Serum IP-10 is useful for identifying renal and overall disease activity in pediatric systemic lupus erythematosus

Abstract

Background

Traditional serological biomarkers often fail to assess systemic lupus erythematosus (SLE) disease activity and discriminate lupus nephritis (LN). The aim of this study was to identify novel markers for evaluating renal and overall disease activity in Chinese patients with pediatric systemic lupus erythematosus (pSLE).

Methods

The study included 46 patients with pSLE (35 girls, 11 boys; average age 13.3 ± 2.6 years) and 31 matched healthy controls (22 girls, 9 boys; average age 12.3 ± 2.4 years). The SLE Disease Activity Index (SLEDAI) and renal SLEDAI were used to assess disease activity. Nine different soluble mediators in plasma, including tumor necrosis factor alpha (TNF-α), platelet-derived growth factor-BB (PDGF-BB), interferon (IFN) gamma inducible protein 10 (IP-10), interleukin (IL)-1β, IFN-γ, IL-17A, IL-2, Fas and Fas ligand, were measured by Luminex assay and compared between patients with active and inactive pSLE as well as between patients with pSLE with active and inactive renal disease. Receiver operating characteristic curve analysis was used to measure the discrimination accuracy.

Results

Of the 46 patients with pSLE, 30 (65.2%) had LN. These patients had significantly elevated levels of serum TNF-α, PDGF-BB, IP-10 and Fas. The serum levels of IP-10 were also significantly higher in patients with active pSLE. We found that IP-10 was also more sensitive and specific than conventional laboratory parameters, including anti-double-stranded DNA and complement components C3 and C4, for distinguishing active lupus from quiescent lupus. The serum level of IP-10 was also significantly increased in children with pSLE with active renal disease relative to those with inactive renal disease. There was also a positive correlation between serum IP-10 levels and renal SLEDAI scores as well as with 24 h urine protein.

Conclusions

Serum IP-10 is useful for identifying renal and overall disease activity in children with pSLE.

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References

  1. 1.

    Tsokos GC (2011) Systemic lupus erythematosus. N Engl J Med 365:2110–2121

    CAS  Article  PubMed  Google Scholar 

  2. 2.

    Klein-Gitelman M, Reiff A, Silverman ED (2002) Systemic lupus erythematosus in childhood. Rheum Dis Clin North Am 28:561–577

    Article  PubMed  Google Scholar 

  3. 3.

    Stichweh D, Arce E, Pascual V (2004) Update on pediatric systemic lupus erythematosus. Curr Opin Rheumatol 16:577–587

    CAS  Article  PubMed  Google Scholar 

  4. 4.

    Brunner HI, Gladman DD, Ibanez D, Urowitz MD, Silverman ED (2008) Difference in disease features between childhood-onset and adult-onset systemic lupus erythematosus. Arthritis Rheum 58:556–562

    Article  PubMed  Google Scholar 

  5. 5.

    Mina R, Brunner HI (2010) Pediatric lupus--are there differences in presentation, genetics, response to therapy, and damage accrual compared with adult lupus? Rheum Dis Clin North Am 36:53–80

    Article  PubMed  PubMed Central  Google Scholar 

  6. 6.

    Tarr T, Derfalvi B, Gyori N, Szanto A, Siminszky Z, Malik A, Szabo AJ, Szegedi G, Zeher M (2015) Similarities and differences between pediatric and adult patients with systemic lupus erythematosus. Lupus 24:796–803

    CAS  Article  PubMed  Google Scholar 

  7. 7.

    Hoffman IE, Lauwerys BR, De Keyser F, Huizinga TW, Isenberg D, Cebecauer L, Dehoorne J, Joos R, Hendrickx G, Houssiau F, Elewaut D (2009) Juvenile-onset systemic lupus erythematosus: different clinical and serological pattern than adult-onset systemic lupus erythematosus. Ann Rheum Dis 68:412–415

    CAS  Article  PubMed  Google Scholar 

  8. 8.

