Low-Salt Diet Attenuates B-Cell- and Myeloid-Cell-Driven Experimental Arthritides by Affecting Innate as Well as Adaptive Immune Mechanisms

A link between high sodium chloride (salt) intake and the development of autoimmune diseases was previously reported. These earlier studies demonstrated exacerbation of experimental autoimmune encephalomyelitis and colitis by excess salt intake associated with Th17- and macrophage-mediated mechanisms. Little is known about the impact of dietary salt intake on experimental arthritides. Here, we investigated if salt restriction can exert beneficial effects on collagen-induced arthritis (CIA) and K/BxN serum transfer-induced arthritis (STIA). CIA depends on both adaptive and innate immunity, while STIA predominantly mimics the innate immune cell-driven effector phase of arthritis. In both models, low salt (LS) diet significantly decreased arthritis severity compared to regular salt (RS) and high salt (HS) diet. We did not observe an aggravation of arthritis with HS diet compared to RS diet. Remarkably, in STIA, LS diet was as effective as IL-1 receptor blocking treatment. Complement-fixing anti-CII IgG2a antibodies are associated with inflammatory cell infiltration and cartilage destruction. LS diet reduced anti-CII IgG2a levels in CIA and decreased the anti-CII IgG2a/IgG1 ratios pointing toward a more Th2-like response. Significantly less inflammatory joint infiltrates and cartilage breakdown associated with reduced protein concentrations of IL-1 beta (CIA and STIA), IL-17 (CIA), and the monocyte chemoattractant protein-1 (MCP-1) (CIA) were detected in mice receiving LS diet compared to HS diet. However, we did not find a reduced IL-17A expression in CD4+ T cells upon salt restriction in CIA. Analysis of mRNA transcripts and immunoblots revealed a link between LS diet and inhibition of the p38 MAPK (mitogen-activated protein kinase)/NFAT5 (nuclear factor of activated T-cells 5) signaling axis in STIA. Further experiments indicated a decreased leukodiapedesis under LS conditions. In conclusion, dietary salt restriction ameliorates CIA and STIA, indicating a beneficial role of LS diet during both the immunization and effector phase of immune-mediated arthritides by predominantly modulating the humoral immunity and the activation status of myeloid lineage cells. Hence, salt restriction might represent a supportive dietary intervention not only to reduce cardiovascular risk, but also to improve human inflammatory joint diseases like rheumatoid arthritis.

Prevention of VEGF inhibitor-induced toxicity by salt restriction: the SUN-SALT study

Introduction Vascular endothelial growth factor (VEGF) inhibitors target the formation of new blood vessels required for growth and metastatic spread of a malignant tumor. Although this is an effective anticancer treatment, many patients develop cardiovascular side effects such as hypertension, requiring dose reduction or early termination of treatment. In animals, VEGF inhibitor-induced hypertension is salt-sensitive. Aim To prospectively study whether salt restriction can prevent or attenuate the rise in blood pressure in response to anti-cancer treatment with VEGF inhibitors. Method This is a single centre prospective open-label intervention study. Patients are eligible when treated with a VEGF inhibitor according to standard of care and developing hypertension or a blood pressure rises of 20 mmHg or more during the first treatment cycle. A salt restricted diet (<4 grams/day) including provided salt-less bread is started during the off-treatment period under guidance of a specialized dietitian. The primary endpoint is mean difference in blood pressure rise between the treatment cycle with and the treatment cycle without salt restriction. We aim for a total of 16 patients with a blood pressure rise of at least 20mmHg and/or development of hypertension undergoing the intervention. Results Between 28 November 2019 and 25 March 2021, 45 patients gave informed consent. Fourteen patients developed hypertension and/or a blood pressure rise of at least 20 mmHg after three- four weeks of treatment making them eligible for the intervention. In 10 patients, salt restriction was the only intervention to reduce the blood pressure rise during the following treatment cycle, leading to a reduction in blood pressure rise of 17 mmHg (10 vs 27 mmHg; p<0.001). In four patients antihypertensive treatment was started during the first treatment cycle due to blood pressure rise above 170 mmHg. Salt restriction did not appear to have an important further blood pressure lowering effect, although in one patient the antihypertensive treatment was interrupted during the stop week and salt restriction was sufficient to limit the blood pressure rise in the second cycle. Importantly, the intervention was well tolerated and most patients continued salt restriction after the study finished. Conclusion Applying salt restriction might be an effective and well tolerated intervention to decrease blood pressure rise during treated with VEGF inhibitors. More importantly, this gives important information about the pathogenesis. Further studies of collected blood and 24h urine samples will allow conclusions on the role of endothelin-1, the renin aldosterone system and prostacyclins. FUNDunding Acknowledgement Type of funding sources: Foundation. Main funding source(s): De Merel (Charity aiming for research directly benefiting patients; yearly award, success rate ∼30% “Stichting De Merel”)

