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Alternatively activated macrophages in the pathogenesis of chronic kidney allograft injury

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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.

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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.

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Authors and Affiliations

  1. Department of Pediatrics, Niigata University Medical and Dental Hospital, Asahimachi-dori, 951-8510, Niiagta, Japan

    Yohei Ikezumi, Toshiaki Suzuki, Takeshi Yamada, Hiroya Hasegawa, Utako Kaneko & Akihiko Saitoh

  2. Yoshida Hospital, Niigata, Japan

    Masanori Hara & Toshio Yanagihara

  3. Department of Medicine, Monash Medical Centre, Monash University, Clayton, VIC, Australia

    David J. Nikolic-Paterson

Authors
  1. Yohei Ikezumi
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  2. Toshiaki Suzuki
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  3. Takeshi Yamada
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  4. Hiroya Hasegawa
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  5. Utako Kaneko
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  6. Masanori Hara
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  7. Toshio Yanagihara
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  8. David J. Nikolic-Paterson
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  9. Akihiko Saitoh
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Corresponding author

Correspondence to Yohei Ikezumi.

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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

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  • DOI: https://doi.org/10.1007/s00467-014-3023-0

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