The past 15 years has seen a marked improvement in early graft survival. However, while later graft survival has not kept pace with the remarkable gains made in early (1 year) graft survival. The most common cause of late allograft loss is due to the process of chronic allograft nephropathy (formerly referred to as chronic rejection). Chronic allograft nephropathy can be defined as a chronic deterioration in renal function which cannot be explained by other known processes (e.g., acute rejection, recurrent disease) which is also accompanied by characteristic histologic lesions of interstitial fibrosis, vasculopathy, and glomerular sclerosis. The diagnosis of chronic allograft nephropathy (CAN) is therefore one of exclusion and it is important to search critically for treatable causes of the renal deterioration (particularly if the histologic lesions are nonspecific).
The etiology of chronic allograft nephropathy has to this date not been fully elucidated. Both antigen dependent and antigen independent processes may be important.
In rat cardiac allograft models, both class I and class II MHC mismatches are associated with a mononuclear cell infiltrate which is accompanied by vascular thickening and arteriosclerotic lesions common in clinical chronic rejection in hearts and CAN in kidneys. This effect may be accentuated by acute nonspecific injury as it has been demonstrated that ischemic injury may upregulate class II
MHC molecules important in the allo/inflammatory response. Several animal models have demonstrated a humoral component to the lesion of chronic rejection. Rats tolerant to MHC class I allopeptides show little acute cellular rejection, however do develop antidonor antibodies. These antidonor antibodies, particularly IyGIb closely correlate to the development of vascular lesions in the allograft. Another line of evidence implicating humoral response is that of xenografts, where a lesion similar to chronic rejection develops, which seems to correlate to antidonor antibody and b-lymphocytes in the graft. Much recent interest has centered on the role of transforming growth factor p (TGF-p) and chronic allograft nephropathy. Suthanthiran and colleagues have demonstrated that intragraft TGF-p1 mRNA correlates with the presence of chronic allograft nephropathy in clinical specimens. It is also interesting to note that the fibrotic lesion produced by CsA in the salt depleted Sprague Dawley rat may be secondary to angiotension II mediated TGF-p production and that at least experimentally, maneuvers that decrease AII (e.g., ACE inhibitors) seem to decrease CsA mediated fibrosis in this animal model.
Ischemia and reperfusion injury seems to produce a multitude of changes conducive to end organ damage. It is widely appreciated that ischemia is capable of producing a number of cytotoxic leukocyte mediators which can damage endothelium. In addition, ischemic injury can upregulate a number of cell surface molecules, e.g., adhesion molecules ICAM, VCAM, LFA-1, MHC-1, and II molecules which may contribute to further tissue injury. Halloran has proposed an alternative view of the process whereby through a multiplicity of injuries a state of premature aging occurs and leads to the premature development of fibrosis and sclerosis.
Risk Factors for Chronic Allograft Nephropathy A number of risk factors have been identified to be related to the development of CAN and a decrease in long-term graft survival. It appears that a decrease in the number of donor nephrons relative to recipient body mass may be a correlate to decreased long-term function. The pathophysiology of this relationship may be related to the hyperfiltration theory of renal injury as proposed originally by Brenner. Studies from Minnesota have demonstrated a relationship of acute rejection and the subsequent development of CAN and shortened long-term graft survival. A large retrospective study demonstrated a correlation of CAN and low CsA (Sandimmune formulation) dosage (< 4 mg/kg/day). A similar relationship of low Sandimmune dose and CAN was also demonstrated in a separate singlecenter study. A study from Houston demonstrated a correlation of variability of cyclosporine levels and chronic rejection in their population. Several studies have demonstrated a relationship of the severity of an acute rejection episode and the subsequent development of chronic allograft nephropathy. Reinsmoen has studied the effect of donor hyporesponsiveness in MLC to donor antigen and has shown a correlation of hyporesponsiveness and a decrease in chronic rejection.15 In addition, Kerman has demonstrated an increase in donor anti-HLA antibodies in patients who develop CAN as opposed to those who follow a more benign clinical course.
As can be seen the issue of chronic allograft nephropathy is filled with much uncertainty and remains one of the great areas of future research interest.
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