Hipouricemia con hipercalciuria. Estudio longitudinal y revisión del tema / Hypouricemia with hypercalciuria: Longitudinal study and review of the topic

Antecedentes y objetivo: La asociación de hipouricemia e hipercalciuria es poco frecuente. En 1974 se describió un nuevo síndrome nominado Hipouricemia con hipercalciuria y reducción de la densidad ósea. Posteriormente, se publicaron algunos casos con esa asociación en los que la excreción fraccional de urato era superior a 20/100ml FGR. Hemos analizado una serie de niños que fueron diagnosticados de hipouricemia e hipercalciuria y que fueron controlados evolutivamente. El objetivo del trabajo es intentar conocer si nuestros pacientes podrían estar afectos del síndrome antes mencionado o ser portadores de una variante de hipercalciuria idiopática. Pacientes y métodos: Estudio retrospectivo longitudinal en el que se estudiaron las historias clínicas de 8 pacientes (5V y 3M) diagnosticados de hipouricemia e hipercalciuria en la infancia. Se anotaron la clínica al diagnóstico, los hallazgos ecográficos y densitométricos, y determinadas variables bioquímicas, con especial hincapié en el manejo tubular renal del urato. Los resultados se compararon con los de 36 niños afectos de hipercalciuria idiopática sin hipouricemia (14V y 22M). Resultados: En el grupo con hipouricemia los niveles iniciales de uricemia fueron 1,9 (0,3) mg/dl (rango: 1,5-2) y los del cociente calcio/creatinina en primera orina del día, 0,27 (0,05) mg/mg (rango: 0,23-0,31). En todos los casos la excreción fraccional de urato fue inferior a 20ml/100ml FGR. Los valores de z-DMO fueron menores de −1 en 4/8 casos. En el último control, solo en 3 casos persistía el cociente calcio/creatinina elevado, y en todos la uricemia era superior a 2mg/dl. El valor de z-DMO había mejorado en 5 casos y empeorado en otros 3... (AU)

Background and objective: The association of hypouricemia and hypercalciuria is rare. In 1974 a new syndrome named Hypouricemia with hypercalciuria and decreased bone density was described. Afterwards, some cases with such association were published in which the fractional excretion of urate was higher than 20/100ml FGR. We have analyzed a series of children who were diagnosed with hypouricemia and hypercalciuria and who were monitored. The aim of this study was to determine whether our patients could be affected by the aforementioned syndrome or be carriers of a variant of idiopathic hypercalciuria. Patients and methods: Retrospective longitudinal study in which the medical records of eight patients (5V and 3M) diagnosed with hypouricemia and hypercalciuria in childhood. Clinical features at diagnosis, ultrasound and densitometric findings and selected biochemical variables were noted, with special emphasis on renal tubular handling of urate. Results were compared with 36 children with idiopathic hypercalciuria without hypouricemia (14V and 22M). Results: In the hypouricemia group baseline urate levels were 1.9 (0.3)mg/dl (range: 1.5-2) and first day urine calcium/creatinine ratio 0.27 (0.05)mg/mg (range: 0.23-0.31). In all cases fractional urate excretion was less than 20/100ml FGR. The z-DMO values were less than −1 in 4/8 cases. At the last follow-up only three cases still had an elevated calcium/creatinine ratio and in all of them the urates levels was greater than 2mg/dl. The z-DMO value had improved in five cases and worsened in three others. In relation to the group without hypouricemia, no differences were observed between the various parameters studied including the z-DMO value, with the exception of fractional excretion and tubular urate reabsorption although plasmatic uric acid levels were still significantly lower... (AU)

Hypouricemia with hypercalciuria: Longitudinal study and review of the topic.

