Visual Abstract

Background: Progressive chronic kidney disease (CKD) inevitably leads to salt and water retention and disturbances in the macro-and microcirculation. Objectives: We hypothesize that salt and water dysregulation in advanced CKD may be linked to inflammation and microvascular injury pathways. Methods: We studied 23 CKD stage 5 patients and 11 healthy controls (HC). Tissue sodium concentration was assessed using 23Sodium magnetic resonance (MR) imaging. Hydration status was evaluated using bioimpedance spectroscopy. A panel of inflammatory and endothelial biomarkers was also measured. Results: CKD patients had fluid overload (FO) when compared to HC (overhydration index: CKD = 0.5 ± 1.9 L vs. HC = –0.5 ± 1.0 L; p = 0.03). MR-derived tissue sodium concentrations were predominantly higher in the subcutaneous (SC) compartment (median [interquartile range] CKD = 22.4 mmol/L [19.4–31.3] vs. HC = 18.4 mmol/L [16.6–21.3]; p = 0.03), but not the muscle (CKD = 24.9 ± 5.5 mmol/L vs. HC = 22.8 ± 2.5 mmol/L; p = 0.26). Tissue sodium in both compartments correlated to FO (muscle: r = 0.63, p < 0.01; SC: rs = 0.63, p < 0.01). CKD subjects had elevated levels of vascular cell adhesion molecule (p < 0.05), tumor necrosis factor-alpha (p < 0.01), and interleukin (IL)-6 (p = 0.01) and lower levels of vascular endothelial growth factor-C (p = 0.04). FO in CKD was linked to higher IL-8 (r = 0.51, p < 0.05) and inversely associated to E-selectin (r = –0.52, p = 0.01). Higher SC sodium was linked to higher intracellular adhesion molecule (ICAM; rs = 0.54, p = 0.02). Conclusion: Salt and water accumulation in CKD appears to be linked with inflammation and endothelial activation pathways. Specifically IL-8, E-Selectin (in FO), and ICAM (in salt accumulation) may be implicated in the pathophysiology of FO and merit further investigation.

Guyton AC. Renal function curve – a key to understanding the pathogenesis of hypertension. Hypertension. 1987 Jul;10(1):1–6.
Mitra S. Extracellular hydration, cardiovascular risk, and the interstitium: a three-dimensional view. Kidney Int. 2014 Mar;85(3):510–2.
Steenkamp R, Rao A, Roderick P. UK Renal Registry 17th Annual Report: Chapter 5 Survival and Cause of Death in UK Adult Patients on Renal Replacement Therapy in 2013: National and Centre-specific Analyses. 2013. pp. 107–37.
Onofriescu M, Mardare NG, Segall L, Voroneanu L, Cuşai C, Hogaş S, et al. Randomized trial of bioelectrical impedance analysis versus clinical criteria for guiding ultrafiltration in hemodialysis patients: effects on blood pressure, hydration status, and arterial stiffness. Int Urol Nephrol. 2012 Apr;44(2):583–91.
Babaliche P, Nadpara RA, Maldar A. Association Between Estimated Glomerular Filtration Rate and Microvascular Complications in Type II Diabetes Mellitus Patients: A 1-Year Cross-Sectional Study. J Natl Med Assoc. 2019 Feb;111(1):83–7.
Borrelli S, Garofalo C, Mallamaci F, Tripepi G, Stanzione G, Provenzano M, et al. Short-term blood pressure variability in nondialysis chronic kidney disease patients: correlates and prognostic role on the progression of renal disease. J Hypertens. 2018 Dec;36(12):2398–405.
Starling EH. On the Absorption of Fluids from the Connective Tissue Spaces. J Physiol. 1896 May;19(4):312–26.
Guyton AC, Scheel K, Murphree D; GUYTON AC. SCHEEL K, MURPHREE D. Interstitial Fluid Pressure: III. Its Effect on Resistance to Tissue Fluid Mobility. Circ Res. 1966;19(2):412–9.
