Cold ischaemia, innate immunity and deterioration of the glomerular filtration barrier in antibody-mediated acute rejection

Èlia Ripoll, Víctor Nacher, August Vidal, Esther Herrero, Núria Bolaños, Juan Torras, Josep M. Grinyó, Jesús Ruberte, Immaculada Herrero-Fresneda

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Abstract

Background. In renal transplantation, cold ischaemia (CI) determines acute rejection through innate immunity among others. Acute rejection episodes are a risk factor for late allograft dysfunction and proteinuria. This implies some alteration of the glomerular filtration barrier (GFB). Besides its effects on acute rejection, we hypothesized that CI might somehow damage the GFB being directly responsible for late proteinuria. Methods. On rat kidney allografts suffering from antibody-mediated acute rejection with or without CI and compared with syngeneic grafts, we quantified the gene expression of innate and adaptive immune mediators and assessed the capillary glomerular basement membranes (CapBM) by immunostaining collagen-IV (ColIV). ColIV was also assessed in equivalent groups from a previous chronic study followed up for 24 weeks. Results. CI up-regulated enzymes critical in the stabilization of collagen chains, increasing ColIV deposition and thickening the CapBM. CI increased the C4d and IgG deposits within grafts, amplified innate immunity (heat shock protein 70, fibronectin, Toll-like-receptor-4 and MyD88) and synergized with alloreactivity in triggering adaptive response through CD40. Conclusion. sInitial CI increased the ColIV deposition in CapBM, damaging the GFB and being responsible for part of the proteinuria associated with late allograft dysfunction. This deterioration of the GFB is related to the early innate immunity activation and subsequent up-regulation of CD40 in acute rejected grafts. In chronic rejected allografts, thickened CapBM may be a consequence of an unresolved immuneinflammatory response worsened by CI. © The Author 2012. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.
Original languageEnglish
Pages (from-to)3296-3305
JournalNephrology Dialysis Transplantation
Volume27
Issue number8
DOIs
Publication statusPublished - 1 Aug 2012

Keywords

  • AbAR CD40
  • GFB
  • TLR4
  • cold ischaemia
  • collagen-IV

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    Ripoll, È., Nacher, V., Vidal, A., Herrero, E., Bolaños, N., Torras, J., Grinyó, J. M., Ruberte, J., & Herrero-Fresneda, I. (2012). Cold ischaemia, innate immunity and deterioration of the glomerular filtration barrier in antibody-mediated acute rejection. Nephrology Dialysis Transplantation, 27(8), 3296-3305. https://doi.org/10.1093/ndt/gfs003