RESUMEN

A T217M heterozygous mutation in the SLC22A12 gene caused renal hypouricemia; this patient with IgA nephropathy had no findings other than IgA nephropathy on renal biopsy. Hypouricemia was susceptible to oxidative stress, but IgA nephropathy in the patient with hypouricemia could be treated with steroid pulse therapy without adverse events.

RESUMEN

Serum urate levels are determined by the balance between uric acid production and uric acid excretion capacity from the kidneys and intestinal tract. Dysuricemia, including hyperuricemia and hypouricemia, develops when the balance shifts towards an increase or a decrease in the uric acid pool. Hyperuricemia is mostly a multifactorial genetic disorder involving several disease susceptibility genes and environmental factors. Hypouricemia, on the other hand, is caused by genetic abnormalities. The main genes involved in dysuricemia are xanthine oxidoreductase, an enzyme that produces uric acid, and the urate transporters urate transporter 1/solute carrier family 22 member 12 (URAT1/SLC22A12), glucose transporter 9/solute carrier family 2 member 9 (GLUT9/SLC2A9) and ATP binding cassette subfamily G member 2 (ABCG2). Deficiency of xanthine oxidoreductase results in xanthinuria, a rare disease with marked hypouricemia. Xanthinuria can be due to a single deficiency of xanthine oxidoreductase or in combination with aldehyde oxidase deficiency as well. The latter is caused by a deficiency in molybdenum cofactor sulfurase, which is responsible for adding sulphur atoms to the molybdenum cofactor required for xanthine oxidoreductase and aldehyde oxidase to exert their action. URAT1/SLC22A12 and GLUT9/SLC2A9 are involved in urate reabsorption and their deficiency leads to renal hypouricemia, a condition that is common in Japanese due to URAT1/SLC22A12 deficiency. On the other hand, ABCG2 is involved in the secretion of urate, and many Japanese have single nucleotide polymorphisms that result in its reduced function, leading to hyperuricemia. In particular, severe dysfunction of ABCG2 leads to hyperuricemia with reduced extrarenal excretion.

Asunto(s)

Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2 , Proteínas Facilitadoras del Transporte de la Glucosa , Hiperuricemia , Proteínas de Neoplasias , Transportadores de Anión Orgánico , Ácido Úrico , Xantina Deshidrogenasa , Humanos , Hiperuricemia/etiología , Hiperuricemia/metabolismo , Hiperuricemia/genética , Ácido Úrico/metabolismo , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/genética , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/metabolismo , Transportadores de Anión Orgánico/metabolismo , Transportadores de Anión Orgánico/genética , Proteínas Facilitadoras del Transporte de la Glucosa/metabolismo , Proteínas Facilitadoras del Transporte de la Glucosa/genética , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Xantina Deshidrogenasa/metabolismo , Xantina Deshidrogenasa/genética , Xantina Deshidrogenasa/deficiencia , Animales , Proteínas de Transporte de Catión Orgánico/genética , Proteínas de Transporte de Catión Orgánico/metabolismo , Defectos Congénitos del Transporte Tubular Renal/genética , Defectos Congénitos del Transporte Tubular Renal/etiología , Defectos Congénitos del Transporte Tubular Renal/metabolismo , Cálculos Urinarios/etiología , Cálculos Urinarios/metabolismo , Cálculos Urinarios/genética , Errores Innatos del Metabolismo

Asunto(s)

Mutación , Transportadores de Anión Orgánico , Defectos Congénitos del Transporte Tubular Renal , Humanos , Mutación/genética , Transportadores de Anión Orgánico/genética , Defectos Congénitos del Transporte Tubular Renal/genética , Ácido Úrico/metabolismo , Cálculos Urinarios/genética , Proteínas de Transporte de Catión Orgánico

