Potential therapeutic interventions to avoid or treat chronic allograft dysfunction

Despite the significant improvements that have occurred since the introduction of CsA, long-term renal allograft survival continues to be an area of concern. Management strategies that involve the use of sirolimus offer some promise. A number of observations suggest that sirolimus may have the ability to reduce the rates or slow the progression of chronic nephropathy. First, sirolimus has been shown to inhibit growth-factor-driven proliferation of endothelial and smooth muscle cells in vitro (55, 56). Sirolimus also disrupts signal transduction by a variety of other cytokines such as EGF and PDGE This is significant because cytokine- and growth-factor-stimulated proliferation of endothelial cells, smooth muscle cells, parenchymal cells, and fibroblasts appears to underlie the development of chronic nephropathy (see Fellström, this supplement). Second, sirolimus has been demonstrated in various animal models to inhibit the arterial intimal thickening that typically follows alloimmune or mechanical injury (56-60; see Morris, this supplement). This transplant vasculopathy is a prominent feature in chronic rejection of other organ transplants. Moreover, at least 1 published study has suggested that sirolimus may be able to stabilize and possibly reverse chronic graft vascular disease (61). However, the relative doses of sirolimus used in these animal studies have been higher than those used in humans, so the relationship of these effects to the clinical setting needs to be further studied to define the relevance of these findings. Third, sirolimus, used in combination with CsA, reduces the incidence of acute rejection episodes in humans, one of the most significant predictors of shortened renal allograft survival (62, 63). Thus, an effect of sirolimus to reduce acute rejection episodes or delay their onset is expected to reduce renal allograft loss. Furthermore, clinical trials suggest that sirolimus treatment may allow dose reductions of CsA or a delay in inception of CsA therapy, which might reduce the acute and chronic nephrotoxicity associated with CsA and other CNIs. Since nephrotoxicity may promote or aggravate renal injury and appears to be common in chronic nephropathy (see Fellström and Paul, this supplement), reduced exposure to CNIs may translate into reduced rates of chronic renal allograft dysfunction. There are no currently effective therapies for chronic nephropathy, which is a common cause of late renal allograft loss. Preliminary evidence suggests that sirolimus may eventually prove useful as prophylaxis of or treatment for chronic nephropathy. Thus, sirolimus has come to be regarded as the foundation for maintenance immunosuppressive regimens.