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Liu ID, Willis NS, Craig JC, Hodson EM. Interventions for idiopathic steroid-resistant nephrotic syndrome in children. Cochrane Database Syst Rev 2025; 5:CD003594. [PMID: 40337980 PMCID: PMC12060654 DOI: 10.1002/14651858.cd003594.pub7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 05/09/2025]
Abstract
BACKGROUND Nephrotic syndrome is a condition in which the glomeruli of the kidney leak large amounts of protein from the blood into the urine. Most children who present with their first episode of nephrotic syndrome achieve remission with corticosteroids. Children who fail to respond to corticosteroids in the first episode of nephrotic syndrome (initial resistance) or develop resistance after one or more responses to corticosteroids (delayed resistance) may be treated with immunosuppressive agents, including calcineurin inhibitors (cyclosporin or tacrolimus), and with non-immunosuppressive agents, such as angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. However, response to these agents is limited, so newer agents, including anti-CD20 antibodies (rituximab, ofatumumab) and dual endothelin-angiotensin receptor antagonists (sparsentan), are being assessed for efficacy and safety. This is an update of a review first published in 2004 and updated in 2006, 2010, 2016 and 2019. OBJECTIVES To evaluate the benefits and harms of different interventions used in children with idiopathic nephrotic syndrome, who do not achieve remission following four weeks or more of daily corticosteroid therapy. SEARCH METHODS The Cochrane Kidney and Transplant (CKT) Information Specialist searched the CKT Register of Studies to 28 January 2025 using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE and Embase, conference proceedings, the International Clinical Trials Registry Platform (ICTRP) Search Portal and ClinicalTrials.gov. SELECTION CRITERIA We included randomised controlled trials (RCTs) and quasi-RCTs that compared different immunosuppressive or non-immunosuppressive agents with placebo, prednisone or another agent given orally or parenterally in children aged three months to 18 years with steroid-resistant nephrotic syndrome (SRNS). We included studies that enrolled children and adults, in which paediatric data could not be separated from adult data. DATA COLLECTION AND ANALYSIS Two review authors independently screened the search results, determined study eligibility, assessed risk of bias and extracted study data. We expressed dichotomous outcomes as risk ratios (RRs) with 95% confidence intervals (CIs), and continuous outcomes as mean differences (MDs) with 95% CIs. We used a random-effects model to pool data, and GRADE to assess the certainty of the evidence. The main outcomes of interest were treatment response (complete, partial, or complete or partial remission), kidney failure and adverse events. MAIN RESULTS We included 29 studies (1248 evaluated children). Sixteen studies were at low risk of bias for sequence generation and allocation concealment. Seven and 21 studies were at low risk of performance and detection bias, respectively. Sixteen, 15 and 15 studies were at low risk of attrition bias, reporting bias and other bias, respectively. Compared with placebo, corticosteroid or no treatment, cyclosporin may increase the number who achieve complete remission (RR 3.50, 95% CI 1.09 to 11.20; 4 studies, 74 children) or complete or partial remission (RR 3.15, 95% CI 1.04 to 9.57; 4 studies, 74 children) by two to six months (low-certainty evidence). It is uncertain whether cyclosporin reduces the likelihood of kidney failure or increases the likelihood of worsening hypertension or infection (very low-certainty evidence). Compared with intravenous cyclophosphamide, calcineurin inhibitors may increase the number with complete remission (RR 3.43, 95% CI 1.84 to 6.41; 2 studies, 156 children) and complete or partial remission (RR 1.98, 95% CI 1.25 to 3.13; 2 studies, 156 children) at three to six months (low-certainty evidence), and probably reduces the number with treatment failure (no response, serious infection, persistently elevated creatinine) and medications ceased due to adverse events (moderate-certainty evidence), with little or no increase in serious infections (moderate-certainty evidence). Kidney failure was not reported. Tacrolimus may make little or no difference to the number who achieve complete, or complete or partial remission at six and 12 months compared with cyclosporin, but may reduce the number who relapse during treatment (RR 0.22, 95% CI 0.06 to 0.90; 1 study, 34 children) or the number with worsening hypertension (low-certainty evidence). Hypertrichosis and gingival hyperplasia probably increased with cyclosporin. Kidney failure was not reported. Compared with mycophenolate mofetil (MMF) and dexamethasone, cyclosporin probably makes little or no difference to complete, partial, or complete or partial remission (moderate-certainty evidence), and may make little or no difference to kidney failure, serious infection requiring hospitalisation or hypertension (low-certainty evidence). Among children who have achieved complete remission, tacrolimus compared with MMF may increase the number who maintain complete, partial, or complete or partial response for 12 months, but may make little or no difference to serious adverse events and serious infection (low-certainty evidence). Oral cyclophosphamide plus prednisone compared with prednisone alone may make little or no difference to the number who achieve complete remission (low-certainty evidence) and has uncertain effects on adverse events. Kidney failure was not reported. Compared with oral cyclophosphamide plus intravenous dexamethasone, intravenous cyclophosphamide may make little or no difference to complete, partial, or complete or partial remission at six months. There may be little or no difference in bacterial infections; however, hypertension may decrease (all low-certainty evidence). Kidney failure was not reported. It is uncertain whether rituximab/cyclosporin/prednisolone compared with cyclosporin/prednisolone increases the likelihood of remission or reduces adverse events because the certainty of the evidence is very low. Kidney failure was not reported. AUTHORS' CONCLUSIONS Calcineurin inhibitors may increase the likelihood of complete or partial remission compared with placebo/no treatment or cyclophosphamide. For other regimens, it remains unclear whether the interventions alter outcomes because the certainty of the evidence is low. Further adequately powered, well-designed RCTs are needed to evaluate other regimens for children with idiopathic SRNS. Since SRNS represents a spectrum of diseases, future studies should enrol children from better-defined groups of people with SRNS.
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Affiliation(s)
- Isaac D Liu
- Duke-NUS Medical School; Yong Loo Lin School of Medicine, Singapore, Singapore
| | - Narelle S Willis
- Sydney School of Public Health, The University of Sydney, Sydney, Australia
- Cochrane Kidney and Transplant, Centre for Kidney Research, The Children's Hospital at Westmead, Westmead, Australia
| | - Jonathan C Craig
- Cochrane Kidney and Transplant, Centre for Kidney Research, The Children's Hospital at Westmead, Westmead, Australia
- College of Medicine and Public Health, Flinders University, Adelaide, Australia
| | - Elisabeth M Hodson
- Cochrane Kidney and Transplant, Centre for Kidney Research, The Children's Hospital at Westmead, Westmead, Australia
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Angeletti A, Ghiggeri GM. Anti-CD20 monoclonal antibodies for idiopathic nephrotic syndrome: Advances, challenges, and future directions. Pediatr Nephrol 2025:10.1007/s00467-025-06738-w. [PMID: 40310480 DOI: 10.1007/s00467-025-06738-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/26/2024] [Revised: 02/25/2025] [Accepted: 03/01/2025] [Indexed: 05/02/2025]
Affiliation(s)
- Andrea Angeletti
- Nephrology, Dialysis, and Transplantation, IRCCS Istituto Giannina Gaslini, Via Gaslini 6, Genoa, Italy.
| | - Gian Marco Ghiggeri
- Nephrology, Dialysis, and Transplantation, IRCCS Istituto Giannina Gaslini, Via Gaslini 6, Genoa, Italy.
