scholarly journals Relapse of Nephrotic Syndrome after Adrenocorticotropic Hormone-Induced Remission: Implications of Adrenocorticotropic Hormone Antibodies

2020 ◽  
Vol 51 (5) ◽  
pp. 390-394 ◽  
Author(s):  
Snehal Shrivastava ◽  
Bohan Chen ◽  
Lance D. Dworkin ◽  
Deepak K. Malhotra ◽  
Rujun Gong
Keyword(s):  
Nephrotic Syndrome ◽  
Side Effects ◽  
Adrenocorticotropic Hormone ◽  
De Novo ◽  
Glycogen Synthase ◽  
Therapeutic Modality ◽  
Glomerular Diseases ◽  
Steroid Dependent ◽  
Number Of Patients ◽  
Acth Therapy

Background: Prolonged use of corticosteroids continues to be the mainstay in the management of most proteinuric glomerulopathies, but is limited by extensive side effects. Alternative medications such as adrenocorticotropic hormone (ACTH) have been recently used to treat refractory glomerulopathies and have shown superior outcomes when compared with steroids. However, the clinical responsiveness to ACTH therapy varies considerably with a number of patients exhibiting de novo or acquired resistance. The underlying mechanism remains unknown. Methods: A patient with steroid-dependent focal segmental glomerulosclerosis (FSGS) developed severe steroid side effects impacting quality of life and was converted to repository porcine ACTH therapy. Immediate response in the form of remission of nephrotic syndrome was noted followed by relapse in 10 weeks. Suspecting the role of some ACTH-antagonizing factors, the patient’s serum was examined. Results: Immunoblot-based antibody assay revealed high titers of de novo IgG antibodies in the patient’s serum that were reactive to the porcine corticotropin with negligible cross-reactivity to human corticotropin. In vitro, in cultured B16 melanoma cells that express abundant melanocortin receptors, addition of the patient’s serum substantially abrogated the porcine corticotropin triggered signaling activity of the melanocortinergic pathway, marked by phosphorylation of glycogen synthase kinase 3β, thus suggesting a mitigating effect on the biological functionality of porcine corticotropin. Conclusion: ACTH is a useful alternative therapeutic modality for refractory proteinuric glomerulopathies like FSGS. However, as quintessential therapeutic biologics, natural ACTH, regardless of purity and origin, is inevitably antigenic and may cause the formation of neutralizing antibodies in some sensitive patients, followed by resistance to ACTH therapy. It is imperative to develop ACTH analogues with less immunogenicity for improving its responsiveness in patients with glomerular diseases.

scholarly journals Adrenocorticotropic Hormone for Childhood Nephrotic Syndrome

2018 ◽  
Vol 13 (12) ◽  
pp. 1859-1865 ◽  
Author(s):  
Chia-shi Wang ◽  
Curtis Travers ◽  
Courtney McCracken ◽  
Traci Leong ◽  
Rasheed Gbadegesin ◽  
...  
Keyword(s):  
Nephrotic Syndrome ◽  
Side Effects ◽  
Confidence Interval ◽  
Adrenocorticotropic Hormone ◽  
Control Group ◽  
Disease Relapse ◽  
Steroid Dependent ◽  
Acth Treatment ◽  
First Relapse ◽  
Steroid Dependent Nephrotic Syndrome

