EVOLUTION OF GLOMERULAR-BASEMENT-MEMBRANE CHANGES IN CHRONIC REJECTION

We have investigated the evolution of chronic glomerular changes in th e absence of the recurrence of original disease in an experimental rat model of chronic renal allograft rejection. Using serial graft needle biopsies and serum creatinine levels, we were able to focus on early glomerular changes that are associated with good graft function. The r ecipient rats were divided into 5 groups, 2 with allogeneic (DA to WF) transplants and 3 with syngeneic (DA to DA) transplants. In the first 2 allogeneic groups, one group received cyclosporine (CsA) for 2 week s (n=7) and the other received CsA for 12 weeks (n=5). In the 2-week t reatment group, all allografts developed chronic rejection, compared w ith none in the la-week group. Syngeneic controls received CsA for 2 ( n=3) and 12 weeks (n=3), or no immunosuppression (n=2) in order to exc lude the effects of CsA. The first detectable ultrastructural event wa s slight deposition of electron lucent material in the glomerular base ment membrane, Contrary to previous morphological studies. the initial deposition was not subendothelial, but was within the lamina densa it self. Examination of allogeneic grafts with good graft function and sy ngeneic grafts showed glomerular alterations that were similar to the early changes preceding chronic rejection. The intensity of changes in optimally immunosuppressed allografts was mild, and they were arreste d early in the evolving stage of glomerular basement membrane changes. In the suboptimally immunosuppressed allografts with chronic rejectio n, the glomerular basement membrane changes became more pronounced and extensive in subsequent biopsies. Thus, all recipients in different g roups showed similar glomerular alterations, but to different intensit ies. These results suggest a common pathogenetic mechanism which might be endothelial damage. In chronic rejection, the endothelial damage m ight be immunologically mediated by rejection episodes and progressive , whereas in syngeneic grafts and in allografts without chronic reject ion, perioperative trauma, ischemia, and graft reperfusion may be resp onsible for the self-limiting glomerular changes.