Skin Sodium Content Research Articles

Sodium loading in ambulatory patients with heart failure with reduced ejection fraction: Mechanistic insights into sodium handling.

Sodium restriction was not associated with improved outcomes in heart failure patients in recent trials. The skin might act as a sodium buffer, potentially explaining tolerance to fluctuations in sodium intake without volume overload, but this is insufficiently understood. Therefore, we studied the handling of an increased sodium load in patients with heart failure with reduced ejection fraction (HFrEF). Twenty-one ambulatory, stable HFrEF patients and 10 healthy controls underwent a 2-week run-in phase, followed by a 4-week period of daily 1.2 g (51 mmol) sodium intake increment. Clinical, echocardiographic, 24-h urine collection, and bioelectrical impedance data were collected every 2 weeks. Blood volume, skin sodium content, and skin glycosaminoglycan content were assessed before and after sodium loading. Sodium loading did not significantly affect weight, blood pressure, congestion score, N-terminal pro-brain natriuretic peptide, echocardiographic indices of congestion, or total body water in HFrEF (all p > 0.09). There was no change in total blood volume (4748 ml vs. 4885 ml; p = 0.327). Natriuresis increased from 150 mmol/24 h to 173 mmol/24 h (p = 0.024), while plasma renin decreased from 286 to 88 μU/L (p = 0.002). There were no significant changes in skin sodium content, total glycosaminoglycan content, or sulfated glycosaminoglycan content (all p > 0.265). Healthy controls had no change in volume status, but a higher increase in natriuresis without any change in renin. Selected HFrEF patients can tolerate sodium loading, with increased renal sodium excretion and decreased neurohormonal activation.

Skin sodium content as a predictor of blood pressure response to renal denervation

Patients with treatment resistant hypertension (TRH) are known to have elevated sodium (Na) content in muscle and skin. Renal denervation (RDN) emerged as an adjacent therapeutic option in this group of patients. This analysis aimed at evaluating whether tissue Na content predicts blood pressure (BP) response after RDN in patients with TRH. Radiofrequency-device based RDN was performed in 58 patients with uncontrolled TRH. Office and 24-h ambulatory BP were measured at baseline and after 6 months. To assess tissue Na content Na magnetic resonance imaging (Na-MRI) was performed at baseline prior to RDN. We splitted the study cohort into responders and non-responders based on the median of systolic 24-h ambulatory blood pressure (ABP) reduction after 6 months and evaluated the association between BP response to RDN and tissue Na content in skin and muscle. The study was registered at http://www.clinicaltrials.gov (NCT01687725). Six months after RDN 24-h ABP decreased by −8.6/−4.7 mmHg. BP-Responders were characterized by the following parameters: low tissue sodium content in the skin (p = 0.040), female gender (p = 0.027), intake of aldosterone antagonists (p = 0.032), high baseline 24-h night-time heart rate (p = 0.045) and high LDL cholesterol (p < 0.001). These results remained significant after adjustment for baseline 24-h systolic BP. Similar results were obtained when the median of day-time and night-time ABP reduction after 6 months were used as cut-off criteria for defining BP response to RDN. We conclude that in addition to clinical factors including baseline 24-h ABP Na-MRI may assist to select patients with uncontrolled TRH for RDN treatment.

