Urate reabsorption

Most drugs act by reducing active transport rather than by enhancing it. Thus, drugs that promote uric acid loss (uricosuric agents, such as probenecid and sulfinpyrazone) probably inhibit active urate reabsorption, while pyrazinamide, which reduces urate excretion, may block the active tubular secretion of uric acid. A complicating observation is that a drug may primarily inhibit active reabsorption at one dose and active secretion at another, frequently lower, dose. For example, small amounts of salicylate will decrease total urate ex-... 

Allopurinol, in contrast to the uricosuric drugs, reduces serum urate levels through a competitive inhibition of uric acid synthesis rather than by impairing renal urate reabsorption. This action is accomplished by inhibiting xanthine oxidase, the enzyme involved in the metabolism of hypoxanthine and xanthine to uric acid. After enzyme inhibition, the urinary and blood concentrations of uric acid are greatly reduced and there is a simultaneous increase in the excretion of the more soluble uric acid precursors, xanthine and hypoxanthine. 

The urate-anion exchanger system in brush border membrane vesicle, which mediates hydroxyl ion gradient-dependent urate uptake, is the most likely route for the mediation of urate transport in the first step of urate reabsorption in the proximal tubules. Luminal drugs which inhibit urate reabsorption are inhibiting the transport of urate by blocking the urate/anion exchanger. 

Uricosurics, such as probenecid or benz-bromarone (100 mg/day), promote renal excretion of uric acid. They saturate the organic acid transport system in the proximal renal tubules, making it unavailable for urate reabsorption. When underdosed, they inhibit only the acid secretory system, which has a smaller transport capacity. Urate elimination is then inhibited and a gout attack is possible. In patients with urate stones in the urinary tract, uricosurics are contraindicated. 

Factors that decrease uric acid clearance or increase its production will result in an increase in serum urate concentration. Some of these factors are listed in Table 91-1. Drugs that decrease renal clearance of uric acid through modification of filtered load or one of the tubular transport processes are listed in Table 91-2. By enhancing renal urate reabsorption, insulin resistance is also associated with gout. ... 

Hypermicemia is a common accompaniment of diuretic therapy [94]. It results from three factors (1) the thiazides and other diuretics compete for excretion along a secretory pathway located in the proximal tubule (2) volume contraction induced by the diuretic compromises renal blood flow, leading to reduced delivery of the diuretic to the secretory site and (3) as a result of volume contraction, the proximal tubule, also a site of urate reabsorption, is stimulated to increase... 

Intratubular obstruction due to crystal formation with acetazolamide and stone formation with triamterene has been reported. In addition, uric acid stones, although rare, can result from the administration of those diuretics, which compete with uric acid for secretion, but also from any diuretic that causes severe volume depletion, thus enhancing urate reabsorption and compromising excretion. 

There are two mechanisms by which one drug may nullify the uricosuric action of another. First, the drug may inhibit the secretion of the uricosuric agent, thereby denying it access to its site of action, the luminal aspect of the brush border. Second, the inhibition of urate secretion by one drug may counterbalance the inhibition of urate reabsorption by the other. 

The mechanisms involved in urate reabsorption are not well known. The reabsorptive mechanism in at least a few species represents active transport urate may be reabsorbed from tubular fluid of the Cebus monkey when the concentration of urate is smaller than in the plasma and smaller than that predicted by the transepithelial electrical potential difference at equilibrium. Furthermore, in man and the chimpanzee, the concentration of urate in urine becomes smaller than that in the plasma when the secretion of urate is inhibited by the administration of pyrazinoic or pyrazinamide (Roch-Ramel and Weiner, 1980, review). 

In the rat, micropuncture studies showed that there is no direct coupling between sodium and urate reabsorption (Weinman et al., 1976). However, changes in extracellular volume influence urate reabsorption dehydration increases it, whereas expansion of the extracellular volume depresses it, in the rat as well as in man (Steele 1978, or Emmerson,... 

