Diminished antiproteinuric effect of the angiotensin receptor blocker losartan during high potassium intake in patients with CKD

Background: Angiotensin II type 1 receptor blockers (ARBs) lower blood pressure (BP) and proteinuria and reduce renal disease progression in many-but not all-patients. Reduction of dietary sodium intake improves these effects of ARBs. Dietary potassium intake affects BP and proteinuria. We set out to address the effect of potassium intake on BP and proteinuria response to losartan in non-diabetic proteinuric chronic kidney disease (CKD) patients. Methods: We performed a post hoc analysis of a placebo-controlled interventional cross-over study in 33 non-diabetic proteinuric patients (baseline mean arterial pressure and proteinuria: 105 mmHg and 3.8 g/day, respectively). Patients were treated for 6 weeks with placebo, losartan and losartan/hydrochlorothiazide (HCT), combined with a habitual (∼200 mmol/day) and low-sodium (LS) diet (<100 mmol/day), in randomized order. To analyse the effects of potassium intake, we categorized patients based on median split of 24-h urinary potassium excretion, reflecting potassium intake. Results: Mean potassium intake was stable during all six treatment periods. Losartan and losartan/HCT lowered BP and proteinuria in all treatment groups. Patients with high potassium intake showed no difference in the BP effects compared with patients with low potassium intake. The antiproteinuric response to losartan monotherapy and losartan combined with HCT during the habitual sodium diet was significantly diminished in patients with high potassium intake (20% versus 41%, P = 0.011; and 48% versus 64%, P = 0.036). These differences in antiproteinuric response abolished when shifting to the LS diet. Conclusions: In proteinuric CKD patients, the proteinuria, but not BP-lowering response to losartan during a habitual high-sodium diet was hampered during high potassium intake. Differences disappeared after sodium status change by LS diet

Effects of Water Loading on Observed and Predicted Plasma Sodium, and Fluid and Urine Cation Excretion in Healthy Individuals

Rationale & Objective: The discovery of sodium storage without concurrent water retention suggests the presence of an additional compartment for sodium distribution in the body. The osmoregulatory role of this compartment under hypotonic conditions is not known. Study Design: Experimental interventional study. Setting & Participants: Single-center study of 12 apparently healthy men. Intervention: To investigate whether sodium can be released from its nonosmotic stores after a hypotonic fluid load, a water-loading test (20 mL water/kg in 20 minutes) was performed. Outcomes: During a 240-minute follow-up, we compared the observed plasma sodium concentration ([Na + ]) and fluid and urine cation excretion with values predicted by the Barsoum-Levine and Nguyen-Kurtz formulas. These formulas are used for guidance of fluid therapy during dysnatremia, but do not account for nonosmotic sodium stores. Results: 30 minutes after water loading, mean plasma [Na + ] decreased 3.2 ± 1.6 (SD) mmol/L, after which plasma [Na + ] increased gradually. 120 minutes after water loading, plasma [Na + ] was significantly underestimated by the Barsoum-Levine (−1.3 ± 1.4 mmol/L; P = 0.05) and Nguyen-Kurtz (−1.5 ± 1.5 mmol/L; P = 0.03) formulas. In addition, the Barsoum-Levine and Nguyen-Kurtz formulas overestimated urine volume, while cation excretion was significantly underestimated, with a cation gap of 57 ± 62 (P = 0.009) and 63 ± 63 mmol (P = 0.005), respectively. After 240 minutes, this gap was 28 ± 59 (P = 0.2) and 34 ± 60 mmol (P = 0.08), respectively. Limitations: The compartment from which the mobilized sodium originated was not identified, and heterogeneity in responses to water loading was observed across participants. Conclusions: These data suggest that healthy individuals are able to mobilize osmotically inactivated sodium after an acute hypotonic fluid load. Further research is needed to expand knowledge about the compartment of osmotically inactivated sodium and its role in osmoregulation and therapy for dysnatremias. Funding: This investigator-initiated study was partly supported by a grant from Unilever Research and Development Vlaardingen, The Netherlands B.V. (MA-2014-01914)

Sex-specific associations between potassium intake, blood pressure, and cardiovascular outcomes: the EPIC-Norfolk study.