Diagnostic Challenge in a Patient Presenting with Ascites and Hypergammaglobulinemia

Ascites is defined as the accumulation of intra-peritoneal fluid that can be caused by several diseases. We described a 47-year-old female presenting with low serum-ascites albumin gradient (SAAG) and a markedly high level of serum globulin. Serum protein electrophoresis revealed an M spike in the gamma region. Other laboratory results showed a marked increase in aspartate aminotransferase and alanine aminotransferase and predominantly conjugated hyperbilirubinemia without a sign of dilatation of bile ducts from abdominal ultrasonography examination. Furthermore, the follow-up showed a positive result for the anti-nuclear antibody test. The patient was assessed with autoimmune hepatitis, and the cause of ascites was suggested from portal hypertension although the level of SAAG was low. The ascites condition got improved after salt restriction, diuretics treatment, and abdominal paracentesis. However, the patient passed away because of the intracranial hemorrhage as a result of prolonged INR and APTT due to liver failure.

Effects of Within-Person Variability in Spot Urinary Sodium Measurements on Associations With Blood Pressure and Cardiovascular Disease

Randomized trials of salt restriction have consistently demonstrated that decreasing salt consumption lowers blood pressure, but results of observational studies of salt intake and cardiovascular disease have been conflicting. After excluding individuals with prevalent cardiovascular or kidney disease in the prospective UK Biobank study, we examined the within-person variability in spot urinary sodium excretion and its impact on associations with systolic blood pressure and risk of incident cardiovascular disease. Spearman correlation coefficients were used to assess within-person variability in spot urinary sodium, and associations between sodium and blood pressure were assessed using linear regression in participants with measurements at baseline (N=355 134) and after 9 years (N=33 915). Cox regression was used to assess associations with the risk of cardiovascular disease over the same follow-up period (N=5566 events). The within-person variability in urinary sodium was extreme, with a self-correlation coefficient of 0.35 over 4 years. Each 100 mmol/L higher usual urinary sodium was associated with 3.09 mm Hg higher systolic blood pressure (95% CI, 2.7–3.48) at baseline, but had no association at 9 years (0.97 [−0.44 to 2.37]). Likewise, there was no association between urinary sodium and risk of cardiovascular disease over the same follow-up period (hazard ratio, 1.05, [0.87–1.26]). While spot urinary sodium measurements were associated with immediate effects on blood pressure at baseline, the extreme within-person variability in urinary sodium precluded detection of associations with future blood pressure at resurvey or risk of cardiovascular disease. The limitations of observational studies, irrespective of study size, should be recognized when assessing public policy on salt restriction.

Abstract MP22: Dietary Salt Restriction And High Salt Intake Exaggerate Sympathetic Reflexes And Sensitize Central Autonomic Networks: Potential Mechanisms Of The J-shaped Curve

