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Mesangial C4d deposition is independently associated with poor renal survival in patients with primary focal segmental glomerulosclerosis

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Abstract

Background

C4d deposition is defined as the footprint of immune injury and it is associated with unfavorable renal outcomes in patients with IgA nephropathy. We searched whether mesangial C4d deposition is associated with poor renal survival in patients with primary focal segmental glomerulosclerosis (FSGS).

Methods

Biopsy specimens were stained with anti-C4d antibody. Patients were classified based on mesangial C4d deposition as C4d-negative and C4d-positive. Groups were compared according to baseline and follow-up clinical variables. Factors that predict renal progression and treatment failure were determined using Cox-regression and multivariate logistic regression models, respectively.

Results

Forty-one FSGS patients were followed for a mean of 67.7 ± 40.8 months. C4d-positive group included 18 patients while remaining 23 patients were C4d-negative. Urinary protein excretion and serum creatinine levels at baseline were comparable between groups. Fifteen patients reached the composite primary endpoint which included serum creatinine increasing > 30% from the baseline and reaching > 1.5 mg/dl, and/or evolution to end-stage renal disease (36.6%). In multivariate regression analysis, baseline eGFR (OR 0.71, 95% CI 0.53–0.94; p = 0.016) and mesangial C4d deposition (OR 10.5, 95% CI 1.51–73.18; p = 0.018) were independently associated with treatment failure rates. Mesangial C4d deposition was independently associated with the progression to the primary endpoint (HR 6.54, 95% CI 1.49–28.7, p = 0.013).

Conclusion

We showed for the first time that mesangial C4d deposition is an independent predictor of disease progression and treatment failure in patients with primary FSGS.

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References

  1. D’Agati VD, Kaskel FJ, Falk RJ. Focal segmental glomerulosclerosis. N Engl J Med. 2011;365(25):2398–411

    Article  PubMed  Google Scholar 

  2. Chou Y-H, Lien Y-C, Hu F-C, et al. Clinical outcomes and predictors for ESRD and mortality in primary GN. Clin J Am Soc Nephrol 2012;7(9):1401–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Kitiyakara C, Eggers P, Kopp JB. Twenty-one-year trend in ESRD due to focal segmental glomerulosclerosis in the United States. Am J Kidney Dis. 2004;44(5):815–25.

    Article  PubMed  Google Scholar 

  4. Rosenberg AZ, Kopp JB. Focal segmental glomerulosclerosis. Clin J Am Soc Nephrol. 2017;12:502.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Thurman JM, Wong M, Renner B, et al. Complement activation in patients with focal segmental glomerulosclerosis. PLoS One. 2015;10(9):e0136558.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Liu J, Xie J, Zhang X, et al. Serum C3 and renal outcome in patients with primary focal segmental glomerulosclerosis. Sci Rep. 2017;7:4095.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Zhang Y, Gu Q, Huang J, et al. Clinical significance of IgM and C3 glomerular deposition in primary focal segmental glomerulosclerosis. Clin J Am Soc Nephrol. 2016;11(9):1582–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Sarma JV, Ward PA. The complement system. Cell Tissue Res. 2011;343(1):227–35.

    Article  CAS  PubMed  Google Scholar 

  9. Espinosa M, Ortega R, Sánchez M, et al. Spanish Group for Study of Glomerular Diseases (GLOSEN). Association of C4d deposition with clinical outcomes in IgA nephropathy. Clin J Am Soc Nephrol. 2014;9(5):897–904.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Roos A, Rastaldi MP, Calvaresi N, et al. Glomerular activation of the lectin pathway of complement in IgA nephropathy is associated with more severe renal disease. J Am Soc Nephrol. 2006;17(6):1724–34.

    Article  CAS  PubMed  Google Scholar 

  11. Heybeli C, Unlu M, Yildiz S, Çavdar C, Sarioglu S, Camsari T. IgA nephropathy: association of C4d with clinical and histopathological findings and possible role of IgM. Ren Fail. 2015;37(9):1464–9.

    Article  CAS  PubMed  Google Scholar 

  12. McMullen ME, Hart ML, Walsh MC, Buras J, Takahashi K, Stahl GL. Mannose-binding lectin binds IgM to activate the lectin complement pathway in vitro and in vivo. Immunobiology. 2006;211(10):759–66.

    Article  CAS  PubMed  Google Scholar 

  13. Imai N, Nishi S, Alchi B, et al. Immunohistochemical evidence of activated lectin pathway in kidney allografts with peritubular capillary C4d deposition. Nephrol Dial Transplant. 2006;21(9):2589–95.

