Long term tapering versus standard prednisolone treatment for first episode of childhood nephrotic syndrome: phase III randomised controlled trial and economic evaluation

Abstract Objective To determine whether extending initial prednisolone treatment from eight to 16 weeks in children with idiopathic steroid sensitive nephrotic syndrome improves the pattern of disease relapse. Design Double blind, parallel group, phase III randomised placebo controlled trial, including a cost effectiveness analysis. Setting 125 UK National Health Service district general hospitals and tertiary paediatric nephrology centres. Participants 237 children aged 1-14 years with a first episode of steroid sensitive nephrotic syndrome. Interventions Children were randomised to receive an extended 16 week course of prednisolone (total dose 3150 mg/m 2 ) or a standard eight week course of prednisolone (total dose 2240 mg/m 2 ). The drug was supplied as 5 mg tablets alongside matching placebo so that participants in both groups received the same number of tablets at any time point in the study. A minimisation algorithm ensured balanced treatment allocation by ethnicity (South Asian, white, or other) and age (5 years or less, 6 years or more). Main outcome measures The primary outcome measure was time to first relapse over a minimum follow-up of 24 months. Secondary outcome measures were relapse rate, incidence of frequently relapsing nephrotic syndrome and steroid dependent nephrotic syndrome, use of alternative immunosuppressive treatment, rates of adverse events, behavioural change using the Achenbach child behaviour checklist, quality adjusted life years, and cost effectiveness from a healthcare perspective. Analysis was by intention to treat. Results No significant difference was found in time to first relapse (hazard ratio 0.87, 95% confidence interval 0.65 to 1.17, log rank P=0.28) or in the incidence of frequently relapsing nephrotic syndrome (extended course 60/114 (53%) v standard course 55/109 (50%), P=0.75), steroid dependent nephrotic syndrome (48/114 (42%) v 48/109 (44%), P=0.77), or requirement for alternative immunosuppressive treatment (62/114 (54%) v 61/109 (56%), P=0.81). Total prednisolone dose after completion of the trial drug was 6674 mg for the extended course versus 5475 mg for the standard course (P=0.07). There were no statistically significant differences in serious adverse event rates (extended course 19/114 (17%) v standard course 27/109 (25%), P=0.13) or adverse event rates, with the exception of behaviour, which was poorer in the standard course group. Scores on the Achenbach child behaviour checklist did not, however, differ. Extended course treatment was associated with a mean increase in generic quality of life (0.0162 additional quality adjusted life years, 95% confidence interval −0.005 to 0.037) and cost savings (difference −£1673 ($2160; €1930), 95% confidence interval −£3455 to £109). Conclusions Clinical outcomes did not improve when the initial course of prednisolone treatment was extended from eight to 16 weeks in UK children with steroid sensitive nephrotic syndrome. However, evidence was found of a short term health economic benefit through reduced resource use and increased quality of life. Trial registration ISRCTN16645249; EudraCT 2010-022489-29.

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Steroid-sensitive nephrotic syndrome: an evidence-based update of immunosuppressive treatment in children

Archives of Disease in Childhood ◽

10.1136/archdischild-2015-308924 ◽

2015 ◽

Vol 101 (4) ◽

pp. 404-408 ◽

Cited By ~ 18

Author(s):

Nicholas Larkins ◽

Siah Kim ◽

Jonathan Craig ◽

Elisabeth Hodson

Keyword(s):

