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Predictive prognostic value of glomerular C3 deposition in IgA nephropathy

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Abstract

Background

IgAN is the most common primary glomerulonephritis worldwide. However, the pathogenesis of IgAN remains unknown. Currently, there is evidence that C3 deposition plays a role in disease development. This study aimed to investigate clinical, pathological features, and prognosis of adult IgAN patients with C3 deposition, as well as explore the role of complement activation in disease progression.

Methods

A total of 821 patients with biopsy-proven IgAN were included in this study. Patients were divided into three different groups according to their C3 deposition intensity. Clinical and pathological characteristics were compared between groups. Logistic analysis was used to estimate the relationship between C3 deposition and the Oxford scoring system. Univariate and multivariate Cox proportional hazard regression models were used to analyze the effect of the presence of C3 deposits on the prognosis of patients with IgA nephropathy. Kaplan–Meier survival analysis was used to evaluate the cumulative incidence of renal progression between groups.

Results

Patients with C3 deposition exhibited more severe clinical and pathological features and had a higher score according to the Oxford scoring system. With the increasing intensity of C3 deposition, patients present more hematuria, crescents, heavier interstitial inflammatory cell infiltration and a higher score on segmental sclerosis lesions. Logistic regression identified a positive relationship between C3 deposition and histopathology. Univariate and multivariate Cox regression indicated that C3 deposition was an independent risk factor for IgAN severity. The Kaplan–Meier survival curves indicated that patients with positive C3 deposition had a worse prognosis compared to those without C3 deposition.

Conclusions

Patients with positive glomerular C3 deposition presented with more severe clinical and histopathological characteristics and a higher score on the Oxford scoring system. With the increasing intensity of C3 deposition, IgAN patients were more likely to present with high level of microscopic hematuria, fibrous crescents, interstitial inflammatory cell infiltration, and a higher score on segmental sclerosis lesions. C3 deposition at the time of renal biopsy is likely an independent risk factor for IgA nephropathy severity and progression.

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Data availability

The datasets collected and analyzed in the current study are available from the corresponding author on reasonable request.

References

  1. Li P, Ho K, Szeto C, Yu L, Lai F (2002) Prognostic indicators of IgA nephropathy in the Chinese–clinical and pathological perspectives. Nephrol Dialysis Transplant 17(1):64–69. https://doi.org/10.1093/ndt/17.1.64

    Article  CAS  Google Scholar 

  2. Suzuki H, Kiryluk K, Novak J, Moldoveanu Z, Herr A, Renfrow M, Wyatt R, Scolari F, Mestecky J, Gharavi A, Julian B (2011) The pathophysiology of IgA nephropathy. J Am Soc Nephrol 22(10):1795–1803. https://doi.org/10.1681/asn.2011050464

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  3. Rizk D, Maillard N, Julian B, Knoppova B, Green T, Novak J, Wyatt R (2019) The emerging role of complement proteins as a target for therapy of IgA nephropathy. Front Immunol 10:504. https://doi.org/10.3389/fimmu.2019.00504

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  4. Berger J (1969) IgA glomerular deposits in renal disease. Transpl Proc 1(4):939–944

    CAS  Google Scholar 

  5. Bene M, Faure G (1987) Composition of mesangial deposits in IgA nephropathy: complement factors. Nephron 46(2):219. https://doi.org/10.1159/000184350

    Article  CAS  PubMed  Google Scholar 

  6. Rauterberg E, Lieberknecht H, Wingen A, Ritz E (1987) Complement membrane attack (MAC) in idiopathic IgA-glomerulonephritis. Kidney Int 31(3):820–829. https://doi.org/10.1038/ki.1987.72

    Article  CAS  PubMed  Google Scholar 

  7. Maillard N, Wyatt R, Julian B, Kiryluk K, Gharavi A, Fremeaux-Bacchi V, Novak J (2015) Current understanding of the role of complement in IgA nephropathy. J Am Soc Nephrol 26(7):1503–1512. https://doi.org/10.1681/asn.2014101000

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  8. Endo M, Ohi H, Ohsawa I, Fujita T, Matsushita M, Fujita T (1998) Glomerular deposition of mannose-binding lectin (MBL) indicates a novel mechanism of complement activation in IgA nephropathy. Nephrol Dialysis Transplant 13(8):1984–1990. https://doi.org/10.1093/ndt/13.8.1984

