Renal Urate Homeostasis

The binding of uric acid to plasma proteins is relatively small and probably does not have great physiological significance. However, even this limited binding may be affected by administration of drugs, such as salicylates, phenylbutazone, probenecid, and sulfinpyrazone. These drugs probably affect urate protein binding only secondarily; that is, their principal action is to interfere with renal transport of uric acid, which in turn leads to alterations in plasma urate binding.

The renal mechanisms involved in the handling of uric acid are complex and involve filtration, reabsorption, secretion, and possibly postsecretory reabsorption. The proximal tubule is the principal site of both carrier-mediated reabsorption and secretion of urate. Urate is believed to be transported from the ultrafiltrate to the intracellular space by an anion (hydroxyl, bicarbonate, chloride, or lactate) exchange mechanism in the luminal membrane. This active transport system can be inhibited by drugs, such as probenecid, sulfinpyrazone, and salicylate. The urate accumulated in the cell moves passively across the basolateral membrane and into the peritubular fluid down its electrochemical gradient. Conversely, active tubular secretion of urate occurs as a consequence of carrier-mediated transport across the basolateral membrane of the proximal tubule. The urate accumulated in the cell moves passively across the lu-minal membrane into the ultrafiltrate along its concentration gradient. The carrier-mediated secretion of urate can be inhibited by a variety of organic anions, including the thiazide and loop diuretics.

The intracellular concentration of urate in the proximal tubule will ultimately be determined by the balance of influx and efflux. When the transport of urate from the peritubular fluid is high, there is a net elimination of urate across the luminal membrane. In contrast, when the transport of urate from luminal fluid is high, there is a net reabsorption across the basolateral membrane.

Urate excretion is subject to modification by a variety of organic anions, including uricosuric agents, phenylbutazone, diuretics, radiographic contrast agents, and certain anticancer compounds. A further complicating feature is that drug effects may be biphasic; that is, small amounts may depress urate excretion, while larger doses have uricosuric effects.

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