BACKGROUND AND OBJECTIVE: The association of hypouricemia and hypercalciuria is rare. In 1974 a new syndrome named Hypouricemia with hypercalciuria and decreased bone density was described. Afterwards, some cases with such association were published in which the fractional excretion of urate was higher than 20ml/100ml FGR. We have analyzed a series of children who were diagnosed with hypouricemia and hypercalciuria and who were monitored. The aim of this study was to determine whether our patients could be affected by the aforementioned syndrome or be carriers of a variant of idiopathic hypercalciuria. PATIENTS AND METHODS: Retrospective longitudinal study in which the medical records of eight patients (5V, 3M) diagnosed with hypouricemia and hypercalciuria in childhood. Clinical features at diagnosis, ultrasound and densitometric findings and selected biochemical variables were noted, with special emphasis on renal tubular handling of urate. Results were compared with 36 children with idiopathic hypercalciuria without hypouricemia (14V, 22M). RESULTS: In the hypouricemia group baseline urate levels were 1.9 (0.3) mg/dl (range: 1.5-2) and first day urine calcium/creatinine ratio 0.27 (0.05) mg/mg (range: 0.23-0.31). In all cases fractional urate excretion was less than 20ml/100ml FGR. The z-DMO values were less than -1 in 4/8 cases. At the last follow-up only three cases still had an elevated calcium/creatinine ratio and in all of them the urates levels was greater than 2mg/dl. The z-DMO value had improved in five cases and worsened in three others. In relation to the group without hypouricemia, no differences were observed between the various parameters studied including the z-DMO value, with the exception of fractional excretion and tubular urate reabsorption although plasmatic uric acid levels were still significantly lower. CONCLUSION: Our patients with hypercalciuria and hypouricemia would be affected by a variant of idiopathic hypercalciuria in which, due to an unknown cause, the proximal tubular reabsorption of urate is modestly reduced and improves over time. Hypouricemia with hypercalciuria and decreased bone density may not be a specific entity.

II National Congress of Paediatrics: The fight against child mortality.

In the present work, we present an overview of the contents of the communications presented at the Second National Congress of Paediatrics, held in San Sebastian in 1923, on the occasion of the 100th year anniversary. The problem of infant mortality stands out as a common thread, which in those years was very high in Spain and was a concern of politicians, intellectuals and the medical profession. It is worth noting that some of the proposals and concerns of the paediatricians who attended that congress continue to be relevant today.

Renal diseases that course with hypomagnesemia. Comments on a new hereditary hypomagnesemic tubulopathy.

Renal diseases associated with hypomagnesemia are a complex and diverse group of tubulopathies caused by mutations in genes encoding proteins that are expressed in the thick ascending limb of the loop of Henle and in the distal convoluted tubule. In this paper, we review the initial description, the clinical expressiveness and etiology of four of the first hypomagnesemic tubulopathies described: type 3 Bartter and Gitelman diseases, Autosomal recessive hypomagnesemia with secondary hypocalcemia and Familial hypomagnesemia with hypercalciuria and nephrocalcinosis. The basic biochemical patterns observed in renal tubular hypomagnesemias and the modalities of transport and interaction that occur between the transporters involved in the reabsorption of magnesium in the distal convoluted tubule are described below. Finally, the recent report of a new renal disease with hypomagnesemia, type 2 hypomagnesemia with secondary hypocalcemia caused by reduced TRPM7 channel activity is described.

Enfermedades renales que cursan con hipomagnesemia. Comentarios acerca de una nueva tubulopatía hipomagnesémica de origen genético / Renal diseases that course with hypomagnesemia. Comments on a new hereditary hypomagnesemic tubulopathy

Las enfermedades renales que cursan con hipomagnesemia son un grupo complejo y variopinto de tubulopatías producidas por mutaciones en genes que codifican proteínas que se expresan en la rama gruesa ascendente del asa de Henle y en el túbulo contorneado distal. En el presente artículo revisamos la descripción inicial, la expresividad clínica y la etiología de cuatro de las primeras causas de tubulopatías hipomagnesémicas que se describieron: las enfermedades de Bartter tipo 3 y Gitelman, la hipomagnesemia con hipocalcemia secundaria autosómica recesiva y la hipomagnesemia familiar con hipercalciuria y nefrocalcinosis. A continuación, se describen los patrones bioquímicos básicos que se observan en las hipomagnesemias tubulares renales y las modalidades de transporte e interacción que concurren entre los transportadores implicados en la reabsorción de magnesio en el túbulo contorneado distal. Finalmente, se comunica la reciente descripción de una nueva tubulopatía hipomagnesémica, la hipomagnesemia con hipocalcemia secundaria tipo 2 causada por una reducción de la actividad del canal TRPM7 (AU)

