Skip to main content
SpringerLink
Log in

Mesangial C4d deposition may predict progression of kidney disease in pediatric patients with IgA nephropathy

  • Original Article
  • Published:
Pediatric Nephrology Aims and scope Submit manuscript

An Erratum to this article was published on 17 March 2017

Abstract

Background

Data on the risk factors for chronic kidney disease in children with immunoglobulin A nephropathy (IgAN) are scarce. This study was aimed at investigating whether glomerular C4d immunostaining is a prognostic marker in pediatric IgAN.

Methods

In this retrospective cohort study, 47 patients with IgAN biopsied from 1982 to 2010 were evaluated. Immunohistochemistry for C4d was performed in all cases. For analysis, patients were grouped according to positivity or not for C4d in the mesangial area. Primary outcome was a decline in baseline estimated glomerular filtration rate (eGFR) by 50% or more.

Results

Median follow-up was 8.3 years. Median renal survival was 13.7 years and the probability of a 50% decline in eGFR was 13% over 10 years. Nine children exhibited the primary outcome and 4 developed end-stage renal disease (ESRD). Compared with C4d-negative patients (n = 10), C4d-positive patients (n = 37) presented higher baseline proteinuria (1.66 ± 0.68 vs 0.47 ± 0.19 g/day/1.73 m2, p < 0.001), a progressive decline in eGFR (−10.04 ± 19.38 vs 1.70 ± 18.51 ml/min/1.73 m2/year; p = 0.045), and more frequently achieved the primary outcome (50.0 vs 10.8%, p = 0.013), and ESRD (30.0 vs 2.7%, p = 0.026). No difference was observed in Oxford classification variables. Baseline proteinuria, endocapillary hypercellularity and mesangial C4d deposition were associated with primary outcome in univariate analysis. Proteinuria and mesangial C4d deposition at baseline independently predicted the decline in eGFR. Renal survival was significantly reduced in C4d-positive patients (8.6 vs 15.1 years in C4d-negative patients, p < 0.001).

Conclusions

In this exclusively pediatric cohort, positivity for C4d in the mesangial area was an independent predictor of renal function deterioration in IgAN.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Wyatt RJ, Julian BA (2013) IgA nephropathy. N Engl J Med 368:2402–2414

    Article  CAS  PubMed  Google Scholar 

  2. Gutiérrez E, Zamora I, Ballarín JA, 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, Grupo de Estudio de Enfermedades Glomerulares de la Sociedad Española de Nefrología (GLOSEN) (2012) Long-term outcomes of IgA nephropathy presenting with minimal or no proteinuria. J Am Soc Nephrol 23:1753–1760

    Article  PubMed Central  PubMed  Google Scholar 

  3. Lv J, Shi S, Xu D, Zhang H, Troyanov S, Cattran DC, Wang H (2013) Evaluation of the Oxford classification of IgA nephropathy: a systematic review and meta-analysis. Am J Kidney Dis 62:891–899

    Article  PubMed  Google Scholar 

  4. Taal MW, Brenner BM (2006) Predicting initiation and progression of chronic kidney disease: developing renal risk scores. Kidney Int 70:1694–1705

    Article  CAS  PubMed  Google Scholar 

  5. Taal MW, Brenner BM (2008) Renal risk scores: progress and prospects. Kidney Int 73:1216–1219

    Article  CAS  PubMed  Google Scholar 

  6. Tangri N, Stevens LA, Griffith J, Tighiouart H, Djurdjev O, Naimark D, Levin A, Levey AS (2011) A predictive model for progression of chronic kidney disease to kidney failure. JAMA 305:1553–1559

    Article  CAS  PubMed  Google Scholar 

  7. Bartosik LP, Lajoie G, Sugar L, Cattran DC (2001) Predicting progression in IgA nephropathy. Am J Kidney Dis 38:728–735

