Dermal tissue remodeling and non-osmotic sodium storage in kidney patients

Ryanne S Hijmans, Marco van Londen, Kwaku A Sarpong, Stephan J L Bakker, Gerjan J Navis, Twan T R Storteboom, Wilhelmina H A de Jong, Robert A Pol, Jacob van den Born, Ryanne S Hijmans, Marco van Londen, Kwaku A Sarpong, Stephan J L Bakker, Gerjan J Navis, Twan T R Storteboom, Wilhelmina H A de Jong, Robert A Pol, Jacob van den Born

Abstract

Background: Excess dietary sodium is not only excreted by the kidneys, but can also be stored by non-osmotic binding with glycosaminoglycans in dermal connective tissue. Such storage has been associated with dermal inflammation and lymphangiogenesis. We aim to investigate if skin storage of sodium is increased in kidney patients and if this storage is associated with clinical parameters of sodium homeostasis and dermal tissue remodeling.

Methods: Abdominal skin tissue of 12 kidney patients (5 on hemodialysis) and 12 healthy kidney donors was obtained during surgery. Skin biopsies were processed for dermal sodium measurement by atomic absorption spectroscopy, and evaluated for CD68+ macrophages, CD3+ T-cells, collagen I, podoplanin + lymph vessels, and glycosaminoglycans by qRT-PCR and immunohistochemistry.

Results: Dermal sodium content of kidney patients did not differ from healthy individuals, but was inversely associated with plasma sodium values (p < 0.05). Compared to controls, kidney patients showed dermal tissue remodeling by increased CD68+ macrophages, CD3+ T-cells and Collagen I expression (all p < 0.05). Also, both N- and O-sulfation of heparan sulfate glycosaminoglycans were increased (all p < 0.05), most outspoken in hemodialysis patients. Plasma and urinary sodium associates with dermal lymph vessel number (both p < 0.05), whereas loss of eGFR, proteinuria and high systolic blood pressure associated with dermal macrophage density (all p < 0.05).

Conclusion: Kidney patients did not show increased skin sodium storage compared to healthy individuals. Results do indicate that kidney failure associates with dermal inflammation, whereas increased sodium excretion and plasma sodium associate with dermal lymph vessel formation and loss of dermal sodium storage capacity. Trial registration The cohort is registered at clinicaltrials.gov as NCT (September 6, 2017). NCT, NCT03272841. Registered 6 September 2017-Retrospectively registered, https://clinicaltrials.gov.

Keywords: Kidney; Remodeling; Skin; Sodium; Transplantation.

Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Plasma sodium (a), urinary sodium excretion (b) and dermal sodium concentration (c) in healthy individuals (donors) and kidney patients (recipients). Mann–Whitney and Kruskall Wallis were used to test differences between two or more groups. *p < 0.01
Fig. 2
Fig. 2
Dermal inflammation in kidney patients (recipients) and healthy individuals (donors). Immunohistochemical expression and quantification of CD68+ macrophages, MCP-1 and CD3+ T-cells. Magnification ×200. a. The mRNA expression of MCP-1 and VCAM-1 by qRT-PCR analysis (b). Values are expressed in fold increase compared to the mean of the donors. Mann–Whitney and Kruskall Wallis were used to test differences between two or more groups. *p < 0.05 compared to donors
Fig. 3
Fig. 3
Dermal fibrosis in kidney patients (recipients) and healthy individuals (donors). Immunohistochemical expression and quantification of α-SMA+ myofibroblasts. Magnification ×200. a. The mRNA expression of collagen I on qRT-PCR analysis (b). Values are expressed in fold increase compared to the mean of the donors. Mann–Whitney and Kruskall Wallis were used to test differences between two or more groups. *p < 0.05 and **p < 0.01 compared to donors
Fig. 4
Fig. 4
Dermal lymphangiogenesis in kidney patients (recipients) and healthy individuals (donors). Immunohistochemical expression and quantification of Podoplanin + lymph vessels. Magnification ×200. a The mRNA expression of Podoplanin and VEGF-C on qRT-PCR analysis (b). Values are expressed in fold increase compared to the mean of the donors. Mann–Whitney and Kruskall Wallis were used to test differences between two or more groups. *p < 0.05 compared to donors or compared to non-dialysis (preemptive) patients
Fig. 5
Fig. 5
Dermal GAGs in kidney patients (recipients) and healthy individuals (donors). Immunohistochemical expression and quantification of GAGs and versican and mRNA expression of enzymes involved in the synthesis of HS-GAG (a, b), CS/DS-GAG (c, d) and HA-GAG (e, f). Photos: magnification ×200. For qRT-PCR data, values are expressed in fold increase compared to the mean of the donors. Mann–Whitney and Kruskall Wallis were used to test differences between two or more groups. *p < 0.05
Fig. 6
Fig. 6
Diagram reflecting the number (indicated by black numbers) of associations (indicated by arrows) among clinical data, dermal sodium and tissue remodeling responses. Green arrows indicate positive associations, red arrows indicate negative associations

