Associations Between Cyclosporine Therapy and Interstitial Fibrosis in Renal Allograft Biopsies1,2

A retrospective masked study of 120 consecutive renal transplant biopsies was performed to evaluate the potential associations of cyclosporine (CsA) therapy and other factors on the degree and progression of interstitial fibrosis (IF). Allograft biopsies were obtained from patients receiving CsA (CsA+; n = 59) and not receiving CsA (CsA-; n = 46); pretransplant donor biopsies were used as controls (n = 15). IF was evaluated by histologic grading (0-3+) as well as by quantitative morphometric measurements of Masson's trichrome stain positive material. Other biopsy measurements included the pattern of IF (focal, diffuse; graded 0-3+), and tubular epithelial cell reactivity, necrosis, and vacuolization (each graded 0-3+). Potential confounding variables were also considered, including time interval between transplant and biopsy; creatinine levels at the time of biopsy, 2 weeks and 10 weeks postbiopsy, and the last stable (baseline) creatinine prior to biopsy; recipient age, clinical evidence of rejection, and duration of rejection reactions; transplant number; and postbiopsy graft outcome. No significant difference in any measure of IF was found between all CsA+ vs. CsA- patients, although both groups showed a highly significant increase in IF compared with control pretransplant donor biopsies. Similarly, no differences in tubular changes or the patterns of fibrosis were identified between CsA groups. However, since the mean interval between transplant and biopsy was significantly (P less than 0.04) greater for the CsA- group, measures of creatinine and IF were normalized by the time interval between transplant and biopsy, and were stratified into biopsies obtained before or after 6 months posttransplant. By this stratification and normalization, both the baseline creatinine (P less than 0.01) and the degree of IF as measured by morphometry (P less than 0.04) were significantly higher in the CsA+ group, but only for biopsies obtained greater than 6 months posttransplant. Evaluation of biopsies less than 6 months posttransplant normalized by interval showed no suggested differences between the CsA+ and CsA- groups in terms of creatinine levels or any measure of IF. Tubular epithelial changes were not different in the CsA+ and CsA- groups within either period. These results suggest that CsA therapy is not associated with increased interstitial fibrosis in renal allografts prior to 6 months posttransplant, after which there is a significant increase in fibrosis relative to patients not receiving CsA.