Relationships among the histologic pattern, intensity, and phenotypes of T cells infiltrating renal allografts

The evaluation of renal allograft rejection by routine histologic evaluation of transplant biopsy is often a diagnostic problem. Advances in monoclonal antibody and immunohistochemical technology have led to their application in characterizing the phenotype of peripheral blood lymphocytes in transplant recipients, as well as the infiltrating lymphocytes in renal biopsy specimens (both tissue and aspiration cytology samples). Recent reports suggest that the relative number of infiltrating T cells and the T cell phenotypic subset ratio may have some association with graft survival. However, most allograft biopsy studies have not examined the relationship of the intensity and phenotype of T cells to the histologic pattern of infiltration, while fine-needle aspiration cytology (FNAC) and peripheral blood analysis do not allow for this assessment. To examine the association of histologic pattern with the intensity and phenotype of T cell infiltrates, immunoperoxidase labeling of cells using monoclonal antibodies was evaluated in 66 renal allograft biopsies performed because of clinical suspicion of rejection. Our findings indicate that the ratio of T helper-inducer (Leu 3) cells to T suppressor-cytotoxic (Leu 2) cells is significantly lower in the pattern of diffuse renal cortex infiltration (cortical diffuse [CD] pattern) when compared with other histologic patterns (cortical aggregate or perivascular), regardless of the overall intensity of the T cell infiltrate. A significant difference in T cell phenotypes was also found among different histologic patterns as expressed by Leu 3/Leu 2 ratios and by the number of Leu 2 cells. An increase in the overall intensity of T cell infiltrate was not associated with significant changes in T cell phenotype seen in any pattern, but an increase in the intensity of the cortical diffuse T cell infiltrate was associated with a significant decrease in the Leu 3/Leu 2 ratio (P less than 0.04), which was due to an increase in the population of Leu 2 cells (P less than 0.002). Interestingly, increases in the intensity of either cortical aggregate or perivascular T cell infiltrates were associated with significant increases in both Leu 3 and Leu 2 cells, as well as a tendency towards higher Leu 3/Leu 2 ratios. These findings indicate that evaluation of T cell infiltrates by phenotype in renal allografts is dependent upon the pattern as well as the intensity of infiltrate.     

Associations between cyclosporine therapy and interstitial fibrosis in renal allograft biopsies

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.