Clinically stable human renal allografts contain histological and RNA-based findings that correlate with deteriorating graft function

Background. Chronic rejection (CR) remains idiopathic, difficult to prospec tively identify, and once detected, unresponsive to increased immunosuppres sion. We hypothesized that clinically stable human renal allografts have on going evidence of injury and immune activity, and that this correlates with the worsening of allograft function characteristic of CR. Methods. The allografts of 40 stable renal allograft recipients were biopsi ed 25 years after transplantation, Biopsies were processed for histology an d RNA extraction. RNA was evaluated by semi-quantitative RT-polymerase chai n reaction for CD3 gamma mRNA (a marker of T cell receptor turnover), and m RNA from cytokine genes previously shown to be transcribed during acute rej ection tumor necrosis factor-alpha isterferon-gamma, interleukin- (IL) 1 be ta, IL-2, IL-4, IL-6, and IL-8. Clinical parameters including urine protein and glomerular filtration rate were measured the day of biopsy. Findings w ere then compared with clinical outcome to establish associations between s ubclinical inflammation and graft dysfunction. Allograft function was measu red again 2-3 years after biopsy and correlated with findings at the time o f biopsy. Results. Cytokine transcripts and histological evidence of injury were dete cted in more than two-thirds of stable grafts. The degree of the lymphocyti c in filtrate correlated with the degree of proteinuria (P=0.034) and histo logical fibrosis (P=0.005). Similarly, the degree of intragraft CD3 gamma t ranscription correlated with increasing proteinuria (P=0.043), IL-6 and IL- 8 transcripts were also correlated with evidence of graft injury. After 2 y ears, those biopsies originally found to have evidence of fibrosis, tubular atrophy, or CD3 gamma transcription had worsening graft function as determ ined by creatinine and glomerular filtration rate. Conclusions, These data demonstrate that significant injury and immune acti vity can be detected in patients who are stable on clinical grounds. Undete cted subclinical graft injury may be a cause of chronic allograft rejection .