title: 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.
authors.affiliation: Department of Pediatrics, Niigata University Medical and Dental Hospital, Asahimachi-dori, 951-8510, Niiagta, Japan, ikezumi@med.niigata-u.ac.jp.
authors.forename: Yohei
authors.initials: Y
authors.lastname: Ikezumi
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Suzuki
authors.forename: Takeshi
authors.initials: T
authors.lastname: Yamada
authors.forename: Hiroya
authors.initials: H
authors.lastname: Hasegawa
authors.forename: Utako
authors.initials: U
authors.lastname: Kaneko
authors.forename: Masanori
authors.initials: M
authors.lastname: Hara
authors.forename: Toshio
authors.initials: T
authors.lastname: Yanagihara
authors.forename: David J
authors.initials: DJ
authors.lastname: Nikolic-Paterson
authors.forename: Akihiko
authors.initials: A
authors.lastname: Saitoh
mesh_terms: D000293:Adolescent; D000328:Adult; D064591:Allografts; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D001284:Atrophy; D015415:Biomarkers / Q000378:metabolism; D001706:Biopsy; D002478:Cells, Cultured; D002648:Child; D003907:Dexamethasone / Q000494:pharmacology; D005260:Female; D005355:Fibrosis; D006801:Humans; D007150:Immunohistochemistry; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D007668:Kidney / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D016030:Kidney Transplantation / Q000009:adverse effects*; D008262:Macrophage Activation / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D008297:Male; D010641:Phenotype; D011956:Receptors, Cell Surface / Q000378:metabolism; D051436:Renal Insufficiency, Chronic / Q000175:diagnosis / Q000276:immunology* / Q000378:metabolism; D012189:Retrospective Studies; D013997:Time Factors; D016896:Treatment Outcome; D055815:Young Adult; D000098902:CD163 Antigen; D000097382:CD68 Molecule
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D015415:Biomarkers; D003907:Dexamethasone; D007166:Immunosuppressive Agents; D011956:Receptors, Cell Surface; D000098902:CD163 Antigen; C067980:CD68 antigen, human; D000097382:CD68 Molecule