Biology Reference
In-Depth Information
Chronic Disease in the Transplanted Allograft
Chronic rejection is a leading cause of allograft loss and in many transplant centers
is the most common reason that allograft recipients receive a second transplant
(Evans et al. 1999; Hosenpud 1999). In the case of renal allograft recipients, the
loss of the transplanted organs secondary to acute rejection has fallen dramatically
with the availability of newer immunosuppressive agents, yet the incidence of
chronic graft rejection and graft loss has remained relatively unchanged over the
last decade. This complication of allograft transplantation is of utmost importance
to recipients of cardiac and liver allografts because of the limited number of organs
available for transplantation and the need for retransplatation if chronic rejection
results in graft dysfunction and loss. A important observation in 1989 described the
increased incidence of cardiac allograft rejection in patients with HCMV infection
(Grattan et al. 1989). Subsequently, several other transplant centers reported this
clinical association and distinctive histological changes in coronary arteries to
patients with cardiac allograft rejection and HCMV infection (McDonald et al.
1989; Loebe et al. 1990; Koskinen et al. 1993; Paavonen et al. 1993). Ultimately, it
has been reported that the most common cause of cardiac allograft loss is the develop-
ment of cardiac allograft vasculopathy (CAV), a disease process most investigators
believe to be a form of allograft rejection (Hosenpud et al. 1991; Hosenpud 1999;
Valantine 2004; Mehra 2006). This disease is characterized by the progressive,
diffuse concentric narrowing of allograft vasculature with loss of distal small vessels
and by a clinical course that is relentlessly progressive. The histopathological
findings in this disease are in contrast to focal narrowing of coronary vessels in
normal individuals with atherosclerotic artery disease. Similarly, up to 10% of
hepatic allografts are lost to chronic rejection in which hepatic endothelium is
damaged and mononuclear cells infiltrate the intima. In addition, the bile duct
epithelium is damaged and intrahepatic bile ducts are lost, a histopathologic finding
that has been termed the vanishing bile duct syndrome (Hubscher et al. 1991). In
both diseases, HCMV has been implicated in the acceleration of these processes.
Similar vascular diseases are reported in renal allografts undergoing chronic rejection,
although the association between HCMV infection and glomerular disease remains
controversial (Richardson et al. 1981; Castro et al. 1983; Herrera et al. 1986).
HCMV infection has been associated with chronic renal allograft rejection and
graft dysfunction from interstitial fibrosis and loss of renal tubules (Vazquez-
Martul et al. 2004). Histologically, chronic renal rejection is defined by the degree
of tubulointerstitial fibrosis, indicating that, similar to observations in CAV in car-
diac allografts, fibrosis is the end-stage outcome of chronic renal allograft rejection
(Racusen et al. 1999; Vazquez-Martul et al. 2004; Hartmann et al. 2006). Rodent
models of chronic renal allograft rejection have been developed and infection with
rat CMV has been associated with acceleration of graft rejection in the rat model
(Lautenschlager et al. 1997; Soots et al. 1998).
As a result of the clinical association of CMV infections with chronic allograft
dysfunction, clinical trials with antiviral agents have been carried out in an attempt
to limit this posttransplant complication. Although the results are far from definitive,
