In 8 healthy male volunteers, urinary excretion (UE) and fractional clearance (FC) of pepsinogen A (PGA), beta 2-microglobulin (beta 2-m) and albumin were measured after 6 days high protein diet (HPD; 2.0 g/kg/day) and compared to values obtained after 6 days low protein diet (LPD; 0.5 g/kg/day). In addition, the effect of an acute protein load (APL; 500 g beef) on these variables were measured. Both chronic and acute protein loading induced a rise in glomerular filtration rate (GFR) of about 10% together with a parallel rise in effective renal plasma flow. UE PGA and FC PGA increased both after HPD (UE PGA 1,707 +/- 1,106 ng/min; FC PGA 23 +/- 12%) as compared to LPD (UE PGA 1,200 +/- 987 ng/min, p less than 0.01; FC PGA 18 +/- 12%, p less than 0.05), and after APL (UE PGA 2,276 +/- 1,389 ng/min; FC PGA 26 +/- 16%) as compared to baseline (UE PGA 1,418 +/- 965 ng/min, p less than 0.02; FC PGA 21 +/- 12%, p less than 0.05). UE and FC of beta 2-m and albumin were not affected by protein loading. As PGA is nearly freely filtered, it is concluded that the increase in fractional PGA clearance reflects a decrease in fractional tubular PGA reabsorption. Our results suggest that an increase in fractional protein clearance after protein loading is not necessarily due to an impaired glomerular permselectivity but represents a decreased fractional tubular reabsorption as a result of a GFR-mediated increase in filtered load without a concomitant increase in tubular reabsorption.