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.
- Publikační typ
- časopisecké články MeSH
Renal hypouricemia sometimes leads to exercise-induced acute kidney injury (EIAKI) of unknown pathogenesis. In order to elucidate the various pathological conditions associated with hypouricemia, we analyzed the effects of low uric acid level on energy metabolism. We have modified semi-ischemic forearm exercise test and performed this test in one Japanese healthy volunteer, three patients with hereditary renal hypouricemia and one patient with hereditary xanthinuria of Czech origin. Forearm exercise was performed by squeezing a hand dynamometer with the sphygmomanometer cuff pressure kept at the mean arterial pressure. Venous blood was drawn five times (before exercise, 3, 10, 30, 45 minutes after the start of exercise) in each tests. The mean plasma lactate concentration increased from a baseline of 1.3 (range 0.7-1.8 mmol/L) to 4.0 (range 2.0-5.5 mmol/L) at 3 minutes after the start of exercise. The plasma hypoxanthine concentrations were quite low before exercise (0-2.9 μmol/L), but increased markedly to a range of 13.6-28.8 μmol/L after 10 minute forearm ischemia. Our protocol allowed us to conclude that the load was sufficient for observing metabolic changes in temporally hypoxia and in following recovery phase. The test was well tolerated and safe, we did not observe any adverse reactions including EIAKI.
- MeSH
- dospělí MeSH
- hypoxanthin krev MeSH
- ischemie komplikace patofyziologie MeSH
- kyselina mléčná krev MeSH
- kyselina močová krev MeSH
- lidé středního věku MeSH
- lidé MeSH
- močové kameny komplikace MeSH
- předloktí krevní zásobení patofyziologie MeSH
- vrozené poruchy tubulárního transportu komplikace MeSH
- zátěžový test * MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- MeSH
- akutní poškození ledvin krev prevence a kontrola moč MeSH
- alopurinol aplikace a dávkování MeSH
- antioxidancia aplikace a dávkování MeSH
- cystinóza krev diagnóza moč MeSH
- diferenciální diagnóza MeSH
- dítě MeSH
- Fanconiho syndrom krev diagnóza moč MeSH
- genetické testování MeSH
- kyselina močová krev metabolismus moč MeSH
- ledvinové kanálky metabolismus MeSH
- lidé MeSH
- močové kameny krev diagnóza genetika moč MeSH
- přenašeče organických aniontů genetika MeSH
- proteiny přenášející organické kationty genetika MeSH
- proteiny usnadňující transport glukosy genetika MeSH
- renální reabsorpce MeSH
- syndrom nepřiměřené sekrece ADH krev diagnóza moč MeSH
- vrozené poruchy tubulárního transportu krev diagnóza genetika moč MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- kazuistiky MeSH
- MeSH
- dítě MeSH
- kyselina močová krev moč MeSH
- lidé MeSH
- nemoci ledvin krev diagnóza moč MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- kazuistiky MeSH
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.
- MeSH
- dítě MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- močové kameny genetika MeSH
- mutační analýza DNA MeSH
- přenašeče organických aniontů genetika MeSH
- proteiny přenášející organické kationty genetika MeSH
- proteiny usnadňující transport glukosy genetika MeSH
- vrozené poruchy tubulárního transportu genetika MeSH
- Xenopus MeSH
- zvířata MeSH
- Check Tag
- dítě MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- kazuistiky MeSH
Hyperuricemia depends on the balance of endogenous production and renal excretion of uric acid. Transporters for urate are located in the proximal tubule where uric acid is secreted and extensively reabsorbed: secretion is principally ensured by the highly variable ABCG2 gene. Enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT) plays a central role in purine metabolism and its deficiency is an X-linked inherited metabolic disorder associated with clinical manifestations of purine overproduction. Here we report the case of a middle-aged man with severe chronic tophaceous gout with a poor response to allopurinol and requiring repeated surgical intervention. We identified the causal mutations in the HPRT1 gene, variant c.481G>T (p.A161S), and in the crucial urate transporter ABCG2, a heterozygous variant c.421C>A (p.Q141K). This case shows the value of an analysis of the genetic background of serum uric acid.
