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Background Tissue sodium (Na+) content in patients on maintenance hemodialysis (MHD) and peritoneal dialysis (PD) was previously explored using 23Na+ magnetic resonance imaging (23NaMRI). Larger studies would provide a better understanding of Na+ stores in patients on dialysis as well as the factors influencing this Na+ accumulation. Methods In this cross-sectional study, we quantified the calf muscle and skin Na+ content in 162 subjects (10 PD, 33 MHD patients and 119 controls) using 23NaMRI. Plasma levels of interleukin-6 (IL-6) and high-sensitivity C-reactive protein (hsCRP) were measured to assess systemic inflammation. Sixty-four subjects had repeat 23NaMRI scans that were analyzed to assess the repeatability of the 23NaMRI measurements. Results Patients on MHD and PD exhibited significantly higher muscle and skin Na+ accumulation compared with controls. African American patients on dialysis exhibited greater muscle and skin Na+ content compared with non–African Americans. Multivariable analysis showed that older age was associated with both higher muscle and skin Na+ and male sex was associated with increased skin Na+ deposition. Greater ultrafiltration was associated with lower skin Na+ in patients on PD (Spearman’s ρ = −0.68, P = 0.035). Higher plasma IL-6 and hsCRP levels correlated with increased muscle and skin Na+ content in the overall study population. Patients with higher baseline tissue Na+ content exhibited greater variability in tissue Na+ stores on repeat measurements. Conclusions Our findings highlight greater muscle and skin Na+ content in dialysis patients compared with controls without kidney disease. Tissue Na+ deposition and systemic inflammation seen in dialysis patients might influence one another bidirectionally.

Therapeutic inhibition of the sodium–glucose co-transporter 2 (SGLT2) leads to substantial loss of energy (in the form of glucose) and additional solutes (in the form of Na+ and its accompanying anions) in urine. However, despite the continuously elevated solute excretion, long-term osmotic diuresis does not occur in humans with SGLT2 inhibition. Rather, patients on SGLT2 inhibitor therapy adjust to the reduction in energy availability and conserve water. The metabolic adaptations that are induced by SGLT2 inhibition are similar to those observed in aestivation — an evolutionarily conserved survival strategy that enables physiological adaptation to energy and water shortage. Aestivators exploit amino acids from muscle to produce glucose and fatty acid fuels. This endogenous energy supply chain is coupled with nitrogen transfer for organic osmolyte production, which allows parallel water conservation. Moreover, this process is often accompanied by a reduction in metabolic rate. By comparing aestivation metabolism with the fuel switches that occur during therapeutic SGLT2 inhibition, we suggest that SGLT2 inhibitors induce aestivation-like metabolic patterns, which may contribute to the improvements in cardiac and renal function observed with this class of therapeutics. SGLT2 inhibitors induce a number of metabolic adaptations in response to increased glucose and Na+ excretion. This Perspective article describes how these adaptations suggest that SGLT2 inhibition triggers a body water-conserving mechanism, and discusses how these metabolic adjustments may contribute to the favourable cardiovascular and renal outcomes of this class of therapeutics.

OBJECTIVE Lipedema is characterized by pain, fatigue, and excessive adipose tissue and sodium accumulation of the lower extremities. This case-control study aims to determine whether sodium or vascular dysfunction is present in the central nervous system. METHODS Brain magnetic resonance imaging was performed at 3 T in patients with lipedema (n = 15) and control (n = 18) participants matched for sex, age, race, and BMI. Standard anatomical imaging and intracranial angiography were applied to evaluate brain volume and vasculopathy, respectively; arterial spin labeling and sodium magnetic resonance imaging were applied to quantify cerebral blood flow (CBF) (milliliters per 100 grams of tissue/minute) and brain tissue sodium content (millimoles per liter), respectively. A Mann-Whitney U test (significance criteria P

We recently reported that a 4% high-salt diet + saline for drinking (HS + saline) leads to a catabolic state, reduced heart rate, and suppression of cardiovascular energy expenditure in mice. We suggested that HS + saline reduces heart rate via the suppression of the sympathetic nervous system to compensate for the high salt intake-induced catabolic state. To test this hypothesis, we directly measured renal sympathetic nerve activity (RSNA) in conscious Sprague-Dawley (SD) rats using a radiotelemetry system. We confirmed that HS + saline induced a catabolic state. HS + saline decreased heart rate, while also reducing RSNA in SD rats. In contrast, Dahl salt-sensitive (DSS) rats exhibited no change in heart rate and increased RSNA during high salt intake. Renal denervation significantly decreased heart rate and attenuated the catabolic state independent of blood pressure in DSS rats fed HS + saline, suggesting that salt-sensitive animals were unable to decrease cardiovascular energy consumption due to abnormal renal sympathetic nerve activation during high salt intake. These findings support the hypothesis that RSNA mediates heart rate during high salt intake in SD rats. However, the insensitivity of heart rate and enhanced RSNA observed in DSS rats may be additional critical diagnostic factors for salt-sensitive hypertension. Renal denervation may benefit salt-sensitive hypertension by reducing its effects on catabolism and cardiovascular energy expenditure.

Hyperosmolality is common in critically ill patients during body fluid volume reduction. It is unknown whether this is only a result of decreased total body water or an active osmole-producing mechanism similar to that found in aestivating animals, where muscle degradation increases urea levels to preserve water. We hypothesized that fluid volume reduction in critically ill patients contributes to a shift from ionic to organic osmolytes similar to mechanisms of aestivation. We performed a post-hoc analysis on data from a multicenter observational study in adult intensive care unit (ICU) patients in the postresuscitative phase. Fluid, electrolyte, energy and nitrogen intake, fluid loss, estimated glomerular filtration rate (eGFR), and estimated plasma osmolality (eOSM) were registered. Contributions of osmolytes Na+, K+, urea, and glucose to eOSM expressed as proportions of eOSM were calculated. A total of 241 patients were included. eOSM increased (median change 7.4 mOsm/kg [IQR−1.9–18]) during the study. Sodium's and potassium's proportions of eOSM decreased (P ClinicalTrials.org Identifier: NCT03972475.

Aim We have reported earlier that a high salt intake triggered an aestivation‐like natriuretic‐ureotelic body water conservation response that lowered muscle mass and increased blood pressure. Here, we tested the hypothesis that a similar adaptive water conservation response occurs in experimental chronic renal failure. Methods In four subsequent experiments in Sprague Dawley rats, we used surgical 5/6 renal mass reduction (5/6 Nx) to induce chronic renal failure. We studied solute and water excretion in 24‐hour metabolic cage experiments, chronic blood pressure by radiotelemetry, chronic metabolic adjustment in liver and skeletal muscle by metabolomics and selected enzyme activity measurements, body Na+, K+ and water by dry ashing, and acute transepidermal water loss in conjunction with skin blood flow and intra‐arterial blood pressure. Results 5/6 Nx rats were polyuric, because their kidneys could not sufficiently concentrate the urine. Physiological adaptation to this renal water loss included mobilization of nitrogen and energy from muscle for organic osmolyte production, elevated norepinephrine and copeptin levels with reduced skin blood flow, which by means of compensation reduced their transepidermal water loss. This complex physiologic‐metabolic adjustment across multiple organs allowed the rats to stabilize their body water content despite persisting renal water loss, albeit at the expense of hypertension and catabolic mobilization of muscle protein. Conclusion Physiological adaptation to body water loss, termed aestivation, is an evolutionary conserved survival strategy and an under‐studied research area in medical physiology, which besides hypertension and muscle mass loss in chronic renal failure may explain many otherwise unexplainable phenomena in medicine.

