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Dietary potassium restriction attenuates urinary sodium wasting in the generalized form of pseudohypoaldosteronism type 1.

ABSTRACT: Owing to its rarity and severe nature, the treatment for generalized pseudohypoaldosteronism type 1 (PHA1), a genetic disorder in the epithelial sodium channel (ENaC), is exclusively experience-based. In particular, the usefulness of dietary potassium restriction in PHA1 remains unclear with the absence of theoretical background to elucidate its utility. First, we demonstrated the effect of potassium restriction in a 13-month-old patient with ENaC ?-subunit gene mutations via a retrospective chart review; reduction of daily dietary potassium intake from 40 to 20 mEq induced rapid restoration of volume depletion, as evidenced by weight gain, elevation of the serum sodium level from 133 to 141 mEq/L, decreased urinary sodium excretion, and normalized renin activity. The serum potassium level decreased from 5.6 to 4.5 mEq/L. Next, we attempted to elucidate the pathophysiological basis of the usefulness of potassium restriction, leveraged by the increased knowledge regarding the roles of with-no-lysine kinases (WNKs) in the distal nephron. When potassium is restricted, the WNK signal will turn "on" in the distal nephron via reduction in the intracellular chloride level. Consequently, the sodium reabsorption from the Na+Cl- cotransporter (NCC) in the distal convoluted tubule and possibly from pendrin in the ?-intercalated cell will increase. Thus, potassium restriction causes NCC and pendrin to compensate for the non-functional ENaC in the collecting duct. In conclusion, dietary potassium restriction is one of the indispensable treatments for generalized PHA1.

SUBMITTER: Adachi M

PROVIDER: S-EPMC7148393 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Dietary potassium restriction attenuates urinary sodium wasting in the generalized form of pseudohypoaldosteronism type 1.

Adachi Masanori M Tajima Toshihiro T Muroya Koji K

CEN case reports 20200103 2

Owing to its rarity and severe nature, the treatment for generalized pseudohypoaldosteronism type 1 (PHA1), a genetic disorder in the epithelial sodium channel (ENaC), is exclusively experience-based. In particular, the usefulness of dietary potassium restriction in PHA1 remains unclear with the absence of theoretical background to elucidate its utility. First, we demonstrated the effect of potassium restriction in a 13-month-old patient with ENaC γ-subunit gene mutations via a retrospective cha ...[more]

PMID: 31900739

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Project description:Background and objectivesMetabolomics is a relatively new field of "-omics" research, focusing on high-throughput identification of small molecular weight metabolites. Diet has both acute and chronic effects on metabolic profiles; however, alterations in response to dietary sodium restriction (DSR) are completely unknown. The goal of this study was to explore changes in urine metabolites in response to DSR, as well as their association with previously reported improvements in vascular function with DSR.Design, setting, participants, & measurementsUsing stored urine samples from a 10-week randomized placebo-controlled crossover study of DSR in 17 middle-aged/older adults (six men and 11 women; mean age 62±8 years) who had moderately elevated systolic BP (130-159 mmHg) and were otherwise healthy, a liquid chromatography/mass spectrometry-based analysis of 289 metabolites was performed. This study identified metabolites that were significantly altered between the typical (153±29 mmol/d) and low (70±29 mmol/d) sodium conditions, as well as their baseline (typical sodium) association with responsiveness to previously reported improvements in vascular endothelial function (brachial artery flow-mediated dilation) and large elastic artery stiffness (aortic pulse wave velocity).ResultsOf the 289 metabolites surveyed, 10 were significantly altered (nine were upregulated and one was downregulated) during the low sodium condition, and eight of these exceeded our prespecified clinically significant threshold of a >40% change. These metabolites were involved in biologic pathways broadly related to cardiovascular risk, nitric oxide production, oxidative stress, osmotic regulation, and metabolism. One metabolite, serine, was independently (positively) associated with previously reported improvements in the primary vascular outcome of brachial artery flow-mediated dilation.ConclusionsThis proof-of-concept study provides the first evidence that DSR is a stimulus that induces significant changes in urinary metabolomic profiles. Moreover, serine was independently associated with corresponding changes in vascular endothelial function after DSR. Larger follow-up studies will be required to confirm and further elucidate the metabolic pathways that are altered in response to DSR.