- MeSH
- ABC transportér z rodiny G, člen 2 genetika MeSH
- chronická nemoc MeSH
- dna (nemoc) genetika metabolismus MeSH
- genetické pozadí * MeSH
- hypoxanthinfosforibosyltransferasa nedostatek genetika metabolismus MeSH
- kyselina močová metabolismus MeSH
- lidé středního věku MeSH
- lidé MeSH
- mutace MeSH
- nádorové proteiny genetika MeSH
- přenašeče organických aniontů genetika MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- kazuistiky MeSH
Hypouricemia is defined as a serum urate levels less than 2 mg/dL (119 µmol/L). Primary hypouricemia is caused by disorders of purine metabolism and transport. This laboratory finding is sometimes overlooked and, following two genetic defects, should be considered in differential diagnosis of unexplained hypouricemia. Hereditary xanthinuria is autosomal recessive and due to mutations in xanthine oxidase, leading to over-production of xanthine and minimal production of urate. Patients have very low serum urate levels and suffer from elevated levels of xanthine in the urine, leading to xanthine stones, haematuria, and sometimes occult chronic kidney failure. Hypouricemia is the key to diagnosis. Hereditary renal hypouricemia is a new genetic defect of renal transport of uric acid. Two types were distinguished: a) renal hypouricemia type 1, caused by the defects in the SLC22A12 gene coding the human urate transporter 1 (hURAT1) and b) renal hypouricemia type 2, caused by the defects in the SLC2A9 gene, which encodes GLUT9 transporter. This disorder predisposes patients to exercise-induced acute renal failure and/or nephrolithiasis. Diagnosis is based on two markers: hypouricemia (<119 µmol/L) and increased fractional excretion of uric acid (>10%). Over one hundred cases were identified in Japan and and this number is unique worldwide. Several patients were described in Macedonia. We were able to detect four Czech families with hereditary xanthinuria and eight cases of hereditary renal hypouricemia. In conclusion, hereditary xanthinuria and hereditary renal hypouricemia are still unrecognized conditions. Patients with unexplained hypouricemia need detailed purine metabolic investigations.
- MeSH
- dítě MeSH
- dospělí MeSH
- genetická predispozice k nemoci * MeSH
- kyselina močová metabolismus MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- močové kameny genetika metabolismus MeSH
- poruchy metabolismu purinů a pyrimidinů genetika metabolismus MeSH
- puriny metabolismus MeSH
- vrozené poruchy tubulárního transportu genetika metabolismus MeSH
- Check Tag
- dítě MeSH
- dospělí MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Renal hypouricemia (RHUC) is a heterogeneous inherited disorder characterized by impaired tubular uric acid (UA) transport with severe complications, such as acute kidney injury (AKI). Type 1 is caused by a loss-of-function mutation in the SLC22A12 gene (URAT1), type 2 in the SLC2A9 gene (GLUT9). This article describes three Czech families with RHUC type 1. The serum UA in the probands was 0.9, 1.1 and 0.5 mg/dl and expressed as an increase in the fractional excretion of UA (48, 43 and 39%). The sequencing analysis of SLC22A12 revealed three novel variants: p.G366R, p.T467M and a deletion p.L415_G417del. A detailed metabolic investigation in proband C for progressive visual failure supported suspicion of neuronal ceroid lipofuscinosis type 7 conditioned by the mutation in the MFSD8 gene. Functional studies showed significantly decreased urate uptake and a mis-localized URAT1 signal in p.G366R, p.L415_G417del and p.T467M. Furthermore, colocalization studies showed accumulation of URAT1 protein in the endoplasmic reticulum. The findings suggest that loss-of-function mutations cause RHUC via loss of UA absorption partly by protein misfolding. However, they do not necessarily lead to AKI and a possible genotype-phenotype correlation was not proposed. Furthermore, results confirm an uneven geographical and ethnic distribution of SLC22A12 variants; the p.L415_G417del mutation predominates in the Roma ethnic group in the Czech Republic.
- MeSH
- absorpce MeSH
- akutní poškození ledvin diagnóza etiologie genetika MeSH
- alely * MeSH
- dítě MeSH
- dospělí MeSH
- endoplazmatické retikulum metabolismus MeSH
- frekvence genu * MeSH
- heterozygot MeSH
- kyselina močová moč MeSH
- lidé MeSH
- membránové transportní proteiny genetika MeSH
- močové kameny komplikace diagnóza etnologie genetika MeSH
- mutace * MeSH
- neuronální ceroidlipofuscinózy diagnóza etiologie genetika MeSH
- přenašeče organických aniontů genetika metabolismus MeSH
- proteiny přenášející organické kationty genetika metabolismus MeSH
- rodokmen MeSH
- Romové genetika MeSH
- vrozené poruchy tubulárního transportu komplikace diagnóza etnologie genetika MeSH
- Xenopus MeSH
- zvířata MeSH
- Check Tag
- dítě MeSH
- dospělí MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- kazuistiky MeSH
- práce podpořená grantem MeSH
- Geografické názvy
- Česká republika MeSH