Salt (NaCl) is a prerequisite for life. Excessive intake of salt, however, is said to increase disease risk, including hypertension, arteriosclerosis, heart failure, renal disease, stroke, and cancer. Therefore, considerable research has been expended on the mechanism of sodium handling based on the current concepts of sodium balance. The studies have necessarily relied on relatively short-term experiments and focused on extremes of salt intake in humans. Ultra-long-term salt balance has received far less attention. We performed long-term salt balance studies at intakes of 6, 9, and 12 g/day and found that although the kidney remains the long-term excretory gate, tissue and plasma sodium concentrations are not necessarily the same and that urinary salt excretion does not necessarily reflect total-body salt content. We found that to excrete salt, the body makes a great effort to conserve water, resulting in a natriuretic-ureotelic principle of salt excretion. Of note, renal sodium handling is characterized by osmolyte excretion with anti-parallel water reabsorption, a state-of-affairs that is achieved through the interaction of multiple organs. In this review, we discuss novel sodium and water balance concepts in reference to our ultra-long-term study. An important key to understanding body sodium metabolism is to focus on water conservation, a biological principle to protect from dehydration, since excess dietary salt excretion into the urine predisposes to renal water loss because of natriuresis. We believe that our research direction is relevant not only to salt balance but also to cardiovascular regulatory mechanisms.

Objectives Sodium (Na+) is stored in the skin and muscle and plays an important role in immune regulation. In animal models, increased tissue Na+ is associated with activation of the immune system, and high salt intake exacerbates autoimmune disease and worsens hypertension. However, there is no information about tissue Na+ and human autoimmune disease. We hypothesized that muscle and skin Na+ content is (a) higher in patients with systemic lupus erythematosus (SLE) than in control subjects, and (b) associated with blood pressure, disease activity, and inflammation markers (interleukin (IL)-6, IL-10 and IL-17 A) in SLE. Methods Lower-leg skin and muscle Na+ content was measured in 23 patients with SLE and in 28 control subjects using 23Na+ magnetic resonance imaging. Demographic and clinical information was collected from interviews and chart review, and blood pressure was measured. Disease activity was assessed using the SLE Disease Activity Index (SLEDAI). Plasma inflammation markers were measured by multiplex immunoassay. Results Muscle Na+ content was higher in patients with SLE (18.8 (16.7–18.3) mmol/L) than in control subjects (15.8 (14.7–18.3) mmol/L; p + content was also higher in SLE patients than in controls, but this difference was not statistically significant. Among patients with SLE, muscle Na+ was associated with SLEDAI and higher concentrations of IL-10 after adjusting for age, race, and sex. Skin Na+ was significantly associated with systolic blood pressure, but this was attenuated after covariate adjustment. Conclusion Patients with SLE had higher muscle Na+ content than control subjects. In patients with SLE, higher muscle Na+ content was associated with higher disease activity and IL-10 concentrations.

Chronic renal failure leads to muscle mass loss and hypertension, which according to textbook teaching occur secondary to an inability of the kidneys to excrete solutes and water. We found instead that rats with experimental chronic renal failure constantly lost body water, because their kidneys could not sufficiently concentrate the urine. Physiological adaptation to body water loss, termed aestivation, is an evolutionary conserved survival strategy that relies on complex physiologic-metabolic adjustment across multiple organs to prevent otherwise lethal dehydration. We show that rats with chronic renal failure utilize these ancient water conservation motifs to successfully stabilize their body water. Metabolic aestivation responses to chronic renal failure require nitrogen-rich organic osmolyte production. Continuous endogenous energy and nitrogen supply from skeletal muscle in support of this metabolic requirement explains “renal” muscle mass loss. Accompanying circulatory aestivation responses are designed to limit skin water loss. This process requires vasoconstriction, which explains “renal” hypertension.

Long-term elevated blood sugar levels result in tissue matrix compositional changes in patients with diabetes mellitus type 2 (T2DM). We hypothesized that hemodialysis patients with T2DM might accumulate more tissue sodium than control hemodialysis patients. To test this, 23Na magnetic resonance imaging (23Na MRI) was used to estimate sodium in skin and muscle tissue in hemodialysis patients with or without T2DM. Muscle fat content was estimated by 1H MRI and tissue sodium content by 23Na MRI pre- and post-hemodialysis in ten hemodialysis patients with T2DM and in 30 matched control hemodialysis patients. We also assessed body fluid distribution with the Body Composition Monitor. 1H MRI indicated a tendency to higher muscle fat content in hemodialysis patients with T2DM compared to non-diabetic hemodialysis patients. 23Na MRI indicated increased sodium content in muscle and skin tissue of hemodialysis patients with T2DM compared to control hemodialysis patients. Multi-frequency bioimpedance was used to estimate extracellular water (ECW), and excess ECW in T2DM hemodialysis patients correlated with HbA1c levels. Sodium mobilization during hemodialysis lowered muscle sodium content post-dialysis to a greater degree in T2DM hemodialysis patients than in control hemodialysis patients. Thus, our findings provide evidence that increased sodium accumulation occurs in hemodialysis patients with T2DM and that impaired serum glucose metabolism is associated with disturbances in tissue sodium and water content.

OBJECTIVE To test the hypothesis that tissue sodium and adipose content are elevated in patients with lipedema; if confirmed, this could establish precedence for tissue sodium and adipose content representing a discriminatory biomarker for lipedema. METHODS Participants with lipedema (n = 10) and control (n = 11) volunteers matched for biological sex, age, BMI, and calf circumference were scanned with 3.0-T sodium and conventional proton magnetic resonance imaging (MRI). Standardized tissue sodium content was quantified in the calf skin, subcutaneous adipose tissue (SAT), and muscle. Dixon MRI was employed to quantify tissue fat and water volumes of the calf. Nonparametric statistical tests were applied to compare regional sodium content and fat-to-water volume between groups (significance: two-sided P ≤ 0.05). RESULTS Skin (P = 0.01) and SAT (P = 0.04) sodium content were elevated in lipedema (skin: 14.9 ± 2.9 mmol/L; SAT: 11.9 ± 3.1 mmol/L) relative to control participants (skin: 11.9 ± 2.0 mmol/L; SAT: 9.4 ± 1.6 mmol/L). Relative fat-to-water volume in the calf was elevated in lipedema (1.2 ± 0.48 ratio) relative to control participants (0.63 ± 0.26 ratio; P

