Chronic renal allograft rejection is an increasing problem with few therapeutic options. Progression of many renal disease, in native kidneys, appears to proceed by several common pathways. In particular, hypertension, including intra renal hypertension, contributes, in many instances, to the decay of renal function in various intrinsic renal diseases. We propose that such pathways occur in the clinically rejecting kidney and that in particular hypertension is an important contributing pathway. Moreover, in the renin-angiotensin aldosterone system is intimately associated with progression in many renal diseases and may be so in chronic rejection. We propose to conduct two sets of studies to assess the role of hemodynamic manipulations by employing angiotensin II receptor blockade in patients with biopsy proven chronic rejection. First, we propose to study the short-term hemodynamic and glomerular permselective response to angiotensin II blockade in a small number of patients. Elements of the circulating renin-angiotensin systems will be defined in these patients. In addition, the genotype of the patients and their donor kidneys, with respect to the angiotensin converting enzyme ACE polymorphism, will be defined. In the second set of studies, a long-term test of the efficacy of angiotensin II receptor blockade on slowing the progression of decay in renal function will be undertaken in patients with biopsy proven chronic rejection. In these latter studies, the relation to ACE polymorphisms of the donor and the recipient will be surveyed as well. We hypothesize that the interruption of the renin- angiotensin system by AT1 receptor blocker will reduce glomerular permselective defects in the initial studies and also will reduce aldosterone levels. In the second studies, we hypothesize that this same pharmacologic manipulation will slow the decay in renal function. Together, these studies should provide both a mechanistic understanding of renin-angiotensin system and chronic rejection and also test a therapy that has been remarkable effective in the links between the native kidney disease but insufficiently examined in the setting of chronic rejection.
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