Abstract
Lupus nephritis is one of the most severe manifestations of systemic lupus erythematous. Renal involvement in patients with systemic lupus erythematous is an important cause of morbidity and mortality. The pathogenesis of lupus nephritis involve multiple factors, wich include genetic predisposition, epigenetic regulation and environmental interaction. Conventional clinical parameters such as creatinine clearance, proteinuria, urinary sediments, antibodies anti-double- strand DNA and complement proteins they are not enough sensitive or specific to detect disease activity. In the last decades, “Omics” technologies (Proteomic, genomic, transcriptomic, metobolomic) have been used in an extensive way looking for biomarkers, which allowed to discovery variants associated with systemic lupus erythematous and lupus nephritis. Such findings have expanded our knowledge about molecular basis of disease and they have been very important to identification of potential therapeutic targets to prediction of disease and early treatment. In this review, we resume some of recent studies focused in identification of biomarkers associated with lupus nephritis in diverse biological fluids.References
1. Li, Y., Fang, X. & Li, Q.-Z. Biomarker profiling for lupus nephritis. Genomics Proteomics Bioinformatics 2013;11,158–165
2. Cervera, R. et al. Systemic lupus erythematosus in Europe at the change of the millennium: lessons from the ‘Euro- Lupus Project’. Autoimmun. Rev. 2006;5,180–186.
3. Gurevitz, S. L., Snyder, J. A., Wessel, E. K., Frey, J. & Williamson, B. A. Systemic lupus erythematosus: a review of the disease and treatment options. Consult. Pharm. J. Am. Soc. Consult. Pharm. 2013;28,110–121.
4. Liu, C.-C., Manzi, S. & Ahearn, J. M. Biomarkers for systemic lupus erythematosus: a review and perspective. Curr. Opin. Rheumatol. 2005;17,543–549.
5. Oelzner, P. et al. Anti-C1q antibodies and antiendothelial cell antibodies in systemic lupus erythematosus - relationship with disease activity and renal involvement. Clin. Rheumatol. 2003;22,271–278.
6. Moroni, G. et al. Are laboratory tests useful for monitoring the activity of lupus nephritis? A 6-year prospective study in a cohort of 228 patients with lupus nephritis. Ann. Rheum. Dis. 2009;68,234–237.
7. Esdaile, J. M. et al. Routine immunologic tests in systemic lupus erythematosus: is there a need for more studies? J. Rheumatol. 1996;23,1891–1896.
8. Reyes-Thomas, J., Blanco, I. & Putterman, C. Urinary Biomarkers in Lupus Nephritis. Clin. Rev. Allergy Immunol. 2011;40,138–150.
9. Illei, G. G. & Lipsky, P. E. Biomarkers in systemic lupus erythematosus. Curr. Rheumatol. Rep. 2004;6,382–390.
10. Illei, G. G., Tackey, E., Lapteva, L. & Lipsky, P. E. Biomarkers in systemic lupus erythematosus: II. Markers of disease activity. Arthritis Rheum. 2004;50,2048–2065.
11. Manoharan, A. & Madaio, M. P. Biomarkers in Lupus Nephritis. Rheum. Dis. Clin. N. Am. 2010;36,131–143.
12. Simón, J. A., Cabiedes, J., Ortiz, E., Alcocer-Varela, J. & Sánchez-Guerrero, J. Anti-nucleosome antibodies in patients with systemic lupus erythematosus of recent onset. Potential utility as a diagnostic tool and disease activity marker. Rheumatol. Oxf. Engl. 2004;43,220–224.
13. Marto, N., Bertolaccini, M. L., Calabuig, E., Hughes, G. R. V. & Khamashta, M. A. Anti-C1q antibodies in nephritis:
correlation between titres and renal disease activity and positive predictive value in systemic lupus erythematosus.
Ann. Rheum. Dis. 2005;64,444–448.
14. Panda, A. K. et al. Mannose binding lectin: a biomarker of systemic lupus erythematosus disease activity. Arthritis Res. Ther. 2012;14,R218.