    Huggins JL, Holland MJ, Brunner HI (2016) Organ involvement other than lupus nephritis in childhood-onset systemic lupus erythematosus. Lupus 25:857–863

    CAS  Article  PubMed  Google Scholar 

  9. 9.

    Weiss JE, Sison CP, Ilowite NT, Gottlieb BS, Eberhard BA (2007) Flares in pediatric systemic lupus erythematosus. J Rheumatol 34:1341–1344

    PubMed  Google Scholar 

  10. 10.

    Liu CC, Manzi S, Ahearn JM (2005) Biomarkers for systemic lupus erythematosus: a review and perspective. Curr Opin Rheumatol 17:543–549

    CAS  Article  PubMed  Google Scholar 

  11. 11.

    Esdaile JM, Abrahamowicz M, Joseph L, MacKenzie T, Li Y, Danoff D (1996) Laboratory tests as predictors of disease exacerbations in systemic lupus erythematosus. Why some tests fail. Arthritis Rheum 39:370–378

    CAS  Article  PubMed  Google Scholar 

  12. 12.

    Jacob N, Stohl W (2011) Cytokine disturbances in systemic lupus erythematosus. Arthritis Res Ther 13:228

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Munroe ME, Vista ES, Guthridge JM, Thompson LF, Merrill JT, James JA (2014) Proinflammatory adaptive cytokine and shed tumor necrosis factor receptor levels are elevated preceding systemic lupus erythematosus disease flare. Arthritis Rheumatol 66:1888–1899

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Gröndal G, Gunnarsson I, Rönnelid J, Rogberg S, Klareskog L, Lundberg I (2000) Cytokine production, serum levels and disease activity in systemic lupus erythematosus. Clin Exp Rheumatol 18:565–570

    PubMed  Google Scholar 

  15. 15.

    Adhya Z, Borozdenkova S, Karim MY (2011) The role of cytokines as biomarkers in systemic lupus erythematosus and lupus nephritis. Nephrol Dial Transplant 26:3273–3280

    CAS  Article  PubMed  Google Scholar 

  16. 16.

    Becker-Merok A, Ostli-Eilersten G, Lester S, Nossent J (2013) Circulating interferon-α2 levels are increased in the majority of patients with systemic lupus erythematosus and are associated with disease activity and multiple cytokine activation. Lupus 22:155–163

    CAS  Article  PubMed  Google Scholar 

  17. 17.

    Chun HY, Chung JW, Kim HA, Yun JM, Jeon JY, Ye YM, Kim SH, Park HS, Suh CH (2007) Cytokine IL-6 and IL-10 as biomarkers in systemic lupus erythematosus. J Clin Immunol 27:461–466

    CAS  Article  PubMed  Google Scholar 

  18. 18.

    Menke J, Amann K, Cavagna L, Blettner M, Weinmann A, Schwarting A, Kelley VR (2015) Colony-stimulating factor-1: a potential biomarker for lupus nephritis. J Am Soc Nephrol 26:379–389

    Article  PubMed  Google Scholar 

  19. 19.

    Smith EM, Jorgensen AL, Midgley A, Oni L, Goilav B, Putterman C, Wahezi D, Rubinstein T, Ekdawy D, Corkhill R, Jones CA, Marks SD, Newland P, Pilkington C, Tullus K, Beresford MW (2017) International validation of a urinary biomarker panel for identification of active lupus nephritis in children. Pediatr Nephrol 32(2):283–295

    Article  PubMed  Google Scholar 

  20. 20.

    Watson L, Tullus K, Pilkington C, Chesters C, Marks SD, Newland P, Jones CA, Beresford MW (2014) Urine biomarkers for monitoring juvenile lupus nephritis: a prospective longitudinal study. Pediatr Nephrol 29(3):397–405

    Article  PubMed  Google Scholar 

  21. 21.