#4196 MAGNETIC RESONANCE IMAGING ASSESSMENT OF SKIN AND MUSCLE SODIUM IN HAEMODIALYSIS

Abstract Background and Aims Haemodialysis (HD) is life sustaining for patients with end-stage kidney disease (ESKD) but is associated with a marked increase in incidence of cardiovascular disease (CVD) and high annual mortality rates. Sodium balance is regulated by the kidneys in health but has to be achieved by sodium removal during HD for those with ESKD. Recent evidence suggests that non-osmotically stored sodium in the muscle and/or skin may be a critical factor impacting the development of hypertension and CVD. Sodium magnetic resonance imaging (23Na MRI) allows assessment of skin and muscle sodium storage and may provide a valuable tool in evaluating sodium storage in dialysis patients. In this study, we used 23Na MRI to measure muscle and skin sodium content in younger and older healthy individuals and people receiving HD, and investigated the effect of a single dialysis session on muscle and skin sodium content. Method 23Na MRI was acquired on a 3T Philips Ingenia scanner using a custom-made 23Na RF coil. 3D GRE 23Na scans (3 × 3 × 30mm3, 10 slices) were acquired in a 15-minute scan. Four reference bottles of increasing sodium concentration were placed in the RF coil above the leg to calibrate sodium concentration. In the same imaging session, 1H MR images were acquired to delineate muscle groups, skin structures and tissue water content. 23Na concentration maps were generated using custom software and regions of interest of each muscle and the skin were manually segmented. Data was collected on 14 younger (23-38yrs,7M:7F) and three older (66-77yrs,3M:1F) healthy volunteers (HVs), and 5 male HD patients (55-68 yrs) who had been on HD for more than 3-months. HD patients underwent a pre-dialysis 23Na MRI calf scan, then had their usual dialysis session with a dialysate Na prescription of 137 mmol/L, followed by a repeat 23Na MRI calf scan post dialysis. Patient demographics, dialysis vintage, residual renal function, and ultrafiltration volume were collected, along with blood samples at the start and end of the dialysis session, including serum sodium. Results Figure 1 shows 23Na images in the younger and older HV group and HD patients pre-dialysis. Muscle and skin sodium was increased in older HVs compared to younger, with HD patients pre-dialysis tending to be lower than older HVs (Fig. 2). HD patients’ demographics and clinical measures pre- and post-dialysis are shown in Table 1. HD treatment reduced muscle sodium whilst skin sodium showed little change (Fig. 3). Conclusion We have optimised methods for measuring muscle and skin sodium. 23Na concentration in muscle and skin is higher in older subjects. HD patients’ 23Na values fall between those observed in the older and younger HV groups. These values are consistent with published data from patients dialysed against 137mmol/l sodium dialysate, but lower than other studies in which dialysate sodium levels were higher. Further studies are planned to study the effect of dialysate sodium on skin and muscle sodium concentrations and mechanistic links to cardiovascular disease.

A KETOGENIC DIET REDUCES TISSUE SODIUM CONTENT: AN EXPLORATORY STUDY

Objective: Hypertension and diabetes are a substantial global public health problem. The prevalence of these diseases will further increase in the near future, leading to increased health and socioeconomic costs. Hence efficient therapeutic approaches are urgently needed. It has been previously shown that nutritional approaches including a very-low carbohydrate, or a ketogenic diet potentially decrease body weight, blood pressure and glucose levels in patients with type 2 diabetes along with an overall significant reduction in their pill burden. However, the detailed physiological mechanisms underlying the observed induction and maintenance of diabetes remission remain largely unknown. Previous studies have shown that the skin could be a buffer system for sodium and that skin sodium content could be both a pathogenic cause and a marker of hypertension and salt sensitivity. Since a nutritionally created metabolic milieu such as nutritional ketosis can lower blood pressure, we hypothesize that this dietary approach also reduces tissue sodium content. Design and method: By using 7-T 23Na MRI technique, we performed an exploratory study and analyzed skin and muscle sodium concentration before, and after a 6-week ketogenic diet in three healthy probands. Nutritional ketosis was verified by frequent check of blood ketone (beta-hydroxybutyrate; BOHB) levels greater than 0.3 mmol/L. Results: Preliminary data of our planned exploratory study (in patients with chronic kidney disease and type 2 diabetes mellitus and healthy probands) demonstrated that compared to baseline 6 weeks of ketogenic diet decreased tissue sodium content in the skin (16.6 ± 2.1 vs. 12.6 ± 2.1 mmol/L), in the medial gastrocnemius muscle (20.5 ± 0.9 vs. 16.7 ± 0.7 mmol/L), in the lateral gastrocnemius muscle (19.7 ± 1.0 vs. 16.0 ± 1.0 mmol/L) and in the soleus muscle (13.1 ± 0.8 vs. 11.5 ± 0.5 mmol/L). Conclusions: Our results indicate a massive reduction of tissue sodium concentration in healthy volunteers in response to a ketogenic diet which might be associated with the observed clinical benefits and be implicated in the anti-hypertensive effects of this powerful dietary intervention. Findings of this study could have an impact on future treatment strategies of various chronic diseases.

