The W258X mutation in SLC22A12 is the predominant cause of Japanese renal hypouricemia

Recently, a urate transporter, hURAT1 (human uric acid transporter 1) encoded by SLC22A12, was isolated from the human kidney. hURAT1 is presumed to play the central role in reabsorption of urate from glomerular filtrate. In the present study, we analyzed SLC22A12 in seven unrelated Japanese patients with renal hypouricemia whose serum level of urate was less than 1.0 mg/dl, and their family members. We performed direct DNA sequencing of the exon and exon-intron boundaries of SLC22A12 using genomic DNA. Six of the seven patients (86%) possess mutations in SLC22A12. In five patients, a homozygous G to A transition at nucleotide 774 within exon 4 of SLC22A12, which forms a stop codon (TGA) at codon 258 (TGG), was identified (W258X). In one patient, the C to T transition within exon 3, which changes threonine at codon 217 to methionine (T217 M), and the W258X mutation were found (compound heterozygote). Thus, among 12 mutational alleles in six patients, 11 were the W258X mutation (92%). Family members with the heterozygous W258X mutation (carriers) show relatively low levels of serum urate. The present study demonstrates that homozygous W258X mutation is the predominant genetic cause of idiopathic renal hypouricemia in Japanese patients.     

Analysis of Mutations in the Urate Transporter 1 (URAT1) Gene of Japanese Patients with Hypouricemia in Northern Japan and Review of the Literature

Background. Renal hypouricemia is an autosomal recessive disorder resulting from inactivating mutations in the urate transporter 1 (URAT1) encoded by SLC22A12. To date, 10 mutations have been identified and W258X in the URAT1 gene is the predominant cause in middle to southwestern Japan. However, it is still unclear whether there is a regional specific distribution of mutations in northern Japan. In this study, we analyzed mutations in the URAT1 gene of five Japanese patients with renal hypouricemia in northern Japan. Methods. Peripheral blood mononuclear cells were isolated from patients with hypouricemia and healthy control subjects. A mutation analysis of the URAT1 gene was performed completely by direct automated sequencing of polymerase chain reaction-amplified DNA products. Results. We identified two mutations. These mutations [c.269G>A (R90H) and c.774G>A (W258X)] have been reported in Japanese patients. Two of five patients were homozygotes (W258X), two carried single heterozygous mutations (W258X), and the remaining one was a compound heterozygote (R90H and W258X). Conclusions. Our study suggests that there is no regional different distribution of the URAT1 genetic mutations in Japanese with renal hypouricemia.     

A case of acute renal failure after exercise with renal hypouricemia demonstrated compound heterozygous mutations of uric acid transporter 1

Familial renal hypouricemia is a hereditary disease characterized by extraordinary high renal uric acid (UA) clearance and is associated with acute renal failure (ARF). A 17-year-old Japanese male developed ARF after anerobic exercise. Renal function improved completely after approximately 2 weeks of hydration treatment. After remission, hypouricemia became evident (1.0 mg/dL) from the initial level of UA (4.8 mg/dL) and fractional excretion of uric acid (FEUA) was >50%. His parents showed normal levels of UA and FEUA. Polymerase chain reaction of a urate anion exchanger known to regulate UA level [SLC22A12 gene: UA transporter 1 (URAT1)] demonstrated compound heterozygous mutations (Q297X and R90H). Thus, we describe a Japanese male with hypouricemia complicated by anerobic exercise-induced ARF, with definite demonstration of a genetic abnormality in the responsible gene, URAT1.     

Analysis of mutations in the urate transporter 1 (URAT1) gene of Japanese patients with hypouricemia in northern Japan and review of the literature

BACKGROUND: Renal hypouricemia is an autosomal recessive disorder resulting from inactivating mutations in the urate transporter 1 (URAT1) encoded by SLC22A12. To date, 10 mutations have been identified and W258X in the URAT1 gene is the predominant cause in middle to southwestern Japan. However, it is still unclear whether there is a regional specific distribution of mutations in northern Japan. In this study, we analyzed mutations in the URAT1 gene of five Japanese patients with renal hypouricemia in northern Japan. METHODS: Peripheral blood mononuclear cells were isolated from patients with hypouricemia and healthy control subjects. A mutation analysis of the URAT1 gene was performed completely by direct automated sequencing of polymerase chain reaction-amplified DNA products. RESULTS: We identified two mutations. These mutations [c.269G>A (R90H) and c.774G>A (W258X)] have been reported in Japanese patients. Two of five patients were homozygotes (W258X), two carried single heterozygous mutations (W258X), and the remaining one was a compound heterozygote (R90H and W258X). CONCLUSIONS: Our study suggests that there is no regional different distribution of the URAT1 genetic mutations in Japanese with renal hypouricemia.     

