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Urinary clusterin—a novel urinary biomarker associated with pediatric lupus renal histopathologic features and renal survival

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Abstract

Background

Lupus nephritis (LN) is a major risk factor for systemic lupus erythematous (SLE)-related morbidity and mortality. With the aim of bypassing renal biopsy, we analyzed urinary biomarkers for their ability to predict renal histopathologic features and end-stage kidney disease (ESKD).

Methods

Urinary albumin, ß2-microglobulin (B2M), cystatin C, kidney injury molecule-1 (KIM-1), monocyte chemoattractant protein 1 (MCP-1), clusterin, calbindin, interleukin-18 (IL-18), neutrophil gelatinase-associated lipocalin (NGAL), trefoil factor 3 (TFF3), osteopontin, and glutathione S-transferase π (GST-π) levels were measured at time of renal biopsy. Renal histopathologies were carefully reviewed.

Results

Urine from 60 pediatric SLE cases with LN, 29 without and 22 healthy controls were collected. Median age at SLE diagnosis was 12.92 years (range = 4.27–17.30 years) and 10 cases progressed to ESKD during a period of 4.12 ± 2.17 years. Urinary albumin and clusterin were significantly elevated (p = 0.035 and 0.048, respectively) in patients with tubulointerstitial renal lesions. Urinary clusterin among all urinary markers, performed best at predicting ESKD with cutoff of 0.61 × 10−4 (AUC = 0.804; p = 0.002). Interestingly, elevation of urinary clusterin likely resulted from local over-expression in tubulointerstitial tissue since the level of serum clusterin was not concomitantly higher (p = 0.424).

Conclusion

Urinary biomarkers are emerging as non-invasive indicators for lupus-related renal histopathology and renal outcome prediction in pediatric SLE patients. Urinary clusterin, a newly identified biomarker, is an indicator that shows an association with tubulointerstitial renal lesions and demonstrates the best ability to predict ESKD.

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References

  1. Huang JL, Yeh KW, Yao TC, Huang YL, Chung HT, Ou LS, Lee WI, Chen LC (2010) Pediatric lupus in Asia. Lupus 19:1414–1418

    Article  PubMed  CAS  Google Scholar 

  2. 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 

  3. United States Renal Data System (2016) Chapter 8: Pediatric ESRD. Am J Kidney Dis 67:S239–S258

    Article  Google Scholar 

  4. Smith EMD, Beresford MW (2017) Urinary biomarkers in childhood lupus nephritis. Clin Immunol 185:21–31

    Article  PubMed  CAS  Google Scholar 

  5. Greloni G, Scolnik M, Marin J, Lancioni E, Quiroz C, Zacariaz J, De la Iglesia Niveyro P, Christiansen S, Pierangelo MA, Varela CF, Rosa-Diez GJ, Catoggio LJ, Soriano ER (2014) Value of repeat biopsy in lupus nephritis flares. Lupus Sci Med 1:e000004

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. Li Y, Tucci M, Narain S, Barnes EV, Sobel ES, Segal MS, Richards HB (2006) Urinary biomarkers in lupus nephritis. Autoimmun Rev 5:383–388

    Article  PubMed  CAS  Google Scholar 

  7. 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 32:283–295

    Article  PubMed  Google Scholar 

  8. Bonventre JV, Vaidya VS, Schmouder R, Feig P, Dieterle F (2010) Next-generation biomarkers for detecting kidney toxicity. Nat Biotechnol 28:436–440

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. McMahon GM, Waikar SS (2013) Biomarkers in nephrology: Core curriculum 2013. Am J Kidney Dis 62:165–178

    Article  PubMed  PubMed Central  Google Scholar 

  10. Wang Y, Chen J, Chen L, Tay YC, Rangan GK, Harris DC (1997) Induction of monocyte chemoattractant protein-1 in proximal tubule cells by urinary protein. J Am Soc Nephrol 8:1537–1545

    PubMed  CAS  Google Scholar 

  11. Rinnert M, Hinz M, Buhtz P, Reiher F, Lessel W, Hoffmann W (2010) Synthesis and localization of trefoil factor family (TFF) peptides in the human urinary tract and TFF2 excretion into the urine. Cell Tissue Res 339:639–647

