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Abstract: Background: The aims of this prospective study were to determine the prevalence of clinically silent rejection changes and of nephrotoxicity of calcineurin inhibitors among repeated protocol biopsies of transplanted kidneys and to assess their impacts on chronic graft function and damage at the end of 1 year. Methods: We performed 424 protocol biopsies among 158 patients over the first year after transplantation. We monitored parameters of graft function and progression of chronic changes among subjects with clinically silent rejection or toxicity for comparison with a control cohort showing normal histological findings. The results of statistical tests were considered to be significant at a level of P < .05. Results: At 3 weeks, 3 months, and 12 months, there were normal histological findings among 30 (19%), 21 (14.8%), and 14 (11.3%) patients, respectively; subclinical rejection changes occurred in 49 (31%), 36 (25.4%), and 20 (16.2%) grafts, respectively. At the third week, histological signs of toxicity occurred in 33 (20.9%) patients with significant persistence despite reductions in calcineurin inhibitor doses. At the end of 1 year of follow-up, both subclinical and toxic changes produced similar increases in chronic changes as quantified by the Banff score and were significantly different from the control group (P < .05). Serum creatinine concentrations and glomerular filtration rates did not accurately reflect the degree of graft damage in the early posttransplantation period. Conclusions: Subclinical rejection and toxic changes among a significant proportion of grafts are associated with progression of chronic changes already over the first year following transplantation. Hence they represent independent risk factors for the development of irreversible graft damage. Protocol biopsy seems to be an important method to monitor immunosuppressive therapy. [Copyright &y& Elsevier]