S-27-2: RENAL WATER LOSS-INDUCED SKIN WATER CONSERVATION LEADS TO HIGH BLOOD PRESSURE IN SPONTANEOUSLY HYPERTENSIVE RATS

Objective: Although previous studies have demonstrated the pathophysiological basis of hypertension in basic and clinical sciences, the decisive mechanism of essential hypertension remains to be clarified. We recently reported that 5/6 nephrectomized rats exhibited renal water loss due to impaired renal concentration ability and that the renal water loss triggered suppression of transepidermal water loss (TEWL). This skin water conservation was achieved by skin vasoconstriction-mediated reduction in skin vascular mass, which increased blood pressure in 5/6 nephrectomized rats. In this study, we examined the effect of renal and skin water handling on high blood pressure in spontaneously hypertensive rats (SHR). Design and method: We used male 9 weeks old SHR and its control normotensive Wistar Kyoto rats (WKY) in this study. The rats were kept in metabolic cages to collect urine for 24 hours. We also collected urine under water deprivation. After the urine collection, the rats were sacrificed and their plasma and tissues were collected. Skin sodium and potassium content were measured by the ashing-flame photometer method. In a separate experiment, we compared blood pressure and TEWL in anesthetized SHR and WKY. Body temperature was raised by elevating room temperature. Results: Compared with WKY, SHR exhibited a significant increase in urine volume and a decrease in urine osmolality. There were no significant differences in plasma osmole concentrations, urinary sodium, potassium, and urea excretion between the groups. SHR showed significantly higher urine volume and lower urine osmolarity than WKY even in water deprivation, suggesting that SHR has renal water loss. SHR exhibited significantly lower TEWL and higher blood pressure and skin sodium and potassium content compared with WKY. Skin vasodilation induced by elevating body temperature significantly reduced blood pressure in SHR but not WKY. Conclusions: These findings suggest that renal water loss due to the impaired renal concentration ability induces suppression of TEWL and skin osmole accumulation in SHR. This skin water conservation leads to high blood pressure via skin vasoconstriction to reduce skin vascular mass and TEWL. Skin water conservation as a compensatory mechanism for renal water loss may be a key mechanism and novel therapeutic target for essential hypertension.

The SGLT2 inhibitor empagliflozin reduces tissue sodium content in patients with chronic heart failure: results from a placebo-controlled randomised trial

IntroductionSodium-glucose co-transporter 2 (SGLT2) inhibitors have cardiovascular protective properties in addition to the metabolic effects and represent a cornerstone of treating patients with chronic heart failure (CHF). We hypothesised that empagliflozin reduces tissue sodium content in patients with CHF.MethodsIn a double-blind, randomised (2:1), placebo-controlled, parallel-group, clinical trial, 74 patients with NYHA class II–III CHF and an ejection fraction of 49% or less received empagliflozin 10 mg once daily or placebo for 3 months. In each patient, tissue sodium content of the lower leg was assessed non-invasively by sodium-MRI (23Na-MRI) at baseline, after 1 and 3 months of treatment.ResultsAfter 1 and 3 months treatment with empagliflozin (n = 48), a significant decrease in skin sodium content was observed (1 month: 22.8 ± 6.1 vs. 21.6 ± 6.0 AU, p = 0.039; 3 months: 22.9 ± 6.1 vs. 21.6 ± 6.1 AU, p = 0.013), while there was no change in muscle sodium and muscle water content. In direct comparison, the change in skin sodium content between baseline and 3 months was − 1.3 ± 3.5 AU in the empagliflozin group versus 0.6 ± 3.5 AU in the placebo group (p for between-group difference = 0.022). No significant difference regarding change in muscle sodium and in muscle water content was observed after 3 months treatment between the two groups.ConclusionThis trial showed a significant decrease in skin sodium content after 1 and 3 months of treatment with empagliflozin. The decrease in skin sodium content may reflect a decrease in subclinical micro-oedema or/and in non-osmotic bound tissue sodium, both reported to impair left ventricular function.Trial registration numberNCT03128528 (http://www.clinicaltrials.gov).Trial registration date25th April 2017.

Contributions of renal water loss and skin water conservation to blood pressure elevation in spontaneously hypertensive rats.

We recently reported that skin vasoconstriction to suppress transepidermal water loss (TEWL) leads to hypertension in renal injury model rats with impaired urine concentration ability. In this study, we investigated the pathogenesis of hypertension in spontaneously hypertensive rats (SHRs) from the perspective of renal water loss and skin water conservation. We compared the urinary concentration ability, body sodium and water balance, blood pressure, and TEWL in SHRs and control normotensive Wistar-Kyoto rats (WKYs). SHRs showed significantly higher urine volume and lower urinary osmolality than those of WKYs, while there were no significant differences in water intake, urinary osmolyte excretion, and plasma osmolarity between the groups. SHRs exhibited significantly higher blood pressure, skin sodium content, and lower TEWL compared with those is WKYs. Skin vasodilation, induced by elevating body temperature, increased TEWL in both SHRs and WKYs, and significantly reduced blood pressure in SHRs but not WKYs. These findings suggest that physiological adaptation can reduce dermal water loss in SHRs to compensate for renal water loss. Vasoconstriction required for successful cutaneous water conservation explains SHR hypertension. Renal concentration ability and skin barrier function for water conservation may become a novel therapeutic target for essential hypertension.

Tissue Sodium Storage in Patients With Heart Failure: A New Therapeutic Target?