    Article  PubMed  CAS  Google Scholar 

  12. Petri M, Orbai AM, Alarcon GS, Gordon C, Merrill JT, Fortin PR, Bruce IN, Isenberg D, Wallace DJ, Nived O, Sturfelt G, Ramsey-Goldman R, Bae SC, Hanly JG, Sanchez-Guerrero J, Clarke A, Aranow C, Manzi S, Urowitz M, Gladman D, Kalunian K, Costner M, Werth VP, Zoma A, Bernatsky S, Ruiz-Irastorza G, Khamashta MA, Jacobsen S, Buyon JP, Maddison P, Dooley MA, van Vollenhoven RF, Ginzler E, Stoll T, Peschken C, Jorizzo JL, Callen JP, Lim SS, Fessler BJ, Inanc M, Kamen DL, Rahman A, Steinsson K, Franks AG Jr, Sigler L, Hameed S, Fang H, Pham N, Brey R, Weisman MH, McGwin G Jr, Magder LS (2012) Derivation and validation of the systemic lupus international collaborating clinics classification criteria for systemic lupus erythematosus. Arthritis Rheum 64:2677–2686

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  14. Borchers AT, Leibushor N, Naguwa SM, Cheema GS, Shoenfeld Y, Gershwin ME (2012) Lupus nephritis: a critical review. Autoimmun Rev 12:174–194

    Article  PubMed  Google Scholar 

  15. 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 (2004) The classification of glomerulonephritis in systemic lupus erythematosus revisited. J Am Soc Nephrol 15:241–250

    Article  PubMed  Google Scholar 

  16. Austin HA 3rd, Muenz LR, Joyce KM, Antonovych TA, Kullick ME, Klippel JH, Decker JL, Balow JE (1983) Prognostic factors in lupus nephritis. Contribution of renal histologic data. Am J Med 75:382–391

    Article  PubMed  Google Scholar 

  17. Mina R, von Scheven E, Ardoin SP, Eberhard BA, Punaro M, Ilowite N, Hsu J, Klein-Gitelman M, Moorthy LN, Muscal E, Radhakrishna SM, Wagner-Weiner L, Adams M, Blier P, Buckley L, Chalom E, Chedeville G, Eichenfield A, Fish N, Henrickson M, Hersh AO, Hollister R, Jones O, Jung L, Levy D, Lopez-Benitez J, McCurdy D, Miettunen PM, Quintero-del Rio AI, Rothman D, Rullo O, Ruth N, Schanberg LE, Silverman E, Singer NG, Soep J, Syed R, Vogler LB, Yalcindag A, Yildirim-Toruner C, Wallace CA, Brunner HI, Carra SLES (2012) Consensus treatment plans for induction therapy of newly diagnosed proliferative lupus nephritis in juvenile systemic lupus erythematosus. Arthritis Care Res 64:375–383

    Article  Google Scholar 

  18. Youden WJ (1950) Index for rating diagnostic tests. Cancer 3:32–35

    Article  PubMed  CAS  Google Scholar 

  19. Schwartz GJ, Work DF (2009) Measurement and estimation of GFR in children and adolescents. Clin J Am Soc Nephrol 4:1832–1843

    Article  PubMed  Google Scholar 

  20. Gladman DD, Ibanez D, Urowitz MB (2002) Systemic lupus erythematosus disease activity index 2000. J Rheumatol 29:288–291

    PubMed  Google Scholar 

  21. Giannico G, Fogo AB (2013) Lupus nephritis: is the kidney biopsy currently necessary in the management of lupus nephritis? Clin J Am Soc Nephrol 8:138–145

    Article  PubMed  Google Scholar 

  22. Yu F, Wu LH, Tan Y, Li LH, Wang CL, Wang WK, Qu Z, Chen MH, Gao JJ, Li ZY, Zheng X, Ao J, Zhu SN, Wang SX, Zhao MH, Zou WZ, Liu G (2010) Tubulointerstitial lesions of patients with lupus nephritis classified by the 2003 International Society of Nephrology and Renal Pathology Society system. Kidney Int 77:820–829

    Article  PubMed  Google Scholar 

  23. Hsieh C, Chang A, Brandt D, Guttikonda R, Utset TO, Clark MR (2011) Predicting outcomes of lupus nephritis with tubulointerstitial inflammation and scarring. Arthritis Care Res 63:865–874

    Article  Google Scholar 

  24. Wu CY, Chien HP, Yang HY, Yao TC, Tseng MH, Yu MC, Yeh KW, Huang JL (2017) Role of tubulointerstitial lesions in predicting renal outcome among pediatric onset lupus nephritis—A retrospective cohort study. J Microbiol Immunol Infect. https://doi.org/10.1016/j.jaci.2016.12.687

  25. Shannan B, Seifert M, Leskov K, Willis J, Boothman D, Tilgen W, Reichrath J (2006) Challenge and promise: roles for clusterin in pathogenesis, progression and therapy of cancer. Cell Death Differ 13:12–19

    Article  PubMed  CAS  Google Scholar 

  26. Rosenberg ME, Silkensen J (1995) Clusterin: physiologic and pathophysiologic considerations. Int J Biochem Cell Biol 27:633–645

