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Summary Background & aims High potassium intake has been suggested to lower the risk for renal and cardiovascular outcome, but data are conflicting. This may be explained by the use of different methods for potassium intake assessment across studies. Also, most data are limited to the general population. We investigated the optimal potassium intake, as measured with multiple 24-h urine samples, in patients with a clinical indication for 24-h urine collection, for prevention of cardiorenal disease. Methods We performed a retrospective cohort study in 541 outpatient subjects with an estimated glomerular filtration rate >60 mL/min/1.73 m2 who had sampled a 24-h urine collection between 1998 and 1999, and had at least 1 additional collection during a 17-year follow-up. We assessed incidence of renal (i.e. renal replacement therapy, 60% decline in estimated glomerular filtration rate or death) and cardiovascular disease (i.e. cardiovascular event or death). Results Average age of subjects was 47 years. Estimated mean potassium intake was 74 mmol/day and remained similar during follow-up. The highest tertile of estimated potassium intake was associated with a significant 76% reduction in renal outcome, and 73% decrease of cerebrovascular events, while no effect for overall cardiovascular outcome was found. A 20-mmol increase in potassium intake during follow-up was associated with a 24% reduction in renal outcome. Conclusions Our data demonstrate that high estimated potassium intake is associated with improved renal outcome and less cerebrovascular events in outpatient subjects with preserved kidney function.

Type 1 diabetes patients are more prone to have hypertension than healthy individuals, possibly mediated by increased blood pressure (BP) sensitivity to high salt intake. The classical concept proposes that the kidney is central in salt-mediated BP rises, by insufficient renal sodium excretion leading to extracellular fluid volume expansion. Recent animal-derived findings, however, propose a causal role for disturbance of macrophage-mediated lymphangiogenesis. Its relevance for humans, specifically type 1 diabetes patients, is unknown. The present study aimed to assess responses of type 1 diabetes patients to a dietary salt load with regard to BP, extracellular fluid volume (using precise iohexol measurements), and CD163+ macrophage and lymphatic capillary density in skin biopsies. Also, macrophage expression of HLA-DR (a proinflammatory marker) and CD206 (an anti-inflammatory marker) was assessed. Type 1 diabetes patients (n = 8) showed a salt-sensitive BP increase without extracellular fluid volume expansion. Whereas healthy controls (n = 12), who had no BP increase, showed increased skin CD163+ and HLA-DR+ macrophages and dilation of lymphatic skin vasculature after the dietary salt load, these changes were absent (and in case of HLA-DR more heterogenic) in type 1 diabetes patients. In conclusion, we show that salt sensitivity in type 1 diabetes patients cannot be explained by the classical concept of extracellular fluid volume expansion. Rather, we open up a potential role for macrophages and the lymphatic system. Future studies on hypertension and diabetes need to scrutinize these phenomena.

Background and Aims In daily clinical practice, individual-level sodium (Na) intake is often estimated by measuring Na excretion in a single 24h urine collection, but long-term Na balance studies indicate that 7 consecutive 24h urine collections are needed. However, this approach is not feasible in clinical settings. In this study, we investigate whether the use of repeated spot urine sampling is an appropriate alternative for repeated 24h urine collections. Method We performed a post-hoc analysis of a metabolic ward study in 8 healthy male adults who consumed a 7-day diet with a fixed amount of Na (200 mmol/d). Urine was collected in four daily intervals: 7-13h, 13-19h, 19-23h and 23-7h. After reaching steady state, we estimated Na intake with 1 and 3 consecutive 24h urine collections and 3-day spot urine sampling, using the Kawasaki formula with measured 24h urine creatinine excretion. Results: On day 5, mean 24h Na excretion matched intake, indicating that steady state was achieved (Fig A). Mean and standard deviation of absolute differences between estimated and measured Na intake (ΔNa) for each method were: 18.8 ±14.6 mmol (3 x spot urine 7-13h), 32.3 ±18.7 mmol (3 x spot urine 13-19h), 74.6 ±30.0 mmol (3 x spot urine 19-23h), 28.2 ±19.8 mmol (3 x spot urine 23-7h), 29.8 ±23.9 mmol (1 x 24h urine) and 22.9 ±11.3 mmol (3 x 24h urine) (Fig B). With the exception of the 19-23h spot urine collection period, the accuracy of 3-day spot urine sampling did not significantly differ from accuracy of 1 and 3 consecutive 24h urine collections. When combining the pre-night and morning spot urine collections (19-7h), the accuracy of the estimation did not improve (ΔNa 28.7 ±19.6 mmol). Conclusion 3-day spot urine sampling did not perform significantly different than 1 and 3 24h urine collections for estimation of individual-level Na intake. Adequately powered studies need to confirm whether repeated spot urine sampling is an accurate and low burden alternative to repeated 24h urine collections.

