Tubular Uric Acid Transport Research Articles

POS-407 Bariatric surgery repairs renal tubular uric acid transport in MS patients through circulating exosomes

Metabolic surgery is increasingly becoming recognized as a more effective treatment for patients with metabolic syndrome as compared to lifestyle modification and medical management alone. Kidney plays a crucial role in maintaining the homeostasis of uric acid. The aim of the study was to imply that Whether circulating exosomes are involved in the change of renal uric acid transporter after weight loss surgery in patients with metabolic syndrome. We analyzed the basic data and blood and urine biochemical indicators of 30 normal people and 30 patients with metabolic syndrome preoperative and postoperative. The plasma exosomes of this cohort was extracted, and the human renal tubular epithelial cells were co-cultured with EVs. We determined the expressions of uric acid transporters URAT1, GLUT9 and ABCG2 on renal tubular epithelial cells by q-PCR and Western Blot. Compared with normal cohort, patients with metabolic syndrome have higher blood pressure, higher BMI, higher blood sugar, higher blood lipids and uric acid levels (P<0.001), but these biochemical indexes can return to near normal levels after bariatric surgery. The BMI of patients with metabolic syndrome was positively correlated with blood uric acid (R2 =0.14, P<0.001), then there was no significant correlation between BMI and 24-hour uric acid. The human renal tubular epithelial cells were co-cultured with EVs. The expression of URAT1, GLUT9 and ABCG2 on the cells was detected by q-PCR and Western Blot. Compared with the renal tubular epithelial cells stimulated by circulating EV after operation,the expression of URAT1 and GLUT9 on renal tubular epithelial cells stimulated by circulating EV from the preoperative increased (P<0.05), and the expression of ABCG2 decreased (P<0.05). Our results confirm that patients undergoing bariatric surgery changes in the composition of circulating extracellular vesicle , which can regulate renal tubular uric acid transporter, thereby affect renal uric acid metabolism.

Coexistence of autosomal dominant polycystic kidney disease type 1 and hereditary renal hypouricemia type 2: A model of early-onset and fast cyst progression.

Autosomal dominant polycystic kidney disease (ADPKD) is a heterogeneous inherited disease characterized by renal and extrarenal manifestations with progressive fluid-filled cyst development leading to end-stage renal disease. The rate of disease progression in ADPKD exhibits high inter- and intrafamilial variability suggesting involvement of modifier genes and/or environmental factors. Renal hypouricemia (RHUC) is an inherited disorder characterized by impaired tubular uric acid transport with severe complications, such as acute kidney injury and chronic kidney disease (CKD). However, the two disorders have distinct and well-delineated genetic, biochemical, and clinical findings. Only a few cases of coexistence of ADPKD and RHUC (type 1) in a single individual have been reported. We report a family with two members: an ADPKD 24-year-old female which presented bilateral renal cysts in utero and hypouricemia since age 5, and her mother with isolated hypouricemia. Next-generation sequencing identified two mutations in two genes PKD1 and SLC2A9 in this patient and one isolated SLC2A9 mutation in her mother, showing RHUC type 2, associated to CKD. The coexistence of these two disorders provides evidence of SLC2A9 variant could act as a modifier change, with synergistic actions, that could promote cystogenesis and rapid ADPKD progression. This is the first case of coexistence of PKD1 and SLC2A9 mutations treated with tolvaptan.

A heterozygous variant in the SLC22A12 gene in a Sri Lanka family associated with mild renal hypouricemia

BackgroundRenal hypouricemia is a rare heterogeneous inherited disorder characterized by impaired tubular uric acid transport, reabsorption insufficiency and /or acceleration of secretion. The affected individuals are predisposed to nephrolithiasis and recurrent episodes of exercise-induced acute kidney injury. Type 1 is caused by dysfunctional variants in the SLC22A12 gene (URAT1), while type 2 is caused by defects in the SLC2A9 gene (GLUT9). To date, more than 150 patients with the loss-of-function mutations for the SLC22A12 gene have been found (compound heterozygotes and/or homozygotes), most of whom are Japanese and Koreans.Case presentationHerein, we report a nine year old Sri Lankan boy with renal hypouricemia (serum uric acid 97 μmol/L, fractional excretion of uric acid 33%).The sequencing analysis of SLC22A12 revealed a potentially deleterious missense variant c.1400C > T (p.T467 M, rs200104135) in heterozygous state. This variant has been previously identified in homozygous and/or compound heterozygous state with other causative SLC22A12 variant c.1245_1253del (p.L415_G417del) in Roma population.ConclusionsThis is the first identification of a family with mild renal hypouricemia1 associated to the p.T467 M variant. Detailed investigations of urate blood and urine concentrations in patients with unexplained hypouricemia are needed and renal hypouricemia should also be considered in patients other than those from Japan and/or Korea. Our finding confirms an uneven geographical and ethnic distribution of Romany prevalent SLC22A12 variant that need to be considered in Asian patients (population data Genome Aggregation Database: allele frequency in South Asia 0.007055, in East Asia 0.001330).