Nephrotic Syndrome ◽

Immunosuppressive Agents ◽

Immunosuppressive Treatment ◽

Current Evidence ◽

Upper Respiratory Tract ◽

Glomerular Diseases ◽

Steroid Dependent ◽

Steroid Sensitive Nephrotic Syndrome ◽

Steroid Sensitive ◽

Risk Of Relapse

Nephrotic syndrome is one of the most common paediatric glomerular diseases, with an incidence of around two per 100 000 children per year. Corticosteroids are the mainstay of treatment, with 85%–90% of children going into remission with an 8-week course of treatment. Unfortunately, nephrotic syndrome follows a relapsing and remitting course in the majority, with 90% relapsing at least once. About half will progress to frequently relapsing nephrotic syndrome (FRNS) or steroid-dependent nephrotic syndrome (SDNS). Different initial steroid regimens have been evaluated since the first trials in Europe and America in the 1960s. Most trials have been designed to evaluate the optimal duration of the initial therapy, rather than different cumulative doses of corticosteroid, or the management of relapses. Until recently, these data suggested that an initial treatment duration of up to 6 months reduced the number of children developing a relapse, without evidence of increased steroid toxicity. Recently, three large, well-designed randomised control trials were published, which demonstrated no significant reduction in risk of relapse or of developing FRNS by extended treatment compared with 2 or 3 months. While there are few trial data to guide the treatment of individual relapses in steroid-sensitive nephrotic syndrome (SSNS), there is some evidence that a short course of corticosteroid therapy during upper respiratory tract infection may prevent relapse. In patients with FRNS or SDNS who continue to relapse despite low-dose alternate-day steroids a number of non-corticosteroid, steroid-sparing immunosuppressive agents (cyclophosphamide, ciclosporin, tacrolimus, mycophenolate mofetil, levamisole, rituximab) have been shown to reduce the risk of relapse and of FRNS. However, there are limited head-to-head data to inform which agent should be preferred. In this article, we review recent data from randomised trials to update paediatricians on the current evidence supporting interventions in SSNS.

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Extending initial prednisolone treatment in a randomized control trial from 3 to 6 months did not significantly influence the course of illness in children with steroid-sensitive nephrotic syndrome

Kidney International ◽

10.1038/ki.2014.240 ◽

2015 ◽

Vol 87 (1) ◽

pp. 217-224 ◽

Cited By ~ 49

Author(s):

Aditi Sinha ◽

Abhijeet Saha ◽

Manish Kumar ◽

Sonia Sharma ◽

Kamran Afzal ◽

...

Keyword(s):

Nephrotic Syndrome ◽

Randomized Control Trial ◽

Course Of Illness ◽

Prednisolone Treatment ◽

Steroid Sensitive Nephrotic Syndrome ◽

Steroid Sensitive ◽

Randomized Control

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Levamisole in Children with Idiopathic Nephrotic Syndrome: Clinical Efficacy and Pathophysiological Aspects

Journal of Clinical Medicine ◽

10.3390/jcm8060860 ◽

2019 ◽

Vol 8 (6) ◽

pp. 860 ◽

Cited By ~ 7

Author(s):

Anne K. Mühlig ◽

Jun Young Lee ◽

Markus J. Kemper ◽

Andreas Kronbichler ◽

Jae Won Yang ◽

...

Keyword(s):

Nephrotic Syndrome ◽

Idiopathic Nephrotic Syndrome ◽

Low Frequency ◽

Glomerular Diseases ◽

Steroid Dependency ◽

Randomized Controlled ◽

Steroid Dependent ◽

Frequent Relapses ◽

Steroid Sensitive Nephrotic Syndrome ◽

Steroid Sensitive

Steroid sensitive nephrotic syndrome is one of the most common pediatric glomerular diseases. Unfortunately, it follows a relapsing and remitting course in the majority of cases, with 50% of all cases relapsing once or even more often. Most children with idiopathic nephrotic syndrome respond initially to steroid therapy, nevertheless repeated courses for patients with relapses induce significant steroid toxicity. Patients with frequent relapses or steroid dependency thus require alternative treatment, such as cyclophosphamide, cyclosporine, tacrolimus, mycophenolate mofetil, levamisole, or rituximab. To reduce the relapse rate, several drugs have been used. Among these, levamisole has been considered the least toxic and least expensive therapy. Several randomized controlled trials (RCT) showed that levamisole is effective in reducing the relapse risk in steroid sensitive forms of nephrotic syndrome with a low frequency of side effects. Levamisole is a synthetic imidazothiazole derivative with immune-modulatory properties. In this article, we review recent data from randomized trials and observational studies to assess the efficacy of levamisole in frequently relapsing nephrotic syndrome and steroid-dependent nephrotic syndrome.

