Tubular Secretion Of Uric Acid Research Articles

Hypouricemia and hyperuricosuria as expressions of renal tubular damage in primary biliary cirrhosis.

Renal tubular damage, in particular, renal tubular acidosis is associated with primary biliary cirrhosis (PBC), but hypouricemia has not been described. We studied four patients with PBC whose serum uric acid levels were 1.4 to 1.8 mg per dl, and compared their renal and liver functions with those of 11 patients with PBC whose serum uric acid levels were normal. In the patients with PBC and hypouricemia, uric acid clearance (Cua) and the ratio of Cua and creatinine clearance (Cua/Ccr) were high enough to cause hypouricemia. Elevated Cua/Ccr was suppressed by administration of pyrazinamide, a blocker of tubular secretion of uric acid, but was not affected by probenecid; the effects of drugs on Cua/Ccr were similar to those reported in Wilson's disease. Elevation in Cua/Ccr was associated with increased serum bilirubin and urinary copper excretion. These observations indicate that hypouricemia and hyperuricosuria, which may be caused by defective postsecretory reabsorption of uric acid, are additional indicators of renal tubular damage in PBC.

Interaction between allopurinol and pyrazinamide

Pyrazinamide (PZA) is increasingly used with isoniazid and rifampicin, in short-course antituberculous chemotherapy in service programme conditions. Complicating arthralgias occur due to hyperuricaemia induced by the inhibition of renal tubular secretion of uric acid by pyrazinoic acid, the main PZA metabolite. Allopurinol (Al), a hypouricaemic agent, provides no substantial clinical improvement. Pharmacokinetics of PZA and its metabolites were studied in six healthy volunteers, in a cross-over design, after a single oral dose of PZA alone and, in a second trial, after the same dose together with Al. Plasma and urinary concentrations were measured by high pressure liquid chromatography with a column of cation exchange resin. Analysis of the pharmacokinetic parameters showed that Al induced marked changes in levels of PZA metabolites and accumulation of pyrazinoic acid. Despite decreasing uric acid synthesis, allopurinol increased plasma concentrations of pyrazinoic acid, which is directly responsible for the inhibition of renal urate secretion. Other drugs, which do not involve xanthine oxidase inhibition, should be used in the treatment of this side effect of chemotherapy.

Renal Handling of Uric Acid: Hypouricemia and Tubular Urate Secretion

<h3>To the Editor.</h3> —In the November 1985 issue of theArchives, Shichiri et al¹reported on three patients with inappropriate secretion of antidiuretic hormone syndrome, and increased renal clearance of uric acid. In two patients, the fractional excretion of uric acid (Cur/Ccr) increased to 435% and 267%, with respect to mean baseline values in response to probenecid administration. They conclude that in both patients increased urate excretion is the result of enhanced tubular secretion of uric acid. This conclusion is based on the assumption of a four-component model for urate excretion. The authors were provided evidence for this model by Steele and Rieselbach.² Review of the literature shows that in 1967, these authors did not propose that reabsorption of secreted urate could modulate the amount of uric acid appearing in the final urine specimen. Evidence for a postsecretory reabsorptive mechanism of urate relates to the canceling effect of

Mechanisms of hypouricemia in the syndrome of inappropriate secretion of antidiuretic hormone.

Hypouricemia seen with hyponatremia related to the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) results from an increase in uric acid renal clearance. We studied the mechanism of the increase of uric acid excretion in 6 SIADH patients through pyrazinamide (PZA), which decreases tubular secretion of uric acid, and sulfinpyrazone (SPZ) which decreases post-secretory reabsorption of uric acid. 3 g of PZA decreased the absolute uric acid excretion from 428 +/- 244 to 105 +/- 47 micrograms/min (mean +/- SD, p less than 0.01), and 300 mg of SPZ increased the uric acid to creatinine clearance ratio from 0.31 +/- 0.05 to 0.52 +/- 0.05 mg/dl glomerular filtration rate (mean +/- SEM, p less than 0.001), which represent an increment about half of that observed in the control group. The increase of uric acid clearance in SIADH seems to result from a decrease in the post-secretory reabsorption of uric acid. After SPZ, we saw a decrease of natriuresis from 5.6 +/- 1.4 to 1.8 +/- 0.3 mmol/h (p less than 0.001), without any change of urinary flow or urinary potassium excretion.

A Case of Uric Acid Renal Stone with Hypouricemia Caused by Tubular Reabsorptive Defect of Uric Acid

A 60-year-old man had a uric acid stone in the kidney and laboratory findings of hypouricemia (1.1mg. per 100ml.) and increased uric acid clearance (43ml. per minute per 1.73m.2). Clearance of uric acid exceeded the, endogenous creatinine clearance after administration of pyrazinamide, an inhibitor of renal tubular secretion of uric acid. It was suggested that our patient had a complete defective mechanism for uric acid reabsorption, resulting in hyperuricuria and the formation of the uric acid stone.

