Exercise-induced Acute Renal Failure Research Articles

Characterization of a Compound Heterozygous SLC2A9 Mutation That Causes Hypouricemia.

Renal hypouricemia is a rare genetic disorder. Hypouricemia can present as renal stones or exercise-induced acute renal failure, but most cases are asymptomatic. Our previous study showed that two recessive variants of SLC22A12 (p.Trp258*, pArg90His) were identified in 90% of the hypouricemia patients from two independent cohorts: the Korean genome and epidemiology study (KoGES) and the Korean Cancer Prevention Study (KCPS-II). In this work, we investigate the genetic causes of hypouricemia in the rest of the 10% of unsolved cases. We found a novel non-synonymous mutation of SLC2A9 (voltage-sensitive uric acid transporter) in the whole-exome sequencing (WES) results. Molecular dynamics prediction suggests that the novel mutation p.Met126Val in SLCA9b (p.Met155Val in SLC2A9a) hinders uric acid transport through a defect of the outward open geometry. Molecular analysis using Xenopus oocytes confirmed that the p.Met126Val mutation significantly reduced uric acid transport but does not affect the SLC2A9 protein expression level. Our results will shed light on a better understanding of SLC2A9-mediated uric acid transport and the development of a uric acid-lowering agent.

URAT1 and GLUT9 mutations in Spanish patients with renal hypouricemia

BackgroundRenal hypouricemia (RHUC), a rare inherited disorder characterized by impaired uric acid (UA) reabsorption in the proximal tubule, is caused by mutations in SLC22A12 or SLC2A9. Most mutations have been identified in Japanese patients, and only a few have been detected in Europeans. MethodsWe report clinical, biochemical and genetics findings of fourteen Spanish patients, six Caucasians and eight of Roma ethnia, diagnosed with idiopathic RHUC. Two of the patients presented exercise-induced acute renal failure and another one had several episodes of nephrolithiasis and four of them had progressive deterioration of renal function, while the rest were asymptomatic. ResultsMolecular analysis revealed SLC22A12 mutations in ten of the patients, and SLC2A9 mutations in the other four. A new heterozygous SLC22A12 missense mutation, c.1427C>A (p.A476D), was identified in two affected members of the same family. The rest of the patients presented homozygous, heterozygous or compound heterozygous mutations that have been previously identified in patients with RHUC; SLC22A12 p.T467M and p.L415_G417del, and SLC2A9 p.T125M. Expression studies in Xenopus oocytes revealed that c.1427C>A reduced UA transport but did not alter the location of URAT1 protein on the plasma membrane. ConclusionsThe biochemical and clinical features of our patients together with the genetic analysis results confirmed the diagnosis of RHUC. This is the first report describing SLC22A12 and SLC2A9 mutations in Spanish patients.

A novel homozygous GLUT9 mutation cause recurrent exercise-induced acute renal failure and posterior reversible encephalopathy syndrome

Renal hypouricemia (RHU) is an autosomal recessive hereditary disease characterized by impaired renal urate reabsorption and subsequent profound hypouricemia. There are two types of RHU, type 1 and type 2, caused by the loss-of-function mutation of SLC22A12 and SLC2A9 genes, respectively. RHU predisposes affected people to exercise-induced acute renal failure (EIARF), posterior reversible encephalopathy syndrome (PRES) and nephrolithiasis. A Chinese patient had experienced three episodes of EIARF and one episode of PRES. The investigations showed profound hypouricemia and significantly increased renal excretion of UA. Cranial magnetic resonance imaging showed communicating hydrocephalus. Renal biopsy displayed interlobular artery intimal thickening with reduction of lumen and acute tubulointerstitial injury. The mutational analysis revealed a homozygous splice-site mutation in the SLC2A9 gene encoding glucose transporter 9. The patient was diagnosed as RHU type 2 caused by a loss-of-function mutation of the SLC2A9 gene. Consequently, he was strictly prohibited from strenuous exercise. During the 5-year follow-up, EIARF and PRES never recurred. Strenuous exercise may induce systemic (including renal and cerebrovascular) vasoconstriction eventually resulting in EIARF and PRES in patients with RHU. To our knowledge, this is the first report of a homozygous splice-site mutation in the SLC2A9 gene, renal arteriolar chronic lesion, concurrence of RHU and communicating hydrocephalus.

