liability is controversial, this report may be considered as an evidence of hypokalemia potentiating clarithromycin induced QTc prolongation.

Optimal nutrition for predialysis chronic kidney disease.

Diet potentially plays a major role in the progression and complications of predialysis CKD. Moderate protein consumption along with a diet low in sodium might slow kidney disease progression. Increasing vegetable protein intake might decrease serum phosphorus, uremic toxins, and kidney damage. Because obesity might be an important factor in the increasing prevalence of CKD, dietary strategies targeting obesity might also benefit CKD progression. In those with more advanced CKD, dietary calcium and phosphorus restriction could minimize vascular calcification. Dietary fiber and vitamin D supplementation might also be important to decrease inflammation in CKD.

Más allá del sodio: cambios en la dieta y su efecto en hipertensión / Beyond sodium: diet changes and their effect on hypertension

Resumen: La hipertensión arterial (HTA) es un importante factor de riesgo cardiovascular y su prevalencia aumenta con la edad, dado el aumento de la expectativa de vida de nuestra población esta condición constituye una prioridad a nivel de salud pública. Tanto para el tratamiento como para la prevención de la HTA son importantes las medidas no farmacológicas como cambios en el estilo de vida y especialmente la alimentación. Además de la restricción de sodio, existen otras medias dietéticas que han demostrado estar asociadas con un mejor control de la HTA en diversos ensayos clínicos, tales como la reducción del peso corporal, la dieta rica en frutas y verduras, el mayor consumo de potasio y magnesio, la vitamina D, los ácidos grasos ome-ga-3, los flavonoides y la disminución de la ingesta de sacarosa, fructosa, cafeína y alcohol. Dado la gran prevalencia de HTA en nuestro país del orden de un 26,9 por ciento, es importante dar a conocer medidas dietéticas que nos permitirán un mejor control de la presión en pacientes hipertensos y un retraso de la aparición de esta enfermedad en sujetos sanos, además de su incorporación en campañas de educación nutricional poblacional por parte de las autoridades sanitarias.

Hypertension is an important cardiovascular risk factor and its prevalence increases with age. Given the rising life expectancy in Chile, the prevention of hypertension is a priority for public health policies. Non pharmacological therapies, such as life style and diet changes are especially important. In addition to sodium restriction, several clinical studies have shown that other dietary interventions, such as an increased fruit and vegetable content of diet, higher intake of potassium and magnesium, vitamin D, omega-3 fatty acids, flavonoids, decreased intake of sucrose, fructose, caffeine and alcohol, lead to better control of hypertension. Given de high prevalence of hypertension in Chile (26.9 per cent overall) better information about the benefits of diet changes might be very important in order to help prevent and delay the appearance of hypertension. Appropriate public educational policies should be implemented by the sanitary authorities.

Active potassium supplementation might be mandatory during laparoscopic adrenalectomy for primary hyperaldosteronism.

BACKGROUND AND PURPOSE: It is well recognized that monitoring of the serum potassium level during laparoscopic adrenalectomy for primary hyperaldosteronism is critical. Nevertheless, the guideline for prevention and management of hypokalemia during the operation has not been established to date. In this study, we investigated whether active potassium supplementation could prevent electrolyte imbalance during laparoscopic adrenalectomy for primary hyperaldosteronism. PATIENTS AND METHODS: From January 2007 to May 2011, 35 patients underwent transperitoneal laparoscopic adrenalectomy for primary hyperaldosteronism (Conn's syndrome). The hemodynamic and electrolyte changes during the operation were recorded serially. In first 10 patients (group A), potassium was replaced passively on demand. Based on this result, potassium was actively supplemented during the operation in the subsequent 25 patients (group B). The perioperative parameters, hemodynamic changes, and serum potassium levels were analyzed and compared between the two groups. RESULTS: The patients' demographic data, initial blood pressure, and serum electrolyte levels were similar in both groups. The operative time was shorter in group B (P=0.035). The mean serum potassium level was decreased by 0.7 mmol/L during the first 30 minutes in group A. Based on this result, potassium was actively supplemented from the beginning of the operation in group B. The mean hypokalemic events were 4 ± 2 in group A. None of the patients in group B, however, experienced hypokalemia. The hemodynamic events (sudden increase of blood pressure) and mean blood pressure changes during the operation were similar in both groups. CONCLUSION: Our results demonstrate that serum potassium levels are constantly decreasing during laparoscopic adrenalectomy for primary aldosteronism. Active supplementation of potassium during the operation might prevent a hypokalemic event.

Protective effect of dietary potassium against cardiovascular damage in salt-sensitive hypertension: possible role of its antioxidant action.

