Possible role for rare TRPM7 variants in patients with hypomagnesaemia with secondary hypocalcaemia.

BACKGROUND: Hypomagnesaemia with secondary hypocal-caemia (HSH) is a rare autosomal recessive disorder caused by pathogenic variants in TRPM6, encoding the channel-kinase transient receptor potential melastatin type 6. Patients have very low serum magnesium (Mg2+) levels and suffer from muscle cramps and seizures. Despite genetic testing, a subgroup of HSH patients remains without a diagnosis. METHODS: In this study, two families with an HSH phenotype but negative for TRPM6 pathogenic variants were subjected to whole exome sequencing. Using a complementary combination of biochemical and functional analyses in overexpression systems and patient-derived fibroblasts, the effect of the TRPM7-identified variants on Mg2+ transport was examined. RESULTS: For the first time, variants in TRPM7 were identified in two families as a potential cause for hereditary HSH. Patients suffer from seizures and muscle cramps due to magnesium deficiency and episodes of hypocalcaemia. In the first family, a splice site variant caused the incorporation of intron 1 sequences into the TRPM7 messenger RNA and generated a premature stop codon. As a consequence, patient-derived fibroblasts exhibit decreased cell growth. In the second family, a heterozygous missense variant in the pore domain resulted in decreased TRPM7 channel activity. CONCLUSIONS: We establish TRPM7 as a prime candidate gene for autosomal dominant hypomagnesaemia and secondary hypocalcaemia. Screening of unresolved patients with hypocalcaemia and secondary hypocalcaemia may further establish TRPM7 pathogenic variants as a novel Mendelian disorder.

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.

Update of the Spanish clinical practice guideline for urinary tract infection in infants and children. Summary of recommendations for diagnosis, treatment and follow-up.

The management of urinary tract infection (UTI) in infants and children has changed significantly over the past few decades based on scientific evidence that questioned the efficacy of strategies used to prevent kidney injury and subsequent progression to chronic kidney disease, which is very unlikely in most paediatric cases. However, there is still substantial heterogeneity in its management and uncertainty regarding the diagnosis, indication of imaging tests, treatment or follow-up in these patients. The Spanish clinical practice guideline has been updated through the review of the literature published since 2009 and a rigorous evaluation of current clinical practice aspects, taking into account the evidence on the benefits of each intervention in addition to its risks and drawbacks to attempt to provide more precise recommendations.

Low factor H-related 5 levels contribute to infection-triggered haemolytic uraemic syndrome and membranoproliferative glomerulonephritis.

Dysregulation of the alternative complement pathway is a major pathogenic mechanism in two rare renal diseases: atypical haemolytic uraemic syndrome (aHUS) and membranoproliferative glomerulonephritis (MPGN). We report on a 66-year-old male with chronic hepatitis C virus (HCV) infection and a combined liver-kidney transplant that was diagnosed with MPGN at the age of 63 years and a 5-year-old boy who presented with aHUS at the age of 21 months following a Streptococcus pneumoniae infection. Both patients carried similar frameshift variants in the complement CFHR5 gene that segregate with reduced levels of factor H-related 5 (FHR-5). We conclude that low FHR-5 levels may predispose to viral and bacterial infections that then trigger different renal phenotypes.

Complement Activation and Thrombotic Microangiopathies.

BACKGROUND AND OBJECTIVES: Atypical hemolytic uremic syndrome is a form of thrombotic microangiopathy caused by dysregulation of the alternative complement pathway. There is evidence showing complement activation in other thrombotic microangiopathies. The aim of this study was to evaluate complement activation in different thrombotic microangiopathies and to monitor treatment response. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Complement activation was assessed by exposing endothelial cells to sera or activated-patient plasma-citrated plasma mixed with a control sera pool (1:1)-to analyze C5b-9 deposits by immunofluorescence. Patients with atypical hemolytic uremic syndrome (n=34) at different stages of the disease, HELLP syndrome (a pregnancy complication characterized by hemolysis, elevated liver enzymes, and low platelet count) or severe preeclampsia (n=10), and malignant hypertension (n=5) were included. RESULTS: Acute phase atypical hemolytic uremic syndrome-activated plasma induced an increased C5b-9 deposition on endothelial cells. Standard and lower doses of eculizumab inhibited C5b-9 deposition in all patients with atypical hemolytic uremic syndrome, except in two who showed partial remission and clinical relapse. Significant fibrin formation was observed together with C5b-9 deposition. Results obtained using activated-plasma samples were more marked and reproducible than those obtained with sera. C5b-9 deposition was also increased with samples from patients with HELLP (all cases) and preeclampsia (90%) at disease onset. This increase was sustained in those with HELLP after 40 days, and levels normalized in patients with both HELLP and preeclampsia after 6-9 months. Complement activation in those with malignant hypertension was at control levels. CONCLUSIONS: The proposed methodology identifies complement overactivation in patients with atypical hemolytic uremic syndrome at acute phase and in other diseases such as HELLP syndrome and preeclampsia. Moreover, it is sensitive enough to individually assess the efficiency of the C5 inhibition treatment.

