Acute kidney graft rejection morphology and immunology

Human kidney allo-transplantation is a successful treatment for end-stage renal failure. The main complication is acute rejection. Although much information has been accumulated on the genetic factors, the clinical and morphological features and the immunological mechanisms involved in acute rejection much remains to be learned. Histological evaluation of needle biopsies is considered one of the most valuable tools in monitoring the transplant. However, very few parameters specific for acute rejection exist and the histological evaluation is complicated by a limited knowledge of the morphology and immunology in well-functioning allografts. The study was undertaken to enlighten the morphological and immunological alterations in the renal allotransplant by biopsiing patients consecutively before and after transplantation. Special emphasis was by immunohistochemistry put on activated cellular infiltrates and adhesion molecules. Studies with cultured human tubular cells were performed to obtain information on mechanisms involved in the regulation of MHC molecules and the intercellular adhesion molecule-1 (ICAM-1). In situ hybridization formats were developed in order to investigate donor-recipient traffic of cellular components and to evaluate the possible influence of cytomegalovirus-infection. Finally, renal changes induced by cyclosporine was sought in a group of patients with chronic uveitis receiving long-term cyclosporine treatment. Arteritis and endocapillary glomerulitis was found to be the only reliable parameters specific to acute rejection. All other morphological parameters showed a continuum of changes from nonrejecting to rejecting patients. Thus, tubulitis and dense mononuclear cellular infiltrates were strongly indicative of acute rejection. Immunohistochemically, strong expression of ICAM-1, vascular cellular adhesion molecule-1 and MHC class II antigens on tubular and endothelial cells along with interleukin-2-receptor bearing infiltrates of T-lymphocytes and significant presence of macrophages were highly correlated with acute rejection. Contrarily, the phenotype of T-lymphocytes including the ratio of CD4+/CD8(+)-lymphocytes, the presence of B-cells or deposits of immunoglobulins and complement factors showed no significant correlation in patients with acute rejection. The in vitro studies confirmed that cytokines such as interleukin-1, tumor necrosis factor and gamma-interferon produced by inflammatory cells are involved in the regulation of ICAM-1 and MHC class II antigens on likely target cells such as tubular epithelial cells. Renal CMV-infection was rare. CMV was not found to induce any changes specifically associated with acute or chronic rejection. Cyclosporine induced tubular atrophy, interstitial fibrosis, glomerulosclerosis and hyaline arteriolar degeneration in kidneys from long-term treated uveitis patients but not in renal transplanted patients. Conclusively, the study confirms the value of pre- and postoperative renal biopsies for the monitoring of renal transplantation. It also stresses the importance of the implementation of molecular biological techniques to obtain more information on the immunological and inflammatory processes involved in acute rejection.