Project description:Systolic BP and large elastic artery stiffness both increase with age and are reduced by dietary sodium restriction. Production of the natriuretic hormone marinobufagenin, an endogenous ?1 Na+,K+-ATPase inhibitor, is increased in salt-sensitive hypertension and contributes to the rise in systolic BP during sodium loading.The hypothesis was that dietary sodium restriction performed in middle-aged/older adults (eight men and three women; 60 ± 2 years) with moderately elevated systolic BP (139 ± 2/83 ± 2 mmHg) would reduce urinary marinobufagenin excretion as well as systolic BP and aortic pulse-wave velocity (randomized, placebo-controlled, and crossover design). This study also explored the associations among marinobufagenin excretion with systolic BP and aortic pulse-wave velocity across conditions of 5 weeks of a low-sodium (77 ± 9 mmol/d) and 5 weeks of a normal-sodium (144 ± 7 mmol/d) diet.Urinary marinobufagenin excretion (weekly measurements; 25.4 ± 1.8 versus 30.7 ± 2.1 pmol/kg per day), systolic BP (127 ± 3 versus 138 ± 5 mmHg), and aortic pulse-wave velocity (700 ± 40 versus 843 ± 36 cm/s) were lower during the low- versus normal-sodium condition (all P<0.05). Across all weeks, marinobufagenin excretion was related with systolic BP (slope=0.61, P<0.001) and sodium excretion (slope=0.46, P<0.001). These associations persisted during the normal- but not the low-sodium condition (both P<0.005). Marinobufagenin excretion also was associated with aortic pulse-wave velocity (slope=0.70, P=0.02) and endothelial cell expression of NAD(P)H oxidase-p47phox (slope=0.64, P=0.006).These results show, for the first time in humans, that dietary sodium restriction reduces urinary marinobufagenin excretion and that urinary marinobufagenin excretion is positively associated with systolic BP, aortic stiffness (aortic pulse-wave velocity), and endothelial cell expression of the oxidant enzyme NAD(P)H oxidase. Importantly, marinobufagenin excretion is positively related to systolic BP over ranges of sodium intake typical of an American diet, extending previous observations in rodents and humans fed experimentally high-sodium diets.

Project description:BackgroundThe relation between sodium intake and cardiovascular disease remains controversial, owing in part to inaccurate assessment of sodium intake. Assessing 24-hour urinary excretion over a period of multiple days is considered to be an accurate method.MethodsWe included individual-participant data from six prospective cohorts of generally healthy adults; sodium and potassium excretion was assessed with the use of at least two 24-hour urine samples per participant. The primary outcome was a cardiovascular event (coronary revascularization or fatal or nonfatal myocardial infarction or stroke). We analyzed each cohort using consistent methods and combined the results using a random-effects meta-analysis.ResultsAmong 10,709 participants, who had a mean (±SD) age of 51.5±12.6 years and of whom 54.2% were women, 571 cardiovascular events were ascertained during a median study follow-up of 8.8 years (incidence rate, 5.9 per 1000 person-years). The median 24-hour urinary sodium excretion was 3270 mg (10th to 90th percentile, 2099 to 4899). Higher sodium excretion, lower potassium excretion, and a higher sodium-to-potassium ratio were all associated with a higher cardiovascular risk in analyses that were controlled for confounding factors (P≤0.005 for all comparisons). In analyses that compared quartile 4 of the urinary biomarker (highest) with quartile 1 (lowest), the hazard ratios were 1.60 (95% confidence interval [CI], 1.19 to 2.14) for sodium excretion, 0.69 (95% CI, 0.51 to 0.91) for potassium excretion, and 1.62 (95% CI, 1.25 to 2.10) for the sodium-to-potassium ratio. Each daily increment of 1000 mg in sodium excretion was associated with an 18% increase in cardiovascular risk (hazard ratio, 1.18; 95% CI, 1.08 to 1.29), and each daily increment of 1000 mg in potassium excretion was associated with an 18% decrease in risk (hazard ratio, 0.82; 95% CI, 0.72 to 0.94).ConclusionsHigher sodium and lower potassium intakes, as measured in multiple 24-hour urine samples, were associated in a dose-response manner with a higher cardiovascular risk. These findings may support reducing sodium intake and increasing potassium intake from current levels. (Funded by the American Heart Association and the National Institutes of Health.).

