Urate excretion

Renal impairment - Some degree of renal impairment may be present in patients with gout. A daily dosage of 1 g may be adequate. However, if necessary, the daily dosage may be increased by 0.5 g increments every 4 weeks within tolerance (usually not more than 2 g/day) if symptoms of gouty arthritis are not controlled or the 24 hour urate excretion is not more than 700 mg. Probenecid may not be effective in chronic renal insufficiency, particularly when the glomerular filtration rate is 30 mL/minute or less. 

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-... 

Urate excretion is subject to modification by a variety of organic anions, including uricosuric agents. 

Allopurinol is especially indicated in the treatment of chronic tophaceous gout, since patients receiving it show a pronounced decrease in their serum and urinary uric acid levels. Because it does not depend on renal mechanisms for its efficacy, allopurinol is particularly beneficial for patients who already have developed renal uric acid stones, patients with excessively high urate excretion (e.g., above 1,200 mg in 24 hours), patients with a variety of blood disorders (e.g., leukemia, polycythemia vera), patients with excessive tophus deposition, and patients who fail to respond well to the uricosuric drugs. 

Ichida K, Hosoyamada M, Hisatome I, Enomoto A, Hikita M, Endou H, Hosoya T (2004) Clinical and molecular analysis of patients with renal hypouricemia in Japan influence of the URAT1 gene on urinary urate excretion. J Am Soc Nephrol 15 164-173... 

Patients with Lesch-Nyhan syndrome may also suffer from gout, which is due to an accumulation of urate in the body with deposition of crystals of sodium urate in the joints and kidneys. However, gout more commonly occurs due to failure of urate excretion by the kidneys, or due to accumulation of P-Rib-PP for reasons other than a deficiency of HG-PRTase. 

Pyrazinamide is one of the most powerful drugs available for the inhibition of urate excretion in man, consistently providing a 80-90% reduction in the renal clearance of uric acid (1401, 1403). 2-Morpholinocarbonylpyrazine and its 6-methoxy derivative are claimed to have antidiabetic activity (948, 949, 1351, 1387, 1404), and some 2-(p-ureidosulfonylphenethylcarbamoyl)pyrazines have been shown to have hypoglycemic activity in mice (1405). The effect of 2-amino-3-hydroxy-carbamoylpyrazine on DNA synthesis by Erlich ascites tumor cells in vitro has been investigated (1406) as well as the inhibition by 2-amino-3-hydroxycarbamoylpyrazine on L-histidine carboxylyase (1407) many 2-hydroxyimidazo[4,5-6]pyrazines (prepared from 2-amino-3-hydrazinocarbonylpyrazines with nitrous acid) are potent hypotensive agents in animals (880,891,963,1181). 

In low dosages (up to 2 g/day), aspirin reduces urate excretion and blocks the effects of probenecid and other uricosuric agents (116). However, in 11 patients with gout, aspirin 325 mg/day had no effect on the uricosuric action of probenecid (117). In higher dosages (over 5 g/day), salicylates increase urate excretion and inhibit the effects... 

In low dosages (up to 2g/day), aspirin reduces urate excretion and blocks the effects of sulfinpyrazone. In higher dosages (over 5g/day), salicylates increase urate excretion. 

Gutman AB, Yu TF. Renal function and gout with a commentary on the renal regulation of urate excretion, and the role of the kidney in the pathogenisisof gout. Am J Med 1957 23 600-622. 

Steele TFI, Manuel MA, Boner G. Diuretics, urate excretion and sodium reabsorption effect of acetazolamide and urinary alkali-nization. Nephron 1975 14 48-61. 

Hyperuricemia has been found associated with myxedema, where it is accompanied by normal or low urinary urate excretion. On the other hand, hyperthyroidism is usually found with slightly increased urinary excretion (L8, M16). These variations have been interpreted in terms of changes in pool size and the relative role of extrarenal excretion (L7). 

Spectrophotometric analysis of urinary inhibition on the active forms (HMW-UK and LMW-UK) revealed a significant difference between subjects with and without renal calculi (VI). A positive correlation exists between the percentage of inhibition and the urinary urate concentration. Urate inhibits both the LMW-UK and the HMW-UK, but not plasmin. These results are in perfect agreement with reports that stone patients have higher urinary urate concentrations (C2). These observations may explain why allopurinol is administered to kidney stone patients. Allopurinol causes a decrease in urinary urate excretion by inhibiting the xanthine oxidase, which could cause a higher urinary urokinase activity. 

Emmerson BT, Mirosch W, Douglas JB. The relative contributions of tubular reabsorption and secretion to urate excretion in lead nephropathy. Aust NZ J Med 1971 4 353-362. 