Preclinical data suggest sodium deposited (without water) in tissues may lead to aberrant remodeling and systemic inflammation, independently of fluid overload in patients with heart failure (HF). Tissue salt storage can be measured noninvasively and quantitatively with 23Na-magnetic resonance imaging. We aimed to investigate the possibility that patients with HF complicated by renal dysfunction are subject to higher tissue sodium concentration exposure than patients with chronic kidney disease alone. We conducted an exploratory study including 18 patients with HF, 34 hemodialysis patients (with no meaningful renal clearance of sodium), and 31 patients with chronic kidney disease, with glomerular filtration rate matched to the patients with HF. Every patient underwent 23Na-magnetic resonance imaging of the calf, to quantify tissue sodium and allow comparison among the 3 patient groups. There were no differences in age, sex, and body mass index between groups. Median (interquartile range) skin sodium content in HF (31 [23-37] mmol/L) was very high and indistinguishable from skin sodium content in hemodialysis patients (30 [22-35] mmol/L), P=0.6. Patients with HF exhibited significantly higher skin sodium content than matched estimated glomerular filtration rate chronic kidney disease patients (22 [19-26] mmol/L), P=0.005. Median muscle sodium content in patients with HF was significantly higher than in patients with chronic kidney disease, P=0.002. There was no relationship with estimated glomerular filtration rate in patients with HF. We report a significant correlation between skin sodium and urinary sodium (P=0.04) but no correlation with muscle sodium. Patients who were assessed as being volume depleted (sodium excretion fraction <1%) had lower skin sodium content than patients with sodium excretion fraction >1% (P=0.03). We have demonstrated that patients with HF characteristically have very high levels of skin sodium storage, comparable to well-characterized extreme levels seen in patients with end-stage kidney disease requiring hemodialysis. 23Na-magnetic resonance imaging may allow precision medicine in the management of this challenging group of patients with HF. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03004547.

Reduced tissue sodium content is related to improvement of vascular function in patients with chronic heart failure treated with the SGLT2 inhibitor empagliflozin

Abstract Background Large randomized controlled trials have demonstrated that SGLT2 inhibitors produce cardiovascular benefits beyond their metabolic effects. One of the assumed underlying mechanisms is the reduction of the left ventricular afterload. Factors aggravating the afterload are impaired vascular function (ventricular-arterial coupling) as well as high tissue sodium content, which exerts enhanced hypertrophic stimuli and exaggerated response to vasoconstrictors. Purpose We hypothesized that the SGLT2 inhibitor empagliflozin leads to afterload reduction in patients with chronic heart failure (CHF) by reducing tissue sodium content and improving vascular function and that these changes are related to each other. Methods In a randomized (2:1), investigator initiated, double-blind, placebo controlled, parallel-group, prospective clinical study, patients with CHF NYHA II-III and an ejection fraction of 49% or less were randomized to empagliflozin 10mg once daily or placebo. In each patient, we assessed vascular parameters under resting conditions (Sphygmocor) and 24-hour daily life conditions (Mobilograph), including central systolic pressure (cSBP) and central pulse pressure (cPP) among others. In parallel, we measured tissue (skin and muscle) sodium content of the lower leg by Sodium-MRI, at baseline and after 1 month of therapy. Results A total of 74 patients (men: n=62), aged 66±9 years, with a mean ejection fraction of 39±9% were included. Only 24% of the patients had type 2 diabetes. After 1 month treatment with empagliflozin, a decrease of skin sodium content was observed (22.8±6.1 vs. 21.6±6.0 mmol/l, p=0.039), while there was no significant change in muscle sodium and muscle water content. A decrease of cSBP (117.1±14.5 vs. 110.7±11.3 mmHg, p&amp;lt;0.001) and cPP (41.4±8.8 vs. 38.4±8.5 mmHg, p=0.004) under resting conditions was observed after 1 month treatment with empagliflozin, while changes in the placebo group were not significant for cSBP (117.0±18.1 vs. 116.3±15.0 mmHg, p=0.759) and cPP (40.6±9.1 vs. 39.4±8.6 mmHg, p=0.422). Similarly, there was a decrease of cSBP and cPP in patients with empagliflozin treatment under ambulatory conditions, but not in the placebo group. In the whole group, we observed a significant correlation between change in skin sodium content and change in vascular parameters such as cSBP (r=0.364, p=0.004) and cPP (r=0.250, p=0.054) after 1 month of treatment with empagliflozin or placebo. Conclusion(s) Significant changes in skin sodium content induced by empagliflozin and a significant correlation between changes in skin sodium content and vascular function suggest that a reduction of tissue sodium content may be one of the mechanisms underlying the beneficial effects of SGLT2 inhibitors in heart failure. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Boehringer Ingelheim International GmbH.