Montani JP, Van Vlet BN. Integrated Renal Regulation of Sodium Excreation. In: Michel B, editor. Sodium in Health and Disease. 1st Editio. New York: Informa Healthcare USA, Inc; 2008. pp. 175–99.
Titze J, Shakibaei M, Schafflhuber M, Schulze-Tanzil G, Porst M, Schwind KH, et al. Glycosaminoglycan polymerization may enable osmotically inactive Na+ storage in the skin. Am J Physiol Heart Circ Physiol. 2004 Jul;287(1):H203–8.
Titze J, Dahlmann A, Lerchl K, Kopp C, Rakova N, Schröder A, et al. Spooky sodium balance. Kidney Int. 2014 Apr;85(4):759–67.
Kopp C, Linz P, Wachsmuth L, Dahlmann A, Horbach T, Schöfl C, et al. (23)Na magnetic resonance imaging of tissue sodium. Hypertension. 2012 Jan;59(1):167–72.
Dahlmann A, Dörfelt K, Eicher F, Linz P, Kopp C, Mössinger I, et al. Magnetic resonance-determined sodium removal from tissue stores in hemodialysis patients. Kidney Int. 2015 Feb;87(2):434–41.
Schneider MP, Raff U, Kopp C, Scheppach JB, Toncar S, Wanner C, et al. Skin Sodium Concentration Correlates with Left Ventricular Hypertrophy in CKD. J Am Soc Nephrol. 2017 Jun;28(6):1867–76.
Mitsides N, Cornelis T, Broers NJ, Diederen NM, Brenchley P, Heitink-Ter Braak N, et al. Inflammatory and angiogenic factors linked to longitudinal microvascular changes in hemodialysis patients irrespective of treatment dose intensity. Kidney Blood Press Res. 2017;42(5):905–18.
Dekker MJ, Marcelli D, Canaud BJ, Carioni P, Wang Y, Grassmann A, et al.; MONDO Initiative. Impact of fluid status and inflammation and their interaction on survival: a study in an international hemodialysis patient cohort. Kidney Int. 2017 May;91(5):1214–23.
Mitsides N, Cornelis T, Broers NJ, Diederen NM, Brenchley P, van der Sande FM, et al. Extracellular overhydration linked with endothelial dysfunction in the context of inflammation in haemodialysis dependent chronic kidney disease. PLoS One. 2017 Aug;12(8):e0183281.
Slagman MC, Kwakernaak AJ, Yazdani S, Laverman GD, van den Born J, Titze J, et al. Vascular endothelial growth factor C levels are modulated by dietary salt intake in proteinuric chronic kidney disease patients and in healthy subjects. Nephrol Dial Transplant. 2012 Mar;27(3):978–82.
Charlson M, Wells MT, Ullman R, King F, Shmukler C. The Charlson Comorbidity Index Can Be Used Prospectively to Identify Patients Who Will Incur High Future Costs. PLoS One. 2014;9(12):e112479.
Chamney PW, Wabel P, Moissl UM, Müller MJ, Bosy-Westphal A, Korth O, et al. A whole-body model to distinguish excess fluid from the hydration of major body tissues. Am J Clin Nutr. 2007 Jan;85(1):80–9.
Wizemann V, Wabel P, Chamney P, Zaluska W, Moissl U, Rode C, et al. The mortality risk of overhydration in haemodialysis patients. Nephrol Dial Transplant. 2009 May;24(5):1574–9.
Hung SC, Kuo KL, Peng CH, Wu CH, Lien YC, Wang YC, et al. Volume overload correlates with cardiovascular risk factors in patients with chronic kidney disease. Kidney Int. 2014 Mar;85(3):703–9.
Wiig H, Schröder A, Neuhofer W, Jantsch J, Kopp C, Karlsen TV, et al. Immune cells control skin lymphatic electrolyte homeostasis and blood pressure. J Clin Invest. 2013 Jul;123(7):2803–15.
Jantsch J, Binger KJ, Müller DN, Titze J. Macrophages in homeostatic immune function. Front Physiol. 2014 May;5:146.
