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PubMed1982

Net urate reabsorption in the Dalmatian coach hound with a note on automated measurement of urate in species with low plasma urate.

A progressive reduction of renal blood flow and glomerular filtration rate induced by the stepwise clamping of a Goldblatt clamp increases the urate over creatinine clearance ratio from 1.2 to 1.9 in normal urate-secreting Dalmatian dogs. These clearance data support the existence of a predominant postreabsorptive secretory flux of urate in the normal Dalmatian dog. In contrast, in Dalmatians loaded with pyrazinoic acid which suppresses urate secretion, net reabsorption of urate is unmasked and the urate over creatinine clearance ratio decreases with the progressive reduction in glomerular filtration rate (down to 0.44). It is concluded that the net reabsorption of urate measured by conventional clearance techniques after pharmacologic depression of the urate secretory flux probably reflects true urate reabsorption in the nephron of this species.

Absorption↗

PubMed1976

Renal urate transport during variations in urate synthesis in the rat.

In order to determine the effect of intrarenal synthesis of urate upon the urinary urate excretion in the rat, we effected large changes in urate synthesis by increasing it with allopurinol. Hypoxanthine infusion increased plasma urate rapidly and also increased the urinary urate excretion and its renal clearance. However, when the plasma urate was maintained constant, hypoxanthine had no effect upon renal urate transport. Conversely, allpurinol infusion rapidly diminished the plasma urate, urinary urate excretion and its renal clearance. Again, the maintenance of a constant plasma urate concentration prevented any change in urate transport during allopurinol. The urinary degradative purine metabolic pattern was altered predictably by hypoxanthine and allopurinol. Assuming than any putative intrarenal component of urate synthesis would be affected predictably and consistently by hypoxanthine and allopurinol, these results suggest that changes in intrarenal urate synthesis are not an important determinant of urate excretion in the rat.

Allantoin↗

PubMed1999

Ammonium and sodium urates precipitating from synthetic urine and fine structure of urate renal calculi.

A study of ammonium and sodium urate precipitation in vitro and the fine structure of several urate renal calculi was carried out to contribute to an understanding of the participation of ammonium and sodium urates in urolithiasis. Ammonium urate precipitated in vitro in two different morphologies: a typical spherulite morphology formed at high supersaturation and disorganized needle-like crystals formed at low supersaturation. In all cases sodium urate precipitated in vitro as bundles of curved fibrils, its crystallization being inhibited by calcium in concentrations between 20 and 60 mg/l depending on the sodium urate supersaturation. From a collection of 1300 renal calculi, only three had ammonium urate as their main component (0.2%), three were mixed calculi (0.2%) consisting of ammonium urate and calcium oxalate (two) or uric acid (one), and in one calculus ammonium urate was present as a minor component. Only in a mixed calculus of uric acid and calcium oxalate was sodium urate detected in a very low quantity. The study of the fine structure of the renal calculi constituted mainly by ammonium urate demonstrated similar patterns in which spherulites, needle-like individual crystals and an amorphous mass of ammonium urate with abundant organic matter in non-organized structures coexist. As minor components, struvite or calcium oxalate crystals were found. A general mechanism of the formation of such calculi is proposed.

Chemical Precipitation↗

PubMed1986

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 levels. 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 micrograms/min/1.73 m2 in controls and 2,215 +/- 738 micrograms/min/1.73 m2 in patients with gout (P less than 0.01). Forty-four patients had a daily uric acid excretion rate below 700 mg/1.73 m2, 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 micrograms/min/1.73 m2) than in controls (922 +/- 136 micrograms/min/1.73 m2; P less than 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.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed2006

Using serum urate levels to determine the period free of gouty symptoms after withdrawal of long-term urate-lowering therapy: a prospective study.

