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PubMed1981

Properties of two urate oxidases modified by the covalent attachment of poly(ethylene glycol).

Poly(ethylene glycol) of 5 000 daltons has been attached covalently to preparations of urate oxidase (urate: oxygen oxidoreductase, EC 1.7.3.3) from hog liver and Candida utilis. Attachment of sufficient poly(ethylene glycol) to either urate oxidase renders the enzyme incapable of eliciting antibody production in mice, or of reacting with antibodies to the unmodified enzyme. The poly(ethylene glycol) : urate oxidase conjugates exhibit higher Km and lower V values than the unmodified urate oxidases. Optimal pH values are increased for the poly(ethylene glycol) : urate oxidases, and optimal temperatures are decreased. The blood circulating lives of the modified urate oxidases following intravenous injection are much longer than those of the unmodified urate oxidases: repetitive injections over a period of 90 days dd not alter the blood circulating lives of the poly(ethylene glycol) : urate oxidases. The unmodified enzymes, on the other hand, were cleared from the blood with extreme rapidity after a few intravenous injections.

Animals↗
PubMed1996

[Abnormalities in urate metabolism: concept and classification].

Most of the primates, unlike other mammals, have mutations in urate oxidase gene and cannot catabolize urate in the bodies. In addition to the genetic defects, some human subjects have various abnormalities in urate metabolism. Urate metabolism abnormalities are classified into two categories, hyperuricemia and hypouricemia. Usually, the urate pool size of an adult male is about 1,200 mg, and 700 mg urate is produced daily. The production is balanced by the excretion of urate into urine (500 mg) and intestine (200 mg). If this balance is disturbed, either hyperuricemia or hypouricemia occurs. According to the mechanisms, hyperuricemia is classified into overproduction and underexcretion, and hypouricemia into underproduction and overexcretion. Overproduction of ruate is caused by PRPP synthetase superactivity, HPRT deficiency, leukemia and alcohol ingestion. Underexcretion of urate is caused by renal insufficiency and treatment by diuretics. Underproduction of urate is caused by xanthine dehydrogenase deficiency, purine nucleoside deficiency and allopurinol treatment. Overexcretion of urine is caused by familial renal hypouricemia, Fanconi's syndrome, diabetes mellitus and treatments with benzbromarone and probenecid. All of these conditions are classified, according to other aspects, into primary and secondary, and genetic and non-genetic abnormalities.

Adult↗
PubMed1981

The effect of lead upon urate nucleation.

Lead urate was crystallized from solutions originally containing 0.595 mM (10 mg%) urate and 0.297 mM PbCl2. In the absence of lead, monosodium urate does not nucleate unless the urate concentration exceeds 80 mg%. Lead urate crystals were negatively birefringent and had a distinct x-ray powder diffraction pattern. Crystals of monosodium urate nucleated on lead urate seed crystals when the urate concentration was 10 mg%. These studies indicate that with physiologic conditions of temperature, pH, and ionic strength, spontaneous nucleation of lead urate can be demonstrated.

Chemical Phenomena↗
PubMed2005

Renal urate handling: clinical relevance of recent advances.

Urate is the major inert end product of purine degradation in higher primates in contrast to most other mammals because of the genetic silencing of hepatic oxidative enzyme uricase. The kidney plays a dominant role in urate elimination. The kidney excretes 70% of the daily urate production. Therefore, it is important to understand renal urate handling mechanism because the under excretion of urate has been implicated in the development of hyperuricemia that leads to gout. The urate transport systems exist in the proximal tubule but they are complicated because of their bidirectional transport and the species differences. Recently, we have identified the urate-anion exchanger URAT1 (SLC22A12) in the human kidney and found that defects in SLC22A12 lead to idiopathic renal hypouricemia. URAT1 is targeted by uricosuric and antiuricosuric agents that affect urate excretion. Molecular identification of urate transporting proteins will lead to the new drug development for hyperuricemia.

Animals↗
PubMed1992

Urate excretion by the cat kidney.

1. The renal handling of urate by the cat kidney was investigated during continuous infusion of urate. 2. Fractional urate excretion (FE(UA)) in cats was 0.57 +/- 0.04, indicating net reabsorption of urate. In contrast, FE(UA) in rabbits was 1.76 +/- 0.08, reflecting net secretion of urate. 3. Fractional PAH excretion (FE(PAH)) was 3.94 +/- 0.26 in cats and 4.12 +/- 0.76 in rabbits, showing net secretion in both species. 4. FE(UA) in cats was dependent on urine flow, but was independent of plasma urate concentration. 5. The urate excretion in cats was enhanced by probenecid, but was insensitive to PAH and PZA. 6. The PAH excretion in cats was reduced by probenecid, but was unaltered by urate and PZA. 7. These results indicate that urate is handled in the cat kidney by a unique transport system which is distinct from that for organic anions.