    Article  CAS  PubMed  Google Scholar 

  8. Cattran DC, Coppo R, Cook HT, Feehally J, Roberts ISD, Troyanov S, Alpers CE, Amore A, Barratt J, Berthoux F, Bonsib S, Bruijn JA, D’Agati V, D’Amico G, Emancipator S, Emma F, Ferrario F, Fervenza FC, Florquin S, Fogo A, Geddes CC, Groene HJ, Haas M, Herzenberg AM, Hill PA, Hogg RJ, Hsu SI, Jennette JC, Joh K, Julian BA, Kawamura T, Lai FM, Leung CB, Li LS, Li PK, Liu ZH, Mackinnon B, Mezzano S, Schena FP, Tomino Y, Walker PD, Wang H, Weening JJ, Yoshikawa N, Zhang H, Working Group of the International IgA Nephropathy Network and the Renal Pathology Society (2009) The Oxford classification of IgA nephropathy: rationale, clinicopathological correlations, and classification. Kidney Int 76:534–554

    Article  PubMed  Google Scholar 

  9. Roberts ISD, Cook HT, Troyanov S, Alpers CE, Amore A, Barratt J, Berthoux F, Bonsib S, Bruijn JA, Cattran DC, Coppo R, D’Agati V, D’Amico G, Emancipator S, Emma F, Feehally J, Ferrario F, Fervenza FC, Florquin S, Fogo A, Geddes CC, Groene HJ, Haas M, Herzenberg AM, Hill PA, Hogg RJ, Hsu SI, Jennette JC, Joh K, Julian BA, Kawamura T, Lai FM, Li LS, Li PK, Liu ZH, Mackinnon B, Mezzano S, Schena FP, Tomino Y, Walker PD, Wang H, Weening JJ, Yoshikawa N, Zhang H, Working Group of the International IgA Nephropathy Network and the Renal Pathology Society (2009) The Oxford classification of IgA nephropathy: pathology definitions, correlations, and reproducibility. Kidney Int 76:546–556

    Article  PubMed  Google Scholar 

  10. Fabiano RC, Pinheiro SV, de Almeida AS, Silva AC (2016) Immunoglobulin A nephropathy: pathological markers of renal survival in pediatric patients. Nephrology (Carlton) 21:995–1002

    Article  CAS  Google Scholar 

  11. Mina SN, Murphy MW (1985) IgA nephropathy. A comparative study of the clinicopathologic features in children and adults. Am J Clin Pathol 83:669–675

    Article  CAS  PubMed  Google Scholar 

  12. Okada K, Funai M, Kawakami K, Kagami S, Yano I, Kuroda Y (1990) IgA nephropathy in Japanese children and adults: a comparative study of clinicopathological features. Am J Nephrol 10:191–197

    Article  CAS  PubMed  Google Scholar 

  13. Ikezumi Y, Suzuki T, Imai N, Ueno M, Narita I, Kawachi H, Shimizu F, Nikolic-Paterson DJ, Uchiyama M (2006) Histological differences in new-onset IgA nephropathy between children and adults. Nephrol Dial Transplant 21:3466–3474

    Article  PubMed  Google Scholar 

  14. Hastings MC, Moldoveanu Z, Suzuki H, Berthoux F, Julian BA, Sanders JT, Renfrow MB, Novak J, Wyatt RJ (2013) Biomarkers in IgA nephropathy: relationship to pathogenetic hits. Expert Opin Med Diagn 7:615–627

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  15. Fabiano RC, Pinheiro SV, Simões e Silva AC (2016) Immunoglobulin A nephropathy: a pathophysiology view. Inflamm Res 65:757–770

    Article  CAS  PubMed  Google Scholar 

  16. Bellur SS, Troyanov S, Cook HT, Roberts IS (2011) Immunostaining findings in IgA nephropathy: correlation with histology and clinical outcome in the Oxford classification patient cohort. Nephrol Dial Transplant 26:2533–2536

    Article  PubMed  Google Scholar 

  17. Rauterberg EW, Lieberknecht HM, Wingen AM, Ritz E (1987) Complement membrane attack (MAC) in idiopathic IgA-glomerulonephritis. Kidney Int 31:820–829

    Article  CAS  PubMed  Google Scholar 

  18. Wyatt RJ, Julian BA (1988) Activation of complement in IgA nephropathy. Am J Kidney Dis 12:437–442

    Article  CAS  PubMed  Google Scholar 

  19. Espinosa M, Ortega R, Gómez-Carrasco JM, López-Rubio F, López-Andreu M, López-Oliva MO, Aljama P (2009) Mesangial C4d deposition: a new prognostic factor in IgA nephropathy. Nephrol Dial Transplant 24:886–891