A high prevalence of renal hypouricemia caused by inactive SLC22A12 in Japanese

BACKGROUND: Recently, SLC22A12 has been identified as a urate-anion exchanger in the human kidney. METHODS: We screened for polymorphisms of SLC22A12 and conducted an association study between genetic polymorphisms and urate levels in an epidemiologic cohort representing the general population in Japan. Functional significance of mutations was assessed by oocyte expression analysis. RESULTS: We found five missense, one nonsense, and one deletion mutations [R90H, A226V, R228E, W258Stop, Q312L, D313A (deletion of 313D-333P), and R477H] in 24 subjects with hypouricemia recruited from an epidemiologic cohort (Suita Study) representing the general population in Japan (N= 1875). A statistical analysis indicated that the 90H (N= 14), 477H (N= 5), and 258Stop (hetero + homo N= 82 + 3) alleles were associated with hypouricemia. The alleles 228E and 313A (deletion of 313D-333P) were found just once in the total population. In vitro oocyte expression analysis indicated that 313A (deletion of 313D-333P) had no urate transport activity, indicating that this is a newly identified mutation for idiopathic renal hypouricemia. Intriguingly, the allele frequency of 258Stop was unexpectedly high (2.37%). However, this inactivating mutation does not seem to be harmful in the general population. The effects of common polymorphisms of SLC22A12 were also investigated. Based on linkage disequilibrium, 16 common polymorphisms were categorized into six distinct groups, and six representative genotypes were determined. None of these six common polymorphisms affected the serum uric acid level. A haplotype analysis also suggested that these common genotypes/haplotypes were not important in determining the serum uric acid levels in the general population. CONCLUSION: SLC22A12 is a major gene for hypouricemia but not hyperuricemia in Japanese.     

Prevalence of hypouricaemia and SLC22A12 mutations in healthy Korean subjects

Aim: Mutations in the SLC22A12 gene, which encodes a uric acid transporter, URAT1, are associated with renal hypouricaemia. This study was designed to measure serum uric acid (Sua) levels and allele frequencies of two common mutations in SLC22A12, W258X and R90H, in healthy Korean subjects. Methods: A total of 909 unrelated Korean adults (male : female, 1:1.23; mean age, 48.4 ± 11.0 years) were recruited among those who had taken a routine health check-up in a health centre in 2003. None of them had hypertension, diabetes mellitus, kidney diseases or liver diseases. Genotyping for W258X and R90H was performed using the TaqMan method. Results: The prevalences of hyperuricaemia (Sua levels, >416 µmol/L) and hypouricaemia (Sua levels, <178 µmol/L) were 4.6% and 3.3%, respectively. A marked male preponderance in the hyperuricaemic group was noted, and the men revealed higher Sua than the women. The Sua showed a positive correlation with serum creatinine level and blood pressure. In the hypouricaemic group, the allele frequencies of W258X and R90H were 11.7% and 6.7%, respectively, and the proportion of subjects with one or both of the mutant alleles was 33.3%. Hyperuricaemic subjects never had either mutation. Conclusion: The W258X and/or R90H mutations in the SLC22A12 gene are one of the major factors responsible for hypouricaemia, and one-third of the hypouricaemic subjects had one or both of the mutant alleles.     

Clinical and molecular analysis of patients with renal hypouricemia in Japan-influence of URAT1 gene on urinary urate excretion

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.     

