The Impact of Uremic Toxicity Induced Inflammatory Response on the Cardiovascular Burden in Chronic Kidney Disease

Ligia Maria Claro, Andrea N Moreno-Amaral, Ana Carolina Gadotti, Carla J Dolenga, Lia S Nakao, Marina L V Azevedo, Lucia de Noronha, Marcia Olandoski, Thyago P de Moraes, Andréa E M Stinghen, Roberto Pécoits-Filho, Ligia Maria Claro, Andrea N Moreno-Amaral, Ana Carolina Gadotti, Carla J Dolenga, Lia S Nakao, Marina L V Azevedo, Lucia de Noronha, Marcia Olandoski, Thyago P de Moraes, Andréa E M Stinghen, Roberto Pécoits-Filho

Abstract

Uremic toxin (UT) retention in chronic kidney disease (CKD) affects biological systems. We aimed to identify the associations between UT, inflammatory biomarkers and biomarkers of the uremic cardiovascular response (BUCVR) and their impact on cardiovascular status as well as their roles as predictors of outcome in CKD patients. CKD patients stages 3, 4 and 5 (n = 67) were recruited and UT (indoxyl sulfate/IS, p-cresil sulfate/pCS and indole-3-acetic acid/IAA); inflammatory biomarkers [Interleukin-6 (IL-6), high sensitivity C reactive protein (hsCRP), monocyte chemoattractant protein-1 (MCP-1), soluble vascular adhesion molecule-1 (sVCAM-1), soluble intercellular adhesion molecule-1 (sICAM-1) and soluble Fas (sFas)] and BUCVRs [soluble CD36 (sCD36), soluble receptor for advanced glycation end products (sRAGE), fractalkine] was measured. Patients were followed for 5.2 years and all causes of death was used as the primary outcome. Artery segments collected at the moment of transplantation were used for the immunohistochemistry analysis in a separate cohort. Estimated glomerular filtration rate (eGFR), circulating UT, plasma biomarkers of systemic and vascular inflammation and BUCVR were strongly interrelated. Patients with plaque presented higher signs of UT-induced inflammation and arteries from CKD patients presented higher fractalkine receptor (CX3CR1) tissue expression. Circulating IS (p = 0.03), pCS (p = 0.007), IL-6 (p = 0.026), sFas (p = 0.001), sCD36 (p = 0.01) and fractalkine (p = 0.02) were independent predictors of total mortality risk in CKD patients. Our results reinforce the important role of uremic toxicity in the pathogenesis of cardiovascular disease (CVD) in CKD patients through an inflammatory pathway.

Keywords: fractalkine (CX3CL1); fractalkine receptor (CX3CR1); inflammatory biomarkers; sCD36; sRAGE; uremic toxins.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
The scatter plots (a–c) show the relationship between the concentrations of UTs and glomerular filtration rate (GFR) in CKD patients in pre-dialysis. Similarly, the scatter plots (d–f) show the correlation with biomarkers of the uremic cardiovascular response and GFR.
Figure 2
Figure 2
(A) Graph with the total percentage (%) of tissue expression of fractalkine receptor (CX3CR1) by immunohistochemistry (IHC). * p = 0.002, significant difference between donor and CKD receptor tissue expression of CX3CR1; t Student (p < 0.05). Demonstrative images showing the negative (B) and immunopositivity (C) (red arrow) tissue expression of CX3CR1 for medium power field (200×), in the renal arteries.
Figure 3
Figure 3
Cox regression univariate analysis for evaluating the relationship between independent co-variables and clinical outcomes in CKD patients of the study.
Figure 4
Figure 4
Flow chart of the study.

