Non-corticosteroid immunosuppressive medications for steroid-sensitive nephrotic syndrome in children.
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ABSTRACT:
SUBMITTER: Larkins NG
PROVIDER: S-EPMC7160055 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The use of corticosteroids in the treatment of steroid-sensitive nephrotic (SSNS) syndrome in children has evolved surprisingly slowly since the ISKDC consensus over 50 years ago. From a move towards longer courses of corticosteroid to treat the first episode in the 1990s and 2000s, more recent large, well-designed randomized controlled trials (RCTs) have unequivocally shown no benefit from an extended course, although doubt remains whether this applies across all age groups. With regard to prevention of relapses, daily ultra-low-dose prednisolone has recently been shown to be more effective than low-dose alternate-day prednisolone. Daily low-dose prednisolone for a week at the time of acute viral infection seems to be effective in the prevention of relapses but the results of a larger RCT are awaited. Recently, corticosteroid dosing to treat relapses has been questioned, with data suggesting lower doses may be as effective. The need for large RCTs to address the question of whether corticosteroid doses can be reduced was the conclusion of the authors of the recent corticosteroid therapy for nephrotic syndrome in children Cochrane update. This review summarizes development in thinking on corticosteroid use in SSNS and makes suggestions for areas that merit further scrutiny.
| S-EPMC7896825 | biostudies-literature
Project description:BackgroundConventional meta-analyses and randomized controlled trials have shown inconsistent results regarding the efficacy of immunosuppressants for pediatric steroid-resistant nephrotic syndrome (SRNS).ObjectiveTo conduct a network meta-analysis aimed at evaluating the efficacy and safety of available immunosuppressive agents in pediatric patients with SRNS.Study methodsMEDLINE, the Cochrane Central Register of Controlled Trials, and EMBASE were searched on January 2017. Data from randomized controlled trials (RCTs) were included. The main outcomes analyzed were efficacy [number/portion with complete remission (CR), number/portion with partial remission (PR), and total number/portion in remission (TR)] and safety [adverse secondary event (ASE) rates].ResultsA meta-analysis of 18 RCTs showed that tacrolimus was more efficacious for achieving CR than intravenous (i.v.) cyclophosphamide, mycophenolate mofetil (MMF), oral cyclophosphamide, leflunomide, chlorambucil, azathioprine, and plaebo/nontreatment (P/NT), and more efficacious than i.v. cyclophosphamide, oral cyclophosphamide, and P/NT in terms of TR outcomes. Cyclosporin was associated with a greater CR rate than i.v. cyclophosphamide, MMF, oral cyclophosphamide, chlorambucil, azathioprine, or P/NT, and associated with a greater TR rate than i.v. cyclophosphamide, oral cyclophosphamide, or P/NT. MMF was found to be more efficacious than i.v. cyclophosphamide and oral cyclophosphamide in terms of TR.ConclusionsTacrolimus and cyclosporine may be preferred initial treatments for children with SRNS. MMF may be another option for this patient population. Further studies of the efficacy and safety of these three drugs in children with SRNS should be pursued.
| S-EPMC5641191 | biostudies-literature
Project description:GWAS on a cohort of European ancestry comprising 422 SSNS cases and 5,642 matched controls.
| EGAS00001003607 | EGA
Project description:AimThe aim was to investigate the population pharmacokinetics of levamisole in children with steroid-sensitive nephrotic syndrome.MethodsNon-linear mixed effects modelling was performed on samples collected during a randomized controlled trial. Samples were collected from children who were receiving 2.5 mg kg(-1) levamisole (or placebo) orally once every other day. One hundred and thirty-six plasma samples were collected from 38 children from India and Europe and included in the analysis. A one compartment model described the data well.ResultsThe apparent clearance rate (CL/F) and distribution volume (V/F) were 44 l h(-1) 70 kg(-1) and 236 l 70 kg(-1) , respectively; estimated interindividual variability was 32-42%. In addition to allometric scaling of CL/F and V/F to body weight, we identified a significant proportional effect of age on CL/F (-10.1% per year). The pharmacokinetics parameters were not affected by gender, tablet strength or study centre. The median (interquartile range) maximum plasma concentration of levamisole was 438.3 (316.5-621.8) ng ml(-1) , and the median area under the concentration-time curve was 2847 (2267-3761) ng ml(-1) h. Median tmax and t½ values were 1.65 (1.32-2.0) h and 2.60 (2.06-3.65) h, respectively.ConclusionsHere, we present the first pharmacokinetic data regarding levamisole in children with steroid-sensitive nephrotic syndrome. The pharmacokinetic profile of levamisole in children was similar to findings reported in adults, although the elimination rate was slightly higher in children.