Rationale and Objectives Sodium and proton magnetic resonance imaging (23Na/1H-MRI) have shown that muscle and skin can store Na+ without water. In chronic renal failure and in heart failure, Na+ mobilization occurs, but is variable depending on age, dialysis vintage, and other features. Na+ storage depots have not been studied in patients with acute kidney injury (AKI). Materials and Methods We studied 7 patients with AKI (mean age: 51.7 years; range: 25–84) and 14 age-matched and gender-matched healthy controls. All underwent 23Na/1H-MRI at the calf. Patients were studied before and after acute hemodialysis therapy within 5–6 days. The 23Na-MRI produced grayscale images containing Na+ phantoms, which served to quantify Na+ contents. A fat-suppressed inversion recovery sequence was used to quantify H2O content. Results Plasma Na+ levels did not change. Mean Na+ contents in muscle and skin did not significantly change following four to five cycles of hemodialysis treatment (before therapy: 32.7 ± 6.9 and 44.2 ± 13.5 mmol/L, respectively; after dialysis: 31.7 ± 10.2 and 42.8 ± 11.8 mmol/L, respectively; P > .05). Water content measurements did not differ significantly before and after hemodialysis in muscle and skin (P > .05). Na+ contents in calf muscle and skin of patients before hemodialysis were significantly higher than in healthy subjects (16.6 ± 2.1 and 17.9 ± 3.2) and remained significantly elevated after hemodialysis. Conclusions Na+ in muscle and skin accumulates in patients with AKI and, in contrast to patients receiving chronic hemodialysis and those with acute heart failure, is not mobilized with hemodialysis within 5–6 days.

Renal denervation (RDN) has been introduced for reducing blood pressure (BP) in treatment-resistant hypertension (TRH). The precise mechanism how RDN exerts its BP-lowering effects are not yet fully understood. It is widely accepted that sodium (Na+) plays a crucial role in the pathogenesis of hypertensive disease. However, there is increasing evidence of osmotically inactive Na+ storage. We investigated the impact of RDN on Na+ homeostasis using estimation of salt intake, and measurement of tissue Na+ content. In a study 41 patients with TRH (office BP ≥140/90 mmHg and diagnosis confirmed by 24-h ambulatory BP monitoring) underwent RDN. Tissue Na+ content was assessed non-invasively with 3.0 T magnetic resonance imaging before and 6 months after RDN. In addition, 24-h urinary Na+ excretion as an estimate of salt intake and spot urine Na+/K+ excretion were assessed. The study was registered at http://www.clinicaltrials.gov (ID: NCT01687725). There was a significant fall in BP (office: −17 ± 20/−10 ± 12 mmHg; 24-h: −11 ± 13/−6 ± 9 mmHg, all p

The aim of this study is to examine the effects of acute administration of luseogliflozin, the sodium–glucose cotransporter 2 (SGLT2) inhibitor, on renal hemodynamics and tubular functions in anesthetized non-diabetic Sprague Dawley (SD) rats and 5/6 nephrectomized (Nx) SD rats. Renal blood flow (RBF), mean arterial pressure (MAP), and heart rate (HR) were continuously measured and urine was collected directly from the left ureter. Intraperitoneal injection of luseogliflozin (0.9 mg kg−1) did not change MAP, HR, RBF, or creatinine clearance (CrCl) in SD rats (n = 7). Luseogliflozin significantly increased urine volume, which was associated with significantly increased urinary glucose excretion rates (P −1 at baseline to 0.76 ± 0.08 µmol min−1 at 120 min; P P P n = 5–6), luseogliflozin significantly increased urine volume and urinary glucose excretion (P

Blood pressure salt sensitivity and salt resistance are mechanistically imperfectly explained. A prescient systems medicine approach by Guyton and colleagues—more than 50 years ago—suggested how salt intake might influence blood pressure. They proposed that a high-salt diet engenders sodium accumulation, volume expansion, cardiac output adjustments, and then autoregulation for flow maintenance. The autoregulation in all vascular beds increases systemic vascular resistance, causing the kidneys to excrete more salt and water, thus reducing systems to normal and minimizing any changes in blood pressure. This schema, which is remarkably all encompassing, included all regulatory mechanisms Guyton could identify at the time. Guyton introduced the idea that the kidney is central, particularly concerning the regulation of renal pressure natriuresis. Numerous criticisms have been subsequently raised, particularly recently. Kurtz and colleagues argue that the ability of individuals to respond with an appropriate vasodilatory response to increased salt intake is pivotal. Data exist to address that issue. Salt-resistant hypertensive models provide additional information. We identified a mendelian form of hypertension not related to sodium reabsorption in the distal nephron. The hypertension develops because of increased systemic vascular resistance. In addition, we rediscovered a third salt-storage glycose-aminoglycan–related compartment, largely in the skin. This compartment operates independently of renal function, and when perturbed, is associated with salt sensitivity. More recently, we found novel molecular mechanisms demonstrating how large salt quantities are excreted by the kidneys with minimal water losses. We introduce novel interpretations as to how the kidneys excrete salt when the intake is high. The findings could have relevance as to how blood pressure may be regulated at varying salt intakes. Our purposes are to provide the readership with a banquet of thoughts to digest, to pursue Guyton's ideas, and to adjust them accordingly.

Purpose 23Na MRI demonstrated increased tissue sodium concentrations in a number of pathologies. Acute atrophy results in muscle fibre volume shrinking that may result in a relative increase of extracellular volume and might affect sodium concentration. Thus, we hypothesized that local unloading of the calf muscles would lead to a decrease in muscle volume and an increase in muscle tissue sodium concentration. Method One lower leg of 12 healthy male subjects was submitted to a 60 day long period of unloading using the Hephaistos orthosis, while the other leg served as control. 23Na MRI and 2D PD-weighted Dixon turbo spin echo were obtained from the control and orthosis leg using a 3T scanner. For quantification, a sodium reference phantom was used with 10, 20, 30, and 40 mmol/L NaCl solution. Result Tissue sodium concentration (TSC) increased as an effect of unloading in the orthosis leg. Relative increases were 17.4 ± 16.8% (P = 0.005) in gastrocnemius medialis muscle, 11.1 ± 12.5 (P = 0.037) in gastrocnemius lateralis muscle, 16.2 ± 4.7% (P < 0.001) in soleus muscle, 10.0 ± 10.5% (P = 0.009) in the ventral muscle group, and 10.7 ± 10.0% (P = 0.003) in the central muscle group, respectively. TSC in the control leg did not significantly change. In the orthosis leg, muscle volume decreased as follows: medial gastrocnemius muscle: −5.4 ± 8.3% (P = 0.043) and soleus muscle: −7.8 ± 15.0% (P = 0.043). Conclusion Unloading atrophy is associated with an increase in muscle sodium concentration. 23Na MRI is capable of detecting these rather small changes.

