Chronic rejection is dominated by vascular changes, often with intimal thickening and vascular occlusion (
Fig. 5.34B ). Chronically rejecting kidney grafts show glomerulopathy, with duplication of the basement membrane, likely secondary to chronic endothelial injury (
Fig. 5.34C ) and peritubular capillaritis with multilayering of peritubular capillary basement membranes. Interstitial fibrosis and tubular atrophy with loss of renal parenchyma may occur secondary to the vascular lesions (
Fig. 5.34D ). Interstitial mononuclear cell infiltrates are typically sparse.
Methods of Increasing Graft Survival
Because HLA molecules are the major targets in transplant rejection, better matching of the donor and the recipient improves graft survival. HLA matching is more beneficial for living related kidney transplants than for other kinds of transplants, and survival improves with increasing number of loci matched. However, as drugs for immunosuppression have improved, HLA matching is no longer done for heart, lung, liver, and islet transplantation; in such instances, the recipient often needs a transplant urgently and other considerations, such as anatomic compatibility, are of greater importance.
Immunosuppression of the recipient is a necessity in all organ transplantation, except in the case of identical twins. At present, drugs such as cyclosporine, the related FK506, mofetil mycophenolate (MMF), rapamycin, azathioprine, corticosteroids, anti-thymocyte globulin, and monoclonal antibodies (e.g., monoclonal anti-CD3) are used. Cyclosporine and FK506 suppress T cell–mediated immunity by inhibiting transcription of cytokine genes, in particular, the gene for IL-2. Although immunosuppression has made transplantation of many organs feasible, it has its own problems. Suppression of the immune system results in increased susceptibility to opportunistic fungal, viral, and other infections. Reactivation of latent viruses, such as cytomegalovirus (CMV) and polyoma virus, are frequent complications. Immunosuppressed patients also are at increased risk for developing virus-induced tumors, such as Epstein-Barr virus (EBV)–induced lymphomas and human papillomavirus (HPV)–induced squamous cell carcinomas. To circumvent the untoward effects of immunosuppression, much effort is being devoted to induce donor-specific tolerance in host T cells. One strategy is to prevent host T cells from receiving costimulatory signals from donor DCs during the initial phase of sensitization. This can be accomplished by administration of agents that block the interaction of the B7 molecules on the DCs of the graft and the CD28 receptor on host T cells, which, by interrupting the second signal for T cell activation, induces either T cell apoptosis or anergy. Other approaches include injecting into recipients regulatory T cells enriched for cells specific for donor alloantigens; these trials are in their infancy.
Fig. 5.33 Acuteantibody-mediated(humoral)rejection.(A)Graftdamagecausedbyantibodydepositioninvessels.(B)Lightmicrographshowinginflammation(capillaritis)inperitubularcapillaries(arrows) inakidneygraft.(C)ImmunoperoxidasestainshowsC4ddepositioninperitubularcapillariesandaglomerulus.(Courtesy of Dr. Zoltan Laszik, Department of Pathology, University of California, San Francisco, California.)