Initial treatment of steroid-sensitive idiopathic nephrotic syndrome in children with mycophenolate mofetilversusprednisone: protocol for a randomised, controlled, multicentre trial (INTENT study)

IntroductionIdiopathic nephrotic syndrome is the most common glomerular disease in childhood with an incidence of 1.8 cases per 100 000 children in Germany. The treatment of the first episode implies two aspects: induction of remission and sustainment of remission. The recent Kidney Disease Improving Global Outcomes, American Academy of Pediatrics and German guidelines for the initial treatment of the first episode of a nephrotic syndrome recommend a 12-week course of prednisone. Despite being effective, this treatment is associated with pronounced glucocorticoid-associated toxicity due to high-dose prednisone administration over a prolonged period of time. The aim of the INTENT study (Initial treatment of steroid-sensitive idiopathic nephrotic syndrom in children with mycophenolate mofetil versus prednisone: protocol for a randomised, controlled, multicentre trial) is to show that an alternative treatment regimen with mycophenolic acid is not inferior regarding sustainment of remission, but with lower toxicity compared with treatment with glucocorticoids only.Methods and designThe study is designed as an open, randomised, controlled, multicentre trial. 340 children with a first episode of steroid-sensitive nephrotic syndrome and who achieved remission by a standard prednisone regimen will be enrolled in the trial and randomised to one of two treatment arms. The standard care group will be treated with prednisone for a total of 12 weeks; in the experimental group the treatment is switched to mycophenolate mofetil, also for a total of 12 weeks in treatment duration. The primary endpoint is the occurrence of a treated relapse within 24 months after completion of initial treatment.Ethics and disseminationEthics approval for this trial was granted by the ethics committee of the Medical Faculty of the University of Heidelberg (AFmu-554/2014). The study results will be published in accordance with the Consolidated Standards of Reporting Trials statement and the Standard Protocol Items: Recommendations for Interventional Trials guidelines. Our findings will be submitted to major international paediatric nephrology and general paediatric conferences and submitted for publication in a peer-reviewed, open-access journal.Trial registration numberDRKS0006547; EudraCT2014-001991-76; Pre-result.Date of registration30 October 2014; 24 February 2017.

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Randomised controlled trial comparing rituximab to mycophenolate mofetil in children and young adults with steroid-dependent idiopathic nephrotic syndrome: study protocol

BMJ Open ◽

10.1136/bmjopen-2021-052450 ◽

2021 ◽

Vol 11 (11) ◽

pp. e052450

Author(s):

Francesca Lugani ◽

Andrea Angeletti ◽

Pietro Ravani ◽

Marina Vivarelli ◽

Manuela Colucci ◽

...

Keyword(s):

Young Adults ◽

Nephrotic Syndrome ◽

Mycophenolate Mofetil ◽

Idiopathic Nephrotic Syndrome ◽

Link Type ◽

Steroid Dependent ◽

Study Results ◽

Long Term Treatment ◽

Children And Young Adults ◽

Steroid Sparing

IntroductionGlucocorticoids induce remission in 90% of children with idiopathic nephrotic syndrome (INS). Some become steroid-dependent (SD) and require the addition of steroid sparing drugs such as calcineurin-inhibitors (CNI) or cyclophosphamide, to maintain remission. Considering the toxicity of these drugs, alternative interventions are needed for long-term treatment. The anti-CD20 antibody rituximab has shown promising steroid-sparing properties, with conflicting results in complicated forms of SD-INS. Mycophenolate mofetil (MMF) resulted effective in maintaining free-steroid remission, however, studies are limited to few uncontrolled trials with reported different dose of MMF.Methods and analysisThis open-label, two-parallel-arm, superiority controlled randomised clinical trial will enrol children with SD-INS maintained in remission with oral glucocorticoids or CNI. Children and young adults will be randomised to either MMF (1.200 mg/m2) or rituximab (375 mg/m2) infusion. After enrolment, glucocorticoids will be tapered until complete withdrawal. We will enrol 160 children and young adults to detect as significant at the two-sided p value of 0.01 with a power >0.8 a reduction in the risk of 1-year relapse (primary end-point). As secondary endpoints, we will compare the amount of glucocorticoids required to maintain complete remission at 6 and 24 months.Ethics and disseminationThe trial was approved by the local ethics boards (Comitato Etico Regione Liguria CER Liguria https://www.portalericerca-liguria.it/). We will publish the study results at international scientific meetings.Trial registration numbersNCT004585152.

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Antiviral Effect of High-Dose Ivermectin in Adults with COVID-19: A Pilot Randomised, Controlled, Open Label, Multicentre Trial

SSRN Electronic Journal ◽

10.2139/ssrn.3714649 ◽

2020 ◽

Author(s):

Alejandro Krolewiecki ◽

Adrián Lifschitz ◽

Matías Moragas ◽

Marina Travacio ◽

Ricardo Valentini ◽

...