A case of xanthinuria type I with a novel mutation in xanthine dehydrogenase.

Hereditary hypouricemia is generally caused by renal hypouricemia, an autosomal recessive disorder that is characterized by impaired renal tubular uric acid transport, or by xanthinuria, a rare autosomal recessive disorder caused by a deficiency of xanthine dehydrogenase (XDH; xanthinuria type I) or by a deficiency of both XDH and aldehyde oxidase (xanthinuria type II). In contrast to renal hypouricemia, which sometimes leads to exercise-induced acute kidney injury (EIAKI), xanthinuria has not been associated with this disorder. We report here a case of xanthinuria type I due to a compound heterozygous mutation. A 46-year-old woman was found to have undetectable plasma and urinary levels of uric acid. She had no symptoms and no history of EIAKI. Xanthinuria type I was diagnosed following the allopurinol loading test. Mutation analysis revealed a compound heterozygous mutation [c.305A>G (p.Gln102Arg) and c.2567delC (p.Thr856Lysfs*73)] in the XDH gene. Of these two mutations, the former is novel. The patient did not exhibit EIAKI. However, because xanthinuria is a rare disease, the identification of additional cases is necessary to determine whether this disease is complicated with EIAKI.

High frequency of SLC22A12 variants causing renal hypouricemia 1 in the Czech and Slovak Roma population; simple and rapid detection method by allele-specific polymerase chain reaction

Renal hypouricemia is a rare heterogeneous inherited disorder characterized by impaired tubular uric acid transport with severe complications, such as acute kidney injury. Type 1 and 2 are caused by loss-of-function mutations in the SLC22A12 and SLC2A9 gene, respectively. A cohort of 881 randomly chosen ethnic Roma from two regions in Eastern Slovakia and two regions in the Czech Republic participated. Genomic DNA was isolated from buccal swabs and/or from blood samples. The c.1245_1253del and c.1400C>T genotypes were determined using polymerase chain reaction with allele-specific primers in a multiplex arrangement and/or direct sequencing of exon 7 and 9. Allele frequencies and genotypes were tested for Hardy-Weinberg equilibrium using the Chi-square test. 25 subjects were heterozygous and three were homozygous for the c.1245_1253del, while 92 subjects were heterozygous and two were homozygous for the c.1400C>T. Moreover, two participants were compound heterozygotes. Frequencies of the c.1245_1253del and c.1400C>T variants were 1.87 and 5.56 %, respectively. Our finding confirms an uneven geographical and ethnic distribution of SLC22A12 mutant variants. We found that the c.1245_1253del and c.1400C>T variants were present in the Czech and Slovak Roma population at unexpectedly high frequencies. Renal hypouricemia should be kept in mind during differential diagnostic on Roma patients with low serum uric acid concentrations.

Recurrent exercise-induced acute kidney injury by idiopathic renal hypouricemia with a novel mutation in the SLC2A9 gene and literature review

BackgroundIdiopathic renal hypouricemia (iRHUC) is an autosomal recessive hereditary disorder, characterized by impaired tubular uric acid transport, re-absorption insufficiency and/or the acceleration of secretions. Some patients present with severe complications, such as exercise-induced acute kidney injury (EIAKI) and nephrolithiasis.Case presentationHerein, we report the case of a girl with severe iRHUC (serum urate 0.05 mg/dL, fractional excretion of uric acid 295.99%) associated with recurrent EIAKI, in whom the disease was caused by a homozygous mutation (g.68G > A in exon 3) in the SLC2A9 gene. Her family members (father, mother and brother) carried the same mutation but were heterozygous, without any signs of severe hypouricemia.ConclusionsOur findings indicate that iRHUC is a rare disorder but that it should also be considered in patients with EIAKI, especially in those patients who manifest with moderately elevated or normal serum concentrations of uric acid during the acute phase of AKI. Mutational screening of the SLC2A9 gene is necessary for the diagnosis of iRHUC, and homozygous mutations of the SLC2A9 alleles can cause severe hypouricemia. Careful attention should be paid to any signs of hypouricemia during the recovery phase of AKI and long-term follow-up.

