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Background Magnesium (Mg2+) is an essential ion for cell growth, neuroplasticity and muscle contraction. Blood Mg2+ levels <0.7 mmol/L may cause a heterogeneous clinical phenotype, including muscle cramps and epilepsy and disturbances in K+ and Ca2+ homeostasis. Over the last decade, the genetic origin of several familial forms of hypomagnesaemia has been found. In 2000, mutations in FXYD2, encoding the α-subunit of the Na+-K+-ATPase, were identified to cause isolated dominant hypomagnesaemia (IDH) in a large Dutch family suffering from hypomagnesaemia, hypocalciuria and chondrocalcinosis. However, no additional patients have been identified since then. Methods Here, two families with hypomagnesaemia and hypocalciuria were screened for mutations in the FXYD2 gene. Moreover, the patients were clinically and genetically characterized. Results We report a p.Gly41Arg FXYD2 mutation in two families with hypomagnesaemia and hypocalciuria. Interestingly, this is the same mutation as was described in the original study. As in the initial family, several patients suffered from muscle cramps, chondrocalcinosis and epilepsy. Haplotype analysis revealed an overlapping haplotype in all families, suggesting a founder effect. Conclusions The recurrent p.Gly41Arg FXYD2 mutation in two new families with IDH confirms that FXYD2 mutation causes hypomagnesaemia. Until now, no other FXYD2 mutations have been reported which could indicate that other FXYD2 mutations will not cause hypomagnesaemia or are embryonically lethal. [ABSTRACT FROM AUTHOR]

We performed a multi-centre randomized controlled trial to compare the efficacy of mycophenolate mofetil (MMF) to that of cyclosporine A (CsA) in treating children with frequently relapsing nephrotic syndrome and biopsy-proven minimal change disease. Of the 31 randomized initially selected patients, seven were excluded. The remaining 24 children received either MMF 1200 mg/m2 per day ( n = 12) or CsA 4–5 mg/kg per day ( n = 12) during a 12-month period. Of the 12 patients in the MMF group, two discontinued the study medication. Evaluation of the changes from the baseline glomerular filtration rate showed an overall significant difference in favour of MMF over the treatment period ( p = 0.03). Seven of the 12 patients in the MMF group and 11 of the 12 patients in the CsA group remained in complete remission during the entire study period. Relapse rate in the MMF group was 0.83/year compared to 0.08/year in the CsA group ( p = 0.08). None of the patients reported diarrhea. Pharmacokinetic profiles of mycophenolic acid were performed in seven patients. The patient with the lowest area under the curve had three relapses within 6 months. In children with frequently relapsing minimal change nephrotic syndrome, MMF has a favourable side effect profile compared to CsA; however, there is a tendency towards a higher relapse risk in patients treated with MMF. [ABSTRACT FROM AUTHOR]

Steroids are the cornerstone of the treatment of childhood nephrotic syndrome. The optimal duration for the first episode remains a matter of debate. The aim of this study is to determine whether the 8 weeks International Study of Kidney Disease in Children (ISKDC) regimen is equally effective as the 12 weeks steroid regimen from the German society of pediatric nephrology (Arbeitsgemeinschaft für Pädiatrische Nephrologie [APN]). An individual patient data (IPD) meta-analysis of randomized controlled trials reporting on prednisolone treatment for a first episode of childhood nephrotic syndrome was conducted. European trials aimed at investigating the ISKDC and/or APN steroid regimen were selected. The lead investigators of the selected trials were requested to provide the IPD of the specific treatment groups. Four trials included European cohorts using dosing schedules according to the regimens studied. IPD of two trials were available. A significant difference was found in time to first relapse after cessation of steroid treatment between the 8 and 12 weeks treatment group with a median time to relapse of 29 and 63 days, respectively. Moreover, relapse rate ratios during total follow-up were 51% higher for the 8 weeks regimen. Finally, younger children have a significantly lower time to first relapse and frequently relapsing nephrotic syndrome. Conclusions: The results of this IPD meta-analysis suggest that the 8 weeks steroid regimen for a first episode of steroid-sensitive nephrotic syndrome may not be equally effective as the 12 weeks steroid regimen. Moreover, this study highlights the importance of using uniform definitions to enable accurate comparison and interpretation of trial results. Trial registration: Registration number: CRD42020199244, date of registration 16-08-2020 What is Known: • Steroids are the cornerstone of the treatment of childhood nephrotic syndrome, however the optimal duration for the first episode remains a matter of debate. • Currently, the 8 weeks ISKDC protocol and 12 weeks APN protocol are among the most frequently used protocols in Europe. What is New: • The 8 weeks steroid regimen for a first episode of steroid-sensitive nephrotic syndrome may not be equally effective as the 12 weeks steroid regimen for the treatment of a first episode of nephrotic syndrome. • Younger children have a significantly shorter time to first relapse and time to frequent relapsing nephrotic syndrome. [ABSTRACT FROM AUTHOR]