It is well known that high salt intake induces hypertension and cardiovascular damage, while dietary potassium supplementation counteracts these harmful effects. Actually, the protective effect of potassium is strengthened with excess salt as compared with salt depletion. Although the precise mechanisms have not been fully elucidated, in our previous reports, the antihypertensive effect of dietary potassium was accompanied by sympathetic nerve inhibition in salt-sensitive hypertension. Also, potassium supplement suppressed salt-induced insulin resistance. These effects of dietary potassium can explain its cardio- and vasculo-protective action in addition to the potassium supplementation induced decreased salt-induced rise in blood pressure. On the other hand, salt-sensitive hypertension is associated with reactive oxygen species (ROS) overproduction. Moreover, sympathoexcitation can be induced by central ROS upregulation and insulin resistance can be caused by ROS excess in the target organs of insulin, such as skeletal muscle. Conversely, the seemingly different actions of potassium can be explained by the antioxidant effect of dietary potassium; in our recent studies, potassium supplementation inhibits salt-induced progress of cardiac diastolic dysfunction and vascular neointima formation by cuff placement around arteries, associated with the inhibition of regional ROS overproduction, in salt-sensitive hypertension. Thus, it is possible that dietary potassium protects against salt-induced cardiovascular damage by the reduction of ROS generation and by central sympatholytic action and amelioration of insulin resistance induced through its antioxidant effect.

Hypothetical hormonal mechanism by which potassium-rich diets benefit patients with rheumatoid arthritis.

Patients with rheumatoid arthritis (RA) have significantly lower salivary and serum potassium (K) concentration, reduced total body K, and lower dietary K intake than healthy subjects. There may also be a subtle impairment in the hypothalamic-pituitary-adrenal (HPA) axis in patients with RA with both a poor cortisol secretion response as well as a lower adrenocorticotropin hormone (ACTH) response in relation to involved inflammatory factors. Patients with RA also exhibit an impaired Na+, K+-ATPase (NKA) activity which might promote the pro-inflammatory cytokine secretion seen in RA. I will use these facts to support the mechanism I propose. There are no qualitative differences between the effects of endogenous cortisol and exogenously applied synthetic glucocorticoids (GCs), which are widely used to treat RA. All effects are transmitted via the same receptor. The GC, cortisol, plays a role in normal K homeostasis and the reverse is also seen with higher K intake leading to higher cortisol secretion and biosynthesis. Results of a recent clinical trial showed elevated serum cortisol followed K supplementation. I suggest that this is what alleviated RA symptoms. I would like to suggest a "Cortisol-K" theory as a mechanism for De Coti-Marsh's proposed "K theory" while not precluding the possibility of eventual proof of a cure, possibly from effects of K inside cells other than the adrenal glands.

Protective effect of potassium against the hypertensive cardiac dysfunction: association with reactive oxygen species reduction.

Potassium supplementation has a potent protective effect against cardiovascular disease, but the precise mechanism of it against left ventricular abnormal relaxation, relatively early functional cardiac alteration in hypertensive subjects, has not been fully elucidated. In the present study, we investigated the effect of potassium against salt-induced cardiac dysfunction and the involved mechanism. Seven- to 8-week-old Dahl salt sensitive rats were fed normal diet (0.3% NaCl) or high-salt diet (8% NaCl) with or without high potassium (8% KCl) for 8 weeks. Left ventricular relaxation was evaluated by the deceleration time of early diastolic filling obtained from Doppler transmitral inflow, the slope of the pressure curve, and the time constant at the isovolumic relaxation phase. High-salt loading induced a significant elevation of blood pressure and impaired left ventricular relaxation, accompanied by augmentation of reduced nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase activity in the cardiac tissue, measured by the lucigenin chemiluminescence method. Blood pressure lowering by hydralazine could not ameliorate NADPH oxidase activity and resulted in no improvement of left ventricular relaxation. Interestingly, although the blood pressure remained high, potassium supplementation as well as treatment with 4-hydroxy-2,2,6,6-tetramethyl-piperidine-N-oxyl, a superoxide dismutase mimetic, not only reduced the elevated NADPH oxidase activity but also improved the left ventricular relaxation. In conclusion, a high-potassium diet has a potent protective effect on left ventricular active relaxation independent of blood pressure, partly through the inhibition of cardiac NADPH oxidase activity. Sufficient potassium supplementation might be an attractive strategy for cardiac protection, especially in the salt-sensitive hypertensive subjects.

Outcome of pregnancy in a patient with Gitelman syndrome: a case report.

Gitelman syndrome (GS) is an autosomal-recessive condition characterized by hypokalaemia, hypomagnesaemia and hypocalciuria. Though it affects women of child-bearing age very little information is available about its impact on maternal and fetal outcome. We describe the course of pregnancy in a patient with GS which was characterized by a sixfold increase in potassium and magnesium requirements with inability to achieve normal levels despite intravenous supplementation. There was no adverse impact on the course of pregnancy or fetal outcome. The case highlights the variability in the phenotypic presentation of GS and recommends frequent monitoring of electrolytes with supplementation guided by clinical requirements without aiming to achieve normal blood levels.