Acute kidney injury in two children caused by renal hypouricaemia type 2

Renal hypouricaemia is a heterogeneous inherited disorder characterized by impaired tubular uric acid transport with severe complications, such as acute kidney injury and nephrolithiasis. Type 1 is caused by a loss-of-function mutation in the SLC22A12 gene (OMIM #220150), while type 2 is caused by defects in the SLC2A9 gene (OMIM #612076). The cases of two children, a 12- and a 14-year-old boy with acute kidney injury (proband 1: urea 9.4 mmol/l, creatinine 226 μmol/l; proband 2: urea 11.7 mmol/l, creatinine 202 μmol/l) are described. Both are offspring of nonconsanguineous couples in the UK. The concentrations of serum uric acid were consistently below the normal range (0.03 and 0.04 mmol/l) and expressed as an increase in the fractional excretion of uric acid (46 and 93 %). A sequencing analysis of the coding region of uric acid transporters SLC22A12 and SLC2A9 was performed. Analysis of genomic DNA revealed two unpublished missense transitions, p.G216R and p.N333S in the SLC2A9 gene. No sequence variants in SLC22A12 were found. Our findings suggest that homozygous and/or compound heterozygous loss-of-function mutations p.G216R and p.N333S cause renal hypouricaemia via loss of uric acid absorption and do lead to acute kidney injury.

Hypouricemia and tubular transport of uric acid.

Hypouricemia is defined when a serum urate concentration is less than or equal 2.0mg/dl. Differential diagnosis is made by fractional uric acid excretion with the identification of urate transporters and intracellular proteins involved in the tubular transport of uric acid. This review examines current knowledge on uric acid tubular transport and the various clinical situations of hypouricemia.

Age and origin of the G774A mutation inSLC22A12causing renal hypouricemia in Japanese

Renal hypouricemia is an inherited disorder characterized by impaired tubular uric acid transport. Impairment of the function of URAT1, the main transporter for the reabsorption of uric acid at the apical membrane of the renal tubules, causes renal hypouricemia. The G774A mutation in the SLC22A12 gene encoding URAT1 predominates in Japanese renal hypouricemia. From data on linkage disequilibrium between the G774 locus and the 13 markers flanking it (12 single nucleotide polymorphisms and 1 dinucleotide insertion/deletion locus), we here estimate the age of this mutation at approximately 6820 years [95% confidence interval (CI) 1860-11,760 years; median = 2460 years]. This indicates that the origin of the G774A mutation dates back from between the time when the Jomon people predominated in Japan and the time when the Yayoi people started to migrate to Japan from the Korean peninsula. These data are consistent with a recent finding that this G774A mutation was also predominant in Koreans with hypouricemia and indicate that the mutation originated on the Asian continent. Thus, this mutation found in Japanese patients was originally brought by immigrant(s) from the continent and thereafter expanded in the Japanese population either by founder effects or by genetic drift (or both).

Hypo-uricémie, un vieux sujet et de nouveaux concepts

DEFINITION OF HYPOURICEMIA: Hypouricemia (serum uric acid less than 120 micro mol/l) is a biological abnormality often discovered accidentally and with a low prevalence depending on its permanent or transitory nature ranging from 0.15 to 3.38%. NEW PHYSIOLOGICAL CONCEPTS OF ITS PATHOGENESIS: Recently, our knowledge of the physiopathological mechanisms of hypouricemia has been emphasized by the identification of three systems of renal and extra-renal uric acid transport: a Cl/urate (URAT1) transporter, a multispecific organic anion transporter (OAT) and a urate transporter/channel. ETIOLOGY AND COMPLICATIONS OF HYPOURICEMIA: Through questioning, drugs and toxics (allopurinol.) are generally rapidly recognized as responsible for half of the hypouricemia encountered. It can be concomitant to a known disease: severe liver disease, neoplasia, diabetes, AIDS, syndrome of inappropriate antidiuretic hormone secretion. Hypouricemia can also be isolated and justifies the measurement of uric acid clearance, the normality or reduction of which orients towards a deficiency in xanthine-oxydase, the increase in which suggests an abnormality in uric acid transport in the proximal tubule (Fanconi syndrome, primary hereditary anomaly of tubular uric acid transport). Hypouricemia does not appear to expose the patient to any danger, but the onset of nephrolithiasis or acute renal failure secondary to the combination of severe hypouricemia and oxidant stress is always possible.

