title: Chronic rejection of rat renal allograft. I. Histological differentiation between chronic rejection and cyclosporin nephrotoxicity.
abstract: Chronic allograft rejection is both a clinical and a histopathological diagnosis. Until recently, the histological definition of chronic renal allograft rejection was based on clinical diagnostic biopsies, where the evidence was partially obscured by recurrence of the original renal disease, and/or by administration of immunosuppressive drugs. In this communication, we present an experimental rat model for chronic renal allograft rejection, devoid of recurrence of the original disease. By comparing allografts to similarly immunosuppressed syngeneic transplants, we define which histological features should be attributed to chronic rejection and which to cyclosporin nephrotoxicity. Rat renal transplants were performed from DA (Ag-B4, RT1av1) to WF strain (Ag-B2, RT1u) or, for control, to DA strain, and immunosuppressed for 2 or 3 weeks with cyclosporin using a variety of different dosages. The animals were monitored weekly for serum creatinine levels and for blood cyclosporin concentrations, and core needle biopsies were performed on the grafts at regular intervals. At 3 months post-transplantation the animals were sacrificed and a complete histopathological evaluation was performed. Thirty-one histological variables were scored blindly by two investigators and separately for the graft interstitium, glomeruli, tubuli, and the graft vasculature. The following histological alterations were significantly more prominent in allografts than in similarly immunosuppressed syngeneic transplants: the intensity of interstitial inflammation, particularly the degree of pyroninophilia within the inflammatory cell population; the extent of glomerular mesangial matrix increase, basement membrane thickening, and glomerular sclerosis; the increase in the vascular intimal thickness affecting in particular the first and second order branches of the renal artery; and the obliteration of the graft vasculature. These alterations were considered as being primarily due to chronic rejection. In contrast, the extent of interstitial fibrosis and the extent of tubular changes, including tubular epithelial vacuolation, epithelial atrophy, and tubular basement membrane changes, were not significantly different in the allografts as compared to the syngeneic controls. These alterations were attributed primarily to cyclosporin nephrotoxicity. Serial monitoring of the grafts by needle biopsies clarified the sequence of events in the development of the chronic alterations in the transplant. The first event, as expected, was tubulointerstitial pyroninophilic inflammation, resembling that of acute episodes of rejection. This was significantly stronger and appeared earlier in allografts immunosuppressed for 2 rather than for 3 weeks. Vascular alterations developed next. The last to develop were the glomerular lesions.
authors.affiliation: Department of Surgery, Gazi University School of Medicine, Ankara, Turkey.
authors.forename: S
authors.initials: S
authors.lastname: Yilmaz
authors.forename: E
authors.initials: E
authors.lastname: Taskinen
authors.forename: T
authors.initials: T
authors.lastname: Paavonen
authors.forename: A
authors.initials: A
authors.lastname: Mennander
authors.forename: P
authors.initials: P
authors.lastname: Häyry
mesh_terms: D000818:Animals; D003404:Creatinine / Q000097:blood; D016572:Cyclosporine / Q000633:toxicity*; D003937:Diagnosis, Differential; D006084:Graft Rejection; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D016030:Kidney Transplantation / Q000009:adverse effects / Q000276:immunology / Q000473:pathology*; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D011920:Rats, Inbred WF; D013997:Time Factors
chemical_list: D016572:Cyclosporine; D003404:Creatinine