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Plasma Complement Protein C3a Level Was Associated with Abdominal Aortic Calcification in Patients on Hemodialysis

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Abstract

The complement system plays an important role in cardiovascular disease in patients on hemodialysis. Vascular calcification is also one of the major causes of cardiovascular disease. We want to investigate the relationship between complement activation and vascular calcification in dialyzed patients. One hundred eight hemodialysis patients and 65 heathy controls were enrolled prospectively. Plasma C3a, C5a, mannose-binding lectin (MBL), and membrane attack complex (MAC or C5b-9) levels were detected using ELISA. Plasma C3c, fB, fH, C1q, and C4 levels were measured by immunity transmission turbidity. Abdominal aortic calcification (AAC) was measured by abdomen lateral plain radiograph, and the AAC score was calculated. We identified increased level of MBL and decreased level of C3c and complement factor B compared with normal control. However, C1q, complement factor H, and C4 levels remained at a similar level compared with individuals with normal renal function. The C3a and C5a levels increased, without change of MAC. Forty two of 108 HD patients had the AAC score. C3a levels were correlated with AAC score (r = 0.461, p = 0.002). The median C3a concentration was 238.72 (196.96, 323.41) ng/mL. When evaluated as AAC categories (≤ 4, > 5) with ordinal logistic regression, univariate analyses revealed that higher C3a levels were associated with severe AAC, while multivariate analyses adjusted for age, sex, and calcium level showed that higher C3a levels (OR, 6.28 (1.25–31.69); p = 0.03) were associated with severe AAC. The areas under the curve (AUC) for C3a to diagnose severe abdominal aortic calcification were 0.75(0.58–0.92, 0.01). The complement system was activated in patients on hemodialysis. Higher C3a levels are independently associated with severe AAC. Plasma C3a might have a diagnostic value for the severe AAC in HD patients.

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References

  1. Weiner, D. E., Tighiouart, H., Amin, M. G., Stark, P. C., MacLeod, B., Griffith, J. L., Salem, D. N., Levey, A. S., & Sarnak, M. J. (2004). 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, 15, 1307–1315.

    PubMed  Google Scholar 

  2. Ekdahl, K. N., Soveri, I., Hilborn, J., Fellstrom, B., & Nilsson, B. (2017). Cardiovascular disease in haemodialysis: Role of the intravascular innate immune system. Nature Reviews. Nephrology, 13, 285–296.

    CAS  PubMed  Google Scholar 

  3. Bolland, M. J., Wang, T. K., van Pelt, N. C., Horne, A. M., Mason, B. H., Ames, R. W., Grey, A. B., Ruygrok, P. N., Gamble, G. D., & Reid, I. R. (2010). Abdominal aortic calcification on vertebral morphometry images predicts incident myocardial infarction. Journal of Bone and Mineral Research, 25, 505–512.

    CAS  PubMed  Google Scholar 

  4. Craddock, P. R., Fehr, J., Brigham, K. L., Kronenberg, R. S., & Jacob, H. S. (1977). Complement and leukocyte-mediated pulmonary dysfunction in hemodialysis. The New England Journal of Medicine, 296, 769–774.

    CAS  PubMed  Google Scholar 

  5. Hempel, J. C., Poppelaars, F., Gaya da Costa, M., Franssen, C. F., de Vlaam, T. P., Daha, M. R., Berger, S. P., Seelen, M. A., & Gaillard, C. (2017). A: Distinct in vitro complement activation by various intravenous iron preparations. American Journal of Nephrology, 45, 49–59.

    CAS  PubMed  Google Scholar 

  6. Szebeni, J. (2014). Complement activation-related pseudoallergy: A stress reaction in blood triggered by nanomedicines and biologicals. Molecular Immunology, 61, 163–173.

    CAS  PubMed  Google Scholar 

  7. Chenoweth, D. E., Cheung, A. K., & Henderson, L. W. (1983). Anaphylatoxin formation during hemodialysis: Effects of different dialyzer membranes. Kidney International, 24, 764–769.

    CAS  PubMed  Google Scholar 

  8. Poppelaars, F., Gaya da Costa, M., Berger, S. P., Assa, S., Meter-Arkema, A. H., Daha, M. R., van Son, W. J., Franssen, C. F., & Seelen, M. (2016). A: Strong predictive value of mannose-binding lectin levels for cardiovascular risk of hemodialysis patients. Journal of Translational Medicine, 14, 236.

