Alternatively activated macrophages in the pathogenesis of chronic kidney allograft injury

Yohei Ikezumi, Toshiaki Suzuki, Takeshi Yamada, Hiroya Hasegawa, Utako Kaneko, Masanori Hara, Toshio Yanagihara, David J. Nikolic-Paterson, Akihiko Saitoh

Research output: Contribution to journalArticle

28 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1007-1017
Number of pages11
JournalPediatric Nephrology
Volume30
Issue number6
DOIs
Publication statusPublished - 01-06-2015

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Allografts
Fibrosis
Macrophages
Kidney
Wounds and Injuries
Atrophy
Biopsy
Myofibroblasts
Fibroblast Growth Factor 2
Dexamethasone
Smooth Muscle
Actins
Collagen
Retrospective Studies
Transplantation
Urine
Cytokines
Phenotype
Population

All Science Journal Classification (ASJC) codes

  • Pediatrics, Perinatology, and Child Health
  • Nephrology

Cite this

Ikezumi, Yohei ; Suzuki, Toshiaki ; Yamada, Takeshi ; Hasegawa, Hiroya ; Kaneko, Utako ; Hara, Masanori ; Yanagihara, Toshio ; Nikolic-Paterson, David J. ; Saitoh, Akihiko. / Alternatively activated macrophages in the pathogenesis of chronic kidney allograft injury. In: Pediatric Nephrology. 2015 ; Vol. 30, No. 6. pp. 1007-1017.
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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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Ikezumi, Y, Suzuki, T, Yamada, T, Hasegawa, H, Kaneko, U, Hara, M, Yanagihara, T, Nikolic-Paterson, DJ & Saitoh, A 2015, 'Alternatively activated macrophages in the pathogenesis of chronic kidney allograft injury', Pediatric Nephrology, vol. 30, no. 6, pp. 1007-1017. https://doi.org/10.1007/s00467-014-3023-0

Alternatively activated macrophages in the pathogenesis of chronic kidney allograft injury. / Ikezumi, Yohei; Suzuki, Toshiaki; Yamada, Takeshi; Hasegawa, Hiroya; Kaneko, Utako; Hara, Masanori; Yanagihara, Toshio; Nikolic-Paterson, David J.; Saitoh, Akihiko.

In: Pediatric Nephrology, Vol. 30, No. 6, 01.06.2015, p. 1007-1017.

Research output: Contribution to journalArticle

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T1 - Alternatively activated macrophages in the pathogenesis of chronic kidney allograft injury

AU - Ikezumi, Yohei

AU - Suzuki, Toshiaki

AU - Yamada, Takeshi

AU - Hasegawa, Hiroya

AU - Kaneko, Utako

AU - Hara, Masanori

AU - Yanagihara, Toshio

AU - Nikolic-Paterson, David J.

AU - Saitoh, Akihiko

PY - 2015/6/1

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N2 - 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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