Slowly developing renal diseases (SDRD) such as diabetic nephropathy (DN) and hypertensive nephrosclerosis constitute the large majority of disorders leading to end-stage renal disease (ESRD). These disorders are characterized by years to decades without renal functional abnormalities during which renal structural changes are developing. The earliest renal functional abnormalities [such as microalbuminuria in patients with insulin dependent diabetes mellitus (IDDM)] are often associated with already well established renal lesions that may progress independent of the initiating cause. Since the clinical manifestations of these disorders are dependent upon established structural changes, prevention of the early lesions seems a logical goal and thus a useful endpoint for clinical trials. Functional endpoints are impractical at these early stages as they would take too long to manifest. Diabetic nephropathy in IDDM patients is a useful model for such study design, since there is sufficient knowledge of the natural history of the disorder and of the important structural endpoints to allow for the statistical power calculations crucial for study design. More information regarding natural history and structural-functional relationships is needed in non-insulin dependent diabetes, hypertension, and other SDRD before intervention trials using renal structural endpoints can be developed for these important causes of ESRD.