Project description:ObjectivesThis study sought to evaluate the impact of sodium restriction on heart failure (HF) outcomes.BackgroundAlthough sodium restriction is advised for patients with HF, data on sodium restriction and HF outcomes are inconsistent.MethodsWe analyzed data from the multihospital HF Adherence and Retention Trial, which enrolled 902 New York Heart Association functional class II/III HF patients and followed them up for a median of 36 months. Sodium intake was serially assessed by a food frequency questionnaire. Based on the mean daily sodium intake prior to the first event of death or HF hospitalization, patients were classified into sodium restricted (<2,500 mg/d) and unrestricted (≥2,500 mg/d) groups. Study groups were propensity score matched according to plausible baseline confounders. The primary outcome was a composite of death or HF hospitalization. The secondary outcomes were cardiac death and HF hospitalization.ResultsSodium intake data were available for 833 subjects (145 sodium restricted, 688 sodium unrestricted), of whom 260 were propensity matched into sodium restricted (n = 130) and sodium unrestricted (n = 130) groups. Sodium restriction was associated with significantly higher risk of death or HF hospitalization (42.3% vs. 26.2%; hazard ratio [HR]: 1.85; 95% confidence interval [CI]: 1.21 to 2.84; p = 0.004), derived from an increase in the rate of HF hospitalization (32.3% vs. 20.0%; HR: 1.82; 95% CI: 1.11 to 2.96; p = 0.015) and a nonsignificant increase in the rate of cardiac death (HR: 1.62; 95% CI: 0.70 to 3.73; p = 0.257) and all-cause mortality (p = 0.074). Exploratory subgroup analyses suggested that sodium restriction was associated with increased risk of death or HF hospitalization in patients not receiving angiotensin-converting enzyme inhibitor or angiotensin receptor blocker (HR: 5.78; 95% CI: 1.93 to 17.27; p = 0.002).ConclusionsIn symptomatic patients with chronic HF, sodium restriction may have a detrimental impact on outcome. A randomized clinical trial is needed to definitively address the role of sodium restriction in HF management. (A Self-management Intervention for Mild to Moderate Heart Failure [HART]; NCT00018005).

Project description:ImportanceIn 2010, the Institute of Medicine (now the National Academy of Medicine) recommended collecting 24-hour urine to estimate US sodium intake because previous studies indicated 90% of sodium consumed was excreted in urine.ObjectiveTo estimate mean population sodium intake and describe urinary potassium excretion among US adults.Design, setting, and participantsIn a nationally representative cross-sectional survey of the US noninstitutionalized population, 827 of 1103 (75%) randomly selected, nonpregnant participants aged 20 to 69 years in the examination component of the National Health and Nutrition Examination Survey (NHANES) collected at least one 24-hour urine specimen in 2014. The overall survey response rate for the 24-hour urine collection was approximately 50% (75% [24-hour urine component response rate] × 66% [examination component response rate]).Exposures24-hour collection of urine.Main outcomes and measuresMean 24-hour urinary sodium and potassium excretion. Weighted national estimates of demographic and health characteristics and mean electrolyte excretion accounting for the complex survey design, selection probabilities, and nonresponse.ResultsThe study sample (n = 827) represented a population of whom 48.8% were men; 63.7% were non-Hispanic white, 15.8% Hispanic, 11.9% non-Hispanic black, and 5.6% non-Hispanic Asian; 43.5% had hypertension (according to 2017 hypertension guidelines); and 10.0% reported a diagnosis of diabetes. Overall mean 24-hour urinary sodium excretion was 3608 mg (95% CI, 3414-3803). The overall median was 3320 mg (interquartile range, 2308-4524). In secondary analyses by sex, mean sodium excretion was 4205 mg (95% CI, 3959-4452) in men (n = 421) and 3039 mg (95% CI, 2844-3234) in women (n = 406). By age group, mean sodium excretion was 3699 mg (95% CI, 3449-3949) in adults aged 20 to 44 years (n = 432) and 3507 mg (95% CI, 3266-3748) in adults aged 45 to 69 years (n = 395). Overall mean 24-hour urinary potassium excretion was 2155 mg (95% CI, 2030-2280); by sex, 2399 mg (95% CI, 2253-2545) in men and 1922 mg (95% CI, 1757-2086) in women; and by age, 1986 mg (95% CI, 1878-2094) in adults aged 20 to 44 years and 2343 mg (95% CI, 2151-2534) in adults aged 45 to 69 years.Conclusions and relevanceIn cross-sectional data from a 2014 sample of US adults, estimated mean sodium intake was 3608 mg per day. The findings provide a benchmark for future studies.

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Dietary potassium restriction attenuates urinary sodium wasting in the generalized form of pseudohypoaldosteronism type 1.

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Dietary potassium restriction attenuates urinary sodium wasting in the generalized form of pseudohypoaldosteronism type 1.

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