Background and objectivesThere is renewed interest in adrenocorticotropic hormone (ACTH) for the treatment of nephrotic syndrome. We evaluated the efficacy and safety of ACTH in children with frequently relapsing or steroid-dependent nephrotic syndrome in a randomized trial.Design, setting, participants, & measurementsParticipants aged 2–20 years old with frequently relapsing or steroid-dependent nephrotic syndrome were enrolled from 16 sites in the United States and randomized 1:1 to ACTH (repository corticotropin injection) or no relapse-preventing treatment. ACTH treatment regimen was 80 U/1.73 m2 administered twice weekly for 6 months, followed by 40 U/1.73 m2 administered twice weekly for 6 months. The primary outcome was disease relapse during the first 6 months. Participants in the control group were offered crossover to ACTH treatment if they relapsed within 6 months. Secondary outcomes were relapse after ACTH dose reduction and treatment side effects.ResultsThe trial was stopped at a preplanned interim analysis after enrollment of 31 participants because of a lack of discernible treatment efficacy. Fourteen out of 15 (93%) participants in the ACTH arm experienced disease relapse in the first 6 months, with a median time to first relapse of 23 days (interquartile range, 9–32), compared with 15 out of 16 (94%) participants and at a median of 21 days (interquartile range, 14–51) in the control group. There was no difference in the proportion of relapsed patients (odds ratio, 0.93; 95% confidence interval, 0.05 to 16.40; P>0.99) or time to first relapse (hazard ratio, 1.03; 95% confidence interval, 0.50 to 2.15; P=0.93). Thirteen out of 16 participants in the control group crossed over to ACTH treatment. Three out of 28 participants completed 12 months of ACTH treatment; the others exited the trial because of frequent relapses or side effects. There were no disease relapses after ACTH dose reduction among the three participants. Most side effects were mild and similar to side effects of corticosteroids.ConclusionsACTH at 80 U/1.73 m2 administered twice weekly was ineffective at preventing disease relapses in pediatric nephrotic syndrome.

scholarly journals New Aspects of Pathogenesis and Treatment of Membranous Glomerulopathy After the MENTOR Study

2020 ◽  
pp. 46-53
Author(s):  
Maurizio Salvadori ◽  
Aris Tsalouchos
Keyword(s):  
Nephrotic Syndrome ◽  
Adrenocorticotropic Hormone ◽  
Glomerular Diseases ◽  
The Past ◽  
Superior Efficacy ◽  
Novel Drugs ◽  
Membranous Glomerulopathy ◽  
Blocking Mechanisms ◽  
Antigenic Epitopes

Membranous nephropathy (MN) is the major cause of nephrotic syndrome in adults, accounting for 20% of cases with an annual incidence of 1 per 100,000 population. In the past 10 years, the role of podocytes has been identified. Environmental triggers in genetically predisposed patients can activate podocytes to exhibit antigenic epitopes, including PLA2R, THBS1, and NELL1, which become targets of specific autoantibodies with subsequent complement activation. The discovery of these mechanisms has opened a new horizon in the treatment of MN, and novel drugs are available with more specific mechanisms of action. Rituximab, a monoclonal antibody directed against CD20 expressed on B lymphocytes, has been used in several trials and appears to induce remission of nephrotic syndrome in 60% of patients (GEMRITUX trial). The recently published results of the MENTOR trial documented the superior efficacy of rituximab in patients observed for up to 24 months. In MN, the concept of targeting disease control has introduced novel therapies with specific blocking mechanisms, such as belimumab; nonspecific blocking mechanisms, such as those against adrenocorticotropic hormone; and new therapeutic options, such as ofatumumab, bortezomib, and eculizumab, which have recognised the pathological processes involved in the glomerular diseases.

scholarly journals Efficacy and safety of intravenous immunoglobulin with rituximab versus rituximab alone in childhood-onset steroid-dependent and frequently relapsing nephrotic syndrome: protocol for a multicentre randomised controlled trial

BMJ Open ◽  
2020 ◽  
Vol 10 (9) ◽  
pp. e037306
Author(s):  
Julien Hogan ◽  
Aubriana Perez ◽  
Anne-Laure Sellier-Leclerc ◽  
Isabelle Vrillon ◽  
Francoise Broux ◽  
...  
Keyword(s):  
Nephrotic Syndrome ◽  
Side Effects ◽  
Controlled Trial ◽  
Primary Study ◽  
Childhood Onset ◽  
Open Label ◽  
Substantial Impact ◽  
Frequently Relapsing Nephrotic Syndrome ◽  
Steroid Dependent

