Skip to main content

Alternatively activated macrophages in the pathogenesis of chronic kidney allograft injury

Abstract

Background

Prevention of chronic kidney allograft injury (CAI) is a major goal in improving kidney allograft survival; however, the mechanisms of CAI are not clearly understood. The current study investigated whether alternatively activated M2-type macrophages are involved in the development of CAI.

Methods

A retrospective study examined kidney allograft protocol biopsies (at 1 h and at years 1, 5, and 10—a total of 41 biopsies) obtained from 13 children undergoing transplantation between 1991 and 2008 who were diagnosed with CAI: interstitial fibrosis and tubular atrophy (IF/TA) not otherwise specified (IF/TA-NOS).

Results

Immunostaining identified a significant increase in interstitial fibrosis with accumulation of CD68 + CD163+ M2-type macrophages. CD163+ cells were frequently localized to areas of interstitial fibrosis exhibiting collagen I deposition and accumulation of α-smooth muscle actin (SMA) + myofibroblasts. There was a significant correlation between interstitial CD163+ cells and the parameters of interstitial fibrosis (p < 0.0001), and kidney function (r =−0.82, p < 0.0001). The number of interstitial CD163+ cells at years 1 and 5 also correlated with parameters of interstitial fibrosis at years 5 and 10 respectively. Notably, urine CD163 levels correlated with interstitial CD163+ cells (r = 0.79, p < 0.01) and parameters of interstitial fibrosis (p < 0.0001). However, CD3+ T lymphocytic infiltration did not correlate with macrophage accumulation or fibrosis. In vitro, dexamethasone up-regulated expression of CD163 and cytokines (TGF-β1, FGF-2, CTGF) in human monocyte-derived macrophages, indicating a pro-fibrotic phenotype.

Conclusions

Our findings identify a major population of M2-type macrophages in patients with CAI, and suggest that these M2-type macrophages might promote the development of interstitial fibrosis in IF/TA-NOS.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

References

  1. 1.

    Solez K, Axelsen RA, Benediktsson H, Burdick JF, Cohen AH, Colvin RB, Croker BP, Droz D, Dunnill MS, Halloran PF (1993) International standardization of criteria for the histologic diagnosis of renal allograft rejection: the Banff working classification of kidney transplant pathology. Kidney Int 44:411–422

    Article  CAS  PubMed  Google Scholar 

  2. 2.

    Shrestha BM, Haylor J (2014) Biological pathways and potential targets for prevention and therapy of chronic allograft nephropathy. Biomed Res Int 2014:482438

    PubMed Central  PubMed  Google Scholar 

  3. 3.

    Solez K, Colvin RB, Racusen LC, Sis B, Halloran PF, Birk PE, Campbell PM, Cascalho M, Collins AB, Demetris AJ, Drachenberg CB, Gibson IW, Grimm PC, Haas M, Lerut E, Liapis H, Mannon RB, Marcus PB, Mengel M, Mihatsch MJ, Nankivell BJ, Nickeleit V, Papadimitriou JC, Platt JL, Randhawa P, Roberts I, Salinas-Madriga L, Salomon DR, Seron D, Sheaff M, Weening JJ (2007) Banff ‘05 Meeting Report: differential diagnosis of chronic allograft injury and elimination of chronic allograft nephropathy (‘CAN’). Am J Transplant 7:518–526

    Article  CAS  PubMed  Google Scholar 

  4. 4.

    Solez K, Colvin RB, Racusen LC, Haas M, Sis B, Mengel M, Halloran PF, Baldwin W, Banfi G, Collins AB, Cosio F, David DS, Drachenberg C, Einecke G, Fogo AB, Gibson IW, Glotz D, Iskandar SS, Kraus E, Lerut E, Mannon RB, Mihatsch M, Nankivell BJ, Nickeleit V, Papadimitriou JC, Randhawa P, Regele H, Renaudin K, Roberts I, Seron D, Smith RN, Valente M (2008) Banff 07 classification of renal allograft pathology: updates and future directions. Am J Transplant 8:753–760

    Article  CAS  PubMed  Google Scholar 

  5. 5.

    Croker BP, Clapp WL, Abu Shamat AR, Kone BC, Peterson JC (1996) Macrophages and chronic renal allograft nephropathy. Kidney Int Suppl 57:S42–S49

    CAS  PubMed  Google Scholar 

  6. 6.

    Liu G, Yang H (2013) Modulation of macrophage activation and programming in immunity. J Cell Physiol 228:502–512

    Article  CAS  PubMed  Google Scholar 

  7. 7.

    Mantovani A, Biswas SK, Galdiero MR, Sica A, Locati M (2013) Macrophage plasticity and polarization in tissue repair and remodelling. J Pathol 229:176–186

    Article  CAS  PubMed  Google Scholar 

  8. 8.

    Anders HJ, Ryu M (2011) Renal microenvironments and macrophage phenotypes determine progression or resolution of renal inflammation and fibrosis. Kidney Int 80:915–925

    Article  CAS  PubMed  Google Scholar 

  9. 9.

    Mannon RB (2012) Macrophages: contributors to allograft dysfunction, repair, or innocent bystanders? Curr Opin Organ Transplant 17:20–25

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  10. 10.