Tissue sodium content correlates with hypertrophic vascular remodeling in type 2 diabetes

BackgroundProspective studies describe a linkage between increased sodium intake and higher incidence of cardiovascular organ damage and end points. We analyzed whether tissue sodium content in the skin and muscles correlate with vascular hypertrophic remodeling, a risk factor for cardiovascular disease. MethodsIn patients with type 2 diabetes we assessed tissue sodium content and vascular structural parameters of the retinal arterioles. The structural parameters of retinal arterioles assessed by Scanning Laser Doppler Flowmetry were vessel (VD) and lumen diameter (LD), wall thickness (WT), wall-to-lumen ratio (WLR) and wall cross sectional area (WCSA). Tissue sodium content was measured with a 3.0 T clinical 23Sodium-Magnetic Resonance Imaging (23Na-MRI) system. ResultsIn patients with type 2 diabetes (N = 52) we observed a significant correlation between muscle sodium content and VD (p = 0.005), WT (p = 0.003), WCSA (p = 0.002) and WLR (p = 0.013). With respect to skin sodium content a significant correlation has been found with VD (p = 0.042), WT (p = 0.023) and WCSA (p = 0.019). Further analysis demonstrated that tissue sodium content of skin and muscle is a significant determinant of hypertrophic vascular remodeling independent of age, gender, diuretic use and 24-hour ambulatory BP. ConclusionWith the 23Na-MRI technology we could demonstrate that high tissue sodium content is independently linked to hypertrophic vascular remodeling in type 2 diabetes. Trial registrationTrial registration number: NCT02383238Date of registration: March 9, 2015.

Abstract 23: Body Fluid And Sodium Loss Leads To Aldosterone Hypersecretion And Muscle Catabolism In Hepatocellular Carcinoma Rats.

Background: The number of cancer survivors coincides with cardiovascular diseases is increasing, therefore, we are promoting the concept of “Onco-Hypertension” to clarify the mechanism linking cancer and blood pressure. In this study, we evaluated body osmolyte and water imbalance in hepatocellular cancer (HCC) model rats. Methods: Wistar rats were administered diethylnitrosamine (DEN) (1.5 μg/day, p.o.), a carcinogenic drug, for 8 weeks to establish liver cancer. Three weeks after the completion of DEN administration, we investigated blood pressure, tissue osmolyte and water content, and its association with aldosterone secretion. Results: HCC rats significantly reduced blood pressure, skin sodium, potassium, and water content. In the carcass (muscle + bone), dry weight, sodium, potassium, and water content were dramatically reduced without changing bone mass in HCC rats, suggesting that HCC causes muscle wasting to supply osmolyte and water for the dehydrated organs. These osmolytes and water loss were significantly associated with increased urinary aldosterone excretion. Supplementation of 0.25% salt water to drink improved body sodium and water loss and muscle wasting in HCC rats, which were completely suppressed by treatment with spironolactone (75 mg/kg/day, p.o.), a mineralocorticoid receptor (MR) blocker. Conclusion: These findings suggest that HCC causes body osmolyte and water loss, which leads to aldosterone hypersecretion and muscle catabolism to compensate for dehydration. A relatively small amount of salt supplement ameliorates the HCC-induced dehydration and muscle wasting via aldosterone/MR-mediated sodium and water restoration.

Skin Sodium Accumulates in Psoriasis and Reflects Disease Severity

Sodium can accumulate in the skin at concentrations exceeding serum levels. A high sodium environment can lead to pathogenic T helper 17 cell expansion. Psoriasis is a chronic inflammatory skin disease in which IL-17‒producing T helper 17 cells play a crucial role. In an observational study, we measured skin sodium content in patients with psoriasis and in age-matched healthy controls by Sodium-23 magnetic resonance imaging. Patients with PASI > 5 showed significantly higher sodium and water content in the skin but not in other tissues than those with lower PASI or healthy controls. Skin sodium concentrations measured by Sodium-23 spectroscopy or by atomic absorption spectrometry in ashed-skin biopsies verified the findings with Sodium-23 magnetic resonance imaging. Invitro T helper 17 cell differentiation of naive CD4+ cells from patients with psoriasis markedly induced IL-17A expression under increased sodium chloride concentrations. The imiquimod-induced psoriasis mouse model replicated the human findings. Extracellular tracer Chromium-51-EDTA measurements in imiquimod- and sham-treated skin showed similar extracellular volumes, rendering excessive water of intracellular origin. Chronic genetic IL-17A‒driven psoriasis mouse models underlined the role of IL-17A in dermal sodium accumulation and inflammation. Our data describe skin sodium as a pathophysiological feature of psoriasis, which could open new avenues for its treatment.