OBJECTIVE: Withdrawal of urate-lowering therapy (ULT) is associated with recurrence of acute gouty arthritis and tophi, but no data are available about factors associated with recurrence of gouty symptoms. Therefore, life-long therapy prescription is usually advised, but the prospect of life-long therapy may contribute to very low compliance rates. Our objective was to ascertain the outcome of ULT withdrawal after long-term, documented control of serum urate levels. METHODS: We conducted a prospective, long-term, followup study of patients treated with ULT during a 5-year period. Both diagnosis and recurrence of gout were determined based on monosodium urate crystal identification in synovial fluid or material aspirated from tophi. RESULTS: Low average serum urate levels while receiving ULT and during the followup period after ULT withdrawal were statistically associated with the longest period in which patients were free of gouty symptoms, suggesting that depletion and formation of the body's urate pool is dependent on both time and serum urate levels. Patients whose average serum urate levels were <5.05 mg/dl while receiving ULT and <8.75 mg/dl after ULT withdrawal had the longest (>4 years) time to recurrence. CONCLUSION: Proper and long-term reduction of serum urate level is associated with long-term periods in which patients are free of gouty symptoms, probably due to the reduction of the urate pool. These results suggest that 5-year intermittent, instead of life-long, ULT could be offered to patients with good serum urate control during ULT.

Adult↗

PubMed2006

Purine-induced expression of urate oxidase and enzyme activity in Atlantic salmon (Salmo salar). Cloning of urate oxidase liver cDNA from three teleost species and the African lungfish Protopterus annectens.

The peroxisomal enzyme urate oxidase plays a pivotal role in the degradation of purines in both prokaryotes and eukaryotes. However, knowledge about the purine-induced expression of the encoding gene is lacking in vertebrates. These are the first published sequences of fish urate oxidase, which were predicted from PCR amplified liver cDNAs of Atlantic salmon (Salmo salar), Atlantic cod (Gadus morhua), Atlantic halibut (Hippoglossus hippoglossus) and African lungfish (Protopterus annectens). Sequence alignment of different vertebrate urate oxidases revealed amino acid substitutions of putative functional importance in the enzyme of chicken and lungfish. In the adult salmon, expression of urate oxidase mRNA predominated in liver, but was also identified in several nonhepatic organs including brain, but not in skeletal muscle and kidney. Juvenile salmon fed diets containing bacterial protein meal (BPM) rich in nucleic acids showed a significant increase in liver urate oxidase enzyme activity, and urea concentrations in plasma, muscle and liver were elevated. Whereas salmon fed the 18% BPM diet showed a nonsignificant increase in liver mRNA levels of urate oxidase compared with the 0% BPM-fed fish, no further increase in mRNA levels was found in fish receiving 36% BPM. The discrepancy between urate oxidase mRNA and enzyme activity was explained by rapid mRNA degradation or alternatively, post-translational control of the activity. Although variable plasma and liver levels of urate were detected, the substrate increased only slightly in 36% BPM-fed fish, indicating that the uricolytic pathway of Atlantic salmon is intimately regulated to handle high dietary purine levels.

Amino Acid Sequence↗

PubMed1996

Effects of the specific angiotensin II receptor antagonist losartan on urate homeostasis and intestinal urate transport.

Possible mechanisms for the hypouricemic effects of the angiotensin II receptor antagonist losartan were examined using rats with experimental chronic renal failure (CRF) and control animals. The results show that losartan has a uricosuric effect in rats with normal or decreased renal function. Renal clearance of urate was increased 3-fold in CRF rats and 2-fold in control rats after 7 days of intraperitoneal losartan administration. Although the results show that losartan and its metabolite EXP-3174 alter urate and Cl- transport across isolated short-circuited intestine, these agents do not promote urate secretion into the intestinal lumen. Unidirectional urate and Cl- fluxes were reduced across normal rat colon and unaltered in the small intestine in the presence of losartan. In CRF rat colon, net secretion of urate and Cl- was abolished after losartan addition at 10(-5) M. Transport across the small intestine of CRF rats did not change in the presence of a similar concentration of drug. Losartan treatment of CRF rats before the removal of colonic tissues reversed the basal net secretion of urate to net absorption. These results suggest that the changes in intestinal transport observed in the presence of losartan appear to be mediated via the angiotensin II receptor antagonistic action of this drug. Direct determination of the effects of angiotensin II on urate and Cl- transport across colonic tissues from control animals revealed a significant angiotensin II stimulation of urate secretion. These angiotensin II-induced alterations in transport were inhibitable by losartan.