Effect of Nifedipine on Tubular Handling of Uric Acid in Transplanted Kidney on Cyclosporine A Treatment

Hyperuricemia resulting from tubular urate transport defects is a well-known nephrotoxic effect of cyclosporine A (CyA) on renal blood perfusion in organ recipients. The aim of this study was to define the mechanism of the tubular urate transport defect in hyperuricemic renal graft recipients on CyA and to evaluate the effect of nifedipine retard administration on this tubular dysfunction. Tubular uric acid transport was evaluated by the probenecid test in 17 hyperuricemic (group 1) and 6 normouricemic (group 2) renal graft recipients treated with CyA. Maximal urate excretion after probenecid administration was 25.5 +/- 4.6 versus 42.5 +/- 7.7% (p < 0.001) and postsecretory urate reabsorption was 79.2 +/- 8.3 versus 78.5 +/- 9.7% (NS), respectively. The effects of nifedipine retard on renal urate transport were evaluated in 6 hyperuricemic patients. Seven days of nifedipine therapy did not significantly decrease mean serum uric acid levels (7.7 +/- 1.6 to 7.1 +/- 1.1 mg/dl) nor increase urate clearance (3.8 +/- 1.3 to 4.7 +/- 1.6 ml/min/1.73 m2). The uricosuric effect of probenecid was manifested by an increase in tubular urate transport from 25.5 +/- 4.6 to 37.3 +/- 7.2%, p < 0.01, paralleled by an increase in postsecretory urate reabsorption from 20.5 +/- 3.7 to 31.4 +/- 5.7% (p < 0.003). Postsecretory reabsorption expressed as a percentage of secreted urate in both evaluations did not differ significantly (80.3 +/- 6.2 vs. 84.4 +/- 3.1%).(ABSTRACT TRUNCATED AT 250 WORDS)

Purine metabolism in women with primary gout

purpose: Uncontrolled studies have shown that women with gout have higher serum urate concentrations and similar or lower urinary uric acid excretion rates than do men with gout. These observations suggest a more defective tubular transport of uric acid in women than in men with gout. In this prospective study we assessed purine metabolism in women with primary gout under controlled conditions. We also examined whether there are sex-related differences in plasma and urinary purine concentrations among patients with primary gout. subjects and methods: Ten women with crystal-proved primary gout and normal serum creatinine levels (below 116 mmol/L) were studied while they were on a purine-restricted diet and taking no medications known to influence uric acid metabolism. For comparison, 20 men with primary gout and 10 women without gout, matched for age, race, and body mass index, were studied under the same conditions. In each subject, plasma and 24-hour urinary uric acid, hypoxanthine, and xanthine concentrations were measured. The mean of three consecutive determinations for plasma purines and five for urinary purines was used. Standard formulas were used to calculate the renal clearances and the fractional excretion of purines. results: Mean plasma urate, hypoxanthine, and xanthine levels were significantly higher in women patients with primary gout compared with normal women ( P <0.05). Mean 24-hour urinary uric acid excretion was similar in both groups. Daily urinary hypoxanthine and xanthine excretion rates were significantly lower in gouty women patients than in control women ( P <0.05). The renal clearances and the fractional excretion of uric acid, hypoxanthine, and xanthine were markedly lower in women with primary gout than in control women ( P <0.05). Plasma and urinary purine concentrations were similarly increased and diminished, respectively, in women and men patients with primary gout. Plasma urate, hypoxanthine, and xanthine levels were inversely and significantly associated with the fractional excretion of uric acid ( r = −0.520; P = 0.003), hypoxanthine ( r = −0.555; P = 0.002), and xanthine ( r = −0.384; P = 0.040), respectively. conclusion: Women with primary gout have markedly diminished uric acid, hypoxanthine, and xanthine excretion rates. The disturbance of purine metabolism appears to be of a similar magnitude to that observed in gouty men. The absence of significant sex-related differences in plasma and urinary purine concentrations suggests a similar tubular dysfunction for purine excretion in women and men with primary gout.

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.

