Dataset Information

A Randomized Trial of Distal Diuretics versus Dietary Sodium Restriction for Hypertension in Chronic Kidney Disease.

ABSTRACT:

Background

Distal diuretics are considered less effective than loop diuretics in CKD. However, data to support this perception are limited.

Methods

To investigate whether distal diuretics are noninferior to dietary sodium restriction in reducing BP in patients with CKD stage G3 or G4 and hypertension, we conducted a 6-week, randomized, open-label crossover trial comparing amiloride/hydrochlorothiazide (5 mg/50 mg daily) with dietary sodium restriction (60 mmol per day). Antihypertension medication was discontinued for a 2-week period before randomization. We analyzed effects on BP, kidney function, and fluid balance and related this to renal clearance of diuretics.

Results

A total of 26 patients (with a mean eGFR of 39 ml/min per 1.73 m²) completed both treatments. Dietary sodium restriction reduced sodium excretion from 160 to 64 mmol per day. Diuretics produced a greater reduction in 24-hour systolic BP (SBP; from 138 to 124 mm Hg) compared with sodium restriction (from 134 to 129 mm Hg), as well as a significantly greater effect on extracellular water, eGFR, plasma renin, and aldosterone. Both interventions resulted in a similar decrease in body weight and NT-proBNP. Neither approaches decreased albuminuria significantly, whereas diuretics did significantly reduce urinary angiotensinogen and ?2-microglobulin excretion. Although lower eGFR and higher plasma indoxyl sulfate correlated with lower diuretic clearance, the diuretic effects on body weight and BP at lower eGFR were maintained. During diuretic treatment, higher PGE2 excretion correlated with lower free water clearance, and four patients developed mild hyponatremia.

Conclusions

Distal diuretics are noninferior to dietary sodium restriction in reducing BP and extracellular volume in CKD. Diuretic sensitivity in CKD is maintained despite lower diuretic clearance.

Clinical trial registry name and registration number

DD-study: Diet or Diuretics for Salt-sensitivity in Chronic Kidney Disease (DD), NCT02875886.

SUBMITTER: Bovee DM

PROVIDER: S-EPMC7062227 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Publications

A Randomized Trial of Distal Diuretics versus Dietary Sodium Restriction for Hypertension in Chronic Kidney Disease.

Bovée Dominique M DM Visser Wesley J WJ Middel Igor I De Mik-van Egmond Anneke A Greupink Rick R Masereeuw Rosalinde R Russel Frans G M FGM Danser A H Jan AHJ Zietse Robert R Hoorn Ewout J EJ

Journal of the American Society of Nephrology : JASN 20200129 3

<h4>Background</h4>Distal diuretics are considered less effective than loop diuretics in CKD. However, data to support this perception are limited.<h4>Methods</h4>To investigate whether distal diuretics are noninferior to dietary sodium restriction in reducing BP in patients with CKD stage G3 or G4 and hypertension, we conducted a 6-week, randomized, open-label crossover trial comparing amiloride/hydrochlorothiazide (5 mg/50 mg daily) with dietary sodium restriction (60 mmol per day). Antihypert ...[more]

PMID: 31996411

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Project description:Background and objectivesPatients with chronic kidney disease (CKD) are often volume expanded and hypertensive. Few controlled studies have assessed the effects of a sodium-restricted diet (SRD) in CKD.Design, setting, participants, & measurementsWe conducted a randomized crossover trial to evaluate the effect of SRD (target <2 g sodium per day) versus usual diet on hydration status (by bioelectrical impedance spectroscopy) and blood pressure (BP) between May of 2009 and May of 2013. A total of 58 adults with stage 3-4 CKD were enrolled from two academic sites: University of Michigan (n=37) and University of North Carolina at Chapel Hill (n=21); 60% were men, 43% were diabetic, 93% were hypertensive, and mean age was 61 years. Participants followed SRD or usual diet for 4 weeks, followed by a 2-week washout period and a 4-week crossover phase. During the SRD, dieticians provided counseling every 2 weeks, using motivational interviewing techniques.ResultsWhole-body extracellular volume and calf intracellular volume decreased by 1.02 L (95% confidence interval [95% CI], -1.48 to -0.56; P<0.001) and -0.06 L (95% CI, -0.12 to -0.01; P=0.02), respectively, implying decreased fluid content on the SRD compared with usual diet. Significant reductions in urinary sodium (-57.3 mEq/24 h; 95% CI, -81.8 to -32.9), weight (-2.3 kg; 95% CI, -3.2 to -1.5), and 24-hour systolic BP (-10.8 mmHg; 95% CI, -17.0 to -4.6) were also observed (all P<0.01). Albumin-to-creatinine ratio did not change significantly and mean serum creatinine increased slightly (0.1 mg/dl; 95% CI, -0.01 to 0.2; P=0.06). No period or carryover effects were observed. Results were similar when analyzed from phase 1 only before crossover, although P values were modestly larger because of the loss of power.ConclusionsIn this randomized crossover trial, implementation of SRD in patients with CKD stage 3-4 resulted in clinically and statistically significant improvement in BP and hydration status. This simple dietary intervention merits a larger trial in CKD to evaluate effects on major clinical outcomes.

