15-34 Late failure of transplanted organs is caused by chronic injury to the graft.
The success of immunosuppression means that about 90% of cadaveric kidney grafts are still functioning a year after transplantation. There has, however, been little improvement in rates of long-term graft survival: the half-life for functional survival of renal allografts remains about 8 years. Although traditionally the late failure of a transplanted organ has been termed chronic rejection, it is typically difficult to determine whether the cause of chronic allograft injury involves specific immune alloreactivity, nonimmune injury, or both.
The pattern of chronic injury to transplanted organs is variable, depending on the tissue. A major component of late failure of vascularized transplanted organs is a chronic reaction called chronic allograft vasculopathy, which is a prominent cause of injury in heart and kidney allografts. This is charac-terized by concentric arteriosclerosis of graft blood vessels, which leads to hypoperfusion of the graft and its eventual fibrosis and atrophy (Fig. 15.51). Multiple mechanisms may contribute to this form of vascular injury, although the major cause is thought to be recurring, subclinical acute rejection events, whether due to the development of allospecific antibodies reactive to the vascular endothelium of the graft (so-called donor-specific antibodies), or to allograft-reactive effector T cells, or both. Some forms of immunosuppressive therapy (for example, calcineurin inhibitors such as cyclosporin) also cause vascular injury, although this is typically more limited to very small arteries and causes a different pattern of injury, referred to as arteriolar hyalinosis, that is marked by proteinaceous deposits that narrow the vascular lumen. In transplanted livers, chronic rejection is associated with loss of bile ducts, the so-called ‘vanishing bile duct syndrome,’ whereas in transplanted lungs, the major cause of late organ failure is accumulation of scar tissue in the bron-chioles, termed bronchiolitis obliterans. Alloreactive responses can occur months to years after transplantation, and may be associated with gradual loss of graft function that is hard to detect clinically. Other important causes of chronic graft dysfunction include: ischemia– reperfusion injury, which can promote sterile inflammatory signals at the time of grafting due to the restoration of blood flow after a period of poor perfusion of the organ to be transplanted; viral infections that emerge as a result of immunosuppression; and recurrence of the same disease in the allograft that destroyed the original organ. Irrespective of etiology, chronic allograft injury is typically irreversible and progressive, ultimately leading to complete failure of allograft function. 15-35 A variety of organs are transplanted routinely in clinical medicine. Three major advances have made it possible to use organ transplantation rou-tinely in the clinic. First, surgical techniques for performing organ replace-ment have advanced to the point where such surgeries are now relatively routine in most major medical centers. Second, networks of transplantation centers have been organized to procure healthy organs that become available from cadaveric donors. Third, the use of powerful immunosuppressive drugs Endothelial injury enables immune effectors to enter the wall of the artery and to in˜ict increasing damage
Fig. 15.51 Chronic rejection in the blood vessels of a transplanted kidney.