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.

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.

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.

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)