Recurrent exercise-induced acute renal failure in a young Pakistani man with severe renal hypouricemia and SLC2A9compound heterozygosity

BackgroundFamilial renal hypouricemia (RHUC) is a hereditary disease characterized by hypouricemia, high renal fractional excretion of uric acid (FE-UA) and can be complicated by acute kidney failure and nephrolithiasis. Loss-of-function mutations in the SLC22A12 gene cause renal hypouricemia type 1 (RHUC1), whereas renal hypouricemia type 2 (RHUC2) is caused by mutations in the SLC2A9 gene.Case presentationWe describe a 24-year-old Pakistani man who was admitted twice to our hospital for severe exercise-induced acute renal failure (EIARF), abdominal pain and fever; he had very low serum UA levels (0.2 mg/dl the first time and 0.09 mg/dl the second time) and high FE-UA (200% and 732% respectively), suggestive of RHUC. Mutational analyses of both urate transporters revealed a new compound heterozygosity for two distinct missense mutations in the SLC2A9 gene: p.Arg380Trp, already identified in heterozygosity, and p.Gly216Arg, previously found in homozygosity or compound heterozygosity in some RHUC2 patients. Compared with previously reported patients harbouring these mutations, our proband showed the highest FE-UA levels, suggesting that the combination of p.Arg380Trp and p.Gly216Arg mutations most severely affects the renal handling of UA.ConclusionsThe clinical and molecular findings from this patient and a review of the literature provide new insights into the genotype-phenotype correlation of this disorder, supporting the evidence of an autosomal recessive inheritance pattern for RHUC2. Further investigations into the functional properties of GLUT9, URAT1 and other urate transporters are required to assess their potential research and clinical implications.

Molecular Background of Urate Transporter Genes in Patients with Exercise-Induced Acute Kidney Injury

Background/Aims: Exercise-induced acute renal failure [exercise-induced acute kidney injury (EI-AKI)] is defined as AKI due to heavy anaerobic exercise. Although hypouricemia is known to be a risk factor for the onset of EI-AKI, a direct causal link between EI-AKI and serum uric acid has not been established. This study aimed to analyze urate transporter genes in patients with EI-AKI and its molecular mechanism. Methods: Genomic DNA and total RNA were isolated from peripheral blood leukocytes of patients with a history of EI-AKI. Mutations were analyzed by PCR and a direct sequencing method. We first analyzed the SLC22A12 gene, and then the SLC2A9 gene if no mutations were found in SLC22A12. Results: Seventeen patients were enrolled in this study and 16 had mutations: 15 in SLC22A12 and 1 in SLC2A9. Fourteen (82.4%) patients showed hypouricemia, and all of the patients with hypouricemia had either homozygous or compound heterozygous mutations in SLC22A12 or SLC2A9, which confirmed that all of them had renal hypouricemia. Two patients had heterozygous mutations of SLC22A12, and they were not accompanied by hypouricemia. One patient was found to have no mutations in SLC22A12 or SLC2A9. Conclusion: We were able to determine the genetic background of urate transporter genes in patients with EI-AKI. Decreased function of urate transporters, rather than decreased serum uric acid levels, may be of great importance for the onset of EI-AKI.

