The main reason for renal transplant loss is death with function, mostly of cardiovascular reasons, followed by chronic allograft rejection (allograft arteriosclerosis). Both of these conditions are manifestations of vascular fibroproliferative disease, accelerated in the recipient and induced, as a consequence of injury, in the transplant.
Vascular fibroproliferative disease develops slowly and clinical end-points are reached only 5-10 years post transplantation. In order to design clinical studies for the prevention of chronic rejection, surrogate end-points predicting the clinical endpoint are to be developed. It has been shown on numerous single center studies that allograft histology deteriorates faster than allograft function and that that one-year histological index, such as Chronic Allograft Damage Index (CADI), predicts late clinical graft outcome. Recently a blided multicenter study, based on 740 protocol core needle biopsies in 29 centers in NA, Europe and Australia, has confirmed the results of the single center studies.
Also pharmacological therapies for the prevention of chronic rejection are now available and additional protocols will be developed shortly. In a recent blinded multicenter study we demonstrated that leave-out of cyclosporine on triple therapy with sirolimus and steroids, at three months post transplantation, prevents the progression of the CADI-index and, concomitantly, improves the GFR (Mota et al., 2004). The three month time point may, however, be too late for efficient intervention on single patient level, but predictive diagnostic methods to identify patient at risk for chronic rejection are to be designed. One posibility may be biopsy genomics. We have scanned in baboons 40,000 cDNA clones and identified 1600 regulated genes which, at an early time point after vascular injury, predict late generation of late vascular fibroproliferative disease. If analogical expession signatures are seen in allograft biopsy at early time points, for example at one month post transplantation, these signatures may provide the means to identify those patients which need the implementation of proper vasculoprotective therapies.
Acknowledgements: This study was financed by grants from the Sigrid Juselius Foundation, the Academy of Finland and the research funds of the Helsinki University Central Hospital.