RESUMEN
BACKGROUND: A hereditary condition primarily affecting the kidneys and heart has newly been identified: the RRAGD-associated autosomal dominant kidney hypomagnesemia with cardiomyopathy (ADKH-RRAGD). This disorder is characterized by renal loss of magnesium and potassium, coupled with varying degrees of cardiac dysfunction. These range from arrhythmias to severe dilated cardiomyopathy, which may require heart transplantation. Mutations associated with RRAGD significantly disrupt the non-canonical branch of the mechanistic target of rapamycin complex 1 pathway. This disruption hinders the nuclear translocation and transcriptional activity of the transcription factor EB a crucial regulator of lysosomal and autophagic function. SUMMARY: All identified RRAGD variants compromise kidney function, leading to hypomagnesemia and hypokalemia of various severity. The renal phenotype for most of the variants (i.e., S76L, I221K, P119R, P119L) typically manifests in the second decade of life occasionally preceded by childhood symptoms of dilated cardiomyopathy. In contrast, the P88L variant is associated to dilated cardiomyopathy manifesting in adulthood. To date, the T97P variant has not been linked to cardiac involvement. The most severe manifestations of ADKH-RRAGD, particularly concerning electrolyte imbalance and heart dysfunction requiring transplantation in childhood appear to be associated with the S76L, I221K, P119R variants. KEY MESSAGES: This review aimed to provide an overview of the clinical presentation for ADKH-RRAGD, aiming to enhance awareness, promote early diagnosis, and facilitate proper treatment. It also reports on the limited experience in patient management with diuretics, magnesium and potassium supplements, metformin, or calcineurin and SGLT2 inhibitors.
Asunto(s)
Cardiomiopatías , Humanos , Cardiomiopatías/etiología , Cardiomiopatías/diagnóstico , Cardiomiopatías/genética , Cardiomiopatías/terapia , Magnesio/sangre , Defectos Congénitos del Transporte Tubular Renal/genética , Defectos Congénitos del Transporte Tubular Renal/diagnóstico , HipopotasemiaRESUMEN
BACKGROUND: This case report presents a history of familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC). The patient was admitted to the hospital with hypertensive encephalopathy. FHHNC is a rare autosomal recessive disease caused by mutations in CLDN16 or CLDN19, resulting in insufficient magnesium and calcium kidney reabsorption. FHHNC manifestation starts in childhood, and over the years, its development leads to nephrocalcinosis and, consequently, chronic kidney disease (CKD), which is not slowed by routine administration of magnesium and thiazide diuretics. Ultimately, all FHHNC patients need kidney replacement therapy (KRT). CASE PRESENTATION: The patient was a 28-year-old male diagnosed with FHHNC and admitted to the emergency room due to hypertensive encephalopathy. The current situation was the patient's second hospitalization related to a hypertensive emergency caused by under-dialysis. Despite the signs of insufficient functioning of peritoneal dialysis (PD) (the primary chosen form of KRT), the patient refused the proposed conversion to hemodialysis (HD). Symptoms observed upon admission included disorientation, anxiety, and severe hypertension, reaching 213/123 mmHg. Due to his clinical condition, the patient was transferred to the intensive care unit (ICU), where the introduction of continuous veno-venous hemodiafiltration and hypotensive therapy stabilized blood pressure. Within the next few days, his state improved, followed by discharge from ICU. Eventually, the patient agreed to transition from PD to in-center HD. At the time, he was qualified for kidney transplantation, waiting for a compatible donation. CKD and dialysis are factors that significantly affect a patient's quality of life, especially in young patients with congenital diseases like FHHNC. CONCLUSIONS: For the aforementioned reasons, appropriate education and psychological support should be ensured to avoid the harmful effects of therapy non-compliance. Graphical Abstract: https://www.europeanreview.org/wp/wp-content/uploads/Graphical-abstract-1.pdf.