    Article  PubMed  CAS  Google Scholar 

  27. Tschopp J, Chonn A, Hertig S, French LE (1993) Clusterin, the human apolipoprotein and complement inhibitor, binds to complement C7, C8 beta, and the b domain of C9. J Immunol 151:2159–2165

    PubMed  CAS  Google Scholar 

  28. Jenne DE, Tschopp J (1989) Molecular structure and functional characterization of a human complement cytolysis inhibitor found in blood and seminal plasma: identity to sulfated glycoprotein 2, a constituent of rat testis fluid. Proc Natl Acad Sci U S A 86:7123–7127

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Cunin P, Beauvillain C, Miot C, Augusto JF, Preisser L, Blanchard S, Pignon P, Scotet M, Garo E, Fremaux I, Chevailler A, Subra JF, Blanco P, Wilson MR, Jeannin P, Delneste Y (2016) Clusterin facilitates apoptotic cell clearance and prevents apoptotic cell-induced autoimmune responses. Cell Death Dis 7:e2215

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. Rosenberg ME, Girton R, Finkel D, Chmielewski D, Barrie A 3rd, Witte DP, Zhu G, Bissler JJ, Harmony JA, Aronow BJ (2002) Apolipoprotein J/clusterin prevents a progressive glomerulopathy of aging. Mol Cell Biol 22:1893–1902

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Moll S, Menoud PA, French L, Sappino AP, Pastore Y, Schifferli JA, Izui S (1998) Tubular up-regulation of clusterin mRNA in murine lupus-like nephritis. Am J Pathol 152:953–962

    PubMed  PubMed Central  CAS  Google Scholar 

  32. Landolt-Marticorena C, Prokopec SD, Morrison S, Noamani B, Bonilla D, Reich H, Scholey J, Avila-Casado C, Fortin PR, Boutros PC, Wither J (2016) A discrete cluster of urinary biomarkers discriminates between active systemic lupus erythematosus patients with and without glomerulonephritis. Arthritis Res Ther 18:218

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Smith EM, Beresford MW (2016) Urinary biomarkers in childhood lupus nephritis. Clin Immunol 185:21–31

    Article  PubMed  CAS  Google Scholar 

  34. Deshmane SL, Kremlev S, Amini S, Sawaya BE (2009) Monocyte chemoattractant protein-1 (MCP-1): an overview. J Interf Cytokine Res 29:313–326

    Article  CAS  Google Scholar 

  35. Wada T, Yokoyama H, Su SB, Mukaida N, Iwano M, Dohi K, Takahashi Y, Sasaki T, Furuichi K, Segawa C, Hisada Y, Ohta S, Takasawa K, Kobayashi K, Matsushima K (1996) Monitoring urinary levels of monocyte chemotactic and activating factor reflects disease activity of lupus nephritis. Kidney Int 49:761–767

    Article  PubMed  CAS  Google Scholar 

  36. Mishra J, Ma Q, Prada A, Mitsnefes M, Zahedi K, Yang J, Barasch J, Devarajan P (2003) Identification of neutrophil gelatinase-associated lipocalin as a novel early urinary biomarker for ischemic renal injury. J Am Soc Nephrol 14:2534–2543

    Article  PubMed  CAS  Google Scholar 

  37. Gwira JA, Wei F, Ishibe S, Ueland JM, Barasch J, Cantley LG (2005) Expression of neutrophil gelatinase-associated lipocalin regulates epithelial morphogenesis in vitro. J Biol Chem 280:7875–7882

    Article  PubMed  CAS  Google Scholar 

  38. Waanders F, van Timmeren MM, Stegeman CA, Bakker SJ, van Goor H (2010) Kidney injury molecule-1 in renal disease. J Pathol 220:7–16

    Article  PubMed  CAS  Google Scholar 

  39. Schardijn GH, Statius van Eps LW (1987) Beta 2-microglobulin: its significance in the evaluation of renal function. Kidney Int 32:635–641

    Article  PubMed  CAS  Google Scholar 

  40. Brunner HI, Bennett MR, Abulaban K, Klein-Gitelman MS, O'Neil KM, Tucker L, Ardoin SP, Rouster-Stevens KA, Onel KB, Singer NG, Anne Eberhard B, Jung LK, Imundo L, Wright TB, Witte D, Rovin BH, Ying J, Devarajan P (2016) Development of a novel renal activity index of lupus nephritis in children and young adults. Arthritis Care Res 68:1003–1011

    Article  CAS  Google Scholar 

  41. Mori Y, Kishimoto N, Yamahara H, Kijima Y, Nose A, Uchiyama-Tanaka Y, Fukui M, Kitamura T, Tokoro T, Masaki H, Nagata T, Umeda Y, Nishikawa M, Iwasaka T (2005) Predominant tubulointerstitial nephritis in a patient with systemic lupus nephritis. Clin Exp Nephrol 9:79–84