Angiotensin II↗

PubMed2002

Molecular identification of a renal urate anion exchanger that regulates blood urate levels.

Urate, a naturally occurring product of purine metabolism, is a scavenger of biological oxidants implicated in numerous disease processes, as demonstrated by its capacity of neuroprotection. It is present at higher levels in human blood (200 500 microM) than in other mammals, because humans have an effective renal urate reabsorption system, despite their evolutionary loss of hepatic uricase by mutational silencing. The molecular basis for urate handling in the human kidney remains unclear because of difficulties in understanding diverse urate transport systems and species differences. Here we identify the long-hypothesized urate transporter in the human kidney (URAT1, encoded by SLC22A12), a urate anion exchanger regulating blood urate levels and targeted by uricosuric and antiuricosuric agents (which affect excretion of uric acid). Moreover, we provide evidence that patients with idiopathic renal hypouricaemia (lack of blood uric acid) have defects in SLC22A12. Identification of URAT1 should provide insights into the nature of urate homeostasis, as well as lead to the development of better agents against hyperuricaemia, a disadvantage concomitant with human evolution.

Amino Acid Sequence↗

PubMed1994

Hyperuricemia and urate nephropathy in urate oxidase-deficient mice.

Urate oxidase, or uricase (EC 1.7.3.3), is a purine metabolic enzyme that catalyzes the conversion of uric acid to allantoin in most mammals except humans and certain other primates. The loss of urate oxidase in the human during primate evolution predisposes man to hyperuricemia, a metabolic disturbance that can lead to gouty arthritis and renal stones. To create a mouse model for hyperuricemia and gout, and to address the question of whether urate oxidase is essential in lower mammalian species, we have disrupted the urate oxidase gene in the mouse by homologous recombination in embryonic stem cells. Unlike the human situation, urate oxidase deficiency in mice causes pronounced hyperuricemia and urate nephropathy. More than half of the mutant mice died before 4 weeks of age, indicating that urate oxidase is essential in mice. These mutant mice may also serve as animal models for hyperuricemia and its related nephropathy in humans.

Allopurinol↗

PubMedDate not supplied

Mechanisms of cellular interaction with monosodium urate crystals. IgG-dependent and IgG-independent platelet stimulation by urate crystals.

Monosodium urate crystals (MSU) stimulate suspensions of washed platelets or neutrophils. When MSU crystals are coated with IgG, as occurs in plasma, stimulation is markedly enhanced. These studies which use MSU-induced human platelet serotonin secretion as a model examine the nature of cellular recognition mechanisms for MSU crystals and IgG-coated MSU crystals. F(ab')2 fragments of specific anti-Fc antibody blocked and the lipopolysaccharide of Salmonella minnesota R595 enhanced human platelet secretion induced by IgG-coated urate crystals. These agents had little effect on stimulation by uncoated crystals. This indicated that urate crystals stimulate platelets independently of fluid phase IgG. Urate crystals directly stimulated suspensions of washed rabbit platelets which lack Fc receptors. In contrast to human cells, stimulation was blocked by IgG. This again demonstrated IgG-independent cell stimulation by urate crystals. Calcium pyrophosphate dihyrate crystals could trigger human platelet secretion only when coated with IgG. This suggests that when crystals are coated with IgG, the surface-bound IgG alone may be the stimulus to the cell. This was supported by the finding that polyvinylpyridine-N-oxide, a hydrogen acceptor, blocked human platelet stimulation by uncoated, but not IgG-coated, urate crystals. These data indicate that urate crystals (and potentially other surface or particles) can stimulate a mediator cell by at least two mechanisms: by direct stimulation without the mediation of adsorbed IgG or, when coated with IgG, by triggering the cell via immunoglobulin receptors.

Blood Platelets↗

PubMed1980

A micropuncture study of urate excretion by Cebus monkeys employing high performance liquid chromatography with amperometric detection of urate.