Two cases of nephrotic syndrome (NS)-induced acute kidney injury (AKI) associated with renal hypouricemia

Renal hypouricemia is a clinical disorder attributed to an increased renal urate excretion rate and is well known to involve a high risk of urolithiasis and exercise-induced acute kidney injury (AKI). This report concerns two interesting cases of nephrotic syndrome (NS)-induced AKI associated with renal hypouricemia. A 64-year-old female (Case 1) and a 37-year-old male (Case 2) were hospitalized because of AKI (serum creatinine: 2.07 mg/dl and 3.3 mg/dl, respectively), oliguria and NS. They were treated with prednisolone and temporary hemodialysis. Renal function improved, but hypouricemia persisted during hospitalization. Histological findings in both cases led to a diagnosis of minimal change nephrotic syndrome and identification of the diuretic phase of tubulointerstitial damage because of findings such as acute tubular necrosis. Furthermore, distal tubules of Case 2 showed an amorphous mass, possibly a uric acid crystal. Analysis of the two cases with the URAT1 gene, encoded by SLC22A12, found a homozygous mutation in exon 4 (W258stop) of each one. Our cases show that patients with renal hypouricemia may be susceptible to AKI without involvement of exercise if they possess some facilitators. Renal hypouricemic patients should therefore be carefully examined for all complications from renal hypouricemia because of high risk of AKI.     

Hereditary renal hypouricemia: a cause of calcium oxalate urolithiasis in a young female

Although renal hypouricemia is mostly asymptomatic, it is known to present a high risk of exercise-induced acute renal failure, especially in young males. However, there is little information regarding the clinical features of urolithiasis as a complication in childhood renal hypouricemia. Here we report a 4-year old female with idiopathic renal hypouricemia who presented with macroscopic hematuria due to obstructive calcium oxalate urolithiasis. She was treated successfully with percutaneous nephrolithotripsy and thereafter hematuria disappeared. Sequence analysis of the patient and her family's URAT1 gene confirmed a nonsense mutation in exon 4 (W258X). To the best of our knowledge, this is the youngest case of hereditary renal hypouricemia caused by URAT1 gene mutation, which was found by hematuria due to calcium oxalate urolithiasis.     

Non-urate transporter 1-related renal hypouricemia and acute renal failure in an Israeli–Arab family

Idiopathic renal hypouricemia (IRHU) is a rare hereditary disease, predisposing the individual to exercise-induced acute renal failure (EIARF) and nephrolithiasis, and it is characterized by increased clearance of renal uric acid. Most of the described patients are Japanese, who have loss-of-function mutations in the SLC22A12 gene coding for the human urate transporter 1 (URAT1) gene. An 18-year-old youth, who was admitted for EIARF due to IRHU, and six consanguineous Israeli–Arab family members were included in the study. The family members were tested for fractional excretion of uric acid and molecular analysis of the URAT1 gene. Four family members, including the proband, had very low levels of blood uric acid and high rate of fractional excretion (FE urate> 100%) of uric acid. Genetic analysis of the affected family members did not reveal a mutation in the coding regions and intron–exon boundaries of SCL22A12. Haplotype analysis excluded SCL22A12 involvement in the pathogenesis, suggesting a different gene as a cause of the disease. We herein describe the first Israeli–Arab family with IRHU. A non-URAT1 genetic defect that causes decreased reabsorption or, more probably, increased secretion of uric acid, induces IRHU. Further studies are required in order to elucidate the genetic defect. Hilla Bahat and Dganit Dinour contributed equally to the work.     

Functional analysis of novel allelic variants in URAT1 and GLUT9 causing renal hypouricemia type 1 and 2

Background

Renal hypouricemia is a rare 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 (URAT1), while type 2 is caused by defects in the SLC2A9 gene (GLUT9).

Methods and results

In this article we present clinical, biochemical and molecular genetics of two Czech patients. The serum uric acid in the probands was 57 and 98 µmol/l and expressed as an increase in the fractional excretion of uric acid (40 and 18 %). The sequencing analysis of SLC22A12 and SLC2A9 revealed novel variants p.R92C and p.R203C in URAT1 and p.G72D in GLUT9. Functional studies were performed for these novel variants and for previously reported variants p.I118HfsX27, p.G216R and p.N333S in GLUT9 responsible for renal hypouricemia in three probands from Czech Republic and United Kingdom. Functional studies showed significantly decreased urate uptake for all variants. However, urate uptake of GLUT9 variants prepared for both isoforms were not significantly different.

Conclusions

This is the first complex function characterization of non-synonymous allelic variants in patients with renal hypouricemia regarding both GLUT9 isoforms. Our finding of defects in the SLC2A9 and SLC22A12 genes show the following: renal hypouricemia is not restricted to East Asia populations; urate uptake of GLUT9 variants prepared for both isoforms were not significantly different; renal hypouricemia type 2 has more wide clinical variability than type 1; the phenotypic severity of renal hypouricemia is not correlated with results of functional characterizations of URAT1 and GLUT9 variants.

