Urate Secretion Research Articles

Stop-flow studies on tubular transport of uric acid in rats.

A stop-flow technique using pyrazinoic acid(PZO)-treated and -untreated rats was devised to evaluate drug effects on bi-directional transport of uric acid in the tubules. Constant venous infusion of test drugs to PZO-untreated rats was used to estimate their inhibitory effects on urate secretion, while their inhibitory effects on urate reabsorption was studied by intravenous administration as a bolus to PZO-treated rats. Probenecid, tienilic acid and R-(+)-enantiomer of S-8666, which is the uricosuric component of a new uricosuric diuretic, decreased the (Tua/Pua)/(Tin/Pin) value in the distal and proximal tubules by inhibiting urate secretion in PZO-untreated rats. On the other hand, all of these drugs increased the (Tua/Pua)/(Tin/Pin) value in the tubules in PZO-treated rats, which suggested that they also inhibited the reabsorptive flux of urate. This stop-flow technique in rat kidneys showed the possibilities of bi-directional inhibition by these drugs of urate transport in the tubules.

Cause of persistent hypouricemia in outpatients.

We measured serum urate in 3,258 Japanese outpatients. Five of them had persistent hypouricemia. Three also had microhematuria. Four of the five patients were proven to have renal uricosuria with hypouricemia, but otherwise normal tubular function. When tested with both pyrazinamide and benzbromarone, 1 patient had a presecretory reabsorption defect, 2 had postabsorption defects, and 1 an enhanced renal tubular secretion of urate. These results suggest that persistent hypouricemia in outpatients is of very low incidence, is usually caused by an isolated metabolic error of urate transport, and is not related to drug ingestion or systemic disease.

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.

Hypouricemia Due to Increased Tubular Urate Secretion

A 45-year-old woman had hypouricemia (serum uric acid, 1.0–2.3 mg/dl) with increased uric acid clearance (29.8 ± 9.3 ml/min/1.73 m2). Uric acid clearance to creatinine clearance ratio (Cua/

Drug interactions with urate excretion in man.

The effects of pyrazinamide and ampicillin on the uricosuric response to probenecid and benzbromarone were studied in six normal subjects. The amount of uric acid was calculated for the 24 h volume of urine and the urate and creatinine clearances were determined for each of three urinary collection periods in order to calculate the percentage Curate/Ccreatinine. Ampicillin alone caused a significant uricosuria in the 0-2 h (p less than 0.025) and 8-24 h (p less than 0.025) periods. Benzbromarone caused a significant reduction in all the parameters. These observations suggest that high concentrations ampicillin compete with uric acid for reabsorption, but that its delayed uricosuric action can be ascribed to the binding of this dipeptide to a charge-mediated receptor site on the brush border membrane of proximal tubular cells. It would also appear that benzbromarone is secreted by the pyrazinamide-sensitive mechanism for urate secretion as it can cause a paradoxical retention of urate, but leaves the other probenecid-sensitive secretory transport process unoccupied as indicated by the fact that it does not change the kinetics of ampicillin.

Pharmacological Evaluation of Urate Renal Handling in Humans: Pyrazinamide Test vs Combined Pyrazinamide and Probenecid Administration

Uricosuric and antiuricosuric drugs have been utilised widely for the study of tubular urate transport in humans. A normal suppression of urate excretion after pyrazinamide is usually taken as evidence of normal presecretory reabsorption. However, in patients with reduced presecretory reabsorption, during pyrazinamide inhibition of urate secretion unreabsorbed urate might still undergo reabsorption along postsecretory sites, allowing for a normal pyrazinamide suppression of urate excretion. To test this possibility, we have performed the pyrazinamide test both alone and after pretreatment with probenecid, which should block postsecretory urate reabsorption. The test was performed in 8 controls, in 9 patients with 'low-excretory' hyperuricaemia, and in 7 patients with tubular urate wasting. Pyrazinamide-non-suppressible urate excretion after pretreatment with probenecid did not differ from the excretion obtained after pyrazinamide alone in hyperuricaemic patients (mean difference 1.33 +/- 2.3% of filtered urate; P = NS); it was slightly higher in controls (3.4 +/- 3.4; P less than 0.05), but was much higher in patients with tubular urate wasting (19.6 +/- 12.7; P less than 0.005). The pyrazinamide test, performed alone, was normal in three patients with tubular urate wasting, but it was abnormal in all patients after pretreatment with probenecid. These results are consistent with the possibility that, during maximal pyrazinamide effect, some uric acid escaping reabsorption at presecretory sites may undergo reabsorption along postsecretory sites, leading to a quantitative overestimation of presecretory reabsorption. This phenomenon appears to have clinical relevance, especially in patients with abnormal urate reabsorption.(ABSTRACT TRUNCATED AT 250 WORDS)

