The mechanism of proteinuria at high altitude is unclear. Renal function and urinary excretion rate of albumin (Ualb) at rest and during submaximal exercise and transcapillary escape rate of 125I-labeled albumin (TERalb) were investigated in 12 normal volunteers at sea level and after rapid and passive ascent to 4,350 m. The calcium antagonist isradipine (5 mg/day; n = 6) or placebo (n = 6) was administered to abolish hypoxia-induced rises in blood pressure. Lithium clearance and urinary excretion of beta 2-microglobulin were used to evaluate renal tubular function. High altitude increased Ualb from 2.8 to > 5.0 micrograms/min in both groups (P <0.05). In the placebo group, high altitude significantly increased filtration fraction (P <0.05), but this response was abolished by isradipine. Lithium clearance and urinary excretion of beta 2-microglobulin remained unchanged by hypoxia in both groups. Exercise did not reveal any further renal dysfunction. In both groups, high altitude increased TERalb from 4.8 to > 6.7%/h (P <0.05). In conclusion, acute altitude hypoxia increases Ualb despite unchanged tubular function and independent of effects of isradipine on filtration fraction. The elevated TERalb suggests an overall increase in capillary permeability, including the glomerular endothelium, as the critical factor in high-altitude induced albuminuria.