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3
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Floege J, Gibson KL, Vivarelli M, Liew A, Radhakrishnan J, Rovin BH. KDIGO 2025 Clinical Practice Guideline for the Management of Nephrotic Syndrome in Children. Kidney Int 2025; 107:S241-S289. [PMID: 40254391 DOI: 10.1016/j.kint.2024.11.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2024] [Accepted: 11/13/2024] [Indexed: 04/22/2025]
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Yao L, Li Y, Wang P, Xu C, Yu Z. Nucleoporin-associated steroid-resistant nephrotic syndrome. Pediatr Nephrol 2025; 40:629-649. [PMID: 39331077 DOI: 10.1007/s00467-024-06494-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2024] [Revised: 08/01/2024] [Accepted: 08/07/2024] [Indexed: 09/28/2024]
Abstract
Nucleoporins (Nups) are a class of proteins that assemble to form nuclear pore complexes, which are related to nucleocytoplasmic transport, gene expression, and the cell cycle. Pathogenic variants in six genes encoding Nups, NUP85, NUP93, NUP107, NUP133, NUP160, and NUP205, cause monogenic steroid-resistant nephrotic syndrome (SRNS), referred to as nucleoporin-associated SRNS. In this paper, we review the epidemiology, structure and function of Nups, pathogenesis, phenotypes and genotypes, and management of nucleoporin-associated SRNS as well as implications for genetic counseling. Affected individuals exhibit autosomal recessive isolated and syndromic SRNS, whose extrarenal manifestations include neurological disorders, growth and development disorders, cardiovascular disorders, and congenital malformations. The median ages at onset of NUP85-, NUP93-, NUP107-, NUP133-, NUP160-, and NUP205-associated SRNS are 7, 3, 4.1, 9, 7, and 2 years, respectively. Kidney biopsies reveal focal segmental glomerulosclerosis in 89% of patients. Most affected individuals are resistant to immunosuppressants. For the six subtypes of nucleoporin-associated SRNS, patients show progression to kidney failure at median ages of 8.5, 3.7, 6.9, 13, 15, and 7 years, respectively. Only two patients with NUP93-associated SRNS with nephrotic syndrome relapse post-transplant have been reported, and the recurrence rate is 12.5%. Next-generation sequencing using a targeted gene panel is recommended in cases of suspected nucleoporin-associated SRNS for genetic diagnosis. Renin-angiotensin-aldosterone system inhibitors are recommended for patients with nucleoporin-associated SRNS. Once genetic diagnosis is confirmed, immunosuppressant discontinuation should be considered, and kidney transplant is preferred when patients progress to kidney failure. Genetic counselling should be provided for asymptomatic siblings and future siblings of an affected individual. Further studies on the pathogenesis of nucleoporin-associated SRNS are needed to seek new therapeutic interventions.
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Affiliation(s)
- Ling Yao
- Department of Nephrology, Rheumatology and Immunology, Fujian Children's Hospital, College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, 966 Heng Yu Road, Jin'an District, Fuzhou, 350014, Fujian, People's Republic of China
| | - Yuanyuan Li
- Department of Nephrology, Rheumatology and Immunology, Fujian Children's Hospital, College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, 966 Heng Yu Road, Jin'an District, Fuzhou, 350014, Fujian, People's Republic of China
| | - Ping Wang
- Department of Pediatrics, The Military Hospital of 92435 Unit of PLA, Ningde, 352103, China
| | - Chan Xu
- Department of Nephrology, Rheumatology and Immunology, Fujian Children's Hospital, College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, 966 Heng Yu Road, Jin'an District, Fuzhou, 350014, Fujian, People's Republic of China
| | - Zihua Yu
- Department of Nephrology, Rheumatology and Immunology, Fujian Children's Hospital, College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, 966 Heng Yu Road, Jin'an District, Fuzhou, 350014, Fujian, People's Republic of China.
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5
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Chan EYH, Sinha A, Yu ELM, Akhtar N, Angeletti A, Bagga A, Banerjee S, Boyer O, Chan CY, Francis A, Ghiggeri GM, Hamada R, Hari P, Hooman N, Hopf LS, I MI, Ijaz I, Ivanov DD, Kalra S, Kang HG, Lucchetti L, Lugani F, Ma ALT, Morello W, Camargo Muñiz MD, Pradhan SK, Prikhodina L, Raafat RH, Sinha R, Teo S, Tomari K, Vivarelli M, Webb H, Yap HK, Yap DYH, Tullus K. An international, multi-center study evaluated rituximab therapy in childhood steroid-resistant nephrotic syndrome. Kidney Int 2024; 106:1146-1157. [PMID: 39395629 DOI: 10.1016/j.kint.2024.09.011] [Citation(s) in RCA: 10] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2023] [Revised: 09/05/2024] [Accepted: 09/13/2024] [Indexed: 10/14/2024]
Abstract
The efficacy and safety of rituximab in childhood steroid-resistant nephrotic syndrome (SRNS) remains unclear. Therefore, we conducted a retrospective cohort study at 28 pediatric nephrology centers from 19 countries in Asia, Europe, North America and Oceania to evaluate this. Children with SRNS treated with rituximab were analyzed according to the duration of calcineurin inhibitors (CNIs) treatment before rituximab [6 months or more (CNI-resistant) and under 6 months]. Primary outcome was complete/partial remission (CR/PR) as defined by IPNA/KDIGO guidelines. Secondary outcomes included kidney failure and adverse events. Two-hundred-forty-six children (mean age, 6.9 years; 136 boys; 57% focal segmental glomerulosclerosis, FSGS) were followed a median of 32.4 months after rituximab. All patients were in non-remission before rituximab. (146 and 100 children received CNIs for 6 month or more or under 6 months before rituximab, respectively). In patients with CNI-resistant SRNS, the remission rates (CR/PR) at 3-, 6-, 12- and 24-months were 26% (95% confidence interval 19.3-34.1), 35.6% (28.0-44.0), 35.1% (27.2-43.8) and 39.1% (29.2-49.9), respectively. Twenty-five patients were in PR at 12-months, of which 22 had over 50% reduction in proteinuria from baseline. The remission rates among children treated with CNIs under 6 months before rituximab were 42% (32.3-52.3), 52% (41.8-62.0), 54% (44.3-64.5) and 60% (47.6-71.3) at 3-, 6-, 12-, and 24-months. Upon Kaplan-Meier analysis, non-remission and PR at 12-months after rituximab, compared to CR, were associated with significantly worse kidney survival. Adverse events occurred in 30.5% and most were mild. Thus, rituximab enhances remission in a subset of children with SRNS, is generally safe and CR following rituximab is associated with favorable kidney outcome.
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Affiliation(s)
- Eugene Yu-Hin Chan
- Department of Paediatrics, The Chinese University of Hong Kong, Shatin, Hong Kong SAR; Paediatric Nephrology Centre, Department of Paediatric and Adolescent Medicine, Hong Kong Children's Hospital, Kowloon Bay, Hong Kong SAR.