Background and Aims Treatment of dysnatremias is guided by formulas that are based on the Edelman equation, including Adrogue-Madias’ and others. Edelman’s equation is the result of a unique study in which serum sodium concentration ([Na+]), total body exchangeable sodium (Nae+) and potassium (Ke+) and total body water (TBW) were measured in a highly heterogeneous population. Because these observations resulted from steady state observations, the equation might not account for the recently uncovered highly dynamic Na+ body compartment where Na+ is temporarily stored and released without affecting TBW. Various factors that influence this Na+ body compartment have been identified and we questioned as to what extent these factors affect associations between serum [Na+] and [Nae+Ke]/TBW. Method We performed a post-hoc analysis of original data published by Edelman. In the linear regression model, effects of sex, edema (y/n), age and body weight (>/< median split) were examined. Serum [Na+] was calculated by multiplying serum water [Na+] of the original data set by 0.93. Using piecewise regression, we analyzed differences in slope and y-intercept for the regression between serum [Na+] and increasing values of (Nae+Ke)/TBW, in which the clinical characteristics from the subgroups were included as interaction factors . Results Data was available for 85 measurements in 82 patients; 57 males and 25 females. The median age (range) age was 58 (27-90) years and median weight (range) was 59.6 (36.4 – 168.2) kilograms. Median serum [Na+] (range) was 131.4 (103.4 – 150.2) mmol/L. The association between serum [Na+] and (Nae+Ke)/TBW was different for high and low weight categories (figure 1A). Sex, age or presence of edema did not alter the relationship. Piecewise regression showed a significant decrease in slope in the regression between serum [Na+] and (Nae+Ke)/TBW above 149 mmol/L (Nae+Ke)/TBW (figure 1B). Conclusion Edelman equation’s coefficients are significantly affected by weight and total body cation content. In subjects with a low weight and low total body cation content, the Edelman equation seems to adequately predict the course of serum [Na+]. However, the clinical use of the Edelman-based formulas may be hampered in subjects with higher weight and higher total body cation content, which may reflect increased tissue Na+ storage. Our analysis underlines the importance of further research into the role of osmotically inactive Na+ storage in osmoregulation.

Background High potassium intake has been associated with lower blood pressure and a lower incidence of chronic kidney disease and cardiovascular events. In cohort studies, potassium intake is often estimated with a single 24-h urine collection. However, this may not represent actual long-term individual intake. We assessed whether a single baseline versus multiple follow-up measurements of 24-h urine potassium excretion results in different estimates of individual potassium intake and different associations between potassium intake and long-term outcome. Methods We performed a retrospective cohort study in outpatient subjects with an estimated glomerular filtration rate >60 mL/min/1.73 m2 who had sampled a 24-h urine collection at baseline and had ≥1 collection during a 17-year follow-up. Potassium intake was estimated with a single baseline 24-h urine collection but also during 1-year, 5-year, and 15-year follow-up. We used cox regression analysis to assess the association between cardiorenal outcome and estimated potassium intake. Results Average population (n = 541) 24-h potassium excretion was similar at baseline and follow-up but significant individual changes in potassium intake between baseline and follow-up were observed. Forty-four percent of the subjects switched between tertiles of estimated potassium intake when follow-up measurements were used instead of baseline measurements. Hazard ratios for renal and cardiovascular outcomes were 6.9 and 1.7 times higher when follow-up estimates of potassium intake were replaced by baseline estimates. Conclusions Estimated potassium intake and its association with long-term outcome change significantly when multiple follow-ups 24-h urine collections are used for estimation of potassium intake instead of a single baseline measurement.

Globally, average dietary sodium intake is double the recommended amount, whereas potassium is often consumed in suboptimal amounts. High sodium diets are associated with increased cardiovascular and renal disease risk, while potassium may have protective properties. Consequently, patients at risk of cardiovascular and renal disease are urged to follow these recommendations, but dietary adherence is often low due to high sodium and low potassium content in processed foods. Adequate monitoring of intake is essential to guide dietary advice in clinical practice and can be used to investigate the relationship between intake and health outcomes. Daily sodium and potassium intake is often estimated with 24-h sodium and potassium excretion, but long-term balance studies demonstrate that this method lacks accuracy on an individual level. Dietary assessment tools and spot urine collections also exhibit poor performance when estimating individual sodium and potassium intake. Collection of multiple consecutive 24-h urines increases accuracy, but also patient burden. In this narrative review, we discuss current approaches to estimating dietary sodium and potassium intake. Additionally, we explore alternative methods that may improve test accuracy without increasing burden.

IntroductionPatients with type 1 diabetes are susceptible to hypertension, possibly resulting from increased salt sensitivity and accompanied changes in body fluid composition. We examined the effect of a high-salt diet (HSD) in type 1 diabetes on hemodynamics, including blood pressure (BP) and body fluid composition.Research design and methodsWe studied eight male patients with type 1 diabetes and 12 matched healthy controls with normal BP, body mass index, and renal function. All subjects adhered to a low-salt diet and HSD for eight days in randomized order. On day 8 of each diet, extracellular fluid volume (ECFV) and plasma volume were calculated with the use of iohexol and125I-albumin distribution. Hemodynamic measurements included BP, cardiac output (CO), and systemic vascular resistance.ResultsAfter HSD, patients with type 1 diabetes showed a BP increase (mean arterial pressure: 85 (5) mm Hg vs 80 (3) mm Hg; pConclusionsIn the present study, patients with type 1 diabetes show a salt-sensitive BP rise to HSD, which is accompanied by significant increases in plasma volume, CO, HR, and NT-proBNP. Underlying mechanisms for these responses need further research in order to unravel the increased susceptibility to hypertension and cardiovascular disease in diabetes.Trial registration numbersNTR4095 and NTR4788.