IntroductionGuidelines for the treatment of steroid-dependent nephrotic syndrome (SDNS) and frequently relapsing nephrotic syndrome (FRNS) are lacking. Given the substantial impact of SDNS/FRNS on quality of life, strategies aiming to provide long-term remission while minimising treatment side effects are needed. Several studies confirm that rituximab is effective in preventing early relapses in SDNS/FRNS; however, the long-term relapse rate remains high (~70% at 2 years). This trial will assess the association of intravenous immunoglobulins (IVIgs) to rituximab in patients with SDNS/FRNS and inform clinicians on whether IVIg’s immunomodulatory properties can alter the course of the disease and reduce the use of immunosuppressive drugs and their side effects.Methods and analysisWe conduct an open-label multicentre, randomised, parallel group in a 1:1 ratio, controlled, superiority trial to assess the safety and efficacy of a single infusion of rituximab followed by IVIg compared with rituximab alone in childhood-onset FRNS/SDNS. The primary outcome is the occurrence of first relapse within 24 months. Patients are allocated to receive either rituximab alone (375 mg/m²) or rituximab followed by IVIg, which includes an initial Ig dose of 2 g/kg, followed by 1.5 g/kg injections once a month for the following 5 months (maximum dose: 100 g).Ethics and disseminationThe study has been approved by the ethics committee (Comité de Protection des Personnes) of Ouest I and authorised by the French drug regulatory agency (Agence Nationale de Sécurité du Médicament et des Produits de Santé). Results of the primary study and the secondary aims will be disseminated through peer-reviewed publications.Trial registration numberNCT03560011.

scholarly journals Systematic Review and Meta-Analysis of Rituximab for Steroid-Dependent or Frequently Relapsing Nephrotic Syndrome in Children

2021 ◽  
Vol 9 ◽  
Author(s):  
Xia Gao ◽  
Yan Wang ◽  
Zichuan Xu ◽  
Huiying Deng ◽  
Huabin Yang ◽  
...  
Keyword(s):  
Systematic Review ◽  
Nephrotic Syndrome ◽  
Assessment Tool ◽  
Meta Analysis ◽  
Biomedical Literature ◽  
Cochrane Library ◽  
Control Group ◽  
Frequently Relapsing Nephrotic Syndrome ◽  
Steroid Dependent ◽  
Number Of Patients

Objective: To explore the effectiveness and safety of rituximab (RTX) for steroid-dependent or frequently relapsing nephrotic syndrome via a systematic review and meta-analysis.Methods: All the literature about RTX therapy for childhood nephrotic syndrome (NS) on PubMed, Web of Science, Cochrane Library, EMBASE, and Chinese biomedical literature database published before November 1, 2019, were conducted and selected according to the preset criteria. The Cochrane bias risk assessment tool was used to evaluate the quality of the literature included. The outcome data were analyzed by RevMan 5.3 software.Results: There were six RCT studies that met the inclusion criteria with a moderate quality after evaluation. At the end of the treatment, the relapse rate of NS in the RTX group reduced significantly when compared with that in the control group [odds ratio (OR) = 0.11, 95% confidence interval (CI) (0.03, 0.43), p = 0.001]. The number of patients in the RTX group used less steroid or/and calcineurin inhibitors significantly than that in the control group [OR = 0.05, 95% CI (0.01, 0.28), p = 0.0007]. For children who were steroid-dependent, RTX treatment significantly reduced the dosage of the steroid, compared with that in control [standardized mean difference (SMD) = −1.49, 95% CI (−2.00, −0.99), p < 0.00001]. There was no significant reduction in protein excretion between the two groups [SMD = −0.33, 95% CI (−0.71, 0.04), p = 0.08]. Fewer serious adverse reactions of RTX in the six studies were reported and most adverse events were mild.Conclusion: RTX is effective and safe for children with steroid-dependent or frequently relapsing nephrotic syndrome.Systematic Review Registration: Identifier: CRD 42020150933. https://www.crd.york.ac.uk/prospero/. This review has been registered to the PROSPERO on 27 Feb 2020.

