title: Cold ischaemia, innate immunity and deterioration of the glomerular filtration barrier in antibody-mediated acute rejection.
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.
  
  
  CONCLUSIONS
  Initial 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 immune-inflammatory response worsened by CI.
authors.affiliation: Experimental Renal Transplant, Laboratory of Experimental Nephrology, Bellvitge Biomedical Research Institute, University Hospital of Bellvitge (IDIBELL-HUB), L’Hospitalet, Barcelona, Spain.
authors.forename: Èlia
authors.initials: È
authors.lastname: Ripoll
authors.forename: Víctor
authors.initials: V
authors.lastname: Nacher
authors.forename: August
authors.initials: A
authors.lastname: Vidal
authors.forename: Esther
authors.initials: E
authors.lastname: Herrero
authors.forename: Núria
authors.initials: N
authors.lastname: Bolaños
authors.forename: Juan
authors.initials: J
authors.lastname: Torras
authors.forename: Josep M
authors.initials: JM
authors.lastname: Grinyó
authors.forename: Jesús
authors.initials: J
authors.lastname: Ruberte
authors.forename: Immaculada
authors.initials: I
authors.lastname: Herrero-Fresneda
mesh_terms: D000208:Acute Disease; D056704:Adaptive Immunity; D000818:Animals; D050377:Cold Ischemia / Q000009:adverse effects*; D024141:Collagen Type IV / Q000378:metabolism; D004195:Disease Models, Animal; D015870:Gene Expression; D060730:Glomerular Filtration Barrier / Q000473:pathology / Q000503:physiopathology; D006084:Graft Rejection / Q000209:etiology* / Q000276:immunology / Q000473:pathology / Q000503:physiopathology; D007113:Immunity, Innate; D007518:Isoantibodies / Q000378:metabolism; D016030:Kidney Transplantation / Q000009:adverse effects* / Q000276:immunology / Q000473:pathology / Q000502:physiology; D008297:Male; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics; D051381:Rats; D011914:Rats, Inbred BN; D017208:Rats, Wistar; D051197:Toll-Like Receptor 4 / Q000235:genetics; D014184:Transplantation, Homologous; D014185:Transplantation, Isogeneic
chemical_list: D024141:Collagen Type IV; D007518:Isoantibodies; C507781:Myd88 protein, rat; D053594:Myeloid Differentiation Factor 88; C495347:Tlr4 protein, rat; D051197:Toll-Like Receptor 4