    PubMed  PubMed Central  Google Scholar 

  9. Lines, S. W., Richardson, V. R., Thomas, B., Dunn, E. J., Wright, M. J., & Carter, A. M. (2016). Complement and cardiovascular disease--the missing link in haemodialysis patients. Nephron, 132, 5–14.

    CAS  PubMed  Google Scholar 

  10. Szulc, P. (2016). Abdominal aortic calcification: A reappraisal of epidemiological and pathophysiological data. Bone, 84, 25–37.

    CAS  PubMed  Google Scholar 

  11. Nagaraj, N., Matthews, K. A., Shields, K. J., Barinas-Mitchell, E., Budoff, M. J., & El Khoudary, S. R. (2015). Complement proteins and arterial calcification in middle aged women: Cross-sectional effect of cardiovascular fat. The SWAN Cardiovascular Fat Ancillary Study. Atherosclerosis, 243, 533–539.

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Honkanen, E., Kauppila, L., Wikstrom, B., Rensma, P. L., Krzesinski, J. M., Aasarod, K., Verbeke, F., Jensen, P. B., Mattelaer, P., & Volck, B. (2008). Group C s: Abdominal aortic calcification in dialysis patients: Results of the CORD study. Nephrology, Dialysis, Transplantation, 23, 4009–4015.

    PubMed  PubMed Central  Google Scholar 

  13. Kauppila, L. I., Polak, J. F., Cupples, L. A., Hannan, M. T., Kiel, D. P., & Wilson, P. W. (1997). New indices to classify location, severity and progression of calcific lesions in the abdominal aorta: A 25-year follow-up study. Atherosclerosis, 132, 245–250.

    CAS  PubMed  Google Scholar 

  14. Foley, R. N., Parfrey, P. S., & Sarnak, M. J. (1998). Epidemiology of cardiovascular disease in chronic renal disease. Journal of the American Society of Nephrology, 9, S16–S23.

    CAS  PubMed  Google Scholar 

  15. Jha, V., Garcia-Garcia, G., Iseki, K., Li, Z., Naicker, S., Plattner, B., Saran, R., Wang, A. Y., & Yang, C. W. (2013). Chronic kidney disease: Global dimension and perspectives. Lancet, 382, 260–272.

    PubMed  Google Scholar 

  16. Sun, J., Axelsson, J., Machowska, A., Heimburger, O., Barany, P., Lindholm, B., Lindstrom, K., Stenvinkel, P., & Qureshi, A. R. (2016). Biomarkers of cardiovascular disease and mortality risk in patients with advanced CKD. Clinical Journal of the American Society of Nephrology, 11, 1163–1172.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Cohen, S. D., Phillips, T. M., Khetpal, P., & Kimmel, P. L. (2010). Cytokine patterns and survival in haemodialysis patients. Nephrology, Dialysis, Transplantation, 25, 1239–1243.

    CAS  PubMed  Google Scholar 

  18. Galli, F. (2016). Complement and cardiovascular disease - the missing link in haemodialysis patients? Nephron, 134, 103.

    PubMed  Google Scholar 

  19. Poppelaars, F., Gaya da Costa, M., Faria, B., Berger, S. P., Assa, S., Daha, M. R., Medina Pestana, J. O., van Son, W. J., Franssen, C. F. M., & Seelen, M. A. (2018). Intradialytic complement activation precedes the development of cardiovascular events in hemodialysis patients. Frontiers in Immunology, 9, 2070.

    PubMed  PubMed Central  Google Scholar 

  20. Buraczynska, M., Ksiazek, P., Zukowski, P., Benedyk-Lorens, E., & Orlowska-Kowalik, G. (2009). Complement factor H gene polymorphism and risk of cardiovascular disease in end-stage renal disease patients. Clinical Immunology, 132, 285–290.

    CAS  PubMed  Google Scholar 

  21. Hornum, M., Bay, J. T., Clausen, P., Melchior Hansen, J., Mathiesen, E. R., Feldt-Rasmussen, B., & Garred, P. (2014). High levels of mannose-binding lectin are associated with lower pulse wave velocity in uraemic patients. BMC Nephrology, 15(162).