Funder: Dutch Kidney FoundationAIMS: A potassium replete diet is associated with lower blood pressure (BP) and lower risk of cardiovascular disease (CVD). Whether these associations differ between men and women and whether they depend on daily sodium intake is unknown. METHODS AND RESULTS: An analysis was performed in 11 267 men and 13 696 women from the EPIC-Norfolk cohort. Twenty-four hour excretion of sodium and potassium, reflecting intake, was estimated from sodium and potassium concentration in spot urine samples using the Kawasaki formula. Linear and Cox regression were used to explore the association between potassium intake, systolic BP (SBP), and CVD events (defined as hospitalization or death due to CVD). After adjustment for confounders, interaction by sex was found for the association between potassium intake and SBP (P < 0.001). In women, but not in men, the inverse slope between potassium intake and SBP was steeper in those within the highest tertile of sodium intake compared with those within the lowest tertile of sodium intake (P < 0.001 for interaction by sodium intake). Both in men and women, higher potassium intake was associated with a lower risk of CVD events, but the hazard ratio (HR) associated with higher potassium intake was lower in women than in men [highest vs. lowest potassium intake tertile: men: HR 0.93, 95% confidence interval (CI) 0.87-1.00; women: HR 0.89, 95% CI 0.83-0.95, P = 0.033 for interaction by sex]. CONCLUSION: The association between potassium intake, SBP, and CVD events is sex specific. The data suggest that women with a high sodium intake in particular benefit most from a higher potassium intake with regard to SBP

High-salt intake affects sublingual microcirculation and is linked to body weight change in healthy volunteers: a randomized cross-over trial

BACKGROUND: The pathophysiology of salt-sensitive hypertension remains uncertain, but may involve microvascular alterations. High-salt intake decreases microvascular density in hypertensive patients, but due to lack of studies in normotensive patients the causal pathway remains unclear. We studied whether high-salt intake decreases sublingual microvascular density in normotensive individuals and assessed the influence of body weight on changes in microvascular density. METHODS: In an open label randomized cross-over trial 18 healthy men were included to study the effect of a 2-week high-salt (>12 g/day) and low-salt (<3 g/day) diet on microvascular (diameter <20 μm) density with sublingual sidestream darkfield imaging. We used sublingual nitroglycerin (NTG) to recruit microvessels. RESULTS: There was no significant difference in microvascular density between diets (0.96 ± 3.88 mm/mm; P = 0.31, following NTG; and -0.03 ± 1.64 mm/mm; P = 0.95, without NTG). Increased salt intake was correlated with a decrease in microvascular density following NTG (r = -0.47; P = 0.047), but not without NTG (r = 0.06; P = 0.800). The decrease in microvascular density following high-salt intake was significantly larger for those with a large change in body weight as compared with those with a small changer in body weight (-0.79 ± 1.35 and 0.84 ± 1.56 mm/mm respectively, P = 0.031). CONCLUSION: We demonstrate in healthy volunteers that higher salt intake is correlated with decreased sublingual microvascular density following administration of NTG and; larger changes in body weight following high-salt intake coincide with a larger decrease in microvascular density. Changes in microvascular density occurred without blood pressure effects, indicating that high-salt load as such contributes to microvascular changes, and may precede hypertension development

Rationale and Design of a Randomized Placebo-Controlled Clinical Trial Assessing the Renoprotective Effects of Potassium Supplementation in Chronic Kidney Disease

Background/Aims: Dietary potassium (K+) has beneficial effects on blood pressure and cardiovascular (CV) outcomes. Recently, several epidemiological studies have revealed an association between urinary K+ excretion (as proxy for dietary intake) and better renal outcomes in subjects with chronic kidney disease (CKD). To address causality, we designed the "K+ in CKD" study. Methods: The K+ in CKD study is a multicenter, randomized, double blind, placebo-controlled clinical trial aiming to include 399 patients with hypertension, CKD stage 3b or 4 (estimated glomerular filtration rate [eGFR] 15-44 mL/min/1.73 m2), and an average eGFR decline > 2 mL/min/1.73 m2/year. As safety measure, all included subjects will start with a 2-week open-label phase of 40 mmol potassium chloride daily. Patients who do not subsequently develop hyperkalemia (defined as serum K+ >5.5 mmol/L) will be randomized to receive potassium chloride, potassium citrate (both K+ 40 mmol/day), or placebo for 2 years. The primary end point is the difference in eGFR after 2 years of treatment. Secondary end points include other renal outcomes (> 30% decrease in eGFR, doubling of serum creatinine, end-stage renal disease, albuminuria), ambulatory blood pressure, CV events, all-cause mortality, and incidence of hyperkalemia. Several measurements will be performed to analyze the effects of potassium supplementation, including body composition monitoring, pulse wave velocity, plasma renin and aldosterone concentrations, urinary ammonium, and intracellular K+ concentrations. Conclusion: The K+ in CKD study will demonstrate if K+ sup-plementation has a renoprotective effect in progressive CKD, and whether alkali therapy has additional beneficial effects