Alternatively activated macrophages in the pathogenesis of chronic kidney allograft injury

Pediatr Nephrol. 2015 Jun;30(6):1007-17. doi: 10.1007/s00467-014-3023-0. Epub 2014 Dec 9.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Allografts
  • Antigens, CD / metabolism
  • Antigens, Differentiation, Myelomonocytic / metabolism
  • Atrophy
  • Biomarkers / metabolism
  • Biopsy
  • Cells, Cultured
  • Child
  • Dexamethasone / pharmacology
  • Female
  • Fibrosis
  • Humans
  • Immunohistochemistry
  • Immunosuppressive Agents / therapeutic use
  • Kidney / immunology*
  • Kidney / metabolism
  • Kidney / pathology
  • Kidney Transplantation / adverse effects*
  • Macrophage Activation* / drug effects
  • Macrophages / drug effects
  • Macrophages / immunology*
  • Macrophages / metabolism
  • Male
  • Phenotype
  • Receptors, Cell Surface / metabolism
  • Renal Insufficiency, Chronic / diagnosis
  • Renal Insufficiency, Chronic / immunology*
  • Renal Insufficiency, Chronic / metabolism
  • Retrospective Studies
  • Time Factors
  • Treatment Outcome
  • Young Adult

Substances

  • Antigens, CD
  • Antigens, Differentiation, Myelomonocytic
  • Biomarkers
  • CD163 antigen
  • CD68 antigen, human
  • Immunosuppressive Agents
  • Receptors, Cell Surface
  • Dexamethasone