Renal hypouricemia is a disease caused by the dysfunction of renal urate transporters. This disease is known to cause exercise-induced acute kidney injury, but its mechanism has not yet been established. To analyze the mechanism by which hypouricemia causes renal failure, we conducted a semi-ischemic forearm exercise stress test to mimic exercise conditions in five healthy subjects, six patients with renal hypouricemia, and one patient with xanthinuria and analyzed the changes in purine metabolites. The results showed that the subjects with renal hypouricemia had significantly lower blood hypoxanthine levels and increased urinary hypoxanthine excretion after exercise than healthy subjects. Oxidative stress markers did not differ between healthy subjects and hypouricemic subjects before and after exercise, and no effect of uric acid as a radical scavenger was observed. As hypoxanthine is a precursor for adenosine triphosphate (ATP) production via the salvage pathway, loss of hypoxanthine after exercise in patients with renal hypouricemia may cause ATP loss in the renal tubules and consequent tissue damage.

• Keywords
• acute kidney injury, hypouricemia, xanthinuria,
• Publication type
• Journal Article MeSH

Renal hypouricemia (RHUC) is caused by an inherited defect in the main reabsorption system of uric acid, SLC22A12 (URAT1) and SLC2A9 (GLUT9). RHUC is characterized by a decreased serum uric acid concentration and an increase in its excreted fraction. Patients suffer from hypouricemia, hyperuricosuria, urolithiasis, and even acute kidney injury. We report clinical, biochemical, and genetic findings in a cohort recruited from the Košice region of Slovakia consisting of 27 subjects with hypouricemia and relatives from 11 families, 10 of whom were of Roma ethnicity. We amplified, directly sequenced, and analyzed all coding regions and exon-intron boundaries of the SLC22A12 and SLC2A9 genes. Sequence analysis identified dysfunctional variants c.1245_1253del and c.1400C>T in the SLC22A12 gene, but no other causal allelic variants were found. One heterozygote and one homozygote for c.1245_1253del, nine heterozygotes and one homozygote for c.1400C>T, and two compound heterozygotes for c.1400C>T and c.1245_1253del were found in a total of 14 subjects. Our result confirms the prevalence of dysfunctional URAT1 variants in Roma subjects based on analyses in Slovak, Czech, and Spanish cohorts, and for the first time in a Macedonian Roma cohort. Although RHUC1 is a rare inherited disease, the frequency of URAT1-associated variants indicates that this disease is underdiagnosed. Our findings illustrate that there are common dysfunctional URAT1 allelic variants in the general Roma population that should be routinely considered in clinical practice as part of the diagnosis of Roma patients with hypouricemia and hyperuricosuria exhibiting clinical signs such as urolithiasis, nephrolithiasis, and acute kidney injury.

• Keywords
• Roma, SLC22A12, URAT1, ethnic specificity, renal hypouricemia,
• Publication type
• Journal Article MeSH

• Keywords
• Excretion fraction of uric acid *, Hypouricemia *, SLC22A12 *, URAT1 *, Urate transport *,
• MeSH
• Acute Kidney Injury blood   prevention & control   urine   MeSH
• Allopurinol administration & dosage   MeSH
• Antioxidants administration & dosage   MeSH
• Cystinosis blood   diagnosis   urine   MeSH
• Diagnosis, Differential MeSH
• Child MeSH
• Fanconi Syndrome blood   diagnosis   urine   MeSH
• Genetic Testing MeSH
• Uric Acid blood   metabolism   urine   MeSH
• Kidney Tubules metabolism   MeSH
• Humans MeSH
• Urinary Calculi blood   diagnosis   genetics   urine   MeSH
• Organic Anion Transporters genetics   MeSH
• Organic Cation Transport Proteins genetics   MeSH
• Glucose Transport Proteins, Facilitative genetics   MeSH
• Renal Reabsorption MeSH
• Inappropriate ADH Syndrome blood   diagnosis   urine   MeSH
• Renal Tubular Transport, Inborn Errors blood   diagnosis   genetics   urine   MeSH
• Check Tag
• Child MeSH
• Humans MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Case Reports MeSH
• Names of Substances
• Allopurinol MeSH
• Antioxidants MeSH
• Uric Acid MeSH
• Organic Anion Transporters MeSH
• Organic Cation Transport Proteins MeSH
• Glucose Transport Proteins, Facilitative MeSH
• SLC22A12 protein, human MeSH Browser
• SLC2A9 protein, human MeSH Browser

BACKGROUND: Renal 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 PRESENTATION: Herein, 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. CONCLUSIONS: This 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).

• Keywords
• Renal hypouricemia, SLC22A12, URAT1, Uric acid transporters,
• MeSH
• Child MeSH
• Adult MeSH
• Heterozygote * MeSH
• Humans MeSH
• Mutation, Missense * MeSH
• Adolescent MeSH
• Urinary Calculi genetics   MeSH
• Child, Preschool MeSH
• Organic Anion Transporters genetics   MeSH
• Organic Cation Transport Proteins genetics   MeSH
• Renal Tubular Transport, Inborn Errors genetics   MeSH
• Check Tag
• Child MeSH
• Adult MeSH
• Humans MeSH
• Adolescent MeSH
• Male MeSH
• Child, Preschool MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Case Reports MeSH
• Research Support, Non-U.S. Gov't MeSH
• Geographicals
• Sri Lanka MeSH
• Names of Substances
• Organic Anion Transporters MeSH
• Organic Cation Transport Proteins MeSH
• SLC22A12 protein, human MeSH Browser

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.

• Keywords
• GLUT9, Renal hypouricemia, SLC22A12, SLC2A9, URAT1, Uric acid transporters,
• MeSH
• Child MeSH
• Middle Aged MeSH
• Humans MeSH
• Adolescent MeSH
• Urinary Calculi genetics   MeSH
• DNA Mutational Analysis MeSH
• Organic Anion Transporters genetics   MeSH
• Organic Cation Transport Proteins genetics   MeSH
• Glucose Transport Proteins, Facilitative genetics   MeSH
• Renal Tubular Transport, Inborn Errors genetics   MeSH
• Xenopus MeSH
• Animals MeSH
• Check Tag
• Child MeSH
• Middle Aged MeSH
• Humans MeSH
• Adolescent MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Case Reports MeSH
• Names of Substances
• Organic Anion Transporters MeSH
• Organic Cation Transport Proteins MeSH
• Glucose Transport Proteins, Facilitative MeSH
• SLC22A12 protein, human MeSH Browser
• SLC2A9 protein, human MeSH Browser

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.

• Keywords
• Acute kidney injury, Renal hypouricemia, SLC22A12, URAT1,
• MeSH
• Genetic Testing methods   MeSH
• Humans MeSH
• Urinary Calculi genetics   MeSH
• Polymerase Chain Reaction methods   MeSH
• Organic Anion Transporters genetics   MeSH
• Organic Cation Transport Proteins genetics   MeSH
• Retrospective Studies MeSH
• Roma genetics   MeSH
• Renal Tubular Transport, Inborn Errors genetics   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Multicenter Study MeSH
• Research Support, Non-U.S. Gov't MeSH
• Geographicals
• Czech Republic MeSH
• Slovakia MeSH
• Names of Substances
• Organic Anion Transporters MeSH
• Organic Cation Transport Proteins MeSH
• SLC22A12 protein, human MeSH Browser