References

    1. Titze J, Rakova N, Kopp C, Dahlmann A, Jantsch J, Luft FC. Balancing wobbles in the body sodium. Nephrol Dial Transpl. 2016;31:1078–1081. doi: 10.1093/ndt/gfv343.
    1. Hofmeister LH, Perisic S, Titze J. Tissue sodium storage: evidence for kidney-like extrarenal countercurrent systems? Eur J Physiol. 2015;467:551–558. doi: 10.1007/s00424-014-1685-x.
    1. Olde Engberink RHG, Rorije NMG, van der Homan Heide JJ, van den Born B-JH, Vogt L. Role of the vascular wall in sodium homeostasis and salt sensitivity. J Am Soc Nephrol. 2015;26:777–783. doi: 10.1681/ASN.2014050430.
    1. Titze J. Water-free sodium accumulation. Semin Dial. 2009;22:253–255. doi: 10.1111/j.1525-139X.2009.00569.x.
    1. Linz P, Santoro D, Renz W, Rieger J, Ruehle A, Ruff J, et al. Skin sodium measured with 23Na MRI at 7.0 T. NMR Biomed. 2015;28:54–62.
    1. Hijmans RS, Shrestha P, Sarpong KA, Yazdani S, el Masri R, de Jong WHA, et al. High sodium diet converts renal proteoglycans into pro-inflammatory mediators in rats. PLoS ONE. 2017;12:e0178940. doi: 10.1371/journal.pone.0178940.
    1. Fischereder M, Michalke B, Schmöckel E, Habicht A, Kunisch R, Pavelic I, et al. Sodium storage in human tissues is mediated by glycosaminoglycan expression. Am J Physiol Physiol. 2017;313:F319–F325. doi: 10.1152/ajprenal.00703.2016.
    1. Celie JWAM, Rutjes NWP, Keuning ED, Soininen R, Heljasvaara R, Pihlajaniemi T, et al. Subendothelial heparan sulfate proteoglycans become major l-selectin and monocyte chemoattractant protein-1 ligands upon renal ischemia/reperfusion. Am J Pathol. 2007;170:1865–1878. doi: 10.2353/ajpath.2007.070061.
    1. Titze J, Lang R, Ilies C, Schwind KH, Kirsch KA, Dietsch P, et al. Osmotically inactive skin Na+ storage in rats. Am J Physiol Ren Physiol. 2003;285:1108–1117. doi: 10.1152/ajprenal.00200.2003.
    1. Schafflhuber M, Volpi N, Dahlmann A, Hilgers KF, Maccari F, Dietsch P, et al. Mobilization of osmotically inactive Na+ by growth and by dietary salt restriction in rats. Am J Physiol Ren Physiol. 2007;292:1490–1500. doi: 10.1152/ajprenal.00300.2006.
    1. Slagman MCJ, 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;27:978–982. doi: 10.1093/ndt/gfr402.
    1. Brück K, Stel VS, Gambaro G, Hallan S, Volzke H, Arnlo VJ, et al. CKD prevalence varies across the european general population. J Am Soc Nephrol. 2016;27:2135–2147. doi: 10.1681/ASN.2015050542.
    1. Abramowicz D, Hazzan M, Maggiore U, Peruzzi L, Cochat P, Oberbauer R, et al. Does pre-emptive transplantation versus post start of dialysis transplantation with a kidney from a living donor improve outcomes after transplantation? A systematic literature review and position statement by the Descartes Working Group and ERBP. Nephrol Dial Transplant. 2016;31:691–697. doi: 10.1093/ndt/gfv378.
    1. Witczak BJ, Leivestad T, Line PD, Holdaas H, Reisaeter AV, Jenssen TG, et al. Experience from an active preemptive kidney transplantation Program—809 cases revisited. Transplantation. 2009;88:672–677. doi: 10.1097/TP.0b013e3181b27b7e.