     

Homozygous SLC2A9 Mutations Cause Severe Renal Hypouricemia

Hereditary hypouricemia may result from mutations in the renal tubular uric acid transporter URAT1. Whether mutation of other uric acid transporters produces a similar phenotype is unknown. We studied two families who had severe hereditary hypouricemia and did not have a URAT1 defect. We performed a genome-wide homozygosity screen and linkage analysis and identified the candidate gene SLC2A9, which encodes the glucose transporter 9 (GLUT9). Both families had homozygous SLC2A9 mutations: A missense mutation (L75R) in six affected members of one family and a 36-kb deletion, resulting in a truncated protein, in the other. In vitro, the L75R mutation dramatically impaired transport of uric acid. The mean concentration of serum uric acid of seven homozygous individuals was 0.17 ± 0.2 mg/dl, and all had a fractional excretion of uric acid >150%. Three individuals had nephrolithiasis, and three had a history of exercise-induced acute renal failure. In conclusion, homozygous loss-of-function mutations of GLUT9 cause a total defect of uric acid absorption, leading to severe renal hypouricemia complicated by nephrolithiasis and exercise-induced acute renal failure. In addition to clarifying renal handling of uric acid, our findings may provide a better understanding of the pathophysiology of acute renal failure, nephrolithiasis, hyperuricemia, and gout.In most mammals, uric acid (UA) is oxidized by the hepatic enzyme uricase to highly soluble allantoin. In humans, however, this enzyme is inactive as a result of mutational silencing,¹ making UA the end product of purine metabolism. Serum UA concentration depends on both UA production and UA removal by the kidneys and intestinal tract and is high in humans compared with other mammals. Elevation of serum UA levels has been associated with various diseases, including gout, hypertension, and cardiovascular and renal disease.² Conversely, it has been suggested that UA has a beneficial role as a natural antioxidant, and low serum UA levels have been linked to several neurologic diseases.²Studies of renal handling of UA in humans have provided evidence for a historical model of urinary UA excretion, which consists of four components: Free glomerular filtration, tubular absorption, secretion, and postsecretion reabsorption. The location and molecular physiology of the three tubular transport components, however, have not been completely clarified.³The first renal UA transporter, URAT1, was identified in 2002 by Enomoto et al.⁴ The significance of URAT1 in the handling of UA was demonstrated by genetic analysis of Japanese patients with hereditary renal hypouricemia.^4,5 These patients were characterized by very low levels of serum UA, high fractional excretion of UA, and attenuated response of urinary urate excretion to pyrazinamide and probenecid.⁵ Most of these patients were asymptomatic, but some had nephrolithiasis or were predisposed to exercise-induced acute renal failure (EIARF). The Japanese patients were found to possess homozygous or compound heterozygous loss-of-function mutations in the gene SLC22A12 coding for human URAT1; most of them carry at least one allele with the truncation mutation W258X.^4–6Mutations in SLC22A12 seem to be very rare outside Japan. A mutation analysis of renal hypouricemia in Korea showed that three of four patients with URAT1 mutations carried the W258X mutation.⁷ We previously described hereditary hypouricemia as a result of a homozygous SLC22A12 missense mutation (R496C) in three Israeli families of Iraqi origin.⁸ Although serum UA level and fractional excretion of UA were similar to those of the Japanese patients, none of our patients developed EIARF.A recent meta-analysis of 14 genome-wide association scans in Europe demonstrated significant association of serum UA concentration with several other genes, including SLC22A11 coding for organic anion transporter 4 (OAT4), SLC17A1 coding for NPT4, the ATP-binding cassette transporter ABCG2, and SLC2A9 coding for the glucose-facilitated transporter GLUT9.⁹ OAT4,¹⁰ NPT1,¹¹ ABCG2,¹² and GLUT9^13–16 have been shown to be expressed in renal tubular cells and to transport UA in vitro. Recently, heterozygous mutations of GLUT9 were shown to cause renal hypouricemia.¹⁶In this report, we show that homozygous mutations of GLUT9 cause severe hereditary hypouricemia complicated by nephrolithiasis and EIARF. Our findings provide further evidence for the key role played by GLUT9 in renal UA handling.     