140 STOP-FLOW STUDIES ON TUBULAR TRANSPORT OF URIC ACID IN RATS

The species differences in renal tubular transport of uric acid are well known. Among various nonhuman mammalian species, rats belong to a group with a reabsorptive net flux of uric acid in the renal tubules, and hence they have sometimes been used to test uricosuric activity by a clearance technique. The stop-flow technique is also regarded as a useful method for evaluating drug effects on tubular transport of uric acid. This technique has been used with rabbits, dogs and cebus monkeys, but not with rats. Reported here is the utility of a stop-flow technique using rats. The fractional excretion value of uric acid (FEua) in rats with a high urine flow rate was nearly 1.0, which was clearly higher than those in clearance experiments. On the other hand, in pyrazinoic acid (PZO)-treated rats with inhibited secretion of uric acid, the FEua value was much lower than that in non-treated rats, and the stop-flow patterns always indicated a remarkable reabsorption of urate in the proximal tubules corresponding to the secretion of p-aminohippurate. As generally accepted, uricosuric drugs inhibit bidirectional transport of uric acid in the renal tubules. We describe the characteristics of uricosuric drugs using stop-flow techniques with PZO-treated and non-treated rats, and the uricosuric properties of a new uricosuric diuretic, S-8666, which has been developed in our laboratories.

A new uricosuric diuretic, S-8666, in rats and chimpanzees.

5-Dimethylsulfamoyl-6,7-dichloro-2,3-dihydrobenzofuran-2-carboxyli c acid (S-8666) was studied as a possible new uricosuric diuretic agent using rats and chimpanzees. Various new compounds belonging to the 5-sulfamoyl-6,7-dichloro-2,3-dihydrobenzofuran-2-carboxylic acids were clearly diuretic with uricosuric activity in intraperitoneally oxonate-treated rats. S-8666 was chosen as a favorable candidate because its uricosuric activity due to the effects of tubular transport of uric acid were apparently more marked than those of known uricosuric agents such as probenecid, benzbromarone, tienilic acid and indacrinone in oxonate-treated rats. S-8666 was also uricosuric in rats not given urate oxidase inhibitor. The diuretic effect of S-8666 in oxonate-treated rats was as high-ceilinged as that of furosemide, while those of tienilic acid, indacrinone and a known compound of a 5-carbonyl-6,7-dichloro-2,3-dihydrobenzofuran-2-carboxylic acid were rather low-ceilinged. These uricosuric and diuretic activities of S-8666 were manifested by two enantiomers, of which the (+)-enantiomer displayed predominantly uricosuric activity and the (-)-enantiomer, diuretic activity like furosemide. The new compound was also uricosuric and diuretic in chimpanzees, although the potency of the uricosuric activity was similar to that of probenecid and less than that of indacrinone. Thus, it seems that S-8666 is a different type of uricosuric diuretic from known agents which have already been tried in humans.

A New Uricosuric Diuretic, S-8666, in Rats and Chimpanzees

5-Dimethylsulfamoyl-6,7-dichloro-2,3-dihydrobenzofuran-2-carboxylic acid (S-8666) was studied as a possible new uricosuric diuretic agent using rats and chimpanzees. Various new compounds belonging to the 5-sulfamoyl-6,7-dichloro-2,3-dihydrobenzofuran-2-carboxylic acids were clearly diuretic with uricosuric activity in intraperitoneally oxonate-treated rats. S-8666 was chosen as a favorable candidate because its uricosuric activity due to the effects of tubular transport of uric acid were apparently more marked than those of known uricosuric agents such as probenecid, benzbromarone, tienilic acid and indacrinone in oxonate-treated rats. S-8666 was also uricosuric in rats not given urate oxidase inhibitor. The diuretic effect of S-8666 in oxonate-treated rats was as high-ceilinged as that of furosemide, while those of tienilic acid, indacrinone and a known compound of a 5-carbonyl-6,7-dichloro-2,3-dihydrobenzofuran-2-carboxylic acid were rather low-ceilinged. These uricosuric and diuretic activities of S-8666 were manifested by two enantiomers, of which the (+)-enantiomer displayed predominantly uricosuric activity and the (-)-enantiomer, diuretic activity like furosemide. The new compound was also uricosuric and diuretic in chimpanzees, although the potency of the uricosuric activity was similar to that of probenecid and less than that of indacrinone. Thus, it seems that S-8666 is a different type of uricosuric diuretic from known agents which have already been tried in humans.