Net renal reabsorption of endogenous urate was studied by the micropuncture technique in Cebus monkeys in the absence of osmotic diuresis. Most of filtered urate (more than 70%) was reabsorbed in the proximal convoluted tubules. Samples from early distal tubules contained 9% of filtered urate; approximately 18% being reabsorbed between the late proximal and early distal segments. There was no detectable reabsorption along the distal tubule. Fractional delivery of urate to late distal tubules was greater than fractional excretion, implying reabsorption of some 4% of filtered urate in the collecting system. However, we cannot exclude nephron heterogeneity as the cause of the difference. The foregoing results were obtained using the method of Pachla and Kissinger for the determination of urate. Urate is separated by high performance liquid chromatography and detected by an amperometric technique. We found the method to be sufficiently sensitive, precise and specific for renal micropuncture samples.

Animals↗

PubMed1979

Enhancement of urate solubility by connective tissue. II. Inhibition of sodium urate crystallisation by cation exchange.

The urate concentration of the supernatant was greater after supersaturated solutions of sodium urate were incubated in a suspension of CM-Sephadex C-25 than in one of Sephadex G-25. The supernatant urate concentration was greater when the CM-Sephadex had been equilibrated with potassium than with sodium. The results are analogous with those obtained in studies of urate solubility in proteoglycan solutions. They are consistent with the Donnan effect and the hypothesis that the glycosaminoglycans within the proteoglycan molecule function as cation exchangers which, when charged with potassium, exchange with the sodium of the urate molecule, leading to formation of highly soluble potassium urate.

Cation Exchange Resins↗

PubMed1995

Influence of two amounts of dietary casein on uric acid, sodium urate, and ammonium urate urinary activity product ratios of healthy beagles.

Casein has been used as a protein source in diets designed to dissolve canine ammonium urate uroliths and to prevent their recurrence, because it contains fewer purine precursors than do many other sources of protein. However, an important question is whether reduced quantities of dietary casein have any benefit in modifying saturation of urine with urates. To answer this question, activity product ratios of uric acid, sodium urate, and ammonium urate were determined in 24-hour urine samples produced by 6 healthy Beagles during periods of consumption of a 10.4% protein, casein-based (10.4% casein) diet and a 20.8% protein, casein-based (20.8%casein) diet. Significantly lower 24-hour urinary excretions of ammonia and phosphorus were observed when dogs consumed the 10.4% casein diet. These results suggest that use of the 10.4% casein diet in protocols designed for dissolution and prevention of uric acid, sodium urate, and ammonium urate uroliths in dogs may be beneficial.

Ammonia↗

PubMed1995

Diet effect on activity product ratios of uric acid, sodium urate, and ammonium urate in urine formed by healthy beagles.

Urine activity product ratios of uric acid, sodium urate, and ammonium urate and urinary excretion of metabolites were determined in 24-hour samples produced by 6 healthy Beagles during periods of consumption of a low-protein, casein-based diet (diet A) and a high-protein, meat-based diet (diet B). Comparison of effects of diet A with those of diet B revealed: significantly lower activity product ratios of uric acid (P = 0.025), sodium urate (P = 0.045), and ammonium urate (P = 0.0045); significantly lower 24-hour urinary excretion of uric acid (P = 0.002), ammonia (P = 0.0002), sodium (P = 0.01), calcium (P = 0.005), phosphorus (P = 0.0003), magnesium (P = 0.01), and oxalic acid (P = 0.004); significantly (P = 0.0001) higher 24-hour urine pH; and significantly (P = 0.01) lower endogenous creatinine clearance. These results suggest that consumption of diet A minimizes changes in urine that predispose dogs to uric acid, sodium urate, and ammonium urate urolithiasis.

Animals↗

PubMed1994

Prevalence of cystine and urate uroliths in bulldogs and urate uroliths in dalmatians.

