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

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66 Citations (Scopus)


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 alpha-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-beta1, 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
Issue number6
Publication statusPublished - 2015

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