In type 1 diabetes, increases in sodium-lithium countertransport (Na-Li CT), kidney volume (KV), and albumin excretion rate (AER) may precede the development of persistent microalbuminuria. Limited data exist on reversibility of these factors early in the evolution of diabetic nephropathy. A crossover design was used to study the separate effects of enalapril and intensive diabetes management (IDM) on Na-Li CT, KV and AER in 17 children and adolescents with type 1 diabetes (5-10 years duration) with large kidneys (>275 ml/1. 73 m(2)) and predominantly normoalbuminuria. Subjects were randomized to receive 3 months of either enalapril (0.25 mg/kg/day) or IDM, a 3-month washout, followed by the alternate treatment for 3 months. During IDM, HbA1c decreased 2.5% (pre 9.5+/-0.3% (mean+/-SE), post 7.0+/-0.1%, p<0.0001), but was unchanged while on enalapril (pre 8.8+/-0.3%, post 8.5+/-0.3%, p=0.1). A significant decrease in Na-Li CT was seen with IDM (pre 0.43+/-0.05, post 0.36+/-0.04 mmol/l RBC/h, p=0.006) but not angiotensin converting enzyme inhibition (ACE-i) (pre 0.39+/-0.04, post 0.38+/-0.04 mmol/RBC/h, p=0.4). Neither ACE-i nor IDM affected KV or AER. It is concerning that kidney enlargement does not appear reversible at this early stage in the pathogenesis of diabetic nephropathy, although our conclusions are limited by the short duration of intervention and small sample size. The reduction in Na-Li CT with IDM suggests this may be a potentially modifiable risk factor for diabetic nephropathy.