Extensive research has focused on the association between high-sodium intake and hypertension. New ideas about sodium homeostasis decisively influence the existing ideas about this association. Classically, according to the 2-compartment model, sodium particularly accumulates in the extracellular space, where it equally divides between the intravascular and the interstitial compartment. This is followed by commensurate water retention to maintain normal osmolality. The consequent increase in extracellular volume was considered to be the main causative factor for hypertension. However, consecutive studies revealed that increases in sodium load were neither accompanied by the expected increases in total body water or body weight nor could be accounted for by the excreted amounts of sodium in the urine.1–3 In other words, sodium was missing. Accordingly, the existence of nonosmotic sodium buffers was suggested.3 In this review, we will speculate on the implications of this missing sodium with regard to blood pressure regulation by discussing the journey that sodium undertakes from the circulation and state that sodium handling by the blood vessel wall seems crucial in the development and prevention of hypertension. Two meticulously performed balance studies in 2000 and 2002 were the first to point out that something was amiss in the common view about sodium homeostasis. In 2000, Heer et al2 revealed that, in contrast to the common thought, an increase in body sodium induced by high-sodium diet was not paralleled by an increase in total body water. Subsequently, Titze et al3 executed a long-term study of 135 days in healthy volunteers who were confined to spaceflight stimulating conditions. Sodium and other electrolyte intake were carefully monitored. Toward the end of the study, sodium gain exceeded weight gain, which introduced the possibility of a nonosmotic sodium storage compartment. A few years later, this hypothesis was confirmed, as rats …

Background Sodium-induced microcirculatory changes, endothelial surface layer alterations in particular, may play an important role in sodium-mediated blood pressure elevation. However, effects of acute and chronic sodium loading on the endothelial surface layer and microcirculation in humans have not been established. The objective of this study was to assess sodium-induced changes in blood pressure and body weight as primary outcomes and also in microvascular permeability, sublingual microcirculatory dimensions, and urinary glycosaminoglycan excretion in healthy subjects. Methods Twelve normotensive males followed both a low-sodium diet (less than 50 mmol/day) and a high-sodium diet (more than 200 mmol/day) for eight days in randomized order, separated by a crossover period. After the low-sodium diet, hypertonic saline (5 mmol sodium/liter body water) was administered intravenously in 30 min. Results Both sodium interventions did not change blood pressure. Body weight increased with 2.5 (95% CI, 1.7 to 3.2) kg (P < 0.001) after dietary sodium loading. Acute intravenous sodium loading resulted in increased transcapillary escape rate of 125I-labeled albumin (2.7 [0.1 to 5.3] % cpm · g−1 · h–1; P = 0.04), whereas chronic dietary sodium loading did not affect transcapillary escape rate of 125I-labeled albumin (−0.03 [−3.3 to 3.2] % cpm · g−1 · h–1; P = 1.00), despite similar increases of plasma sodium and osmolality. Acute intravenous sodium loading coincided with significantly increased plasma volume, as assessed by the distribution volume of albumin, and significantly decreased urinary excretion of heparan sulfate and chondroitin sulfate. These changes were not observed after dietary sodium loading. Conclusions Our results suggest that intravenous sodium loading has direct adverse effects on the endothelial surface layer, independent of blood pressure.

Summary: Background: Hereditary Multiple Exostoses (HME) is a rare autosomal disorder characterized by the presence of multiple exostoses (osteochondromas) caused by a heterozygous loss of function mutation in EXT1 or EXT2; genes involved in heparan sulfate (HS) chain elongation. Considering that HS and other glycosaminoglycans play an important role in sodium and water homeostasis, we hypothesized that HME patients have perturbed whole body volume regulation and osmolality in response to high sodium conditions. Methods: We performed a randomized cross-over study in 7 male HME patients and 12 healthy controls, matched for age, BMI, blood pressure and renal function. All subjects followed both an 8-day low sodium diet (LSD, 200 mmol/d) in randomized order. After each diet, blood and urine samples were collected. Body fluid compartment measurements were performed by using the distribution curve of iohexol and 125I-albumin. Results: In HME patients, HSD resulted in significant increase of intracellular fluid volume (ICFV) (1.2 L, p = 0.01). In this group, solute-mediated water clearance was significantly lower after HSD, and no changes in interstitial fluid volume (IFV), plasma sodium, and effective osmolality were observed. In healthy controls, HSD did not influence ICFV, but expanded IFV (1.8 L, p = 0.058) and increased plasma sodium and effective osmolality. Conclusion: HME patients show altered body fluid distribution and osmoregulation after HSD compared to controls. Our results might indicate reduced interstitial sodium accumulation capacity in HME, leading to ICFV increase. Therefore, this study provides additional support that HS is crucial for maintaining constancy of the internal environment.