15. Wang, F., Yu, F., Tan, Y., Song, D. & Zhao, M. Serum complement factor H is associated with clinical and pathological activities of patients with lupus nephritis. Rheumatol. Oxf. Engl. 2012;51,2269–2277.
16. Li, Q.-Z. et al. Identification of autoantibody clusters that best predict lupus disease activity using glomerular proteome arrays. J. Clin. Invest. 2005;115,3428–3439.
17. Li, Q.-Z. et al. Protein array autoantibody profiles for insights into systemic lupus erythematosus and incomplete lupus syndromes. Clin. Exp. Immunol. 2007;147,60–70.
18. Egner, W. The use of laboratory tests in the diagnosis of SLE. J. Clin. Pathol. 2000;53,424–432.
19. Quintana, G. et al. Single anti-P ribosomal antibodies are not associated with lupus nephritis in patients suffering from active systemic lupus erythematosus. Autoimmun. Rev. 2010;9,750–755.
20. Filipowicz, W., Bhattacharyya, S. N. & Sonenberg, N. Mechanisms of post-transcriptional regulation by microRNAs: are the answers in sight? Nat. Rev. Genet. 2008;9,102–114.
21. Mitchell, P. S. et al. Circulating microRNAs as stable blood-based markers for cáncer detection. Proc. Natl. Acad. Sci. U. S. A. 2008;105,10513–10518.
22. Zhao, H. et al. A pilot study of circulating miRNAs as potential biomarkers of early stage breast cancer. PloS One 2010;5, e13735.
23. Roth, C. et al. Circulating microRNAs as blood-based markers for patients with primary and metastatic breast cancer. Breast Cancer Res. BCR 2010;12,R90.
24. Te, J. L. et al. Identification of Unique MicroRNA Signature Associated with Lupus Nephritis. PLoS ONE 2010;5, e10344.
25. Dai, Y. et al. Microarray analysis of microRNA expression in peripheral blood cells of systemic lupus erythematosus patients. Lupus 2007;16,939–946.
26. Tang, Y. et al. MicroRNA-146A contributes to abnorma activation of the type I interferon pathway in human lupus by targeting the key signaling proteins. Arthritis Rheum. 2009;60,1065–1075.
27. Wang, G. et al. Serum and urinary cell-free MiR-146a and MiR-155 in patients with systemic lupus erythematosus. J. Rheumatol. 2010;37,2516–2522.
28. Lu, M.-C. et al. Decreased microRNA(miR)-145 and increased miR-224 expression in T cells from patients with systemic lupus erythematosus involved in lupus immunopathogenesis. Clin. Exp. Immunol. 2013;171,91–99.
29. Stagakis, E. et al. Identification of novel microRNA signatures linked to human lupus disease activity and pathogenesis: miR-21 regulates aberrant T cell responses through regulation of PDCD4 expression. Ann. Rheum. Dis. 2011;70,1496–1506.
30. Zhao, X. et al. MicroRNA-125a contributes to elevated inflammatory chemokine RANTES levels via targeting KLF13 in systemic lupus erythematosus. Arthritis Rheum. 2010;62,3425–3435.
31. Wang, G. et al. Serum and urinary free microRNA level in patients with systemic lupus erythematosus. Lupus 2011;20,493–500.
32. Gómez-Guerrero, C., Hernández-Vargas, P., López- ranco, O., Ortiz-Muñoz, G. & Egido, J. Mesangial cells and glomerular inflammation: from the pathogenesis to novel therapeutic approaches. Curr. Drug Targets Inflamm. Allergy 2005;4,341–351.
33. Adhya, Z., Borozdenkova, S. & Karim, M. Y. The role of cytokines as biomarkers in systemic lupus erythematosus and lupus nephritis. Nephrol. Dial. Transplant. Off. Publ. Eur. Dial. Transpl. Assoc. - Eur. Ren. Assoc. 2011;26,3273– 3280.
34. Sabry, A. et al. Proinflammatory cytokines (TNF-alpha and IL-6) in Egyptian patients with SLE: its correlation with disease activity. Cytokine 2006;35,148–153.