Barbaro NR, Foss JD, Kryshtal DO, Tsyba N, Kumaresan S, Xiao L, et al. Dendritic Cell Amiloride-Sensitive Channels Mediate Sodium-Induced Inflammation and Hypertension. Cell Rep. 2017 Oct;21(4):1009–20.
Mitsides N, Cornelis T, Broers NJ, Diederen NM, Brenchley P, van der Sande FM, et al. Cardiovascular and Patient Phenotype of Extended Haemodialysis: A Critical Analysis of Studying a Unique Patient Population. Blood Purif. 2018;45(4):356–63.
Smart SJ, Casale TB. TNF-alpha-induced transendothelial neutrophil migration is IL-8 dependent. Am J Physiol. 1994 Mar;266(3 Pt 1):L238–45.
Sorimachi K, Akimoto K, Hattori Y, Ieiri T, Niwa A. Activation of macrophages by lactoferrin: secretion of TNF-alpha, IL-8 and NO. Biochem Mol Biol Int. 1997 Sep;43(1):79–87.
Lee BT, Ahmed FA, Hamm LL, Teran FJ, Chen CS, Liu Y, et al. Association of C-reactive protein, tumor necrosis factor-alpha, and interleukin-6 with chronic kidney disease. BMC Nephrol. 2015 May;16(1):77.
Hsu HJ, Yen CH, Wu IW, Hsu KH, Chen CK, Sun CY, et al. The association of uremic toxins and inflammation in hemodialysis patients. PLoS One. 2014 Jul;9(7):e102691.
Mori K, Okuno S, Shoji T, Emoto M, Kakutani Y, Yamakawa K, et al. Tumor necrosis factor-related apoptosis-inducing ligand as an independent predictor of mortality in hemodialysis patents. Cytokine. 2013 Mar;61(3):912–6.
Rodrigues SF, Granger DN. Blood cells and endothelial barrier function. Tissue Barriers. 2015 Apr;3(1-2):e978720.
DiStasi MR, Ley K. Opening the flood-gates: how neutrophil-endothelial interactions regulate permeability. Trends Immunol. 2009 Nov;30(11):547–56.
Reitsma S, Slaaf DW, Vink H, van Zandvoort MA, oude Egbrink MG. The endothelial glycocalyx: composition, functions, and visualization. Pflugers Arch. 2007 Jun;454(3):345–59.
Coppolino G, Bolignano D, Campo S, Loddo S, Teti D, Buemi M. Circulating progenitor cells after cold pressor test in hypertensive and uremic patients. Hypertens Res. 2008 Apr;31(4):717–24.
Hojs R, Bevc S, Ekart R. Biomarkers in Hemodialysis Patients. Volume 57. Elsevier Inc.; 2012. .
Takahashi H, Nakagawa S, Wu Y, Kawabata Y, Numabe A, Yanagi Y, et al. A high-salt diet enhances leukocyte adhesion in association with kidney injury in young Dahl salt-sensitive rats. Hypertens Res. 2017 Nov;40(11):912–20.
Shroff RC, Price KL, Kolatsi-Joannou M, Todd AF, Wells D, Deanfield J, et al. Circulating angiopoietin-2 is a marker for early cardiovascular disease in children on chronic dialysis. PLoS One. 2013;8(2):e56273.
Vlahu CA, Lemkes BA, Struijk DG, Koopman MG, Krediet RT, Vink H. Damage of the endothelial glycocalyx in dialysis patients. J Am Soc Nephrol. 2012 Nov;23(11):1900–8.
Malatino LS, Stancanelli B, Cataliotti A, Bellanuova I, Fatuzzo P, Rapisarda F, et al. Circulating E-selectin as a risk marker in patients with end-stage renal disease. J Intern Med. 2007 Oct;262(4):479–87.
Davies SJ, Davenport A. The role of bioimpedance and biomarkers in helping to aid clinical decision-making of volume assessments in dialysis patients. Kidney Int. 2014 Sep;86(3):489–96.
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