Skin sodium is increased in male patients with multiple sclerosis and related animal models

Novel MRI techniques allow a noninvasive quantification of tissue sodium and reveal the skin as a prominent compartment of sodium storage in health and disease. Since multiple sclerosis (MS) immunopathology is initiated in the periphery and increased sodium concentrations induce proinflammatory immune cells, the skin represents a promising compartment linking high sodium concentrations and MS immunopathology. We used a 7-T sodium MRI (23Na-MRI) and inductively coupled plasma mass spectrometry to investigate the skin sodium content in two mouse models of MS. We additionally performed 3-T 23Na-MRI of calf skin and muscles in 29 male relapsing-remitting MS (RRMS) patients and 29 matched healthy controls. Demographic and clinical information was collected from interviews, and disease activity was assessed by expanded disability status scale scoring. 23Na-MRI and chemical analysis demonstrated a significantly increased sodium content in the skin during experimental autoimmune encephalomyelitis independent of active immunization. In male patients with RRMS, 23Na-MRI demonstrated a higher sodium signal in the area of the skin compared to age- and biological sex-matched healthy controls with higher sodium, predicting future disease activity in cranial MRI. In both studies, the sodium enrichment was specific to the skin, as we found no alterations of sodium signals in the muscle or other tissues. Our data add to the recently identified importance of the skin as a storage compartment of sodium and may further represent an important organ for future investigations on salt as a proinflammatory agent driving autoimmune neuroinflammation such as that in MS.

Tissue sodium stores in peritoneal dialysis and hemodialysis patients determined by 23-sodium magnetic resonance imaging.

Tissue sodium content in patients on maintenance hemodialysis (MHD) and peritoneal dialysis (PD) were previously explored using 23Sodium magnetic resonance imaging (23NaMRI). Larger studies would provide a better understanding of sodium stores in patients on dialysis as well as the factors influencing this sodium accumulation. In this cross-sectional study, we quantified the calf muscle and skin sodium 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. Patients on MHD and PD exhibited significantly higher muscle and skin sodium accumulation compared to controls. African American patients on dialysis exhibited greater muscle and skin sodium content compared to non-African Americans. Multivariable analysis showed that older age was associated with both higher muscle and skin sodium. Male sex was also associated with increased skin sodium deposition. Greater ultrafiltration was associated with lower skin sodium in patients on PD (Spearman's rho=-0.68, P = 0.035). Higher plasma IL-6 and hsCRP levels correlated with increased muscle and skin sodium content in the overall study population. Patients with higher baseline tissue sodium content exhibited greater variability in tissue sodium stores on repeat measurements. Our findings highlight greater muscle and skin sodium content in dialysis patients compared to controls without kidney disease. Tissue sodium deposition and systemic inflammation seen in dialysis patients might influence one another bidirectionally.

Abstract 12895: Tissue Sodium Content Increases With Severity of Chronic Heart Failure

Introduction: Heart failure is strongly linked to renal sodium and water retention as well as intravascular and interstitial fluid shifts. Experimental studies demonstrated a non-osmotic sodium storage, bound to proteoglycans, in the extravascular space. New sodium magnetic resonance imaging ( 23 Na-MRI) enables us to quantify tissue (muscle and skin) sodium content in a reliable and accurate way. Hypothesis: We hypothesised that the increase of tissue sodium content is dependent on the severity of chronic heart failure (CHF). Methods: We investigated patients with stable CHF before initiating treatment with an SGLT2-inhibitor within a prospective, placebo-controlled study. We here report the baseline data of 64 patients with CHF, defined as patients with reduced (HFrEF) or mid-range ejection fraction (HFmEF). In each patient, tissue sodium content of the lower leg was assessed non-invasively by a clinical 3.0T 23 Na-MRI. The median NT-proBNP plasma level at baseline was 493.3pg/ml (IQR: 225.8-1122.0pg/ml) and was used as cut off value of CHF severity. Results: Our patients (men: n=54) were 66.9±8.9 years old and had NYHA class II-III; mean muscle sodium content was 19.1±3.8mmol/l and mean skin sodium content was 22.5±5.9mmol/l. Our reference for young healthy subjects are 18.7±2.0 mmol/l for muscle sodium content and 19.6±3.1 mmol/l for skin sodium content. Patients with CHF and NT-proBNP levels above the median showed higher muscle (20.2±3.5 vs 17.9±3.7mmol/l, p=0.008) and skin sodium content (24.1±6.8 vs 20.8±4.4mmol/l, p=0.005) than patients with CHF and NT-proBNP levels below the median. No difference in plasma sodium levels between the two groups (138.0±3.7 vs 138.8±2.1mmol/l, p=0.527) was observed, but patients with NT-proBNP levels above the median had lower urinary sodium excretion over 24 hours (167.0±78.8 vs 172.3±63.4mmol/l, p=0.009). Age was different in the two groups (69.88±8.2 vs 63.8±8.7, p&lt;0.001) with no difference in gender. The number of diagnosed coronary heart disease was similar in the two groups (62.5% vs 59.4%, p=0.802). Conclusion: Concluding, tissue sodium content in patients with stable CHF as assessed by 23 Na-MRI increases with the severity of CHF. A decrease of tissue sodium content might be a future therapeutic goal.

