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PubMed1994

Enhanced enteric excretion of urate in rats with chronic renal failure.

1. The potential contribution of enteric pathways to the extra-renal excretion of uric acid in chronic renal failure was evaluated by measuring [14C]-urate and 36Cl- transport in isolated, short-circuited segments of jejunum, ileum and distal colon from normal rats and rats with chronic renal failure (five-sixths nephrectomized) 6 weeks after surgery. Plasma and urine creatinine and urate concentrations were also determined to establish urate status in chronic renal failure. 2. A 40% reduction in creatinine clearance was observed in the group with chronic renal failure, resulting in a two-fold increase in plasma creatinine concentration (0.064 +/- 0.001 mmol/l, n = 9, to 0.120 +/- 0.008 mmol/l, n = 14). In contrast, there was no change in plasma urate concentration, despite a 75% reduction in urate clearance. 3. The transport studies demonstrated alterations in intestinal urate transport in rats with chronic renal failure compared with normal rats. Net absorption of urate was observed in the distal colon of control rats, whereas a significant secretory flux was observed in rats with chronic renal failure (from 0.88 +/- 0.16 to -1.62 +/- 0.81 nmol h-1 cm-2, n = 12). Urate secretion was induced in the jejunum of the group with chronic renal failure (-0.15 +/- 0.25 in control and -1.67 +/- 0.35 nmol h-1 cm-2 in chronic renal failure, n = 11). Urate transport across the ileum was not altered in chronic renal failure and there was no net flux of urate in either the normal group or the group with chronic renal failure.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Tamm-Horsfall mucoprotein reduces promotion of calcium oxalate crystal aggregation induced by urate in human urine in vitro.

1. Increasing the concentration of dissolved urate promotes calcium oxalate crystallization in urine from which Tamm-Horsfall mucoprotein, an inhibitor of calcium oxalate crystal aggregation, has almost completely been removed. This study aimed to determine whether the effect of urate could be reduced or abolished by a physiological concentration of Tamm-Horsfall mucoprotein. This was approached in two ways. 2. The effect of Tamm-Horsfall mucoprotein on calcium oxalate crystallization induced by urate was tested in ultrafiltered (10 kDa) urine samples from 10 healthy men. Tamm-Horsfall mucoprotein (35 mg/l) was added to half of each specimen, the urate concentration was increased by the addition of sodium urate solution and crystallization was induced by a standard load of oxalate. The remainder of each urine specimen was used as a control; these specimens were treated with an identical amount of urate solution, but contained no Tamm-Horsfall mucoprotein. Tamm-Horsfall mucoprotein had no effect on the urinary metastable limit or on the deposition of calcium oxalate, but significantly reduced the size of the particles precipitated. 3. The effect of increasing the urate concentration in the presence of Tamm-Horsfall mucoprotein was tested. Tamm-Horsfall mucoprotein (35 mg/l) was added to 10 ultrafiltered urine samples as before, the samples were divided, and the concentration of urate was increased in half of each specimen. Compared with the control to which no urate was added, urate significantly reduced the amount of oxalate required to induce spontaneous calcium oxalate nucleation and increased the median volume and the particle size of the material deposited.(ABSTRACT TRUNCATED AT 250 WORDS)

Calcium Oxalate↗
PubMed2002

Anti- and pro-oxidant effects of urate in copper-induced low-density lipoprotein oxidation.

We reported earlier that urate may behave as a pro-oxidant in Cu2+-induced oxidation of diluted plasma. Thus, its effect on Cu2+-induced oxidation of isolated low-density lipoprotein (LDL) was investigated by monitoring the formation of malondialdehyde and conjugated dienes and the consumption of urate and carotenoids. We show that urate is antioxidant at high concentration but pro-oxidant at low concentration. Depending on Cu2+ concentration, the switch between the pro- and antioxidant behavior of urate occurs at different urate concentrations. At high Cu2+ concentration, in the presence of urate, superoxide dismutase and ferricytochrome c protect LDL from oxidation but no protection is observed at low Cu2+ concentration. The use of Cu2+ or Cu+ chelators demonstrates that both copper redox states are required. We suggest that two mechanisms occur depending on the Cu2+ concentration. Urate may reduce Cu2+ to Cu+, which in turn contributes to formation. The Cu2+ reduction is likely to produce the urate radical (UH.-). It is proposed that at high Cu2+ concentration, the reaction of UH.- radical with generates products or intermediates, which trigger LDL oxidation. At low Cu2+ concentration, we suggest that the Cu+ ions formed reduce lipid hydroperoxides to alkoxyl radicals, thereby facilitating the peroxidizing chain reaction. It is anticipated that these two mechanisms are the consequence of complex LDL-urate-Cu2+ interactions. It is also shown that urate is pro-oxidant towards slightly preoxidized LDL, whatever its concentration. We reiterate the conclusion that the use of antioxidants may be a two-edged sword.