Project description:Sodium intake influences blood pressure and proteinuria, yet the impact on long-term outcomes is uncertain in chronic kidney disease (CKD). Accurate assessment is essential for clinical and public policy recommendations, but few large-scale studies use 24-h urine collections. Recent studies that used spot urine sodium and associated estimating equations suggest that they may provide a suitable alternative, but their accuracy in patients with CKD is unknown.We compared the accuracy of 4 equations [the Nerbass, INTERSALT (International Cooperative Study on Salt, Other Factors, and Blood Pressure), Tanaka, and Kawasaki equations] that use spot urine sodium to estimate 24-h sodium excretion in patients with moderate to advanced CKD.We evaluated the accuracy of spot urine sodium to predict mean 24-h urine sodium excretion over 9 mo in 129 participants with stage 3-4 CKD. Spot morning urine sodium was used in 4 estimating equations. Bias, precision, and accuracy were assessed and compared across each equation.The mean age of the participants was 67 y, 52% were female, and the mean estimated glomerular filtration rate was 31 ± 9 mL · min(-1) · 1.73 m(-2) The mean ± SD number of 24-h urine collections was 3.5 ± 0.8/participant, and the mean 24-h sodium excretion was 168.2 ± 67.5 mmol/d. Although the Tanaka equation demonstrated the least bias (mean: -8.2 mmol/d), all 4 equations had poor precision and accuracy. The INTERSALT equation demonstrated the highest accuracy but derived an estimate only within 30% of mean measured sodium excretion in only 57% of observations. Bland-Altman plots revealed systematic bias with the Nerbass, INTERSALT, and Tanaka equations, underestimating sodium excretion when intake was high.These findings do not support the use of spot urine specimens to estimate dietary sodium intake in patients with CKD and research studies enriched with patients with CKD. The parent data for this study come from a clinical trial that was registered at clinicaltrials.gov as NCT00785629.

Project description:BackgroundObesity and sedentary lifestyle are major health problems and key features to develop cardiovascular disease. Data on the effects of lifestyle interventions in diabetics with chronic kidney disease (CKD) have been conflicting.Study designSystematic review.PopulationDiabetes patients with CKD stage 3 to 5. SEARCH STRATEGY AND SOURCES: Medline, Embase and Central were searched to identify papers.InterventionEffect of a negative energy balance on hard outcomes in diabetics with CKD.OutcomesDeath, cardiovascular events, glycaemic control, kidney function, metabolic parameters and body composition.ResultsWe retained 11 studies. There are insufficient data to evaluate the effect on mortality to promote negative energy balance. None of the studies reported a difference in incidence of Major Adverse Cardiovascular Events. Reduction of energy intake does not alter creatinine clearance but significantly reduces proteinuria (mean difference from -0.66 to -1.77 g/24 h). Interventions with combined exercise and diet resulted in a slower decline of eGFR (-9.2 vs. -20.7 mL/min over two year observation; p<0.001). Aerobic and resistance exercise reduced HbA1c (-0.51 (-0.87 to -0.14); p = 0.007 and -0.38 (-0.72 to -0.22); p = 0.038, respectively). Exercise interventions improve the overall functional status and quality of life in this subgroup. Aerobic exercise reduces BMI (-0.74% (-1.29 to -0.18); p = 0.009) and body weight (-2.2 kg (-3.9 to -0.6); p = 0.008). Resistance exercise reduces trunk fat mass (-0,7±0,1 vs. +0,8 kg ±0,1 kg; p = 0,001-0,005). In none of the studies did the intervention cause an increase in adverse events.LimitationsAll studies used a different intervention type and mixed patient groups.ConclusionsThere is insufficient evidence to evaluate the effect of negative energy balance interventions on mortality in diabetic patients with advanced CKD. Overall, these interventions have beneficial effects on glycaemic control, BMI and body composition, functional status and quality of life, and no harmful effects were observed.