  22. Satomura, A., Endo, M., Fujita, T., Ohi, H., Ohsawa, I., Fuke, Y., Matsumoto, K., Sudo, S., Matsushita, M., & Fujita, T. (2006). Serum mannose-binding lectin levels in maintenance hemodialysis patients: Impact on all-cause mortality. Nephron. Clinical Practice, 102, c93–c99.

    CAS  PubMed  Google Scholar 

  23. Ketteler, M., Bongartz, P., Westenfeld, R., Wildberger, J. E., Mahnken, A. H., Bohm, R., Metzger, T., Wanner, C., Jahnen-Dechent, W., & Floege, J. (2003). Association of low fetuin-A (AHSG) concentrations in serum with cardiovascular mortality in patients on dialysis: A cross-sectional study. Lancet, 361, 827–833.

    CAS  PubMed  Google Scholar 

  24. Stenvinkel, P., Wang, K., Qureshi, A. R., Axelsson, J., Pecoits-Filho, R., Gao, P., Barany, P., Lindholm, B., Jogestrand, T., Heimburger, O., Holmes, C., Schalling, M., & Nordfors, L. (2005). Low fetuin-A levels are associated with cardiovascular death: Impact of variations in the gene encoding fetuin. Kidney International, 67, 2383–2392.

    CAS  PubMed  Google Scholar 

  25. Honda, H., Qureshi, A. R., Heimburger, O., Barany, P., Wang, K., Pecoits-Filho, R., Stenvinkel, P., & Lindholm, B. (2006). Serum albumin, C-reactive protein, interleukin 6, and fetuin A as predictors of malnutrition, cardiovascular disease, and mortality in patients with ESRD. American Journal of Kidney Diseases, 47, 139–148.

    CAS  PubMed  Google Scholar 

  26. Dunkelberger, J. R., & Song, W. C. (2010). Complement and its role in innate and adaptive immune responses. Cell Research, 20, 34–50.

    CAS  PubMed  Google Scholar 

  27. Kang, Y. S., Do, Y., Lee, H. K., Park, S. H., Cheong, C., Lynch, R. M., Loeffler, J. M., Steinman, R. M., & Park, C. G. (2006). A dominant complement fixation pathway for pneumococcal polysaccharides initiated by SIGN-R1 interacting with C1q. Cell, 125, 47–58.

    CAS  PubMed  Google Scholar 

  28. Matsuoka, K., Park, K. A., Ito, M., Ikeda, K., & Takeshita, S. (2014). Osteoclast-derived complement component 3a stimulates osteoblast differentiation. Journal of Bone and Mineral Research, 29, 1522–1530.

    CAS  PubMed  Google Scholar 

  29. Bastos Goncalves, F., Voute, M. T., Hoeks, S. E., Chonchol, M. B., Boersma, E. E., Stolker, R. J., & Verhagen, H. J. (2012). Calcification of the abdominal aorta as an independent predictor of cardiovascular events: A meta-analysis. Heart, 98, 988–994.

    PubMed  Google Scholar 

  30. Lee, S. M., Lee, H. W., Son, Y. K., Kim, S. E., & An, W. S. (2017). Abdominal aortic calcification score among several vascular calcification scores of plain radiograph is the most reliable predictor of severe coronary artery calcification in dialysis patients. Renal Failure, 39, 729–735.

    PubMed  PubMed Central  Google Scholar 

  31. Figueiredo, C. P., Rajamannan, N. M., Lopes, J. B., Caparbo, V. F., Takayama, L., Kuroishi, M. E., Oliveira, I. S., Menezes, P. R., Scazufca, M., Bonfa, E., & Pereira, R. M. (2013). Serum phosphate and hip bone mineral density as additional factors for high vascular calcification scores in a community-dwelling: The Sao Paulo Ageing & Health Study (SPAH). Bone, 52, 354–359.