    Article  CAS  PubMed  Google Scholar 

  20. Maeng Y-I, Kim M-K, Park J-B, Cho C-H, Oh H-K, Sung WJ, Park K-K (2013) Glomerular and tubular C4d depositions in IgA nephropathy: relations with histopathology and with albuminuria. Int J Clin Exp Pathol 6:904–910

    PubMed Central  PubMed  Google Scholar 

  21. Sahin OZ, Yavas H, Taslı F, Gibyeli DG, Ersoy R, Uzum A, Cirit M (2014) Prognostic value of glomerular C4d staining in patients with IgA nephritis. Int J Clin Exp Pathol 7:3299–3304

    PubMed Central  PubMed  Google Scholar 

  22. Espinosa M, Ortega R, Sánchez M, Segarra A, Salcedo MT, González F, Camacho R, Valdivia MA, Cabrera R, López K, Pinedo F, Gutierrez E, Valera A, Leon M, Cobo MA, Rodriguez R, Ballarín J, Arce Y, García B, Muñoz MD, Praga M, Spanish Group for Study of Glomerular Diseases (GLOSEN) (2014) Association of C4d deposition with clinical outcomes in IgA nephropathy. Clin J Am Soc Nephrol 9:897–904

    Article  PubMed Central  PubMed  Google Scholar 

  23. Nasri H, Ahmadi A, Rafieian-Kopaei M, Bashardoust B, Nasri P, Mubarak M (2015) Association of glomerular C4d deposition with various demographic data in IgA nephropathy patients; a preliminary study. J Nephropathol 4:19–23

    PubMed Central  PubMed  Google Scholar 

  24. Galla JH (1995) IgA nephropathy. Kidney Int 47:377–387

    Article  CAS  PubMed  Google Scholar 

  25. IBGE (2000) Censo 2000. Brazilian Institute of Geography and Statistics, Rio de Janeiro, http://www.ibge.gov.br/home/estatistica/populacao/censo2000/populacao/censo2000_populacao.pdf

    Google Scholar 

  26. National High Blood Pressure Education Program Working Group on High Blood Pressure in Children and Adolescents (2004) Fourth report on the diagnosis, evaluation, and treatment of high blood pressure in children and adolescents. Pediatrics 114:555–576

    Article  Google Scholar 

  27. Shima Y, Nakanishi K, Hama T, Mukaiyama H, Togawa H, Hashimura Y, Kaito H, Sako M, Iijima K, Yoshikawa N (2012) Validity of the Oxford classification of IgA nephropathy in children. Pediatr Nephrol 27:783–792

    Article  PubMed  Google Scholar 

  28. Schwartz GJ, Brion LP, Spitzer A (1987) The use of plasma creatinine concentration for estimating glomerular filtration rate in infants, children, and adolescents. Pediatr Clin N Am 34:571–590

    Article  CAS  Google Scholar 

  29. Schwartz GJ, Muñoz A, Schneider MF, Mak RH, Kaskel F, Warady BA, Furth SL (2009) New equations to estimate GFR in children with CKD. J Am Soc Nephrol 20:629–637

    Article  PubMed Central  PubMed  Google Scholar 

  30. Mestecky J, Raska M, Julian BA, Gharavi AG, Renfrow MB, Moldoveanu Z, Novak L, Matousovic K, Novak J (2013) IgA nephropathy: molecular mechanisms of the disease. Annu Rev Pathol 8:217–240

    Article  CAS  PubMed  Google Scholar 

  31. Faria B, Henriques C (2015) Combined C4d and CD3 immunostaining predicts immunoglobulin (Ig) A nephropathy progression. Clin Exp Immunol 179:354–361

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  32. Roos A, Rastaldi MP, Calvaresi N, Oortwijn BD, Schlagwein N, van Gijlswijk-Janssen DJ, Stahl GL, Matsushita M, Fujita T, van Kooten C, Daha MR (2006) Glomerular activation of the lectin pathway of complement in IgA nephropathy is associated with more severe renal disease. J Am Soc Nephrol 17:1724–1734

