Does Sodium Intake Induce Systemic Inflammatory Response? A Systematic Review and Meta-Analysis of Randomized Studies in Humans

Experimental studies suggest that sodium induced inflammation might be another missing link leading to atherosclerosis. To test the hypothesis that high daily sodium intake induces systemic inflammatory response in humans, we performed a systematic review according to PRISMA guidelines of randomized controlled trials (RCTs) that examined the effect of high versus low sodium dose (HSD vs. LSD), as defined per study, on plasma circulating inflammatory biomarkers. Eight RCTs that examined CRP, TNF-a and IL-6 were found. Meta-analysis testing the change of each biomarker in HSD versus LSD was possible for CRP (n = 5 studies), TNF-a (n = 4 studies) and IL-6 (n = 4 studies). The pooled difference (95% confidence intervals) per biomarker was for: CRP values of 0.1(−0.3, 0.4) mg/L; TNF-a −0.7(−5.0, 3.6) pg/mL; IL-6 −1.1(−3.3 to 1.1) pg/mL. Importantly, there was inconsistency between RCTs regarding major population characteristics and the applied methodology, including a very wide range of LSD (460 to 6740 mg/day) and HSD (2800 to 7452 mg/day). Although our results suggest that the different levels of daily sodium intake are not associated with significant changes in the level of systemic inflammation in humans, this outcome may result from methodological issues. Based on these identified methodological issues we propose that future RCTs should focus on young healthy participants to avoid confounding effects of comorbidities, should have three instead of two arms (very low, “normal” and high) of daily sodium intake with more than 100 participants per arm, whereas an intervention duration of 14 days is adequate.

[1]  M. Yannakoulia,et al.  Levels of dietary sodium intake: diverging associations with arterial stiffness and atheromatosis. , 2021, Hellenic journal of cardiology : HJC = Hellenike kardiologike epitheorese.

[2]  A. Mavropoulos.  On the Role of Salt in Immunoregulation and Autoimmunity , 2020, Mediterranean journal of rheumatology.

[3]  M. Woodward,et al.  Effect of dose and duration of reduction in dietary sodium on blood pressure levels: systematic review and meta-analysis of randomised trials , 2020, BMJ.

[4]  Y. Manios,et al.  Current Data on Dietary Sodium, Arterial Structure and Function in Humans: A Systematic Review , 2019, Nutrients.

[5]  E. Latz,et al.  Western Diet and the Immune System: An Inflammatory Connection. , 2019, Immunity.

[6]  J. Kroon,et al.  Salt increases monocyte CCR2 expression and inflammatory responses in humans. , 2019, JCI insight.

[7]  A. Balogh,et al.  The role of sodium in modulating immune cell function , 2019, Nature Reviews Nephrology.

[8]  L. Kheirandish-Gozal,et al.  Obstructive Sleep Apnea and Inflammation: Proof of Concept Based on Two Illustrative Cytokines , 2019, International journal of molecular sciences.

[9]  J. Mu,et al.  Effect of Salt Intake on the Serum Cardiotrophin-1 Levels in Chinese Adults , 2018, Annals of Nutrition and Metabolism.

[10]  A. Ortiz,et al.  Salt Intake and Immunity , 2018, Hypertension.

[11]  M. Kleinewietfeld,et al.  The role of salt for immune cell function and disease , 2018, Immunology.

[12]  R. Scrivo,et al.  The role of dietary sodium intake on the modulation of T helper 17 cells and regulatory T cells in patients with rheumatoid arthritis and systemic lupus erythematosus , 2017, PloS one.

[13]  D. O. Dragunov,et al.  [Correlations of IL-18 and IL-6 with sodium consumption in patients with arterial hypertension and diabetes mellitus]. , 2017, Kardiologiia.

[14]  Wen-jie Ji,et al.  Th17/Treg Imbalance Induced by Dietary Salt Variation Indicates Inflammation of Target Organs in Humans , 2016, Scientific Reports.

[15]  D. Hafler,et al.  Sodium chloride inhibits the suppressive function of FOXP3+ regulatory T cells. , 2015, The Journal of clinical investigation.

