Computerized histomorphometric assessment of protocol renal transplant biopsy specimens for surrogate markers of chronic rejection

Background. Chronic transplant rejection has emerged as the commonest cause of long-term renal allograft failure, and early identification of those gr afts at risk could allow the targeting of specific therapies aimed at delay ing this process. This study explores the usefulness of quantitative immuno histochemistry in defining biopsy-based surrogate markers of allograft dama ge. Methods. A consecutive series of 52 renal transplant recipients immunosuppr essed with cyclosporine were studied. Needle core transplant biopsies were performed at 1, 3, and 6 months postoperatively, Immunostaining for collage n III, and smooth muscle actin, tenascin, and infiltrating leukocytes was p erformed using an indirect immunoperoxidase technique. The interstitial are a stained (%) was measured using a semiautomatic image analysis system. The results were related to glomerular filtration rates (GFR) measured at 6, 1 2, and 24 months after transplantation using rank correlation coefficients. Results. The area fraction of immunostained collagen III correlated with 6- month GFR (r=-0.42, P=0.005) and was predictive of 12 month GFR (r=-0.32, P =0.03). An area fraction of immunostained collagen In: of >40% at 6 months was associated with a significantly lower GFR at 24 months, compared with a percentage area of less than or equal to 40% (31+/-4 versus 45+/-4 ml/min/ 1.73 m(2), P=0.01). Furthermore, a collagen III of >40% at 6 months identif ied patients who were at risk of progressive deterioration in graft functio n. Conclusions. Grafts with poorer long-term function can be predicted using 6 -month protocol biopsy specimens immunostained for collagen III. This shoul d prove to be a useful ad interim surrogate marker of allograft damage in s tudies addressing the effects of new immunosuppressive agents on the develo pment of chronic rejection.