Background Recent data suggest that sodium (Na+) is stored in the muscle and skin without commensurate water retention in maintenance hemodialysis (MHD) patients. In this study, we hypothesized that excessive Na+ accumulation would be associated with abnormalities in peripheral insulin action. Methods Eleven MHD patients and eight controls underwent hyperinsulinemic–euglycemic–euaminoacidemic clamp studies to measure glucose (GDR) and leucine disposal rates (LDR), as well as lower left leg 23Na magnetic resonance imaging to measure Na+ concentration in the muscle and skin tissue. Results The median GDR and LDR levels were lower, and the median muscle Na+ concentration was higher in MHD patients compared with controls. No significant difference was found regarding skin Na+ concentration between group comparisons. Linear regression revealed inverse relationships between muscle Na+ concentration and GDR and LDR in MHD patients, whereas no relationship was observed in controls. There was no association between skin Na+ content and GDR or LDR in either MHD patients or controls. Conclusions These data suggest that excessive muscle Na+ content might be a determinant of IR in MHD patients, although the causality and mechanisms remain to be proven.

International audience; Space medicine and new technology such as magnetic resonance imaging of tissue sodium stores (23NaMRI) have changed our understanding of human sodium homeostasis and pathophysiology. It has become evident that body sodium comprises 3 main components. Two compartments have been traditionally recognized, namely one that is circulating and systemically active via its osmotic action, and one slowly exchangeable pool located in the bones. The third, recently described pool represents sodium stored in skin and muscle interstitium, and it is implicated in cell and biologic activities via local hypertonicity and sodium clearance mechanisms. This in-depth review provides a comprehensive view on the pathophysiology and existing knowledge gaps of systemic hemodynamic and tissue sodium accumulation in dialysis patients. Furthermore, we discuss how the combination of novel technologies to quantitate tissue salt accumulation (e.g., 23NaMRI) with devices to facilitate the precise attainment of a prescribed hemodialytic sodium mass balance (e.g., sodium and water balancing modules) will improve our therapeutic approach to sodium management in dialysis patients. While prospective studies are required, we think that these new diagnostic and sodium balancing tools will enhance our ability to pursue more personalized therapeutic interventions on sodium and water management, with the eventual goal of improving dialysis patient outcomes.

Objective. Skin fibrosis is the predominant feature of SSc and arises from excessive extracellular matrix deposition. Glycosaminoglycans are macromolecules of the extracellular matrix, which facilitate Na(+) accumulation in the skin. We used (23)Na-MRI to quantify Na(+) in skin. We hypothesized that skin Na(+) might accumulate in SSc and might be a biomarker for skin fibrosis. Methods. In this observational case–control study, skin Na(+) was determined by (23)Na-MRI using a Na(+) volume coil in 12 patients with diffuse cutaneous SSc and in 21 control subjects. We assessed skin fibrosis by the modified Rodnan skin score prior to (23)Na-MRI and on follow-up 12 months later. Results. (23)Na-MRI demonstrated increased Na(+) in the fibrotic skin of SSc patients compared with skin from controls [mean (s.d.): 27.2 (5.6) vs 21.4 (5.3) mmol/l, P < 0.01]. Na(+) content was higher in fibrotic than in non-fibrotic SSc skin [26.2 (4.8) vs 19.2 (3.4) mmol/l, P < 0.01]. Furthermore, skin Na(+) amount was correlated with changes in follow-up modified Rodnan skin score (R(2) = 0.68). Conclusions. (23)Na-MRI detected increased Na(+) in the fibrotic SSc skin; high Na(+) content was associated with progressive skin disease. Our findings provide the first evidence that (23)Na-MRI might be a promising tool to assess skin Na(+) and thereby predict progression of skin fibrosis in SSc.

Humans have had a long and complex relationship with salt. Although highly valued in many societies, dietary salt has long been associated with high blood pressure1–3 and, more recently, with other diseases.4–6 Some individuals with hypertension often display salt-sensitive blood pressure changes, which is a condition more prevalent among blacks, older people, and individuals with renal insufficiency or diabetes mellitus.7–9 In general, for those with salt-sensitive hypertension, excess sodium intake is associated with higher blood pressure, whereas a low-salt diet decreases blood pressure.3 In spite of this well-known association, the basic molecular and cellular mechanisms underlying the effects of salt on blood pressure regulation are still not well understood. Furthermore, individuals with high blood pressure are at increased risk for multiple diseases (ie, coronary artery disease, heart failure, stroke, and renal disease) although at present whether or not a high dietary salt intake can directly lead to these diseases (ie, in the absence of hypertension) is not known. Our understanding of the effect of salt on health has grown even more complex recently. Researchers have reported a new connection between salt and autoimmunity: a high-salt diet was shown to accelerate autoimmune activity in a mouse model of multiple sclerosis.10,11 In addition, a close connection between hypertension and the immune system has been revealed.12–16 However, the causal relationships between salt, immunity, and hypertension (eg, how salt could mediate interactions between the immune system and the vasculature, brain, or kidney to increase blood pressure) are not well understood. The National Heart, Lung, and Blood Institute convened a Working Group (WG) in 2014 to discuss this new emerging scientific area in hypertension research. The WG brought together experts from diverse backgrounds including hypertension, epidemiology, preeclampsia, cardiovascular disease, …

Sodium and potassium intake are modifiable determinants of hypertension in the general population but have not been studied in patients with systemic lupus erythematosus (SLE). We examined the relationship between urinary excretion of sodium and potassium, as an estimate of intake, and blood pressure in patients with SLE. We studied 178 SLE patients and 86 controls, matched for age, sex, and race. Urine sodium (Na+) and potassium (K+) were measured by flame photometry. Blood pressure was the average of two resting measurements. The associations between systolic (SBP) and diastolic blood pressures (DBP) and estimated 24-hour urinary Na+, K+, and Na+:K+ ratio were tested. The estimated mean 24-hour urinary K+ excretion was lower, and the Na+:K+ ratio was higher in patients with SLE than controls. There were no significant differences in the estimated 24-hour urinary Na+. In patients with SLE, a higher urinary Na+:K+ ratio was associated with higher SBP (β coefficient = 4.01, p = 0.023) and DBP (β coefficient = 4.41, p = 0.002) after adjusting for age, sex, and race. SLE patients had significantly lower estimated 24-hour urinary K+ and higher estimated 24-hour urinary Na+: K+ ratio than controls. The urinary Na+:K+ ratio was significantly associated with SBP and DBP.