Renal diseases associated with hypomagnesemia are a complex and diverse group of tubulopathies caused by mutations in genes encoding proteins that are expressed in the thick ascending limb of the loop of Henle and in the distal convoluted tubule. In this paper, we review the initial description, the clinical expressiveness and etiology of four of the first hypomagnesemic tubulopathies described: Type 3 Bartter and Gitelman diseases,Autosomal recessive hypomagnesemia with secondary hypocalcemia and Familial hypomagnesemia with hypercalciuria and nephrocalcinosis. The basic biochemical patterns observed in renal tubular hypomagnesemias and the modalities of transport and interaction that occur between the transporters involved in the reabsorption of magnesium in the distal convoluted tubule are described below. Finally, the recent report of a new renal disease with hypomagnesemia, Type 2 hypomagnesemia with secondary hypocalcemia caused by reduced TRPM7 channel activity is described (AU)

II Congreso Nacional de Pediatría. La lucha contra la mortalidad infantil / II National Congress of Paediatrics: The fight against child mortality

En el presente trabajo se presenta una aproximación a los contenidos de las ponencias del IICongreso Nacional de Pediatría, celebrado en San Sebastián en 1923, con ocasión del centenario del mismo. Se destaca como hilo conductor de las mismas el problema de la mortalidad infantil, que en aquellos años era muy elevada en España y era una preocupación de políticos, de intelectuales y de la clase médica. Se constata que alguna de las propuestas y preocupaciones de los pediatras que asistieron a dicho congreso siguen vigentes hoy en día.(AU)

In this work, we present an overview of the contents of the communications presented at the Second National Congress of Paediatrics, held in San Sebastian in 1923, on the occasion of the 100th year anniversary. The problem of infant mortality stands out as a common thread, which in those years was very high in Spain and was a concern of politicians, intellectuals and the medical profession. It is worth noting that some of the proposals and concerns of the paediatricians who attended that congress continue to be relevant today.(AU)

Autosomal dominant distal renal tubular acidosis in two pediatric patients with mutations in the SLC4A1 gene. Can the maximum urinary pCO2 test be normal?

Primary distal renal tubular acidosis (dRTA) is a rare tubulopathy characterised by the presence of hyperchloremic metabolic acidosis. It is caused by the existence of a defect in the function of the H+ -ATPase located on the luminal side of the α-intercalated cells or the Cl - HCO3- (AE1) anion exchanger located on the basolateral side. Patients do not acidify the urine after acid overload (NH4Cl) or after stimulating H+ secretion by obtaining a high intratubular concentration of an anion such as chlorine (pH is measured) or HCO3- (urinary pCO2 is measured). We present a family with autosomal dominant dRTA produced by a heterozygous mutation in the SLC4A1 gene in which the two paediatric members showed a test of normal maximum urinary pCO2. Our hypothesis is that since the H + -ATPase is intact, at least initially, the stimulation induced by intratubular electronegativity to secrete H + could be effective, which would allow the maximum urinary pCO2 to be paradoxically normal, which could explain the onset, moderate presentation of symptoms and late diagnosis in patients with this mutation. This is the first documented case of a dominant dRTA in Mexico.

Acidosis tubular renal distal autosómica dominante en dos pacientes pediátricos con mutaciones en el gen SLC4A1. ¿La prueba de la pCO2 urinaria máxima puede ser normal? / Autosomal dominant distal renal tubular acidosis in two pediatric patients with mutations in the SLC4A1 gene. Can the maximum urinary pCO2 test be normal?