Project description:BackgroundPotassium regulation in the body is primarily done in the kidney. In addition to this, hyperkalemia, occurs in approximately 10% of individuals with chronic kidney disease (CKD) and is associated with elevated all-cause mortality. Individuals with CKD are often told to restrict dietary potassium (K), however, this recommendation is based on low quality evidence. Reduced quality of life, limited dietary choices and nutritional deficiencies are all potential negative outcomes that may occur when restricting dietary K in CKD patients. There is a need for randomized controlled trials investigating the impact of dietary K modification on serum K concentrations in people with CKD.MethodsA randomized 2-period crossover design comparing a liberalized K fruit and vegetable diet where participants will be required to consume ~ 3500 mg of dietary K daily, to a standard K restricted diet where participants will be required to consume < 2000 mg of dietary K daily. All participants will begin on a liberalized K run-in period for 2 weeks where they will receive fruit and vegetables home deliveries and for safety will have clinical chemistry, including serum potassium measurements taken after 1 week. Participants will then be randomized into either liberalized K or standard K diet for six weeks and then crossover to the other intervention for another 6 weeks after a 2-week washout period.Discussion30 male and female CKD outpatients, ≥ 18 years of age, who have an estimated glomerular filtration rate (eGFR) between 15 and 45 ml/min/1.73m2 and serum K between 4.5 and 5.5 mEq/L. This design would have greater than 80% power to detect a difference of 0.35 mEq/L serum K between groups. Anthropometric measurements, clinical chemistry, dietary recalls, physical function assessments, as well as a quality of life assessments will also be measured in this trial. These findings will provide high quality evidence for, or against, recommendations for dietary K restriction in individuals living with CKD. The removal of K restriction could provide individuals living with CKD more dietary choice leading to improved dietary status and quality of life.Trial registrationThis trial has received approval from the University of Manitoba Research Ethics board (HS25191 (B2021:104)).

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:Background: High sodium intake is known to increase blood pressure and is difficult to measure in epidemiologic studies.Objective: We examined the effect of sodium intake on metabolites within the DASH (Dietary Approaches to Stop Hypertension Trial)-Sodium Trial to further our understanding of the biological effects of sodium intake beyond blood pressure.Design: The DASH-Sodium Trial randomly assigned individuals to either the DASH diet (low in fat and high in protein, low-fat dairy, and fruits and vegetables) or a control diet for 12 wk. Participants within each diet arm received, in random order, diets containing high (150 nmol or 3450 mg), medium (100 nmol or 2300 mg), and low (50 nmol or 1150 mg) amounts of sodium for 30 d (crossover design). Fasting blood samples were collected at the end of each sodium intervention. We measured 531 identified plasma metabolites in 73 participants at the end of their high- and low-sodium interventions and in 46 participants at the end of their high- and medium-sodium interventions (N = 119). We used linear mixed-effects regression to model the relation between each log-transformed metabolite and sodium intake. We also combined the resulting P values with Fisher's method to estimate the association between sodium intake and 38 metabolic pathways or groups.Results: Six pathways were associated with sodium intake at a Bonferroni-corrected threshold of 0.0013 (e.g., fatty acid, food component or plant, benzoate, ?-glutamyl amino acid, methionine, and tryptophan). Although 82 metabolites were associated with sodium intake at a false discovery rate ?0.10, only 4-ethylphenylsufate, a xenobiotic related to benzoate metabolism, was significant at a Bonferroni-corrected threshold (P < 10-5). Adjustment for coinciding change in blood pressure did not substantively alter the association for the top-ranked metabolites.Conclusion: Sodium intake is associated with changes in circulating metabolites, including gut microbial, tryptophan, plant component, and ?-glutamyl amino acid-related metabolites. This trial was registered at clinicaltrials.gov as NCT00000608.

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.

Dataset Information

A Randomized Trial of Distal Diuretics versus Dietary Sodium Restriction for Hypertension in Chronic Kidney Disease.

Background

Methods

Results

Conclusions

Clinical trial registry name and registration number

Publications

A Randomized Trial of Distal Diuretics versus Dietary Sodium Restriction for Hypertension in Chronic Kidney Disease.

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