Sodium can be buffered in the skin, which mechanism is altered during aging and in certain diseases such as hypertension. High salt environment can promote autoimmunity by expanding pathogenic IL-17 producing T helper (Th17) cells. Psoriasis is a relapsing and remitting inflammatory autoimmune disease affecting the skin and joints and involves proinflammatory Th17 cells. Here we tested the hypothesis if psoriatic skin has a higher sodium content in mice and humans. We used two psoriasis mouse models; the K14-IL-17A ind/+ mice overexpressing IL-17A in K14-positive keratinocytes and the imiquimod (IMQ) mouse model by applying 62.5 mg IMQ cream (5%) on the shaved back and ears of FVB/N mice for 5 days daily. End of the study skins of mice were collected, weighted, dried and ashed to measure water and sodium content. Additionally, skin sodium and water content were measured in psoriasis patients and aged matched healthy controls by non-invasive 23 Na-MRI on non-affected flexor site of the lower leg and by 23 Na-spectroscopy to compare affected and non-affected sites of the leg. K14-IL-17A ind/+ mice had significantly higher sodium content compared to control IL-17A ind/+ mice (0.191±0.021 vs. 0.137±0.023 mg/g dry weight) together with an elevated water content. IMQ-treated back skin had significantly higher sodium content compared to untreated ventral skin of the same mice (0.175±0.023 vs. 0.143±0.014 mg/g dry weight), whereas sham mice had a significantly lower content in both regions (0.116±0.010 vs. 0.107±0.005 mg/g dry weight). IMQ treatment led to significant expansion of IL-17 producing γδT cells in the skin, regional lymph nodes and in the spleen with typical skin lesions. Patients with psoriasis area and severity index (PASI) >5 had significantly higher sodium content in the skin compared to those with lower PASI or with healthy controls (17.73±1.52 vs. 14.32±1.54 vs. 14.30±2.59 AU, respectively); this elevation was water coupled. PASI significantly correlated with skin sodium content (Pearson’s r=0.598, P5 has higher sodium content in the affected skin compared to non-affected skin of the same patient. Data from animal models and humans argue for higher sodium accumulation in the inflamed skin.

Accurately collected 24-hour urine collections are presumed to be valid for estimating salt intake in individuals. We performed 2 independent ultralong-term salt balance studies lasting 105 (4 men) and 205 (6 men) days in 10 men simulating a flight to Mars. We controlled dietary intake of all constituents for months at salt intakes of 12, 9, and 6 g/d and collected all urine. The subjects’ daily menus consisted of 27 279 individual servings, of which 83.0% were completely consumed, 16.5% completely rejected, and 0.5% incompletely consumed. Urinary recovery of dietary salt was 92% of recorded intake, indicating long-term steady-state sodium balance in both studies. Even at fixed salt intake, 24-hour urine collection for sodium excretion (UNaV) showed infradian rhythmicity. We defined a ±25 mmol deviation from the average difference between recorded sodium intake and UNaV as the prediction interval to accurately classify a 3-g difference in salt intake. Because of the biological variability in UNaV, only every other daily urine sample correctly classified a 3-g difference in salt intake (49%). By increasing the observations to 3 consecutive 24-hour collections and sodium intakes, classification accuracy improved to 75%. Collecting seven 24-hour urines and sodium intake samples improved classification accuracy to 92%. We conclude that single 24-hour urine collections at intakes ranging from 6 to 12 g salt per day were not suitable to detect a 3-g difference in individual salt intake. Repeated measurements of 24-hour UNaV improve precision. This knowledge could be relevant to patient care and the conduct of intervention trials.

Sodium balance is achieved within a matter of days and everything that enters should come out; sodium stores are of questionable relevance and sodium accumulation is accompanied by weight gain. Careful balance studies oftentimes conflicted with this view, and long-term studies suggested that total body sodium (TBNa) fluctuates independent of intake or body weight. We recently performed the opposite experiment in that we fixed sodium intake for weeks at three levels of sodium intake and collected all urine made. We found weekly (circaseptan) patterns in sodium excretion that were inversely related to aldosterone and directly related to cortisol. TBNa was not dependent on sodium intake, but instead exhibited far longer (greater than or equal to monthly) infradian rhythms independent of extracellular water, body weight or blood pressure. To discern the mechanisms further, we delved into sodium magnetic resonance imaging (Na-MRI) to identify sodium storage clinically. We found that sodium stores are greater in men than in women, increase with age and are higher in hypertensive than normotensive persons. We have suggestive evidence that these sodium stores can be mobilized, also in dialysis patients. The observations are in accordance with our findings that immune cells regulate a hypertonic interface in the skin interstitium that could serve as a protective barrier. Returning to our balance studies, we found that due to biological variability in 24-h sodium excretion, collecting urine for a day could not separate 12, 9 or 6 g/day sodium intakes with the precision of tossing a coin. Every other daily urine sampling correctly classified a 3-g difference in salt intake less than half the time, making the gold standard 24-h urine collection of little value in predicting salt intake. We suggest that wobbles in expected outcomes can lead to novel clinical insights even with respect to banal salt questions.

OBJECTIVE: Hypertension is highly prevalent in patients with rheumatoid arthritis (RA). In other populations, high sodium (Na(+)) and low potassium (K(+)) intake are associated with an increased risk of hypertension, and in animal models a high salt intake exacerbated arthritis. Patients with RA have many comorbidities associated with salt-sensitivity, but their salt intake and its relationship to blood pressure and inflammation is unknown. METHODS: Using the Kawasaki formula, Na(+) and K(+) urinary excretion (reflecting intake) was estimated in 166 patients with RA and 92 controls, frequency matched for age, sex, and race. Inflammatory markers and disease activity were measured in RA patients. We tested the associations between blood pressure and Na(+) and K(+) excretion. RESULTS: Estimated 24 hour Na(+) excretion was similarly high in both RA (median [IQR] 5.1 g, [3.9 g–6.6 g]) and controls (4.9 g, [4.0 g–6.5 g]), p=0.9; despite higher rates of hypertension in RA (54% vs. 39%, p=0.03). The Na(+):K(+) excretion ratio was significantly higher in RA (2.0 [1.6–2.4]) vs. 1.7 [1.5–2.1]), p=0.02] compared to controls. In RA, a lower K(+) excretion was inversely correlated with diastolic blood pressure (adjusted-β= -1.79, p=0.04). There was no significant association between Na(+) or K(+) excretion and inflammatory markers. CONCLUSIONS: Despite a similar Na(+) excretion, patients with RA had higher rates of hypertension than controls, a finding compatible with increased salt sensitivity. Patients with RA had a lower Na(+):K(+) excretion ratio than controls, and lower K(+) excretion was associated with higher diastolic blood pressure in RA.

The pathogenesis of left ventricular hypertrophy in patients with CKD is incompletely understood. Sodium intake, which is usually assessed by measuring urinary sodium excretion, has been inconsistently linked with left ventricular hypertrophy. However, tissues such as skin and muscle may store sodium. Using 23sodium-magnetic resonance imaging, a technique recently developed for the assessment of tissue sodium content in humans, we determined skin sodium content at the level of the calf in 99 patients with mild to moderate CKD (42 women; median [range] age, 65 [23-78] years). We also assessed total body overhydration (bioimpedance spectroscopy), 24-hour BP, and left ventricular mass (cardiac magnetic resonance imaging). Skin sodium content, but not total body overhydration, correlated with systolic BP (r=0.33, P=0.002). Moreover, skin sodium content correlated more strongly than total body overhydration did with left ventricular mass (r=0.56, P

We have previously reported that sodium is stored in skin and muscle. The amounts stored in hemodialysis (HD) patients are unknown. We determined whether (23)Na magnetic resonance imaging (sodium-MRI) allows assessment of tissue sodium and its removal in 24 HD patients and 27 age-matched healthy controls. We also studied 20 HD patients before and shortly after HD with a batch dialysis system with direct measurement of sodium in dialysate and ultrafiltrate. Age was associated with higher tissue sodium content in controls. This increase was paralleled by an age-dependent decrease of circulating levels of vascular endothelial growth factor-C (VEGF-C). Older (60 years) HD patients showed increased sodium and water in skin and muscle and lower VEGF-C levels compared with age-matched controls. After HD, patients with low VEGF-C levels had significantly higher skin sodium content compared with patients with high VEGF-C levels (low VEGF-C: 2.3 ng/ml and skin sodium: 24.3 mmol/l; high VEGF-C: 4.1 ng/ml and skin sodium: 18.2 mmol/l). Thus, sodium-MRI quantitatively detects sodium stored in skin and muscle in humans and allows studying sodium storage reduction in ESRD patients. Age and VEGF-C-related local tissue-specific clearance mechanisms may determine the efficacy of tissue sodium removal with HD. Prospective trials on the relationship between tissue sodium content and hard end points could provide new insights into sodium homeostasis, and clarify whether increased sodium storage is a cardiovascular risk factor.