La acidosis tubular renal distal (ATRd) primaria es una tubulopatía poco frecuente caracterizada por la presencia de acidosis metabólica hiperclorémica. Está generada por la existencia de un defecto en la función de la H+-ATPasa situada en el lado luminal de las células α-intercaladas o del intercambiador de aniones Cl−-HCO3− (AE1) ubicado en el lado basolateral. Los pacientes no acidifican la orina tras una sobrecarga ácida (NH4Cl) o tras estimular la secreción de H+ mediante la obtención de una elevada concentración intratubular de un anión como cloro (se mide el pH) o HCO3− (se mide la pCO2 urinaria). Se presenta una familia con ATRd autosómica dominante producida por una mutación heterocigota en el gen SLC4A1 en la que los 2 miembros en edad pediátrica mostraron una prueba de la pCO2 urinaria máxima normal. Nuestra hipótesis es que al estar intacta, al menos inicialmente, la H+-ATPasa, podría ser efectivo el estímulo inducido por la electronegatividad intratubular para secretar H+ lo que permitiría que la pCO2 urinaria máxima fuera paradójicamente normal, lo que pudiera explicar el inicio tardío, la presentación moderada de los síntomas y el diagnóstico en edades más avanzadas, en los pacientes con dicha mutación. Este es el primer caso documentado de una ATRd dominante en México. (AU)

Primary distal renal tubular acidosis (dRTA) is a rare tubulopathy characterized by the presence of hyperchloremic metabolic acidosis. It is caused by the existence of a defect in the function of the H+-ATPase located on the luminal side of the α-intercalated cells or the Cl− HCO3− (AE1) anion exchanger located on the basolateral side. Patients do not acidify the urine after acid overload (NH4Cl) or after stimulating H+ secretion by obtaining a high intratubular concentration of an anion such as chlorine (pH is measured) or HCO3− (urinary pCO2 is measured). We present a family with autosomal dominant dRTA produced by a heterozygous mutation in the SLC4A1 gene in which the two pediatric members showed a test of normal maximum urinary pCO2. Our hypothesis is that since the H+-ATPase is intact, at least initially, the stimulation induced by intratubular electronegativity to secrete H+ could be effective, which would allow the maximum urinary pCO2 to be paradoxically normal, which could explain the onset, moderate presentation of symptoms and late diagnosis in patients with this mutation. This is the first documented case of a dominant dRTA in Mexico. (AU)

Pathogenic Variants of SLC22A12 (URAT1) and SLC2A9 (GLUT9) in Spanish Patients with Renal Hypouricemia: Founder Effect of SLC2A9 Variant c.374C>T; p.(T125M).

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.

Reflections on TRP and TP/GFR in the definition of renal phosphate loss: conceptual review.

BACKGROUND: Fractional tubular reabsorption of phosphate (TRP) has been used for over 60 years to establish the existence of renal phosphate loss. It is a parameter of corrected volume per decilitre of glomerular filtration rate (GFR). Later, a mass parameter per dl GFR called TP/GFR (tubular PO4 reabsorption per dl GFR) was devised which some authors have sought to substitute for TRP. The aim of the present work is to attempt to demonstrate that TRP and TP/GFR are similar parameters and, in certain aspects, TRP is more effective for diagnosis. METHODS: Data were gathered on the metabolism of phosphate corresponding to a group of healthy children without hypophosphatemia (n = 47), a group of patients with idiopathic hypercalciuria (n = 27), and ten patients diagnosed with X-linked hypophosphatemia (XLH). The TRP, the TP/GFR, and the percent tubular reabsorption of phosphate were calculated. RESULTS: All the patients with XLH presented TRP values lower than 95 ml/dl GFR and of TP/GFR equal to or lower than 2.8 mg/dl GFR. In the total sample, a direct correlation was observed between TRP and TP/GFR (r = 0.65; p = 0.01). The TRP and the percent tubular reabsorption of phosphate values were the same in the three groups (r = 1; p = 0.01). CONCLUSIONS: TRP and TP/GFR are similar parameters. TRP is more effective than TP/GFR given that in renal hypophosphatemia it is always below 95% and above 95% in reduced phosphatemia and normal kidney proximal tubular function. There is no solid reason for using TP/GFR rather than TRP. A higher resolution version of the Graphical abstract is available as Supplementary information.

Gout associated with reduced renal excretion of uric acid. Renal tubular disorder that nephrologists do not treat.