Novel URAT1 mutations caused acute renal failure after exercise in two Chinese families with renal hypouricemia

Renal hypouricemia (RHUC), as an infrequent hereditary disease, is associated with severe complications such as exercise-induced acute renal failure (EIARF). Loss-of-function mutations in urate transporter gene URAT1 (Type 1) and in glucose transporter gene GLUT9 (Type 2) are major causes of this disorder. In this study, URAT1 and GLUT9 were screened in two uncorrelated families from mainland China and a total of five mutations were identified in exons, including two novel heterozygous URAT1 mutations. In four members of the first family, c.151delG (p.A51fsX64) in exon 1 was detected, which resulted in a frameshift and truncated the original 553-residue-protein to 63 amino acid protein. A missense mutation c.C1546A (p.P516T) in exon 9 in GLUT9 was revealed in the second family, which caused a functional protein substitution at codon 516. These two novel mutations were neither identified in the subsequent scanning of 200 ethnically matched healthy control subjects with normal serum UA level nor in a 1000 genome project database. Thus our report identifies two novel loss-of-function mutations (c.151delG in URAT1 and p.P516T in GLUT9) which cause RHUC and renal dysfunction in two independent RHUC pedigrees.

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.

A Case of Recurrent Exercise-Induced Acute Renal Failure and Renal Hypouricemia with R90H Mutation in a SCL22A12 Gene

Acute renal failure with severe loin pain and patch renal ischemia after anaerobic exercise (ALPE) is a rare cause of exercise-induced acute kidney injury. Some ALPE patients also have renal hypouricemia. Mutations in the SCL22A12 gene are among the major factors of hypouricemia. Education for the prevention of relapse and genetic counseling should be recommended to ALPE patients with renal hypouricemia. This paper reports a 25-year-old man who showed recurrent exercise-induced ARF and renal hypouricemia with R90H mutation in his SCL22A12 gene.

Pathogenic GLUT9 Mutations Causing Renal Hypouricemia Type 2 (RHUC2)

Renal hypouricemia (MIM 220150) is an inherited disorder characterized by low serum uric acid levels and has severe complications such as exercise-induced acute renal failure and urolithiasis. We have previously reported that URAT1/SLC22A12 encodes a renal urate-anion exchanger and that its mutations cause renal hypouricemia type 1 (RHUC1). With the large health-examination database of the Japan Maritime Self-Defense Force, we found two missense mutations (R198C and R380W) of GLUT9/SLC2A9 in hypouricemia patients. R198C and R380W occur in highly conserved amino acid motifs in the “sugar transport proteins signatures” that are observed in GLUT family transporters. The corresponding mutations in GLUT1 (R153C and R333W) are known to cause GLUT1 deficiency syndrome because arginine residues in this motif are reportedly important as the determinants of the membrane topology of human GLUT1. Therefore, on the basis of membrane topology, the same may be true of GLUT9. GLUT9 mutants showed markedly reduced urate transport in oocyte expression studies, which would be the result of the loss of positive charges in those conserved amino acid motifs. Together with previous reports on GLUT9 localization, our findings suggest that these GLUT9 mutations cause renal hypouricemia type 2 (RHUC2) by their decreased urate reabsorption on both sides of the renal proximal tubule cells. However, a previously reported GLUT9 mutation, P412R, was unlikely to be pathogenic. These findings also enable us to propose a physiological model of the renal urate reabsorption via GLUT9 and URAT1 and can lead to a promising therapeutic target for gout and related cardiovascular diseases.