    CAS  PubMed  Google Scholar 

  32. Hutcheson, J. D., Goettsch, C., Bertazzo, S., Maldonado, N., Ruiz, J. L., Goh, W., Yabusaki, K., Faits, T., Bouten, C., Franck, G., Quillard, T., Libby, P., Aikawa, M., Weinbaum, S., & Aikawa, E. (2016). Genesis and growth of extracellular-vesicle-derived microcalcification in atherosclerotic plaques. Nature Materials, 15, 335–343.

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Shanahan, C. M. (2007). Inflammation ushers in calcification: A cycle of damage and protection? Circulation, 116, 2782–2785.

    PubMed  Google Scholar 

  34. Carter, A. M., Prasad, U. K., & Grant, P. J. (2009). Complement C3 and C-reactive protein in male survivors of myocardial infarction. Atherosclerosis, 203, 538–543.

    CAS  PubMed  Google Scholar 

  35. Muscari, A., Bozzoli, C., Gerratana, C., Zaca, F., Rovinetti, C., Zauli, D., La Placa, M., & Puddu, P. (1988). Association of serum IgA and C4 with severe atherosclerosis. Atherosclerosis, 74, 179–186.

    CAS  PubMed  Google Scholar 

  36. Engstrom, G., Hedblad, B., Janzon, L., & Lindgarde, F. (2007). Complement C3 and C4 in plasma and incidence of myocardial infarction and stroke: A population-based cohort study. European Journal of Cardiovascular Prevention and Rehabilitation, 14, 392–397.

    PubMed  Google Scholar 

  37. Kostner, K. M., Fahti, R. B., Case, C., Hobson, P., Tate, J., & Marwick, T. H. (2006). Inflammation, complement activation and endothelial function in stable and unstable coronary artery disease. Clinica Chimica Acta, 365, 129–134.

    CAS  Google Scholar 

  38. Hoffmeister, H. M., Ehlers, R., Buttcher, E., Kazmaier, S., Szabo, S., Beyer, M. E., Steinmetz, A., & Seipel, L. (2002). Comparison of C-reactive protein and terminal complement complex in patients with unstable angina pectoris versus stable angina pectoris. The American Journal of Cardiology, 89, 909–912.

    PubMed  Google Scholar 

  39. Speidl, W. S., Exner, M., Amighi, J., Mlekusch, W., Sabeti, S., Kastl, S. P., Zorn, G., Maurer, G., Wagner, O., Huber, K., Minar, E., Wojta, J., & Schillinger, M. (2007). Complement component C5a predicts restenosis after superficial femoral artery balloon angioplasty. Journal of Endovascular Therapy, 14, 62–69.

    PubMed  Google Scholar 

  40. Speidl, W. S., Katsaros, K. M., Kastl, S. P., Zorn, G., Huber, K., Maurer, G., Wojta, J., & Christ, G. (2010). Coronary late lumen loss of drug eluting stents is associated with increased serum levels of the complement components C3a and C5a. Atherosclerosis, 208, 285–289.

    CAS  PubMed  Google Scholar 

  41. Persson, L., Boren, J., Robertson, A. K., Wallenius, V., Hansson, G. K., & Pekna, M. (2004). Lack of complement factor C3, but not factor B, increases hyperlipidemia and atherosclerosis in apolipoprotein E−/− low-density lipoprotein receptor −/− mice. Arteriosclerosis, Thrombosis, and Vascular Biology, 24, 1062–1067.

    CAS  PubMed  Google Scholar 

  42. Buono, C., Come, C. E., Witztum, J. L., Maguire, G. F., Connelly, P. W., Carroll, M., & Lichtman, A. H. (2002). Influence of C3 deficiency on atherosclerosis. Circulation, 105, 3025–3031.

    CAS  PubMed  Google Scholar 

  43. Yang, X., Peterson, L., Thieringer, R., Deignan, J. L., Wang, X., Zhu, J., Wang, S., Zhong, H., Stepaniants, S., Beaulaurier, J., Wang, I. M., Rosa, R., Cumiskey, A. M., Luo, J. M., Luo, Q., Shah, K., Xiao, J., Nickle, D., Plump, A., Schadt, E. E., Lusis, A. J., & Lum, P. Y. (2010). Identification and validation of genes affecting aortic lesions in mice. The Journal of Clinical Investigation, 120, 2414–2422.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Patel, S., Thelander, E. M., Hernandez, M., Montenegro, J., Hassing, H., Burton, C., Mundt, S., Hermanowski-Vosatka, A., Wright, S. D., Chao, Y. S., & Detmers, P. A. (2001). ApoE(−/−) mice develop atherosclerosis in the absence of complement component C5. Biochemical and Biophysical Research Communications, 286, 164–170.