Abstract P180: Effect Of Sunitinib Treatment On Skin Sodium Accumulation In Patients With Metastatic Renal Cancer: A Pilot Study

Angiogenesis is required for invasive tumor growth and metastasis which is controlled mainly by vascular endothelial growth factors (VEGF). Novel strategies for cancer treatment target VEGF signaling. These agents are featured by adverse events including hypertension. New concepts suggest that besides the kidneys, the skin also plays a role in body sodium homeostasis and blood pressure regulation by a VEGF-C–dependent buffering mechanism. Here, we tested the hypothesis that changes in blood pressure correspond to tissue sodium accumulation during sunitinib treatment of metastatic renal cell carcinoma patients (https://clinicaltrials.gov/identifier: NCT04368546; Charité ethical approval EA1/044/15).Male patients (n=4) took sunitinib according to the standard treatment protocol, 50 mg once daily, taken for 4 weeks followed by a 2-weeks off treatment period. Measurements were performed at baseline (before sunitinib treatment), and over a complete on-off-on period. Tissue sodium content was measured using non-invasive 23Na-MRI; skin sodium was measured in a group (n=5) of age-matched healthy subjects, as well. Blood pressure was measured according to AHA guidelines. Blood withdrawal followed after ca. 45 minutes of sitting to measure VEGF-A, VEGF-C, endothelin-1, renin and aldosterone levels.Elevated systolic blood pressure under sunitinib treatment decreased to the baseline level in the off-treatment phase (130.5 mmHg vs 117.5 mmHg, respectively, p&lt;0.05). Plasma endothelin-1 levels mirrored directly and VEGF-A levels inversely the blood pressure changes. Baseline skin sodium content was similar to the skin sodium level of healthy controls. Skin sodium content was elevated after the first on-treatment phase and stayed high in all the following measurements in comparison to control subjects. Patients had high baseline VEGF-C levels that decreased after the first treatment with sunitinib and stayed low independently of further treatment phase.In conclusion, sunitinib treatment suppresses VEGF-C levels permanently which is associated with sustained elevated skin sodium levels. Furthermore, we confirmed the association between plasma endothelin-1 levels and blood pressure changes during sunitinib treatment protocol.

P4993Tissue sodium concentration emerged as a determinant of hypertrophic vascular remodeling in type 2 diabetes

Abstract Background Studies describe a linkage between greater sodium intake and higher incidence of organ damage and cardiovascular end points. Sodium intake is usually assessed by measuring 24-hour urinary sodium excretion, which is prone to high fluctuation. For the assessment of tissue sodium a new technique (23Na-MRI) has been developed. We analyzed whether tissue sodium is linked to vascular remodeling of small resistance vessels in patients with type-2 diabetes. Methods In patients with type 2 diabetes we assessed tissue sodium content and vascular structural parameters of the retinal arterioles, since structural changes of resistance vessels (150–300 μm) can be non-invasively and reliably assessed in the retinal circulation by Scanning Laser Doppler Flowmetry (SLDF). Patients with antidiabetic medication were off the therapy (antihypertensives were kept constant) for 4 weeks. The structural parameters of retinal arterioles assessed were outer- and inner diameter (OD &amp; ID), wall thickness (WT), wall-to-lumen ratio (WLR) and wall cross sectional area (WCSA). Tissue sodium content was assessed non-invasively with a 3.0 T clinical MRI system in each patient. Subject placed their lower legs in the center of a 23Na knee coil and sodium content in skin and muscle (musculus triceps surae) were measured. Results In patients with type 2 diabetes (N=52) we observed a significant correlation between tissue sodium content (muscle and skin) and OD, WT and WCSA and a trend has been noticed between muscle sodium content and ID and WLR. Multiple linear regression analysis demonstrated that tissue sodium content is a significant determinant of hypertrophic vascular remodeling as indicated by increased WT and WCSA, independent of age, gender and 24-hour ambulatory diastolic blood pressure. Correlation coefficients Muscle sodium content (mmol/l) Skin sodium content (mmol/l) OD (μmol) r=0.402, p=0.003 r=0.299, p=0.033 ID (μmol) r=0.265, p=0.058 r=0.202, p=0.154 WT (μm) r=0.402, p=0.003 r=0.313, p=0.026 WLR r=0.247, p=0.078 r=0.171, p=0.230 WCSA (μm2) r=0.417, p=0.002 r=0.322, p=0.021 Conclusion With the novel 23Na-MRI technology, we could demonstrate that high tissue sodium concentration is linked to with hypertrophic vascular remodeling of retinal arterioles. Thus, the reduction of tissue sodium content may emerge as a therapeutic target.