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Hipercalciuria , Hipertensión , Nefrocalcinosis , Humanos , Masculino , Adulto , Nefrocalcinosis/terapia , Nefrocalcinosis/diagnóstico , Hipercalciuria/terapia , Hipercalciuria/diagnóstico , Diálisis Renal , Defectos Congénitos del Transporte Tubular Renal/genética , Defectos Congénitos del Transporte Tubular Renal/terapia , Defectos Congénitos del Transporte Tubular Renal/diagnóstico , Crisis HipertensivaRESUMEN
Acute rhabdomyolysis (AR) leading to acute kidney injury has many underlying etiologies, however, when the primary trigger is exercise, the most usual underlying cause is either a genetic muscle disorder or unaccustomed intense exercise in a healthy individual. Three adult men presented with a history of exercise intolerance and episodes of acute renal impairment following intense exercise, thought to be due to AR in the case of two, and dehydration in one. The baseline serum CK was mildly raised between attacks in all three patients and acutely raised during attacks in two of the three patients. Following referral to a specialized neuromuscular centre, further investigation identified very low serum urate (<12 umol/L). In all three men, genetic studies confirmed homozygous mutations in SLC2A9, which encodes for facilitated glucose transporter member 9 (GLUT9), a major regulator of urate homeostasis. Hereditary hypouricaemia should be considered in people presenting with acute kidney injury related to intense exercise. Serum urate evaluation is a useful screening test best undertaken after recovery.
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Lesión Renal Aguda , Defectos Congénitos del Transporte Tubular Renal , Rabdomiólisis , Cálculos Urinarios , Masculino , Adulto , Humanos , Ácido Úrico , Cálculos Urinarios/genética , Cálculos Urinarios/complicaciones , Cálculos Urinarios/diagnóstico , Defectos Congénitos del Transporte Tubular Renal/genética , Defectos Congénitos del Transporte Tubular Renal/complicaciones , Defectos Congénitos del Transporte Tubular Renal/diagnóstico , Proteínas Facilitadoras del Transporte de la Glucosa/genética , Lesión Renal Aguda/genética , Mutación , Rabdomiólisis/genética , Rabdomiólisis/complicacionesRESUMEN
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.
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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/genéticaRESUMEN
Neurological disorders, including seizures, migraine, depression, and intellectual disability, are frequently associated with hypomagnesemia. Specifically, magnesium (Mg2+) channel transient receptor potential melastatin (TRPM) 6 and TRPM7 are essential for brain function and development. Both channels are also localized in renal and intestinal epithelia and are crucial for Mg2+(re)absorption. Cyclin M2 (CNNM2) is located on the basolateral side of the distal convoluted tubule. In addition, it plays a role in the maintenance of plasma Mg2+ levels along with TRPM6, which is present at the apical level. The CNNM2 gene is crucial for renal magnesium handling, brain development, and neurological functioning. Here, we identified a novel mutation in the CNNM2 gene causing a cognitive delay in a girl with hypomagnesemia. We suggest testing for CNNM2 mutation in patients with neurological impairment and hypomagnesemia.
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Trastornos de Alimentación y de la Ingestión de Alimentos/diagnóstico , Discapacidad Intelectual/complicaciones , Defectos Congénitos del Transporte Tubular Renal/diagnóstico , Adolescente , Proteínas de Transporte de Catión/genética , Trastornos de Alimentación y de la Ingestión de Alimentos/genética , Femenino , Humanos , Discapacidad Intelectual/genética , Defectos Congénitos del Transporte Tubular Renal/complicaciones , Defectos Congénitos del Transporte Tubular Renal/genéticaRESUMEN
We report 2 consecutive siblings who presented with unilateral and bilateral macular scars, respectively (initially presumed in the older sibling to be from congenital toxoplasmosis), who also developed chronic kidney disease. Both underwent genetic testing and were positive for a mutation in CLDN19, confirming the diagnosis of familial hypomagnesemia with hypercalciuria and nephrocalcinosis with severe ocular involvement. One of our patients had the unique finding of mild foveal hypoplasia, which is not typically associated with CLDN19 mutations.