RESUMEN

Idiopathic renal hypouricemia is an autosomal recessive hereditary disease, characterized by hypouricemia and high renal fractional excretion of uric acid, and can be complicated by acute kidney injury after anaerobic exercise. However, no report has suggested tachycardia-induced acute kidney injury complicated with renal hypouricemia. We herein report the case of a 12-year-old female with tachycardia-induced acute kidney injury complicated with renal hypouricemia. It is an important issue that the tachycardias and acute kidney injury due to renal hypouricemia can be deteriorating factors for each other through the reactive oxygen species. Learning objective: Renal hypouricemia is rare, with a frequency of 0.2-0.4 %, but is often overlooked and can produce acute kidney injury after exercise. Tachyarrhythmia can be an inducer of acute kidney injury in patients with renal hypouricemia.

RESUMEN

Renal hypouricemia (RHUC) is a rare autosomal recessive disorder characterized by impaired renal tubular uric acid reabsorption and abnormally high uric acid clearance, which may be manifested by reduced serum uric acid (SUA) levels and elevated fractional excretion of uric acid (FE-UA >10%). Most RHUC patients are often asymptomatic or have accidentally decreased SUA levels during health examinations, while others develop kidney stones and exercise-induced acute kidney injury (EIAKI). We now report a case of RHUC complicated with an asymptomatic kidney stone, and we identified a heterozygous mutation of c.269G > A (p.R90H) and a novel heterozygous mutation of c.674C > G (p.T225R) in the SLC22A12 gene in the patient through whole exon gene detection (NGS method). This case offers valuable insights into the mechanisms, clinical management, and prognosis of RHUC and its associated complications.

RESUMEN

BACKGROUND: Hereditary renal hypouricemia (RHUC) is a heterogenous disorder characterized by defective uric acid (UA) reabsorption resulting in hypouricemia and increased fractional excretion of UA. RHUC is an important cause of exercise-induced acute kidney injury (EIAKI), nephrolithiasis and posterior reversible encephalopathy syndrome (PRES). We present here an unusual case of a patient with RHUC who presented with recurrent EIAKI and had two heterozygous mutations in the SLC2A9 gene. CASE PRESENTATION: A 43-year old man was admitted to our clinic because of bilateral loin pain, nausea and sleeplessness for 3 days after strenuous exercise. The laboratory results revealed increased levels of blood urea nitrogen (BUN) (15 mmol/l) and serum creatinine (Scr) (450 µmol/l), while the UA level was extremely low at 0.54 mg/dl, and his fractional excretion of urate (FE-UA) was 108%. The patient had an episode of acute kidney injury after playing soccer approximately 20 years ago, and on routine physical examination, his UA was less than 0.50 mg/dl. In view of the marked hypouricemia and high FE-UA, a diagnosis of RHUC was suspected, which led us to perform mutational screening of the SLC22A12 and SLC2A9 genes. DNA sequencing revealed no mutation in SLC22A12 gene, but two heterozygous mutations in the SLC2A9 gene. CONCLUSIONS: This is a rare report of a patient with RHUC2 due to the mutation of SLC2A9. And this unique symptom of EIAKI and decreased or normal serum concentrations of UA warrant more attention as an early cue of RHUC.

Asunto(s)

Lesión Renal Aguda , Transportadores de Anión Orgánico , Síndrome de Leucoencefalopatía Posterior , Masculino , Humanos , Adulto , Síndrome de Leucoencefalopatía Posterior/complicaciones , Síndrome de Leucoencefalopatía Posterior/diagnóstico , Síndrome de Leucoencefalopatía Posterior/genética , Proteínas Facilitadoras del Transporte de la Glucosa/genética , Lesión Renal Aguda/etiología , Lesión Renal Aguda/complicaciones , Heterocigoto , Mutación , Ácido Úrico , Transportadores de Anión Orgánico/genética , Proteínas de Transporte de Catión Orgánico/genética

