Renal handling of urate in healthy man in hyperuricaemia and renal insufficiency: circadian fluctuation, effect of water diuresis and of uricosuric agents

Läng, Florian; Greger, R.; Oberleithner, Hans; Griss, E.; Lang, Katherine; Pastner, D.; Dittrich, P.; Deetjen, P.

doi:10.1111/j.1365-2362.1980.tb00035.x

Cited by 25 publications

(13 citation statements)

References 17 publications

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“…Correlation of serum urate levels with CUA/Ccr of the renal hypouricemia patients and the controls are shown in Figure 4. The curve plotted is similar to that previously reported using healthy volunteers (21). Although the areas on the curve representing the homozygotes and compound heterozygotes, the heterozygotes and patients with wild-type URAT1, and the controls overlapped, each group is distinctively clustered.…”

Section: Genotype-phenotype Correlation In Renal Hypouricemiasupporting

confidence: 79%

Clinical and Molecular Analysis of Patients with Renal Hypouricemia in Japan-Influence of URAT1 Gene on Urinary Urate Excretion

Ichida

Hosoyamada²,

Hisatome³

et al. 2004

Journal of the American Society of Nephrology

351

353

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Abstract. Renal hypouricemia is an inherited and heterogeneous disorder characterized by increased urate clearance (CUA). The authors recently established that urate was reabsorbed via URAT1 on the tubular apical membrane and that mutations in SLC22A12 encoding URAT1 cause renal hypouricemia. This study was undertaken to elucidate and correlate clinical and genetic features of renal hypouricemia. The SLC22A12 gene was sequenced in 32 unrelated idiopathic renal hypouricemia patients, and the relationships of serum urate levels, and CUA/creatinine clearance (Ccr) to SLC22A12 genotype were examined. Uricosuric (probenecid and benzbromarone) and anti-uricosuric drug (pyrazinamide) loading tests were also performed in some patients. Three patients had exercise-induced acute renal failure (9.4%), and four patients had urolithiasis (12.5%). The authors identified eight new mutations and two previously reported mutations that result in loss of function. Thirty patients had SLC22A12 mutations; 24 homozygotes and compound heterozygotes, and 6 heterozygotes. Mutation G774A dominated SLC22A12 mutations (74.1% in 54 alleles). Serum urate levels were significantly lower and CUA/Ccr was significantly higher in heterozygotes compared with healthy subjects; these changes were even more significant in homozygotes and compound heterozygotes. These CUA/Ccr relations demonstrated a gene dosage effect that corresponds with the difference in serum urate levels. In contrast to healthy subjects, the CUA/Ccr of patients with homozygous and compound heterozygous SLC22A12 mutations was unaffected by pyrazinamide, benzbromarone, and probenecid. The findings indicate that SLC22A12 was responsible for most renal hypouricemia and that URAT1 is the primary reabsorptive urate transporter, targeted by pyrazinamide, benzbromarone, and probenecid in vivo.Approximately 90% of all urate that is filtered through the glomerulus is eventually reabsorbed. A four-component hypothesis has been proposed to explain the renal urate transport mechanisms; it includes glomerular filtration, presecretory reabsorption, secretion, and postsecretory reabsorption (1,2). Renal hypouricemia is a common inherited and heterogeneous disorder characterized by impaired tubular urate transport (3). The incidence of renal hypouricemia has been reported to be 0.12 to 0.72% (4,5), and exercise-induced acute renal failure and nephrolithiasis have been reported as complications (6).Renal hypouricemia has been classified into the following five types according to responses to the anti-uricosuric drug pyrazinamide, and the uricosuric drug, probenecid: (a) a presecretory reabsorptive defect with an attenuated response to both pyrazinamide and probenecid (3); (b) a post-secretory reabsorptive defect when pyrazinamide suppressible urate clearance (CUA) is not influenced by probenecid (7); (c) total inhibition of urate reabsorption when pyrazinamide induces elimination of CUA exceeding the rate of glomerular filtration (8); (d) enhanced secretion when the pyrazinamide suppressible CUA ...