    Article  CAS  PubMed  Google Scholar 

  14. Lei X, Liu C, Azadzoi K, et al. A novel IgM–H-Ficolin complement pathway to attack allogenic cancer cells in vitro. Sci Rep. 2015;5:7824.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Zacho RM, Jensen L, Terp R, Jensenius JC, Thiel S. Studies of the pattern recognition molecule H-ficolin: specificity and purification. J Biol Chem. 2012;287(11):8071–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Levey AS, Stevens LA, Schmid CH, et al. A new equation to estimate glomerular filtration rate. Ann Intern Med. 2009;150:604–12.

    Article  PubMed  PubMed Central  Google Scholar 

  17. D’Agati V. Pathologic classification of focal segmental glomerulosclerosis. Semin Nephrol 2003;23(2):117–34.).

    Article  PubMed  Google Scholar 

  18. Liu J, Xie J, Zhang X, et al. Serum C3 and renal outcome in patients with primary focal segmental glomerulosclerosis. Sci Rep. 2017;7(1):4095. https://doi.org/10.1038/s41598-017-03344-1. (Published 2017 Jun 22).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Kidney Disease. Improving Global Outcomes (KDIGO) Glomerulonephritis Work Group: KDIGO clinical practice guideline for glomerulonephritis. Kidney Int Suppl. 2012;2:139–274.

    Article  Google Scholar 

  20. Cohen D, Colvin RB, Daha MR, et al. Pros and cons for C4d as a biomarker. Kidney Int. 2012;81(7):628–39.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Segarra A, Romero K, Agraz I, et al. Mesangial C4d deposits in early IgA nephropathy. Clin J Am Soc Nephrol. 2018;13(2):258–264.

    Article  CAS  PubMed  Google Scholar 

  22. Strassheim D, Renner B, Panzer S, et al. IgM contributes to glomerular injury in FSGS. J Am Soc Nephrol. 2013;24(3):393–406.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Panzer SE, Laskowski J, Renner B, et al. IgM exacerbates glomerular disease progression in complement induced glomerulopathy. Kidney Int. 2015;88(3):528–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Arnold JN, Wormald MR, Suter DM, et al. Human serum IgM glycosylation: identification of glycoforms that can bind to mannan-binding lectin. J Biol Chem. 2005;280(32):29080–7.

    Article  CAS  PubMed  Google Scholar 

  25. Niyonzima N, Samstad EO, Aune MH, et al. Reconstituted high-density lipoprotein attenuates cholesterol crystal-induced inflammatory responses by reducing complement activation. J Immunol. 2015;195(1):257–64.

    Article  CAS  PubMed  Google Scholar 

  26. Norata GD, Pirillo A, Ammirati E, Catapano AL. Emerging role of high density lipoproteins as a player in the immune system. Atherosclerosis. 2012;220(1):11–21.

    Article  CAS  PubMed  Google Scholar 

  27. Pollak MR. The genetic basis of FSGS and steroid-resistant nephrosis. Semin Nephrol. 2003;23:141.

    Article  CAS  PubMed  Google Scholar 

  28. Hommos MS, De Vriese AS, Alexander MP, et al. The incidence of primary vs secondary focal segmental glomerulosclerosis: a clinicopathologic study. Mayo Clin Proc. 2017;92(12):1772–1781.

    Article  PubMed  Google Scholar 

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Acknowledgements

We thank to Professor Hulya Ellidokuz for her contribution on statistical analysis.

Funding

Our study was supported by Dokuz Eylul University Coordinating Subcommittee For Scientific Research Projects (DEU BAP) (Grant number 2018.KB.SAG.040).

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Authors and Affiliations

  1. School of Medicine, Department of Internal Medicine, Division of Nephrology, Dokuz Eylul University, Balcova, Izmir, Turkey

    Cihan Heybeli, Mehmet Asi Oktan, Serkan Yıldız & Ali Celik

  2. Department of Pathology, Dokuz Eylul University, Izmir, Turkey

    Mehtat Ünlü & Sülen Sarıoglu

Authors
  1. Cihan Heybeli
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  2. Mehmet Asi Oktan
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  3. Serkan Yıldız
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  4. Mehtat Ünlü
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  5. Ali Celik
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  6. Sülen Sarıoglu
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Correspondence to Cihan Heybeli.

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All the authors have declared no competing interest.

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

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This study was approved by the ethics committee of our faculty (IRB approval number:2017/22-03).

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Heybeli, C., Oktan, M.A., Yıldız, S. et al. Mesangial C4d deposition is independently associated with poor renal survival in patients with primary focal segmental glomerulosclerosis. Clin Exp Nephrol 23, 650–660 (2019). https://doi.org/10.1007/s10157-018-01688-0

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  • DOI: https://doi.org/10.1007/s10157-018-01688-0

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