Diagnostic Tests for Primary Renal Hypouricemia

Primary renal hypouricemia is a genetic disorder characterized by defective renal uric acid (UA) reabsorption with complications such as nephrolithiasis and exercise-induced acute renal failure. The known causes are: defects in the SLC22A12 gene, encoding the human urate transporter 1 (hURAT1), and also impairment of voltage urate transporter (URATv1), encoded by SLC2A9 (GLUT9) gene. Diagnosis is based on hypouricemia (<119 μmol/L) and increased fractional excretion of UA (>10%). To date, the cases with mutations in hURAT1 gene have been reported in East Asia only. More than 100 Japanese patients have been described. Hypouricemia is sometimes overlooked; therefore, we have set up the flowchart for this disorder. The patients were selected for molecular analysis from 620 Czech hypouricemic patients. Secondary causes of hyperuricosuric hypouricemia were excluded. The estimations of (1) serum UA, (2) excretion fraction of UA, and (3) analysis of hURAT1 and URATv1 genes follow. Three transitions and one deletion (four times) in SLC22A12 gene and one nucleotide insertion in SLC2A9 gene in seven Czech patients were found. Three patients had acute renal failure and urate nephrolithiasis. In addition, five nonsynonymous sequence variants and three nonsynonymous sequence variants in SLC2A9 gene were found in two UK patients suffering from acute renal failure. Our finding of the defects in SLC22A12 and SLC2A9 genes gives further evidence of the causative genes of primary renal hypouricemia and supports their important role in regulation of serum urate levels in humans.

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 2weeks of hydration treatment. After remission, hypouricemia became evident (1.0mg/dL) from the initial level of UA (4.8mg/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.

Two novel homozygous SLC2A9 mutations cause renal hypouricemia type 2

Elevated serum uric acid (UA) is associated with gout, hypertension, cardiovascular and renal disease. Hereditary renal hypouricemia type 1 (RHUC1) is caused by mutations in the renal tubular UA transporter URAT1 and can be complicated by nephrolithiasis and exercise-induced acute renal failure (EIARF). We have recently shown that loss-of-function homozygous mutations of another UA transporter, GLUT9, cause a severe type of hereditary renal hypouricemia with similar complications (RHUC2). Two unrelated families with renal hypouricemia were clinically characterized. DNA was extracted and SLC22A12 and SLC2A9 coding for URAT1 and GLUT9, respectively, were sequenced. Transport studies into Xenopus laevis oocytes were utilized to evaluate the function of the GLUT9 mutations found. A molecular modeling study was undertaken to structurally characterize and probe the effects of these mutations. Two novel homozygous GLUT9 missense mutations were identified: R171C and T125M. Mean serum UA level of the four homozygous subjects was 0.15 ± 0.06 mg/dL and fractional excretion of UA was 89-150%. None of the affected subjects had nephrolithiasis, EIARF or any other complications. Transport assays revealed that both mutant proteins had a dramatically reduced ability to transport UA. Modeling showed that both R171C and T125M mutations are located within the inner channel that transports UA between the cytoplasmic and extracellular regions. This is the second report of renal hypouricemia caused by homozygous GLUT9 mutations. Our findings confirm the pivotal role of GLUT9 in UA transport and highlight the similarities and differences between RHUC1 and RHUC2.

Diffusion-weighted MRI of exercise-induced acute renal failure (ALPE)

Acute renal failure with severe loin pain induced by anaerobic exercise (ALPE) is a rare condition that is accompanied by wedge-shaped contrast enhancement on computed tomography (CT) without evidence of rhabdomyolysis. In two pediatric cases with ALPE, we tried to determine the relationship between findings from CT and magnetic resonance imaging (MRI). Case 1 involved a 13-year-old Japanese girl with a diagnosis of ALPE with normo-uricemia. Contrast-enhanced CT after 24 and 48 h showed a wedge-shaped excretion delay for the contrast media. A clear wedge-shaped signal hyperintensity matching the CT images was obtained by diffusion-weighted MRI. Case 2 involved a 16-year-old boy who presented with a second attack of ALPE after diagnosis of ALPE with hypouricemia 1 year earlier. Only diffusion-weighted imaging was performed. Clear wedge-shaped signal hyperintensity was apparent, similar to Case 1. MRI is safer than contrast-enhanced CT for patients with ALPE. Diffusion-weighted MRI is a very useful examination for diagnosing ALPE, providing noninvasive detection of lesions peculiar to ALPE.