High dietary salt intake is associated with hypertension; the prevalence of salt-sensitive hypertension increases with age. We hypothesized that tissue Na + might accumulate in hypertensive patients and that aging might be accompanied by Na + deposition in tissue. We implemented 23 Na magnetic resonance imaging to measure Na + content of soft tissues in vivo earlier, but had not studied essential hypertension. We report on a cohort of 56 healthy control men and women, and 57 men and women with essential hypertension. The ages ranged from 22 to 90 years. 23 Na magnetic resonance imaging measurements were made at the level of the calf. We observed age-dependent increases in Na + content in muscle in men, whereas muscle Na + content did not change with age in women. We estimated water content with conventional MRI and found no age-related increases in muscle water in men, despite remarkable Na + accumulation, indicating water-free Na + storage in muscle. With increasing age, there was Na + deposition in the skin in both women and men; however, skin Na + content remained lower in women. Similarly, this sex difference was found in skin water content, which was lower in women than in men. In contrast to muscle, increasing Na + content was paralleled with increasing skin water content. When controlled for age, we found that patients with refractory hypertension had increased tissue Na + content, compared with normotensive controls. These observations suggest that 23 Na magnetic resonance imaging could have utility in assessing the role of tissue Na + storage for cardiovascular morbidity and mortality in longitudinal studies.

Background. Recent experimental findings demonstrate vascular endothelial growth factor C (VEGF-C)-mediated water-free storage of salt in the interstitium, which prevents a salt-sensitive blood pressure state. It is unknown whether this mechanism plays a role in salt homeostasis and regulation of blood pressure in humans as well. Therefore, we investigated circulating VEGF-C levels and blood pressure during different well-controlled salt intake in chronic kidney disease (CKD) patients and in healthy subjects.Methods. In two crossover studies, non-diabetic proteinuric CKD patients (n = 32) and healthy subjects (n = 31) were treated with consecutively a low-sodium diet (LS, aim 50 mmol Na+/day) and a high-sodium diet (HS, aim 200 mmol Na+/day) in random order, during two 6-week (CKD patients) and two 1-week periods (healthy subjects).Results. We found that VEGF-C levels are higher during HS than during LS in CKD patients (P = 0.034) with a trend towards higher VEGF-C in healthy subjects as well (P = 0.070). In CKD patients, HS was associated with higher NT-proBNP levels (P = 0.005) and body weight (P = 0.013), consistent with extracellular volume (ECV) expansion and with higher blood pressure (P Discussion. Our findings support a role for VEGF-C-mediated salt homeostasis in humans. Considering the salt sensitivity of blood pressure, this buffering mechanism appears to be insufficient in proteinuric CKD patients. Future studies are needed to provide causality and to substantiate the clinical and therapeutic relevance of this VEGF-C regulatory mechanism in humans.

Background— Angiotensin (Ang) II–induced target-organ damage involves innate and acquired immunity. Mice deficient for the helix-loop-helix transcription factor inhibitor of differentiation (Id2 −/− ) lack Langerhans and splenic CD8a+ dendritic cells, have reduced natural killer cells, and have altered CD8 T-cell memory. We tested the hypothesis that an alteration in the number and quality of circulating blood cells caused by Id2 deletion would ameliorate Ang II–induced target-organ damage. Methods and Results— We used gene-deleted and transgenic mice. We conducted kidney and bone marrow transplants. In contrast to Ang II–infused Id2 +/− , Id2 −/− mice infused with Ang II remained normotensive and failed to develop albuminuria or renal damage. Bone marrow transplant of Id2 +/− bone marrow to Id2 −/− mice did not restore the blunted blood pressure response to Ang II. Transplantation of Id2 −/− kidneys to Id2 +/− mice also could not prevent Ang II–induced hypertension and renal damage. We verified the Ang II resistance in Id2 −/− mice in a model of local tissue Ang II production by crossing hypertensive mice transgenic for rat angiotensinogen with Id2 −/− or Id2 +/− mice. Angiotensinogen-transgenic Id2 +/− mice developed hypertension, albuminuria, and renal injury, whereas angiotensinogen-transgenic Id2 −/− mice did not. We also found that vascular smooth muscle cells from Id2 −/− mice showed an antisenescence phenotype. Conclusions— Our bone marrow and kidney transplant experiments suggest that alterations in circulating immune cells or Id2 in the kidney are not responsible for Ang II resistance. The present studies identify a previously undefined role for Id2 in the pathogenesis of Ang II–induced hypertension.

Objective: Angiogenesis inhibition with the VEGF-inhibitor sunitinib, an established anti-cancer therapy, induces hypertension and proteinuria. Exposed to osmotic stress, the mononuclear-phagocyte-system (MPS) cells produces VEGF-C and exert homeostatic regulatory activity by promoting lymphatic Na+ drainage; interference with this process resulted in salt-sensitive hypertension. Therefore, we hypothesized that sunitinib, via blockade of the VEGF pathway, leads to Na+ accumulation in the skin and salt-sensitive hypertension. Design and Methods: In male WKY rats, mean arterial pressure (MAP) was monitored telemetrically during oral treatment with sunitinib (7 mg/kg.day, n=7-8) or vehicle (n=7-8) after a normal salt diet (NSD: 0.5-1.0% NaCl and tap water) or a high salt diet (HSD: 8% NaCl and saline water) for 2 weeks. After 8 days of sunitinib or vehicle administration, 24-h urine was collected. After sacrificing, blood was collected for biochemical measurements, skin for Na+ concentration ([Na+]) using dry-ashing, and ears for staining of MPS cells (CD68). Results: MAP during NSD was 101±0.9 mmHg. HSD increased MAP by 27±3 mmHg (P Conclusions: Angiogenesis inhibition-induced hypertension is salt-sensitive. The parallel increases in BP and skin [Na+], in the face of unaltered plasma [Na+] and bodyweight, support the existence of a Na+-buffering compartment in the skin that may contribute to the salt-dependent volume and BP homeostasis during VEGF inhibition.

Nutrients are required for the structure and function of every cell and each body system, regardless of the environment. However, changes in environment can have significant effects on nutrient metabolism and requirements. Thus, defining the nutrient requirements for spaceflight and ensuring the provision and intake of those nutrients are primary issues for crew health and mission success.

