The purpose of these experiments was to determine whether reported changes in substrate metabolism by isolated glomeruli from rats with aminonucleoside nephrosis could be explained by the glomerular changes associated with proteinuria or, alternatively, whether these metabolic changes and proteinuria were synchronous but causally unrelated events. Aminonucleoside of puromycin produced proteinuria within 7 days when injected intraperitoneally or subcutaneously. However, when aminonucleoside of puromycin as well as adenine were given, the onset of proteinuria was delayed until after day 7. A significant reduction in U-14C-glucose oxidation to CO2 was found at day 7 by glomeruli from rats given aminonucleoside of puromycin intraperitoneally but no significant changes were found with aminonucleoside of puromycin given subcutaneously on days 7 and 9 and aminonucleoside of puromycin+ adenine given subcutaneously on days 7 and 9. Rats given daunomycin or adriamycin had developed proteinuria by day 14. U-14C-glucose oxidation to CO2 was significantly reduced on day 14 in glomeruli from rats given daunomycin but no significant changes were found on day 21 with daunomycin, or on days 14 and 21 with adriamycin. There was a reduction in pyruvic-acid carbon metabolism but not in glutamine-carbon oxidation 14 days after treatment with daunomycin. These results suggest that the observed changes in glomerular metabolism occur independently of, albeit synchronous with, the development of proteinuria. A causal relationship between these metabolic alterations and proteinuria therefore may be unlikely.