[16]  G. Schelling,et al.  Effects of dietary salt levels on monocytic cells and immune responses in healthy human subjects: a longitudinal study. , 2015, Translational research : the journal of laboratory and clinical medicine.

[17]  G. Koçak,et al.  Salt Intake Is Associated with Inflammation in Chronic Heart Failure , 2014, International cardiovascular research journal.

[18]  Majid Ezzati,et al.  Global sodium consumption and death from cardiovascular causes. , 2014, The New England journal of medicine.

[19]  S. Yusuf,et al.  Urinary sodium and potassium excretion, mortality, and cardiovascular events. , 2014, The New England journal of medicine.

[20]  Jiming Liu,et al.  Estimating the sample mean and standard deviation from the sample size, median, range and/or interquartile range , 2014, BMC Medical Research Methodology.

[21]  David W. Johnson,et al.  A randomized trial of sodium-restriction on kidney function, fluid volume and adipokines in CKD patients , 2014, BMC Nephrology.

[22]  G. Jürgens,et al.  Compared with usual sodium intake, low- and excessive-sodium diets are associated with increased mortality: a meta-analysis. , 2014, American Journal of Hypertension.

[23]  P. Clifton,et al.  Postprandial effects of a high salt meal on serum sodium, arterial stiffness, markers of nitric oxide production and markers of endothelial function. , 2014, Atherosclerosis.

[24]  C. Zoccali,et al.  Procalcitonin and the inflammatory response to salt in essential hypertension: a randomized cross-over clinical trial , 2013, Journal of hypertension.

[25]  N. Yosef,et al.  Sodium chloride drives autoimmune disease by the induction of pathogenic TH17 cells , 2013, Nature.

[26]  L. C. Martin,et al.  Effect of dietary sodium restriction on body water, blood pressure, and inflammation in hemodialysis patients: a prospective randomized controlled study , 2013, International Urology and Nephrology.

[27]  Merlin C. Thomas,et al.  Activation of the Renin-Angiotensin System Mediates the Effects of Dietary Salt Intake on Atherogenesis in the Apolipoprotein E Knockout Mouse , 2012, Hypertension.

[28]  J. Sterne,et al.  The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials , 2011, BMJ : British Medical Journal.

[29]  Y. Sharabi,et al.  High-salt diet increases plasma adiponectin levels independent of blood pressure in hypertensive rats: the role of the renin–angiotensin–aldosterone system , 2010, Journal of hypertension.

[30]  S. Lewis,et al.  Impact of adopting low sodium diet on biomarkers of inflammation and coagulation: a randomised controlled trial. , 2010, Journal of nephrology.

[31]  G. Licata,et al.  Long-term effects of dietary sodium intake on cytokines and neurohormonal activation in patients with recently compensated congestive heart failure. , 2009, Journal of cardiac failure.

[32]  T. McKeever,et al.  Is higher sodium intake associated with elevated systemic inflammation? A population-based study. , 2009, The American journal of clinical nutrition.

[33]  M. Safar,et al.  Sodium, arterial stiffness, and cardiovascular mortality in hypertensive rats. , 2007, American journal of hypertension.

[34]  T. Mickleborough,et al.  Dietary salt, airway inflammation, and diffusion capacity in exercise-induced asthma. , 2005, Medicine and science in sports and exercise.

[35]  Z. Massy,et al.  Dietary salt restriction accelerates atherosclerosis in apolipoprotein E-deficient mice. , 2005, Atherosclerosis.

[36]  K. Williams,et al.  Atherosclerosis--an inflammatory disease. , 1999, The New England journal of medicine.

[37]  M. Alderman,et al.  Dietary sodium intake and mortality: the National Health and Nutrition Examination Survey (NHANES I) , 1998, The Lancet.

[38]  G. Smith,et al.  Bias in meta-analysis detected by a simple, graphical test , 1997, BMJ.

[39]  C. Begg,et al.  Operating characteristics of a rank correlation test for publication bias. , 1994, Biometrics.