OBJECTIVE: Na+ can be stored in muscle and skin without commensurate water accumulation. The aim of this study was to assess Na+ and H2O in muscle and skin with MRI in acute heart failure patients before and after diuretic treatment and in a healthy cohort. METHODS: Nine patients (mean age 78 years; range 58-87) and nine age and gender-matched controls were studied. They underwent 23Na/1H-MRI at the calf with a custom-made knee coil. Patients were studied before and after diuretic therapy. 23Na-MRI gray-scale measurements of Na+-phantoms served to quantify Na+-concentrations. A fat-suppressed inversion recovery sequence was used to quantify H2O content. RESULTS: Plasma Na+-levels did not change during therapy. Mean Na+-concentrations in muscle and skin decreased after furosemide therapy (before therapy: 30.7+/-6.4 and 43.5+/-14.5 mmol/L; after therapy: 24.2+/-6.1 and 32.2+/-12.0 mmol/L; p

The vitamin B-complex group and vitamin C are the so-called water-soluble vitamins, which dissolve in water and are not stored by the body (IOM (Institute of Medicine) Standing Committee on the Scientific Evaluation of Dietary Reference Intakes 1998). As they are eliminated in urine, a continuous daily supply in the diet is required. Eight of the water-soluble vitamins are known as the vitamin B-complex group: folate (folic acid), thiamin (vitamin B1), riboflavin (vitamin B2), niacin (vitamin B3), vitamin B6 (pyridoxine), vitamin B12, biotin, and pantothenic acid. B vitamins fall into two categories. They are involved in the reactions of intermediary metabolism related to energy production and redox status, or they are involved in the transfer of single-carbon units (IOM (Institute of Medicine) Standing Committee on the Scientific Evaluation of Dietary Reference Intakes 1998). Moreover, vitamin C is a water-soluble vitamin and it is essential for humans, as we do not have the ability to biosynthesize the compound from glucose due to the lack of gulonolactone oxidase. Vitamin C functions physiologically as a water-soluble antioxidant. It is a matter of concern that water-soluble vitamins are easily destroyed or washed out during food storage and preparation. Despite the presence of fruits and vegetables in the daily diet, nutrient loss is possible during the storage and processing of food. This is also of concern for spaceflight and especially for long-term spaceflight. The space radiation environment is another critical factor that must be controlled for an adequate intake of water-soluble vitamins (Smith and Zwart 2008). Not all water-soluble vitamins are critical or of concern for crewmembers. In the following discussions, only the spaceflight-relevant water-soluble vitamins are pointed out.

Background: Sodium accumulation has been considered to take place in the extracellular space, leading to water retention and weight gain. This traditional view has been questioned by recent studies that showed sodium accumulation in humans without expansion of the extracellular volume. We investigated sodium balance and its impact on body weight (BW) during a long-term balance study. Methods: Three healthy subjects were confined to a terrestrial MIR simulator for 135 days under conditions simulating a long-term spaceflight. During the entire isolation period, we meticulously measured daily sodium balance and its contribution to BW. Results: During the study period, subjects accumulated between 2,973 and 7,324 mmol of sodium and gained between 5.1 and 9.3 kg in weight. In all subjects, there was a positive correlation between changes in total-body sodium (ΔTBS) content and BW, reflecting sodium-associated volume expansion. However, toward the end of isolation, sodium gain exceeded weight gain, suggesting that sodium accumulated in an osmotically inactive form. Especially at the onset of the experiment, two subjects showed inverse correlations between ΔTBS and BW. Conclusion: The finding of sodium gain without weight gain is in contradiction to the widely accepted theory that changes in TBS levels are accompanied by changes in extracellular volume. We suggest the existence of a sodium reservoir with the ability to store significant amounts of sodium in an osmotically inactive form. This reservoir might be located in bone, dense connective tissue, or cartilage. © 2002 by the National Kidney Foundation, Inc.

The lymphocyte adaptor protein LNK (also known as SH2B3) is primarily expressed in hematopoietic and endothelial cells, where it functions as a negative regulator of cytokine signaling and cell proliferation. Single-nucleotide polymorphisms in the gene encoding LNK are associated with autoimmune and cardiovascular disorders; however, it is not known how LNK contributes to hypertension. Here, we determined that loss of LNK exacerbates angiotensin II-induced (Ang II-induced) hypertension and the associated renal and vascular dysfunction. At baseline, kidneys from Lnk-/- mice exhibited greater levels of inflammation, oxidative stress, and glomerular injury compared with WT animals, and these parameters were further exacerbated by Ang II infusion. Aortas from Lnk-/- mice exhibited enhanced inflammation, reduced nitric oxide levels, and impaired endothelial-dependent relaxation. Bone marrow transplantation studies demonstrated that loss of LNK in hematopoietic cells is primarily responsible for the observed renal and vascular inflammation and predisposition to hypertension. Ang II infusion increased IFN-γ-producing CD8+ T cells in the spleen and kidneys of Lnk-/- mice compared with WT mice. Moreover, IFN-γ deficiency resulted in blunted hypertension in response to Ang II infusion. Together, these results suggest that LNK is a potential therapeutic target for hypertension and its associated renal and vascular sequela.

The widely accepted concept of body fluid and electrolyte homeostasis is that Na(+) is restricted mainly to the extracellular fluid and K(+) to the intracellular space, where both ions act to hold water and thereby control the extracellular and intracellular fluid volume by their osmotic activity. Na(+) accumulation thus inevitably leads to water retention. The constancy of the extracellular volume is the task of the kidneys, which control the total body Na(+) content. More recent data have questioned this traditional view, suggesting that large amounts of Na(+) can be accumulated without accompanying water retention by osmotically inactive Na(+) retention, or by osmotically neutral Na(+)/K(+) exchange. Besides the control of the body Na(+) content by the kidneys, redistribution of body electrolytes hence provides an extrarenal regulatory alternative in the maintenance of body fluid volume and blood pressure control.

Current teaching states that when sodium intake is increased from low to high levels, total-body sodium (TBNa) and water increase until daily sodium excretion again equals intake. When sodium intake is reduced, sodium excretion briefly exceeds intake until the excess TBNa and water are eliminated, at which point sodium excretion again equals intake. However, careful balance studies oftentimes conflict with this view and long-term studies suggest that TBNa fluctuates independent of intake or body weight. We recently performed the opposite experiment in that we fixed sodium intake for several weeks at three levels of sodium intake and collected all urine made. We found weekly (circaseptan) patterns in sodium excretion that were inversely related to aldosterone and directly to cortisol. TBNa was not dependent on sodium intake but instead exhibited far longer (≥ monthly) infradian rhythms independent of extracellular water, body weight, or blood pressure. The findings are consistent with our ideas on tissue sodium storage and its regulation that we developed on the basis of animal research. We are implementing (23)Na-magnetic resonance imaging (MRI) to pursue open questions on sodium balance in patients. Our findings could be relevant to therapeutic strategies for hypertension and target-organ damage.