The fact that these drugs inhibit urate reabsorption does not imply that the FE of urate will increase the excretion of urate depends on the relative drug sensitivity of the secretory mechanism versus that of the reabsorptive mechanism in different species. It is well known that probenecid is antiuricosuric in rabbits (Moller, 1966). 

This discrepancy is easily explained by results of previous studies which we have performed in rats using microperfusion techniques in single nephron segments. From these experiments it is apparent (Fig. 3) that fractional urate reabsorption in the loop of Henle dramatically decreases when intraluminal flow rate increases. At physiological flow rates of 10 nl/min urate reabsorption is 3 times higher than at a perfusion rate of 40 nl/min (2). Meanwhile our findings have been extended by Senekjian et al. (8), who demonstrated that also in the convoluted part of the proximal tubule urate reabsorption decreases with luminal flow rate. 

Fig. 3 Effect of liminal flow rate on fractional urate reabsorption in the loops of Henle. Microperfusion studies in the rat (means SEM).

The proximal flow dependency of urate reabsorption offers an interpretation for several unexplained findings It is well known (1,5,8,12) that the expansion of extracellular volume leads to uricosuria. Volume expansion, however, may increase glomerular tration rate (GFR) and it reduces sodium chloride and water reabsorption in the proximal tubule. Both effects result in an augmentation of intratubular flow rate. Since the proximal tubule has a limited distensibility, linear flow velocity is accelerated and contact time inversely shortened. This in turn limits urate reabsorption and leads to uricosuria. If during volume expansion intratubular flow rate is kept constant by experimental means-as Senekjian et al, have shown (8)-then no uricosuric effect occurs. 

EVIDENCE FOR A URATE REABSORPTIVE DEFECT IN PATIENTS WITH WILSON S DISEASE... 

To test the hypothesis that part or all of renal tubular reabsorption of urate occurs distal to urate secretion, pyrazinamide suppression tests were carried out after inhibition of urate reabsorption. Probenecid or sulfinpyrazone was used to block urate reabsorption. 

Thus, the most direct interpretation of the results of the present study is that urate reabsorption occurs, at least in part, distal to the urate secretoi site. Under these circumstances, the decrease in urate excretion which follows inhibition of urate secretion by pyrazinamide is a measure of urate secretion less the portion of this secretion that is reabsorbed. Unless reabsorption of secreted urate is inhibited, pyrazinamide administration does not provide a measure of total urate secretion. 

Alternative interpretations of these results appear less probable. Pyrazinamide, or its active metabolite, pyrazinoic acid, might competitively inhibit the effect of probenecid cuid sulfinpyrazone on urate reabsorption. Since the ability to suppress probenecid or sulfinpyrazone induced uricosuria is shown by several drugs which inhibit urate secretion, including aspirin, pyrazinamide, and lactate, the proposal of cin additional effect for these drugs is uneconomical. Moreover, this competitive inhibition of drug effects does not explain the apparent excessive urate secretion (as measured by pyrazinamide suppression) observed when uricosuria resulted from water diuresis. 

The pyrazinamide suppression test underestimates urate secretion. Uricosuria induced by probenecid and sulfinpyrazone appears to represent, at least in part, inhibition of post-secretory urate reabsorption. 

Hyperuricemia, uric acid overproduction, and hyperuricosuria are frequent clinical features of sickle cell anemia. Uric acid overproduction may result in hyperuricemia in some patients with sickle cell anemia. However, in other patients, enhanced urate excretion permits maintenance of a normal serum uric acid despite uric acid overproduction. Hyperuricosuria in normouricemic patients with sickle cell anemia may result from enhanced tTobular secretion of urate but is more likely to represent diminished urate reabsorption at a post-secretory site. Hyperuricosuria may protect the young patient with sickle cell anemia from gouty arthritis and tophi but may also increase the risk of tubular deposition of urate and nephropathy. 

These results indicate that both drugs significantly decreased urate reabsorption in the proximal tubule. Furthermore delayed excretion was markedly reduced in benziodarone-treated animals but was unchanged after benzbromarone infusion. These drug effects were not related to changes in tubular transit times, urine flow rates, injection rates and so on... which were similar in the three animal groups. 

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