35. El-Shafey, E. M., El-Nagar, G. F., El-Bendary, A. S., Sabry, A. A. & Selim, A.-G. A. Serum soluble interleukin-2 receptor alpha in systemic lupus erythematosus. Iran. J. Kidney Dis. 2008;2,80–85.
36. Badot, V. et al. Serum soluble interleukin 7 receptor is strongly associated with lupus nephritis in patients with systemic lupus erythematosus. Ann. Rheum. Dis. 2013;72,453–456.
37. Fu, Q. et al. Association of elevated transcript levels of interferon-inducible chemokines with disease activity and organ damage in systemic lupus erythematosus patients. Arthritis Res. Ther. 2008;10,R112.
38. Segerer, S., Nelson, P. J. & Schlöndorff, D. Chemokines, chemokine receptors, and renal disease: from basic science to pathophysiologic and therapeutic studies. J. Am. Soc. Nephrol. JASN 2000;11,152–176.
39. Alzawawy, A., Zohary, M., Ablordiny, M. & Eldalie, M. Estimation of monocyte-chemoattractantprotein-1 (Mcp-1) level in patients with lupus nephritis. Int. J. Rheum. Dis. 2009;12,311–318.
40. Viedt, C. & Orth, S. R. Monocyte chemoattractant protein-1 (MCP-1) in the kidney: does it more than simply attract monocytes? Nephrol. Dial. Transplant. Off. Publ. Eur. Dial. Transpl. Assoc. - Eur. Ren. Assoc. 2002;17,2043–2047.
41. Sánchez-Muñoz, F., Amezcua-Guerra, L., Macías- alacios, M., Márquez-Velasco, R. & Bojalil, R. Vanin-1 as a potential novel biomarker for active nephritis in systemic lupus erythematosus. Lupus 2013;22,333–335.
42. Dhaun, N. et al. Urinary endothelin-1 in chronic kidney disease and as a marker of disease activity in lupus nephritis.
Am. J. Physiol. Renal Physiol. 2009;296,F1477–1483.
43. Pitashny, M. et al. Urinary lipocalin-2 is associated with renal disease activity in human lupus nephritis. Arthritis Rheum. 2007;56,1894–1903.
44. Wu, T. et al. Elevated urinary VCAM-1, P-selectin, soluble TNF receptor-1, and CXC chemokine ligand 16 in multiple murine lupus strains and human lupus nephritis. J. Immunol. Baltim. Md 1950 2007;179,7166–7175.
45. Kiani, A. N. et al. Urinary vascular cell adhesionmolecule, but not neutrophil gelatinase-associated lipocalin, is associated with lupus nephritis. J. Rheumatol. 2012;39,1231–1237.
46. Iwano, M. et al. Urinary levels of IL-6 in patients with active lupus nephritis. Clin. Nephrol. 1993;40,16–21.
47. Tsai, C. Y., Wu, T. H., Yu, C. L., Lu, J. Y. & Tsai, Y. Y. ncreased excretions of beta2-microglobulin, IL-6, and IL-8 and decreased excretion of Tamm-Horsfall glycoprotein in urine of patients with active lupus nephritis. Nephron 2000;85,207–214.
48. Avihingsanon, Y. et al. Measurement of urinary chemokine and growth factor messenger RNAs: a noninvasive monitoring in lupus nephritis. Kidney Int. 2006;69,747–753.
49. Chicheportiche, Y. et al. TWEAK, a new secreted ligand in the tumor necrosis factor family that weakly induces apoptosis.
J. Biol. Chem. 1997;272,32401–32410.
50. Campbell, S., Michaelson, J., Burkly, L. & Putterman, C. The role of TWEAK/Fn14 in the pathogenesis of inflammation and systemic autoimmunity. Front. Biosci. J. Virtual Libr. 2004;9,2273–2284.