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Cicatriz/congénito , Claudinas , Enfermedades Hereditarias del Ojo/diagnóstico , Mácula Lútea/patología , Defectos Congénitos del Transporte Tubular Renal/diagnóstico , Claudinas/genética , Enfermedades Hereditarias del Ojo/genética , Humanos , Mutación , Defectos Congénitos del Transporte Tubular Renal/genética , HermanosAsunto(s)
Hipercalciuria/sangre , Hipercalciuria/diagnóstico , Laboratorios de Hospital , Deficiencia de Magnesio/sangre , Magnesio/sangre , Nefrocalcinosis/sangre , Nefrocalcinosis/diagnóstico , Defectos Congénitos del Transporte Tubular Renal/sangre , Defectos Congénitos del Transporte Tubular Renal/diagnóstico , Servicio de Urgencia en Hospital , Humanos , Hipercalciuria/patología , Nefrocalcinosis/patología , Defectos Congénitos del Transporte Tubular Renal/patología , Enfermedades no DiagnosticadasAsunto(s)
Automatización de Laboratorios/métodos , Calcio/sangre , Hipercalciuria/sangre , Hipercalciuria/diagnóstico , Hipocalcemia/sangre , Magnesio/sangre , Nefrocalcinosis/sangre , Nefrocalcinosis/diagnóstico , Defectos Congénitos del Transporte Tubular Renal/sangre , Defectos Congénitos del Transporte Tubular Renal/diagnóstico , Índice de Severidad de la Enfermedad , Servicio de Urgencia en Hospital , Humanos , Hipercalciuria/terapia , Unidades de Cuidados Intensivos , Deficiencia de Magnesio/sangre , Nefrocalcinosis/terapia , Defectos Congénitos del Transporte Tubular Renal/terapiaAsunto(s)
Hipercalciuria/complicaciones , Nefrocalcinosis/complicaciones , Defectos Congénitos del Transporte Tubular Renal/complicaciones , Convulsiones/etiología , Anciano , Humanos , Hipercalciuria/diagnóstico , Masculino , Nefrocalcinosis/diagnóstico , Defectos Congénitos del Transporte Tubular Renal/diagnóstico , Convulsiones/fisiopatologíaAsunto(s)
Diabetes Mellitus Tipo 2/terapia , Deficiencia de Magnesio/orina , Magnesio/orina , Anciano , Análisis Químico de la Sangre , Glucemia/análisis , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/orina , Diagnóstico Diferencial , Femenino , Hemoglobina Glucada/análisis , Glucosuria/complicaciones , Humanos , Hipotiroidismo/complicaciones , Deficiencia de Magnesio/diagnóstico , Deficiencia de Magnesio/etiología , Poliuria/etiología , Defectos Congénitos del Transporte Tubular Renal/diagnóstico , UrinálisisRESUMEN
The maintenance of magnesium (Mg2+) homeostasis is essential for human life. The Cystathionine-ß-synthase (CBS)-pair domain divalent metal cation transport mediators (CNNMs) have been described to be involved in maintaining Mg2+ homeostasis. Among these CNNMs, CNNM2 is expressed in the basolateral membrane of the kidney tubules where it is involved in Mg2+ reabsorption. A total of four patients, two of them with a suspected disorder of calcium metabolism, and two patients with a clinical diagnosis of primary tubulopathy were screened for mutations by Next-Generation Sequencing (NGS). We found one novel likely pathogenic variant in the heterozygous state (c.2384C>A; p.(Ser795*)) in the CNNM2 gene in a family with a suspected disorder of calcium metabolism. In this family, hypomagnesemia was indirectly discovered. Moreover, we observed three novel variants of uncertain significance in heterozygous state in the other three patients (c.557G>C; p.(Ser186Thr), c.778A>T; p.(Ile260Phe), and c.1003G>A; p.(Asp335Asn)). Our study shows the utility of Next-Generation Sequencing in unravelling the genetic origin of rare diseases. In clinical practice, serum Mg2+ should be determined in calcium and PTH-related disorders.