    1. Weiner DE, Tighiouart H, Amin MG, Stark PC, MacLeod B, Griffith JL, et al. Chronic kidney disease as a risk factor for cardiovascular disease and all-cause mortality: a pooled analysis of community-based studies. J Am Soc Nephrol. 2004;15:1307–1315. doi: 10.1097/01.ASN.0000123691.46138.E2.
    1. Poppelaars F, Faria B, da Gaya Costa M, Franssen CFM, van Son WJ, Berger SP, et al. The Complement System in Dialysis: a Forgotten Story? Front Immunol. 2018;9:71. doi: 10.3389/fimmu.2018.00071.
    1. Jofre R, Rodriguez-Benitez P, Lopez-Gomez JM, Perez-Garcia R. Inflammatory syndrome in patients on hemodialysis. J Am Soc Nephrol. 2006;17:S274–S280. doi: 10.1681/ASN.2006080926.
    1. van den Born J, Gunnarsson K, Bakker MA, Kjellén L, Kusche-Gullberg M, Maccarana M, et al. Presence of N-unsubstituted glucosamine units in native heparan sulfate revealed by a monoclonal antibody. J Biol Chem. 1995;270:31303–31309. doi: 10.1074/jbc.270.52.31303.
    1. Nguyen MK, Kurtz I. Is the osmotically inactive sodium storage pool fixed or variable? J Appl Physiol. 2007;90095:445–447. doi: 10.1152/japplphysiol.00614.2006.
    1. Kopp C, Linz P, Dahlmann A, Hammon M, Jantsch J, Müller DN, et al. 23Na magnetic resonance imaging-determined tissue sodium in healthy subjects and hypertensive patients. Hypertension. 2015;61:635–640. doi: 10.1161/HYPERTENSIONAHA.111.00566.
    1. 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;87:434–441. doi: 10.1038/ki.2014.269.
    1. Schrijvers BF, Flyvbjerg A, De Vriese AS. The role of vascular endothelial growth factor (VEGF) in renal pathophysiology. Kidney Int. 2004;65:2003–2017. doi: 10.1111/j.1523-1755.2004.00621.x.
    1. Nykänen AI, Sandelin H, Krebs R, Keränen MAI, Tuuminen R, Kärpänen T, et al. Targeting lymphatic vessel activation and CCL21 production by vascular endothelial growth factor receptor-3 inhibition has novel immunomodulatory and antiarteriosclerotic effects in cardiac allografts. Circulation. 2010;121:1413–1422. doi: 10.1161/CIRCULATIONAHA.109.910703.
    1. Yazdani S, Navis GJ, Hillebrands JL, van Goor H, van den Born J. Lymphangiogenesis in renal diseases: passive bystander or active participant? Med: Expert Rev Mol; 2014.
    1. Machnik A, Neuhofer W, Jantsch J, Dahlmann A, Tammela T, Derer W, et al. Macrophages regulate salt-dependent volume and blood pressure by a vascular endothelial growth factor-C-dependent buffering mechanism. Nat Med. 2009;15:545–552. doi: 10.1038/nm.1960.
    1. Selvarajah V, Mäki-Petäjä KM, Pedro L, Bruggraber SFA, Burling K, Goodhart AK, et al. Novel mechanism for buffering dietary salt in humans novelty and significance. Hypertension. 2017;70:930–937. doi: 10.1161/HYPERTENSIONAHA.117.10003.
    1. Kopp C, Beyer C, Linz P, Dahlmann A, Hammon M, Jantsch J, et al. Na+ deposition in the fibrotic skin of systemic sclerosis patients detected by 23Na-magnetic resonance imaging. Rheumatology. 2016;56:kew371.
    1. Silver L, Christie R, Dahl L. Connective tissue as a major sodium reservoir. Fed. Proc. 1957;16:372.
    1. Sugár D, Agócs R, Tatár E, Tóth G, Horváth P, Sulyok E, et al. The contribution of skin glycosaminoglycans to the regulation of sodium homeostasis in rats. Physiol Res. 2017;67:777–785.