Animals↗
PubMed1997

Molecular cloning and functional reconstitution of a urate transporter/channel.

Maintenance of urate homeostasis requires urate efflux from urate-producing cells with subsequent renal and gastrointestinal excretion. The molecular basis for urate transport, however, has not been identified. A novel full-length cDNA encoding a 322-amino acid protein, designated UAT (urate transporter), has been cloned from a rat renal cDNA library by antibody screening. UAT mRNA transcripts that approximate 1.55 kilobases are present, but differentially expressed in various rat tissues. Recombinant UAT protein that was expressed from the cloned cDNA in Escherichia coli and purified via immobilized metal affinity chromatography has been functionally reconstituted as a highly selective urate transporter/channel in planar lipid bilayers. The IgG fraction of the polyclonal antibody that was used to select the UAT clone from the cDNA library, but not nonimmune IgG, blocked urate channel activity. Based on the wide tissue distribution of the mRNA for UAT we propose that UAT provides the molecular basis for urate flux across cell membranes, allowing urate that is formed during purine metabolism to efflux from cells and serving as an electrogenic transporter that plays an important role in renal and gastrointestinal urate excretion.

Amino Acid Sequence↗
PubMed1969

Effect of drugs on urate binding to plasma proteins.

The effect of various drugs on urate binding to plasma proteins was investigated in normal subjects. Whereas allopurinol, aspirin, phenylbutazone, probenecid, and sulphinpyrazone all significantly reduced plasma urate concentrations, only aspirin, phenylbutazone, and probenecid significantly impaired urate binding. Colchicine and indomethacin in the doses administered had no significant effect on plasma urate concentrations or binding. In the case of aspirin, urate binding was reduced to 25% of normal, and this effect was quickly abolished after cessation of therapy. Phenylbutazone reduced urate binding to 56% and probenecid to 46% of normal; this impairment was still detected four days after cessation of therapy. Drugs may impair urate binding by competition for plasma protein binding sites, with displacement of bound urate. Impairment of urate binding in vivo by administration of certain drugs may be relevant to the precipitation of acute gouty arthritis, to the formation of gouty tophi, and to the augmentation of uricosuria. Furthermore, the role of drugs must be seriously considered during all studies on urate binding in patients with gout.

Adult↗
PubMed1975

Characteristics of urate influx in the rat nephron.

Permeability of the tubular epithelium to urate presented on the peritubular side was studied in anesthetized rats during mannitol diuresis by capillary microinjections of [14C]urate and [3H]inulin, [14C]PAH and [3H]inulin, or [14C]urate and [3H]PAH. Recovery of isotopes was determined in urine collected serially from the injected and contralateral kidney. Appearance and peak excretion of urate in the experimental but not in the contralateral kidney preceded inulin and coincided with PAH, indicating proximal permeability to urate. Recovery of urate was higher from the injected than from the contralateral kidney. Urate precession and recovery did not change after addition of PAH (1.5-6.4 mm) to [14C]urate-[3H]inulin solutions, whereas they decreased significantly in the experimental kidney after pyrazinoate (1.6-3.2 mM) addition. On the other hand, no effect of urate on [14C]PAH-[3H]inulin injections was detectable. These findings are suggestive of a carrier-mediated transtubular influx of urate in rat proximal tubule. Absence of competition with PAH may suggest differences in the secretory mechanisms for organic acids.

Aminohippuric Acids↗
PubMed1976

Urate reabsorption in proximal convoluted tubule of the rat kidney.