Recurrent URAT1 gene mutations and prevalence of renal hypouricemia in Japanese

Recent identification of the urate transporter in the kidney (URAT1, encoded by SLC22A12) led to the molecular elucidation of idiopathic renal hypouricemia, which is a predisposition toward exercise-induce acute renal failure. One Japanese patient with renal hypouricemia demonstrated compound heterozygous mutations of the URAT1 gene (Q297X and IVS2+1G>A). It was suggested that these two mutations are recurrent mutations of the URAT1 gene in a Japanese population. In addition, we expect the prevalence of renal hypouricemia, 0.23%, from the analysis of serum urate levels in 1,730 Japanese children.     

The population-specific distribution and frequencies of genomic variants in the<Emphasis Type="Italic"> SLC3A1</Emphasis> and<Emphasis Type="Italic"> SLC7A9</Emphasis> genes and their application in molecular genetic testing of cystinuria

Cystinuria is a common inherited aminoaciduria resulting in nephrolithiasis. Mutations in two genes, SLC3A1 and SLC7A9, have been identified in cystinuric patients. Considering the population-specific distribution of genetic variants in the SLC3A1 gene, we focused our study on mutations in SLC3A1 and SLC7A9 described more than once in the literature. We evaluated the usefulness of this restricted analysis as a diagnostic approach. Furthermore, the data obtained were used to estimate the frequency of heterozygote carriers of SLC3A1 mutations in the general European population. A total of 22 unclassified cystinuric patients were screened for genetic variants in four exons of both SLC3A1 and SLC7A9 in which the most common mutations have been identified. For screening, we used single strand conformation polymorphism analysis (SSCP), restriction assays, real-time PCR and direct sequencing. In total, we identified mutations in 17 of our 22 patients, including a new mutation (R365Q) as well as a novel polymorphism (c.1035G/A) within the SLC3A1 gene. An ethnic influence on the distribution of mutations was confirmed: T216M in SLC3A1 is the major mutation in south-eastern Europe, whereas M467T in SLC3A1 is mainly found in western Europe. A complex duplication in SLC3A1 is restricted to German patients. Generally, we could show that a stepwise analysis directed to the most common mutations in the two cystinuria genes is sufficient to detect variants in more than 75% of patients of European origin. The test consists of nine different PCR-based approaches and therefore represents a low-cost, reliable and timesaving diagnostic tool.     

A case of renal hypouricemia caused by urate transporter 1 gene mutations

Hypouricemia is a common disorder in the general population. Herein, renal hypouricemia caused by human urate transporter 1 (hURAT1) gene mutations in a Japanese patient with intellectual disability is reported. She had compound heterozygous mutations in this gene (W258X and IVS2+1G>A), nevertheless, she showed no clinical manifestations such as urolithiasis and exercise-induced acute renal failure. Restriction enzyme analysis with HphI was useful to screen the IVS2+1G>A mutation in hURAT1 gene.     

Urinary excretion of total cystine and the dibasic amino acids arginine,lysine and ornithine in relation to genetic findings in patients with cystinuria treated with sulfhydryl compounds

Advances in molecular genetics have brought a deeper understanding of cystinuria. This autosomal recessive disease, which is caused by a defective tubular reabsorption of cystine and the three dibasic amino acids arginine, lysine and ornithine, results in a lifelong risk of renal stone formation because of the low solubility of cystine in urine. Mutations detected within the two genes known to be associated with cystinuria, SLC3A1 (related to type I) and SLC7A9 (related to non-type I), cannot, however, in all cases explain the disease. Inasmuch as a high urinary concentration of cystine is the basis of stone formation in these patients, our aim was to measure urinary total cystine, arginine, lysine and ornithine, in patients currently lacking a full genetic explanation for their disease. Thirty-three patients with cystinuria who were on long-term treatment with tiopronin or D-penicillamine were divided into two groups. Group 1 comprised eight patients who carried mutation in one of the SLC3A1 alleles and two patients who completely lacked mutations both in the SLC3A1 and the SLC7A9 genes, that is genetic findings discordant with the increased urinary excretion of cystine and the dibasic amino acids in these patients. Group 2 comprised 23 patients homozygous for mutations within SLC3A1, that is genetic findings in accordance with the excretion pattern of classic type I cystinuria. When the two groups were compared, Group 1 had a significantly higher total urinary excretion of cystine (p<0.01) as well as of arginine, lysine and ornithine (p<0.05) than Group 2. Also, when the two patients without mutations were excluded from the calculations, there still was a significant difference in the urinary excretion of total cystine (p<0.05). This suggests that the two patients without any detected mutations in the two known cystine transport genes also contributed to the difference. These unexpected findings indicate that an additional gene or genes participate in the urinary cystine reabsorption in the cystinuric patients who currently are without a full genetic explanation for their disease.     