In contrast to AL amyloidosis, where clonal plasma cells in bone marrow produce immunoglobulins that are amyloidogenic, and familial amyloidoses in which a mutant protein forms amyloid fibrils, the incidence of AA amyloidoses has been reduced since the treatment of infectious diseases and rheumatoid arthritis improved. AA amyloidoses are due to amyloid formed from serum amyloid A, an acute phase protein produced in response to inflammation. With the reduction of chronic infectious diseases such as tuberculosis or osteomyelitis from the western hemisphere, AA amyloidosis is rarely seen; however, it still occurs in patients with rheumatoid arthritis, inflammatory bowel disease or untreated Mediterranean fever. We report an unusual case of chronic hidradenitis suppurativa leading to AA amyloidosis.

Hypertension is a common disorder with uncertain etiology. In the last several years, it has become evident that components of both the innate and adaptive immune system play an essential role in hypertension. Macrophages and T cells accumulate in the perivascular fat, the heart and the kidney of hypertensive patients and in animals with experimental hypertension. Various immunosuppressive agents lower blood pressure and prevent end-organ damage. Mice lacking lymphocytes are protected against hypertension, and adoptive transfer of T cells, but not B cells in the animals restores their blood pressure response to stimuli such as angiotensin II or high salt. Recent studies have shown that mice lacking macrophages have blunted hypertension in response to angiotensin II and that genetic deletion of macrophages markedly reduces experimental hypertension. Dendritic cells have also been implicated in this disease. Many hypertensive stimuli have triggering effects on the central nervous system and signals arising from the circumventricular organ seem to promote inflammation. Studies have suggested that central signals activate macrophages and T cells, which home to the kidney and vasculature and release cytokines, including IL-6 and IL-17, which in turn cause renal and vascular dysfunction and lead to blood pressure elevation. These recent discoveries provide a new understanding of hypertension and provide novel therapeutic opportunities for treatment of this serious disease.

Schmaderer et al1 indicate that they had no success increasing blood pressure further in spontaneously hypertensive rats after giving them clodronate-laden liposomes. They studied spontaneously hypertensive rats and Wistar-Kyoto control rats with radiotelemetry. We cannot explain the findings of this carefully done study; however, we have no data on salt intake and interstitial sodium contents in these animals, no histology was shown, and no information on macrophage disposition was given. We are not macrophage biologists. …

Catheter-based renal sympathetic denervation for resistant hypertension: A multicenter safety and proof-of-principle cohort study. Lancet 373: 1275–1281, 2009 {#article-title-2} 1886 1888 Upon the initiative of Smithwick and Thompson (1) of the Massachusetts General Hospital, resection of the splanchnic nerves through a posterior infradiaphragmatic approach plus removal of the sympathetic chain from the level of the eighth dorsal ganglion to the second lumbar ganglion had been used with relative frequency in cases of desperate hypertension at the time when antihypertensive medication was not yet available. In the hands of other investigators, the results were spectacular in a minority of patients but not quite satisfactory in many patients (2,3). Despite improvement of headache, reversal of papilledema in malignant hypertension, etc. , the long-term reduction of BP was quite variable and the 5-yr mortality remained approximately 40% (2). A 10-yr follow-up compared 100 patients who were subjected to thoracolumbar sympathectomy with 1500 patients who received symptomatic therapy. Lasting BP reduction was seen only in one third of the patients (4). Whereas the average BP levels were reduced, occasional BP spikes were not. The average difference of preoperative to postoperative systolic BP values was 21 mmHg. The authors saw reduction of cerebrovascular accidents and less progression of proteinuria and renal dysfunction, but 10-yr mortality was still 41%. Against this background, once effective antihypertensive medication was available, this relatively crude procedure fell out of favor and remained a sleeping beauty. With today's better insight into the role of sympathetic activity in the genesis of hypertension and particularly the role of the kidney in sympathetic activation, there has been a renaissance in the interest of the renal sympathetic nervous system, including its role in primary hypertension—apart from its undoubted role in the hypertension of chronic kidney disease (5–10). Renal disease and, in animal experiments, even minor renal tissue damage such as injection of minute volumes of phenol, trigger afferent signals that ascend via …

markdownabstractAngiogenesis inhibition with the VEGF-inhibitor sunitinib, an established anti-cancer therapy, induces hypertension and proteinuria. Exposed to osmotic stress, the Mononuclear-phagocyte-system cells produces VEGF-C and exert homeostatic regulatory activity by promoting lymphatic Na+ drainage; interference with this process resulted in salt-sensitive hypertension. Therefore, we hypothesized that sunitinib via blockade of the VEGF pathway leads to Na+ accumulation in the skin and salt-sensitive hypertension. In male WKY rats, mean arterial pressure (MAP) was monitored telemetrically during oral treatment with sunitinib (7 mg/kg.day, n = 4-8) or vehicle (n = 4-8) after a normal salt diet (NSD: 0.5-1.0% NaCl and tap water) or a high salt diet (HSD: 8% NaCl and saline water) for 2 weeks. After 8 days of sunitinib or vehicle administration, 24-h urine was collected. After sacrificing, blood was collected for biochemical measurements and skin for Na+ concentration ([Na+]) using dry-ashing. MAP during NSD was 101 ± 0.9 mmHg. HSD increased MAP by 27 ± 3 mmHg (P

Background Sodium and potassium intake are modifiable determinants of blood pressure in the general population. Higher sodium and lower potassium urinary excretion, as well as a higher sodium:potassium ratio, are associated with elevated blood pressure. The prevalence of hypertension and cardiovascular disease are increased in systemic lupus erythematosus (SLE), but the contribution of sodium and potassium intake is not known. Objectives To examine the hypothesis that urinary excretion of sodium and potassium are related to blood pressure in SLE. Methods We studied 178 patients with SLE and 86 controls frequency-matched for age, sex, and race. First morning urine specimens were collected and urine sodium and potassium concentrations measured by flame photometry. The Kawasaki formula, a validated method that incorporates age, sex, height, weight, and urinary creatinine, was used to estimate 24 hour urine sodium and potassium excretion. Blood pressure was the average of two resting measurements. Fisher9s exact and Mann-Whitney U tests were used to compare categorical and continuous variables, respectively. The associations between systolic (SBP) and diastolic blood pressures (DBP) with estimated 24 hour urinary sodium, potassium, and sodium:potassium ratio were tested using Spearman correlation and then modeled using linear regression adjusting for age, sex, and race. Two-sided p values Results SLE patients and controls had a similar mean age (40.8±12.4 vs. 41.2±12.0, p=0.76), were predominantly female (88% vs. 86%, p=0.70) and Caucasian (68% vs. 72%, p=0.67). Compared to controls, SLE patients had significantly higher rates of hypertension (44% vs. 19%, p Conclusions SLE patients had significantly lower estimated 24 hour urinary potassium and higher estimated 24 hour urinary sodium:potassium ratio than control subjects. The estimated 24 hour urinary sodium:potassium ratio was significantly associated with SBP and DBP in SLE patients. Further studies are needed to evaluate the impact of diets with low sodium and high potassium content on blood pressure in SLE patients. Disclosure of Interest None declared