Renal handling of uric acid in gout: Impaired tubular transport of urate not dependent on serum urate levels

Metabolic studies were conducted in 56 patients with primary gout and in ten normal subjects to assess differences in the tubular transport mechanisms of urate. Renal handling of uric acid was examined by means of pyrazinamide and probenecid tests at increased and pharmacologically reduced serum urate concentrations in both groups. Patients with gout showed similar serum urate levels and glomerular filtration rates than controls at both serum urate levles. Pyrazinamide decreased urinary uric acid excretion to less than 1.0% of the urate filtered load in both groups at increased and diminished serum urate concentrations. The maximum uricosuric response promoted by probenecid at high serum urate levels was (mean ± SD) 3,707 ± 443 μg/min/1.73 m 2 in controls and 2,215 ± 738 μg/min/1.73 m 2 in patients with gout ( P < 0.01). Forty-four patients had a daily uric acid excretion rate below 700 mg/1.73 m 2, and all of them showed a diminished uricosuric response to probenecid. When serum urate was reduced in normal subjects and 30 patients to a mean of 2.1 and 2.3 mg/dL, respectively, probenecid elicited a significantly lower urate excretion rate in gout (532 ± 202 μg/min/1.73 m 2) than in controls (922 ± 136 μg/min/1.73 m 2; P < 0.01). Among these 30 patients examined in their basal state and at decreased serum urate levels, uric acid excretion following probenecid was normal in six and diminished in 24 in both situations. The difference between maximum uricosuria and basal urate excretion was not increased in gouty patients. [2- 14C]uric acid kinetics showed a metabolic clearance rate of 6.3 ± 1.5 L/24 h/m 2 in five gouty normoexcretors and 3.5 ± 0.8 L/24 h/m 2 in three underexcretors ( P < 0.01), classified according to both 24-hour uric acid excretion and the uricosuric response elicited by probenecid. These data suggest an impaired tubular secretion of urate in most patients with gout that is not normalized by decreasing serum urate levels. The impaired tubular transport of urate may contribute to increased serum urate in primary gout.

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

Renal handling of uric acid: hypouricemia and tubular urate secretion

Renal handling of uric acid: hypouricemia and tubular urate secretion

Urate transport in the proximal tubule: in vivo and vesicle studies.

The transport of urate in the mammalian nephron is largely confined to the proximal tubule. Depending on the species, net reabsorption or net secretion is observed. The rat, like the human and the mongrel dog, demonstrates net reabsorption of urate and has been the most extensively studied species. The unidirectional reabsorption and secretion of urate in the rat proximal tubule occur via a passive and presumably paracellular route and by a mediated transcellular route. The reabsorption of urate, and possibly its secretion, can occur against an electrochemical gradient. A variety of drugs and other compounds affect the reabsorption and secretion of urate. The effects of these agents depend on their site of application (luminal or blood), concentration, and occasionally their participation in transport processes that do not have affinity for urate. Recent studies with renal brush border and basolateral membrane vesicles from the rat and brush border vesicles from the dog have determined the mechanisms for urate transport across the luminal and antiluminal membranes of the proximal tubule cell. Brush border membrane vesicles contain an anion exchanger with affinity for urate, hydroxyl ion, bicarbonate, chloride, lactate, p-aminohippurate (PAH), and a variety of other organic anions. Basolateral membrane vesicles contain an anion exchanger with affinity for urate and chloride but not for PAH. Both membrane vesicle preparations also permit urate translocation by simple diffusion. A model for the transcellular reabsorption and secretion of urate in the rat proximal tubule is proposed. This model is based on the vesicle studies, and it can potentially explain the majority of urate transport data obtained with in vivo techniques.

Net tubular secretion of bicarbonate by the alligator kidney. Antimammalian response to acetazolamide

Net tubular secretion of bicarbonate by the alligator kidney was demonstrated during acute clearance experiments where the animals were infused with an isosmotic solution of one-half 5% mannitol and one-half 0.9% NaCl. Tubular secretion of bicarbonate averaged 3.38 mumoles/min in animals with a mean wt of 1.0 kg. During these experiments, mean tubular secretion of urate was 0.51 mumole/min and urinary ammonia excretion was 4.3 mumoles/min. Urinary pNH3 was high and ranged from 22,231 to 41,223 mm Hg X 10(-6). The administration of acetazolamide 25 mg/kg resulted in abolition of bicarbonate secretion, which was replaced by bicarbonate reabsorption. At the same time, the tubular secretion of urate fell by 70% and the excretion of ammonia fell by 77%. This is the first time that net tubular secretion of bicarbonate is demonstrated in a living animal. Acetazolamide has an antimammalian effect. It is proposed that the alligator that lives with a low plasma bicarbonate concentration (10 mM) possesses a kidney in which the renal tubular cells secrete bicarbonate in the tubular lumen and hydrogen at the peritubular site, in contrast to that which takes place in mammalia and other animal species.