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Proteínas de Transporte de Catión/genética , Magnesio/sangre , Defectos Congénitos del Transporte Tubular Renal/diagnóstico , Adolescente , Adulto , Proteínas de Transporte de Catión/química , Codón sin Sentido , Femenino , Heterocigoto , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Lactante , Masculino , Polimorfismo de Nucleótido Simple , Defectos Congénitos del Transporte Tubular Renal/genética , Análisis de Secuencia de ADNRESUMEN
Magnesium wasting is a frequent side effect of epidermal growth factor receptor (EGFR)-antibody treatment as magnesium-absorption mechanisms are dependent on EGFR signaling. EGFR-inhibition results in decreased renal reabsorption. There is evidence that hypomagnesemia during cetuximab treatment correlates with response. The prognostic role of hypomagnesemia during bevacizumab treatment has not been studied yet. Here, we evaluate the prognostic value of hypomagnesemia in patients with metastatic colorectal cancer treated with FOLFIRI plus cetuximab or bevacizumab as first-line therapy. A total of 391 of 752 patients of the firstline irinotecan study population had magnesium levels measured at baseline and for the first three cycles (6 weeks) of treatment. Of those, 240 had Rat Sarkoma wildtype tumors. Overall hypomagnesemia was more common in the cetuximab compared to the bevacizumab arm (80 vs. 43%, P < 0.005). During therapy, magnesium showed a time-dependent decrease to 80% of baseline in the cetuximab and to 89% in the bevacizumab arm. Whereas magnesium continued to decrease over time in the cetuximab-treated patients, it remained stable in the bevacizumab-treated. Overall response rate (ORR) was associated with higher magnesium at week 6 (20.9 vs. 79.1%, P = 0.041). Bevacizumab-treated patients with magnesium levels below the median value at week 6 had a significantly longer progression-free survival (PFS; 11.7 vs. 9.9 months, P = 0.034; hazard ratio 0.73) and a trend towards longer overall survival (OS) (29.6 vs. 23.2 months, P = 0.089; hazard ratio 0.77). Hypomagnesemia at predefined time points and magnesium nadir had no significant effect on ORR, OS and PFS in the cetuximab arm. Our data show different magnesium kinetics in patients with metastatic colorectal cancer treated with cetuximab or bevacizumab. For patients treated with cetuximab, hypomagnesemia did not have an impact on response and survival. Hypomagnesemia might have a prognostic value in bevacizumab treatment.
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Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias Colorrectales/tratamiento farmacológico , Hipercalciuria/diagnóstico , Magnesio/sangre , Nefrocalcinosis/diagnóstico , Defectos Congénitos del Transporte Tubular Renal/diagnóstico , Anciano , Bevacizumab/administración & dosificación , Camptotecina/administración & dosificación , Cetuximab/administración & dosificación , Neoplasias Colorrectales/patología , Femenino , Fluorouracilo/administración & dosificación , Estudios de Seguimiento , Humanos , Hipercalciuria/sangre , Hipercalciuria/inducido químicamente , Irinotecán/administración & dosificación , Leucovorina/administración & dosificación , Masculino , Nefrocalcinosis/sangre , Nefrocalcinosis/inducido químicamente , Pronóstico , Defectos Congénitos del Transporte Tubular Renal/sangre , Defectos Congénitos del Transporte Tubular Renal/inducido químicamente , Estudios Retrospectivos , Tasa de SupervivenciaRESUMEN
Electrolyte homeostasis is maintained by the kidney through a complex transport function mostly performed by specialized proteins distributed along the renal tubules. Pathogenic variants in the genes encoding these proteins impair this function and have consequences on the whole organism. Establishing a genetic diagnosis in patients with renal tubular dysfunction is a challenging task given the genetic and phenotypic heterogeneity, functional characteristics of the genes involved and the number of yet unknown causes. Part of these difficulties can be overcome by gathering large patient cohorts and applying high-throughput sequencing techniques combined with experimental work to prove functional impact. This approach has led to the identification of a number of genes but also generated controversies about proper interpretation of variants. In this article, we will highlight these challenges and controversies.