RESUMEN

Renal hypouricemia (RHUC) is a rare hereditary disorder caused by loss-of-function mutations in the SLC22A12 (RHUC type 1) or SLC2A9 (RHUC type 2) genes, encoding urate transporters URAT1 and GLUT9, respectively, that reabsorb urate in the renal proximal tubule. The characteristics of this disorder are low serum urate levels, high renal fractional excretion of urate, and occasional severe complications such as nephrolithiasis and exercise-induced acute renal failure. In this study, we report two Spanish (Caucasian) siblings and a Pakistani boy with clinical characteristics compatible with RHUC. Whole-exome sequencing (WES) analysis identified two homozygous variants: a novel pathogenic SLC22A12 variant, c.1523G>A; p.(S508N), in the two Caucasian siblings and a previously reported SLC2A9 variant, c.646G>A; p.(G216R), in the Pakistani boy. Our findings suggest that these two mutations cause RHUC through loss of urate reabsorption and extend the SLC22A12 mutation spectrum. In addition, this work further emphasizes the importance of WES analysis in clinical settings.

Asunto(s)

Transportadores de Anión Orgánico , Defectos Congénitos del Transporte Tubular Renal , Masculino , Humanos , Secuenciación del Exoma , Ácido Úrico , Defectos Congénitos del Transporte Tubular Renal/genética , Biología Computacional , Enfermedades Raras , Transportadores de Anión Orgánico/genética , Proteínas de Transporte de Catión Orgánico/genética , Proteínas Facilitadoras del Transporte de la Glucosa/genética

RESUMEN

BACKGROUND: There are two known types of exercise-induced acute renal failure. One is the long-known myoglobinuria-induced acute renal failure due to severe rhabdomyolysis, and the other is the recently recognized non-myoglobinuria-induced acute renal failure with mild rhabdomyolysis. Exercise-induced acute renal failure was first reported in 1982. Non-myoglobinuria-induced acute renal failure is associated with severe low back pain and patchy renal vasoconstriction, and it is termed post-exercise acute renal failure because it usually occurs hours after exercise. It is also called acute renal failure with severe loin pain and patchy renal ischemia after anaerobic exercise (ALPE). AIM: To makes a significant contribution to medical literature as it presents a study that investigated a not-widely-known type of exercise-induced acute renal failure known as ALPE. METHODS: We performed a database search selecting papers published in the English or Japanese language. A database search was lastly accessed on September 1, 2022. The results of this study were compared with those reported in other case series. RESULTS: The study evaluated renal hypouricemia as a key risk factor of ALPE. The development of ALPE is due to the sum of risk factors such as exercise, hypouricemia, nonsteroidal anti-inflammatory drugs, vasopressors, and dehydration. CONCLUSION: In conclusion, hypouricemia plays a key role in the development of ALPE and is often associated with anaerobic exercise. The development of ALPE is a result of the cumulative effects of risk factors such as exercise, hypouricemia, NSAIDs, vasopressors, and dehydration.

RESUMEN

Renal hypouricemia (RHUC) is a rare inherited disorder characterized by impaired urate reabsorption in the proximal tubule resulting in low urate serum levels and increased urate excretion. Some patients may present severe complications such as exercise-induced acute renal failure and nephrolithiasis. RHUC is caused by inactivating mutations in the SLC22A12 (RHUC type 1) or SLC2A9 (RHUC type 2) genes, which encode urate transporters URAT1 and GLUT9, respectively. In this study, our goal was to identify mutations associated with twenty-one new cases with RHUC through direct sequencing of SLC22A12 and SLC2A9 coding exons. Additionally, we carried out an SNPs-haplotype analysis to determine whether the rare SLC2A9 variant c.374C>T; p.(T125M), which is recurrent in Spanish families with RHUC type 2, had a common-linked haplotype. Six intragenic informative SNPs were analyzed using PCR amplification from genomic DNA and direct sequencing. Our results showed that ten patients carried the SLC22A12 mutation c.1400C>T; p.(T467M), ten presented the SLC2A9 mutation c.374C>T, and one carried a new SLC2A9 heterozygous mutation, c.593G>A; p.(R198H). Patients carrying the SLC2A9 mutation c.374C>T share a common-linked haplotype, confirming that it emerged due to a founder effect.