Coexistència de la malaltia de Wilkie i la síndrome del trencanous / Coexistencia de enfermedad de Wilkie y síndrome del cascanueces / Simultaneous occurrence of Wilkie and nutcracker syndromes

Introducció. La síndrome de l’artèria mesentèrica superior,o malaltia de Wilkie, i la síndrome de compressió de lavena renal esquerra, o síndrome del trencanous, són pocfreqüents. Normalment estan provocades per una compressió extrínseca del duodè o de la vena renal esquerra, respectivament, a causa d’una disminució de l’angle entrel’artèria mesentèrica superior i l’aorta.Cas clínic. Adolescent de 15 anys que va consultar a urgències per dolor abdominal de cinc mesos d’evolució localitzata l’epigastri, acompanyat de vòmits, proteïnúria i pèrdua depes. La pacient havia consultat prèviament en altres centresi s’havien descartat patologies urgents quirúrgiques. Es vacompletar l’estudi amb una tomografia computada abdominal amb diagnòstic de síndrome de l’artèria mesentèricasuperior i síndrome del trencanous. La pacient va ingressara la planta d’hospitalització i es va tractar de forma conservadora amb una dieta hipercalòrica; el trànsit intestinal i laproteïnúria van millorar, i va poder ser remesa a domicili icontrolada ambulatòriament de forma multidisciplinària.Comentari. Els problemes secundaris a la compressió aortomesentèrica poden donar quadres compatibles amb la síndrome de l’artèria mesentèrica superior i la síndrome deltrencanous. El diagnòstic d’aquests quadres pot resultarcomplex per la incidència baixa i per la simptomatologiainespecífica que els caracteritza. El tractament conservador representa la primera línia de tractament, però en alguns casos pot no ser suficient. Per tot això és necessarifer un maneig multidisciplinari d’aquests pacients. (AU)

Introducción. El síndrome de la arteria mesentérica superior o deWilkie y el síndrome del cascanueces son poco frecuentes. Normalmente están producidos por una compresión extrínseca delduodeno o de la vena renal izquierda, respectivamente, debido a una disminución del ángulo entre la arteria mesentérica superior yla aorta.Caso clínico. Adolescente de 15 años que consultó a urgencias pordolor abdominal de cinco meses de evolución localizado en epigastrio, acompañado de vómitos, proteinuria y pérdida de peso. Lapaciente había consultado previamente en otros centros descartando patologías urgentes quirúrgicas. Se completó el estudio conuna tomografía computarizada abdominal con diagnóstico de síndrome de la arteria mesentérica superior o de Wilkie y síndrome delcascanueces. La paciente ingresó en planta de hospitalización y setrató de forma conservadora con una dieta hipercalórica con mejoría del tránsito intestinal y de la proteinuria, y pudo ser remitida adomicilio y controlada ambulatoriamente de forma multidisciplinar.Comentario. Los problemas secundarios a la compresión aortomesentérica pueden dar cuadros compatibles con el síndrome de laarteria mesentérica superior o de Wilkie y el síndrome del cascanueces. El diagnóstico de estos cuadros puede resultar complejo por subaja incidencia y por la sintomatología inespecífica que los caracteriza. El tratamiento conservador representa la primera línea de tratamiento, pero en algunos casos puede no ser suficiente. Por estosmotivos es necesario un manejo multidisciplinar de estos pacientes. (AU)

Introduction. The superior mesenteric artery syndrome or Wilkiesyndrome and the nutcracker syndrome are rare. They are normallycaused by extrinsic compression of the duodenum or the left renalvein respectively, due to a narrowing of the angle between the superior mesenteric artery and the aorta.Case report. A 15-year-old girl presented to the emergency roomwith a five-month history of abdominal pain located in the epigastrium, accompanied by vomiting, proteinuria, and weight loss. Thepatient had previously consulted in other centers, and urgent surgical conditions were ruled out. The study was completed with anabdominal computed tomography scan, which led to the diagnosisof superior mesenteric artery or Wilkie syndrome, and nutcrackersyndrome. The patient was admitted to the hospital and treatedconservatively with a hypercaloric diet with improvement in intestinal transit and proteinuria. She was discharged to continue thefollow-up with a multidisciplinary team. Comment. Problems secondary to aortomesenteric compression cangive symptoms like superior mesenteric artery or Wilkie syndromeand nutcracker syndrome. The diagnosis of these conditions canbe complex due to their low incidence and the non-specific symptomatology that characterizes them. Conservative treatment represents the first line of treatment, but in some cases it may not beenough. For these reasons, multidisciplinary management of thesepatients is necessary. (AU)

Eculizumab in a child with atypical haemolytic uraemic syndrome and haemophagocytic lymphohistiocytosis triggered by cytomegalovirus infection.