Keyword(s):

Multicentre Trial ◽

Antiviral Effect ◽

High Dose ◽

Open Label ◽

Randomised Controlled

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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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Short-Term Steroid Regimen for Adult Steroid-Sensitive Minimal Change Disease

American Journal of Nephrology ◽

10.1159/000495352 ◽

2018 ◽

Vol 49 (1) ◽

pp. 54-63 ◽

Cited By ~ 2

Author(s):

Takaya Ozeki ◽

Takayuki Katsuno ◽

Hiroki Hayashi ◽

Sawako Kato ◽

Yoshinari Yasuda ◽

...

Keyword(s):

Nephrotic Syndrome ◽

Minimal Change Disease ◽

Minimal Change ◽

First Episode ◽

Short Term ◽

Short Term Treatment ◽

Steroid Dose ◽

Steroid Sensitive ◽

Steroid Regimen ◽

Frequent Relapse

Background: In pediatric patients with steroid-sensitive nephrotic syndrome, recent trials have revealed that a 2-month, short-term steroid regimen is not inferior to an extended steroid course. However, the optimal duration of initial steroid therapy for adult steroid-sensitive minimal change disease (MCD) remains unclear. Objectives: The aim of present study was to evaluate the effectiveness of a 2-month, short-term steroid regimen in the treatment of adult steroid-sensitive MCD patients. Method: This was a prospective observational study. Adult patients with steroid-sensitive MCD (n = 35) who were initiated on a short-term steroid regimen between January 2015 and June 2016 were included. The details of the regimen are as follows: (1) prednisolone was administered at an initial dose of 0.8–1.0 mg/kg/day and continued for 4–6 weeks and (2) dosage was reduced to 0.5–0.6 mg/kg/alternate day and continued for 4 weeks. Control patients (n = 140), who were treated using conventional steroid administration, were selected from our previous adult MCD cohort. All patients fulfilled the following criteria: biopsy-proven MCD, age ≥20 years, first episode of nephrotic syndrome, and attainment of complete remission within 4 weeks. The following parameters of patients who received short-term treatment regimen and control patients were compared: any relapse and frequent relapse, adverse events caused by steroid treatment and cumulative steroid dose. Results: Throughout the observation period (median: 17.3 months), 24 (68.6%) patients in the short-term group developed at least one relapse. The short-term regimen showed earlier occurrence of any relapse than the conventional regimen (adjusted hazard ratio [aHR] 2.45; 95% CI 1.51–3.97; p < 0.001), but there was no difference in frequent relapse (aHR 1.31; 95% CI 0.43–3.99; p = 0.63). None of the patients showed any symptoms of adrenal insufficiency after discontinuation of corticosteroids. The cumulative steroid dose during the observational period was significantly lower in the short-term group than in the conventional group. Conclusions: The short-term steroid regimen may represent an effective treatment option that ensures lower steroid exposure when treating adult steroid-sensitive MCD patients.

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Lipoprotein (a) as a Predictor of Steroid Dependence in Paediatric Steroid Sensitive Nephrotic Syndrome

JOURNAL FOR CLINICAL AND DIAGNOSTIC RESEARCH ◽

10.7860/jcdr/2021/46262.14409 ◽

2021 ◽

Author(s):

Surupa Basu ◽

Sushmita Banerjee ◽

Pranab Roy ◽

Apurba Ghosh

Keyword(s):

Nephrotic Syndrome ◽

First Episode ◽

Urine Protein ◽

Lipoprotein A ◽

Steroid Dependence ◽

Steroid Dependency ◽

Steroid Dependent ◽

Steroid Sensitive ◽

One Year ◽

Lipid Parameters

Introduction: Lipoprotein a {Lp(a)} increases in Nephrotic Syndrome (NS). Although the majority of paediatric NS are steroid sensitive, relpase and steroid dependence are commonly seen in this cases. Lp(a) is an LDL-like lipoprotein that consists of an LDL particle to which the glycoprotein apolipoprotein(a) {apo(a)} is attached. Aim: To evaluate the potential of Lp(a), measured on admission, for the prediction of relapse/steroid dependency. Materials and Methods: Children (n=36) with first episode NS were recruited in this prospective observational case-control study and followed up for one year. They were tested at presentation for Lp(a) (mg/dL) and standard tests such as haemoglobin, albumin, protein, cholesterol, triglyceride, and urine protein. Children received standard therapy for NS, and were followed for a period of one year from diagnosis to record days to initial remission, relapse episodes, steroid dependence etc. Patients were categorised as: no relapse (NR), Infrequent Relapse (IFR), frequent relapse (FR) and Steroid Dependent (SD) as per standard definitions. Fifteen healthy volunteers were also tested for lipid profile and Lp(a) levels. Results: Of 36 cases (median age 3 years, 19 males), there were 15NR, 7IFR, 2FR and 12SD. The mean Lp(a) of the NS group (165.2±120.4 mg/dL) was higher than controls (30.52±21.9 mg/dL) (p<0.0001). All the lipid parameters except HDL-cholesterol were significantly higher in the NS group. Within the NS group, Lp(a) showed significant correlation (Spearman-rho) with albumin (p=0.0062,r=0.47), but no correlation with lipid parameters or urine protein. Comparison of Lp(a)levels in the NS groups revealed that the SD patients had a high Lp(a)(222.0±115.7 mg/dL) compared to NR (129.7±120.1 mg/dL) (p=0.02). Conclusion: Concentration of plasma Lp(a) in patients with SDNS was higher compared to patients who did not suffer any relapse, and this concentration may serve as a marker for prediction of SDNS.