Background: A decrease in sodium intake has been shown to lower blood pressure, but data from cohort studies on the association with cardiovascular and renal outcomes are inconsistent. In these studies, sodium intake was often estimated with a single baseline measurement, which may be inaccurate considering day-to-day changes in sodium intake and sodium excretion. We compared the effects of single versus repetitive follow-up 24-hour urine samples on the relation between sodium intake and long-term cardiorenal outcomes. Methods: We selected adult subjects with an estimated glomerular filtration rate >60 mL/min/1.73m 2 , an outpatient 24-hour urine sample between 1998 and 1999, and at least 1 collection during a 17-year follow-up. Sodium intake was estimated with a single baseline collection and the average of samples collected during a 1-, 5-, and 15-year follow-up. We used Cox regression analysis and the landmark approach to investigate the relation between sodium intake and cardiovascular (cardiovascular events or mortality) and renal (end-stage renal disease: dialysis, transplantation, and/or >60% estimated glomerular filtration rate decline, or mortality) outcomes. Results: We included 574 subjects with 9776 twenty-four–hour urine samples. Average age was 47 years, and 46% were male. Median follow-up was 16.2 years. Average 24-hour sodium excretion, ranging from 3.8 to 3.9 g (165–170 mmol), was equal among all methods ( P =0.88). However, relative to a single baseline measurement, 50% of the subjects had a >0.8-g (>34-mmol) difference in sodium intake with long-term estimations. As a result, 45%, 49%, and 50% of all subjects switched between tertiles of sodium intake when the 1-, 5-, or 15-year average was used, respectively. Consequently, hazard ratios for cardiorenal outcome changed up to 85% with the use of sodium intake estimations from short-term (1-year) and long-term (5-year) follow-up instead of baseline estimations. Conclusions: Relative to a single baseline 24-hour sodium measurement, the use of subsequent 24-hour urine samples resulted in different estimations of an individual’s sodium intake, whereas population averages remained similar. This finding had significant consequences for the association between sodium intake and long-term cardiovascular and renal outcomes.

Various studies suggest that evening dosing of antihypertensive drugs may be more effective. In line, a randomized open-label trial in 19,084 hypertensive patients recently demonstrated that evening dosing of at least one antihypertensive drug resulted in a 3.3 mmHg lower systolic night-time blood pressure and 1.3 mmHg lower systolic 48-hour blood pressure when compared to morning dosing. Cardiovascular outcomes were reduced by 45% in the evening dosing group, which is remarkable as previous meta-analyses have shown that a systolic blood pressure reduction of 3 mmHg is associated with a 7% reduction in cardiovascular outcome. Although this discrepancy may be partly explained by specific beneficial effects related to evening dosing, it is likely that the open-label trial design may have affected the study outcome in different ways. Also, the safety of evening dosing in elderly hypertensive patients and the consequences for therapy compliance in the clinical setting remain to be established.

Lowering blood pressure (BP) can lead to an initial decline in estimated glomerular filtration rate (eGFR). However, there is debate how much eGFR decline is acceptable. We performed a post hoc analysis of ACCORD-BP (Action to Control Cardiovascular Risk in Diabetes-Blood Pressure) and SPRINT (Systolic Blood Pressure Intervention Trial), which randomized patients to intensive or standard systolic BP-targets. We determined the relation between initial decline in mean arterial pressure and eGFR. Subsequently, we stratified patients to BP-target and initial eGFR decrease and assessed the relation with annual eGFR decline after 1 year. A total of 13 266 patients with 41 126 eGFR measurements were analyzed. Up to 10 mm Hg of BP-lowering, eGFR did not change. Hereafter, there was a linear decrease of 3.4% eGFR (95% CI, 2.9%–3.9%) per 10 mm Hg mean arterial pressure decrease. The observed eGFR decline based on 95% of the subjects varied from 26% after 0 mm Hg to 46% with a 40 mm Hg mean arterial pressure decrease. There was no difference in eGFR slope ( P =0.37) according to initial eGFR decline and BP-target, with a decrease of 1.24 (95% CI, 1.09–1.39), 1.20 (95% CI, 0.97–1.43), and 1.14 (95% CI, 0.77–1.50) in the 5%, 5% to 20%, and >20% stratum during intensive and 0.95 (95% CI, 0.81–1.09), 1.23 (95% CI, 0.97–1.49), and 1.17 (95% CI, 0.65–1.69) mL/minute per 1.73 m 2 per year during standard treatment. In patients at high cardiovascular risk with and without diabetes mellitus, we found no association between initial eGFR and annual eGFR decline during BP-lowering treatment. Our results support that an eGFR decrease up to 20% after BP lowering can be accepted and suggest that the limit can be extended up to 46% depending on the achieved BP reduction. Registration— URL: https://www.clinicaltrials.gov ; Unique identifier: NCT00000620, NCT01206062.

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).

In recent times, the traditional nephrocentric, two-compartment model of body sodium has been challenged by long-term sodium balance studies and experimental work on the dermal interstitium and endothelial surface layer. In the new paradigm, sodium can be stored without commensurate water retention in the interstitium and endothelial surface layer, forming a dynamic third compartment for sodium. This has important implications for sodium homeostasis, osmoregulation and the hemodynamic response to salt intake. Sodium storage in the skin and endothelial surface layer may function as a buffer during periods of dietary depletion and excess, representing an extra-renal mechanism regulating body sodium and water. Interstitial sodium storage may also serve as a biomarker for sodium sensitivity and cardiovascular risk, as well as a target for hypertension treatment. Furthermore, sodium storage may explain the limitations of traditional techniques used to quantify sodium intake and determine infusion strategies for dysnatraemias. This review is aimed at outlining these new insights into sodium homeostasis, exploring their implications for clinical practice and potential areas for further research for paediatric and adult populations.