References

    1. Go A.S., Chertow G.M., Fan D., McCulloch C.E., Hsu C.Y. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N. Engl. J. Med. 2004;351:1296–1305. doi: 10.1056/NEJMoa041031.
    1. Lekawanvijit S., Krum H. Cardiorenal syndrome: Acute kidney injury secondary to cardiovascular disease and role of protein-bound uraemic toxins. J. Physiol. 2014;592:3969–3983. doi: 10.1113/jphysiol.2014.273078.
    1. Jourde-Chiche N., Dou L., Cerini C., Dignat-George F., Brunet P. Vascular incompetence in dialysis patients--protein-bound uremic toxins and endothelial dysfunction. Semin. Dial. 2011;24:327–337. doi: 10.1111/j.1525-139X.2011.00925.x.
    1. Stenvinkel P., Ketteler M., Johnson R.J., Lindholm B., Pecoits-Filho R., Riella M., Heimbürger O., Cederholm T., Girndt M. IL-10, IL-6, and TNF-alpha: Central factors in the altered cytokine network of uremia--the good, the bad, and the ugly. Kidney Int. 2005;67:1216–1233. doi: 10.1111/j.1523-1755.2005.00200.x.
    1. Borges N.A., Barros A.F., Nakao L.S., Dolenga C.J., Fouque D., Mafra D. Protein-Bound Uremic Toxins from Gut Microbiota and Inflammatory Markers in Chronic Kidney Disease. J. Ren. Nutr. 2016;26:396–400. doi: 10.1053/j.jrn.2016.07.005.
    1. Ito S., Yoshida M. Protein-bound uremic toxins: New culprits of cardiovascular events in chronic kidney disease patients. Toxins. 2014;6:665–678. doi: 10.3390/toxins6020665.
    1. Moradi H., Sica D.A., Kalantar-Zadeh K. Cardiovascular burden associated with uremic toxins in patients with chronic kidney disease. Am. J. Nephrol. 2013;38:136–148. doi: 10.1159/000351758.
    1. Rossi M., Campbell K.L., Johnson D.W., Stanton T., Vesey D.A., Coombes J.S., Weston K.S., Hawley C.M., McWhinney B.C., Ungererf J.P.J., et al. Protein-bound uremic toxins, inflammation and oxidative stress: A cross-sectional study in stage 3–4 chronic kidney disease. Arch. Med. Res. 2014;45:309–317. doi: 10.1016/j.arcmed.2014.04.002.
    1. Kaminski T.W., Pawlak K., Karbowska M., Mysliwiec M., Pawlak D. Indoxyl sulfate - the uremic toxin linking hemostatic system disturbances with the prevalence of cardiovascular disease in patients with chronic kidney disease. BMC Nephrol. 2017;18:35. doi: 10.1186/s12882-017-0457-1.
    1. Manabe I. Chronic inflammation links cardiovascular, metabolic and renal diseases. Circ. J. 2011;75:2739–2748. doi: 10.1253/circj.CJ-11-1184.
    1. Barreto F.C., Barreto D.V., Liabeuf S., Meert N., Glorieux G., Temmar M., Choukroun G., Vanholder R., Massy Z.A. and on behalf of the European Uremic Toxin Work Group (EUTox). Serum indoxyl sulfate is associated with vascular disease and mortality in chronic kidney disease patients. Clin. J. Am. Soc. Nephrol. 2009;4:1551–1558. doi: 10.2215/CJN.03980609.
    1. Liabeuf S., Barreto D.V., Barreto F.C., Meert N., Glorieux G., Schepers E., Temmar M., Choukroun G., Vanholder R., Massy Z.A., et al. Free p-cresylsulphate is a predictor of mortality in patients at different stages of chronic kidney disease. Nephrol. Dial. Transpl. 2010;25:1183–1191. doi: 10.1093/ndt/gfp592.
    1. Lin C.J., Liu H.L., Pan C.F., Chuang C.K., Jayakumar T., Wang T.J., Chen H.H., Wu C.J. Indoxyl sulfate predicts cardiovascular disease and renal function deterioration in advanced chronic kidney disease. Arch. Med. Res. 2012;43:451–456. doi: 10.1016/j.arcmed.2012.08.002.