Renal Function in the Penguin (Spheniscus Demersus) with Special Reference to the Role of the Renal Portal System and Renal Portal Valves

The general morphology and direction of blood-flow in the renal portal complex, as well as the histochemistry, innervation and pharmacology of the renal portal valves were studied. The origin of the copious mucus present in the cloacal fluid was found to be in the collecting tubules and branches of the ureters. By simulating renal portal conditions in one of two groups of birds an attempt was made to study the role of the renal portal blood system. Significantly higher water diuresis was recorded in the closed valve group. Increased amounts of potassium were secreted by the open vale group while sodium was reabsorbed in significantly higher amounts in the closed valve group. No evidence to support the hypothesis that the renal portal system promotes renal tubular secretion of uric acid was found, but the high concentration of urea recorded and the trend for urea values to be higher in the closed valve group, suggests that the renal portal system may be implicated in urea secretion.

Hypouricemia due to isolated renal tubular defect: Dalmatian dog mutation in man

A twenty-three year old man was found to have low serum urate concentrations (0.9 to 1.8 mg/100 ml) during evaluation for recurrent urinary calcium oxalate stones. His urinary clearance of uric acid was markedly increased (30 to 46 ml/minute), and was only minimally decreased after administration of pyrazinamide, an inhibitor of renal tubular secretion of uric acid. No other renal tubular abnormalities were detected. His sister also was hypouricemic and had an increased renal clearance of uric acid. We suggest that this man had a genetically determined renal abnormality affecting tubular reabsorption of uric acid; a similar defect is present in the Dalmatian coachhound. The association of idiopathic hypercalciuria with the renal uric acid reabsorptive defect in this case is probably fortuitous.

Uricosuric effect of radiocontrast agents. A study in man of four commonly used preparations.

The administration of standard doses of four commonly used radiocontrast agents, iopanoic acid (Telepaque®), calcium ipodate (Oragrafin®), meglumine iodipamide (Cholografin®), and sodium diatrizoate (Hypaque®) to 2 to 12 patients is followed by a decrease in the serum urate concentration, an increase in the urinary excretion of uric acid, and an increase in the renal clearance of uric acid. This uricosuric effect of these agents appears to be caused by enhanced renal tubular secretion of uric acid. Telepaque and Oragrafin were found to have a more potent effect than Cholografin and Hypaque. In addition, the duration of the uricosuric effect of these agents, which is 5 and 6 days for Telepaque and Oragrafin, respectively, and 1 day for Cholografin and Hypaque, correlates with the duration of their reported renal excretion. The possibility that acute renal failure occasionally precipitated by these agents may be related to their uricosuric effect is discussed.

Effect of glycine loading on plasma and urinary uric acid and amino acids in normal and gouty subjects

A single oral dose of glycine, 100 mg/kg body weight, a physiologic load, was given to ten normal men and seventeen patients with primary gout. The ensuing uricosuria, chiefly due to increased renal clearance of uric acid, was relatively greater in the gouty subjects. That the uricosuria was not due to competition between glycine and uric acid for a common reabsorptive mechanism was shown by giving probenecid, which increased renal excretion of uric acid but not of glycine or other amino acids. Pyrazinamide abolished the glycine-induced uricosuria, which is therefore assumed to be due to enhanced tubular secretion of uric acid. Glycine loading increased urinary excretion of ammonium to about the same degree in gouty and nongouty subjects; there does not seem to be any defect in utilization of glycine for renal formation of ammonia in gout. In the six normal and seven gouty subjects so examined, glycine loading evoked a similar marked increase in plasma glycine and serine, and a significant increase in urinary excretion not only of glycine and serine but also of a variety of other monoamino-monocarboxylic acids, consistent with a common tubular reabsorptive mechanism for these amino acids. The gouty subjects showed no statistically significant aberration in the response of plasma and urinary free amino acids to glycine loading.

Hyperuricemia in glycogen-storage disease type 1.

THE ASSOCIATION of hyperuricemia with glycogen-storage disease (GSD) type 1 or von Gierke's disease has been described in 20 patients.1In some of these patients gouty arthropathy and nephropathy have occurred.2-4The mechanism responsible for hyperuricemia has not been delineated, but is thought to result from altered renal tubular function.5Normally, 90%-95% of the uric acid which is filtered at the glomeruli is reabsorbed by the proximal renal tubules. The major portion which appears in the urine seems to be secreted by the distal renal tubules.6It has been hypothesized that the hyperlacticacidemia which these patients manifest either enhances renal tubular reabsorption or inhibits renal tubular secretion of uric acid, thereby decreasing uric acid clearance (Cur) and producing hyperuricemia.3 The purpose of this study was to determine the effect of lactic acid and glucose in the development of hyperuricemia in patients with GSD type

Uricosuric Drugs, with Special Reference to Probenecid and Sulfinpyrazone

This chapter discusses the uricosuric drugs, with special reference to probenecid and sulfinpyrazone. Uricosuric drugs increase urinary uric acid excretion by inhibiting renal tubular reabsorption of uric acid, and thereby reduce the plasma urate concentration and enhance the renal clearance of uric acid. The compounds possessing authentic uricosuric properties are of diverse structure, with no apparent coninion coniponent, but virtually all are organic acids; a striking and inexplicable exception is zoxazolamine, a weak base yet one of the most potent of the uricosuric drugs. The uricosuria produced by these various agents really represents a net renal response, since the acidic uricosuric drugs are all secreted by the same “organic acid system” of renal tubular transport, in common with uric acid, and in the process may also competitively inhibit, to greater or lesser degree, the tubular secretion of uric acid. When there is a dual action on tubular reabsorption and secretion of uric acid, the net effect, whether it is to augment or to diminish urinary elimination of uric acid, varies with the nature of the drug, the dosage employed, and the species treated.