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Defectos Congénitos del Transporte Tubular Renal/genética , Animales , Heterogeneidad Genética , Pruebas Genéticas/métodos , Pruebas Genéticas/normas , Humanos , Fenotipo , Defectos Congénitos del Transporte Tubular Renal/diagnóstico , Defectos Congénitos del Transporte Tubular Renal/metabolismoRESUMEN
Autosomal dominant polycystic kidney disease (ADPKD) is a heterogeneous inherited disease characterized by renal and extrarenal manifestations with progressive fluid-filled cyst development leading to end-stage renal disease. The rate of disease progression in ADPKD exhibits high inter- and intrafamilial variability suggesting involvement of modifier genes and/or environmental factors. Renal hypouricemia (RHUC) is an inherited disorder characterized by impaired tubular uric acid transport with severe complications, such as acute kidney injury and chronic kidney disease (CKD). However, the two disorders have distinct and well-delineated genetic, biochemical, and clinical findings. Only a few cases of coexistence of ADPKD and RHUC (type 1) in a single individual have been reported. We report a family with two members: an ADPKD 24-year-old female which presented bilateral renal cysts in utero and hypouricemia since age 5, and her mother with isolated hypouricemia. Next-generation sequencing identified two mutations in two genes PKD1 and SLC2A9 in this patient and one isolated SLC2A9 mutation in her mother, showing RHUC type 2, associated to CKD. The coexistence of these two disorders provides evidence of SLC2A9 variant could act as a modifier change, with synergistic actions, that could promote cystogenesis and rapid ADPKD progression. This is the first case of coexistence of PKD1 and SLC2A9 mutations treated with tolvaptan.
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Proteínas Facilitadoras del Transporte de la Glucosa/genética , Enfermedades Renales Poliquísticas/genética , Defectos Congénitos del Transporte Tubular Renal/genética , Canales Catiónicos TRPP/genética , Lesión Renal Aguda/complicaciones , Lesión Renal Aguda/diagnóstico , Lesión Renal Aguda/genética , Lesión Renal Aguda/patología , Adulto , Preescolar , Femenino , Humanos , Mutación/genética , Enfermedades Renales Poliquísticas/complicaciones , Enfermedades Renales Poliquísticas/diagnóstico , Enfermedades Renales Poliquísticas/patología , Riñón Poliquístico Autosómico Dominante/complicaciones , Riñón Poliquístico Autosómico Dominante/diagnóstico , Riñón Poliquístico Autosómico Dominante/genética , Riñón Poliquístico Autosómico Dominante/patología , Insuficiencia Renal Crónica/complicaciones , Insuficiencia Renal Crónica/diagnóstico , Insuficiencia Renal Crónica/genética , Insuficiencia Renal Crónica/patología , Defectos Congénitos del Transporte Tubular Renal/complicaciones , Defectos Congénitos del Transporte Tubular Renal/diagnóstico , Defectos Congénitos del Transporte Tubular Renal/patología , Adulto JovenRESUMEN
Donnai-Barrow syndrome (DBS) is an autosomal recessive disorder characterized by typical craniofacial features, vision and hearing loss, intellectual disability, agenesis of the corpus callosum (ACC), congenital diaphragmatic hernia (CDH), and omphalocele. This condition is associated with loss-of-function mutations in the LRP2 gene. Few cases have been described in the literature. In our case, CDH and ACC were prenatally diagnosed by ultrasound, and the fetus was the product of a first-degree union. Single-nucleotide polymorphism-microarray showed large regions of homozygosity. Whole exome sequencing (WES) was performed and revealed a homozygous frameshift pathogenic variant in LRP2 (c.6978dupG). Here, we present a case of DBS, which diagnosed prenatally via WES in a fetus with CDH and ACC.