    Marks SD, Shah V, Pilkington C, Tullus K (2010) Urinary monocyte chemoattractant protein-1 correlates with disease activity in lupus nephritis. Pediatr Nephrol 25(11):2283–2288

    Article  PubMed  Google Scholar 

  22. 22.

    Xia LP, Li BF, Shen H, Lu J (2015) Interleukin-27 and interleukin-23 in patients with systemic lupus erythematosus: possible role in lupus nephritis. Scand J Rheumatol 44:1–6

    CAS  Article  Google Scholar 

  23. 23.

    Neville LF, Mathiak G, Bagasra O (1997) The immunobiology of interferon-gamma inducible protein 10 kD (IP-10): a novel, pleiotropic member of the C-X-C chemokine superfamily. Cytokine Growth Factor Rev 8:207–219

    CAS  Article  PubMed  Google Scholar 

  24. 24.

    Johnson RJ, Floege J, Couser WG, Alpers CE (1993) Role of platelet-derived growth factor in glomerular disease. J Am Soc Nephrol 4:119–128

    CAS  PubMed  Google Scholar 

  25. 25.

    Hochberg MC (1997) Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 40:1725

    CAS  Article  PubMed  Google Scholar 

  26. 26.

    Buyon JP, Petri MA, Kim MY, Kalunian KC, Grossman J, Hahn BH, Merrill JT, Sammaritano L, Lockshin M, Alarcón GS, Manzi S, Belmont HM, Askanase AD, Sigler L, Dooley MA, Von Feldt J, McCune WJ, Friedman A, Wachs J, Cronin M, Hearth-Holmes M, Tan M, Licciardi F (2005) The effect of combined estrogen and progesterone hormone replacement therapy on disease activity in systemic lupus erythematosus: a randomized trial. Ann Intern Med 142:953–962

    CAS  Article  PubMed  Google Scholar 

  27. 27.

    Hahn BH, MA MM, Wilkinson A, Wallace WD, Daikh DI, Fitzgerald JD, Karpouzas GA, Merrill JT, Wallace DJ, Yazdany J, Ramsey-Goldman R, Singh K, Khalighi M, Choi SI, Gogia M, Kafaja S, Kamgar M, Lau C, Martin WJ, Parikh S, Peng J, Rastogi A, Chen W, Grossman JM, American College of Rheumatology (2012) American College of Rheumatology guidelines for screening, treatment, and management of lupus nephritis. Arthritis Care Res (Hoboken) 64:797–808

    Article  Google Scholar 

  28. 28.

    Weening JJ, D’Agati VD, Schwartz MM, Seshan SV, Alpers CE, Appel GB, Balow JE, Bruijn JA, Cook T, Ferrario F, Fogo AB, Ginzler EM, Hebert L, Hill G, Hill P, Jennette JC, Kong NC, Lesavre P, Lockshin M, Looi LM, Makino H, Moura LA, Nagata M, International Society of Nephrology Working Group on the Classification of Lupus Nephritis (2004) The classification of glomerulonephritis in systemic lupus erythematosus revisited. Kidney Int 65:521–530

    Article  PubMed  Google Scholar 

  29. 29.

    Gupta R, Aggarwal A, Sinha S, Rajasekhar L, Yadav A, Gaur P, Misra R, Negi VS (2016) Urinary osteoprotegerin: a potential biomarker of lupus nephritis disease activity. Lupus 25:1230–1236

    CAS  Article  PubMed  Google Scholar 

  30. 30.

    Tahghighi F, Ziaee V, Moradinejad MH, Rezaei A, Harsini S, Soltani S, Sadr M, Mahmoudi M, Aghighi Y, Rezaei N (2015) Tumor necrosis factor-alpha single nucleotide polymorphisms in juvenile systemic lupus erythematosus. Hum Immunol 76:533–536

    CAS  Article  PubMed  Google Scholar 

  31. 31.