LOCALIZATION AND PYRAZINAMIDE INHIBITION OF DISTAL TRANSTUBULAR MOVEMENT OF URIC ACID-2-C14 WITH A MODIFIED STOP-FLOW TECHNIQUE.

Renal tubular secretion of uric acid has been demonstrated in several mammalian species including the rabbit (1), mongrel and Dalmatian dog (24), and man (7). Although secretion was easily delineated in the Dalmatian coach hound (4-6), special experimental conditions were necessary for its substantiation in other species. Uric acid clearance in excess of simultaneous creatinine clearance, indicative of tubular secretion of urate, was noted by Poulsen and Praetorius in rabbits made hyperuricemic by the intravenous infusion of urate (1). In 1959, Gutman, Yfi, and Berger (7) documented tubular secretion of uric acid in patients with reduced glomerular filtration, who were given infusions of uric acid and mannitol and treated with large doses of sulfinpyrazone in order to suppress tubular reabsorption. One year later tubular secretion of urate was reported in the mongrel dog under similar conditions of an osmotic diuresis and an intravenous infusion of uric acid (2, 3). Efforts to localize the site of tubular urate secretion in the mongrel dog by stop-flow analysis have yielded conflicting results. Yu and his colleagues (3, 8) reported peak net tubular secretion in the distal segment of the nephron. However, Kessler, Hierholzer, and Gurd (6), utilizing the same experimental procedure except for the administration of probenecid, found no evidence for distal tubular secretion of urate.

Renal function in gout: II. Effect of uric acid loading on renal excretion of uric acid

Thirteen non-gouty and twelve gouty men to whose regular diet was added 4 gm. of ribonucleic acid (RNA) daily, developed increases in plasma uric acid, urinary excretion of uric acid and derived parameters, without significant differences in the mean increments in non-gouty and gouty subjects. Ten non-gouty and seventeen gouty men were given intravenous injections of 1.1 to 2.5 gm. uric acid to impose even greater demands upon the tubular mechanisms for transfer of uric acid, and again the mean increments in the urinary excretion of uric acid and uric acid clearance in non-gouty and gouty subjects were indistinguishable. Pyrazinoic acid, a potent inhibitor of tubular secretion of uric acid, was found to suppress the urinary elimination of rapidly infused uric acid in gouty and non-gouty subjects alike.The data indicate that gouty subjects can excrete large extraneous loads of uric acid with as much facility as normal man, and support the view that this obtains also for the usually smaller and more slowly delivered endogenous uric acid loads natural to gout. The results thus argue against any intrinsic defect, peculiar to gout, in the renal mechanisms for excretion of uric acid.Briefly reviewed is the evidence that tubular secretion of uric acid occurs in non-gouty and gouty man, indeed that virtually all the uric acid appearing in the urine ordinarily derives from tubular secretion, hence virtually all the filtered uric acid ordinarily must be reabsorbed. It is pointed out that in this version of the filtration-reabsorption-secretion hypothesis there need be no simple relationship between the filtered and excreted uric acid, a dissociation found in gout that has been interpreted by others as indicating a primary tubular defect in transfer of uric acid. The implications of the filtration-reabsorption-secretion hypothesis in respect to other aspects of the renal regulation of uric acid are discussed in relation to excretion of uric acid in normal and gouty man under natural and artificial conditions of uric acid loading.The present study, limited to over-all clearances, gives no information as to the precise mechanisms or quantitative aspects of tubular secretion of uric acid in normal or gouty man, nor does it explain just how renal excretion of large and rapidly imposed uric acid loads is regulated.

Renal tubular secretion of uric acid in the mongrel dog.

Renal tubular secretion of uric acid was demonstrated in mongrel dogs receiving sodium urate intravenously when an osmotic diuresis was induced by the administration of mannitol. Under these conditions the excretion of urate was greatly augmented and in the majority of experiments the renal clearance of urate exceeded the clearance of creatinine. The high rate of excretion was attributed to a combination of tubular secretion and reduced urate reabsorption, the latter resulting from osmotic diuresis. The administration of probenecid at the height of diuresis tended to reduce the clearance of urate, suggesting that this drug may inhibit tubular secretion of urate. A study of the effect of urinary pH on uric acid excretion indicated that this acid is not excreted by nonionic diffusion.