We present the case of a 21-month-old girl with two rare and life-threatening conditions, atypical haemolytic uraemic syndrome (aHUS) and haemophagocytic lymphohistiocytosis (HLH), triggered by a cytomegalovirus (CMV) infection. Soon after admission, the girl became anuric and required continuous venovenous haemodiafiltration.Initial treatments included methylprednisolone, fibrinogen and plasma infusion (for HLH), plasmapheresis (for thrombotic microangiopathy), immunoglobulins (for inflammation), ganciclovir (for CMV infection) and the antibiotic cefotaxime. On day 5, eculizumab (600 mg) was given for aHUS, with rapid improvement in haematological and nephrological parameters. Despite a subsequent isolated episode of right heart thrombosis that resolved with heparin treatment, the patient showed a favourable response to eculizumab (300 mg/15 days), with improved renal function, normal haematological values, and no treatment complications. In conclusion, eculizumab effectively treated aHUS in this case despite a comorbid immunological disease.

[Conservative versus interventional treatment of primary vesicoureteral reflux in children]. / Tratamiento médico-conservador versus intervencionista del reflujo vesicoureteral primario en el niño.

OBJECTIVES: To assess the efficacy of medical and surgical treatment of vesicoureteral reflux (VUR) in children using recurrence of urinary tract infections, renal scarring and renal function as end-points. METHODS/RESULTS: We performed a MEDLINE search for articles. We selected only randomized clinical trials and meta-analysis that analyzed medical versus surgical treatment of VUR in children. A total of 820 patients were included in all studies. We found no statistatically significant differences between surgically and medically treated patients in terms of scarring, kidney function or recurrence of urinary tract infections. There was only a significant decrease in the frequency of febrile UTI in patients who were surgically corrected, compared with those receiving antibiotics alone (RR 0.43). CONCLUSIONS: We found no clinically significant differences between surgical and medical treatment for VUR in terms of kidney function or renal scarring. We suggest that a child with UTI and VUR should be treated conservatively at first.

[Current status of antibiotic prophylaxis in primary vesicoureteral reflux in children]. / Situación actual de la profilaxis antibiótica en el reflujo vesicoureteral primario en el niño.

OBJECTIVES: To assess the efficacy of antibiotic prophylaxis for prevention of urinary infections and renal parenchymal damage in children with primary vesicoureteral reflux (VUR). METHODS/RESULTS: A search based on MEDLINE and The Cochrane Library was performed selecting those clinical trials and meta-analysis which compared antibiotic prophylaxis (either continuous or intermittent) and placebo or no treatment at all in children with primary VUR. Three systematic reviews were chosen for assessing the efficacy of prophylaxis of urinary infections including trials with a predominant paediatric population without known VUR. Results showed that the use of antibiotics decreased the risk of urinary infection. The quality of the trials was, however, insufficient and therefore of questionable results. We also selected two randomized controlled trials in children with reflux: one had limited information as the degree of reflux was not stated; the second assessed the results in a population of 113 children with VUR grade I to III (55 receiving prophylaxis and 58 not) following acute pyelonephritis. There were no differences with regard to the risk of urinary infection or the risk of renal parenchymal damage. CONCLUSIONS: There is not enough evidence supporting generalized use of antibiotics to prevent urinary infections. No benefit in prophylaxis has been proven for VUR grades I to III. There is no data for high grade VUR. It will be necessary to perform more trials in order to establish more accurate recommendations on prevention of urinary infections in the presence of VUR.