Via the kidney. The majority of urate is excreted via the kidney. Renal handling of urate is complex. It is freely filtered at the glomerulus, but 99% is reabsorbed in the proximal tubule. The distal tubules also secrete urate, but again much is reabsorbed. The amount of urate excreted in the urine is around 0% of that filtered at the glomerulus. 

The symptoms of acute gout respond to anli-innammatory drugs suchasindomelh-acin. but it should be noted that these drugs have no direct effect on the serum urate level. Low-dose aspirin should be avoided as it inhibits renal urate excretion. Treatment must also be directed at the hyperuricaemia. Drugs such as probenecid which promote urate excretion can be used prophylactically. A diet which is low in purines and alcohol may be prescribed in an effort to reduce the plasma urate concentration. Allopurinol, a specific inhibitor of the enzyme xanthine oxidase which catalyzes the oxidation... 

CNS Edema, worsening of renal function in renal/cardiac and cirrhotic patients Decreased effectiveness of antihypertensive medications Decreased effectiveness of diuretic medications Decreased urate excretion (especially with aspirin) Hyperkalemia Headache... 

Low doses (1 or 2 g/day) can decrease urate excretion and elevate plasma urate concentrations intermediate doses (2 or 3 g/day) may not alter urate excretion large doses (more than 5 g/day) induce uricosuria and lower plasma urate levels. However, such large doses are tolerated poorly. Even small doses of salicylate can block the effects 0/probenecid and other uricosuric agents that decrease tubular reabsorption of uric acid. 

Certain drugs, particularly thiazide diuretics (see Chapter 28) and immunosuppressant agents (especially cyclosporine) may impair urate excretion and thereby increase the risk of gout. 

The drug inhibits urate excretion, rarely precipitating an acute flare of gout. Other adverse effects are arthralgias, nausea and vomiting, dysuria, malaise, and fever. 

More is known about the competition of foreign substances, such as pra-aminohippurate (PAH) and pyrazinoic acid for urate transport. In man the excretion of urate is not decreased by the administration of PAH whereas pyrazinoic acid has a clear-cut effect (Boner and Steele, 1973, Steele and Rieselbach, 1967). In the Cebus monkey pyrazinoic acid also inhibits the secretion of urate, whereas PAH does not. The same is true for the rat. In other species, such as the pig and the rabbit, PAH is a good inhibitor of secretion whereas pyrazinoic acid is not (Simmonds et al., 1976, Schali and Roch-Ramel, 1980b). Thus the systems involved in urate excretion do not appear to be identical in all mammalian species (Weiner, 1979, Roch-Ramel and Weiner, 1980, for review). 

Emmerson, B.T. Abnormal urate excretion associated with renal and systemic disorders, drugs, and toxins. In W.N. Kelley, I.M. Weiner (eds.). Handbook of Experimental Pharmacology,... 

M/>ller, J.V. Clearance experiments on the effect of probenecid on urate excretion in the rabbit. Acta Pharmacol. Toxicol. (Kbh.) 23 321-328 (1966). 

Roch-Ramel, F., I.M. Weiner Inhibition of urate excretion by pyrazinoate a micropuncture study. Am. J. Physiol. 229 1604-1608 (1975). 

Roch-Ramel, F., D. de Rougemont, G. Peters, I.M. Weiner Micropuncture study of urate excretion by the kidney of the rat, the Cebus monkey and the rabbit. In S. Silbernagl, F. Lang, R. Greger (eds.). Amino Acid Transport and Uric Acid Transport. Symposium Innsbruck, June 1975. Stuttgart Thieme, 1976b, p. 188-192. 

Roch-Ramel, F., D. Diezi-Chomety, L. Roth, I.M. Weiner A micropuncture study of urate excretion by Cebus monkeys employing high performance liquid chromatography with amperometric detection of urate. Pfluegers Arch. 383 203-207 (1980a). 

Fractional excretion of urate in man follows a distinct circadian rhythm. This rhythm is monophasic and normally parallels that of urine flow rate (Fig. 1). However, if urine flow rate is enhanced by excessive drinking of tap water, there is no concomittant increase of urate excretion (6). On the other hand, if osmotic diuresis is induced by the infusion of mannitol, uric acid excretion increases significantly (Fig. 2). 

Fig. 4 Fractional urate excretion (FEy ) as a function of glomerular filtration rate (GFR) in patients with renal insufficiency.

Altered isotonic fluid reabsorption in the proximal nephron mediates variations of fractional urate excretion during circadian rhythm, diuretic treatment, renal insufficiency. 

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