Observational cohort studies suggest that severe salt restriction increases cardiovascular morbidity/mortality, and the relationship between cardiovascular morbidity and dietary salt intake resembles a J-shaped curve. A high salt diet exaggerates sympathetic nerve activity (SNA) and arterial blood pressure (ABP) responses to several cardiovascular reflexes in salt-resistant animals. This study assessed whether salt restriction also exaggerates cardiovascular reflex responses and sensitizes central autonomic networks. To test this hypothesis, male Sprague-Dawley rats were fed low (0.01% NaCl), normal (0.1% NaCl), and high (4.0% NaCl) salt diet for 14-21 days. Baseline mean ABP was not different across groups (low: 104±4, normal: 107±4, high: 107±4mmHg). Activation of sciatic afferents (1ms pulse, 500uA, 5s duration, 2-20Hz) produced significantly greater increases in renal SNA (5Hz; low: 196±12, normal: 136±9, high: 177±8%, n=8, P<0.05) and ABP (5Hz; low: 29±3, normal: 16±1, high: 24±2 mmHg, n=8, P<0.05) of rats fed low and high versus normal NaCl diets. Activation of the aortic depressor nerve (2ms pulse, 500uA, 15s duration, 2-20Hz) produced significantly greater decreases in renal SNA (5Hz; low: -55±9, normal: -34±8, high: -63±13%, n=7-8, P<0.05) and ABP (5Hz; low: -31±3, normal: -15±5, high: -32±5 mmHg, n=7-8, P<0.05) of rats fed low and high versus normal NaCl diets. To test whether dietary salt intake sensitized central sympathetic circuits, microinjection of L-glutamate (0.1-1nmol, 30nL) in the rostral ventrolateral medulla produced significantly greater increases in renal SNA (0.1nmol; low: 212±15, normal: 149±8, high: 183±17%, n=7-8, P<0.05) and ABP (0.1Hz; low: 20±2, normal: 12±2, high: 22±2 mmHg, n=7-8, P<0.05) of rats fed low and high versus normal NaCl diets. Finally, rats fed low or high NaCl versus normal NaCl diets displayed exaggerated cardiovascular responses to cage switch or mild restraint and increased 24-h blood pressure variability. The present findings show that severe salt restriction and excess dietary salt intake exaggerate sympathetic and cardiovascular responses, and may be explained by a parallel change in the sensitivity of central autonomic networks to resemble a J-shaped curve.

Use of Salt-Restriction Spoons and Its Associations with Urinary Sodium and Potassium in the Zhejiang Province of China: Results of a Population-Based Survey

In China, a major source of sodium is salt added during cooking. In this context, use of a salt-restriction spoon (SRS) has been promoted in public health campaigns and by health care providers. To describe use of and factors associated with SRS use, knowledge of correct use, and actual correct use. This study is a population-based, representative survey of 7512 residents, aged 18 to 69 years, of China’s Zhejiang Province. The survey, which was conducted in 2017 using a multistage random sampling strategy, collected demographic information, SRS use, and physical measurements; a 24-h urine collection was obtained from 1,496 of the participants. The mean age of the participants was 44.8 years, 50.1% were females, and over 1/3 (35.3%) were classified as hypertensive. Mean 24-h urinary sodium and potassium excretions were 167.3(72.2) mmol/24 h and 38.2(18.2) mmol/24 h, respectively. Only 12.0% (899/7512) of participants once used or were currently using SRS; of the 899 users, 73.4% knew how to use the SRS correctly, and just 46.5% actually used it correctly. SRS use was more commonly associated with behavioral factors rather than socio-demographic factors. Initiation of SRS use by health care providers was associated with correct technical knowledge of SRS. Lower sodium-to-potassium ratio was associated with SRS use, while SRS use was not associated with urinary sodium and potassium excretion. Use of SRS was uncommon in Zhejiang Province of China. Given that a common source of sodium in China is salt added during cooking, use of SRS is an appealing strategy, ideally as part of a multi-component campaign.

Factors Affecting Salt Reduction Measure Adoption among Chinese Residents

China has the highest mortality rate caused by diseases and conditions associated with its high-salt diet. Since 2016, China has initiated a national salt reduction campaign that aims at promoting the usage of salt information on food labels and salt-restriction spoons and reducing condiment and pickled food intake. However, factors affecting individuals’ decisions to adopt these salt reduction measures remain largely unknown. By comparing the performances of logistic regression, stepwise logistic regression, lasso logistic regression and adaptive lasso logistic regression, this study aims to fill this gap by analyzing the adoption behaviour of 1610 individuals from a nationally representative online survey. It was found that the practices were far from adopted and only 26.40%, 22.98%, 33.54% and 37.20% reported the adoption of labelled salt information, salt-restriction spoons, reduced condiment use in home cooking and reduced pickled food intake, respectively. Knowledge on salt, the perceived benefits of salt reduction, participation in nutrition education and training programs on sodium reduction were positively associated with using salt information labels. Adoption of the other measures was largely explained by people’s awareness of hypertension risks and taste preferences. It is therefore recommended that policy interventions should enhance Chinese individuals’ knowledge of salt, raise the awareness of the benefits associated with a low-salt diet and the risks associated with consuming excessive salt and reshape their taste choices.