Renal Handling of Urate in the Syndrome of Inappropriate Secretion of Antidiuretic Hormone

Three patients with the syndrome of inappropriate secretion of antidiuretic hormone had elevated uric acid clearances. Their uric acid clearances decreased markedly after the administration of pyrazinamide. Probenecid was given to two of them and it produced large increases in uric acid clearance. These data suggest that enhanced secretion in the renal tubules was responsible for the increased clearance of uric acid. This article provides evidence that hypouricemia in the syndrome of inappropriate secretion of antidiuretic hormone is due to increased tubular urate secretion.

DIMINISHED TUBULAR SECRETION OF URATE IN GOUT NOT DEPENDENT ON SERUM URATE LEVELS: 128

To determine whether an impaired tubular transport mechanism for urate could differentiate the pathogenesis of gouty hyperuricemia and if serum urate influences the renal handling of uric acid, we conducted metabolic studies in 56 patients with primary gout. Tubular reabsorption of urate was normal. Tubular secretory rate was 29.3 ± 8.7 percent of filtered urate as compared to 42.4 ± 4.3 percent in 10 normal subjects for a similar urate filtered load (P < 0.01). Among 30 patients examined in the basal state and at pharmacologically reduced serum urate levels, 24 showed a diminished and 6 normal tubular urate secretion in both states of uricemia. According to the probenecid test, 45 patients evidenced a diminished uricosuric response and 11 normal urate excretion rates. This classification was similar to that obtained by the 24-h urinary urate excretion and was identical to that established by means of [2-14C]uric acid in 8 selected patients. We conclude that an impaired tubular secretion of urate may differentiate gouty underexcretors from uric acid overproducers. Increased serum urate is not the cause but a consequence of the impaired tubular urate secretory mechanism in gout.

HYPOURICEMIA DUE TO RENAL URATE WASTING: DIFFERENT TYPES OF TUBULAR TRANSPORT DEFECTS: 94

Intrarenal handling of uric acid was evaluated in five patients with diminished serum urate levels (1.4 to 2.0 mg/dl) and increased renal clearance of uric acid (22.9 to 65.3 ml/min/1.73 m2). One patient with kappa light-chain disease and Fanconi syndrome showed a blunted uric acid excretion response to both pyrazinamide and probenecid, indicating a defective tubular reabsorption of urate. Three patients had recurrent calcium oxalate nephrolithiasis and one infant bening idiopathic hematuria. In addition to hyperuricosuria the infant and two patients with recurrent urolithiasis showed renal hypercalciuria. All evidenced normal responses to pyrazinamide. Compared to normal subjects, three patients showed a diminished and one an increased uricosuric response to probenecid. The former were considered to have a defective tubular urate postsecretory reabsorption and the latter an enhanced tubular secretion of urate. These results indicate that (1) hypouricemia may provide an important clue for the existence of an underlying disease, and (2) tubular urate transport defects may be of pathogenic importance in patients with recurrent calcium nephrolithiasis.

Effects of SITS on urate transport by isolated, perfused snake renal tubules.

Effects of an inhibitor of membrane anion-exchange transport processes, 4-acetamido-4'-isothiocyano-2,2'-disulfonic stilbene (SITS), on urate transport by isolated, perfused snake (Thamnophis spp.) proximal renal tubules were studied. SITS (10(-4) mol/l) in the luminal perfusate had absolutely no effect on net urate secretion (Jneturate) or on net fluid absorption (JV). This observation is compatible with other data that give no support to the concept of a mediated transport step for urate from the cells to the lumen. SITS (10(-4) mol/l) in the bathing medium reversibly inhibited Jneturate without affecting JV. At the time of maximum inhibition of Jneturate, the concentration of urate in the cell water was increased and the apparent permeability of the luminal membrane to urate was decreased, but the urate efflux across the peritubular membrane and the apparent permeability of the peritubular membrane to urate were unchanged. There was no evidence of significant intracellular binding or trapping of urate. Although an increase in the initial rate of urate transport into the cells across the peritubular membrane could not be demonstrated conclusively in nonperfused tubules, the results still suggest that SITS in the bathing medium may inhibit Jneturate by inhibiting urate movement from the cells to the lumen while actually enhancing transport from the bathing medium into the cells.