Recurrent EIARF and PRES With Severe Renal Hypouricemia by Compound Heterozygous SLC2A9 Mutation

Renal hypouricemia (RHU) is a hereditary disease that predisposes affected people to exercise-induced acute renal failure (EIARF). In most patients with RHU, the disorder is caused by loss-of-function mutations in SLC22A12 (solute carrier family 22, member 12), which encodes urate transporter 1 (URAT1). Patients with RHU without any mutations in the URAT1 gene were recently found to have a mutation in the glucose transporter 9 (GLUT9) gene (SLC2A9 [solute carrier family 2, member 9]). Central nervous system complications seem to be rare in patients with RHU with SLC22A12 mutations. Here, we report the case of a girl with severe RHU (serum urate: 5.9 μmol/L [0.1 mg/dL]) associated with recurrent EIARF in whom the disease was caused by a compound heterozygous mutation in SLC2A9, a nonsense mutation in the paternal allele (p.G207X in exon 7), and a large duplication (c.1-2981_1204+16502) in the maternal allele detected by reverse-transcription polymerase chain reaction (PCR), semiquantitative PCR, long PCR, and direct sequencing. The episodes of EIARF were complicated by posterior reversible encephalopathy syndrome (PRES), which suggested a relationship between PRES and GLUT9 or severe hypouricemia. This is the second report of mutations of both alleles of SLC2A9 that resulted in severe hypouricemia. Our findings indicate that even a nonsense mutation responsible for the heterozygous status of SLC2A9 did not cause severe hypouricemia, and they lend support to previous speculation that mutations of both SLC2A9 alleles cause severe hypouricemia. Our case shows that GLUT9, unlike URAT1, may play a specific role in exercise-induced PRES.

A Case of Exercise-induced Acute Renal Failure with G774A Mutation in SCL22A12 Causing Renal Hypouricemia

Acute renal failure with severe loin pain which develops after anaerobic exercise is rare. One of predisposing factors of exercise-induced acute renal failure is renal hypouricemia. Idiopathic renal hypouricemia is a genetic disorder characterized by hypouricemia with abnormally high renal tubular uric acid excretion. The mutation in SCL22A12 gene which encodes renal uric acid transporter, URAT1, is the known major cause of this disorder. We here described a 25-yr-old man showing idiopathic renal hypouricemia with G774A mutation in SCL22A12 who presented exercise-induced acute renal failure. There have been a few reports of mutational analysis in Korean idiopathic renal hypouricemia without acute renal failure. This is the first report of genetically diagnosed idiopathic renal hypouricemia with exercise-induced acute renal failure in Korea.

URAT1 mutations cause renal hypouricemia type 1 in Iraqi Jews

Hereditary renal hypouricemia may be complicated by nephrolithiasis or exercise-induced acute renal failure. Most patients described so far are of Japanese origin and carry the truncating mutation W258X in the uric acid transporter URAT1 encoded by SLC22A12. Recently, we described severe renal hypouricemia in Israeli patients with uric acid transporter GLUT9 (SLC2A9) loss-of-function mutations. Renal hypouricemia in Iraqi Jews has been previously reported, but its molecular basis has not been ascertained. Three Jewish Israeli families of Iraqi origin with hereditary hypouricemia and hyperuricosuria were clinically characterized. DNA was extracted and the URAT1 gene was sequenced. Transport studies into Xenopus laevis oocytes were utilized to evaluate the function of URAT1 mutants found. A missense URAT1 mutation, R406C, was detected in all three families. Two affected siblings were found to carry in addition a homozygous missense URAT1 mutation, G444R. Both mutations dramatically impaired urate uptake into X. laevis oocytes. Moreover, we demonstrate for the first time that URAT1 facilitates urate efflux, which was abolished in the mutants, indicating also a secretion defect. Homozygous patients had serum uric acid concentrations of 0.5-0.8 mg% and a fractional excretion of uric acid of 50-85%. Most individuals studied were asymptomatic, two had nephrolithiasis and none developed exercise-induced acute renal failure. The URAT1 R406C mutation detected in all three families is likely to be the founder mutation in Iraqi Jews. Our findings contribute to a better definition of the different types of hereditary renal hypouricemia and suggest that the phenotype of this disorder depends mainly on the degree of inhibition of uric acid transport.