Animals↗
PubMed1989

Solubility of uric acid and supersaturation of monosodium urate: why is uric acid so highly soluble in urine?

The solubility of uric acid and the stability of supersaturation of monosodium urate (NaU) were studied in buffer solutions containing 150 mM sodium in the physiological urinary pH range at 37C. The solubility of uric acid increased with the rise in pH, and the total dissolved urate (undissociated uric acid + urate anion) concentration did not change during seven-day incubation in the pH range below 6.6. In this pH range, the calculated concentration of undissociated uric acid was constant (about six mg./dl.). Consequently, the increasing solubility of uric acid with the rise in pH depended solely on the increase of urate anion. As much as 220 mg./dl. of uric acid could be dissolved for 24 hours at pH 7.0. But following seven-day incubation the total dissolved urate concentration decreased to 16 mg./dl. due to NaU crystallization. The stability of NaU supersaturation depended not only on the concentration of sodium and urate anion but also on time and pH. When monopotassium urate crystals were incubated for seven days, the total dissolved urate concentration decreased according to NaU crystallization; the higher the pH, the more marked the decrease. However, at least some 80 mg./dl. of total dissolved urate was stable up to pH 8.2 within 24 hours. These findings can well explain why NaU crystals are seldom formed in the normal urine. Urinary stasis and/or pathological high urinary pH may cause NaU crystallization.

Buffers↗
PubMed1997

Urate protects a blood-sucking insect against hemin-induced oxidative stress.

Urate at high concentrations (up to 5 mM) is found in the hemolymph of the blood-sucking bug, Rhodnius prolixus. Increased urate levels are observed in the days following a blood meal. Injecting hemin into the hemocoel increases both urate titer and TBARS formation in the hemolymph. The urate response to hemin injection seems to arise from increased synthesis by the fat body as urate secretion by this organ is stimulated in vitro by incubation with hemin, and markedly counteracted by allopurinol. Allopurinol injection also results in increased TBARS formation in the hemolymph. High O2 atmospheric conditions also increases hemolymph urate levels, confirming that urate release represents an antioxidant response. Urate concentrations at the range reported here might account for almost all free radical scavenging activity of the hemolymph, as deduced from TRAP assay experiments, indicating that this is the major low molecular weight protection of this insect against oxidative insult. Since large amounts of hemin are produced in the midgut following blood digestion, increased urate hemolymph levels are suggested to be an important protective biochemical adaptation to allow blood feeding.

Animals↗
PubMed1983

Effect of anion exchange inhibitors and para-aminohippurate on the transport of urate in the rat proximal tubule.

The present studies were designed to examine the effect of some anion exchange inhibitors and para-aminohippurate (PAH) on urate transport in the proximal tubule of the rat utilizing microperfusion techniques. The addition of SITS, DIDS, or furosemide to the luminal perfusion solution resulted in a decreased rate of absorption of water and 2-14C-urate. In addition, the presence of PAH in the luminal microperfusion solution resulted in a lower rate of urate absorption. The absorptive flux of urate was significantly higher, however, when PAH was added to the solution microperfusing the capillaries. The capillary to lumen secretory flux of urate was significantly higher when PAH or unlabeled urate was added to the luminal perfusion solution and significantly lower when PAH was added to the capillary perfusion solution. The addition of SITS to either the capillary or luminal microperfusion solution resulted in lower secretory and absorptive fluxes of urate. These studies suggest that both the secretion and reabsorption of urate in the proximal convoluted tubule of the rat is influenced by some anion exchange inhibitors and PAH. The results are considered in conjunction with recent in vitro data suggesting that urate transport is mediated by a process of anion exchange.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMed1992

Single kidney function: early and late changes in urate transport after nephrectomy.