Background: C3 glomerulopathy (C3G) is a rare kidney disorder characterized by predominant glomerular depositions of complement C3. C3G can be subdivided into dense deposit disease (DDD) and C3 glomerulonephritis (C3GN). This study describes the long-term follow-up with extensive complement analysis of 29 Dutch children with C3G. Methods: Twenty-nine C3G patients (19 DDD, 10 C3GN) diagnosed between 1992 and 2014 were included. Clinical and laboratory findings were collected at presentation and during follow-up. Specialized assays were used to detect rare variants in complement genes and measure complement-directed autoantibodies and biomarkers in blood. Results: DDD patients presented with lower estimated glomerular filtration rate (eGFR). C3 nephritic factors (C3NeFs) were detected in 20 patients and remained detectable over time despite immunosuppressive treatment. At presentation, low serum C3 levels were detected in 84% of all patients. During follow-up, in about 50% of patients, all of them C3NeF-positive, C3 levels remained low. Linear mixed model analysis showed that C3GN patients had higher soluble C5b-9 (sC5b-9) and lower properdin levels compared to DDD patients. With a median follow-up of 52 months, an overall benign outcome was observed with only six patients with eGFR below 90 ml/min/1.73 m2 at last follow-up. Conclusions: We extensively described clinical and laboratory findings including complement features of an exclusively pediatric C3G cohort. Outcome was relatively benign, persistent low C3 correlated with C3NeF presence, and C3GN was associated with higher sC5b-9 and lower properdin levels. Prospective studies are needed to further elucidate the pathogenic mechanisms underlying C3G and guide personalized medicine with complement therapeutics. [ABSTRACT FROM AUTHOR]

Nephrotic syndrome in childhood is a common entity in the field of pediatric nephrology. The optimal treatment of children with nephrotic syndrome is often debated. Previously conducted studies have shown significant variability in nephrotic syndrome management, especially in the choice of steroid-sparing drugs. In the Netherlands, a practice guideline on the management of childhood nephrotic syndrome has been available since 2010. The aim of this study was to identify practice variations and opportunities to improve clinical practice of childhood nephrotic syndrome in the Netherlands. A digital structured survey among Dutch pediatricians and pediatric nephrologists was performed, including questions regarding the initial treatment, relapse treatment, kidney biopsy, additional immunosuppressive treatment, and supportive care. Among the 51 responses, uniformity was seen in the management of a first presentation and first relapse. Wide variation was found in the tapering of steroids after alternate day dosing. Most pediatricians and pediatric nephrologists (83%) would perform a kidney biopsy in case of steroid-resistant nephrotic syndrome, whereas for frequent relapsing and steroid-dependent nephrotic syndrome this was 22% and 41%, respectively. Variation was reported in the steroid-sparing treatment. Finally, significant differences were present in the supportive treatment of nephrotic syndrome. Conclusion: Substantial variation was present in the management of nephrotic syndrome in the Netherlands. Differences were identified in steroid tapering, use of steroid coverage during stress, choice of steroid-sparing agents, and biopsy practice. To promote guideline adherence and reduce practice variation, factors driving this variation should be assessed and resolved. What is Known: • National and international guidelines are available to guide the management of childhood nephrotic syndrome. • Several aspects of the management of childhood nephrotic syndrome, including the choice of steroid-sparing drugs and biopsy practice, are controversial and often debated among physicians. What is New: • Significant practice variation is present in the management of childhood nephrotic syndrome in the Netherlands, especially in the treatment of FRNS, SDNS, and SRNS. • The recommendation on the steroid treatment of a first episode of nephrotic syndrome in the KDIGO guideline leaves room for interpretation and is likely the cause of substantial differences in steroid-tapering practices among Dutch pediatricians and pediatric nephrologists. [ABSTRACT FROM AUTHOR]

Background Children with renal diseases who are treated with glucocorticoids are at increased risk of developing osteoporosis and fractures. However, there is no common strategy for prevention of corticosteroid-induced osteoporosis. The present systematic review was performed to determine whether prevention of bone loss by calcium (Ca), vitamin D (vit D) and/or bisphosphonates is justified, safe and efficacious in children treated with steroids for various renal diseases. Methods Data sources: Medline, Embase, Central were searched from 1961 up to 2012. Randomized controlled trials (RCTs) and observational studies concerning children ≤18 years with renal diseases requiring steroids were included. Results The search strategy retrieved 2482 studies. Four RCTs including 166 patients and one observational study including 100 children met our eligibility criteria. One RCT and the observational study concerned treatment with Ca/vit D, one RCT with bisphosphonates and two RCTs with a combination of both therapies. All described a significant improvement in bone mineral density (BMD) in the treatment group compared with the control group. Conclusions Ca combined with vit D is recommended to prevent bone disease in children with renal diseases treated with steroids. Because of side effects, bisphosphonates should be reserved for the treatment of severe osteoporosis when Ca and/or vit D supplementation has failed. [ABSTRACT FROM AUTHOR]