    1. Pecoits-Filho R., Heimburger O., Barany P., Suliman M., Fehrman-Ekholm I., Lindholm B., Stenvinkel P. Associations between circulating inflammatory markers and residual renal function in CRF patients. Am. J. Kidney Dis. 2003;41:1212–1218. doi: 10.1016/S0272-6386(03)00353-6.
    1. Stinghen A.E., Goncalves S.M., Martines E.G., Nakao L.S., Riella M.C., Aita C.A., Pecoits-Filho R. Increased plasma and endothelial cell expression of chemokines and adhesion molecules in chronic kidney disease. Nephron Clin. Pract. 2009;111:c117–c126. doi: 10.1159/000191205.
    1. Dou L., Sallee M., Cerini C., Poitevin S., Gondouin B., Jourde-Chiche N., Fallague K., Brunet P., Calaf R., Dussol B., et al. The cardiovascular effect of the uremic solute indole-3 acetic acid. J. Am. Soc. Nephrol. 2015;26:876–887. doi: 10.1681/ASN.2013121283.
    1. Dalboni M.A., Sardenberg C., Andreoli M.C., Watanabe R., Canziani M.E., Santos B.F., Liangos O., Jaber B.L., Draibe S., Cendoroglo M. Soluble Fas: A novel marker of inflammation in uremia. Artif. Organs. 2003;27:687–691. doi: 10.1046/j.1525-1594.2003.07274.x.
    1. El-Agroudy A.E., El-Baz A. Soluble Fas: A useful marker of inflammation and cardiovascular diseases in uremic patients. Clin. Exp. Nephrol. 2010;14:152–157. doi: 10.1007/s10157-009-0261-8.
    1. Kim H.Y., Yoo T.H., Hwang Y., Lee G.H., Kim B., Jang J., Yu H.T., Kim M.C., Cho J.Y., Lee C.J., et al. Indoxyl sulfate (IS)-mediated immune dysfunction provokes endothelial damage in patients with end-stage renal disease (ESRD) Sci. Rep. 2017;7:3057. doi: 10.1038/s41598-017-03130-z.
    1. Chmielewski M., Bragfors-Helin A.C., Stenvinkel P., Lindholm B., Anderstam B. Serum soluble CD36, assessed by a novel monoclonal antibody-based sandwich ELISA, predicts cardiovascular mortality in dialysis patients. Clin. Chim. Acta. 2010;411:2079–2082. doi: 10.1016/j.cca.2010.09.009.
    1. Huh H.Y., Lo S.K., Yesner L.M., Silverstein R.L. CD36 induction on human monocytes upon adhesion to tumor necrosis factor-activated endothelial cells. J. Biol. Chem. 1995;270:6267–6271. doi: 10.1074/jbc.270.11.6267.
    1. Lekawanvijit S., Kompa A.R., Krum H. Protein-bound uremic toxins: A long overlooked culprit in cardiorenal syndrome. Am. J. Physiol. Ren. Physiol. 2016;311:F52–F62. doi: 10.1152/ajprenal.00348.2015.
    1. Kashiyama K., Sonoda S., Muraoka Y., Suzuki Y., Kamezaki F., Tsuda Y., Araki M., Tamura M., Takeuchi M., Abe H., et al. Coronary plaque progression of non-culprit lesions after culprit percutaneous coronary intervention in patients with moderate to advanced chronic kidney disease: Intravascular ultrasound and integrated backscatter intravascular ultrasound study. Int. J. Cardiovasc. Imaging. 2015;31:935–945. doi: 10.1007/s10554-015-0633-y.
    1. Ross R. Atherosclerosis-an inflammatory disease. N. Engl. J. Med. 1999;340:115–126. doi: 10.1056/NEJM199901143400207.
    1. Jofre R., Rodriguez-Benitez P., Lopez-Gomez J.M., Perez-Garcia R. Inflammatory syndrome in patients on hemodialysis. J. Am. Soc. Nephrol. 2006;17:S274–S280. doi: 10.1681/ASN.2006080926.
    1. Vanholder R., De Smet R. Pathophysiologic effects of uremic retention solutes. J. Am. Soc. Nephrol. 1999;10:1815–1823.