Renal urate transport was studied by means of pyrazinamide (PZA) and probenecid (PB): (a) before and at 2, 6, 24 weeks (24 patients), (b) 1 to 30 years after uninephrectomy in 27 and 12 patients with Ccr greater than 80 and 30 to 70 ml/min, respectively. Uninephrectomy was followed by important tubular urate transport modifications during at least two weeks, which lead to a marked uricosuria as indicated by significant increase in FEur (mean value +/- SD, 0.228 +/- 0.059 vs. 0.097 +/- 0.014 and 0.099 +/- 0.019 in normals and chronically diseased solitary kidneys). Reduced response to PZA and PB suggests a diminished reabsorptive capacity for urate mainly at the presecretory site which persisted after FENa normalization. Tubular compensations were presumably complete at six weeks, since pattern of urate transport returned to normal with an almost complete reabsorption of filtered urate load (99%) and a percentage of postsecretory reabsorption (80%) very close to those seen in normal subjects with a pair of kidneys. The adjustment in urate excretion in solitary kidneys was achieved by a significant increase of secreted urate as compared with 50% of pre-uninephrectomy values. Thus, increased urate secretion by the remaining intact organ is sufficient to maintain urate balance with a normal serum level.

Adult↗
PubMed1992

Calcium oxalate crystallization in urine: role of urate and glycosaminoglycans.

Increasing the concentration of urate promotes the crystallization of calcium oxalate in human urine. In this study the possibility that this effect might be attributable to the attenuation of the inhibitory activity of urinary glycosaminoglycans (GAGs) was explored. Urine sample were collected from 20 men with no history of urolithiasis and the intact GAGs removed by 10 kDa ultrafiltration. Ten of these specimens, designated type A, spontaneously precipitated calcium oxalate crystals when the median urate concentration was increased from 3.13 to 7.33 mmol/liter by the addition of a saturated solution of sodium urate. In the remaining more dilute urines, which were designated type B, spontaneous calcium oxalate crystallization did not occur when the median urate concentration was raised from 2.20 to 6.40 mmol/liter. In these samples crystallization was induced by a standard load of oxalate above the empirically determined metastable limit. Addition of urate significantly reduced the median metastable limit from the control value of 125 to 46 mumol oxalate, and the volume of calcium oxalate deposited was increased fourfold from 25,000 to 104,000 microns 3/microliters. The median size of the precipitated particles was also increased in the presence of urate from 12.06 microns to 14.3 microns; this was confirmed by scanning electron microscopy, which demonstrated that the crystals precipitated in the presence of added urate, though individually smaller, were markedly more numerous and more highly aggregated than those deposited in the control. Re-ultrafiltration of the urines to which urate had been added did not alter the urate concentration, and SEM examination of the ultrafiltration membranes did not reveal the presence of any particulate material.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

Classical and channel-like urate transporters in rabbit renal brush border membranes.

The precise mechanism by which urate is transported across rabbit renal proximal tubule luminal membranes has not been defined. To determine whether urate flux across this membrane represents simple diffusion or transport on specific carriers, urate uptake was examined in brush border membrane vesicles that were prepared by a Mg+(+)-aggregation technique and then exposed to CuCl2. Na(+)-independent, voltage sensitive urate transport was demonstrated in these Cu+(+)-exposed vesicles. Transport was trans-stimulated by urate and cis inhibited by pyrazinoic acid and oxonate. A small fraction of transported urate and urate in the extravesicular fluid was oxidized to allantoin. Kinetic analysis revealed the presence of two kinetically distinct transporters; a channel-like carrier that was inhibited by pyrazinoic acid and oxonate, and a high-affinity, classical, saturable carrier that was inhibited by higher concentrations of oxonate. These studies provide the first direct evidence for carrier-mediated urate transport in rabbit renal brush-border membranes and demonstrate that the rabbit transporter(s) share a number of properties with the urate uniporter in rat proximal tubule cell membranes.

Animals↗
PubMed1993

Dissolved urate promotes calcium oxalate crystallization: epitaxy is not the cause.

1. Increasing the concentration of dissolved urate promotes the crystallization of calcium oxalate from urine. The possibility was investigated that this effect may be caused by heterogeneous nucleation of calcium oxalate by particles of crystalline urate. 2. Urine samples were collected from 10 healthy men, centrifuged and filtered, and a solution of sodium urate was added to increase the medium urate concentration from 2.2 to 5.6 mmol/l. Calcium oxalate crystallization was induced by the addition of oxalate, followed by incubation for 90 min in a shaking waterbath at 37 degrees C. The crystalline material was filtered out and the urate concentration was determined in the filtrate. 3. No difference in the urate concentration before and after induction of calcium oxalate crystallization was observed. These findings were confirmed by infra-red spectroscopy, X-ray powder diffraction and ultraviolet wet chemical analysis with detection limits of 5-10, 1.0 and 0.055%, respectively; urate was not detected in the calcium oxalate crystals. 4. In addition, three urine samples were collected and passed through 10 kDa ultrafiltration membranes to remove any colloidal particles which might have been present. The urate concentration was increased and an oxalate load was added as before, prior to incubation at 37 degrees C in a shaking water bath for 5 min, followed by passage through 10 kDa ultrafiltration membranes. Scanning electron microscopy revealed no particles on the membranes thereby indicating that colloidal or crystalline urate was not formed early in the crystallization experiments.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed2003

Hyperuricemia, low urine urate excretion and target organ damage in arterial hypertension.