Asunto(s)
Anomalías Múltiples/genética , Agenesia del Cuerpo Calloso/genética , Pérdida Auditiva Sensorineural/genética , Hernias Diafragmáticas Congénitas/genética , Proteína 2 Relacionada con Receptor de Lipoproteína de Baja Densidad/genética , Miopía/genética , Proteinuria/genética , Defectos Congénitos del Transporte Tubular Renal/genética , Anomalías Múltiples/diagnóstico , Anomalías Múltiples/diagnóstico por imagen , Anomalías Múltiples/patología , Adulto , Agenesia del Cuerpo Calloso/diagnóstico , Agenesia del Cuerpo Calloso/diagnóstico por imagen , Agenesia del Cuerpo Calloso/patología , Agenesia del Cuerpo Calloso/terapia , Consanguinidad , Femenino , Pérdida Auditiva Sensorineural/diagnóstico , Pérdida Auditiva Sensorineural/diagnóstico por imagen , Pérdida Auditiva Sensorineural/patología , Hernias Diafragmáticas Congénitas/diagnóstico , Hernias Diafragmáticas Congénitas/diagnóstico por imagen , Hernias Diafragmáticas Congénitas/patología , Homocigoto , Humanos , Lactante , Recién Nacido , Discapacidad Intelectual/diagnóstico , Discapacidad Intelectual/genética , Discapacidad Intelectual/patología , Discapacidad Intelectual/terapia , Mutación con Pérdida de Función/genética , Miopía/diagnóstico , Miopía/diagnóstico por imagen , Miopía/patología , Diagnóstico Prenatal/métodos , Proteinuria/diagnóstico , Proteinuria/diagnóstico por imagen , Proteinuria/patología , Defectos Congénitos del Transporte Tubular Renal/diagnóstico , Defectos Congénitos del Transporte Tubular Renal/diagnóstico por imagen , Defectos Congénitos del Transporte Tubular Renal/patología , Ultrasonografía , Secuenciación del Exoma/métodosRESUMEN
We presented an update in the field of hypouricemia, which is defined as a serum urate concentration of < 2 mg/dL (119 µmol/L), for the practicing rheumatologist, who usually is the consulting physician in cases of disorders of urate metabolism. We performed a narrative review through a literature search for original and review articles in the field of human hypouricemia published between January 1950 and July 2018. We divided the etiology of hypouricemia into two main categories: those associated with a decrease in urate production and those promoting the elimination of urate via the kidneys. The most common conditions associated with these categories are discussed. Furthermore, the etiology of hypouricemia may be associated with certain medications prescribed by the practicing rheumatologists, such as the following: urate-lowering drugs (allopurinol and febuxostat); recombinant uricase (pegloticase); uricosuric agents (probenecid, benzbromarone); urate transporter URAT1 inhibitor (lesinurad); angiotensin II receptor blocker (losartan); fenofibrate; high-dose trimethoprim-sulfamethoxazole; some NSAID; and high-dose salicylate therapy. The rheumatologist is considered an expert in the metabolism of urate and its associated pathological conditions. Therefore, specialists must recognize hypouricemia as a biomarker of various pathological and potentially harmful conditions, highlighting the importance of conducting a deeper clinical investigation to reach a more accurate diagnosis and treatment.