    Article  CAS  Google Scholar 

  9. Roos A, Rastaldi M, Calvaresi N, Oortwijn B, Schlagwein N, van Gijlswijk-Janssen D, Stahl G, Matsushita M, Fujita T, van Kooten C, Daha M (2006) Glomerular activation of the lectin pathway of complement in IgA nephropathy is associated with more severe renal disease. J Am Soc Nephrol 17(6):1724–1734. https://doi.org/10.1681/asn.2005090923

    Article  CAS  PubMed  Google Scholar 

  10. Tian S, Yang X, Luo J, Guo H (2020) Clinical and prognostic significance of C1q deposition in IgAN patients-a retrospective study. Int Immunopharmacol 88:106896. https://doi.org/10.1016/j.intimp.2020.106896

    Article  CAS  PubMed  Google Scholar 

  11. Nam K, Joo Y, Lee C, Lee S, Kim J, Yun H, Park J, Chang T, Ryu D, Yoo T, Chin H, Kang S, Jeong H, Lim B, Han S (2020) Predictive value of mesangial C3 and C4d deposition in IgA nephropathy. Clin Immunol (Orlando, Fla) 211:108331. https://doi.org/10.1016/j.clim.2019.108331

    Article  CAS  Google Scholar 

  12. Wu J, Hu Z, Wang Y, Hu D, Yang Q, Li Y, Dai W, Zhu F, Yang J, Wang M, Zhu H, Liu L, He X, Han M, Yao Y, Pei G, Zeng R, Xu G (2021) Severe glomerular C3 deposition indicates severe renal lesions and a poor prognosis in patients with immunoglobulin A nephropathy. Histopathology 78(6):882–895. https://doi.org/10.1111/his.14318

    Article  PubMed  Google Scholar 

  13. Levey A, de Jong P, Coresh J, El Nahas M, Astor B, Matsushita K, Gansevoort R, Kasiske B, Eckardt K (2011) The definition, classification, and prognosis of chronic kidney disease: a KDIGO Controversies Conference report. Kidney Int 80(1):17–28. https://doi.org/10.1038/ki.2010.483

    Article  PubMed  Google Scholar 

  14. Jennette J (1988) The immunohistology of IgA nephropathy. Am J Kidney Dis 12(5):348–352. https://doi.org/10.1016/s0272-6386(88)80022-2

    Article  CAS  PubMed  Google Scholar 

  15. Kim S, Koo H, Lim B, Oh H, Yoo D, Shin D, Lee M, Doh F, Park J, Yoo T, Kang S, Choi K, Jeong H, Han S (2012) Decreased circulating C3 levels and mesangial C3 deposition predict renal outcome in patients with IgA nephropathy. PLoS One 7(7):e40495. https://doi.org/10.1371/journal.pone.0040495

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  16. Katafuchi R, Nagae H, Masutani K, Tsuruya K, Mitsuiki K (2019) Comprehensive evaluation of the significance of immunofluorescent findings on clinicopathological features in IgA nephropathy. Clin Exp Nephrol 23(2):169–181. https://doi.org/10.1007/s10157-018-1619-6

    Article  CAS  PubMed  Google Scholar 

  17. Kawasaki Y, Maeda R, Ohara S, Suyama K, Hosoya M (2018) Serum IgA/C3 and glomerular C3 staining predict severity of IgA nephropathy. Pediatrics Int 60(2):162–167. https://doi.org/10.1111/ped.13461

    Article  CAS  Google Scholar 

  18. Pei G, Qin A, Wang S, Tan L, Tang Y, Qin W (2020) Effect of serum IgA/C3 and glomerular C3 staining on clinical prognosis in patients with IgA nephropathy. Zhonghua Yi Xue Za Zhi 100(30):2372–2377. https://doi.org/10.3760/cma.j.cn112137-20200313-00745

    Article  CAS  PubMed  Google Scholar 

  19. Stefan G, Stancu S, Boitan B, Zugravu A, Petre N, Mircescu G (2020) Is there a role for IgA/C3 ratio in IgA nephropathy prognosis? An outcome analysis on an European population. Iran J Kidney Dis 14(6):470–477

    PubMed  Google Scholar 

  20. Park S, Kim H, Park J, Chang T, Kang E, Ryu D, Yoo T, Chin H, Jeong H, Kang S, Lim B, Han S (2020) Relationship between complement deposition and the Oxford classification score and their combined effects on renal outcome in immunoglobulin A nephropathy. Nephrol Dialysis Transplant 35(12):2103–2137. https://doi.org/10.1093/ndt/gfz161