Asunto(s)

Cálculos Renales , Transportadores de Anión Orgánico , Humanos , Ácido Úrico , Efecto Fundador , Proteínas Facilitadoras del Transporte de la Glucosa/genética , Proteínas de Transporte de Catión Orgánico/genética , Transportadores de Anión Orgánico/genética

RESUMEN

BACKGROUND: Although hyperuricemia is a widely studied condition with well-known effects on the kidneys, hypouricemia is usually considered a biochemical abnormality of no clinical significance despite the fact that it can be a sign or major finding of serious metabolic or genetic diseases affecting kidney health. In this study, we aimed to investigate and emphasize the clinical significance of hypouricemia. METHODS: Patients were evaluated retrospectively for persistent hypouricemia defined as serum uric acid concentrations of < 2 mg/dL on at least 3 different occasions. According to the blood and urine uric acid (UA) levels, the patients were classified as having hypouricemia due to UA underproduction vs. overexcretion. Demographic, clinical, and genetic characteristics were noted for analysis. RESULTS: Fourteen patients (n = 14; M/F 8/6) with persistent hypouricemia were identified. Hypouricemia due to underproduction was the cause of 42.8% of these cases. All of the patients with a uric acid level of 0 mg/dL (n = 4) had hypouricemia due to underproduction. The median serum uric acid level was 0.85 (0-1.6) mg/dL. Isolated hypouricemia and hypouricemia with metabolic acidosis were equally distributed. Among the patients with hypouricemia due to underproduction, the final diagnoses were xanthine dehydrogenase deficiency (n = 5) and alkaptonuria (n = 1). In the overexcretion group, the final diagnoses were nephropathic cystinosis (n = 6), distal renal tubular acidosis (n = 1), and hereditary renal hypouricemia (n = 1). The diagnostic lag was longer for patients with isolated hypouricemia compared to other patients (p = 0.001). CONCLUSIONS: Hypouricemia may reflect underlying genetic or metabolic diseases, early diagnosis of which could help preserve kidney function. A higher resolution version of the Graphical abstract is available as Supplementary information.

Asunto(s)

Acidosis Tubular Renal , Azotemia , Errores Innatos del Metabolismo , Defectos Congénitos del Transporte Tubular Renal , Humanos , Niño , Adolescente , Ácido Úrico , Estudios Retrospectivos , Defectos Congénitos del Transporte Tubular Renal/diagnóstico , Defectos Congénitos del Transporte Tubular Renal/genética

RESUMEN

Exercise-induced acute kidney injury (EIAKI) is frequently complicated with renal hypouricemia (RHUC). In patients with RHUC, limiting anaerobic exercise can prevent EIAKI. However, it is challenging to reduce exercise intensity in athletes. We herein report a 16-year-old Japanese football player with familial RHUC with compound heterozygous mutations in urate transporter 1 (URAT1) who presented with recurrent EIAKI. As prophylaxis (hydration during exercise) could not prevent EIAKI, febuxostat was initiated. EIAKI was not observed for 16 months despite exercising intensively. Hence, non-purine-selective xanthine oxidoreductase inhibitors may decrease the incidence of EIAKI in athletes with RHUC.