| S-EPMC4541972 | biostudies-literature
Project description:Glucocorticoid resistance complicates the treatment of ~20% of children with nephrotic syndrome, yet the molecular basis for resistance remains unclear. We generated the transcriptome profile by RNA sequencing of peripheral blood leukocytes from children obtained both at initial nephrotic syndrome presentation and after ~7 weeks of glucocorticoid therapy to identify genes or a gene panel able to differentiate steroid sensitive from steroid resistant nephrotic syndrome. RNA -seq analysis was followed by in-silico algorithm-based approaches and subsequent biochemical analyses on relevant candidate gene with important roles in podocyte and glomerular pathophysiology, using both patient samples and experimental models of nephrotic syndrome and podocyte injury.
2021-02-16 | GSE145969 | GEO
Project description:BackgroundSteroid-sensitive nephrotic syndrome (SSNS) is associated with a relapsing-remitting course that can be stressful for parents. As little is known of parental distress at the first onset of SSNS, this study aims to describe parental distress and everyday problems in mothers and fathers of a child with newly diagnosed SSNS participating in a randomized controlled trial of levamisole added to corticosteroids.MethodsTo assess distress, the Distress Thermometer for Parents (DT-P) was used, which includes questions on distress (thermometer score 0-10, ≥ 4 "clinical distress") and presence of everyday problems in six domains: practical, social, emotional, physical, cognitive, and parenting. The DT-P was completed 4 weeks after the onset of SSNS. Total sum and individual items of everyday problems were compared with reference data from mothers and fathers of the Dutch general population.ResultsThere was no difference in clinically elevated parental distress between SSNS mothers (n = 37) and fathers (n = 25) and reference parents. Compared to reference fathers, fathers of a child with SSNS scored significantly higher on emotional problems (P = 0.030), while mothers experienced more parenting problems (P = 0.002). Regression analyses showed that lower parental age and having a girl with SSNS were significantly associated with more practical problems and higher distress thermometer scores, respectively.ConclusionsFour weeks after onset, SSNS mothers and fathers experience equal distress as reference parents. However, both parents endorsed significantly more everyday problems. Therefore, monitoring parental distress, even in the first weeks of the disease, could contribute to timely interventions and prevent worsening of problems.Clinical trial registryDutch Trial Register ( https://onderzoekmetmensen.nl/en/trial/27331 ). A higher resolution version of the Graphical abstract is available as Supplementary information.
| S-EPMC10584702 | biostudies-literature
Project description:The pathogenesis of childhood-onset nephrotic syndrome (NS), disparity in incidence of NS among races, and variable responses to therapies in children with NS have defied explanation to date. In the last 20 years over 50 genetic causes of steroid-resistant nephrotic syndrome (SRNS) have been identified, and at least two disease loci for two pathologic variants of SRNS (focal segmental glomerulosclerosis and membranous nephropathy) have been defined. However, the genetic causes and risk loci for steroid-sensitive nephrotic syndrome (SSNS) remain elusive, partly because SSNS is relatively rare and also because cases of SSNS vary widely in phenotypic expression over time. A recent study of a well-defined modest cohort of children with SSNS identified variants in HLA-DQA1 as a risk factor for SSNS. Here we review what is currently known about the genetics of SSNS and also discuss how recent careful phenotypic and genomic studies reinforce the role of adaptive immunity in the molecular mechanisms of SSNS.