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High Concentration of C5a-Induced Mitochondria-Dependent Apoptosis in Murine Kidney Endothelial Cells

International Journal of Molecular Sciences ◽

10.3390/ijms20184465 ◽

2019 ◽

Vol 20 (18) ◽

pp. 4465 ◽

Cited By ~ 4

Author(s):

I-Jung Tsai ◽

Wei-Chou Lin ◽

Yao-Hsu Yang ◽

Yu-Lin Tseng ◽

Yen-Hung Lin ◽

...

Keyword(s):

Endothelial Cells ◽

Nephrotic Syndrome ◽

Cytochrome C ◽

Idiopathic Nephrotic Syndrome ◽

Mitochondrial Damage ◽

High Dose ◽

High Concentration ◽

Cytochrome C Release ◽

Ros Formation ◽

High Concentrations

Patients with a relapse of idiopathic nephrotic syndrome have significantly increased levels of serum complement component 5a (C5a), and proteinuria has been noted in mice treated with C5a via changes in permeability of kidney endothelial cells (KECs) in established animal models. However, the apoptosis of KECs treated with high concentrations of C5a has also been observed. As mitochondrial damage is known to be important in cell apoptosis, the aim of this study was to examine the association between C5a-induced mouse KEC apoptosis and mitochondrial damage. Mouse KECs were isolated and treated with different concentrations of C5a. Cell viability assays showed that a high-concentration mouse recombinant protein C5a (rmC5a) treatment reduced mouse KEC growth. Cell cycle phase analysis, including apoptosis (sub-G1 phase) showed an increased percentage of the subG1 phase with a high-concentration rmC5a treatment. Cytochrome c and caspase 3/9 activities were significantly induced in the mouse KECs after a high-dose rmC5a (50 ng/mL) treatment, and this was rescued by pretreatment with the C5a receptor (C5aR) inhibitor (W-54011) and N-acetylcysteine (NAC). Reactive oxygen species (ROS) formation was detected in C5a-treated mouse KECs; however, W-54011 or NAC pretreatment inhibited high-dose rmC5a-induced ROS formation and also reduced cytochrome c release, apoptotic cell formation, and apoptotic DNA fragmentation. These factors determined the apoptosis of mouse KECs treated with high-dose C5a through C5aR and subsequently led to apoptosis via ROS regeneration and cytochrome c release. The results showed that high concentrations of C5a induced mouse KEC apoptosis via a C5aR/ROS/mitochondria-dependent pathway. These findings may shed light on the potential mechanism of glomerular sclerosis, a process in idiopathic nephrotic syndrome causing renal function impairment.

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Open-Label Clinical Trials of Oral Pulse Dexamethasone for Adults with Idiopathic Nephrotic Syndrome

American Journal of Nephrology ◽

10.1159/000497064 ◽

2019 ◽

Vol 49 (5) ◽

pp. 377-385 ◽

Cited By ~ 1

Author(s):

Monique E. Cho ◽

Mary H. Branton ◽

David A. Smith ◽

Linda Bartlett ◽

Lilian Howard ◽

...

Keyword(s):

Nephrotic Syndrome ◽

Adverse Events ◽

Idiopathic Nephrotic Syndrome ◽

High Dose ◽

Open Label ◽

Serious Adverse Events ◽

Oral Dexamethasone ◽

Dose Oral ◽

Pulse Dexamethasone ◽

Daily Prednisone

Background: In adults with primary focal segmental glomerulosclerosis (FSGS), daily prednisone may induce complete remissions (CR) and partial remissions (PR), but relapses are frequent and adverse events are common. Methods: We carried out 2 open-label, uncontrolled trials to explore the efficacy and tolerability of pulse oral dexamethasone as an alternative to daily prednisone. We enrolled adult patients with proteinuria > 3.5 g/day despite the use of renin-angiotensin-aldosterone blockade. In the first trial, we enrolled 14 subjects with FSGS and administered 4 dexamethasone doses (25 mg/m2) daily for 4 days, repeated every 28 days over 32 weeks. The second trial involved a more intensive regimen. Eight subjects received 4 dexamethasone doses of 50 mg/m2 every 4 weeks for 12 weeks, followed by 4 doses of 25 mg/m2 every 4 weeks for 36 weeks; subjects were randomized to 2 doses every 2 weeks or 4 doses every 4 weeks. Results: In the first trial, we enrolled 13 subjects with FSGS and 1 with minimal change disease and found a combined CR and PR rate of 36%. In the second trial, we enrolled 8 subjects. The combined CR and PR rate was 29%. Analysis combining both trials showed a combined CR and PR rate of 33%. Adverse events were observed in 32% of subjects, with mood symptoms being most common. There were no serious adverse events related to the study. Conclusion: We conclude that high dose oral dexamethasone is well tolerated by adults with idiopathic nephrotic syndrome and may have some efficacy.

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