51. Schwartz, N. et al. Urinary TWEAK and the activity of lupus nephritis. J. Autoimmun. 2006;27,242–250.
52. Schwartz, N. et al. Urinary TWEAK as a biomarker of lupus nephritis: a multicenter cohort study. Arthritis Res. Ther. 2009;11,R143.
53. Suzuki, M. et al. Initial Validation of a Novel Protein Biomarker Panel for Active Pediatric Lupus Nephritis. Pediatr. Res. 2009;65,530–536.
54. Brunner, H. I. et al. Association of noninvasively measured renal protein biomarkers with histologic features of lupus nephritis. Arthritis Rheum. 2012;64,2687–2697.
2. Cervera, R. et al. Systemic lupus erythematosus in Europe at the change of the millennium: lessons from the ‘Euro- Lupus Project’. Autoimmun. Rev. 2006;5,180–186.
3. Gurevitz, S. L., Snyder, J. A., Wessel, E. K., Frey, J. & Williamson, B. A. Systemic lupus erythematosus: a review of the disease and treatment options. Consult. Pharm. J. Am. Soc. Consult. Pharm. 2013;28,110–121.
4. Liu, C.-C., Manzi, S. & Ahearn, J. M. Biomarkers for systemic lupus erythematosus: a review and perspective. Curr. Opin. Rheumatol. 2005;17,543–549.
5. Oelzner, P. et al. Anti-C1q antibodies and antiendothelial cell antibodies in systemic lupus erythematosus - relationship with disease activity and renal involvement. Clin. Rheumatol. 2003;22,271–278.
6. Moroni, G. et al. Are laboratory tests useful for monitoring the activity of lupus nephritis? A 6-year prospective study in a cohort of 228 patients with lupus nephritis. Ann. Rheum. Dis. 2009;68,234–237.
7. Esdaile, J. M. et al. Routine immunologic tests in systemic lupus erythematosus: is there a need for more studies? J. Rheumatol. 1996;23,1891–1896.
8. Reyes-Thomas, J., Blanco, I. & Putterman, C. Urinary Biomarkers in Lupus Nephritis. Clin. Rev. Allergy Immunol. 2011;40,138–150.
9. Illei, G. G. & Lipsky, P. E. Biomarkers in systemic lupus erythematosus. Curr. Rheumatol. Rep. 2004;6,382–390.
10. Illei, G. G., Tackey, E., Lapteva, L. & Lipsky, P. E. Biomarkers in systemic lupus erythematosus: II. Markers of disease activity. Arthritis Rheum. 2004;50,2048–2065.
11. Manoharan, A. & Madaio, M. P. Biomarkers in Lupus Nephritis. Rheum. Dis. Clin. N. Am. 2010;36,131–143.
12. Simón, J. A., Cabiedes, J., Ortiz, E., Alcocer-Varela, J. & Sánchez-Guerrero, J. Anti-nucleosome antibodies in patients with systemic lupus erythematosus of recent onset. Potential utility as a diagnostic tool and disease activity marker. Rheumatol. Oxf. Engl. 2004;43,220–224.
13. Marto, N., Bertolaccini, M. L., Calabuig, E., Hughes, G. R. V. & Khamashta, M. A. Anti-C1q antibodies in nephritis:
correlation between titres and renal disease activity and positive predictive value in systemic lupus erythematosus.
Ann. Rheum. Dis. 2005;64,444–448.
14. Panda, A. K. et al. Mannose binding lectin: a biomarker of systemic lupus erythematosus disease activity. Arthritis Res. Ther. 2012;14,R218.
15. Wang, F., Yu, F., Tan, Y., Song, D. & Zhao, M. Serum complement factor H is associated with clinical and pathological activities of patients with lupus nephritis. Rheumatol. Oxf. Engl. 2012;51,2269–2277.
16. Li, Q.-Z. et al. Identification of autoantibody clusters that best predict lupus disease activity using glomerular proteome arrays. J. Clin. Invest. 2005;115,3428–3439.
17. Li, Q.-Z. et al. Protein array autoantibody profiles for insights into systemic lupus erythematosus and incomplete lupus syndromes. Clin. Exp. Immunol. 2007;147,60–70.