    Article  CAS  PubMed  Google Scholar 

  33. Maillard N, Wyatt RJ, Julian BA, Kiryluk K, Gharavi A, Fremeaux-Bacchi V, Novak J (2015) Current understanding of the role of complement in IgA nephropathy. J Am Soc Nephrol 26:1503–1512

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  34. Onda K, Ohsawa I, Ohi H, Tamano M, Mano S, Wakabayashi M, Toki A, Horikoshi S, Fujita T, Tomino Y (2011) Excretion of complement proteins and its activation marker C5b-9 in IgA nephropathy in relation to renal function. BMC Nephrol 12:64

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  35. Van Es LA, de Heer E, Vleming LJ, van der Wal A, Mallat M, Bajema I, Bruijn JA, de Fijter JW (2008) GMP-17-positive T-lymphocytes in renal tubules predict progression in early stages of IgA nephropathy. Kidney Int 73:1426–1433

    Article  PubMed  Google Scholar 

  36. Heybeli C, Unlu M, Yildiz S, Cavdar C, Sarioglu S, Camsari T (2015) IgA nephropathy: association of C4d with clinical and histopathological findings and possible role of IgM. Ren Fail 37:1464–1469

    Article  CAS  PubMed  Google Scholar 

  37. Daha MR, van Kooten C (2016) Role of complement in IgA nephropathy. J Nephrol 29:1–4

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors dedicate this work to the deceased Professor José Silvério Santos Diniz, founder of the Pediatric Nephrology Unit, Clinics Hospital, Federal University of Minas Gerais, Brazil. The authors thank Dr Luiz Sérgio Bahia Cardoso, Dr Maria Goretti Moreira Guimarães Penido, and all other colleagues who processed medical records, managed patients, performed renal biopsies, and assisted with follow-up.

Author information

Authors and Affiliations

  1. Division of Clinical Nephrology, Clinics Hospital, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil

    Rafaela Cabral Gonçalves Fabiano

  2. Division of Renal Pathology, Clinics Hospital, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil

    Stanley de Almeida Araújo & Eduardo Alves Bambirra

  3. Department of Pediatrics, Pediatric Nephrology Unit, Faculty of Medicine, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil

    Eduardo Araújo Oliveira, Ana Cristina Simões e Silva & Sérgio Veloso Brant Pinheiro

  4. Interdisciplinary Laboratory of Medical Investigation, Faculty of Medicine, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil

    Ana Cristina Simões e Silva

  5. Universidade Federal de Minas Gerais—Faculdade de Medicina, Avenida Alfredo Balena 190/sala 331, Belo Horizonte, Minas Gerais, Brazil, 30130-100

    Sérgio Veloso Brant Pinheiro

Authors
  1. Rafaela Cabral Gonçalves Fabiano
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Stanley de Almeida Araújo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Eduardo Alves Bambirra
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Eduardo Araújo Oliveira
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ana Cristina Simões e Silva
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Sérgio Veloso Brant Pinheiro
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sérgio Veloso Brant Pinheiro.

Ethics declarations

Conflicts of interest

The authors have no conflicts to declare.

Ethical aspects

The Ethics Committee of the Federal University of Minas Gerais approved the study, according to the principles of the Declaration of Helsinki (National protocol CAAE18196713.4.0000.5149).

Financial support

FAPEMIG (Fundação de Amparo à Pesquisa do Estado de Minas Gerais, Brazil), CNPq (Conselho Nacional de Desenvolvimento Científico e Tecnológico, Brazil), and CAPES (Coordenação de Aperfeiçoamento de Pessoal de Nível Superior).

Additional information

An erratum to this article is available at http://dx.doi.org/10.1007/s00467-017-3644-1.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Fabiano, R.C.G., de Almeida Araújo, S., Bambirra, E.A. et al. Mesangial C4d deposition may predict progression of kidney disease in pediatric patients with IgA nephropathy. Pediatr Nephrol 32, 1211–1220 (2017). https://doi.org/10.1007/s00467-017-3610-y

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00467-017-3610-y

Keywords

Search

Navigation