    Article  CAS  Google Scholar 

  21. Wan J, Fukuda N, Endo M, Tahira Y, Yao E, Matsuda H, Ueno T, Matsumoto K (2007) Complement 3 is involved in changing the phenotype of human glomerular mesangial cells. J Cell Physiol 213(2):495–501. https://doi.org/10.1002/jcp.21129

    Article  CAS  PubMed  Google Scholar 

  22. Tang S, Lai K, Sacks S (2002) Role of complement in tubulointerstitial injury from proteinuria. Kidney Blood Press Res 25(2):120–126. https://doi.org/10.1159/000063520

    Article  CAS  PubMed  Google Scholar 

  23. Wang Z, Xie X, Li J, Zhang X, He J, Wang M, Lv J, Zhang H (2021) Complement activation is associated with crescents in IgA nephropathy. Front Immunol 12:676919. https://doi.org/10.3389/fimmu.2021.676919

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  24. Cattran D, Coppo R, Cook H, Feehally J, Roberts I, Troyanov S, Alpers C, Amore A, Barratt J, Berthoux F, Bonsib S, Bruijn J, D’Agati V, D’Amico G, Emancipator S, Emma F, Ferrario F, Fervenza F, Florquin S, Fogo A, Geddes C, Groene H, Haas M, Herzenberg A, Hill P, Hogg R, Hsu S, Jennette J, Joh K, Julian B, Kawamura T, Lai F, Leung C, Li L, Li P, Liu Z, Mackinnon B, Mezzano S, Schena F, Tomino Y, Walker P, Wang H, Weening J, Yoshikawa N, Zhang H (2009) The Oxford classification of IgA nephropathy: rationale, clinicopathological correlations, and classification. Kidney Int 76(5):534–545. https://doi.org/10.1038/ki.2009.243

    Article  PubMed  Google Scholar 

  25. Chen D, Liu J, Duan S, Chen P, Tang L, Zhang L, Feng Z, Cai G, Wu J, Chen X (2018) Clinicopathological features to predict progression of IgA nephropathy with mild proteinuria. Kidney Blood Press Res 43(2):318–328. https://doi.org/10.1159/000487901

    Article  CAS  PubMed  Google Scholar 

  26. Biancone L, David S, Della Pietra V, Montrucchio G, Cambi V, Camussi G (1994) Alternative pathway activation of complement by cultured human proximal tubular epithelial cells. Kidney Int 45(2):451–460. https://doi.org/10.1038/ki.1994.59

    Article  CAS  PubMed  Google Scholar 

  27. Schejbel L, Schmidt I, Kirchhoff M, Andersen C, Marquart H, Zipfel P, Garred P (2011) Complement factor H deficiency and endocapillary glomerulonephritis due to paternal isodisomy and a novel factor H mutation. Genes Immun 12(2):90–99. https://doi.org/10.1038/gene.2010.63

    Article  CAS  PubMed  Google Scholar 

  28. Nasri H, Sajjadieh S, Mardani S, Momeni A, Merikhi A, Madihi Y, Ghiessari A, Emami Naieni A (2013) Correlation of immunostaining findings with demographic data and variables of Oxford classification in IgA nephropathy. J Nephropathol 2(3):190–195. https://doi.org/10.12860/jnp.2013.30

    Article  PubMed Central  PubMed  Google Scholar 

  29. Trimarchi H, Barratt J, Cattran D, Cook H, Coppo R, Haas M, Liu Z, Roberts I, Yuzawa Y, Zhang H, Feehally J (2017) Oxford classification of IgA nephropathy 2016: an update from the IgA Nephropathy Classification Working Group. Kidney Int 91(5):1014–1021. https://doi.org/10.1016/j.kint.2017.02.003

    Article  PubMed  Google Scholar 

  30. Gutiérrez E, Zamora I, Ballarín J, Arce Y, Jiménez S, Quereda C, Olea T, Martínez-Ara J, Segarra A, Bernis C, García A, Goicoechea M, García de Vinuesa S, Rojas-Rivera J, Praga M (2012) Long-term outcomes of IgA nephropathy presenting with minimal or no proteinuria. J Am Soc Nephrol 23(10):1753–1760. https://doi.org/10.1681/asn.2012010063

    Article  PubMed Central  PubMed  Google Scholar 

  31. Bellur S, Lepeytre F, Vorobyeva O, Troyanov S, Cook H, Roberts I (2017) Evidence from the Oxford classification cohort supports the clinical value of subclassification of focal segmental glomerulosclerosis in IgA nephropathy. Kidney Int 91(1):235–243. https://doi.org/10.1016/j.kint.2016.09.029