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Cyclophosphamide in frequent-relapsing or steroid-dependent nephrotic syndrome: Review of 38 patients

Paediatrica Indonesiana ◽

10.14238/pi45.1.2005.18-23 ◽

2016 ◽

Vol 45 (1) ◽

pp. 18

Author(s):

Yulia Iriani ◽

Taralan Tambunan ◽

Sudigdo Sastroasmoro

Keyword(s):

Nephrotic Syndrome ◽

Cyclophosphamide Therapy ◽

Steroid Dependent ◽

Steroid Sensitive Nephrotic Syndrome ◽

Steroid Sensitive ◽

The Mean ◽

One Year ◽

Steroid Dependent Nephrotic Syndrome ◽

Better Than

Background Steroid-sensitive nephrotic syndrome (SSNS) in chil-dren is characterized by relapsing courses in a substantial propor-tion of affected individuals. Children with frequent-relapsing neph-rotic syndrome (FRNS) or steroid-dependent nephrotic syndrome(SDNS) are at risk of severe steroid toxicity and need individual-ized treatment. Previous studies have elucidated that cyclophos-phamide (CPA) reduced the risk of relapses and increased thelength of subsequent remissions in children with relapsing SSNS.Methods This retrospective study evaluated 38 patients (26 FRNSand 12 SDNS) after cyclophosphamide therapy to elucidate theefficacy of CPA in FRNS or SDNS in the Department of Child Health,Cipto Mangunkusumo Hospital. All patients were treated with CPA(2 mg/kg per day) for 8 weeks, in combination with prednisone.Results The median (range) duration of follow up was 45 months(24-140 months) for FRNS and 29 months (24-63 months) forSDNS. The mean relapse rate one year prior to CPA therapy inFRNS and SDNS were 3.8 relapses/year (95%CI 3.4; 4.2) and 4.0relapses/year (95%CI 3.3; 4.7), which were reduced to 1.6 relapses/year (95% CI 1.1; 2.1) and 2.3 relapses/year (95%CI 1.5;3.2), re-spectively. The overall rate of cumulative sustained good response(complete remission or infrequent relapses) was 65% after 36months. Frequent relapsing versus steroid-dependent status wassignificantly correlated with rate of sustained good response after36 months (85% versus 15%) with OR=23 (95%CI 3.1;225.2).Conclusion The efficacy of cyclophosphamide therapy in themanagement of FRNS is better than in SDNS

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P0478CLINICOPATHOLOGICAL CHARACTERISTICS AND TREATMENT OUTCOMES OF IGM NEPHROPATHY

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfaa142.p0478 ◽

2020 ◽

Vol 35 (Supplement_3) ◽

Author(s):

Amir Shabaka ◽

Fabio Procaccini ◽

Serena Gatius ◽

Elena Valdes ◽

Isabel Galan Carrillo ◽

...

Keyword(s):