18. Egner, W. The use of laboratory tests in the diagnosis of SLE. J. Clin. Pathol. 2000;53,424–432.
19. Quintana, G. et al. Single anti-P ribosomal antibodies are not associated with lupus nephritis in patients suffering from active systemic lupus erythematosus. Autoimmun. Rev. 2010;9,750–755.
20. Filipowicz, W., Bhattacharyya, S. N. & Sonenberg, N. Mechanisms of post-transcriptional regulation by microRNAs: are the answers in sight? Nat. Rev. Genet. 2008;9,102–114.
21. Mitchell, P. S. et al. Circulating microRNAs as stable blood-based markers for cáncer detection. Proc. Natl. Acad. Sci. U. S. A. 2008;105,10513–10518.
22. Zhao, H. et al. A pilot study of circulating miRNAs as potential biomarkers of early stage breast cancer. PloS One 2010;5, e13735.
23. Roth, C. et al. Circulating microRNAs as blood-based markers for patients with primary and metastatic breast cancer. Breast Cancer Res. BCR 2010;12,R90.
24. Te, J. L. et al. Identification of Unique MicroRNA Signature Associated with Lupus Nephritis. PLoS ONE 2010;5, e10344.
25. Dai, Y. et al. Microarray analysis of microRNA expression in peripheral blood cells of systemic lupus erythematosus patients. Lupus 2007;16,939–946.
26. Tang, Y. et al. MicroRNA-146A contributes to abnorma activation of the type I interferon pathway in human lupus by targeting the key signaling proteins. Arthritis Rheum. 2009;60,1065–1075.
27. Wang, G. et al. Serum and urinary cell-free MiR-146a and MiR-155 in patients with systemic lupus erythematosus. J. Rheumatol. 2010;37,2516–2522.
28. Lu, M.-C. et al. Decreased microRNA(miR)-145 and increased miR-224 expression in T cells from patients with systemic lupus erythematosus involved in lupus immunopathogenesis. Clin. Exp. Immunol. 2013;171,91–99.
29. Stagakis, E. et al. Identification of novel microRNA signatures linked to human lupus disease activity and pathogenesis: miR-21 regulates aberrant T cell responses through regulation of PDCD4 expression. Ann. Rheum. Dis. 2011;70,1496–1506.
30. Zhao, X. et al. MicroRNA-125a contributes to elevated inflammatory chemokine RANTES levels via targeting KLF13 in systemic lupus erythematosus. Arthritis Rheum. 2010;62,3425–3435.
31. Wang, G. et al. Serum and urinary free microRNA level in patients with systemic lupus erythematosus. Lupus 2011;20,493–500.
32. Gómez-Guerrero, C., Hernández-Vargas, P., López- ranco, O., Ortiz-Muñoz, G. & Egido, J. Mesangial cells and glomerular inflammation: from the pathogenesis to novel therapeutic approaches. Curr. Drug Targets Inflamm. Allergy 2005;4,341–351.
33. Adhya, Z., Borozdenkova, S. & Karim, M. Y. The role of cytokines as biomarkers in systemic lupus erythematosus and lupus nephritis. Nephrol. Dial. Transplant. Off. Publ. Eur. Dial. Transpl. Assoc. - Eur. Ren. Assoc. 2011;26,3273– 3280.
34. Sabry, A. et al. Proinflammatory cytokines (TNF-alpha and IL-6) in Egyptian patients with SLE: its correlation with disease activity. Cytokine 2006;35,148–153.
35. El-Shafey, E. M., El-Nagar, G. F., El-Bendary, A. S., Sabry, A. A. & Selim, A.-G. A. Serum soluble interleukin-2 receptor alpha in systemic lupus erythematosus. Iran. J. Kidney Dis. 2008;2,80–85.
36. Badot, V. et al. Serum soluble interleukin 7 receptor is strongly associated with lupus nephritis in patients with systemic lupus erythematosus. Ann. Rheum. Dis. 2013;72,453–456.