| | - Aditi Sinha
- Division of Nephrology, Department of Pediatrics, Indian Council of Medical Research Advanced Center for Research in Nephrology, India Institute of Medical Sciences, New Delhi, India
| | - Ellen L M Yu
- Clinical Research Center, Princess Margaret Hospital, Lai Chi Kok, Hong Kong SAR
| | - Naureen Akhtar
- Department of Pediatric Nephrology, University of Child Health Sciences, The Children's Hospital Lahore, Pakistan
| | - Andrea Angeletti
- Division of Nephrology, Dialysis, and Transplantation, IRCCS (Scientific Institute for Research and Health Care) Istituto Giannina Gaslini, Genoa, Italy
| | - Arvind Bagga
- Division of Nephrology, Department of Pediatrics, Indian Council of Medical Research Advanced Center for Research in Nephrology, India Institute of Medical Sciences, New Delhi, India
| | - Sushmita Banerjee
- Department of Pediatrics, Calcutta Medical Research Institute, Kolkata, India
| | - Olivia Boyer
- Néphrologie Pédiatrique, Centre de Référence du Syndrome Néphrotique de l'Enfant et de l'Adulte, Hôpital Necker Enfants Malades, Assistance publique-hôpitaux de Paris (APHP), Institut Imagine, Institut national de la santé et de la recherche médicale (INSERM) U1163, Université de Paris, Paris, France
| | - Chang-Yien Chan
- Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Department of Paediatrics, Khoo Teck Puat-National University Children's Medical Institute, National University Health System, Singapore
| | - Anna Francis
- Department of Nephrology, Queensland Children's Hospital, Brisbane, Australia
| | - Gian Marco Ghiggeri
- Division of Nephrology, Dialysis, and Transplantation, IRCCS (Scientific Institute for Research and Health Care) Istituto Giannina Gaslini, Genoa, Italy
| | - Riku Hamada
- Department of Nephrology and Rheumatology, Tokyo Metropolitan Children's Medical Center, Tokyo, Japan
| | - Pankaj Hari
- Division of Nephrology, Department of Pediatrics, Indian Council of Medical Research Advanced Center for Research in Nephrology, India Institute of Medical Sciences, New Delhi, India
| | - Nakysa Hooman
- Aliasghar Clinical Research Development Center, Department of Pediatrics, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Luke Sydney Hopf
- Department of Pediatrics, University Medical Center Hamburg-Eppendorf, University Children's Hospital, Hamburg, Germany
| | - Mohamad Ikram I
- Department of Pediatrics, School of Medical Sciences, Universiti Sains Malaysia, Health Campus, Kota Bharu, Kelantan, Malaysia
| | - Iftikhar Ijaz
- Children Kidney Center, Department of Pediatrics, King Edward Medical University, Lahore, Pakistan
| | - Dmytro D Ivanov
- Department of Nephrology and Renal Replacement Therapy, Shupyk National Healthcare University of Ukraine, Kyiv, Ukraine; Department of Nephrology and Extracorporeal Treatment, Bogomolets National Medical University Kyiv, Kyiv, Ukraine
| | - Suprita Kalra
- Department of Pediatrics, Command Hospital, New Delhi, India
| | - Hee Gyung Kang
- Department of Pediatrics, Kidney Disease Center for Children and Adolescents, Seoul National University Children's Hospital, Seoul National University College of Medicine, Seoul, Korea
| | - Laura Lucchetti
- Division of Nephrology, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | - Francesca Lugani
- Division of Nephrology, Dialysis, and Transplantation, IRCCS (Scientific Institute for Research and Health Care) Istituto Giannina Gaslini, Genoa, Italy
| | - Alison Lap-Tak Ma
- Paediatric Nephrology Centre, Department of Paediatric and Adolescent Medicine, Hong Kong Children's Hospital, Kowloon Bay, Hong Kong SAR
| | - William Morello
- Pediatric Nephrology, Dialysis and Transplant Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milano, Italy
| | - María Dolores Camargo Muñiz
- Department of Pediatrics, Northeast National Medical Center, High Specialty Medical Unit No. 25, Instituto Mexicano del Seguro Social, Monterrey, N.L., México
| | - Subal Kumar Pradhan
- Division of Pediatric Nephrology, Sardar Vallabhbhai Patel Post Graduate Institute of Paediatrics (SVPPGIP) and Srirama Chandra Bhanja (SCB) Medical College, Cuttack, Odisha, India
| | - Larisa Prikhodina
- Division of Inherited & Acquired Kidney Diseases, Veltishev Research Clinical Institute for Pediatrics & Children Surgery, Pirogov Russian National Research Medical University, Moscow, Russia; Russian Medical Academy of Continuous Postgraduate Education, Moscow, Russia
| | - Reem H Raafat
- Division of Pediatric Nephrology and Pediatric Kidney Transplant, Joe DiMaggio Children's Hospital, Memorial Health System, Hollywood, Florida, USA
| | - Rajiv Sinha
- Division of Paediatric Nephrology, Institute of Child Health, Kolkata, India
| | - Sharon Teo
- Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Department of Paediatrics, Khoo Teck Puat-National University Children's Medical Institute, National University Health System, Singapore
| | - Kouki Tomari
- Department of General Pediatrics, Okinawa Prefectural Nanbu Medical Center and Children's Medical Center, Okinawa, Japan
| | - Marina Vivarelli
- Laboratory of Nephrology and Clinical Trial Center, Bambino Gesù Children's Hospital, IRCCS (Scientific Institute for Research and Health Care), Rome, Italy
| | - Hazel Webb
- Department of Paediatric Nephrology, Great Ormond Street Hospital for Children NHS Trust, London, UK
| | - Hui Kim Yap
- Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Department of Paediatrics, Khoo Teck Puat-National University Children's Medical Institute, National University Health System, Singapore
| | - Desmond Yat-Hin Yap
- Division of Nephrology, Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong.
| | - Kjell Tullus
- Department of Paediatric Nephrology, Great Ormond Street Hospital for Children NHS Trust, London, UK.
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Yokota S, Kamei K, Fujinaga S, Hamada R, Inaba A, Nishi K, Sato M, Ogura M, Sakuraya K, Ito S. Efficacy of rituximab and risk factors for poor prognosis in patients with childhood-onset steroid-resistant nephrotic syndrome: a multicenter study. Pediatr Nephrol 2024; 39:2979-2988. [PMID: 38834892 DOI: 10.1007/s00467-024-06422-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2024] [Revised: 05/11/2024] [Accepted: 05/11/2024] [Indexed: 06/06/2024]
Abstract
BACKGROUND The efficacy of rituximab in steroid-resistant nephrotic syndrome (SRNS) is controversial. We previously reported that rituximab in combination with methylprednisolone pulse therapy (MPT) and immunosuppressants was associated with favorable outcomes. We determined risk factors for poor response following rituximab treatment, which remains unknown. METHODS This retrospective study included 45 patients with childhood-onset SRNS treated with rituximab across four pediatric kidney facilities. Treatment effects were categorized as complete remission (CR), partial remission (PR), and no remission (NR) at one year after rituximab treatment. The primary outcome was the rate of CR, PR, and NR. Risk factors for non-CR were calculated with multivariate logistic regression. Adverse events and the relationship between disease status at one year and long-term prognosis were also evaluated. RESULTS The rates of CR, PR, and NR at one year were 69%, 24%, and 7%, respectively. The median time from rituximab administration to CR was 90 days. The median follow-up period after rituximab administration was 7.4 years. In multivariate analysis, significant risk factors for poor response were the pathologic finding of focal segmental glomerular sclerosis and a long interval between SRNS diagnosis and rituximab administration. The rates of CR were 90.3% and 21.4% in patients receiving rituximab within and after 6 months following SRNS diagnosis, respectively (p < 0.001). Five patients developed chronic kidney disease stage G5, including 2 of the 11 patients with PR and all 3 patients with NR, whereas none of the 31 patients with CR developed chronic kidney disease stage G5. CONCLUSION Early administration of rituximab in combination with MPT and immunosuppressants might achieve favorable outcomes in patients with SRNS.
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Affiliation(s)
- Shunsuke Yokota
- Division of Nephrology and Rheumatology, National Center for Child Health and Development, 2-10-1, Okura, Setagaya-ku, Tokyo, 157-8535, Japan
- Division of Nephrology, Saitama Children's Medical Center, Saitama, Japan
| | - Koichi Kamei
- Division of Nephrology and Rheumatology, National Center for Child Health and Development, 2-10-1, Okura, Setagaya-ku, Tokyo, 157-8535, Japan.