| S-EPMC5276801 | biostudies-literature
Project description:BackgroundNephrotic syndrome is the most common kidney disease in children worldwide. Our aim was to critically appraise the quality of recent Clinical Practice Guidelines (CPGs) for idiopathic steroid-sensitive nephrotic syndrome (SSNS) in children in addition to summarize and compare their recommendations.MethodsSystematic review of CPGs. We identified clinical questions and eligibility criteria and searched and screened for CPGs using bibliographic and CPG databases. Each included CPG was assessed by four independent appraisers using the Appraisal of Guidelines for REsearch & Evaluation II (AGREE-II) instrument. We summarized the recommendations in a comparison practical table.ResultsOur search retrieved 282 citations, of which three CPGs were eligible and appraised: Kidney Disease: Improving Global Outcomes (KDIGO) 2012, Japan Society for Pediatric Nephrology (JSPN) 2014, and American Academy of Pediatrics (AAP) 2009. Among these, the overall assessment of two evidence-based CPGs scored > 70% (KDIGO and JSPN), which was consistent with their higher scores in the six domains of the AGREE II Instrument. In domain 3 (rigor of development), KDIGO, JSPN, and AAP scored 84%, 74%, and 41%, respectively. In domain 5 (applicability), they scored 22%, 16%, and 19%, respectively, and in domain 6 (editorial independence), they scored 94%, 65%, and 88%, respectively.ConclusionsThe methodological quality of the KDIGO CPG was superior, followed by JSPN and AAP CPGs with the relevant recommendations for use in practice.Systematic review registrationThe protocol was registered in the Center for Open Science (OSF) DOI: 10.17605/OSF.IO/6QTMD and in the International prospective register of systematic reviews PROSPERO 2020 CRD42020197511 .
| S-EPMC8112064 | biostudies-literature
Project description:This study assessed HRQoL and emotional and behavioral difficulties (EBD) and associated variables in children with first onset SSNS. While relapsing steroid-sensitive nephrotic syndrome (SSNS) in children is associated with lower health-related quality of life (HRQoL), little is known about first onset. Four weeks after onset, children (2-16 years) and/or their parents who participated in a randomized placebo-controlled trial, completed the Pediatric Quality of Life Inventory 4.0 (PedsQL) and Strengths and Difficulties Questionnaire (SDQ) to measure HRQoL and EBD, respectively. Total and subscale scores and the proportion of children with impaired HRQoL (> 1 SD below the mean of the reference group) or SDQ clinical scores (< 10th and > 90th percentile) were compared to the Dutch general population (reference group). Regression analyses were used to identify associated variables. Compared to the reference group, children 8-18 years reported significantly lower total HRQoL, and physical and emotional functioning. A large proportion (> 45%) of these children had impaired HRQoL. There were no differences in HRQoL between children 2-7 years and the reference group, except for higher scores on social functioning (5-7 years). Similar proportions of SSNS and reference children scored within the clinical range of SDQ subscales. Age, sex, and steroid side-effects were negatively associated with HRQol and/or EBD. Conclusion: This study showed that HRQoL and EBD are affected in children of different ages with first onset SSNS. This calls for more awareness from healthcare providers and routinely monitoring of HRQoL and EBD in daily clinical care to prevent worsening of symptoms. Clinical trial registry: Netherlands Trial Register ( https://trialsearch.who.int/ ; NTR7013), date of registration: 02 June 2018. What is Known: • Health-related quality of life (HRQoL) is lower and emotional and behavioral difficulties (EBD) is more affected in children with frequently-relapsing and steroid-dependent nephrotic syndrome. What is New: • HRQoL and EBD are affected in children with first onset steroid-sensitive nephrotic syndrome compared to a reference group of the Dutch general population. • To what extent HRQoL and EBD are affected depends on the age of the patient.
| S-EPMC10587200 | biostudies-literature
Project description:Advances in genome science in the last 20 years have led to the discovery of over 50 single gene causes and genetic risk loci for steroid resistant nephrotic syndrome (SRNS). Despite these advances, the genetic architecture of childhood steroid sensitive nephrotic syndrome (SSNS) remains poorly understood due in large part to the varying clinical course of SSNS over time. Recent exome and genome wide association studies from well-defined cohorts of children with SSNS identified variants in multiple MHC class II molecules such as HLA-DQA1 and HLA-DQB1 as risk factors for SSNS, thus stressing the central role of adaptive immunity in the pathogenesis of SSNS. However, evidence suggests that unknown second hit risk loci outside of the MHC locus and environmental factors also make significant contributions to disease. In this review, we examine what is currently known about the genetics of SSNS, the implications of recent findings on our understanding of pathogenesis of SSNS, and how we can utilize these results and findings from future studies to improve the management of children with nephrotic syndrome.
| S-EPMC6361778 | biostudies-literature