Asunto(s)
Defectos Congénitos del Transporte Tubular Renal/diagnóstico , Defectos Congénitos del Transporte Tubular Renal/tratamiento farmacológico , Uricosúricos/uso terapéutico , Cálculos Urinarios/diagnóstico , Cálculos Urinarios/tratamiento farmacológico , Biomarcadores , Humanos , ReumatólogosRESUMEN
BACKGROUND: Renal hypouricemia (RHUC) is an inherited heterogenous disorder caused by faulty urate reabsorption transporters in the renal proximal tubular cells. Anaerobic exercise may induce acute kidney injury in individuals with RHUC that is not caused by exertional rhabdomyolysis; it is called acute renal failure with severe loin pain and patchy renal ischemia after anaerobic exercise (ALPE). RHUC is the most important risk factor for ALPE. However, the mechanism of onset of ALPE in patients with RHUC has not been elucidated. The currently known genes responsible for RHUC are SLC22A12 and SLC2A9. CASE PRESENTATION: A 37-year-old man presented with loin pain after exercising. Despite having a healthy constitution from birth, biochemical examination revealed hypouricemia, with a uric acid (UA) level of < 1 mg/dL consistently at every health check. We detected acute kidney injury, with a creatinine (Cr) level of 4.1 mg/dL, and elevated bilirubin; hence, the patient was hospitalized. Computed tomography revealed no renal calculi, but bilateral renal swelling was noted. Magnetic resonance imaging detected cuneiform lesions, indicating bilateral renal ischemia. Fractional excretion values of sodium and UA were 0.61 and 50.5%, respectively. Urinary microscopy showed lack of tubular injury. The patient's older sister had hypouricemia. The patient was diagnosed with ALPE. Treatment with bed rest, fluid replacement, and nutrition therapy improved renal function and bilirubin levels, and the patient was discharged on day 5. Approximately 1 month after onset of ALPE, his Cr, UA, and TB levels were 0.98, 0.8, and 0.9 mg/dL, respectively. We suspected familial RHUC due to the hypouricemia and family history and performed genetic testing but did not find the typical genes responsible for RHUC. A full genetic analysis was opposed by the family. CONCLUSIONS: To the best of our knowledge, this is the first report of ALPE with hyperbilirubinemia. Bilirubin levels may become elevated as a result of heme oxygenase-1 activation, occurring in exercise-induced acute kidney injury in patients with RHUC; this phenomenon suggests renal ischemia-reperfusion injury. A new causative gene coding for a urate transporter may exist, and its identification would be useful to clarify the urate transport mechanism.
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Lesión Renal Aguda , Ejercicio Físico/fisiología , Hiperbilirrubinemia , Riñón , Defectos Congénitos del Transporte Tubular Renal , Ácido Úrico/sangre , Cálculos Urinarios , Lesión Renal Aguda/diagnóstico , Lesión Renal Aguda/etiología , Lesión Renal Aguda/fisiopatología , Lesión Renal Aguda/terapia , Adulto , Dietoterapia/métodos , Fluidoterapia/métodos , Proteínas Facilitadoras del Transporte de la Glucosa/genética , Humanos , Hiperbilirrubinemia/diagnóstico , Hiperbilirrubinemia/etiología , Riñón/irrigación sanguínea , Riñón/diagnóstico por imagen , Riñón/metabolismo , Pruebas de Función Renal/métodos , Masculino , Anamnesis , Transportadores de Anión Orgánico/genética , Proteínas de Transporte de Catión Orgánico/genética , Defectos Congénitos del Transporte Tubular Renal/diagnóstico , Defectos Congénitos del Transporte Tubular Renal/etiología , Defectos Congénitos del Transporte Tubular Renal/genética , Defectos Congénitos del Transporte Tubular Renal/fisiopatología , Defectos Congénitos del Transporte Tubular Renal/terapia , Cálculos Urinarios/diagnóstico , Cálculos Urinarios/etiología , Cálculos Urinarios/fisiopatología , Cálculos Urinarios/terapiaRESUMEN
Differentiating between inherited renal hypouricemia and transient hypouricemic status is challenging. Here, we aimed to describe the genetic background of hypouricemia patients using whole-exome sequencing (WES) and assess the feasibility for genetic diagnosis using two founder variants in primary screening. We selected all cases (N = 31) with extreme hypouricemia (<1.3 mg/dl) from a Korean urban cohort of 179,381 subjects without underlying conditions. WES and corresponding downstream analyses were performed for the discovery of rare causal variants for hypouricemia. Two known recessive variants within SLC22A12 (p.Trp258*, pArg90His) were identified in 24 out of 31 subjects (77.4%). In an independent cohort, we identified 50 individuals with hypouricemia and genotyped the p.Trp258* and p.Arg90His variants; 47 of the 50 (94%) hypouricemia cases were explained by only two mutations. Four novel coding variants in SLC22A12, p.Asn136Lys, p.Thr225Lys, p.Arg284Gln, and p.Glu429Lys, were additionally identified. In silico studies predict these as pathogenic variants. This is the first study to show the value of genetic diagnostic screening for hypouricemia in the clinical setting. Screening of just two ethnic-specific variants (p.Trp258* and p.Arg90His) identified 87.7% (71/81) of Korean patients with monogenic hypouricemia. Early genetic identification of constitutive hypouricemia may prevent acute kidney injury by avoidance of dehydration and excessive exercise.