| | - Shuichiro Fujinaga
- Division of Nephrology, Saitama Children's Medical Center, Saitama, Japan
| | - Riku Hamada
- Division of Nephrology and Rheumatology, Tokyo Metropolitan Children's Medical Center, Tokyo, Japan
| | - Aya Inaba
- Department of Pediatrics, Yokohama City University Medical Center, Kanagawa, Japan
| | - Kentaro Nishi
- Division of Nephrology and Rheumatology, National Center for Child Health and Development, 2-10-1, Okura, Setagaya-ku, Tokyo, 157-8535, Japan
| | - Mai Sato
- Division of Nephrology and Rheumatology, National Center for Child Health and Development, 2-10-1, Okura, Setagaya-ku, Tokyo, 157-8535, Japan
| | - Masao Ogura
- Division of Nephrology and Rheumatology, National Center for Child Health and Development, 2-10-1, Okura, Setagaya-ku, Tokyo, 157-8535, Japan
| | - Koji Sakuraya
- Division of Nephrology, Saitama Children's Medical Center, Saitama, Japan
| | - Shuichi Ito
- Division of Nephrology and Rheumatology, National Center for Child Health and Development, 2-10-1, Okura, Setagaya-ku, Tokyo, 157-8535, Japan
- Department of Pediatrics, Graduate School of Medicine, Yokohama City University, Kanagawa, Japan
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7
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Angeletti A, Bin S, Kajana X, Spinelli S, Bigatti C, Caridi G, Candiano G, Lugani F, Verrina EE, La Porta E, Magnasco A, Bruschi M, Cravedi P, Ghiggeri GM. Combined Rituximab and Daratumumab Treatment in Difficult-to-Treat Nephrotic Syndrome Cases. Kidney Int Rep 2024; 9:1892-1896. [PMID: 38899172 PMCID: PMC11184257 DOI: 10.1016/j.ekir.2024.04.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2024] [Revised: 03/28/2024] [Accepted: 04/01/2024] [Indexed: 06/21/2024] Open
Affiliation(s)
- Andrea Angeletti
- Nephrology, Dialysis and Transplantation Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy
| | - Sofia Bin
- Translational Transplant Research Center and Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Xhuliana Kajana
- Nephrology, Dialysis and Transplantation Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy
| | - Sonia Spinelli
- Nephrology, Dialysis and Transplantation Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy
| | - Carolina Bigatti
- Nephrology, Dialysis and Transplantation Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy
| | - Gianluca Caridi
- Nephrology, Dialysis and Transplantation Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy
| | - Giovanni Candiano
- Nephrology, Dialysis and Transplantation Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy
| | - Francesca Lugani
- Nephrology, Dialysis and Transplantation Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy
| | - Enrico E. Verrina
- Nephrology, Dialysis and Transplantation Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy
| | - Edoardo La Porta
- Nephrology, Dialysis and Transplantation Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy
| | - Alberto Magnasco
- Nephrology, Dialysis and Transplantation Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy
| | - Maurizio Bruschi
- Nephrology, Dialysis and Transplantation Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy
| | - Paolo Cravedi
- Translational Transplant Research Center and Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Gian Marco Ghiggeri
- Nephrology, Dialysis and Transplantation Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy
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Saiteja P, Deepthi B, Krishnasamy S, Sravani M, Krishnamurthy S. Intravenous cyclophosphamide therapy in children with calcineurin inhibitor-resistant steroid-resistant nephrotic syndrome in a resource-limited setting. Pediatr Nephrol 2024; 39:1149-1160. [PMID: 37947902 DOI: 10.1007/s00467-023-06187-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2023] [Revised: 09/01/2023] [Accepted: 09/26/2023] [Indexed: 11/12/2023]
Abstract
BACKGROUND In pediatric steroid-resistant nephrotic syndrome (SRNS), calcineurin inhibitors (CNIs) are recommended as first-line therapy, with efficacy ranging between 60 and 80%, implying a substantial proportion will exhibit CNI resistance. Which alternate immunosuppressive therapy should be used in non-genetic pediatric SRNS exhibiting CNI resistance is especially relevant in low- to middle-income countries (LMIC), where the prohibitive costs of certain drugs such as monoclonal antibodies often determine therapy choice. METHODS The primary objective was to assess the efficacy of intravenous cyclophosphamide in a proportion of children aged 1-18 years with CNI-resistant SRNS with a complete response (CR) or partial response (PR) at 6 months from commencement of pulse therapy. The secondary objectives were to assess the proportion and profile of infections and adverse effects. RESULTS Of 90 children with idiopathic SRNS presenting between January 2013 and December 2022, 29 (32.2%) had CNI resistance and were enrolled. They were administered monthly intravenous cyclophosphamide pulses (6 pulses). Median (IQR) duration of follow-up was 48 (29.5, 63.5) months. At the end of 6 months of cyclophosphamide therapy, 13 (44.8%) attained CR and 4 (13.8%) attained PR, with an overall cyclophosphamide success rate of 58.6%. The efficacy of intravenous cyclophosphamide was higher in secondary (9/10; 90%) versus primary CNI resistance (8/19; 42.1%) (p = 0.029). Three children (3/29; 10.3%) developed systemic infections within 12 months of initiation of cyclophosphamide therapy, similar to the rate of systemic infections among children receiving CNI for SRNS management (6/41; 14.6%) (p = 0.85). CONCLUSIONS It is prudent to try intravenous cyclophosphamide in CNI-resistant SRNS in LMIC, given the reasonable cost and good efficacy rates (58.6%).
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Affiliation(s)
- Paraselli Saiteja
- Pediatric Nephrology Services, Department of Pediatrics, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Pondicherry, 605006, India
| | - Bobbity Deepthi
- Pediatric Nephrology Services, Department of Pediatrics, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Pondicherry, 605006, India
| | - Sudarsan Krishnasamy
- Pediatric Nephrology Services, Department of Pediatrics, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Pondicherry, 605006, India
| | - Madhileti Sravani
- Pediatric Nephrology Services, Department of Pediatrics, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Pondicherry, 605006, India
| | - Sriram Krishnamurthy
- Pediatric Nephrology Services, Department of Pediatrics, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Pondicherry, 605006, India.
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9
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Nozu K, Sako M, Tanaka S, Kano Y, Ohwada Y, Morohashi T, Hamada R, Ohtsuka Y, Oka M, Kamei K, Inaba A, Ito S, Sakai T, Kaito H, Shima Y, Ishikura K, Nakamura H, Nakanishi K, Horinouchi T, Konishi A, Omori T, Iijima K. Rituximab in combination with cyclosporine and steroid pulse therapy for childhood-onset multidrug-resistant nephrotic syndrome: a multicenter single-arm clinical trial (JSKDC11 trial). Clin Exp Nephrol 2024; 28:337-348. [PMID: 38010466 PMCID: PMC10955017 DOI: 10.1007/s10157-023-02431-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2023] [Accepted: 10/21/2023] [Indexed: 11/29/2023]
Abstract
BACKGROUND Only 80% of children with idiopathic nephrotic syndrome respond well to glucocorticoid therapy. Multidrug-resistant nephrotic syndrome (MRNS) is associated with a poor kidney prognosis. Several retrospective studies have identified rituximab as an effective treatment for MRNS; however, prospective studies are required to assess its efficacy and safety. METHODS We conducted a multicenter, non-blinded, single-arm trial to investigate the efficacy and safety of rituximab in patients with childhood-onset MRNS who were resistant to cyclosporine and more than three courses of steroid pulse therapy. The enrolled patients received four 375 mg/m2 doses of rituximab in combination with baseline cyclosporine and steroid pulse therapy. The primary endpoint was a > 50% reduction in the urinary protein/creatinine ratio from baseline on day 169. Complete and partial remissions were also evaluated. RESULTS Six patients with childhood-onset MRNS were enrolled. All patients were negative for pathogenic variants of podocyte-related genes. On day 169, five patients (83.3%) showed a > 50% reduction in the urinary protein/creatinine ratio, two patients showed partial remission, and two patients showed complete remission. No deaths occurred and severe adverse events occurred in two patients (infection in one patient and acute kidney injury in one patient). Three patients needed treatment for moderate-to-severe infection. CONCLUSIONS The study treatment effectively reduced the urinary protein/creatinine ratio in patients with childhood-onset MRNS. The adverse events in this study were within the expected range; however, attention should be paid to the occurrence of infections.