Urate reabsorption was examined in the rat utilizing clearance and in vivo microperfusion techniques. In control rats, the fractional excretion of urate averaged 12.5 +/- 1.3% of the filtered load, with 60-70% of perfused urate reabsorbed at 2 mm of perfused tubule length (urate efflux). Increasing the perfusion concentration of urate to 6, 12, and 25 mg/100 ml did not alter the fractional rate of reabsorption. The acute administration of chlorothiazide resulted in a fall in GFR and Curate such that the fractional excretion was unchanged from controls and averaged 13.3 +/- 2.0%, without an associated change in urate reabsorption from proximal perfusates despite the presence of significant inhibition of sodium and water reabsorption. By contrast, the chronic administration of chlorothiazide accompanied by a low-sodium diet resulted in a significantly lower fractions excretion rate of urate of 7.95 +/- 0.5% and a significant increase in reabsorption of sodium and water as well as urate from microperfusates, In control rats receiving an infusion of 5% mannitol in isotonic saline, urate secretion was demonstrated by the urinary precession of [2-14C]urate from [methoxy-3H]inulin following placement of these isotopes on the surface of the kidney. The additional infusion of chlorothiazide did not alter this pattern of isotope recovery in the urine.

Animals↗
PubMed1980

Micropuncture study of tubular transport of urate and PAH in the pig kidney.

At physiological plasma urate concentration (Purate) (0.05 mg/dl), net secretion of urate occurred in the convoluted part of the proximal tubule of micropunctured anesthetized pigs. The fraction of filtered urate delivered to the point of micropuncture ((TF/P)urate/(TF/P)polyfructosan) was 4.8 +/- 0.5 (mean +/- SE, n =10). Urate was reabsorbed from lower tubular segments, since the fractional excretion of urate (FEurate) was only 2.1. Saturation of secretion as well as reabsorption occurred at Purate of 1.6 mg/dl. p-Aminohippurate (PAH) secretion also occurred mainly in the pars convoluta of the proximal tubule: (TF/P)PAH/(TF/P)polyfructosan was 4.0 +/- 0.4 (n = 11), whereas the FEPAH was 4.5 +/- 0.5 (n = 5). Thus, the pars recta does not contribute significantly to the net secretion of either urate or PAH. PAH was a competitive inhibitor of urate secretion. At a PPAH of 60 mg/dl there was overall net reabsorption of urate. Accordingly, in the pig PAH and urate seem to be secreted by the same transport mechanism.

Absorption↗
PubMed1983

Urate transport via anion exchange in dog renal microvillus membrane vesicles.

The transport of urate was evaluated in brush border membrane vesicles isolated from the dog renal cortex. It was previously shown that uphill urate and p-aminohippurate (PAH) uptake into these membrane vesicles results from imposing an outwardly directed OH- gradient. In the present study, the OH- gradient-stimulated uptake of urate was inhibited by external Cl-. In the absence of OH- gradients, imposing an outwardly directed Cl- gradient induced the transient accumulation of urate against its concentration gradient (overshoot), whereas imposing an inwardly directed Cl- gradient induced the transient uphill efflux of urate (undershoot). The effects of Cl- gradients on urate transport persisted when the diffusion potentials caused by the Cl- gradients were negated by superimposing K+ gradients in the presence of the K+ ionophore valinomycin. The dose-response curves for three different inhibitors were identical for the OH- and Cl- gradient-stimulated modes of urate uptake. The uptake of PAH was also stimulated by imposing an outwardly directed Cl- gradient. The dose-response curves for probenecid inhibition were identical for the OH- and Cl- gradient-stimulated modes of PAH uptake. Finally, the existence of a Na+ cotransport pathway for urate or PAH could not be demonstrated. We conclude that the principal mechanism for urate transport in dog renal microvillus membrane vesicles is via an anion exchanger with affinity for urate, PAH, OH-, and Cl-. This anion exchanger may play an important role in mediating organic anion reabsorption and secretion in the proximal tubule.

Animals↗
PubMed1985

Carrier-mediated concentrative urate transport in rat renal membrane vesicles.