A New Uricosuric Diuretic, S-8666, in Rats and Chimpanzees

5-Dimethylsulfamoyl-6,7-dichloro-2,3-dihydrobenzofuran-2-carboxylic acid (S-8666) was studied as a possible new uricosuric diuretic agent using rats and chimpanzees. Various new compounds belonging to the 5-sulfamoyl-6,7-dichloro-2,3-dihydrobenzofuran-2-carboxylic acids were clearly diuretic with uricosuric activity in intraperitoneally oxonate-treated rats. S-8666 was chosen as a favorable candidate because its uricosuric activity due to the effects of tubular transport of uric acid were apparently more marked than those of known uricosuric agents such as probenecid, benzbromarone, tienilic acid and indacrinone in oxonate-treated rats. S-8666 was also uricosuric in rats not given urate oxidase inhibitor. The diuretic effect of S-8666 in oxonate-treated rats was as high-ceilinged as that of furosemide, while those of tienilic acid, indacrinone and a known compound of a 5-carbonyl-6,7-dichloro-2,3-dihydrobenzofuran-2-carboxylic acid were rather low-ceilinged. These uricosuric and diuretic activities of S-8666 were manifested by two enantiomers, of which the ( + )-enantiomer displayed predominantly uricosuric activity and the (-)-enantiomer, diuretic activity like furosemide. The new compound was also uricosuric and diuretic in chimpanzees, although the potency of the uricosuric activity was similar to that of probenecid and less than that of indacrinone. Thus, it seems that S-8666 is a different type of uricosuric diuretic from known agents which have already been tried in humans.

Decreased Renal Excretion of Uric Acid Following Diuretic Administration in Rats

In order to evaluate the cause of diuretic-induced hyperuricemia which has been well documented in clinical studies, clearance experiments were performed in rats using furosemide and trichlormethiazide. The net flux in the tubular transport of uric acid was reabsorptive, and the fractional excretion of uric acid responded sensitively to the transtubular transport inhibitors, sodium probenecid and pyrazinoic acid. When the hemoconcentration was induced by highly potent doses of test diuretics, the inuiin clearance and the fractional excretion of uric acid clearly decreased. The contraction of body fluid produced by intraperitoneal administration of polyethylene glycol resulted in marked decrease of inuiin clearance and fractional excretion of uric acid. The decrease of uric acid excretory capacity under the treatment with trichlormethiazide was completely corrected by saline loading. Moreover, no significant change was found in the pyrazinoic acid-suppressibie fractional excretion of uric acid between the diuretic-treated rats and the control animals. These studies suggest that furosemide- and trichlormethiazide-induced changes in the renal handling of uric acid are mediated by the fluid volume contraction and that the decrease in fractional excretion of uric acid by test diuretics is the result of reabsorptive enhancement of uric acid.

Decreased renal excretion of uric acid following diuretic administration in rats.

In order to evaluate the cause of diuretic-induced hyperuricemia which has been well documented in clinical studies, clearance experiments were performed in rats using furosemide and trichlormethiazide . The net flux in the tubular transport of uric acid was reabsorptive, and the fractional excretion of uric acid responded sensitively to the transtubular transport inhibitors, sodium probenecid and pyrazinoic acid. When the hemoconcentration was induced by highly potent doses of test diuretics, the inulin clearance and the fractional excretion of uric acid clearly decreased. The contraction of body fluid produced by intraperitoneal administration of polyethylene glycol resulted in marked decrease of inulin clearance and fractional excretion of uric acid. The decrease of uric acid excretory capacity under the treatment with trichlormethiazide was completely corrected by saline loading. Moreover, no significant change was found in the pyrazinoic acid-suppressible fractional excretion of uric acid between the diuretic-treated rats and the control animals. These studies suggest that furosemide- and trichlormethiazide -induced changes in the renal handling of uric acid are mediated by the fluid volume contraction and that the decrease in fractional excretion of uric acid by test diuretics is the result of reabsorptive enhancement of uric acid.

Renal uric acid clearance in human neonates

Renal clearance of uric acid was examined in 40 premature and term infants during the first 24 hours of life. Creatinine clearance and uric acid clearance increased with increasing gestational age. Serum uric acid concentration (r = -0.31, P less than 0.05) and fractional excretion of uric acid (r = -0.50, P less than 0.01) were inversely related to gestational age; FEUA was nearly 70% at 29 to 31 weeks gestational age, and decreased to a mean value of 39 +/- 14% (+/- SD) at 38 to 40 weeks gestational age. The decline in FEUA with advancing gestational age appears to represent alterations in net renal tubular transport of uric acid, because the filtered load of uric acid increased with gestational age. Postnatal clearance studies were performed in 18 premature infants of 29 to 35 weeks gestational age; FEUA also declined during early postnatal development (r = -0.44, P less than 0.01). In all studies, a relationship between FEUA and fractional excretion of sodium was observed. The high basal excretion of uric acid in infants may increase the risk of acute uric acid nephropathy when excretion demands are increased.