    Lin YJ, Chen RH, Wan L, Sheu JC, Huang CM, Lin CW, Chen SY, Lai CH, Lan YC, Hsueh KC, Tsai CH, Lin TH, Huang YM, Chao K, Chen DY, Tsai FJ (2009) Association of TNF-α gene polymorphisms with systemic lupus erythematosus in Taiwanese patients. Lupus 18:974–979

    Article  PubMed  Google Scholar 

  32. 32.

    Angelo HD, da Silva HA, Asano NM, Muniz MT, de Mascena Diniz Maia M, de Souza PR (2012) Tumor necrosis factor alpha promoter polymorphism 308G/a in Brazilian patients with systemic lupus erythematosus. Hum Immunol 73:1166–1170

    CAS  Article  PubMed  Google Scholar 

  33. 33.

    Arora V, Verma J, Marwah V, Kumar A, Anand D, Das N (2012) Cytokine imbalance in systemic lupus erythematosus: a study on northern Indian subjects. Lupus 21:595–603

    Article  Google Scholar 

  34. 34.

    Sinicato NA, Postal M, Peres FA, Pelicari Kde O, Marini R (2014) Dos Santos Ade O, Ramos CD, Appenzeller S (2014) Obesity and cytokines in childhood-onset systemic lupus erythematosus. J Immunol Res 2014:162047. https://doi.org.10.1155/2014/162047

  35. 35.

    Iida H, Seifert R, Alpers CE, Gronwald RG, Phillips PE, Pritzl P, Gordon K, Gown AM, Ross R, Bowen-Pope DF, Johnson RK (1991) Platelet-derived growth factor (PDGF) and PDGF receptor are induced in mesangial proliferative nephritis in the rat. Proc Natl Acad Sci USA 88:6560–6564

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  36. 36.

    Ostendorf T, Kunter U, Grone HJ, Bahlmann F, Kawachi H, Shimizu F, Koch KM, Janjic N, Floege J (2001) Specific antagonism of PDGF prevents renal scarring in experimental glomerulonephritis. J Am Soc Nephrol 12:909–918

    CAS  PubMed  Google Scholar 

  37. 37.

    Floege J, Eng E, Young BA, Alpers CE, Barrett TB, Bowen-Pope DF, Johnson RJ (1993) Infusion of platelet-derived growth factor or basic fibroblast growth factor induces selective glomerular mesangial cell proliferation and matrix accumulation in rats. J Clin Invest 92:2952–2962

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  38. 38.

    Isaka Y, Fujiwara Y, Ueda N, Kaneda Y, Kamada T, Imai E (1993) Glomerulosclerosis induced by in vivo transfection of transforming growth factor-beta or platelet-derived growth factor gene into the rat kidney. J Clin Invest 92:2597–2601

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  39. 39.

    Cheng J, Zhou T, Liu C, Shapiro JP, Brauer MJ, Kiefer MC, Barr PJ, Mountz JD (1994) Protection from Fas-mediated apoptosis by a soluble form of the Fas molecule. Science 263:1759–1762

    CAS  Article  PubMed  Google Scholar 

  40. 40.

    Papoff G, Cascino I, Eramo A, Starace G, Lynch DH, Ruberti G (1996) An N-terminal domain shared by Fas/Apo-1 (CD95) soluble variants prevents cell death in vitro. J Immunol 156:4622–4630

    CAS  PubMed  Google Scholar 

  41. 41.

    Misra R, Gupta R (2015) Biomarkers in lupus nephritis. Int J Rheum Dis 18:219–232

    Article  PubMed  Google Scholar 

  42. 42.

    Kong KO, Tan AW, Thong BY, Lian TY, Cheng YK, Teh CL, Koh ET, Chng HH, Law WG, Lau TC, Leong KP, Leung BP, Howe HS (2009) Enhanced expression of interferon-inducible protein-10 correlates with disease activity and clinical manifestations in systemic lupus erythematosus. Clin Exp Immunol 156:134–140

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  43. 43.