Hydrochlorothiazide and skin cancer Hydrochlorothiazide is a frequently prescribed diuretic with known photosensitizing properties. Recently, a large case-control study in a Danish population found an association between the use of hydrochlorothiazide and an increased risk of developing non-melanoma skin cancer. These data suggest that it may be wise to limit the use of hydrochlorothiazide for the treatment of hypertension. We reviewed the current literature to examine whether a causal relationship between hydrochlorothiazide and non-melanoma skin cancer exists. We consider that the evidence for a causal relationship is limited and contradicting. Moreover, we found that other antihypertensive agents such as calcium blockers and angiotensin receptor blockers are also associated with basal cell carcinoma. Based on the current literature, there seems to be insufficient evidence to advice against the use of hydrochlorothiazide.

AIMS: It has been suggested that sulodexide is able to lower blood pressure (BP). This may be attributed to its ability to restore the endothelial surface layer (ESL). As ESL perturbation is known to be related to the degree of kidney damage, we investigated whether albuminuria, reflecting ESL status, modified the BP-lowering potential of sulodexide.METHODS: A post hoc analysis of the double-blind, randomized, placebo-controlled sulodexide microalbuminuria (Sun-MICRO) and macroalbuminuria (Sun-MACRO) studies, including 1056 microalbuminuric and 843 macroalbuminuric subjects with type 2 diabetes receiving maximal tolerated renin-angiotensin-aldosterone system inhibitor therapy, was carried out. We compared the effect of placebo and sulodexide on systolic BP (SBP) among albuminuria groups.RESULTS: Analysis of covariance, including data from both trials, showed that baseline urine albumin-to-creatinine ratio (UACR) was the only modifier of the SBP response (interaction with treatment P = 0.001). In subjects with an UACR >1000 mg g-1 , sulodexide lowered SBP by 4.6 mmHg [95% confidence interval (CI) 3.6, 5.6; P < 0.001] compared with placebo, whereas a 2.3 mmHg (95% CI 0.9,3.7; P = 0.001) reduction was seen in subjects with a UACR of 300-1000 mg g-1 . Sulodexide did not lower SBP in subjects with a UACR CONCLUSION: The BP-reducing potency of sulodexide is modified by the degree of albuminuria in subjects with type 2 diabetes. As ESL status deteriorates with increasing albuminuria and nephropathy severity, this suggests that ESL restoration may represent a new target for BP treatment in subjects with diabetic nephropathy.

Glycosaminoglycans in the skin interstitium and endothelial surface layer have been shown to be involved in local sodium accumulation without commensurate water retention. Dysfunction of heparan sulfate glycosaminoglycans may therefore disrupt sodium and water homeostasis. In this study, we investigated the effects of combined heterozygous loss of heparan sulfate polymerization genes (exostosin glycosyltransferase 1 and 2; Ext1+/-Ext2+/-) on sodium and water homeostasis. Sodium storage capacity was decreased in Ext1+/-Ext2+/- mice as reflected by a 77% reduction in endothelial surface layer thickness and a lower skin sodium-to-glycosaminoglycan ratio. Also, these mice were characterized by a higher heart rate, increased fluid intake, increased plasma osmolality and a decreased skin water and sodium content, suggesting volume depletion. Upon chronic high sodium intake, the initial volume depletion was restored but no blood pressure increase was observed. Acute hypertonic saline infusion resulted in a distinct blood pressure response: we observed a significant 15% decrease in control mice whereas blood pressure did not change in Ext1+/-Ext2+/- mice. This differential blood pressure response may be explained by the reduced capacity for sodium storage and/or the impaired vasodilation response, as measured by wire myography, which was observed in Ext1+/-Ext2+/- mice. Together, these data demonstrate that defective heparan sulfate glycosaminoglycan synthesis leads to abnormal sodium and water homeostasis and an abnormal response to sodium loading, most likely caused by inadequate capacity for local sodium storage.

Background: The intake of sodium, chloride, and potassium is considered important to healthy nutrition and cardiovascular disease risk. Estimating the intake of these electrolytes is difficult and usually predicated on urine collections, commonly for 24 h, which are considered the gold standard. We reported on data earlier for sodium but not for potassium or chloride. Objective: We were able to test the value of 24-h urine collections in a unique, ultra-long–term balance study conducted during a simulated trip to Mars. Design: Four healthy men were observed while ingesting 12 g salt/d, 9 g salt/d, and 6 g salt/d, while their potassium intakewasmaintained at 4 g/d for 105 d. Six healthy men were studied while ingesting 12 g salt/d, 9 g salt/d, and 6 g salt/d, with a re-exposure of 12 g/d, while their potassium intake was maintained at 4 g/d for 205 d. Food intake and other constituents were recorded every day for each subject. All urine output was collected daily. Results: Long-term urine recovery rates for all 3 electrolytes were very high. Rather than the expected constant daily excretion related to daily intake, we observed remarkable daily variation in excretion, with a 7-d infradian rhythm at a relatively constant intake. We monitored 24-h aldosterone excretion in these studies and found that aldosterone appeared to be the regulator for all 3 electrolytes. We report Bland–Altman analyses on the value of urine collections to estimate intake. Conclusions: A single 24-h urine collection cannot predict sodium, potassium, or chloride intake; thus, multiple collections are necessary. This information is important when assessing electrolyte intake in individuals.