Tratamiento médico-conservador versus intervencionista del reflujo vesicoureteral primario en el niño / Conservative versus interventional treatment of primary vesicoureteral reflux in children

Objetivo: Valorar la estrategia de tratamiento del reflujo vesico-ureteral primario (RVU) en el niño, teniendo en cuenta su repercusión sobre la aparición de infecciones urinarias, daño parenquimatoso renal y alteración de la función renal. Métodos/Resultado: Se realiza una búsqueda en MEDLINE de la literatura, seleccionando ensayos clínicos y metaanálisis que comparen el tratamiento intervencionista (quirúrgico o endoscópico) y conservador (profilaxis antibiótica o medidas higiénicas) del RVU en el niño. Los ECA seleccionados agrupan un total de 820 niños afectos de RVU y aleatorizados a recibir tratamiento médico o quirúrgico. Los resultados muestran que no existen diferencias en el número global de infecciones urinarias, aunque los niños operados padecen menos pielonefritis (RR 0.43). Ambos grupos presentaron igual número de nuevas cicatrices renales y de progresión de las ya existentes. No se encontraron diferencias en la afectación de la función renal, valorada como aparición de hipertensión arterial o disminución del filtrado glomerular. Conclusiones. El tratamiento quirúrgico del RVU no aporta ventajas sobre el conservador en cuanto a preservación del funcionalismo renal o aparición de nuevas cicatrices. El tratamiento conservador sería la elección inicial prioritaria (AU)

Objectives: To assess the efficacy of medical and surgical treatment of vesicoureteral reflux (VUR) in children using recurrence of urinary tract infections, renal scarring and renal function as end-points. Methods/Results: We performed a MEDLINE search for articles. We selected only randomized clinical trials and meta-analysis that analyzed medical versus surgical treatment of VUR in children. A total of 820 patients were included in all studies. We found no statistatically significant differences between surgically and medically treated patients in terms of scarring, kidney function or recurrence of urinary tract infections. There was only a significant decrease in the frequency of febrile UTI in patients who were surgically corrected, compared with those receiving antibiotics alone (RR 0.43). Conclusions: We found no clinically significant differences between surgical and medical treatment for VUR in terms of kidney function or renal scarring. We suggest that a child with UTI and VUR should be treated conservatively at first (AU)

Situación actual de la profilaxis antibiótica en el reflujo vesicoureteral primario en el niño / Current status of antibiotic prophylaxix in primary vesicoureteral reflux in children

Objetivo: Valorar la eficacia de la profilaxis antibiótica en la prevención de las infecciones urinarias y del daño parenquimatoso renal en niños con Reflujo Vesicoureteral primario (RVU). Métodos/Resultado. Se realiza una búsqueda de la literatura en MEDLINE y The Cochrane Library seleccionando ensayos clínicos y metaanálisis que comparen la profilaxis antibiótica (continua ó discontinua) y placebo ó ningún tratamiento en niños con RVU primario. Seleccionamos 3 revisiones sistemáticas que evalúan la eficacia de la profilaxis para prevenir las infecciones de orina y que incluyen estudios en los cuales predomina una población de niños sin RVU conocido. Los resultados mostraron que los antibióticos redujeron el riesgo de infección urinaria. La calidad de los estudios fue deficiente y por lo tanto los resultados son cuestionables. Seleccionamos además dos ensayos clínicos en niños con reflujo, uno con información limitada pues se desconoce el grado de RVU y otro que evalúa los resultados en una población de 113 niños con RVU grado I a III (55 con profilaxis y 58 sin profilaxis) después de una pielonefritis aguda. No existen diferencias en el riesgo de infección urinaria ni tampoco en el riesgo de lesión en el parénquima renal. Conclusiones. Las pruebas que apoyan el uso generalizado de antibióticos para prevenir las infecciones urinarias son débiles. No se ha demostrado un beneficio de la profilaxis en los RVU grado I a III. No se dispone de información en RVU de alto grado. Se requieren estudios adicionales para poder establecer unas recomendaciones más precisas con el objetivo de prevenir las infecciones de orina en niños con RVU (AU)

Objectives: To assess the efficacy of antibiotic prophylaxis for prevention of urinary infections and renal parenchymal damage in children with primary vesicoureteral reflux (VUR). Methods/Results. A search based on MEDLINE and The Cochrane Library was performed selecting those clinical trials and meta-analysis which compared antibiotic prophylaxis (either continuous or intermittent) and placebo or no treatment at all in children with primary VUR. Three systematic reviews were chosen for assessing the efficacy of prophylaxis of urinary infections including trials with a predominant paediatric population without known VUR. Results showed that the use of antibiotics decreased the risk of urinary infection. The quality of the trials was, however, insufficient and therefore of questionable results. We also selected two randomized controlled trials in children with reflux: one had limited information as the degree of reflux was not stated; the second assessed the results in a population of 113 children with VUR grade I to III (55 receiving prophylaxis and 58 not) following acute pyelonephritis. There were no differences with regard to the risk of urinary infection or the risk of renal parenchymal damage. Conclusions. There is not enough evidence supporting generalized use of antibiotics to prevent urinary infections. No benefit in prophylaxis has been proven for VUR grades I to III. There is no data for high grade VUR. It will be necessary to perform more trials in order to establish more accurate recommendations on prevention of urinary infections in the presence of VUR (AU)