Nephrotic Syndrome ◽

Kidney Disease ◽

Immunosuppressive Treatment ◽

Microscopic Hematuria ◽

Igm Nephropathy ◽

Steroid Resistant ◽

Steroid Dependent ◽

Steroid Sensitive ◽

Igm Deposits

Abstract Background and Aims IgM nephropathy (IgMN) is a controversial clinicopathological entity that is characterized by the presence of dominant diffuse mesangial IgM deposits, with diverse clinical presentations and varying response to supportive or immunosuppressive treatment. The aim of our study was to determine the clinical features, histopathological characteristics and treatment outcomes in patients with IgMN. Method We conducted a multicenter retrospective observational study that included patients that had undergone a kidney biopsy between January 1990 and December 2018. We identified 40 patients with mesangial proliferative glomerulopathy with dominant IgM deposits. Patients with the presence of systemic diseases (systemic lupus erythematosus, rheumatoid arthritis, diabetes mellitus or paraproteinemia) were excluded, as well as those with incomplete histological or follow-up data. Demographic, clinical, analytical, and histological data were collected, and the different treatment regimens were compared for achieving clinical remission and prevention of kidney disease progression. Results 33 patients were identified with primary mesangial IgM nephropathy, with a median post-biopsy follow-up of 7.3 (2.8-11.1) years. Mean age of presentation was 34.9±19.0 years, 51.5% were females. The most frequent initial manifestation was nephrotic syndrome in 54.5% of cases, followed by proteinuria with microscopic hematuria in 21.2%, proteinuria in 19.1%, and isolated microhematuria in 3% of patients. On presentation, mean eGFR measured by CKD-EPI was 102.9±38.9 ml/min, median proteinuria was 3.3 g/24h (IQR 1.13-4.88), 69.7% had microscopic hematuria and 27.3% presented with hypertension. Light microscopy revealed mesangial hypercellularity and expansion in 81.8% and 78.8% respectively, 6.6% showed extracapillary proliferation, 33.3% showed segmental sclerosis, 39.4% had mild to moderate interstitial fibrosis, and 46.9% had vascular hyaline deposits. On immunofluorescence all patients showed diffuse mesangial IgM deposits, along with subdominant mesangial deposits of IgG (6.1%), IgA (6%), C3 (39.4%), C1q (27.3%) and Lambda (3%). In nephrotic patients, 16.7% were steroid-resistant, whereas 40% of steroid-sensitive patients were steroid-dependent. 41.7% of steroid-sensitive and nondependent IgMN patients developed a median 3.5 relapses during follow-up. 12 nephrotic patients (3 steroid-resistant and 9 steroid-dependent) received immunosuppressive treatment; 5 patients were initially treated with oral cyclophosphamide, 5 with a calcineurin inhibitor (CNI) and 2 with chlorambucil. All steroid-dependent or resistant patients treated with cyclophosphamide or chlorambucil achieved partial or complete clinical remission. Out of the five patients treated with a CNI, 3 attained remission whereas the other two were switched to cyclophosphamide and chlorambucil respectively after which remission was obtained. No patients progressed to end-stage kidney disease. Conclusion IgMN is a rare mesangial proliferative glomerulopathy with a varying clinical and morphological spectrum. It commonly presents as nephrotic syndrome, and is frequently associated with microscopic hematuria. Clinical course is variable, with frequent relapses and a high prevalence of steroid dependence. Complete remission can be achieved with immunosuppressive therapy in cases of steroid-dependent or resistant IgMN, particularly with cytotoxic agents.

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Association between HLA alleles and sub-phenotype of childhood steroid-sensitive nephrotic syndrome

World Journal of Pediatrics ◽

10.1007/s12519-021-00489-y ◽

2022 ◽

Author(s):

Hao Lee ◽

Li Wang ◽

Fen-Fen Ni ◽

Xue-Ying Yang ◽

Shi-Pin Feng ◽

...

Keyword(s):