[2-14C]Urate uptake and efflux were studied in brush border and basolateral membrane vesicles of rat renal cortex that were exposed to 20 microM copper chloride. In the presence of inwardly directed NaCl gradients urate uptake was maintained at levels in excess of chemical equilibrium. Comparison of glucose and chloride uptakes revealed that equilibrium glucose uptake was not affected by copper, but chloride failed to reach equilibrium in copper-exposed vesicles. It is suggested that the persistence of an electrolyte gradient could provide a driving force to raise the concentration of free intravesicular urate above that in the media. Preincubation of vesicles with unlabeled urate failed to diminish uptake of added urate; rather, urate uptake was trans stimulated. Uptake of labeled urate was also significantly accelerated when an outward gradient for unlabeled urate was created. Pyrazinoic and oxonic acids also trans stimulated urate uptake. The demonstration of accelerated homeo- and heteroexchange diffusion indicates that transport is carrier mediated in both brush border and basolateral vesicles. Outwardly directed hydroxyl gradients failed to influence urate uptake in either the presence or absence of copper or NaCl. Thus, this carrier, which is active only in the presence of trace amounts of copper, is distinct from a urate/anion exchanger.

Animals↗
PubMed1991

Indirect Na+ dependency of urate and p-aminohippurate transport in pig basolateral membrane vesicles.

Membrane vesicles were used to study the basolateral transport of urate and p-aminohippurate (PAH) in the proximal tubule of the pig kidney. Consistent with a cooperation between a Na(+)-2-oxoglutarate cotransporter and a 2-oxoglutarate-urate or a 2-oxoglutarate-PAH exchanger, urate and PAH uptakes were stimulated in presence of extravesicular 2-oxoglutarate when an inwardly directed Na+ gradient was applied. Both transports exhibited, however, different characteristics. The optimal 2-oxoglutarate concentration for stimulating uptakes was 10 microM for PAH and 150 microM for urate. Extravesicular chloride was required to observe a stimulation of PAH uptake but not of urate uptake. Transports of both PAH and urate exhibited different affinity sequences for various organic anions. Stimulated PAH uptake was inhibited by probenecid greater than cold PAH greater than urate = pyrazinoate greater than lactate, whereas stimulated urate uptake was inhibited by probenecid greater than cold urate greater than PAH and not by pyrazinoate or lactate. These results are consistent with independent transport processes for urate and PAH in pig basolateral membrane vesicles, both being indirectly driven by an inwardly directed Na+ gradient.

Animals↗
PubMed2003

Serum urate as an independent predictor of poor outcome and future vascular events after acute stroke.

BACKGROUND AND PURPOSE: Serum urate concentration is associated with cardiovascular disease, and hyperuricemia predicts first-ever stroke. We explored the association of admission urate level with mortality, placement, and risk of further vascular events after acute stroke. METHODS: In patients with ischemic stroke or primary intracranial hemorrhage, we determined the association of urate level with 90-day placement (alive at home, good outcome; dead or living in care, poor outcome) and with the subsequent occurrence of ischemic stroke, myocardial infarction, or vascular death. In multivariate analysis (logistic regression for 90-day placement, proportional-hazards regression for time to further vascular event), we adjusted for stroke severity (modified National Institutes of Health stroke scale) and other clinical, biochemical, and radiological variables known to influence stroke outcome. RESULTS: We studied 3731 patients and measured serum urate in 2498. Elevated urate level predicted a lower chance of good 90-day outcome (odds ratio, 0.78 per additional 0.1 mmol/L; 95% confidence interval [CI], 0.67 to 0.91) independently of stroke severity and other prognostic factors. Vascular event risk increased with urate level (relative hazard, 1.27 per additional 0.1 mmol/L; 95% CI, 1.18 to 1.36). Higher urate levels have a greater effect on vascular event rates in the presence of diabetes (additional relative hazard, 1.22 per additional 0.1 mmol/L; 95% CI, 1.06 to 1.41). CONCLUSIONS: Independently of other prognostic factors, higher serum urate levels predicted poor outcome (dead or in care) and higher vascular event rates. The role of urate in stroke pathophysiology remains uncertain, but intervention to lower urate may be worth considering.

Acute Disease↗
PubMed1971

Urate-2-14C transport in the rat nephron.

