NIPS.April.Second Notebook

0886-1714/99 5.00 © 1999 Int. Union Physiol. Sci./Am.Physiol. Soc. 80 The renal urate handling in humans has been explained for many years by a “four-component model.” The purpose of this review is to reevaluate the validity of the theory behind this hypothetical model in the light of the transport mechanisms that were characterized recently in the apical membrane (brush-border membrane; BBM) of human proximal tubule. In humans, the uricase gene is not expressed, and uric acid is the end product of purine metabolism. It is a trioxypurine of which only the hydroxyl group in position 8 (pKa 5.75) is dissociable at physiological pH. The kidney plays a predominant role in its elimination, two-thirds of the daily production of uric acid being excreted by the renal route and the other one-third being eliminated by the gastrointestinal tract. In the plasma, 98% of the uric acid is dissociated and present as sodium urate, which is freely filtered, being bound by <5% to plasma proteins. Thus uric acid enters the proximal tubule in its anionic form, its concentration in the ultrafiltate being close to that of plasma. Both uric acid and urate, being hydrophilic, hardly permeate the tubular cells in the absence of facilitated mechanisms. The transport mechanisms for urate, as for organic anions in general, are localized in the proximal tubule (Fig. 1). In humans, urate is extensively reabsorbed, which results in excretion of ~10% of the filtered load of urate (FEurate = renal clearance of urate/glomerular filtration rate = 10%) (1). In the mammalian proximal tubule, micropuncture and microperfusion studies, as well as earlier stop-flow techniques, demonstrated that urate is bidirectionally transported with a predominance of reabsorption, in species such as rats, dogs, and Cebus monkeys, or secretion, as in pigs and rabbits (13). The distal parts of the nephron and the collecting ducts are hardly permeable to urate. A simplified scheme of urate handling by the nephron of reabsorbing mammals is provided in Fig. 1. In humans, experiments on renal handling of urate hitherto have been limited to the study of the effects of urate loading and of the different drugs interfering with urate excretion in vivo. Such experiments demonstrated a secretory transport for urate in a group of male gout patients with low filtration rates infused with uric acid and a uricosuric drug, when the FEurate rose from values below the filtration load (reabsorption) to values slightly exceeding the filtration load (secretion) (6). Urate secretion is also observed in hereditary hypouricemia, in which an increase in renal urate clearance is caused by a specific inborn error of urate transport (14). These observations suggest that urate is not only reabsorbed but also secreted in humans as in other mammals, reabsorption being predominant. Many attempts have been made to estimate the respective importance of the reabsorptive and secretory fluxes in pharmacological experiments, by measuring the effects of uricosuric and antiuricosuric drugs, in an endeavor to selectively inhibit the reabsorption or the secretion of urate.