Asunto(s)

Lesión Renal Aguda , Transportadores de Anión Orgánico , Humanos , Adolescente , Xantina Deshidrogenasa , Transportadores de Anión Orgánico/genética , Proteínas de Transporte de Catión Orgánico/genética , Lesión Renal Aguda/etiología , Lesión Renal Aguda/prevención & control , Inhibidores Enzimáticos

RESUMEN

Objective Both renal hypouricemia (RHU) and gout are associated with renal dysfunction and urolithiasis. The difference in renal complications associated with RHU and gout, however, has not been studied. We characterized the urate metabolism and complications of patients with RHU and compared them with patients with gout. Methods Eighteen patients with RHU who had a serum uric acid (SUA) level <2 mg/dL (10 men and 8 women), 44 patients with gout (44 men) and 16 normouricemic patients (4 men and 12 women) were included. The blood and urinary biochemical data were evaluated. A genetic analysis of uric acid transporter 1 (URAT1) was also conducted in 15 cases with RHU. Results The SUA level of RHU was 0.9±0.5/mg/dL, and the Uur/Ucr and Cur/Ccr were 0.56±0.14% and 45.7±18.0%, respectively. A genetic analysis of URAT1 in 15 RHU patients showed that 13 harbored a URAT1 gene mutation, whereas 2 harbored the wild-type gene. The SUA level was significantly lower in RHU patients (n=11) than in either gout patients (n=44) or normouricemic patients (n=16). This reduction was accompanied by the elevation of Cua/Ccr. Urinary beta 2-microglobulin levels were higher in RHU patients than in gout or normouricemia patients. Cua/Ccr correlated with normalized urinary beta 2-microglobulin levels. The prevalence of urolithiasis was 18.2% in RHU cases and 6.8% in gout cases. A homozygous URAT1 mutation was associated with urolithiasis. Conclusion Besides urolithiasis, RHU can be associated with tubular dysfunction, such as elevated urinary beta 2-microglobulin levels.

Asunto(s)

Gota , Cálculos Urinarios , Masculino , Humanos , Femenino , Ácido Úrico , Microglobulina beta-2 , Gota/complicaciones , Gota/genética , Cálculos Urinarios/complicaciones , Cálculos Urinarios/genética

RESUMEN

Hypouricemia is defined as a level of serum uric acid below 2 mg/dl. Renal hypouricemia is related to genetic defects of the uric acid tubular transporters urate transporter 1 and glucose transporter 9. Patients with renal hypouricemia can be completely asymptomatic or can develop uric acid kidney stones or acute kidney injury, particularly after exercise. Renal hypouricemia is especially challenging to diagnose in patients with acute kidney injury, due to the nonspecific clinical, hematochemical and histological features. No common features are reported in the literature that could help clinicians identify renal hypouricemia-acute kidney injury. Currently available guidelines on diagnosis and management of renal hypouricemia provide limited support in defining clues for the differential diagnosis of renal hypouricemia, which is usually suspected when hypouricemia is found in asymptomatic patients. In this paper we report a case of renal hypouricemia-acute kidney injury developing after exercise. We carried out a review of the literature spanning from the first clinical description of renal hypouricemia in 1974 until 2022. We selected a series of clinical features suggesting a diagnosis of renal hypouricemia-acute kidney injury. This may help clinicians to suspect renal hypouricemia in patients with acute kidney injury and to avoid invasive, costly and inconclusive exams such as renal biopsy. Considering the excellent outcome of the patients reported in the literature, we suggest a "wait-and-see" approach with supportive therapy and confirmation of the disease via genetic testing.

Asunto(s)

Lesión Renal Aguda , Defectos Congénitos del Transporte Tubular Renal , Cálculos Urinarios , Humanos , Ácido Úrico , Lesión Renal Aguda/diagnóstico , Cálculos Urinarios/etiología , Cálculos Urinarios/genética