Genetic Analysis of Human Urate Transporter 1 (hURAT1) and Glucose Transporter 9 (GLUT9) in Taiwanese Patients with Idiopathic Renal Hypouricemia

Background: The phenotypic characteristics of idiopathic renal hypouricemia (IRH) include impaired renal uric acid re-absorption, low serum uric acid levels, and severe complications such as exercise-induced acute renal failure (EIARF) and nephrolithiasis. IRH is increasingly reported to be associated with inactivating mutations in either SLC22A12 gene encoding the human urate acid transporter 1 (hURAT1) or 5LC2A9 gene encoding glucose transporter 9 (GLUT9) in proximal tubules. Mutations in hURAT1 or GLUT9 have not been reported in Taiwanese patients with IRH. Purpose: To investigate the phenotypic and genetic characteristics in Taiwanese patients with IRH. Patients: Six Taiwanese patients (5 males and 1 female, mean age 30±23 years) with hypouricemia (serum uric acid concentration＜2.3 mg/dL) and concomitant excessive renal uric acid excretion (FE(subscript UA)＞10%) from five unrelated families were enrolled. Their clinical symptoms and biochemical studies were recorded. Methods: Molecular analysis of both SLC22A12 and 5LC2A9 genes was performed by polymerase chain reaction (PCR)-single strand conformation polymorphism (SSCP) and direct sequencing. Results: Serum uric acid concentration was 1.16±0.23 mg/dl with a fractional excretion of uric acid of 61±12%. Two male patients experienced exercise-induced acute renal failure requiring hemodialysis. None of them had nephrocalcinosis or uric acid stone. Despite a negative mutation in 5LC2J49, four novel SLC22A12 mutations (W120R, M2 15L, T2 17M and T467M) and one recurrent homozygous (R90H) mutations were identified in five patients. Conclusion: EIARF can develop in Taiwanese patients with IRH, and most of them are males. Mutations in 5LC22A 12 rather than 5LC2A9 cause IRH in patients with FE(subscript UA)＜100%. Other candidate genes need to be identified for IRH patients without 5LC22J4 12 and SLC2A9 gene mutations.

運動後急性腎不全（ALPE）

運動後急性腎不全（ALPE）

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.

Evaluation of the proximal tubular function in individuals with primary renal hypouricemia: an NMR‐based metabonomic study

Primary renal hypouricemia (PRH) refers to a rare condition of increased renal urate clearance, caused by an isolated inborn error of membrane transport of urate in the renal proximal tubule. Several cases of exercise-induced acute renal failure and urolithiasis have been reported. This is the first study that assessed tubular function in PRH using NMR-based metabonomic urine analysis. The study groups consisted of 36 unrelated asymptomatic subjects with PRH, defined as serum uric acid levels (sUA) <2.5 mg/dL and fractional excretion of uric acid (FEUA) >10%, after exclusion of diseases and drugs that may affect urate homeostasis, and 39 sex and age-matched healthy individuals with normal sUA levels (>4.0 mmol/L) and FEUA<10%. Individuals with primary hypouricemia presented similar biochemical profiles to the controls without significant differences with regard to FE of electrolytes and renal threshold for phosphate excretion. Individuals with primary hypouricemia were differentiated from healthy individuals in the orthogonal signal correction/partial least-squares-discriminant analysis models of the NMR data with a statistically significant separation. The components that contributed to this separation were the lower levels of hippurate, creatinine, and trimethylaminoxide, and the higher levels of phenylalanine, alanine, glycine, glutamate, acetate, and of an unidentified metabolite (3.3 ppm) observed in hypouricemic subjects compared with controls. Primary hypouricemia, though considered an isolated renal tubular defect, is often associated with a more generalized proximal tubular disorder that mimics a partial Fanconi syndrome.