AIMS Sulodexide is a highly purified mixture of glycosaminoglycans that has been studied for its anti-albuminuric potential. Considering the effects of glycosaminoglycans on endothelial function and sodium homeostasis, we hypothesized that sulodexide may lower blood pressure (BP). In this meta-analysis, we therefore investigated the antihypertensive effects of sulodexide treatment. METHODS We selected randomized controlled trials that investigated sulodexide treatment of at least 4 weeks and measured BP at baseline and after treatment. Two reviewers independently extracted data on study design, risk of bias, population characteristics and outcome measures. In addition, we contacted authors and pharmaceutical companies to provide missing data. RESULTS Eight studies, totalling 3019 subjects (mean follow-up 4.4 months) were included. Mean age was 61 years and mean baseline BP was 135/75 mmHg. Compared with control treatment, sulodexide resulted in a significant systolic (2.2 mmHg [95% CI 0.3, 4.1], P = 0.02) and diastolic BP reduction (1.7 mmHg [95% CI 0.6, 2.9], P = 0.004). Hypertensive patients displayed the largest systolic BP and diastolic BP reductions (10.2/5.4 mmHg, P

Thiazide diuretics are recommended as first-line therapy for hypertension and are among the most commonly prescribed drugs worldwide. According to their molecular structure, thiazide diuretics can be divided in thiazide-type (TT) and thiazide-like (TL) diuretics. TL diuretics have a longer elimination half-life compared with TT diuretics and have been shown to exert additional pharmacological effects, which may differently affect cardiovascular risk. In this meta-analysis, we compared the effects of TT and TL diuretics on cardiovascular events and mortality. Randomized, controlled studies in adult hypertensive patients that compared TT or TL diuretics with placebo or antihypertensive drugs and had ≥1 year follow-up were included. Primary outcome was cardiovascular events; secondary outcomes included coronary events, heart failure, cerebrovascular events, and all-cause mortality. Meta-regression analysis was used to identify confounders and correct for the achieved blood pressure reductions. Twenty-one studies with >480 000 patient-years were included. Outcomes were not affected by heterogeneity in age, sex, and ethnicity among included studies, whereas larger blood pressure reductions were significantly associated with increased risk reductions for all outcomes ( P P =0.049) and a 21% additional risk reduction for heart failure ( P =0.023) when compared with TT diuretics. The incidence of adverse events was comparable among TT, TL diuretics, and other antihypertensive therapy. Our data suggest that the best available evidence seems to favor TL diuretics as the drug of choice when thiazide treatment is considered for hypertension.

Excessive sodium intake is associated with both hypertension and an increased risk of cardiovascular events, presumably because of an increase in extracellular volume. The extent to which sodium intake affects extracellular volume and BP varies considerably among individuals, discriminating subjects who are salt-sensitive from those who are salt-resistant. Recent experiments have shown that, other than regulation by the kidney, sodium homeostasis is also regulated by negatively charged glycosaminoglycans in the skin interstitium, where sodium is bound to glycosaminoglycans without commensurate effects on extracellular volume. The endothelial surface layer is a dynamic layer on the luminal side of the endothelium that is in continuous exchange with flowing blood. Because negatively charged glycosaminoglycans are abundantly present in this layer, it may act as an intravascular buffer compartment that allows sodium to be transiently stored. This review focuses on the putative role of the endothelial surface layer as a contributor to salt sensitivity, the consequences of a perturbed endothelial surface layer on sodium homeostasis, and the endothelial surface layer as a possible target for the treatment of hypertension and an expanded extracellular volume.

We thank Graudal and Mente for their interest in our article.1 We would like to clarify the authors’ comment that the confidence intervals indicate no outcome difference between baseline and follow-up measurements. The overlapping confidence intervals do not indicate absence of significance between both regression lines because they reflect confidence intervals that accompany the hazard ratios compared with a 2-g sodium intake. Moreover, we want to stress that both regression lines are based on the same dependent variable (ie, estimated sodium intake) and do not represent 2 different interventions. Therefore, these data seem to be a logical consequence of the large changes in sodium excretion …