ADRENOCORTICOTROPHIC HORMONE (ACTH) THERAPY OF THE NEPHROTIC SYNDROME IN CHILDREN

PEDIATRICS ◽  
1952 ◽  
Vol 10 (5) ◽  
pp. 543-566
Author(s):  
JACK METCOFF ◽  
CHARLES P. RANCE ◽  
WESTON M. KELSEY ◽  
NOBUYUKI NAKASONE ◽  
CHARLES A. JANEWAY
Keyword(s):  
Renal Function ◽  
Nephrotic Syndrome ◽  
Extracellular Fluid ◽  
Active Phase ◽  
Normal Diet ◽  
Protein Levels ◽  
Number Of Patients ◽  
Duration Of Disease ◽  
Acth Therapy ◽  
Adequate Dosage

The clinical and physiologic features characterizing the administration of 56 courses of ACTH therapy to 45 children with the nephrotic syndrome have been reviewed. The intramuscular administration of ACTH in daily doses of 150 to 200 mg./sq.m./ 24 hours for at least 8 and usually 10 days resulted in complete diuresis in 38 of 47 (81%) such courses, in 68% of all courses, and in 34 of 45 (75%) patients treated. Approximately 50% of the patients undergoing diuresis have maintained clinical remissions of three months or longer. Twelve of 16 such patients have been in clinical remission for over 6 months; 6 of these, for over 12 months. Induced diuresis and remission were associated with considerable improvement in renal function, particularly glomerular filtration rate and filtration fraction. Some diminution of proteinuria and increased serum protein levels were observed after diuresis, and serum cholesterol fell toward normal levels. Rather consistent but minimal changes in serum electrolyte patterns were noted. An increase of 2 to 4 mM/1. in Na, slight alkalosis and a fall in serum K were usual responses. ACTH therapy of the nephrotic syndrome in children may be hazardous. Four patients died as a result of complications associated with therapy. The principal complications were infection, severe hypertension and hypotonicity of the extracellular fluid. Prompt recognition and treatment of these disorders with immediate withdrawal of ACTH therapy required constant vigilance and careful supervision. For this reason, this method of treatment is not considered to he a safe outpatient procedure. The mechanisms responsible for diuresis and remission induced by ACTH therapy are not yet clear. Adequate dosage, normal diet without salt restriction but without added or excessive salt, and possibly a limited period of reduced renal function appear to favor diuresis. Neither the age of the patient nor the (chronologic) duration of disease appear to influence the outcome in children. Although ACTH therapy may not effect a cure, it does appear to alter the course favorably in a relatively significant number of patients treated, and therefore at the present time appears to be the treatment of choice for the active phase of the nephrotic syndrome in children. A preventive or curative agent is still to be found.

Therapeutic Effect of Chai-Ling-Tang (Sairei-to) on the Steroid-dependent Nephrotic Syndrome in Children

1995 ◽  
Vol 23 (03n04) ◽  
pp. 255-260 ◽  
Author(s):  
Xiao-Yun Liu
Keyword(s):  
Nephrotic Syndrome ◽  
Side Effects ◽  
Toxic Effect ◽  
Cytotoxic Agents ◽  
Short Term ◽  
Prednisone Dosage ◽  
Steroid Dependent ◽  
Steroid Dependent Nephrotic Syndrome ◽  
Negative Conversion

37 children with steroid-dependent nephrotic syndrome (SDNS) were administered with Chai-Ling-Tang (Sairei-to) under corticosteroid. After treatment with Chai-Ling-Tang, relapse was markedly improved, time for negative conversion of proteinuria shortened, prednisone dosage significantly reduced, and side effects eased. 32 children with SDNS treated with prednisone and cyclophosphamide served as control. Results showed that short-term and long-term relapse and average prednisone dosage were similar between these two groups. It is considered that Chai-Ling-Tang may be a useful substitute for patients with SDNS who fail to respond to or manifest severe toxic effect from cytotoxic agents.

scholarly journals Inflammatory and JAK-STAT Pathways as Shared Molecular Targets for ANCA-Associated Vasculitis and Nephrotic Syndrome

2018 ◽  
Author(s):  
Sean Eddy ◽  
Viji Nair ◽  
Laura H. Mariani ◽  
Felix H. Eichinger ◽  
John Hartman ◽  
...  
Keyword(s):  
Nephrotic Syndrome ◽  
Target Genes ◽  
De Novo ◽  
Interstitial Fibrosis ◽  
Kidney Diseases ◽  
Structural Features ◽  
Glomerular Diseases ◽  
Anca Associated Vasculitis ◽  
Starting Point ◽  
Renal Biopsies

