Normally, the small amount of albumin which passes through the glomerular capillary wall is almost completely reabsorbed in the proximal tubule, via an endocytic mechanism, but the reabsorptive process can be overwhelmed if the filtered load of albumin is too large. To examine the factors that control the fractional reabsorption of albumin (f), we developed a mathematical model which assumes saturable endocytosis kinetics with a maximum reabsorptive capacity, V(max), and which includes the effects of flow and diffusion in the lumen. Limitations in albumin transport from the bulk tubule fluid to the endocytic sites at the bases of the microvilli had only a modest (8%) effect on the value of V(max) needed to fit micropuncture data on tubule albumin concentrations in rats. For moderate changes in filtered load, there was much greater sensitivity of f to SNGFR than to the albumin concentration of the filtrate (C(0)). A 50% increase in SNGFR was predicted to cause four- to fivefold increases in albumin excretion in rats or humans. For large increases in C(0), as might result from defects in glomerular sieving, there was a threshold at which the reabsorptive process became saturated and f fell sharply. That threshold corresponded to sieving coefficients of 10(-3) to 10(-2), the higher values occurring at reduced SNGFR. The predictions of the present model contrast with those of one proposed recently by Smithies (32), which does not include the effects of tubule flow rate.