    Article  PubMed  Google Scholar 

  42. Omokawa A, Wakui H, Okuyama S, Togashi M, Ohtani H, Komatsuda A, Ichinohasama R, Sawada K (2008) Predominant tubulointerstitial nephritis in a patient with systemic lupus erythematosus: phenotype of infiltrating cells. Clin Nephrol 69:436–444

    Article  PubMed  CAS  Google Scholar 

  43. O'Dell JR, Hays RC, Guggenheim SJ, Steigerwald JC (1985) Tubulointerstitial renal disease in systemic lupus erythematosus. Arch Intern Med 145:1996–1999

    Article  PubMed  CAS  Google Scholar 

  44. Park MH, D'Agati V, Appel GB, Pirani CL (1986) Tubulointerstitial disease in lupus nephritis: relationship to immune deposits, interstitial inflammation, glomerular changes, renal function, and prognosis. Nephron 44:309–319

    Article  PubMed  CAS  Google Scholar 

  45. Brunner HI, Bennett MR, Mina R, Suzuki M, Petri M, Kiani AN, Pendl J, Witte D, Ying J, Rovin BH, Devarajan P (2012) Association of noninvasively measured renal protein biomarkers with histologic features of lupus nephritis. Arthritis Rheum 64:2687–2697

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  46. Hammad A, Mosaad Y, Elhanbly S, Youssef H, El Refaaey A, Elhusseini F, Bakr A (2013) Urinary neutrophil gelatinase-associated lipocalin as a marker of severe lupus nephritis in children. Lupus 22:486–491

    Article  PubMed  CAS  Google Scholar 

  47. Nath KA (1992) Tubulointerstitial changes as a major determinant in the progression of renal damage. Am J Kidney Dis 20:1–17

    Article  PubMed  CAS  Google Scholar 

  48. Hodgin JB, Whelan J, Markowitz GS, Stokes MB (2009) Giant cell tubulitis with immune complex deposits in a patient with lupus nephritis. Am J Kidney Dis 53:513–517

    Article  PubMed  Google Scholar 

  49. Zhang X, Nagaraja HN, Nadasdy T, Song H, McKinley A, Prosek J, Kamadana S, Rovin BH (2012) A composite urine biomarker reflects interstitial inflammation in lupus nephritis kidney biopsies. Kidney Int 81:401–406

    Article  PubMed  CAS  Google Scholar 

  50. Wu JY, Yeh KW, Huang JL (2014) Early predictors of outcomes in pediatric lupus nephritis: focus on proliferative lesions. Semin Arthritis Rheum 43:513–520

    Article  PubMed  Google Scholar 

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Acknowledgements

The authors thank Chang Gung foundation, Linko Chang Gung Memorial Hospital tissue bank for patient samples, and Pi-Shuang Chu for her assistance in data gathering.

Funding

This work was supported by the Chang Gung Memorial Hospital (CMRPG3D1352) and the Ministry of Science and Technology, Taiwan (MOST106-2314-B-182A-139-MY3).

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Authors and Affiliations

  1. Division of Allergy, Asthma, and Rheumatology, Department of Pediatrics, Chang Gung Memorial Hospital Linko branch, Taoyuan, Taiwan

    Chao-Yi Wu & Jing-Long Huang

  2. Chang Gung University, College of Medicine, Taoyuan, Taiwan

    Chao-Yi Wu, Huang-Yu Yang, Hui-Ping Chien, Min-Hua Tseng & Jing-Long Huang

  3. Department of Nephrology, Chang Gung Memorial Hospital Linko branch, Taoyuan, Taiwan

    Huang-Yu Yang

  4. Department of Pathology, Chang Gung Memorial Hospital Linko branch, Taoyuan, Taiwan

    Hui-Ping Chien

  5. Division of Pediatric Nephrology, Department of Pediatrics, Chang Gung Memorial Hospital Linko branch, Taoyuan, Taiwan

    Min-Hua Tseng

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  1. Chao-Yi Wu
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Correspondence to Jing-Long Huang.

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A written informed consent was collected from all the subjects participating in the study and/or their legal guardian. The research was in compliance with the Declaration of Helsinki and was approved by the CGMH Institutional Review Board (IRB No.: 103-1246A3).

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The authors declare that they have no competing interests.

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Wu, CY., Yang, HY., Chien, HP. et al. Urinary clusterin—a novel urinary biomarker associated with pediatric lupus renal histopathologic features and renal survival. Pediatr Nephrol 33, 1189–1198 (2018). https://doi.org/10.1007/s00467-018-3924-4

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  • DOI: https://doi.org/10.1007/s00467-018-3924-4

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