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Affiliation(s)
- Kandai Nozu
- Department of Pediatrics, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-Cho, Chuo-Ku, Kobe, 650-0017, Japan.
| | - Mayumi Sako
- Division for Clinical Trials, Department of Clinical Research Promotion, Clinical Research Center, National Center for Child Health and Development, Tokyo, Japan
| | - Seiji Tanaka
- Department of Pediatrics, Kurume University School of Medicine, Kurume, Japan
| | - Yuji Kano
- Department of Pediatrics, Dokkyo Medical University School of Medicine, Tochigi, Japan
| | - Yoko Ohwada
- Department of Pediatrics, Dokkyo Medical University School of Medicine, Tochigi, Japan
| | - Tamaki Morohashi
- Department of Pediatrics, Nihon University School of Medicine, Tokyo, Japan
| | - Riku Hamada
- Department of Nephrology, Tokyo Metropolitan Children's Medical Center, Tokyo, Japan
| | - Yasufumi Ohtsuka
- Department of Pediatrics, Saga University School of Medicine, Saga, Japan
| | - Masafumi Oka
- Department of Pediatrics, Saga University School of Medicine, Saga, Japan
| | - Koichi Kamei
- Division of Nephrology and Rheumatology, National Center for Child Health and Development, Tokyo, Japan
| | - Aya Inaba
- Department of Pediatrics, Graduate School of Medicine, Yokohama City University, Yokohama, Japan
| | - Shuichi Ito
- Department of Pediatrics, Graduate School of Medicine, Yokohama City University, Yokohama, Japan
| | - Tomoyuki Sakai
- Department of Pediatrics, Shiga University of Medical Science, Shiga, Japan
| | - Hiroshi Kaito
- Department of Nephrology, Hyogo Prefectural Kobe Children's Hospital, Kobe, Japan
| | - Yuko Shima
- Department of Pediatrics, Wakayama Medical University, Wakayama, Japan
| | - Kenji Ishikura
- Department of Pediatrics, Kitasato University School of Medicine, Kanagawa, Japan
| | - Hidefumi Nakamura
- Clinical Research Center, National Center for Child Health and Development, Tokyo, Japan
| | - Koichi Nakanishi
- Department of Child Health and Welfare (Pediatrics), Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan
| | - Tomoko Horinouchi
- Department of Pediatrics, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-Cho, Chuo-Ku, Kobe, 650-0017, Japan
| | - Akihide Konishi
- Clinical and Translational Research Center, Kobe University Hospital, Kobe, Japan
| | - Takashi Omori
- Clinical and Translational Research Center, Kobe University Hospital, Kobe, Japan
| | - Kazumoto Iijima
- Department of Pediatrics, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-Cho, Chuo-Ku, Kobe, 650-0017, Japan
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Zhang Y, Yang J, Li J, Sun J, Zhou L, Xu D, Sha W, Dai L, Shen L. Rituximab may affect T lymphocyte subsets balance in primary membranous nephropathy. BMC Nephrol 2024; 25:86. [PMID: 38448810 PMCID: PMC10918849 DOI: 10.1186/s12882-024-03521-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2023] [Accepted: 02/24/2024] [Indexed: 03/08/2024] Open
Abstract
BACKGROUND The aim of this study was to investigate the effects and significance of rituximab (RTX) on the levels of T lymphocyte subsets in patients diagnosed with primary membranous nephropathy (PMN). METHODS A total of 58 PMN patients and 25 healthy donors were chosen as the subjects. Among the PMN patients, 40 individuals received RTX treatment and completed at least 6 months of follow-up. All subjects underwent flow cytometry analysis to determine the peripheral blood lymphocyte subsets. The changes in anti-PLA2R antibody titers and 24-hour urinary protein levels were evaluated by ELISA and Biuret method before and after treatment. RESULTS (1) The PMN group exhibited a significantly greater percentage of peripheral blood CD3-CD19+ B cells than the healthy group, which is consistent with the findings of previous reports. Additionally, compared with those in the peripheral blood of healthy individuals, the numbers of CD4+ central memory T cells, CD4+ effector memory T cells, CD4+/CD8+, and CD4+CD25+ T cells in the PMN peripheral blood were markedly greater. However, the number of peripheral blood Treg cells was reduced in the PMN group. (2) After 6 months of RTX treatment, PMN patients exhibited significant decreases in anti-PLA2R antibody titers, 24-hour urinary protein levels, and peripheral blood CD3-CD19+ B cells. Importantly, RTX administration decreased CD4+CD25+ T cells and CD4+/CD8+ in the peripheral blood of PMN patients and improved Treg cell levels. (3) RTX treatment induced alterations in the CD4+ T lymphocyte subsets in PMN patients, which did not correlate with B lymphocyte counts or anti-PLA2R antibody titers. CONCLUSIONS RTX treatment might have a beneficial impact on cellular immunity by effectively restoring the balance of CD4+ T lymphocyte subsets in PMN patients, which is beyond its effects on B cells and antibody production. TRIAL REGISTRATION The research was registered at the First Affiliated Hospital of Soochow University. REGISTRATION NUMBER MR-32-23-016211. Registration Date: May 31, 2023.
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Affiliation(s)
- Yuanyuan Zhang
- Department of Nephrology, The First Affiliated Hospital of Soochow University, Suzhou, PR China
- Department of Nephrology, Suzhou Hospital, Affiliated Hospital of Medical School, Nanjing University, Suzhou, PR China
| | - Jingjing Yang
- Department of Nephrology, BenQ Medical Center, Suzhou, PR China
| | - Jianzhong Li
- Department of Nephrology, The First Affiliated Hospital of Soochow University, Suzhou, PR China
| | - Jiani Sun
- Department of Nephrology, The First Affiliated Hospital of Soochow University, Suzhou, PR China
| | - Ling Zhou
- Department of Nephrology, The First Affiliated Hospital of Soochow University, Suzhou, PR China
| | - Deyu Xu
- Department of Nephrology, The First Affiliated Hospital of Soochow University, Suzhou, PR China
| | - Wengang Sha
- Department of Nephrology, The First Affiliated Hospital of Soochow University, Suzhou, PR China
| | - Lan Dai
- Jiangsu Institute of Hematology, Key Laboratory of Thrombosis and Hemostasis of Ministry of Health, The First Affiliated Hospital of Soochow University, Suzhou, PR China.
| | - Lei Shen
- Department of Nephrology, The First Affiliated Hospital of Soochow University, Suzhou, PR China.
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11
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Angeletti A, Bruschi M, Kajana X, La Porta E, Spinelli S, Caridi G, Lugani F, Verrina EE, Ghiggeri GM. Biologics in steroid resistant nephrotic syndrome in childhood: review and new hypothesis-driven treatment. Front Immunol 2023; 14:1213203. [PMID: 37705972 PMCID: PMC10497215 DOI: 10.3389/fimmu.2023.1213203] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2023] [Accepted: 08/14/2023] [Indexed: 09/15/2023] Open
Abstract
Nephrotic syndrome affects about 2-7 per 100,000 children yearly and accounts for less than 15% of end stage kidney disease. Steroids still represent the cornerstone of therapy achieving remission in 75-90% of the cases The remaining part result as steroid resistant nephrotic syndrome, characterized by the elevated risk of developing end stage kidney disease and frequently presenting disease recurrence in case of kidney transplant. The pathogenesis of nephrotic syndrome is still far to be elucidated, however, efficacy of immune treatments provided the basis to suggest the involvement of the immune system in the pathogenesis of the disease. Based on these substrates, more immune drugs, further than steroids, were administered in steroid resistant nephrotic syndrome, such as antiproliferative and alkylating agents or calcineurin inhibitors. However, such treatments failed in inducing a sustained remission. In last two decades, the developments of monoclonal antibodies, including the anti-CD20 rituximab and inhibitor of B7-1 abatacept, represented a valid opportunity of treatment. However, also the effectiveness of biologics resulted limited. We here propose a new hypothesis-driven treatment based on the combining administration of rituximab with the anti-CD38 monoclonal antibody daratumumab (NCT05704400), sustained by the hypothesis to target the entire B-cells subtypes pool, including the long-lived plasmacells.