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Section: Genotype-phenotype Correlation In Renal Hypouricemiasupporting

confidence: 79%

Clinical and Molecular Analysis of Patients with Renal Hypouricemia in Japan-Influence of URAT1 Gene on Urinary Urate Excretion

Ichida

Hosoyamada²,

Hisatome³

et al. 2004

Journal of the American Society of Nephrology

351

353

View full text Add to dashboard Cite

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“…However, as previ ously mentioned, by increasing the dose of PB by a factor of two no further uricosuria was observable in 4 uremic patients in the present study. It is also noteworthy that Lang et al [15] attained maximum uricosuria in patients with chronic renal failure using 500 mg of PB only. Furthermore, it is known that alkaline urine decreases the passive nonionic reabsorption of PB.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of the Renal Mechanisms for Urate Homeostasis in Uremic Patients by Probenecid and Pyrazinamide Test

Garyfallos

Magoula

Tsapas

1987

Nephron

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The tubular transport of urate was studied in 47 uremic patients and in 20 normal subjects using probenecid and pyrazinamide tests. There was a marked increase in urate excretion per nephron as the renal function deteriorated. Presecretory reabsorption of urate per nephron, which was almost complete in normal subjects, showed a diminution with increasing severity of chronic renal failure. Until the creatinine clearance had decreased to less than 10 ml/min, the secreted urate per nephron remained almost constant, while in the end stage of renal failure it was markedly decreased. With the progression of renal disease, the postsecretory reabsorption of urate per nephron diminished. In patients with a creatinine clearance less than 10 ml/min, it was 4 times lower than in normal subjects. These findings indicate that urate secretion does not contribute to the increase of urate excretion per nephron at any level of renal failure, whereas the impairment of both reabsorptive components accounts for the augmented urate excretion per nephron in uremic patients.

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“…It is generally believed that most hyperuricemia in subjects with normal glomerular filtration rates results from a significant inefficiency of the kidneys to clear urate [6,7]. Urate is filtered at the glomerulus, then reabsorbed, and is also secreted by the renal tubules [8].…”

Section: Introductionmentioning

confidence: 99%

Fractional clearance of urate: validation of measurement in spot-urine samples in healthy subjects and gouty patients

et al. 2012

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IntroductionHyperuricemia is the greatest risk factor for gout and is caused by an overproduction and/or inefficient renal clearance of urate. The fractional renal clearance of urate (FCU, renal clearance of urate/renal clearance of creatinine) has been proposed as a tool to identify subjects who manifest inefficient clearance of urate. The aim of the present studies was to validate the measurement of FCU by using spot-urine samples as a reliable indicator of the efficiency of the kidney to remove urate and to explore its distribution in healthy subjects and gouty patients.MethodsTimed (spot, 2-hour, 4-hour, 6-hour, 12-hour, and 24-hour) urine collections were used to derive FCU in 12 healthy subjects. FCUs from spot-urine samples were then determined in 13 healthy subjects twice a day, repeated on 3 nonconsecutive days. The effect of allopurinol, probenecid, and the combination on FCU was explored in 11 healthy subjects. FCU was determined in 36 patients with gout being treated with allopurinol. The distribution of FCU was examined in 118 healthy subjects and compared with that from the 36 patients with gout.ResultsNo substantive or statistically significant differences were observed between the FCUs derived from spot and 24-hour urine collections. Coefficients of variation (CVs) were both 28%. No significant variation in the spot FCU was obtained either within or between days, with mean intrasubject CV of 16.4%. FCU increased with probenecid (P < 0.05), whereas allopurinol did not change the FCU in healthy or gouty subjects. FCUs of patients with gout were lower than the FCUs of healthy subjects (4.8% versus 6.9%; P < 0.0001).ConclusionsThe present studies indicate that the spot-FCU is a convenient, valid, and reliable indicator of the efficiency of the kidney in removing urate from the blood and thus from tissues. Spot-FCU determinations may provide useful correlates in studies investigating molecular mechanisms underpinning the observed range of efficiencies of the kidneys in clearing urate from the blood.Trial RegistrationACTRN12611000743965

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Renal handling of urate in healthy man in hyperuricaemia and renal insufficiency: circadian fluctuation, effect of water diuresis and of uricosuric agents

Cited by 25 publications

References 17 publications

Clinical and Molecular Analysis of Patients with Renal Hypouricemia in Japan-Influence of URAT1 Gene on Urinary Urate Excretion

Clinical and Molecular Analysis of Patients with Renal Hypouricemia in Japan-Influence of URAT1 Gene on Urinary Urate Excretion

Evaluation of the Renal Mechanisms for Urate Homeostasis in Uremic Patients by Probenecid and Pyrazinamide Test

Fractional clearance of urate: validation of measurement in spot-urine samples in healthy subjects and gouty patients

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