Intrarenal transport of urate-2-(14)C was studied in anesthetized rats using the microinjection technic. During saline diuresis, small volumes of urate-2-(14)C (0.24-0.48 mM) and inulin-(3)H were injected into surface proximal and distal convoluted tubules, and ureteral urine was collected serially. Total (74-96%) and direct (57-84%) urate recovery increased significantly the more distal the puncture site. Delayed recovery (+/-20%) remained approximately the same regardless of localization of the microinjection. After proximal injections, total and direct recoveries of urate-2-(14)C were significantly higher in rats treated with probenecid, pyrazinoate, or PAH than during saline diuresis alone, while the excretion rates were comparable after distal injection. Delayed recovery was not altered by drug administration. The decreased proximal reabsorption of urate is presumably due to an effect of the drugs on the luminal membrane of the nephron. For perfusion at high urate concentrations, nonradioactive urate was added to the injectate (0.89-1.78 mM). Urate-2-(14)C recovery was almost complete and there was no delayed excretion, demonstrating saturation kinetics. These findings are compatible with a carrier-mediated mechanism for urate transport probably located at the luminal border of the proximal tubular epithelium. No definitive evidence for urate secretion was found in these studies.

Aminohippuric Acids↗
PubMed1985

Paradoxical effects of pyrazinoate and nicotinate on urate transport in dog renal microvillus membranes.

The effects of pyrazinoate and nicotinate on urate transport in microvillus membrane vesicles isolated from canine renal cortex were evaluated. An outwardly directed gradient of pyrazinoate stimulated uphill urate accumulation, suggesting urate-pyrazinoate exchange. An inside-alkaline pH gradient stimulated uphill pyrazinoate accumulation, which suggested pyrazinoate-OH- exchange. Pyrazinoate-OH- exchange and urate-OH- exchange were similarly sensitive to inhibitors, implying that both processes occur via the same transport system. In addition, an inward Na+ gradient stimulated uphill pyrazinoate accumulation, suggesting Na+-pyrazinoate cotransport. Inhibitor studies demonstrated that Na+-pyrazinoate cotransport takes place via the same pathway that mediates Na+-lactate cotransport in these membrane vesicles. Previously we found that urate does not share this Na+-dependent cotransport pathway. Nicotinate inhibited transport of pyrazinoate by the anion exchange pathway and the Na+ cotransport pathway, suggesting that it is a substrate for both transport systems. Finally, in the presence of an inward Na+ gradient, low doses of pyrazinoate or nicotinate stimulated urate uptake, and higher doses of pyrazinoate or nicotinate inhibited urate accumulation, thereby mimicking in vitro the paradoxical effects of drugs on renal urate excretion that have been observed in vivo. These findings indicate that the paradoxical effect of uricosuric drugs at low doses to cause urate retention may result at least in part from stimulation of urate reabsorption across the luminal membrane of the proximal tubular cell.

Animals↗
PubMed1994

Body lead stores and urate excretion in men with chronic renal disease.

OBJECTIVE: To determine the relationship of urate excretion to body lead stores in patients with chronic renal disease without previous lead exposure. METHODS: We compared 40 male subjects in 3 groups, on the basis of their serum creatinine and histories of gout, with serum urate, creatinine clearance, urate clearance, daily urate excretion, fractional urate excretion, and body lead stores. Group 1 consisted of 10 patients with normal serum creatinine levels and no evidence of gout. Group 2 contained 10 men with gout and abnormal serum creatinine levels. Group 3 included 20 subjects with abnormal serum creatinine levels and no evidence of gout. All patients received EDTA mobilization tests and 72 h urine collections. The total amount of lead excreted over 72 h was estimated as the body lead stores. An ANOVA test with Fisher pairwise least significant difference, correlation coefficients, and multiple linear regression test were used to measure any statistical significance among these variables. A p value < 0.05 was considered significant. RESULTS: Lead stores and serum urate were significantly higher in gouty patients with renal insufficiency than those of other groups, but the urate excretion of gouty patients was not relatively increased. Not only was there a significant correlation between creatinine clearance and urate excretion, but body lead stores also appeared to be negatively related to urate excretion in our patients, even though body lead stores in these subjects were within the normal range. CONCLUSION: Our findings suggest that lead may play a role in gouty patients with impaired renal function and chronic low level environmental lead exposure may subtly affect urate excretion in patients with chronic renal disease.