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Affiliation(s)
- Andrea Angeletti
- Division of Nephrology, Dialysis, Transplantation, IRCCS Istituto Giannina Gaslini, Genova, Italy
- Laboratory of Molecular Nephrology, IRCCS Istituto Giannina Gaslini, Genova, Italy
| | - Maurizio Bruschi
- Division of Nephrology, Dialysis, Transplantation, IRCCS Istituto Giannina Gaslini, Genova, Italy
- Department of Experimental Medicine (DIMES), University of Genoa, Genoa, Italy
| | - Xhuliana Kajana
- Laboratory of Molecular Nephrology, IRCCS Istituto Giannina Gaslini, Genova, Italy
| | - Edoardo La Porta
- Division of Nephrology, Dialysis, Transplantation, IRCCS Istituto Giannina Gaslini, Genova, Italy
- Laboratory of Molecular Nephrology, IRCCS Istituto Giannina Gaslini, Genova, Italy
| | - Sonia Spinelli
- Laboratory of Molecular Nephrology, IRCCS Istituto Giannina Gaslini, Genova, Italy
| | - Gianluca Caridi
- Laboratory of Molecular Nephrology, IRCCS Istituto Giannina Gaslini, Genova, Italy
| | - Francesca Lugani
- Division of Nephrology, Dialysis, Transplantation, IRCCS Istituto Giannina Gaslini, Genova, Italy
- Laboratory of Molecular Nephrology, IRCCS Istituto Giannina Gaslini, Genova, Italy
| | - Enrico Eugenio Verrina
- Division of Nephrology, Dialysis, Transplantation, IRCCS Istituto Giannina Gaslini, Genova, Italy
- Laboratory of Molecular Nephrology, IRCCS Istituto Giannina Gaslini, Genova, Italy
| | - Gian Marco Ghiggeri
- Division of Nephrology, Dialysis, Transplantation, IRCCS Istituto Giannina Gaslini, Genova, Italy
- Laboratory of Molecular Nephrology, IRCCS Istituto Giannina Gaslini, Genova, Italy
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12
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Vincenti F, Angeletti A, Ghiggeri GM. State of the art in childhood nephrotic syndrome: concrete discoveries and unmet needs. Front Immunol 2023; 14:1167741. [PMID: 37503337 PMCID: PMC10368981 DOI: 10.3389/fimmu.2023.1167741] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2023] [Accepted: 06/21/2023] [Indexed: 07/29/2023] Open
Abstract
Nephrotic syndrome (NS) is a clinical entity characterized by proteinuria, hypoalbuminemia, and peripheral edema. NS affects about 2-7 per 100,000 children aged below 18 years old yearly and is classified, based on the response to drugs, into steroid sensitive (SSNS), steroid dependent, (SDNS), multidrug dependent (MDNS), and multidrug resistant (MRNS). Forms of NS that are more difficult to treat are associated with a worse outcome with respect to renal function. In particular, MRNS commonly progresses to end stage renal failure requiring renal transplantation, with recurrence of the original disease in half of the cases. Histological presentations of NS may vary from minimal glomerular lesions (MCD) to focal segmental glomerulosclerosis (FSGS) and, of relevance, the histological patterns do not correlate with the response to treatments. Moreover, around half of MRNS cases are secondary to causative pathogenic variants in genes involved in maintaining the glomerular structure. The pathogenesis of NS is still poorly understood and therapeutic approaches are mostly based on clinical experience. Understanding of pathogenetic mechanisms of NS is one of the 'unmet needs' in nephrology and represents a significant challenge for the scientific community. The scope of the present review includes exploring relevant findings, identifying unmet needs, and reviewing therapeutic developments that characterize NS in the last decades. The main aim is to provide a basis for new perspectives and mechanistic studies in NS.
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Affiliation(s)
- Flavio Vincenti
- Division of Nephrology, Department of Medicine and Department of Surgery, University of California San Francisco, San Francisco, CA, United States
| | - Andrea Angeletti
- Nephrology Dialysis and Transplantation, Istituto di Ricerca e Cura a Carattere Scientifico (IRCCS) Istituto Giannina Gaslini, Genoa, Italy
| | - Gian Marco Ghiggeri
- Nephrology Dialysis and Transplantation, Istituto di Ricerca e Cura a Carattere Scientifico (IRCCS) Istituto Giannina Gaslini, Genoa, Italy
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13
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Gomes R, Mosca S, Bastos-Gomes M, Correia-Costa L, Rocha L, Teixeira A, Costa T, Sameiro-Faria M, Matos P, Mota C. Rituximab therapy for childhood onset idiopathic nephrotic syndrome: experience of a Portuguese tertiary center. J Bras Nefrol 2023; 45:326-334. [PMID: 36259942 PMCID: PMC10697169 DOI: 10.1590/2175-8239-jbn-2022-0056en] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Accepted: 08/29/2022] [Indexed: 11/21/2022] Open
Abstract
INTRODUCTION Rituximab (RTX) is a therapeutic option in pediatric difficult-to-treat idiopathic nephrotic syndrome (NS). We aimed to assess the efficacy and safety of RTX use in these patients. METHOD A retrospective study of all patients with idiopathic NS treated with RTX was conducted in a pediatric nephrology division of a tertiary hospital. Demographic, anthropometric, clinical and analytical data were collected prior to treatment and at 6, 12, and 24 months. RESULTS Sixteen patients were included (11 males), with a median (25th-75th percentile, P25-P75) age at diagnosis of 2 (2.0-2.8) years. Fifteen were steroid-sensitive and 1 was steroid-resistant and sensitive to cyclosporine. The median age at administration of RTX was 10 (6.3-14.0) years. Throughout a median follow-up time of 2.5 (1.0-3.0) years, 6 (37.5%) patients achieved partial remission and 7 (43.8%) had no relapses and were not taking any immunosuppressants at the 24-month follow-up visit. Regarding complications, 1 patient presented persistent hypogammaglobulinemia. Compared with the 12-month period before RTX, there was a decrease in the median number of relapses at 6 and 12 months [3 (3.0-4.0) vs 0 (0-0.8) and 0.50 (0-1.0), respectively; p = 0.001] and in the daily steroids dose (mg/kg/day) at 6, 12, and 24 months [0.29 (0.15-0.67)vs [0.10 (0.07-0.13); p = 0.001], [0.12 (0.05-0.22); p = 0.005] and [0.07(0.04-0.18); p = 0.021]], respectively. There was also a reduction in the median BMI z score at 24 months [2.11 (0.45-3.70) vs. 2.93 (2.01-3.98); p = 0.049]. CONCLUSION Our results confirm the efficacy and safety of RTX use in pediatric idiopathic NS and highlight its' potential cardiometabolic benefits.