37. Fu, Q. et al. Association of elevated transcript levels of interferon-inducible chemokines with disease activity and organ damage in systemic lupus erythematosus patients. Arthritis Res. Ther. 2008;10,R112.
38. Segerer, S., Nelson, P. J. & Schlöndorff, D. Chemokines, chemokine receptors, and renal disease: from basic science to pathophysiologic and therapeutic studies. J. Am. Soc. Nephrol. JASN 2000;11,152–176.
39. Alzawawy, A., Zohary, M., Ablordiny, M. & Eldalie, M. Estimation of monocyte-chemoattractantprotein-1 (Mcp-1) level in patients with lupus nephritis. Int. J. Rheum. Dis. 2009;12,311–318.
40. Viedt, C. & Orth, S. R. Monocyte chemoattractant protein-1 (MCP-1) in the kidney: does it more than simply attract monocytes? Nephrol. Dial. Transplant. Off. Publ. Eur. Dial. Transpl. Assoc. - Eur. Ren. Assoc. 2002;17,2043–2047.
41. Sánchez-Muñoz, F., Amezcua-Guerra, L., Macías- alacios, M., Márquez-Velasco, R. & Bojalil, R. Vanin-1 as a potential novel biomarker for active nephritis in systemic lupus erythematosus. Lupus 2013;22,333–335.
42. Dhaun, N. et al. Urinary endothelin-1 in chronic kidney disease and as a marker of disease activity in lupus nephritis.
Am. J. Physiol. Renal Physiol. 2009;296,F1477–1483.
43. Pitashny, M. et al. Urinary lipocalin-2 is associated with renal disease activity in human lupus nephritis. Arthritis Rheum. 2007;56,1894–1903.
44. Wu, T. et al. Elevated urinary VCAM-1, P-selectin, soluble TNF receptor-1, and CXC chemokine ligand 16 in multiple murine lupus strains and human lupus nephritis. J. Immunol. Baltim. Md 1950 2007;179,7166–7175.
45. Kiani, A. N. et al. Urinary vascular cell adhesionmolecule, but not neutrophil gelatinase-associated lipocalin, is associated with lupus nephritis. J. Rheumatol. 2012;39,1231–1237.
46. Iwano, M. et al. Urinary levels of IL-6 in patients with active lupus nephritis. Clin. Nephrol. 1993;40,16–21.
47. Tsai, C. Y., Wu, T. H., Yu, C. L., Lu, J. Y. & Tsai, Y. Y. ncreased excretions of beta2-microglobulin, IL-6, and IL-8 and decreased excretion of Tamm-Horsfall glycoprotein in urine of patients with active lupus nephritis. Nephron 2000;85,207–214.
48. Avihingsanon, Y. et al. Measurement of urinary chemokine and growth factor messenger RNAs: a noninvasive monitoring in lupus nephritis. Kidney Int. 2006;69,747–753.
49. Chicheportiche, Y. et al. TWEAK, a new secreted ligand in the tumor necrosis factor family that weakly induces apoptosis.
J. Biol. Chem. 1997;272,32401–32410.
50. Campbell, S., Michaelson, J., Burkly, L. & Putterman, C. The role of TWEAK/Fn14 in the pathogenesis of inflammation and systemic autoimmunity. Front. Biosci. J. Virtual Libr. 2004;9,2273–2284.
51. Schwartz, N. et al. Urinary TWEAK and the activity of lupus nephritis. J. Autoimmun. 2006;27,242–250.
52. Schwartz, N. et al. Urinary TWEAK as a biomarker of lupus nephritis: a multicenter cohort study. Arthritis Res. Ther. 2009;11,R143.
53. Suzuki, M. et al. Initial Validation of a Novel Protein Biomarker Panel for Active Pediatric Lupus Nephritis. Pediatr. Res. 2009;65,530–536.
54. Brunner, H. I. et al. Association of noninvasively measured renal protein biomarkers with histologic features of lupus nephritis. Arthritis Rheum. 2012;64,2687–2697.
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