Recent developments in kidney transplantation--a critical assessment

Abstract

Rapid advances have been made in decreasing acute rejection rates and improving short-term graft survival in kidney transplant recipients. Whether these advances ultimately will lead to a commensurate improvement in long-term survival is not yet known. In recent years, greater attention has been placed on defining the precise etiology of graft loss, determining how far and with what agents we can minimize immunosuppression, and delineating the nature of both T-cell-mediated as well as antibody-mediated rejection. In addition, with the growing disparity of available organs and patients in need of a transplant, greater attention has been placed on optimizing allocation. In this minireview, we will focus on developments over the last couple of years, paying particular attention to insights, studies and observations that may attempt to elucidate some of these open questions.

Figures

Figure 1. Diagram of postulated events leading to graft damage during kidney transplantation

At engraftment, ischemia-reperfusion injury occurs with activation of Toll-like receptors of the innate immune system and subsequent cytokine release. These pro-inflammatory mediators induce tubular epithelial cells to attract neutrophils and T cells by production of chemokines. Innate immune system activation induces maturation of dendritic cells, leading the transition to the adaptive or antigen-specific phase of transplantation immunity. Dendritic cells activate CD4+ T helper cells through presentation of alloantigen in the context of major histocompatibility complex (MHC) molecules and ligation of appropriate T cell surface costimulatory molecules. After activation, CD4+ T helper cells induce further T cell proliferation, the production of alloantibodies from B cells, activation of macrophages, and differentiation of naïve CD8+ T cells into cytotoxic T lymphocytes. Mononuclear cells, especially cytotoxic T lymphocytes, enter between tubular cells and induce apoptosis by releasing cytolytic granules containing perforin and granzyme or by exposure to FasL on the T cell surface. Tubular cells chronically exposed to transforming growth factor β (TGFβ) may undergo epithelial-mesenchymal transition, an aberrant phenotype evidenced by epithelial cell expression of α-smooth muscle actin and loss of E-cadherin expression. These cells then may migrate to the interstitium and contribute to fibrosis. Both T cells and antibody likely recognize alloantigen on target endothelium. While T cells may cause cytotoxicity directly, alloantibody is usually directed against the MHC molecule, followed by activation of complement. Antigen recognition leads to endothelial secretion of factors that activate the immune and coagulation systems. These activities promote rejection and chronic changes of the endothelium and underlying smooth muscle layer, resulting in the characteristic histopathologic findings of transplant arteriopathy. Alloantigen-independent factors also contribute to tubular and endothelial cell damage.