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Affiliation(s)
- Rita Gomes
- Centro Hospitalar Universitário do Porto, Centro Materno-Infantil do
Norte, Serviço de Pediatria, Porto, Portugal
| | - Sara Mosca
- Centro Hospitalar Universitário do Porto, Centro Materno-Infantil do
Norte, Serviço de Pediatria, Porto, Portugal
| | - Mariana Bastos-Gomes
- Unidade Local de Saúde do Alto Minho, Serviço de Pediatria, EPE,
Viana do Castelo, Portugal
| | - Liane Correia-Costa
- Centro Hospitalar Universitário do Porto, Centro Materno-Infantil do
Norte, Serviço de Pediatria, Unidade de Nefrologia Pediátrica, Porto,
Portugal
| | - Liliana Rocha
- Centro Hospitalar Universitário do Porto, Centro Materno-Infantil do
Norte, Serviço de Pediatria, Unidade de Nefrologia Pediátrica, Porto,
Portugal
| | - Ana Teixeira
- Centro Hospitalar Universitário do Porto, Centro Materno-Infantil do
Norte, Serviço de Pediatria, Unidade de Nefrologia Pediátrica, Porto,
Portugal
| | - Teresa Costa
- Centro Hospitalar Universitário do Porto, Centro Materno-Infantil do
Norte, Serviço de Pediatria, Unidade de Nefrologia Pediátrica, Porto,
Portugal
| | - Maria Sameiro-Faria
- Centro Hospitalar Universitário do Porto, Centro Materno-Infantil do
Norte, Serviço de Pediatria, Unidade de Nefrologia Pediátrica, Porto,
Portugal
| | - Paula Matos
- Centro Hospitalar Universitário do Porto, Centro Materno-Infantil do
Norte, Serviço de Pediatria, Unidade de Nefrologia Pediátrica, Porto,
Portugal
| | - Conceição Mota
- Centro Hospitalar Universitário do Porto, Centro Materno-Infantil do
Norte, Serviço de Pediatria, Unidade de Nefrologia Pediátrica, Porto,
Portugal
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14
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Mishra OP, Sidar M, Batra VV, Prasad R, Singh A, Abhinay A, Mishra A, Yadav AK. Outcomes of children with idiopathic steroid resistant nephrotic syndrome: a single centre observational study. J Bras Nefrol 2023; 45:199-209. [PMID: 36179014 PMCID: PMC10627125 DOI: 10.1590/2175-8239-jbn-2022-0073en] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Accepted: 06/20/2022] [Indexed: 11/22/2022] Open
Abstract
INTRODUCTION Idiopathic steroid resistant nephrotic syndrome (SRNS) has variable outcomes in children. The primary objective of the present study was to assess the cumulative remission rate and the secondary objectives were to assess factors affecting the remission status, kidney function survival, and adverse effects of medications. METHODS One hundred fourteen patients with SRNS were included. Calcineurin inhibitor-based treatment protocol along with prednisolone and angiotensin-converting enzyme inhibitor were used, and patients were followed over 5 years. RESULTS Median age was 4.5 years; 53.5% of cases were between 1 to 5 years of age. Sixty-two patients (54.4%) were at initial stage and 52 (45.6%) were at a late SRNS stage. Median eGFRcr was 83.5 mL/min/1.73m2 at presentation. Of the 110 patients, 63 (57.3%) achieved remission [complete remission 30 (27.3%), partial remission 33 (30%)], and 47 (42.7%) had no remission. Kidney function survival was 87.3% and 14 cases (12.7%) had progression to CKD (G3-8, G4-3, G5-1, and G5D-2). Median duration of follow up was 36 months (IQR 24, 60). Age of onset, cyclosporine/tacrolimus, eGFRcr, and histopathology (MCD/FSGS) did not affect remission. Similarly, remission status in addition to age of onset, drug protocol, and histopathology did not significantly affect kidney function during a period of 5 years. Hypertension, cushingoid facies, short stature, cataract, and obesity were observed in 37.7, 29.8, 25.5, 17.5, and 0.7% of cases, respectively. CONCLUSION About half of the cases achieved remission. Age of onset of disease, cyclosporine/tacrolimus use, and histopathological lesion neither affected remission status nor short-term kidney function survival in SRNS.
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Affiliation(s)
- Om P. Mishra
- Banaras Hindu University, Institute of Medical Sciences, Department
of Pediatrics, Division of Pediatric Nephrology, Varanasi, India
| | - Minketan Sidar
- Banaras Hindu University, Institute of Medical Sciences, Department
of Pediatrics, Division of Pediatric Nephrology, Varanasi, India
| | - Vineeta V. Batra
- G. B. Pant Institute of Post Graduate Medical Education &
Research, Department of Pathology, New Delhi, India
| | - Rajniti Prasad
- Banaras Hindu University, Institute of Medical Sciences, Department
of Pediatrics, Division of Pediatric Nephrology, Varanasi, India
| | - Ankur Singh
- Banaras Hindu University, Institute of Medical Sciences, Department
of Pediatrics, Division of Pediatric Nephrology, Varanasi, India
| | - Abhishek Abhinay
- Banaras Hindu University, Institute of Medical Sciences, Department
of Pediatrics, Division of Pediatric Nephrology, Varanasi, India
| | - Akash Mishra
- Jawahar Lal Institute of Postgraduate Medical Education and
Research, Department of Biostatistics, Puducherry, India
| | - Ashish K. Yadav
- Banaras Hindu University, Institute of Medical Sciences, Center of
Biostatistics, Varanasi, India
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15
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Chan EYH, Yap DYH, Colucci M, Ma ALT, Parekh RS, Tullus K. Use of Rituximab in Childhood Idiopathic Nephrotic Syndrome. Clin J Am Soc Nephrol 2023; 18:533-548. [PMID: 36456193 PMCID: PMC10103321 DOI: 10.2215/cjn.08570722] [Citation(s) in RCA: 26] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Revised: 10/11/2022] [Accepted: 10/31/2022] [Indexed: 12/04/2022]
Abstract
Rituximab is an established therapy in children with idiopathic nephrotic syndrome to sustain short- to medium-term disease remission and avoid steroid toxicities. Recent trials focus on its use as a first-line agent among those with milder disease severity. Rituximab is used in multidrug refractory nephrotic syndrome and post-transplant disease recurrence, although the evidence is much less substantial. Available data suggest that the treatment response to rituximab depends on various patient factors, dosing regimen, and the concomitant use of maintenance immunosuppression. After repeated treatments, patients are found to have an improving response overall with a longer relapse-free period. The drug effect, however, is not permanent, and 80% of patients eventually relapse and many will require an additional course of rituximab. This underpins the importance of understanding the long-term safety profile on repeated treatments. Although rituximab appears to be generally safe, there are concerns about long-term hypogammaglobulinemia, especially in young children. Reliable immunophenotyping and biomarkers are yet to be discovered to predict treatment success, risk of both rare and severe side effects, e.g. , persistent hypogammaglobulinemia, and guiding of redosing strategy. In this review, we highlight recent advances in the use of rituximab for childhood nephrotic syndrome and how the therapeutic landscape is evolving.
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Affiliation(s)
- Eugene Yu-hin Chan
- Paediatric Nephrology Centre, Hong Kong Children's Hospital, Kowloon, Hong Kong
- Department of Paediatric and Adolescent Medicine, Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong
| | - Desmond Yat-hin Yap
- Division of Nephrology, Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Pokfulam, Hong Kong
| | - Manuela Colucci
- Renal Diseases Research Unit, Genetics and Rare Diseases Research Division, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | - Alison Lap-tak Ma
- Paediatric Nephrology Centre, Hong Kong Children's Hospital, Kowloon, Hong Kong
- Department of Paediatric and Adolescent Medicine, Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong
| | - Rulan S. Parekh
- Departments of Medicine and Pediatrics, Women's College Hospital, Hospital for Sick Children and University of Toronto, Toronto, Ontario, Canada
| | - Kjell Tullus
- Department of Paediatric Nephrology, Great Ormond Street Hospital for Children NHS Trust, London, United Kingdom
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Luo N, Shen X, Xia H, Xu Y, Zhong S, Shan H, Zhao L. Efficacy and safety of rituximab in children with steroid-dependent or frequently relapsing nephrotic syndrome: a meta-analysis of randomized controlled trials. Arch Med Sci 2023; 21:588-596. [PMID: 40395883 PMCID: PMC12087312 DOI: 10.5114/aoms/161675] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Accepted: 02/26/2023] [Indexed: 05/22/2025] Open
Abstract
Introduction To explore the efficacy and safety of rituximab (RTX) in children with steroid-dependent nephrotic syndrome (SDNS) or frequently relapsing nephrotic syndrome (FRNS) through meta-analysis. Material and methods Meta-analysis searches were performed before November 30th, 2021, using the PubMed, Embase, Web of Science, and Cochrane Library databases to collect randomized controlled trials (RCTs). FRNS or SDNS children younger than 18 years of age were included. The RTX group was treated with RTX combined with conventional therapy, whereas the control group was given conventional therapy. Review Manager 5.3 and STATA 15.0 were used to perform the statistical analyses. Results Of 1450 screened articles, a total of eight studies eligible for inclusion involving 476 patients were included. As compared to the control group (RR = 1.91, 95% CI: 1.16, 3.14, p < 0.05), RTX did not show significant improvement in the short term (RR = 2.48, 95% CI: 0.85, 7.25, p = 0.10). However, the RTX group achieved a higher short-term complete remission rate when two studies with heterogeneity were excluded (RR = 2.17, 95% CI: 1.65, 2.84, p < 0.001). Proteinuria levels were reduced more effectively in the RTX group (MD = -1.84, 95% CI: -2.42, -1.26, p < 0.001). The RTX group and the control group had no significant differences in adverse events. Conclusions RTX can be considered as an effective and safe treatment option for children with SDNS or FRNS. However, it is necessary to conduct further studies via RCTs to evaluate the persistent long-term effects.