Glomerular function and hyperuricaemia in sickle cell disease.

Renal insufficiency is common in adults with homozygous sickle cell disease, and the contribution of glomerular failure to the hyperuricaemia which is often a feature of the disease has therefore been investigated. In a study of 64 patients between the ages of 15 and 66, serum urate concentration was dependent on renal urate clearance and also on creatinine clearance. The relation between serum urate and creatinine clearance was abnormal in patients with sickle cell disease and it is suggested that this might be caused by high single nephron glomerular filtration rates. Both the amount of urate excreted per millilitre of glomerular filtrate and the fractional excretion of urate increased with falling creatinine clearance, suggesting that the ability to increase tubular urate secretion was preserved. Patients with extensive tubular disease as shown by tubular proteinuria had serum urate concentrations which were not significantly different from those of age and sex matched non-proteinuric patients. Evidence that renal tubular disease interferes with urate secretion and causes hyperuricaemia in patients with sickle cell disease needs to be reinterpreted in the light of these findings.

Lack of effect of low [Ca2+], La3+, and pyrazinoate on urate transport by isolated, perfused snake renal tubules.

Effects of low medium calcium concentration, of lanthanum, and of pyrazinoate on urate transport by isolated, perfused snake (Thamnophis spp.) distal-proximal renal tubules were studied. Removal of calcium from perfusate with 0.18 mmol/l calcium in bathing medium had no effect on net urate secretion (J net urate) or on net fluid absorption (Jv). In the presence of calcium (1.8 mmol/l), lanthanum (2.0 mmol/l) in perfusate alone, in bathing medium alone, or in both perfusate and bathing medium had no effect on J net urate. These findings suggest that urate transport, in contrast to para-aminohippurate (PAH) transport, is not sensitive to calcium entry into the cells and support the concept that urate and PAH are transported by separate mechanisms in these renal tubules. Pyrazinoate (1.0 mmol/l) in the bathing medium had no effect on J net urate or Jv. These findings do not support the idea of a primary urate secretory process uniquely sensitive to pyrazinoate among the vertebrates.

Renal handling of uric acid in patients with recurrent calcium nephrolithiasis and hyperuricosuria.

Hyperuricosuria is a frequent finding in patients with recurrent calcium nephrolithiasis (RCN) that has been related to purine overingestion . The influence of diet and the renal handling of uric acid were investigated in patients with RCN to assess the pathogenic mechanism of excessive urate excretion. Among 50 patients with recurrent nephrolithiasis 42 formed renal stones containing calcium and 9 of these 42 patients demonstrated concomitant asymptomatic hyperuricosuria while on a self-selected diet. Ingestion of a purine-free diet normalized the uric acid excretion in 4 of these 9 patients. The other 5 patients showed persistent hyperuricosuria while on a purine-free diet. In order to assess a possible dysfunction in the renal handling of uric acid, pharmacological tests were undertaken in these 9 patients. Pyrazinamide administration almost completely suppressed urate excretion, excluding a presecretory reabsorption defect. Urate excretion in response to probenecid administration was decreased in 4 patients and increased in 1. This finding is in accordance with a postsecretory reabsorption defect in the former and an augmented tubular secretion of urate in the latter. This study proves that both dietary factors and tubular transport defects are involved in patients with recurrent calcium nephrolithiasis and hyperuricosuria.

Hypouricemia and Renal Tubular Urate Secretion

Hypouricemia and Renal Tubular Urate Secretion

Hypouricemia and Renal Tubular Urate Secretion-Reply

In Reply. —Sanz et al presented an interesting combination of recurrent nephrolithiasis and hypouricemia probably due to increased uric acid secretion. During the past two years, I have encountered five patients with hyperuricosuria due to enhanced uric acid excretion. Three patients had persistent hypouricemia due to an increment in renal tubular urate secretion (of whom two were described in the OctoberArchives). They showed abnormal oral glucose tolerance test results and two of them required treatment for diabetes. The remaining two patients had a syndrome of inappropriate secretion of antidiuretic hormone (SIADH). When their serum sodium levels were decreased, their serum uric acid level fell and excretion of uric acid increased. Pyrazinamide and probenecid therapy was administered and the results were compatible with an increment in renal tubular urate secretion. In diabetes, as well as in SIADH, increased uric acid excretion brings about the lower serum uric acid level. 1-5