    Article  PubMed  Google Scholar 

  32. Yu F, Zhu X, Yuan S, Chen X, Li Z, Qu Z, Liu H, Sun L, Liu F (2021) Predictive value of sub classification of focal segmental glomerular sclerosis in Oxford classification of IgA nephropathy. Ann Med 53(1):587–595. https://doi.org/10.1080/07853890.2021.1897664

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  33. Cybulsky A (2011) Membranous nephropathy. Contrib Nephrol 169:107–125. https://doi.org/10.1159/000313948

    Article  CAS  PubMed  Google Scholar 

  34. Locatelli M, Buelli S, Pezzotta A, Corna D, Perico L, Tomasoni S, Rottoli D, Rizzo P, Conti D, Thurman J, Remuzzi G, Zoja C, Morigi M (2014) Shiga toxin promotes podocyte injury in experimental hemolytic uremic syndrome via activation of the alternative pathway of complement. J Am Soc Nephrol 25(8):1786–1798. https://doi.org/10.1681/asn.2013050450

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  35. Benzing T (2004) Signaling at the slit diaphragm. J Am Soc Nephrol 15(6):1382–1391. https://doi.org/10.1097/01.asn.0000130167.30769.55

    Article  PubMed  Google Scholar 

  36. Wu D, Li X, Yao X, Zhang N, Lei L, Zhang H, Tang M, Ni J, Ling C, Chen Z, Chen X, Liu X (2021) Mesangial C3 deposition and serum C3 levels predict renal outcome in IgA nephropathy. Clin Exp Nephrol 25(6):641–651. https://doi.org/10.1007/s10157-021-02034-7

    Article  CAS  PubMed  Google Scholar 

  37. Maixnerova D, Neprasova M, Skibova J, Mokrisova J, Rysava R, Reiterova J, Jancova E, Merta M, Zadrazil J, Honsova E, Tesar V (2014) IgA nephropathy in Czech patients–are we able reliably predict the outcome? Kidney Blood Press Res 39(6):555–562. https://doi.org/10.1159/000368467

    Article  CAS  PubMed  Google Scholar 

  38. Tan M, Li W, Zou G, Zhang C, Fang J (2015) Clinicopathological features and outcomes of IgA nephropathy with hematuria and/or minimal proteinuria. Kidney Blood Press Res 40(2):200–206. https://doi.org/10.1159/000368495

    Article  CAS  PubMed  Google Scholar 

  39. Caliskan Y, Ozluk Y, Celik D, Oztop N, Aksoy A, Ucar A, Yazici H, Kilicaslan I, Sever M (2016) The clinical significance of uric acid and complement activation in the progression of IgA nephropathy. Kidney Blood Press Res 41(2):148–157. https://doi.org/10.1159/000443415

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We would like to acknowledge the service provided by the Department of Renal Pathology of the First Affiliated Hospital of Zhengzhou University.

Funding

This study was supported by the project of The National Nature Science Fund (face items) [Grant Number 82170721].

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Authors and Affiliations

  1. Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China

    Minhua Xie, Yuze Zhu, Xutong Wang, Jingjing Ren, Haonan Guo, Bo Huang, Shulei Wang, Peiheng Wang, Yiming Liu, Yingchun Liu & Junjun Zhang

  2. Research Institute of Nephrology, Zhengzhou University, Zhengzhou, Henan, China

    Minhua Xie, Yuze Zhu, Xutong Wang, Jingjing Ren, Haonan Guo, Bo Huang, Shulei Wang, Peiheng Wang, Yiming Liu, Yingchun Liu & Junjun Zhang

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  1. Minhua Xie
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Contributions

All authors contributed to the study conception and design. MX designed and drafted the study. YZ and XW performed data analysis, JR and HG wrote the manuscript. BH helped recruit patients. SW, PW, YL, and YL completed the data collection. JZ revised and finalized the final version of the manuscript for publication. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Junjun Zhang.

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Conflict of interest

The authors have no relevant financial or non-financial interests to disclose.

Ethics approval

The study was carried out according to the principles laid out in the World Medical Association’s Declaration of Helsinki and supported by the Ethics Committee of Zhengzhou University (2020-KY-476). All patients provided written informed consent to participate in the study.

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Xie, M., Zhu, Y., Wang, X. et al. Predictive prognostic value of glomerular C3 deposition in IgA nephropathy. J Nephrol 36, 495–505 (2023). https://doi.org/10.1007/s40620-022-01363-4

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