    1. Farber SJ, Schubert M, Schuster N. The binding of cations by chondroitin sulfate. J Clin Invest. 1957;36:1715–1722. doi: 10.1172/JCI103573.
    1. 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 Hear Circ Physiol. 2004;287:203–208. doi: 10.1152/ajpheart.01237.2003.
    1. Schnabelrauch M, Scharnweber D, Schiller J. Sulfated glycosaminoglycans as promising artificial extracellular matrix components to improve the regeneration of tissues. Curr Med Chem. 2013;20:2501–2523. doi: 10.2174/0929867311320200001.
    1. Jantsch J, Schatz V, Friedrich D, Schröder A, Kopp C, Siegert I, et al. Cutaneous Na+ storage strengthens the antimicrobial barrier function of the skin and boosts macrophage-driven host defense. Cell Metab. 2015;21:493–501. doi: 10.1016/j.cmet.2015.02.003.
    1. Wang P, Deger MS, Kang H, Ikizler TA, Titze J, Gore JC. Sex differences in sodium deposition in human muscle and skin. Magn Reson Imaging. 2017;36:93–97. doi: 10.1016/j.mri.2016.10.023.
    1. Kopp C, Linz P, Dahlmann A, Hammon M, Jantsch J, Muller DN, et al. 23Na magnetic resonance imaging-determined tissue sodium in healthy subjects and hypertensive patients. Hypertension. 2013;61:635–640. doi: 10.1161/HYPERTENSIONAHA.111.00566.
    1. Mihai S, Codrici E, Popescu ID, Enciu A-M, Albulescu L, Necula LG, et al. Inflammation-related mechanisms in chronic kidney disease prediction, progression, and outcome. J Immunol Res. 2018;2018:1–16. doi: 10.1155/2018/2180373.
    1. Kooman JP, Dekker MJ, Usvyat LA, Kotanko P, van der Sande FM, Schalkwijk CG, et al. Inflammation and premature aging in advanced chronic kidney disease. Am J Physiol Physiol. 2017;313:F938–F950. doi: 10.1152/ajprenal.00256.2017.
    1. Kuro-o M. The Klotho proteins in health and disease. Nat Rev Nephrol. 2019;15:27–44. doi: 10.1038/s41581-018-0078-3.
    1. Nakano T, Katsuki S, Chen M, Decano JL, Halu A, Lee LH, et al. Uremic toxin indoxyl sulfate promotes proinflammatory macrophage activation via the interplay of OATP2B1 and Dll4-notch signaling. Circulation. 2019;139:78–96. doi: 10.1161/CIRCULATIONAHA.118.034588.
    1. Kaminski TW, Pawlak K, Karbowska M, et al. The impact of antihypertensive pharmacotherapy on interplay between protein-bound uremic toxin (indoxyl sulfate) and markers of inflammation in patients with chronic kidney disease. Int Urol Nephrol. 2019 doi: 10.1007/s11255-018-02064-3.
    1. Zaferani A, Talsma D, Richter MKS, Daha MR, Navis GJ, Seelen MA, et al. Heparin/heparan sulphate interactions with complement–a possible target for reduction of renal function loss? Nephrol Dial Transplant. 2014;29:515–522. doi: 10.1093/ndt/gft243.
    1. Poppelaars F, da Gaya Costa M, Berger SP, Assa S, Meter-Arkema AH, Daha MR, et al. Strong predictive value of mannose-binding lectin levels for cardiovascular risk of hemodialysis patients. J Transl Med. 2016;14:236. doi: 10.1186/s12967-016-0995-5.
    1. Poppelaars F, da Gaya Costa M, Faria B, Berger SP, Assa S, Daha MR, et al. Intradialytic complement activation precedes the development of cardiovascular events in hemodialysis patients. Front Immunol. 2018;9:2070. doi: 10.3389/fimmu.2018.02070.

Source: PubMed

赞助者和合作者

医疗条件

药物干预

3
订阅