Asunto(s)
Pruebas Genéticas , Transportadores de Anión Orgánico/genética , Proteínas de Transporte de Catión Orgánico/genética , Defectos Congénitos del Transporte Tubular Renal/genética , Cálculos Urinarios/genética , Anciano , Femenino , Genotipo , Heterocigoto , Humanos , Masculino , Persona de Mediana Edad , Mutación/genética , Defectos Congénitos del Transporte Tubular Renal/diagnóstico , Defectos Congénitos del Transporte Tubular Renal/patología , Cálculos Urinarios/diagnóstico , Cálculos Urinarios/patología , Desequilibrio Hidroelectrolítico/genética , Secuenciación del ExomaRESUMEN
Idiopathic renal hypouricemia is a rare hereditary condition. Type 2 renal hyperuricemia (RHUC2) is caused by a mutation in the SLC2A9 gene, which encodes a highcapacity glucose and urate transporter, glucose transporter (GLUT)9. RHUC2 predisposes to exerciseinduced acute renal failure (EIARF) and nephrolithiasis, which is caused by a defect in renal tubular urate transport and is characterized by increased clearance of renal uric acid. In the present study a case of a 35yearold Chinese man with EIARF is reported. The patient had isolated renal hypouricemia, with a serum uric acid level of 21 µmol/l and a fractional excretion of uric acid of 200%. The mutational analysis revealed a homozygous mutation (c.857G>A in exon 8) in the SLC2A9 gene. The patient's family members carried the same mutation, but were heterozygous and clinically asymptomatic. In conclusion, to the best of our knowledge, this is the first report of a RHUC2 patient with a GLUT9 mutation, p.W286X, which may be a pathogenic mutation of RHUC2. Further investigation into the functional role of GLUT9 in this novel SLC2A9 mutation is required.
Asunto(s)
Defectos Congénitos del Transporte Tubular Renal/diagnóstico , Defectos Congénitos del Transporte Tubular Renal/genética , Cálculos Urinarios/diagnóstico , Cálculos Urinarios/genética , Adulto , Alelos , Biomarcadores , Biopsia , Análisis Mutacional de ADN , Proteínas Facilitadoras del Transporte de la Glucosa/genética , Homocigoto , Humanos , Masculino , Modelos Biológicos , Mutación , Linaje , Enfermedades Raras , Defectos Congénitos del Transporte Tubular Renal/metabolismo , Defectos Congénitos del Transporte Tubular Renal/terapia , Análisis de Secuencia de ADN , Ultrasonografía , Cálculos Urinarios/metabolismo , Cálculos Urinarios/terapiaRESUMEN
Renal hypouricemia (RHUC) is a disease caused by dysfunction of renal urate reabsorption transporters; however, diagnostic guidance and guidelines for RHUC have been lacking, partly due to the low evidence level of studies on RHUC. This review describes a world-first clinical practice guideline (CPG) and its first version in English for this condition. It was developed following the "MINDS Manual for Guideline Development" methodology, which prioritizes evidence-based medicine. It was published in Japanese in 2017 and later translated into English. The primary goal of this CPG is to clarify the criteria for diagnosing RHUC; another aim is to work towards a consensus on clinical decision-making. One of the CPG's unique points is that it contains textbook descriptions at the expert consensus level, in addition to two clinical questions and recommendations derived from a systematic review of the literature. The guidance shown in this CPG makes it easy to diagnose RHUC from simple blood and urine tests. This CPG contains almost all of the clinical foci of RHUC: epidemiology, pathophysiology, diagnostic guidance, clinical examinations, differential diagnosis, and complications, including exercise-induced acute kidney injury and urolithiasis. A CPG summary as well as a clinical algorithm to assist healthcare providers with a quick reference and notes from an athlete for both physicians and patients are included. We hope that this CPG will help healthcare providers and patients to make clinical decisions, and that it will promote further research on RHUC.