RESUMEN

A genetic defect in urate transporter 1 (URAT1) is the major cause of renal hypouricemia (RHUC). Although RHUC is detected using a serum uric acid (UA) concentration <2.0 mg/dL, the relationship between the genetic state of URAT1 and serum UA concentration is not clear. Homozygosity and compound heterozygosity with respect to mutant URAT1 alleles are associated with a serum UA concentration of <1.0 mg/dL and are present at a prevalence of ~0.1% in Japan. In heterozygous individuals, the prevalence of a serum UA of 1.1−2.0 mg/dL is much higher in women than in men. The frequency of mutant URAT1 alleles is as high as 3% in the general Japanese population. The expansion of a specific mutant URAT1 allele derived from a single mutant gene that occurred in ancient times is reflected in modern Japan at a high frequency. Similar findings were reported in Roma populations in Europe. These phenomena are thought to reflect the ancient migration history of each ethnic group (founder effects). Exercise-induced acute kidney injury (EI-AKI) is mostly observed in individuals with homozygous/compound heterozygous URAT1 mutation, and laboratory experiments suggested that a high UA load on the renal tubules is a plausible mechanism for EI-AKI.

RESUMEN

Hypouricemia is recognized as a rare disorder, defined as a serum uric acid level of 2.0 mg/dL or less. Hypouricemia is divided into an overexcretion type and an underproduction type. The former typical disease is xanthinuria, and the latter is renal hypouricemia (RHUC). The frequency of nephrogenic hypouricemia due to a deficiency of URAT1 is high in Japan, accounting for most asymptomatic and persistent cases of hypouricemia. RHUC results in a high risk of exercise-induced acute kidney injury and urolithiasis. It is vital to promote research on RHUC, as this will lead not only to the elucidation of its pathophysiology but also to the development of new treatments for gout and hyperuricemia.

RESUMEN

Hypouricemia in kidney transplant (KT) recipients is rare since they usually have subnormal kidney function which raises serum uric acid level. Recently, interests in pathogenesis of hypouricemia have been increasing due to the understanding of the role of uric acid transporter in renal hypouricemia (RHUC). We herein report the case of RHUC consequently developed in a KT recipient from a living donor with RHUC diagnosed by the detailed urinary and genetic test. A 73-year-old Japanese man underwent KT, and the donor was his wife who had hypouricemia [serum uric acid (S-UA) 0.6 mg/dL]. Nine months after KT, the recipient's S-UA was low (1.5 mg/dL) with serum creatinine (S-Cr) of 1.56 mg/dL, and fractional excretion of UA (FEUA) was high (59.7%; normal < 10%), indicating RHUC. Regarding the donor's information, S-Cr, S-UA, and FEUA were 0.95 mg/dL, 1.0 mg/dL, and 54.5%, respectively. To investigate further on the pathogenesis of RHUC in both the recipient and the donor, we performed genetic tests. The donor had a homozygous mutation of W258X in the SLC22A12 gene and the recipient had a wild type of W258X. Finally, we reviewed the previous literature on RHUC among KT recipients and discussed the strategy of follow-up for these patients.

Asunto(s)

Trasplante de Riñón , Transportadores de Anión Orgánico , Anciano , Femenino , Humanos , Riñón , Trasplante de Riñón/efectos adversos , Donadores Vivos , Masculino , Transportadores de Anión Orgánico/genética , Proteínas de Transporte de Catión Orgánico/genética , Defectos Congénitos del Transporte Tubular Renal , Ácido Úrico , Cálculos Urinarios

RESUMEN

BACKGROUND: Hereditary renal hypouricemia type 1 (RHUC1) is caused by URAT1/SLC22A12 dysfunction, resulting in urolithiasis and exercise-induced AKI (EIAKI). However, because there is no useful experimental RHUC1 animal model, the precise pathophysiologic mechanisms underlying EIAKI have yet to be elucidated. We established a high HPRT activity Urat1-Uox double knockout (DKO) mouse as a novel RHUC1 animal model for investigating the cause of EIAKI and the potential therapeutic effect of xanthine oxidoreductase inhibitors (XOIs). METHODS: The novel Urat1-Uox DKO mice were used in a forced swimming test as loading exercise to explore the onset mechanism of EIAKI and evaluate related purine metabolism and renal injury parameters. RESULTS: Urat1-Uox DKO mice had uricosuric effects and elevated levels of plasma creatinine and BUN as renal injury markers, and decreased creatinine clearance observed in a forced swimming test. In addition, Urat1-Uox DKO mice had increased NLRP3 inflammasome activity and downregulated levels of Na+-K+-ATPase protein in the kidney, as Western blot analysis showed. Finally, we demonstrated that topiroxostat and allopurinol, XOIs, improved renal injury and functional parameters of EIAKI. CONCLUSIONS: Urat1-Uox DKO mice are a useful experimental animal model for human RHUC1. The pathogenic mechanism of EIAKI was found to be due to increased levels of IL-1ß via NLRP3 inflammasome signaling and Na+-K+-ATPase dysfunction associated with excessive urinary urate excretion. In addition, XOIs appear to be a promising therapeutic agent for the treatment of EIAKI.