    El-Gohary A, Hegazy A, Abbas M, Kamel N, Nasef SI (2016) Serum and urinary interferon-gamma-inducible protein 10 in lupus nephritis. J Clin Lab Anal 30:1135–1138

    CAS  Article  PubMed  Google Scholar 

  44. 44.

    Rose T, Grützkau A, Hirseland H, Huscher D, Dähnrich C, Dzionek A, Ozimkowski T, Schlumberger W, Enghard P, Radbruch A, Riemekasten G, Burmester GR, Hiepe F, Biesen R (2013) IFNα and its response proteins, IP-10 and SIGLEC-1, are biomarkers of disease activity in systemic lupus erythematosus. Ann Rheum Dis 72:1639–1645

    CAS  Article  PubMed  Google Scholar 

  45. 45.

    Abujam B, Cheekatla S, Aggarwal A (2013) Urinary CXCL-10/IP-10 and MCP-1 as markers to assess activity of lupus nephritis. Lupus 22:614–623

    CAS  Article  PubMed  Google Scholar 

  46. 46.

    Fu Q, Chen X, Cui H, Guo Y, Chen J, Shen N, Bao C (2008) Association of elevated transcript levels of interferon-inducible chemokines with disease activity and organ damage in systemic lupus erythematosus. Arthritis Res Ther 10:R112

    Article  PubMed  PubMed Central  Google Scholar 

  47. 47.

    Li H, Ding G (2016) Elevated serum inflammatory cytokines in lupus nephritis patients, in association with promoted hsa-miR-125a. Clin Lab 62:631–638

    CAS  PubMed  Google Scholar 

  48. 48.

    Segerer S, Banas B, Wörnle M, Schmid H, Cohen CD, Kretzler M, Mack M, Kiss E, Nelson PJ, Schlöndorff D, Gröne HJ (2004) CXCR3 is involved in tubulointerstitial injury in human glomerulonephritis. Am J Pathol 164:635–649

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  49. 49.

    Lu J, Kwan BC, Lai FM, Choi PC, Tam LS, Li EK, Chow KM, Wang G, Li PK, Szeto CC (2011) Gene expression of TWEAK/Fn14 and IP-10/CXCR3 in glomerulus and tubulointerstitium of patients with lupus nephritis. Nephrology (Carlton) 16:426–432

    CAS  Article  Google Scholar 

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Acknowledgements

This study was funded by the National Natural Science Foundation of China (81273314, 81571605) and Shanghai Municipal Education Commission (14ZZ105). We also would like to thank the patients and their families who participated in the study for their time and effort.

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Authors

Contributions

All authors were involved in drafting the article or revising it critically for important intellectual content and all authors approved the final version to be published. Tong-xin Chen, Lan-fang Cao and Wei Zhou were responsible for study conception and design. Chen-xing Zhang and Li Cai were responsible for the experiment as well as the analysis and interpretation of data. Kang Shao and Jing Wu were responsible for the acquisition of data. Tong-xin Chen reviewed the final version of the manuscript.

Corresponding author

Correspondence to Tong-xin Chen.

Ethics declarations

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. The study was approved by the Ethics Committee of Shanghai Children’s Medical Center and all participants signed a consent form in order to participate.

Conflicts of interest

The authors declare that they have no competing interests and all authors read and approved the final manuscript and the final version to be published.

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Zhang, Cx., Cai, L., Shao, K. et al. Serum IP-10 is useful for identifying renal and overall disease activity in pediatric systemic lupus erythematosus. Pediatr Nephrol 33, 837–845 (2018). https://doi.org/10.1007/s00467-017-3867-1

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Keywords

  • Pediatric systemic lupus erythematosus
  • Clinical disease activity
  • Active renal disease
  • IP-10