    CAS  PubMed  Google Scholar 

  45. Albrecht, E. A., Chinnaiyan, A. M., Varambally, S., Kumar-Sinha, C., Barrette, T. R., Sarma, J. V., & Ward, P. A. (2004). C5a-induced gene expression in human umbilical vein endothelial cells. The American Journal of Pathology, 164, 849–859.

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Onuma, O. K., Pencina, K., Qazi, S., Massaro, J. M., D'Agostino, R. B., Sr., Chuang, M. L., Fox, C. S., Hoffmann, U., & O'Donnell, C. J. (2017). Relation of risk factors and abdominal aortic calcium to progression of coronary artery calcium (from the Framingham Heart Study). The American Journal of Cardiology, 119, 1584–1589.

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Liu, W. C., Wu, C. C., Hung, Y. M., Liao, M. T., Shyu, J. F., Lin, Y. F., Lu, K. C., & Yeh, K. C. (2016). Pleiotropic effects of vitamin D in chronic kidney disease. Clinica Chimica Acta, 453, 1–12.

    CAS  Google Scholar 

  48. Tangpricha, V., & Wasse, H. (2014). Vitamin D therapy in kidney disease: More vitamin D is necessary. American Journal of Kidney Diseases, 64, 667–669.

    PubMed  Google Scholar 

  49. Hou, Y. C., Liu, W. C., Zheng, C. M., Zheng, J. Q., Yen, T. H., & Lu, K. C. (2017). Role of vitamin D in uremic vascular calcification. BioMed Research International, 2017, 2803579.

    PubMed  PubMed Central  Google Scholar 

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Funding

This study was funded by the National Natural Science Foundation of China (81270820).

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Authors and Affiliations

  1. Renal Division, Department of internal Medicine, Peking University First Hospital, Beijing, 100034, China

    Yaqin Wang, Yuanyi Miao, Kunjing Gong, Xuyang Cheng, Yuqing Chen & Ming-Hui Zhao

  2. Institute of Nephrology, Peking University, Beijing, 100034, China

    Yaqin Wang, Yuanyi Miao, Kunjing Gong, Xuyang Cheng, Yuqing Chen & Ming-Hui Zhao

  3. Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, 100034, China

    Yaqin Wang, Yuanyi Miao, Kunjing Gong, Xuyang Cheng, Yuqing Chen & Ming-Hui Zhao

  4. Key Laboratory of Chronic Kidney Disease Prevention and Treatment, Ministry of Education, Beijing, 100034, China

    Yaqin Wang, Yuanyi Miao, Kunjing Gong, Xuyang Cheng, Yuqing Chen & Ming-Hui Zhao

  5. Peking-Tsinghua Center for Life Sciences, Beijing, People’s Republic of China

    Ming-Hui Zhao

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Contributions

Y.Q.W., Y.Q.C., and M.H.Z. prepared the manuscript. Y.Q.C. and Y.Q.W. designed the study and organized the coordination. Y.Q.W., Y.Y.M, K.J.G., and X.Y.C collected the specimens and basic characteristics of all the patients. Y.Q.W. performed the experiments and the data analysis. All authors read and approved the final manuscript.

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Correspondence to Yuqing Chen.

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The authors declare that they have no conflict of interest.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of Peking University First Hospital and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This article does not contain any studies with animals performed by any of the authors.

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Informed consent was obtained from all individual participants included in the study.

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Supplementary Figure 1

Spearman’s correlation analysis of C3a and AAC score. Spearman’s correlation analysis showed that HD patients’ plasma C3a level were positively correlated with AAC score (r = 0.461, p = 0.002) (PNG 72 kb)

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Wang, Y., Miao, Y., Gong, K. et al. Plasma Complement Protein C3a Level Was Associated with Abdominal Aortic Calcification in Patients on Hemodialysis. J. of Cardiovasc. Trans. Res. 12, 496–505 (2019). https://doi.org/10.1007/s12265-019-09885-2

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