Tissue sodium content in patients with type 2 diabetes mellitus

BackgroundTissue sodium content by 23Na magnetic resonance imaging (MRI) has been found to be increased in arterial hypertension. We analyzed whether tissue sodium content is increased in patients with type-2 diabetes (T2DM). MethodsPatients with T2DM were compared to those with primary hypertension. Patients with T2DM were off any antidiabetic and hypertensive patients off any antihypertensive therapy for at least 4 weeks. Skin and muscle sodium content was assessed non-invasively with a 3.0 T clinical MRI system (Magnetom Verio, Siemens Health Care, Erlangen, Germany) in each patient. ResultsIn patients with T2DM (N = 59) we observed significantly greater muscle sodium content (diabetes: 20.6 ± 3.5 vs hypertension: 16.3 ± 2.5 mmol/l, p < 0.001) and skin sodium content (diabetes: 24.5 ± 7.2 vs hypertension: 20.6 ± 5.7 mmol/l, p = 0.01) than in those with primary hypertension (N = 33). When potential confounders (age, body mass index, gender, systolic and diastolic blood pressure, estimated glomerular filtration rate) were entered in a covariance analysis, both skin sodium content (p = 0.037) and muscle sodium content (p < 0.001) were still clearly elevated. ConclusionPatients with T2DM have greater skin and muscle sodium content. These are the first known data to demonstrate increased tissue sodium content in patients with T2DM, measured by 23Na magnetic resonance imaging. Since tissue sodium content is related to organ damage, therapeutic intervention should aim at reducing tissue sodium content.

SAT-386 Assessment Of Tissue Sodium Content By23Na-MRI In Patients With Adrenal Insufficiency

Patients with chronic primary adrenal insufficiency (PAI) depend on lifelong replacement therapy with gluco- (GC) and mineralocorticoids (MC). Monitoring is based on clinical parameters assessing hemodynamic stability, electrolyte status and plasma renin concentration (PRC). Reduced subjective well-being is however often described by these patients in absence of objectifiable abnormalities, thus suggesting a gap between the concept of adequate hormone substitution and physiological requirements. This study investigated the potential role of 23Na-MRI for noninvasive assessment of sodium status in PAI. Tissue sodium was initially analyzed both in the calf muscle and in the skin of 16 patients with chronic PAI and 16 sex-, age- and BMI-matched controls. Patients were classified into 3 groups (optimal/subtherapeutic/supraphysiological) according to the quality of GC and MC substitution assessed separately by clinical scores based on subjective wellbeing and clinical/laboratory parameters. We additionally performed a longitudinal analysis in 8 patients with newly diagnosed PAI. Muscle and skin sodium content (Muscle-SC, Skin-SC) were determined using a 23NA-MRI protocol on a 3T scanner implementing a 3D sequence. A vial with 100mmol/L of sodium was scanned with every participant. Tissue sodium is presented as the ratio of tissue sodium signal intensity to sodium signal intensity of the reference vial. Muscle-SC was significantly higher in patients with chronic PAI compared to controls (19.1 vs. 16.0, p<0.05), whereas Skin-SC was similar between the two groups (16.1 vs. 17.1). These results were replicated in the subgroups classified as receiving optimal GC and MC replacement, respectively. Skin-SC was significantly correlated with 24h-urine sodium level in the whole cohort. When comparing Muscle-SC and Skin-SC with obtained clinical scores a trend from lower SC for low scores to higher SC for higher scores was observed. The longitudinal analysis of 8 patients with newly diagnosed PAI revealed that Skin-SC was significantly lower at primary diagnosis compared to sex-, age- and BMI-matched controls (12.1 vs. 15.8, p=0.05), whereas the difference in Muscle-SC was less pronounced (14 vs. 16.1, p=0.18). A significant increase in both Muscle- and Skin-SC at follow-up compared to first diagnosis was detected (19.4 vs. 14, p<0.05 and 19.3 vs. 12.1, p<0.05), consistent with a significant decrease in PRC (200 vs. 31.2 ng/l, p<0.05). Interestingly, patients with chronic PAI under replacement therapy exhibited significantly higher Muscle-SC compared to controls. The agreement between tissue SC and clinical scores as well as the significant increase in tissue SC under replacement therapy in newly diagnosed patients indicate that 23Na-MRI might be a quantitative method to assess steroid replacement. Further studies on a larger cohort are, however, needed to prove these initial findings.

Abstract P236: Sodium Accumulates in the Skin of Patients and Mice With Psoriasis

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) &gt;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, P&lt;0.001). Additionally, patients with PASI&gt;5 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.