Adult↗
PubMedDate not supplied

Soluble urate in sera and synovial fluids from patients with different joint disorders.

OBJECTIVE: To evaluate simultaneous serum and synovial fluid (SF) urate levels in various inflammatory and noninflammatory joint disorders and to correlate SF white blood cell (WBC) counts with serum and joint fluid urate levels. METHODS: Sixty-three paired samples of sera and SF from 58 patients including 25 patients with inflammatory arthropathies, 18 patients with gout and 15 patients with noninflammatory joint disorders, were measured for urate concentrations by a UV enzymatic method. RESULTS: In inflammatory arthropathies other than gout, urate concentrations in SF were significantly lower than in paired sera (p < 0.0001). There was no difference between the SF and serum urate levels in noninflammatory arthropathies and in gout. In gout, however, SF urate occasionally were found to be considerably higher than in sera. This phenomenon was observed in fluids with massive amounts of monosodium urate crystals. There was no correlation between SF WBC counts and serum of SF urate levels in any of the disease groups studied. CONCLUSIONS: Serum and synovial fluid levels vary more than previously recognized. SF urate levels tend to reflect serum levels in gout and noninflammatory arthropathies but not in inflammatory joint disorders. Disturbed purine metabolism in inflammatory arthropathies may reflect a component in the pathophysiology of inflammation. The elevations of SF urate levels seen in gout are unique for this disease and most likely reflect crystal dissolution in joints.

Adult↗
PubMed1996

[The mechanisms of urate transport in the kidney and the intestine].

Most urate is secreted from the kidney, but the intestine can also secrete urate. In the kidney, urate is transported in the proximal tubule which shows marked species differences. In human and rat, net urate reabsorption is seen, whereas rabbit and pig show net secretion. The transport of urate in the proximal tubule is bidirectional, reabsorption in S1, secretion in S2, and postsecretory reabsorption in S3. Although the mechanisms of transcellular urate transport are not fully understood, the influx of urate into the proximal tubule cell should be carried out by urate/anion exchanger, and the efflux by potential driven pathway. In the intestine, purine compounds are strongly metabolized to urate, that is transported. When the kidney function is normal, urate is reabsorbed, but in renal insufficiency urate can be excreted from the intestine.

Aged↗
PubMed1997

Effects of uricosuric and antiuricosuric agents on urate transport in human brush-border membrane vesicles.

Inhibition of [14C]-urate uptake by uricosuric and antiuricosuric agents was investigated in human brush-border membrane vesicles, urate being transported either by anion exchange mechanisms or by voltage sensitive pathway. The IC50 for drugs on [14C]-urate uptake in vesicles loaded with 1 mM cold urate or with 5 mM lactate was, respectively: 0.7 and 0.3 microM for benzbromarone; 6 and 4 microM for salicylate; 133 and 13 microM for losartan; 520 and 190 microM for sulfinpyrazone and 807 and 150 microM, for probenecid. The IC50 ratio for [14C]-urate uptake in exchange for cold urate or for lactate varied from about 1 for salicylate to 10 for losartan, supporting the hypothesis that two distinct anion exchangers are involved in urate transport. Application of Hill equation revealed that urate/anion exchangers have more than one binding site, possibly two binding sites with high cooperativity, for benzbromarone and sulfinpyrazone, but only one for probenecid, salicylate and losartan. The uricosuric diuretic, tienilic acid was 10 to 50 times more potent than hydrochlorothiazide, chlorothiazide and furosemide, for inhibiting [14C]-urate uptake in exchange for cold urate. This higher potency is the reason of its uricosuric properties. All uricosuric agents, as well as the antiuricosuric agents, pyrazinoate and ethambutol, had a much lower potency for inhibiting [14C]-urate uptake through the voltage sensitive pathway (apical secretory step) than through the urate/anion exchangers. This suggests that antiuricosuria, induced by pyrazinoate and ethambutol, as well as by low concentrations of uricosuric agents, does not result from an inhibition of the apical voltage sensitive pathway.

Aged↗