Data were evaluated from all dogs admitted to the University of Minnesota Veterinary Teaching Hospital (UMVTH) between June 1, 1981 and Dec 31, 1991. During this period, uroliths were retrieved and analyzed from 452 of 37,574 dogs admitted. The odds that uroliths from Bulldogs were composed of cystine were 32.3 times greater than for other breeds evaluated. The odds that a Bulldog admitted was affected with cystine uroliths were 154.1 times greater than for other breeds. Cystine uroliths were retrieved only from male Bulldogs. The odds that uroliths from Bulldogs were composed of urate were 7.9 times greater than for other breeds. The odds that a Bulldog admitted was affected with urate uroliths were 43.0 times greater than for other breeds. Male Bulldogs were 14.3 times more likely to be affected with urate uroliths than were females. The odds that uroliths from Dalmatians were composed of urate were 228.9 times greater than for other breeds. The odds that a Dalmation admitted was affected with urate uroliths were 122.4 times greater than for other breeds. Male Dalmatians were 16.4 times more likely to be affected with urate uroliths than were females. Data also were evaluated from files of canine uroliths submitted to the Minnesota Urolith Center for quantitative mineral analysis between June 1, 1981 and Dec 31, 1991. During this period, 94 of 11,188 uroliths analyzed were obtained from Bulldogs and 387 were obtained from Dalmatians. The odds that uroliths retrieved from Bulldogs were composed of cystine were 40.7 times greater than for other breeds. Cystine uroliths were retrieved only from male Bulldogs.(ABSTRACT TRUNCATED AT 250 WORDS)

Age Distribution↗

PubMed1991

Apolipoprotein (apo) E inhibits the capacity of monosodium urate crystals to stimulate neutrophils. Characterization of intraarticular apo E and demonstration of apo E binding to urate crystals in vivo.

Factors that modulate the ability of monosodium urate crystals to stimulate leukocytes could regulate gouty inflammation. Lipoproteins that bear apo B-100 and apo E bind to urate crystals and suppress crystal-neutrophil interaction. In this study, we observed that urate crystals, coated with apo E of monocyte origin, had a diminished ability to stimulate neutrophils. Apo E was also detected on the surface of urate crystals recovered from gout patients. Thus, we analyzed apo E in noninflammatory synovial fluid, and found it to be associated with particles of heterogeneous size and of predominantly alpha and pre-beta electrophoretic mobility. Local articular synthesis of at least a portion of synovial fluid apo E was suggested because (a) the synovial fluid/plasma concentration ratio of apo E was significantly higher than that for both apo B and apo A-I, which are not widely synthesized by extrahepatic tissues, (b) cultured rheumatoid synovial cells in first passage secreted apo E, (c) a portion of synovial fluid apo E was heavily sialylated. We conclude that synovial fluids contain apo E that appears partly of local origin. Apo E binds to urate crystals and could modulate gouty inflammation.

Apolipoproteins E↗

PubMed1977

Renal urate excretion in five cases of hypouricemia with an isolated renal defect of urate transport.

Renal urate excretion was studied in two familial, one suspected familial, and two isolated cases of hypouricemia due to a renal defect. All had very low plasma urate concentrations. In four cases, the urate clearances were approximately the same as the creatinine clearances, and in one case reduced to about one-third. In all cases the urate clearances were minimally diminished by both pyrazinamide and probenecid. This renal response to the drugs is probably due to and isolated tubular defect in the reabsorptive transport mechanism of urate. Following intravenous administration of uric acid, one patient excreted uric acid in the urine more rapidly than a normal subject. In this patient, uric acid secretion from renal tubules was clearly demonstrated during infusion of uric acid. In de novo synthesis of purine, no definite abnormalities were found by incorporation of glycine-15N to uric acid.

Adult↗

PubMed1998

Efficacy of urate oxidase (uricozyme) in tumour lysis induced urate nephropathy.

Urate oxidase (uricozyme) is an enzyme of non-human origin capable of oxidizing human uric acid to allantoin, a highly soluble product at renal tubule pH. We report its efficacy in three patients with acute urate nephropathy due to tumour lysis in chronic lymphatic leukaemia and high grade lymphoma. Two patients had an additional obstructive nephropathy due to ureteric urate crystals. An intravenous infusion (100 units/kg in 50 ml saline over 30 min) was given for between two and five consecutive days. All patients showed a rapid fall in serum urate levels with associated diuresis, correction of metabolic disturbance and full resolution of uraemia within a week. The treatment was well tolerated and caused a rapid resolution of clinical symptoms in all cases. We review the literature relating to the use of this agent both in the treatment of hyperuricaemic acute renal failure and gouty arthritis.

Aged↗