title: The role of macrophages in the development of human renal allograft fibrosis in the first year after transplantation.
abstract: The aim of this study was to investigate the role of infiltrating macrophages in renal allograft fibrosis. Forty-six protocol renal allograft biopsies obtained 1 year after transplantation were stained with Sirius red to quantify fibrosis and double stained with CD68 and CD206 to identify the proportion of alternatively activated (M2) macrophages. Biopsies were analyzed for gene expression by microarray, which was correlated with macrophage infiltration and the severity of fibrosis. The number of infiltrating CD68+ cells strongly correlated with the percentage of interstitial fibrosis (r = 0.73, p < 0.0001). Macrophage infiltration at 1 year correlated with renal dysfunction at 1, 12 and 36 months posttransplant (estimated GFR low vs. high: 1 month 78 ± 26 vs. 54 ± 19 mL/min, p < 0.01; 12 months 87 ± 29 vs. 64 ± 19 mL/min, p < 0.05; 36 months 88 ± 33 vs. 60 ± 24 mL/min, p < 0.05). Ninety-two percent of infiltrating macrophages exhibited an M2 phenotype with CD68+ CD206+ dual staining. Gene microarrays demonstrated an alloimmune response with up-regulation of interferon-γ-response genes despite the lack of rejection or inflammatory infiltrate. Consistent with this was the presence of CXCL10 in proximal tubular cells at 3 months. This suggests that M2 macrophage proliferation, or infiltration, was associated with subclinical alloimmune inflammation, tubular injury and progression of fibrosis.
authors.affiliation: Centre for Transplant and Renal Research, Westmead Millennium Institute, University of Sydney at Westmead Hospital, Westmead, NSW, Australia.
authors.forename: D
authors.initials: D
authors.lastname: Toki
authors.forename: W
authors.initials: W
authors.lastname: Zhang
authors.forename: K L M
authors.initials: KL
authors.lastname: Hor
authors.forename: D
authors.initials: D
authors.lastname: Liuwantara
authors.forename: S I
authors.initials: SI
authors.lastname: Alexander
authors.forename: Z
authors.initials: Z
authors.lastname: Yi
authors.forename: R
authors.initials: R
authors.lastname: Sharma
authors.forename: J R
authors.initials: JR
authors.lastname: Chapman
authors.forename: B J
authors.initials: BJ
authors.lastname: Nankivell
authors.forename: B
authors.initials: B
authors.lastname: Murphy
authors.forename: P J
authors.initials: PJ
authors.lastname: O'Connell
mesh_terms: D000328:Adult; D005260:Female; D005355:Fibrosis / Q000503:physiopathology*; D006801:Humans; D016030:Kidney Transplantation; D008264:Macrophages / Q000502:physiology*; D008297:Male; D008875:Middle Aged
keywords: Clinical research/practice; fibrosis; genomics; immunobiology; kidney (allograft) function/dysfunction; kidney transplantation/nephrology; macrophage/monocyte biology; pathology/histopathology; translational research/science