Exercise-induced acute renal failure associated with renal hypouricaemia: results of a questionnaire-based survey in Japan

Ohta, Toshiyuki; Sakano, Takashi; Igarashi, Takashi; Itami, Noritomo; Ogawa, Takahiko

doi:10.1093/ndt/gfh094

Cited by 93 publications

(99 citation statements)

References 20 publications

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“…26 It is thus possible that the lack of UA in plasma of patients with hereditary hypouricemia predisposes them to ischemic acute renal failure. This hypothesis is supported by reported imaging results 27 as well as biopsy results of patients with EIARF showing mainly acute tubular necrosis 28 ; however, EIARF has never been described in patients with xanthinuria, whose serum UA levels are as low as those of patients with renal hypouricemia. We propose a third mechanism for EIARF: Reduced clearance of urate-coupled anions by URAT1 as a result of loss-of-function mutations of either URAT1 or GLUT9 may exert toxic effects on renal proximal tubules, leading to toxic acute tubular necrosis.…”

Section: Transporters (mentioning

confidence: 69%

Homozygous SLC2A9 Mutations Cause Severe Renal Hypouricemia

Dinour¹,

Gray

Campbell

et al. 2010

Journal of the American Society of Nephrology

205

175

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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 Ϯ 0.2 mg/dl, and all had a fractional excretion of uric acid Ͼ150%. 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. 21: 64 -72, 201021: 64 -72, . doi: 10.1681 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. 2 Studies of renal handling of UA in humans have J Am Soc Nephrol

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Section: Transporters (mentioning

confidence: 69%

Homozygous SLC2A9 Mutations Cause Severe Renal Hypouricemia

Dinour¹,

Gray

Campbell

et al. 2010

Journal of the American Society of Nephrology

205

175

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“…7 The antioxidative role of SUA is also supported by the observation of acute kidney injury in patients with renal hypouricemia after strenuous exercise, possibly related to renal vasoconstriction. 8 Similarly, a beneficial role of UA in the nervous system has been suggested, as patients with multiple sclerosis and Parkinson's disease have significantly lower SUA than healthy controls. 9 Hypouricemia is arbitrarily defined as a SUA concentration <2-3 mg/dl.…”

Section: Editorial Effect Of Ua On Vascular Functionmentioning

confidence: 97%

Extremely Low Levels of Serum Uric Acid Are Associated With Endothelial Dysfunction in Humans

Iso

Kurabayashi

2015

Circ J

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978ISO T et al. Circulation JournalOfficial Journal of the Japanese Circulation Society http://www. j-circ.or.jp ative role of UA in CV risk is primarily supported by in vitro study results demonstrating that exposure of cultured endothelial cells to UA induces NADPH oxidase activity and the production of reactive oxygen species. 4 Conversely, the association between hyperuricemia and CV disease is only marginal or may be cofounded by other risk factors, such as hypertension, gout, and male sex. Likewise, hyperuricemia could be a consequence of impaired kidney function, diuretic therapy or oxidative stress, and as such, the role of SUA in conditions associated with oxidative stress is not entirely clear. 2 Increasing experimental and clinical evidence shows that SUA has an antioxidant role in vivo that protects the CV system. Studies have shown a J-shaped relationship of SUA with CV events. 5,6 For instance, the rate of CV events tended to be higher in SUA quartile 1 than in SUA quartile 2 in the PIUMA study ric acid (UA) is the endproduct of purine metabolism in humans. Most serum UA (SUA) is freely filtered in the glomerulus, and approximately 90% of the filtered SUA is reabsorbed, implying that SUA is likely to have a physiological role, rather than simply being a waste of purine metabolism. 1 Furthermore, the SUA level in humans is almost 10-fold higher than those in the majority of other mammals, which supports the hypothesis that the SUA level increased during human evolution as an advantage to humans. 1 Article p 1125Many epidemiological studies have demonstrated that increased SUA is associated with cardiovascular (CV) events in high-risk groups, such as patients with hypertension, heart failure, diabetes, and metabolic syndrome.

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“…However, a recent study reported that subjects having the common nonsense mutation, W258X, which is responsible for renal hypouricemia, showed significantly reduced renal function independently of age, sex, BMI, hypertension, and serum uric acid levels [8]. In addition, renal hypouricemia is known to be associated with two complications, acute kidney injury (AKI) [9,10] and nephrolithiasis [10,11]. Because both AKI and urolithiasis are risk factors for reduced kidney function [12,13], we hypothesized that individuals with hypouricemia may be at greater risk of reduced kidney function.…”

Section: Introductionmentioning

confidence: 99%

Association between Hypouricemia and Reduced Kidney Function: A Cross-Sectional Population-Based Study in Japan

Wakasugi¹,

Kazama²,

Narita³

et al. 2015

Am J Nephrol

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Background: Hypouricemia, conventionally defined as a serum uric acid level of ≤2 mg/dl, is considered a biochemical disorder with no clinical significance. However, individuals with renal hypouricemia have a high risk of urolithiasis and exercise-induced acute kidney injury, both of which are risk factors for reduced kidney function. Methods: To test the hypothesis that individuals with hypouricemia would be at a higher risk of reduced kidney function, we conducted a population-based cross-sectional study using data from the Specific Health Checkups and Guidance System in Japan. Logistic analysis was used to examine the relationship between hypouricemia and reduced kidney function, defined as estimated glomerular filtration rate <60 ml/min/1.73 m². Results: Among 90,710 men (mean age, 63.8 years) and 136,935 women (63.7 years), 193 (0.2%) and 540 (0.4%) were identified as having hypouricemia, respectively. The prevalence of hypouricemia decreased with age in women (p for trend <0.001), but not in men (p for trend = 0.24). Hypouricemia was associated with reduced kidney function in men (odds ratio, 1.83; 95% confidence interval, 1.23-2.74), but not in women (0.61; 0.43-0.86), relative to the reference category (i.e., serum uric acid levels of 4.1-5.0 mg/dl) after adjusting for age, drinking, smoking, diabetes, hypertension, hypercholesterolemia, obesity, and history of renal failure. Sensitivity analyses stratified by diabetic status yielded similar results. Conclusions: This study is the first to provide evidence that hypouricemia is associated with reduced kidney function in men. Further research will be needed to determine the long-term prognosis of individuals with hypouricemia.

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Exercise-induced acute renal failure associated with renal hypouricaemia: results of a questionnaire-based survey in Japan

Abstract: The reason for the heterogeneity in ARF associated with renal hypouricaemia remains unknown. Further studies, especially on molecular mechanisms, are required to establish the best guidance against ARF recurrence.

Cited by 93 publications

References 20 publications

Homozygous SLC2A9 Mutations Cause Severe Renal Hypouricemia

Homozygous SLC2A9 Mutations Cause Severe Renal Hypouricemia

Extremely Low Levels of Serum Uric Acid Are Associated With Endothelial Dysfunction in Humans

Association between Hypouricemia and Reduced Kidney Function: A Cross-Sectional Population-Based Study in Japan

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