    1. Yadav A.K., Lal A., Jha V. Association of circulating fractalkine (CX3CL1) and CX3CR1 (+) CD4 (+) T cells with common carotid artery intima-media thickness in patients with chronic kidney disease. J. Atheroscler. Thromb. 2011;18:958–965. doi: 10.5551/jat.8722.
    1. Liu H., Jiang D. Fractalkine/CX3CR1 and atherosclerosis. Clin. Chim. Acta. 2011;412:1180–1186. doi: 10.1016/j.cca.2011.03.036.
    1. Lucas A.D., Bursill C., Guzik T.J., Sadowski J., Channon K.M., Greaves D.R. Smooth muscle cells in human atherosclerotic plaques express the fractalkine receptor CX3CR1 and undergo chemotaxis to the CX3C chemokine fractalkine (CX3CL1) Circulation. 2003;108:2498–2504. doi: 10.1161/01.CIR.0000097119.57756.EF.
    1. Lin C.J., Wu V., Wu P.C., Wu C.J. Meta-Analysis of the Associations of p-Cresyl Sulfate (PCS) and Indoxyl Sulfate (IS) with Cardiovascular Events and All-Cause Mortality in Patients with Chronic Renal Failure. PLoS ONE. 2015;10:e0132589. doi: 10.1371/journal.pone.0132589.
    1. Richter B., Koller L., Hohensinner P.J., Rychli K., Zorn G., Goliasch G., Berger R., Mörtl D., Maurer G., Huber K., et al. Fractalkine is an independent predictor of mortality in patients with advanced heart failure. Thromb. Haemost. 2012;6:1220–1227.
    1. Leurs P., Lindholm B. The AGE-RAGE pathway and its relation to cardiovascular disease in patients with chronic kidney disease. Arch. Med. Res. 2013;44:601–610. doi: 10.1016/j.arcmed.2013.11.002.
    1. Selvin E., Halushka M.K., Rawlings A.M., Hoogeveen R.C., Ballantyne C.M., Coresh J., Astor B.C. sRAGE and risk of diabetes, cardiovascular disease, and death. Diabetes. 2013;62:2116–2121. doi: 10.2337/db12-1528.
    1. Rebholz C.M., Astor B.C., Grams M.E., Halushka M.K., Lazo M., Hoogeveen R.C., Ballantyne C.M., Coresh J., Selvin E. Association of plasma levels of soluble receptor for advanced glycation end products and risk of kidney disease: The Atherosclerosis Risk in Communities study. Nephrol. Dial. Transpl. 2015;30:77–83. doi: 10.1093/ndt/gfu282.
    1. Loomis S.J., Chen Y., Sacks D.B., Christenson E.S., Christenson R.H., Rebholz C.M., Selvin E. Cross-sectional Analysis of AGE-CML, sRAGE, and esRAGE with Diabetes and Cardiometabolic Risk Factors in a Community-Based Cohort. Clin. Chem. 2017;63:980–989. doi: 10.1373/clinchem.2016.264135.
    1. Goncalves S., Pecoits-Filho R., Perreto S., Barberato S.H., Stinghen A.E., Lima E.G., Fuerbringer S., Sauthier S.M., Riella M.C. Associations between renal function, volume status and endotoxaemia in chronic kidney disease patients. Nephrol. Dial. Transpl. 2006;21:2788–2794. doi: 10.1093/ndt/gfl273.
    1. Guilgen G., Werneck M.L., de Noronha L., Martins A.P., Varela A.M., Nakao L.S., Pecoits-Filho R. Increased calcification and protein nitration in arteries of chronic kidney disease patients. Blood Purif. 2011;32:296–302. doi: 10.1159/000330327.
    1. Levey A.S., Stevens L.A., Schmid C.H., Zhang Y.L., Castro A.F., Feldman H.I., 3rd, Kusek J.W., Eggers P., Van Lente F., Greene T., et al. A new equation to estimate glomerular filtration rate. Ann. Intern. Med. 2009;150:604–612. doi: 10.7326/0003-4819-150-9-200905050-00006.
    1. Levin A., Stevens P.E., Bilous R.W., Coresh J., De Francisco A.L.M., De Jong P.E., Griffith K.E., Hemmelgarn B.R., Iseki K., Lamb E.J., et al. KDIGO 2012 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. Kidney Int. Suppl. 2013;3:1–150.

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