Nephrotic Syndrome ◽

Disease Process ◽

Mediating Effect ◽

Chinese Han ◽

Hla Alleles ◽

Hla System ◽

Steroid Dependent ◽

Steroid Sensitive Nephrotic Syndrome ◽

Steroid Sensitive ◽

The Relationship

Abstract Background Few studies have addressed the effects of human leukocyte antigen (HLA) alleles on different clinical sub-phenotypes in childhood steroid-sensitive nephrotic syndrome (SSNS), including SSNS without recurrence (SSNSWR) and steroid-dependent nephrotic syndrome/frequently relapse nephrotic syndrome (SDNS/FRNS). In this study, we investigated the relationship between HLA system and children with SSNSWR and SDNS/FRNS and clarified the value of HLA allele detection for precise typing of childhood SSNS. Methods A total of 241 Chinese Han individuals with SSNS were genotyped using GenCap-WES Capture Kit, and four-digit resolution HLA alleles were imputed from available Genome Wide Association data. The distribution and carrying frequency of HLA alleles in SSNSWR and SDNS/FRNS were investigated. Additionally, logistic regression and mediating effects were used to examine the relationship between risk factors for disease process and HLA system. Results Compared with SSNSWR, significantly decreased serum levels of complement 3 (C3) and complement 4 (C4) at onset were detected in SDNS/FRNS (C3, P < 0.001; C4, P = 0.018). The average time to remission after sufficient initial steroid treatment in SDNS/FRNS was significantly longer than that in SSNSWR (P = 0.0001). Low level of C4 was further identified as an independent risk factor for SDNS/FRNS (P = 0.008, odds ratio = 0.174, 95% confidence interval 0.048–0.630). The HLA-A*11:01 allele was independently associated with SSNSWR and SDNS/FRNS (P = 0.0012 and P = 0.0006, respectively). No significant HLA alleles were detected between SSNSWR and SDNS/FRNS. In addition, a mediating effect among HLA-I alleles (HLA-B*15:11, HLA-B*44:03 and HLA-C*07:06), C4 level and SDNS/FRNS was identified. Conclusions HLA-I alleles provide novel genetic markers for SSNSWR and SDNS/FRNS. HLA-I antigens may be involved in steroid dependent or frequent relapse in children with SSNS as mediators of immunoregulation.

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Steroid treatment for the first episode of childhood nephrotic syndrome: comparison of the 8 and 12 weeks regimen using an individual patient data meta-analysis

European Journal of Pediatrics ◽

10.1007/s00431-021-04035-w ◽

2021 ◽

Author(s):

Anne M. Schijvens ◽

Nynke Teeninga ◽

Eiske M. Dorresteijn ◽

Steven Teerenstra ◽

Nicholas J. Webb ◽

...

Keyword(s):

Nephrotic Syndrome ◽

Individual Patient Data ◽

Meta Analysis ◽

Steroid Treatment ◽

First Episode ◽

Childhood Nephrotic Syndrome ◽

Steroid Sensitive Nephrotic Syndrome ◽

Steroid Sensitive ◽

First Relapse ◽

Steroid Regimen

AbstractSteroids 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.

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Distribution of serum adiponectin isoforms in pediatric patients with steroid-sensitive nephrotic syndrome

Clinical and Experimental Nephrology ◽

10.1007/s10157-021-02085-w ◽

2021 ◽

Author(s):

Tetsuro Tamai ◽

Kaori Kamijo ◽

Yoshifusa Abe ◽

Satoshi Hibino ◽

Shunsuke Sakurai ◽

...

Keyword(s):

Molecular Weight ◽

Nephrotic Syndrome ◽

Pediatric Patients ◽

Serum Adiponectin ◽

Total Serum ◽

Control Subjects ◽

Remission Period ◽

Total Adiponectin ◽

Steroid Sensitive Nephrotic Syndrome ◽

Steroid Sensitive

Abstract Background Serum adiponectin circulates in three multimeric isoforms: high-molecular-weight (HMW), middle-molecular-weight (MMW), and low-molecular-weight (LMW) isoforms. Potential change in the circulating adiponectin levels in patients with nephrotic syndrome (NS) remain unknown. This study aimed to assess the levels of total adiponectin and the distribution of its isoforms in pediatric patients with NS. Methods We sequentially measured total adiponectin and each adiponectin isoform levels at the onset of NS, initial remission, and during the remission period of the disease in 31 NS patients. We also calculated the ratios of HMW (%HMW), MMW (%MMW), and LMW (%LMW) to total adiponectin incuding 51 control subjects. Results The median of total serum adiponectin levels in patients were 36.7, 36.7, and 20.2 μg/mL at the onset, at initial remission, and during the remission period of NS, respectively. These values were significantly higher than those in control subjects. The median values of %HMW, %MMW, and %LMW values were 56.9/27.0/14.1 at the onset, 62.0/21.8/13.4 at the initial remission, and 58.1/21.7/17.5 at during the remission period of NS, respectively. Compared with control subjects, %HMW at initial remission and %MMW at the onset were high, and the %LMW values at the onset and at initial remission were low. Conclusions In patients with NS, total serum adiponectin levels increase at the onset of the disease, and the ratio of adiponectin isoforms changes during the course of the disease. Further studies are needed to delineate the mechanisms between proteinuria and adiponectin isoforms change.

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