Sodium-induced microcirculatory changes, endothelial surface layer alterations in particular, may play an important role in sodium-mediated blood pressure elevation. However, effects of acute and chronic sodium loading on the endothelial surface layer and microcirculation in humans have not been established. The objective of this study was to assess sodium-induced changes in blood pressure and body weight as primary outcomes and also in microvascular permeability, sublingual microcirculatory dimensions, and urinary glycosaminoglycan excretion in healthy subjects.Twelve normotensive males followed both a low-sodium diet (less than 50 mmol/day) and a high-sodium diet (more than 200 mmol/day) for eight days in randomized order, separated by a crossover period. After the low-sodium diet, hypertonic saline (5 mmol sodium/liter body water) was administered intravenously in 30 min.Both sodium interventions did not change blood pressure. Body weight increased with 2.5 (95% CI, 1.7 to 3.2) kg (P0.001) after dietary sodium loading. Acute intravenous sodium loading resulted in increased transcapillary escape rate of I-labeled albumin (2.7 [0.1 to 5.3] % cpm · g · h; P = 0.04), whereas chronic dietary sodium loading did not affect transcapillary escape rate of I-labeled albumin (-0.03 [-3.3 to 3.2] % cpm · g · h; P = 1.00), despite similar increases of plasma sodium and osmolality. Acute intravenous sodium loading coincided with significantly increased plasma volume, as assessed by the distribution volume of albumin, and significantly decreased urinary excretion of heparan sulfate and chondroitin sulfate. These changes were not observed after dietary sodium loading.Our results suggest that intravenous sodium loading has direct adverse effects on the endothelial surface layer, independent of blood pressure.

Contains fulltext : 175949.pdf (Publisher’s version ) (Open Access) Hypertension is associated with cognitive decline and various forms of dementia, including Alzheimer's disease. In animal models of hypertension, many of Alzheimer's disease characteristics are recapitulated, including brain atrophy, cognitive decline, amyloid beta accumulation and blood brain barrier dysfunction. Removal of amyloid beta and other waste products depends in part on clearance via the brain interstitial fluid (ISF). Here we studied the impact of hypertension on ISF drainage, using spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto rats (WKY). At 8 months, high (500 kD) and low (3 kD) fluorescent molecular weight tracers released passively into the hippocampus showed a drastically enhanced spreading in SHR. Tracer spreading was inhomogeneous, with accumulation at ISF-CSF borders, around arteries, and towards the stratum lacunosum moleculare. These locations stained positively for the astrocyte marker GFAP, and aquaporin 4. Despite enhanced dispersion, clearance of tracers was not affected in SHR. In conclusion, these data indicate enhanced bulk flow of ISF in the hippocampus of hypertensive rats. ISF drains along astrocytes towards the cerebrospinal fluid compartment, which leads to sieving of high molecular weight solutes. Sieving may lead to a local increase in the concentration of waste products and potentially promotes the aggregation of amyloid beta.

Objective The EG regulates vascular homeostasis and has anti-atherogenic properties. SDF imaging allows for noninvasive visualization of microvessels and automated estimation of EG dimensions. We aimed to assess whether microcirculatory EG dimension is related to cardiovascular disease. Methods Sublingual EG dimension was estimated by SDF imaging in healthy volunteers and in patients visiting an outpatient clinic for vascular medicine of a university hospital in Amsterdam, the Netherlands. EG dimension was compared among healthy volunteers, patients with CVD, and patients at low (

Objectives: In the present study, the authors have investigated whether rotational thromboelastometry (ROTEM) could predict thrombocytopenia and hypofibrinogenemia in cardiac surgery using the clot amplitude after 5 minutes (A5). Another parameter, PLTEM, in which the contribution of fibrinogen is eliminated by subtracting a fibrin-specific ROTEM test (FIBTEM) from an extrinsically-activated ROTEM test (EXTEM), was investigated. Furthermore, the turnaround time of ROTEM was compared to conventional laboratory tests.Design: Prospective cohort study.Setting: Single academic medical center.Participants: Ninety-seven patients undergoing cardiac surgery between July 2011 until August 2012.Interventions: The correlations between EXTEM/FIBTEM A5, A10, and maximal clot formation (MCF), EXTEM/PLTEM (A5/A10, and MCF) and platelet count, and FIBTEM (A5/A10, and MCF) and fibrinogen were evaluated using the Pearson's correlation coefficient and receiver-operating characteristic curves. Turnaround times of ROTEM tests and conventional laboratory tests were assessed in the central laboratory.Measurements and Main Results: EXTEM AS and FIBTEM A5 showed an excellent correlation with A10 (R:0.99/1.00) and MCF (R:0.97/0.99). The correlation between EXTEM AS and platelet count (R:0.74) was comparable with the correlation of A10 (R:0.73) and MCF (R:0.70) with platelet count. FIBTEM AS predicted fibrinogen levels (R:0.87) as well as A10 (R:0.86) and MCF (R:0.87). PLTEM AS (R:0.85) correlated better with platelet count than EXTEM A5 (R:0.74; p = 0.04) and showed significantly better area under the curve values than EXTEM for predicting thrombocytopenia (A5 p = 0.012, A10 p = 0.019). Turnaround time for ROTEM tests, 12 minutes, was comparable with emergency requests for platelet count, 13 minutes, and shorter than emergency requests for fibrinogen levels, 37 minutes.Conclusions: Implementation of PLTEM and FIBTEM AS in ROTEM-guided transfusion protocols may improve transfusion management.

