THE CONTRIBUTION OF REDUCED FUNCTIONING MASS TO CHRONIC KIDNEY ALLOGRAFT DYSFUNCTION IN RATS

Chronic renal allograft dysfunction may become manifest months or year s after transplantation by progressive functional deterioration associ ated with morphological changes that include vascular obliteration, gl omerular sclerosis, tubular atrophy, and interstitial fibrosis. Two hy potheses have evolved to explain the etiology of this process, usually described as ''chronic rejection:'' first, that it is primarily an an tigen-dependent phenomenon influenced by continuing host alloresponsiv eness; second, that nonimmunological, alloantigen-independent factors contribute to the progressive changes. Using an established model of c hronic rejection of kidney transplants in rats in which the lesions pr ogress relentlessly over time, we have determined the long-term effect s of superimposing renal mass reduction on the indices of progressive allograft injury. Increasing proteinuria, a reproducible index of kidn ey graft dysfunction, developed after 12 weeks in all recipients of in tact allografts, but was accelerated in kidneys with reduced mass, reg ardless of whether the organ was allogeneic or isogeneic. The coincide nt infiltration of macrophages and expression of cytokines and growth factors were associated with the development of glomerular sclerosis a nd interstitial fibrosis; such functional and morphological alteration s occurred in an accelerated manner in all reduced-mass kidney allogra fts and isografts. Conversely, intact allografts in recipients also be aring a retained native kidney never manifested any chronic changes th roughout the entire follow-up period. These findings emphasize the rol e of alloantigen-independent factors, particularly reduced renal mass, in the multi-factorial etiology of ''chronic rejection'' of kidney tr ansplants.