BACKGROUND: Hyperuricemia can be the consequence of an increased urate production, a decreased renal excretion, or both. An increased prevalence of hyperuricemia has been described in essential hypertensive patients partly due to a decreased renal urinary urate excretion (UUE). Hyperuricemia has been shown to be associated with an increased risk of cardiovascular disease in hypertensive patients in some but not in all epidemiological studies in which this relationship has been investigated. OBJECTIVE: To assess the influence of low UUE in the association between serum urate, renal function and hypertension severity. PATIENTS AND METHODS: This cross-sectional study was carried out in a sample of 677 male hypertensive patients, aged 35-60 years, with essential arterial hypertension consecutively attended in a hospital hypertension unit. The presence of hypertension-related organ damage at diagnosis was classified according to classical WHO criteria as grade 1, 2 or 3. Urate underexcretion was defined as 24-h urinary urate below the product serum urate x 100. RESULTS: Mean serum urate levels were 6.4 +/- 1.6 mg/dl in the total sample. Hyperuricemia (serum urate >7 mg/dl) was present in 28.5% of patients and only 17.0% had underexcretory hyperuricemia. This subgroup of patients exhibited the higher rate of hypertension-related target organ damage (TOD). A multivariate analysis, showed that underexcretory hyperuricemia but not hyperuricemia remained an independent predictor of TOD (odds ratio 2.5. 95% CI 1.6-3.89). Serum urate correlated positively with serum creatinine in hyperuricemic patients (r = 0.50, p < 0.001), but not in patients with underexcretory hyperuricemia (r = 0.21, p = 0.18). CONCLUSIONS: Underexcretory hyperuricemia is strongly related to hypertensive organ damage and this relationship does not seem to be mediated by a decreased renal function. This aspect could underline the predictive value of hyperuricemia independently of serum creatinine. UUE could improve the clinical predictive value of hyperuricemia as a cardiovascular risk factor.

Adult↗
PubMed2004

Function and localization of urate transporter 1 in mouse kidney.

Mouse renal-specific transporter (RST) cDNA, the amino acid sequence of which has 74% identity with that of human urate transporter 1 (hURAT1), is potentially the mouse homologue of hURAT1, the gene responsible for hereditary renal hypouricemia. The aim of this study is to determine the location and characteristics of RST molecule in mouse kidney and investigate urate transport by RST using the Xenopus oocyte expression system. RST transported (14)C-urate in a Michaelis-Menten manner. The K(m) and the V(max) values of RST-dependent urate transport were 1213 +/- 222 micro M and 268.8 +/- 38.0 pmol/oocyte per hr, respectively (n = 3). RST-dependent urate transport was cis-inhibited significantly by 1 mM probenecid (68.7 +/- 9.4%), 50 micro M benzbromarone (67.9 +/- 6.4%), and 10 mM lactate (50.9 +/- 9.5%). However, 1 mM p-aminohippurate (PAH), 1 mM xanthine, and 1 mM oxonate did not inhibit RST-dependent urate transport. Substitution of Cl anion with gluconate in the external solution enhanced RST-dependent urate transport. Pre-injected pyrazinoic acid (PZA) or L-lactate trans-stimulated RST-dependent urate transport. Using immunohistochemistry for mouse kidney, the brush border or intracellular membrane of proximal tubules was stained by an affinity-purified antibody that recognized mouse URAT1 (mURAT1) expressed on Xenopus oocyte. Using Western blotting, anti-mURAT1 antibody detected 70-kD and 62-kD protein bands. The 70-kD protein was N-glycosylated and was identified as a Triton X-100 insoluble brush border membrane protein. RST mRNA and protein levels were higher in male kidneys than female. RST transported urate similar to hURAT1 and, therefore, appears to be mURAT1-the mouse homologue of hURAT1.

Amino Acid Sequence↗
PubMed2003

Influence of leflunomide on renal handling of urate and phosphate in patients with rheumatoid arthritis.