Asunto(s)

Lesión Renal Aguda/tratamiento farmacológico , Hipoxantina Fosforribosiltransferasa/metabolismo , Transportadores de Anión Orgánico/deficiencia , Urato Oxidasa/deficiencia , Xantina Deshidrogenasa/antagonistas & inhibidores , Lesión Renal Aguda/etiología , Lesión Renal Aguda/metabolismo , Alopurinol/farmacología , Animales , Modelos Animales de Enfermedad , Inhibidores Enzimáticos/farmacología , Hipoxantina Fosforribosiltransferasa/genética , Riñón/efectos de los fármacos , Riñón/metabolismo , Riñón/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Nitrilos/farmacología , Transportadores de Anión Orgánico/genética , Esfuerzo Físico , Piridinas/farmacología , Defectos Congénitos del Transporte Tubular Renal/tratamiento farmacológico , Defectos Congénitos del Transporte Tubular Renal/etiología , Defectos Congénitos del Transporte Tubular Renal/metabolismo , ATPasa Intercambiadora de Sodio-Potasio/metabolismo , Urato Oxidasa/genética , Cálculos Urinarios/tratamiento farmacológico , Cálculos Urinarios/etiología , Cálculos Urinarios/metabolismo

RESUMEN

Renal hypouricemia (RHUC) is a hereditary disease that presents with increased renal urate clearance and hypouricemia due to genetic mutations in the urate transporter URAT1 or GLUT9 that reabsorbs urates in the renal proximal tubule. Exercise-induced acute kidney injury (EIAKI) is known to be a complication of renal hypouricemia. In the skeletal muscle of RHUC patients during exhaustive exercise, the decreased release of endothelial-derived hyperpolarization factor (EDHF) due to hypouricemia might cause the disturbance of exercise hyperemia, which might increase post-exercise urinary urate excretion. In the kidneys of RHUC patients after exhaustive exercise, an intraluminal high concentration of urates in the proximal straight tubule and/or thick ascending limb of Henle's loop might stimulate the luminal Toll-like receptor 4-myeloid differentiation factor 88-phosphoinositide 3-kinase-mammalian target of rapamycin (luminal TLR4-MyD88-PI3K-mTOR) pathway to activate the nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome and may release interleukin-1ß (IL-1ß), which might cause the symptoms of EIAKI.

RESUMEN

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 Kosice 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.

RESUMEN

Acute kidney injury after exercise is most commonly secondary to rhabdomyolysis. Non-rhabdomyolysis AKI is secondary to a limited number of disorders of which renal hypouricemia (RHUC) needs a special mention. It is relatively a rare genetic disorder and is reported in Japanese and Ashkenazi Jews. Humans have lost the ability to metabolize uric acid as the "uricase" gene is suppressed. Renal tubules handle uric acid and aid in maintaining serum concentrations in the soluble range. Uric acid excretion is increased in RHUC patients due to proximal tubular defects. This leads to the loss of antioxidant capabilities of the kidney, predisposing them to severe AKI following anaerobic exercise. We report a case of exercise-induced AKI secondary to renal hypouricemia.