Renal transplant loss due to chronic allograft nephropathy (CAN)is widely acknowledgedas a major problem that has increased in relative importance as the incidence of early graft loss from acute rejection has declined. Studies from various centers, including the University of Minnesota, suggest that, after excluding patients dying with afunctioning graft, as many as 80%of patients who will return to dialysis do so becauseof CAN. At the present time there are no therapeutic options once theclinical manifestations of CANhave developed. Testing measures to prevent CANhave not been addressed. The overall purpose of this project is to investigate the role of the renin-angiotensin-aldosterone system (RAAS) in the development of CAN. This system plays an important role in the progression of many experimental andclinical renal diseases. Furthermore, blockade of this system with angiotensin converting enzyme inhibitors andangiotensin II receptor blockers hasyielded beneficial results in retarding injury and progression in numerous intrinsicrenal diseases. This study specifically investigates the long term benefit of the angiotensin II receptor blocker, losartan, in the prevention of cortical interstitial volume expansion (anaccuratepredictor of long term graft function) and graft loss from biopsy proven CANin a 5year, randomized, double masked, placebo controlled study of kidney transplant recipients. This clinical trial will directly test the hypothesis that blockade of the renin angiotensin aldosterone systemwill provide a substantial benefit through blood pressure lowering independent mechanisms, namely, interruption of fibrogenic pathways, anti-proteinuric actions, amelioration of hyperfiltration and possibly some immunomodulatory effects. The proposed studies will also characterize the interstitial ultrastructural compositional changesthat occur in the renal allografts with CAN,the effects of treatment on thesechanges and provide a complete description of the incidence and predictors for the development of transplant glomerulopathy. These studies will also determine the impact of angiotensin IIreceptor blockade on the rate of decline of glomerular filtration rate,as well asthe impact of glomerular size on the rate of graft loss from CAN,the incidence and the progression of post transplant proteinuria, the nature of the permselectivity defects responsible for the proteinuria andwill also explorethe association of proteinuria with graft loss from CAN. This trial will also help construct a profile for the RAAS in the transplant recipients andexplore the relationship betweentwo genes polymorphisms, ACE and TGF-b,and CAN. These studies should help to describe the natural history, nature and pathogenesis of CAN,elucidate early markers and predictors of this important disorder and, perhaps, define a safe and useful preventative strategy.