The assumption that sodium accumulation in the human body is always accompanied by water retention has been challenged by data showing that sodium can be stored nonosmotically. Here we investigated the contribution of nonosmotic sodium storage to short-term sodium homeostasis after hypertonic saline infusion in healthy individuals on a low-sodium diet. During four hours after infusion, we compared the observed changes in plasma sodium concentration and urinary cation excretion with changes that were calculated with the Adrogue-Madias and Nguyen-Kurtz formula, formulations widely implemented to guide the treatment of dysnatremias. We included 12 healthy non-smoking male individuals with normal blood pressure, body mass index, and kidney function. Right after infusion, the average observed plasma sodium change from baseline (3.5 mmol/L) was similar to the predicted changes by the Adrogue-Madias (3.3 mmol/L) and Nguyen-Kurtz formula (3.1 mmol/L). However, the observed plasma sodium concentration change after four hours (–1.8 mmol/L) was very different from the changes as predicted by the Adrogue-Madias (0.4 mmol/L) and the Nguyen-Kurtz formula (–0.9 mmol/L). Moreover, only 47% and 55%, respectively, of the expected sodium and potassium excretion were retrieved in the urine. Thus, healthy individuals are able to osmotically inactivate significant amounts of sodium after hypertonic saline infusion. Further research is needed to uncover factors that determine nonosmotic sodium storage.

This case report describes a cachectic patient with a first hypomanic episode, hypercortisolism and a newly diagnosed large B-cell lymphoma. Hypercortisolism, causing the manic symptoms, may be explained due to low leptin levels as a result of cancer cachexia and fasting. Patients with cancer frequently have psychiatric complications, but manic symptoms are rare. To our knowledge, this is the first report of a patient with a lymphoma presenting with manic symptoms without any cerebral abnormalities.

Dear editor In their meta-analysis, Li et al1 reported a renoprotective benefit of sulodexide in patients with diabetic nephropathy. This was the first meta-analysis to evaluate the potential anti-albuminuric effects of sulodexide in such patients. Albuminuria reduction with renin–angiotensin–aldosterone system inhibitors is known to beneficially affect renal outcome and represents, together with blood pressure control, the cornerstone of diabetic nephropathy treatment.2–6 As (residual) albuminuria is closely related with renal outcome and the reduction in albuminuria is linearly correlated with renoprotection, we need additional measures to reduce the burden of diabetic nephropathy.7 The meta-analysis of Li et al1 therefore addresses a very relevant topic. In the light of two large randomized, placebo-controlled, double-blind clinical trials that did not show any effect of sulodexide on albuminuria, the results of this meta-analysis are surprising, especially since the majority (86%) of patients that were included in this meta-analysis were derived from these trials.8,9 We want to address some crucial points that may underlie these remarkable results. First, in their continuous outcome analysis, Li et al1 excluded the trial of Lewis et al8 for unknown reasons. In our opinion, no valid conclusions can be drawn without taking into account this trial, which represented more than a third of the patients who were included in the meta-analysis. Second, the authors assigned arbitrary weights to the other studies that were included in this analysis. For example, the well-designed, multicenter trial of Packham et al that included 1,248 patients with a mean follow-up of 11 months was assigned a 13% weight,9 while a 21.5% weight was assigned to a single-center trial that included just 36 patients with a follow-up of 3 weeks.10 The authors used a random-effects model and determined weight using the inverse variance method. However, it is unclear how the ratio of mean values and accompanying confidence intervals were calculated. The results of the study by Packham et al that were incorporated in this meta-analysis (log ratio of values 0.99, 95% confidence interval 0.68–1.44) do not seem to correspond with the data that were reported in the original paper (log ratio of values 0.97, 95% confidence interval 0.91–1.03).9 We think the authors should address more thoroughly how these treatment effects were calculated and provide data of these calculations for each study. Both the addition of the trial by Lewis et al8 and adequate assignment of weights may have a significant impact on the outcome and conclusions of this analysis. In a second analysis, the authors assessed the treatment success of sulodexide as a binary outcome. The results of this analysis may raise some concern. First, the authors incorrectly reported that 37 patients participated in the sulodexide group of the study by Dedov et al,10 while only 18 patients were included. Second, it is unclear how the authors calculated the proportion of patients reaching this binary outcome. For instance, Dedov et al stated that “17 of the 18 sulodexide-treated patients showed a trend toward a decrease in AER”.10 This is inconsistent with the proportion of 100% that reached the binary outcome according to Li et al.1 In general, such proportions cannot be extracted from the average albuminuria changes that are often reported in studies. The authors should therefore provide more insight and data of their calculations of this binary outcome. Third, out of three sulodexide doses that were investigated by Gambaro et al,11 the authors chose to only include the highest and most effective dose. Lower sulodexide doses were no predefined reason for exclusion. It remains unclear why these groups were not taken into account. Finally, the characteristics of the included studies were represented incorrectly in their baseline table (eg, the average amount of proteinuria was not 24.5 and 38.9 g/d in the studies of Dedov et al10 and Gambaro et al,11 respectively). Finally, in their discussion section, the authors came up with different mechanisms that may be responsible for the renoprotective effects of sulodexide that were observed in their meta-analysis.1 Besides kidney-specific effects of sulodexide, so far overlooked systemic blood pressure effects of sulodexide have recently been reported.12 Considering that blood pressure regulation is the basis for renoprotective therapy, sulodexide-induced blood pressure effects are of influence. Indeed, these blood pressure effects were shown to correlate well with changes in albuminuria.12 Improved blood pressure control by sulodexide may therefore contribute to the anti-albuminuric characteristics of this agent. Without entering the debate whether sulodexide should be further investigated for a possible renoprotective effect, the authors should revise their analysis and adjust their conclusions accordingly.