Reduction of serum urate and phosphate levels has been observed in patients receiving leflunomide therapy, but the mechanism for such changes has not been evaluated. Thirty-eight patients with rheumatoid arthritis who began leflunomide were studied. Serum urate, creatinine, and phosphate, and 24-hour uric acid, creatinine, and phosphate were measured before, during, and in some instances after leflunomide treatment. Clearances of urate and creatinine, fractional excretion of urate, and tubular reabsorption of phosphate were calculated. Undissociated urinary uric acid was estimated with a nomogram. Twelve patients gave consent to withdraw leflunomide treatment of a 2-week period and underwent a third study. Decreases in serum urate and phosphate levels were observed, with parallel increases in clearances of urate and in fractional excretion of urate, and a reduction in tubular reabsorption of phosphate. Clearances of creatinine and undissociated urinary uric acid remained unchanged. Two weeks after withdrawing the drug, a partial return toward baseline values was observed, but residual changes were apparent. No case of clinical gout was observed. Leflunomide enhances urate and phosphate loss, an effect that partially persisted after 2-week withdrawal. The long-term effect of mild phosphate wasting warrants further investigation. The urate-lowering effect of leflunomide may be useful in monitoring compliance in leflunomide therapy.

Journal Article↗
PubMed1967

The relation between secretion of urate and p-aminohippurate in the rabbit kidney.

1. The renal excretion of urate in the rabbit was examined during infusion of other anions which are secreted by the kidney. A reduction of urate excretion occurred after administration of p-aminohippurate (PAH) and Diodrast which was proportional to the secretory rate of these compounds. On the other hand, urate was a less efficient inhibitor of PAH secretion.2. Stop-flow experiments showed that tubular secretion of urate at maximal values for secretion of PAH and Diodrast was almost completely suppressed.3. 2,4-Dinitrophenol, fumarate, succinate, salicylate, and probenecid depressed the excretion of urate and PAH, but the tubular secretion of urate was apparently more depressed than that of PAH by these inhibitors.4. It is concluded that a common transport system for urate and PAH is involved in the tubular secretion of urate and PAH in the rabbit. However, the affinity of urate for the transport system appears to be smaller than that of PAH.

Acids↗
PubMed1967

The renal accumulation of urate and p-aminohippurate in the rabbit.

1. During intravenous infusion of urate and p-aminohippurate (PAH), the concentration of these two substances in cortex tissue of rabbit kidney exceeded the corresponding plasma concentration.2. Following the administration of 2,4-dinitrophenol, fumarate, succinate, probenecid, and salicylate, accumulation of urate in kidney cortex and renal net secretion of urate were abolished. The accumulation and secretion of PAH were only partially inhibited after infusion of these compounds.3. The renal accumulation of urate was reduced in relation to the inhibition of urate excretion during infusion of various amounts of PAH.4. The combined data indicate a correlation between renal accumulation and excretion of urate and PAH. It appears likely that accumulation of urate and PAH in vivo is due to tubular secretion of these two substances, although in the case of urate a small contribution from tubular reabsorption of urate cannot be excluded.

Acids↗
PubMed1995

Urate transport in Homarus americanus hepatopancreas: studies on membrane vesicles and R cells.

[2-14C]urate uptake was studied in hepatopancreatic basolateral membrane vesicles and in R cell suspensions of the American lobster by Millipore filtration techniques. Unspecific binding of urate to the vesicular membrane was 25.5 +/- 3.0% of equilibrium. Vesicular uptake showed a diffusional and a saturable component (Km) 0.37 +/- 0.04 mM and maximal velocity (Vmax) 16.5 +/- 1.2 pmol urate.mg protein-1.s-1). [2-14C]urate uptake was significantly trans-stimulated by urate. Purine analogues, probenecid, p-aminohippuric acid, pyrazinoic, and oxonic acid cis-inhibited urate transport. Urate uptake was not affected by Na+ or K+ transmembrane gradients but stimulated by 1 mM 2-oxoglutarate at the cis-side in Na(+)-containing media. Cellular urate uptake was inhibited by pyrazinoic acid. Uptake was saturable (Km 0.53 +/- 0.11 mM and Vmax 3.7 +/- 0.4 pmol urate.mg protein-1.s-1) and Na(+)-independent. However, 2-oxoglutarate stimulated uptake in Na(+)-containing media. These results suggest that urate uptake across the basolateral membrane occurs via a specific, Na(+)-independent transport system that may operate in the exchange mode accepting 2-oxoglutarate as countertransported substrate. In vivo, urate uptake thereby would be a tertiary active system driven by a 2-oxoglutarate gradient established across the cell membrane by the operation of a Na(+)-2-oxoglutarate cotransport system.

Animals↗