Gout is recurrent inflammatory arthritis caused by the deposition of monosodium urate crystals in the joints. The risk factors that predispose to suffering from gout include non-modifiable factors such as gender, age, ethnicity and genetics, and modifiable factors such as diet and lifestyle. It has been shown that the heritability of uric acid levels in the blood is greater than 30%, which indicates that genetics play a key role in these levels. Hyperuricaemia is often a consequence of reduced renal urate excretion since more than 70% is excreted by the kidneys, mainly through the proximal tubule. The mechanisms that explain that hyperuricaemia associated with reduced renal urate excretion is, to a large extent, a proximal renal tubular disorder, have begun to be understood following the identification of two genes that encode the URAT1 and GLUT9 transporters. When they are carriers of loss-of-function mutations, they explain the two known variants of renal tubular hypouricaemia. Some polymorphisms in these genes may have an opposite gain-of-function effect, with a consequent increase in urate reabsorption. Conversely, loss-of-function polymorphisms in other genes that encode transporters involved in urate excretion (ABCG2, ABCC4) can lead to hyperuricaemia. Genome-wide association study (GWAS) methods have made it possible to locate new gout-related loci associated with reduced renal urate excretion (NIPAL1, FAM35A).

Feminismo, cuidado infantil y derechos de la infancia. Las feministas en los primeros congresos nacionales de Pediatría / Feminism, childcare and children's rights. Feminists in the first national paediatrics congresses

Analizando la participación de las mujeres en los primeros congresos de Pediatría, llama la atención que una buena parte de ellas pertenecían a organizaciones feministas y que, además de su militancia, tenían una preocupación por los y las menores, por sus aspectos educativos y legales.Se han revisado las actas y publicaciones relacionadas con los cinco primeros congresos nacionales de Pediatría (CNP) (1914-1933), biografías de las participantes y publicaciones sobre el feminismo en los años 20 y 30 del pasado siglo.En los cinco primeros CNP participaron 14 mujeres: un 15% eran del ámbito sanitario, un 65%, del educativo y un 29%, del derecho. Siete de ellas pertenecían a organizaciones feministas (50%). Hay dos generaciones de feministas que participaron en los CNP. La primera militó en la Asociación Nacional de Mujeres Españolas, donde la mayoría de ellas ostentaba cargos orgánicos y su labor profesional fue la educación. La segunda, en torno a Juventud Universitaria Femenina, y su dedicación laboral fue el derecho. Su participación en los CNP fue sobre esos temas, educación y derechos de la infancia. Así mismo, impulsaron otras actividades en defensa de la infancia a nivel social, como las 'cantinas escolares', los 'desayunos escolares' o el 'club infantil' de tiempo libre para las clases más desfavorecidas.Las mujeres que se han estudiado, desde su concepción feminista de la vida, no solo trabajaron por los derechos de la mujer, sino que se esforzaron por mejorar la vida de la infancia y el reconocimiento de sus derechos. (AU)

Analysing the participation of women in the first paediatric congresses, it stands out that many of them belonged to feminist organisations and that, in addition to the pursuit of their cause, they were concerned about children, including educational and legal aspects.We reviewed the minutes and publications related to the first five National Paediatric Congresses (NCPs) (1914-1933), biographies of the participants and publications on feminism in the 1920s and 1930s.Fourteen women participated in the first 5 NPCs, 15% from the health care field, 65% from the field of education and 29% from the field of law. Seven of them belonged to feminist organisations (50%). Two generations of feminists participated in the NPCs. Women from the first generation were actively involved in the National Association of Spanish Women, most of who held positions in administration and worked in the education field. Women from the second generation were organised around the Juventud Universitaria Femenina (University Young Women’s Organization) and worked in law. Their participation in the NPCs had to do with these issues, education and children’s rights. They also promoted other activities to advocate for children at a social level, such as the “school canteens”, “school breakfasts” or the “Children’s Club”, which provided leisure activities for disadvantaged groups.The women whose activity we reviewed, through their feminist perspective of life, not only worked for women’s rights, but also strove to improve the lives of children and to achieve the recognition of their rights. (AU)