Prevention strategies for end stage renal disease are essential, however, environmental nephrotoxicants are seldom considered. We are investigating a broad set of causes of renal function decline, including lead and cadmium dose, blood pressure, diabetes, and age, in a longitudinal study of current and former Korean lead workers and controls. This cohort had three annual evaluations from 1997-2001 and is currently undergoing the fourth evaluation (first of three in the current competing continuation grant (NIEHS 2 R01 ES07198)). We are enrolling 610 participants from the original grant and 200 new current or former lead workers over age 40 years to enrich our population with workers at greater risk for renal function decline. Study subjects have a wide range of lead dose measures and renal outcome data. Analysis to date has identified two potential mechanisms for the adverse renal effects of lead: 1) associations between higher lead levels and worse renal function in older lead workers may be mediated by uric acid; and 2) inverse associations (higher lead dose with higher creatinine clearances) suggest hyperfiltration may be a factor in younger lead workers and those with the ALAD variant allele. Recent research indicates that the adverse impact of lead on renal function may be reduced with chelation, even at lead body burdens previously considered normal. Information on mechanisms for lead-related nephrotoxicity would be extremely useful in targeting therapy. Thus, the specific aims of this supplement are to determine if: 1) lead dose is associated with uric acid measures longitudinally in all participants; 2) uric acid, measures are associated with renal function longitudinally, and, if so, whether associations between lead dose and renal function are altered by adjustment for uric acid, and; 3) lead dose is associated with 6 hemodynamic biomarkers (urinary prostaglandin E2, prostaglandin F2 alpha, 6-keto-prostaglandin F1 alpha, thromboxane B2, and total nitrites/nitrates and plasma renin level), and whether these biomarkers are associated with adverse renal outcomes, at cross-section, in a subset of 200 participants. The proposed work will inform research on specific treatments for high-risk populations, such as those with chronic renal insufficiency who also have increased lead body burdens. [unreadable] [unreadable] [unreadable]