    Ikezumi Y, Suzuki T, Karasawa T, Hasegawa H, Yamada T, Imai N, Narita I, Kawachi H, Polkinghorne KR, Nikolic-Paterson DJ, Uchiyama M (2011) Identification of alternatively activated macrophages in new-onset paediatric and adult immunoglobulin A nephropathy: potential role in mesangial matrix expansion. Histopathology 58:198–210

    Article  PubMed  Google Scholar 

  11. 11.

    Ikezumi Y, Suzuki T, Karasawa T, Hasegawa H, Kawachi H, Nikolic-Paterson DJ, Uchiyama M (2010) Contrasting effects of steroids and mizoribine on macrophage activation and glomerular lesions in rat thy-1 mesangial proliferative glomerulonephritis. Am J Nephrol 31:273–282

    Article  CAS  PubMed  Google Scholar 

  12. 12.

    Lan HY, Mu W, Nikolic-Paterson DJ, Atkins RC (1995) A novel, simple, reliable and sensitive method for multiple immunoenzymic staining: use of microwave oven heating to block antibody crossreactivity and retrieve antigens. J Histochem Cytochem 43:97–102

    Article  CAS  PubMed  Google Scholar 

  13. 13.

    Han Y, Ma FY, Tesch GH, Manthey CL, Nikolic-Paterson DJ (2013) Role of macrophages in the fibrotic phase of rat crescentic glomerulonephritis. Am J Physiol Renal Physiol 304:F1043–1053

    Article  CAS  PubMed  Google Scholar 

  14. 14.

    Tse GH, Hughes J (2013) Macrophages and transplant rejection: a novel future target. Transplantation 96:946–948

    Article  CAS  PubMed  Google Scholar 

  15. 15.

    Kanlaya R, Sintiprungrat K, Thongboonkerd V (2013) Secreted products of macrophages exposed to calcium oxalate crystals induce epithelial mesenchymal transition of renal tubular cells via RhoA-dependent TGF-β1 pathway. Cell Biochem Biophys 67:1207–1215

    Article  CAS  PubMed  Google Scholar 

  16. 16.

    Tan TK, Zheng G, Hsu TT, Lee SR, Zhang J, Zhao Y, Tian X, Wang Y, Wang YM, Cao Q, Wang Y, Lee VW, Wang C, Zheng D, Alexander SI, Thompson E, Harris DC (2013) Matrix metalloproteinase-9 of tubular and macrophage origin contributes to the pathogenesis of renal fibrosis via macrophage recruitment through osteopontin cleavage. Lab Invest 93:434–449

    Article  CAS  PubMed  Google Scholar 

  17. 17.

    Ko GJ, Boo CS, Jo SK, Cho WY, Kim HK (2008) Macrophages contribute to the development of renal fibrosis following ischaemia/reperfusion-induced acute kidney injury. Nephrol Dial Transplant 23:842–852

    Article  CAS  PubMed  Google Scholar 

  18. 18.

    Alidousty C, Rauen T, Hanssen L, Wang Q, Alampour-Rajabi S, Mertens PR, Bernhagen J, Floege J, Ostendorf T, Raffetseder U (2014) Calcineurin-mediated YB-1 dephosphorylation regulates CCL5 expression during monocyte differentiation. J Biol Chem 289:21401–21412

    Article  PubMed  Google Scholar 

  19. 19.

    Höcker B, Tönshoff B (2009) Treatment strategies to minimize or prevent chronic allograft dysfunction in pediatric renal transplant recipients: an overview. Paediatr Drugs 11:381–396

    Article  PubMed  Google Scholar 

  20. 20.

    Yang H (2006) Maintenance immunosuppression regimens: conversion, minimization, withdrawal, and avoidance. Am J Kidney Dis 47:S37–51

    Article  CAS  PubMed  Google Scholar 

  21. 21.

    Ishikawa H (1999) Mizoribine and mycophenolate mofetil. Curr Med Chem 6:575–597

    CAS  PubMed  Google Scholar 

  22. 22.

    Ju MK, Huh KH, Park KT, Kim SJ, Cho BH, Kim CD, So BJ, Kang CM, Lee S, Joo DJ, Kim YS (2013) Mizoribine versus mycophenolate mofetil in combination therapy with tacrolimus for de novo kidney transplantation: evaluation of efficacy and safety. Transplant Proc 45:1481–1486

    Article  CAS  PubMed  Google Scholar 

  23. 23.

    Helal I, Chan L (2011) Steroid and calcineurin inhibitor-sparing protocols in kidney transplantation. Transplant Proc 43:472–477

    Article  CAS  PubMed  Google Scholar 

  24. 24.

    Kristiansen M, Graversen JH, Jacobsen C, Sonne O, Hoffman HJ, Law SK, Moestrup SK (2001) Identification of the haemoglobin scavenger receptor. Nature 409(6817):198–201

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by Grants-in-Aid for Scientific Research (25461618 to Y.I.) from the Ministry of Education, Culture, Sports, Science and Technology of Japan, and Grants-in-Aid for Promotion of Niigata University Research Projects from Niigata University.

Conflicts of interest

No conflicts of interest to declare.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Yohei Ikezumi.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Ikezumi, Y., Suzuki, T., Yamada, T. et al. Alternatively activated macrophages in the pathogenesis of chronic kidney allograft injury. Pediatr Nephrol 30, 1007–1017 (2015). https://doi.org/10.1007/s00467-014-3023-0

Download citation

Keywords

  • Alternatively activated macrophages
  • Chronic allograft injury
  • IF/TA-NOS
  • CD163
  • Fibrosis
  • Urinary CD163