Renal hypouricemia in school-aged children: screening of serum uric acid level before physical training

We present two cases of a 12-year-old Japanese boy and a 14-year-old Japanese girl who had exercise-induced acute renal failure (ARF). They experienced general fatigue, nausea/vomiting, and vague discomfort in the abdomen after physical exercise at school. In case of the boy, abdominal pain subsided, but renal dysfunction lasted 17 days, with peak levels of creatinine 9.4 mg/dl and uric acid 11.3 mg/dl. On the other hand, as the girl had suffered from hypouricemia before, she followed a doctor’s guidance on prevention of ARF. Consequently, she was promptly diagnosed as having exercise-induced ARF associated with hypouricemia, and rapidly recovered from ARF within a week. The difference between their clinical courses suggested a possibility that previous laboratory evaluation of serum uric acid assisted in the management of exercise-induced ARF associated with hypouricemia. School-aged children, especially Japanese and Asian, may be advised to have their serum uric acid measured before starting physical training at school.     

Exercise-induced acute renal failure with renal hypouricemia: a case report and a review of the literature

A previously healthy 16-year-old boy developed acute renal failure following a track race at a local athletic meeting. Several hours after the run, he expressed pain in the loins with nausea and vomiting. After 3 sessions of hemodialysis, he was referred to our hospital. On admission, serum creatinine was elevated to 2.3 mg/dl without an increase in serum uric acid level. After recovery from acute renal failure (ARF), hypouricemia (0.7 mg/dl) became evident in the patient. One year later, he suffered from ARF after a track race with the highest creatinine levels of 1.1 mg/dl. In order to clarify the cause and prognosis of ARF with renal hypouricemia, we summarized the clinical features in 18 patients previously described and our patient. Serum uric acid levels after recovery from ARF were below 1.0 mg/dl in all patients. Renal biopsy in 9 patients showed acute tubular necrosis in 8 patients and uric acid nephropathy in 1. The short-term prognosis of these patients seemed good, although 5 patients needed to undergo hemodialysis in their ARF courses. However, the recurrence of ARF episodes occurred in 6 patients (31.6%) including our patient, indicating that prevention of ARF might be necessary in these patients. More information is required to establish guidance for prevention of ARF.     

Exercise-induced acute renal failure in a patient with renal hypouricemia

We describe a case of exercise-induced acute renal failure (ARF) in a patient with hypouricemia. Following recovery from ARF, the patient’s serum urate concentration was 0.6–0.9 mg/dl, and the ratio of urate clearance to creatinine clearance (C _ua/C _Cr) was 41.9%–56.6%. There was no change in the C _ua/C _Cr following the administration of pyrazinamide or probenecid, suggesting defects of tubular urate/anion exchangers. Because the renal biopsy revealed acute tubular necrosis without uric acid crystals, the ARF of this patient might be due to oxygen free radicals resulting from exercise stress and hypouricemia. Received: 15 March 1999 / Revised: 10 September 1999 / Accepted: 14 September 1999     

Phenotype and genotype of Dent’s disease in three Korean boys

Dents disease is a hereditary renal tubular disorder caused by mutations of the CLCN5 gene and is clinically characterized by low molecular weight proteinuria, hypercalciuria and nephrocalcinosis. This disease has been reported in several countries. However, there are some phenotypic differences between countries, such as hypophosphatemic rickets, progressive renal failure and hematuria. In this study, phenotypes were analyzed in three Korean boys with Dents disease, and genetic diagnoses were performed using a new convenient method using peripheral blood RNA. Gene studies revealed two nonsense mutations, R637X in two patients and E609X in one patient. The phenotypes of the two patients with R637X were very similar to those of Japanese patients, i.e., they presented with asymptomatic proteinuria without rickets, renal failure or hematuria. The E609X patient was diagnosed genetically at 3 months of age before the onset of clinical symptoms because of superimposed furosemide-induced nephrolithiasis. This is the first report to characterize mutations in the CLCN5 gene in Korean patients with Dents disease, and expands the spectrum of CLCN5 mutations by reporting a novel mutation, E609X. In addition, the mutational analysis using peripheral blood RNA can be easily applied in the clinical diagnosis.