Objective This study examined antigen-independent factors in the pathogenesis of chronic rejection of organ transplants. Summary Background Data In addition to alloantigen-dependent events, antigen-independent factors can influence chronic rejection of organ allografts. Initial injury, including early ischemia and acute rejection, may contribute. Methods Kidney isografts were transplanted orthotopically into bilaterally nephrectomized rat recipients and studied functionally, morphologically and immunohistologically, at serial intervals up to 72 weeks after transplantation. Controls included chronically rejecting kidney allografts using a well-established model, non-nephrectomized and uninephrectomized animals with a native kidney that had undergone initial ischemia and uninephrectomized rats whose remaining kidney had been manipulated operatively. Results Allograft recipients developed progressive proteinuria after 12 weeks, with gradual renal failure ultimately leading to death. At the same time. morphologic changes, including progressive arteriosclerosis and glomerulosclerosis, tubular atrophy, and interstitial fibrosis, developed. Immunohistologically, macrophages infiltrated glomeruli during this period and cytokines became upregulated. Comparable changes occurred in isografts, but later, beginning after week 24 and progressing thereafter. The single ischemic kidney in uninephrectomized controls also developed the same lesions; no comparable changes were noted in other control kidneys. Conclusions Antigen-independent functional and morphologic changes occur in long-term kidney isografts that resemble those appearing considerably earlier in allografts that reject chronically. initial injury and extent of functioning renal mass may be important factors for such late changes.