ABSTRACTBackgroundGlomerular diseases of the kidney are presently differentiated, diagnosed and treated according to conventional clinical or structural features. While etiologically diverse, these diseases share common clinical features including but not limited to reduced glomerular filtration rate, increased serum creatinine and proteinuria suggesting shared pathogenic mechanisms across diseases. Renal biopsies from patients with nephrotic syndrome (NS) or ANCA-associated vasculitis (AAV) were evaluated for molecular signals cutting across conventional disease categories as candidates for therapeutic targets.MethodsRenal biopsies were obtained from patients with NS (minimal change disease, focal segmental glomerulosclerosis, or membranous nephropathy) (n=187) or AAV (granulomatosis with polyangiitis or microscopic polyangiitis) (n=80) from the Nephrotic Syndrome Study Network (NEPTUNE) and the European Renal cDNA Bank. Transcriptional profiles were assessed for shared disease mechanisms.ResultsIn the discovery cohort, 10–25% transcripts were differentially regulated versus healthy controls in both NS and AAV, >500 transcripts were shared across diseases. The majority of shared transcripts (60–77%) were validated in independent samples. Therapeutically targetable networks were identified, including inflammatory JAK-STAT signaling. STAT1 eQTLs were identified and STAT1 expression associated with GFR-based outcome. A transcriptional STAT1 activity score was generated from STAT1-regulated target genes which correlated with CXCL10 (p<0.001), a JAK-STAT biomarker, predictors of CKD progression, interstitial fibrosis (r=0.41, p<0.001), and urinary EGF (r=-0.51, p<0.001).ConclusionAAV and NS caused from histopathologically distinct disease categories share common intra-renal molecular pathways cutting across conventional disease classifications. This approach provides a starting point for de novo drug development, and repurposing efforts in rare kidney diseases.

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

2019 ◽  
Vol 8 (6) ◽  
pp. 860 ◽  
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.

Rituximab in childhood steroid-sensitive nephrotic syndrome: are multiple subsequent courses safe and effective?

2020 ◽  
pp. archdischild-2020-319609
Author(s):  
Chantida Subun ◽  
Picha Suwannahitatorn ◽  
Hazel Webb ◽  
Kjell Tullus
Keyword(s):  
Nephrotic Syndrome ◽  
Side Effects ◽  
Age Groups ◽  
Term Treatment ◽  
Street Hospital ◽  
Steroid Dependency ◽  
Great Ormond Street Hospital ◽  
Steroid Dependent ◽  
Long Term Treatment

IntroductionIdiopathic nephrotic syndrome is the most common glomerular disease in children. The majority of patients respond well to steroids. However, the relapse rate is high and many develop steroid dependency. Although other immunosuppressive medicines are successfully used as steroid-sparing agents, some children still have frequent relapsing episodes. Rituximab (RTX), a chimeric anti-CD20 monoclonal antibody, has shown to be effective in treating difficult frequently relapsing/steroid-dependent nephrotic syndrome (FR/SDNS). Data on the effectiveness and long-term treatment outcomes of repeated courses of RTX are, however, scarce.Material and methodsChildren and young people with FR/SDNS, aged 1–18 years, who received RTX at Great Ormond Street Hospital (GOSH) from 2006 to 2018 were reviewed.ResultsDuring these 12 years, 103 children with FR/SDNS received RTX infusions at GOSH. Among these, 58 cases needed repeated courses of RTX: 2, 3, 4, 5, 6 and 7 repeated courses were given to 21, 21, 7, 5, 1 and 3 patients, respectively. The overall median time to relapse post-RTX was 11 months (range 1–53 months). There was no change in relapse-free interval with subsequent courses of RTX. No difference was found between age groups, genders and ethnicities. No severe side effects were noted.ConclusionsRTX seems to be safe even after several repeated courses. However, long-term follow-up and further studies are needed, with a focus on side-effects in particular.

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