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Affiliation(s)
- Ningxin Luo
- Shanghai Children’s Medical Center (SCMC) affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiaoyu Shen
- Shanghai Children’s Medical Center (SCMC) affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Hui Xia
- Shanghai Children’s Medical Center (SCMC) affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yazhen Xu
- Shanghai Children’s Medical Center (SCMC) affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Shuwen Zhong
- Shanghai Children’s Medical Center (SCMC) affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Hongmei Shan
- Shanghai Children’s Medical Center (SCMC) affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Li Zhao
- Shanghai Children’s Medical Center (SCMC) affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Sakr HI, Edrees B, Taher HO, Miliany TT, Gazzaz RY, AlRuwaithi AO, Alamer MF, Metawee ME. Combined Methylprednisolone Pulse Therapy plus Rituximab for Treating a Rare Juvenile Steroid-Resistant Nephrotic Syndrome with Cerebral Venous Sinus Thrombosis: A Case Report. J Cardiovasc Dev Dis 2022; 9:383. [PMID: 36354782 PMCID: PMC9692607 DOI: 10.3390/jcdd9110383] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2022] [Revised: 10/26/2022] [Accepted: 10/27/2022] [Indexed: 10/03/2024] Open
Abstract
Background: Cerebral venous sinus thrombosis (CVST) secondary to nephrotic syndrome (NS) is rarely reported. Additionally, treating steroid-sensitive nephrotic syndrome (SSNS) that changes to steroid resistance (SRNS) is difficult, with many relapses and side effects. Case presentation: A 32-month-old SSNS male child turned into SRNS and developed cerebral venous sinus thrombosis (CVST), a rare complication of NS. As a result of the administration of combined pulse methylprednisolone and IV Rituximab (RTX) therapy, the patient showed marked improvement, the results of urine analysis were remarkably improved, and the child started to respond to treatment. Conclusion: Successful treatment of a rare case of juvenile SSNS behaving as SRNS with the development of CVST could be established using combined steroid pulse therapy, Enoxaparin, and the B lymphocytes monoclonal antibodies RTX.
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Affiliation(s)
- Hader I. Sakr
- Department of Medical Physiology, Faculty of Medicine, Cairo University, Cairo 11511, Egypt
- Medicine Program, Batterjee Medical College, P.O. Box 6231, Jeddah 21442, Saudi Arabia
| | - Burhan Edrees
- Department of Pediatrics, Umm Al-Qura University, Makkah 24451, Saudi Arabia
| | - Hussein Omar Taher
- Medicine Program, Batterjee Medical College, P.O. Box 6231, Jeddah 21442, Saudi Arabia
| | - Tuleen Talal Miliany
- Medicine Program, Batterjee Medical College, P.O. Box 6231, Jeddah 21442, Saudi Arabia
| | - Raneem Yasser Gazzaz
- Medicine Program, Batterjee Medical College, P.O. Box 6231, Jeddah 21442, Saudi Arabia
| | - Asma Omar AlRuwaithi
- Medicine Program, Batterjee Medical College, P.O. Box 6231, Jeddah 21442, Saudi Arabia
| | - Mohammed Fouad Alamer
- Medicine Program, Batterjee Medical College, P.O. Box 6231, Jeddah 21442, Saudi Arabia
| | - Mostafa E. Metawee
- Department of Histology and Cytology, Faculty of Medicine, Al-Azhar University, Cairo 11511, Egypt
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Gomes R, Mosca S, Bastos-Gomes M, Correia-Costa L, Rocha L, Teixeira A, Costa T, Sameiro-Faria M, Matos P, Mota C. Terapia com Rituximabe para síndrome nefrótica idiopática de início na infância: experiência de um centro terciário português. J Bras Nefrol 2022. [DOI: 10.1590/2175-8239-jbn-2022-0056pt] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Resumo Introdução: Rituximabe (RTX) é uma opção terapêutica na síndrome nefrótica (SN) idiopática pediátrica de difícil tratamento. Visamos avaliar eficácia e segurança do uso de RTX nestes pacientes. Método: Realizou-se estudo retrospectivo de todos os pacientes com SN idiopática tratados com RTX, em uma unidade de nefrologia pediátrica de um hospital terciário. Dados demográficos, antropométricos, clínicos e analíticos foram coletados antes do tratamento e aos 6, 12 e 24 meses. Resultados: Incluímos 16 pacientes (11 do sexo masculino), com idade mediana (percentil 25–75, P25–P75) de 2 (2,0–2,8) anos ao diagnóstico. Quinze eram sensíveis a esteroides, e 1 resistente a esteroides e sensível à ciclosporina.A idade mediana na administração do RTX foi 10 (6,3–14,0) anos. Durante um tempo mediano de acompanhamento de 2,5(1,0–3,0) anos, 6 (37,5%) pacientes alcançaram remissão parcial e 7 (43,8%) não tiveram recidivas e não estavam tomando imunossupressor no acompanhamento aos 24 meses. Quanto às complicações,1 paciente apresentou hipogamaglobulinemia persistente. Comparado ao período de12 meses anterior ao RTX, houve diminuição no número mediano de recidivas em 6 e 12 meses [3 (3,0–4,0) vs 0 (0–0,8) e 0,50 (0–1,0), respectivamente; p = 0,001] e na dose diária de esteroides (mg/kg/dia) aos 6, 12 e 24 meses [0,29 (0,15–0,67) >vs [0,10 (0,07–0,13); p = 0,001], [0,12 (0,05–0,22); p = 0,005] e [0,07 (0,04–0,18); p = 0,021], respectivamente. Houve também redução na mediana do escore z do IMC aos 24 meses [2,11 (0,45–3,70) vs 2,93 (2,01–3,98);p = 0,049]. Conclusões: Nossos resultados confirmam a eficácia e segurança do uso de RTX em SN idiopática pediátrica, destacando seus potenciais benefícios cardiometabólicos.
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Affiliation(s)
- Rita Gomes
- Centro Hospitalar Universitário do Porto, Portugal
| | - Sara Mosca
- Centro Hospitalar Universitário do Porto, Portugal
| | | | | | | | - Ana Teixeira
- Centro Hospitalar Universitário do Porto, Portugal
| | - Teresa Costa
- Centro Hospitalar Universitário do Porto, Portugal
| | | | - Paula Matos
- Centro Hospitalar Universitário do Porto, Portugal
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Ambarsari CG, Saraswati M, Laudza GS. Rituximab, Mycophenolic Acid, and Calcineurin Inhibitors Achieve Long-Term Remission in Pediatric Focal Segmental Glomerulosclerosis with Steroid-Resistant and Frequently Relapsing Nephrotic Syndrome: A Report of Two Cases. Case Rep Nephrol Dial 2022; 12:167-177. [PMID: 36518356 PMCID: PMC9743143 DOI: 10.1159/000525776] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2022] [Accepted: 06/19/2022] [Indexed: 11/05/2022] Open
Abstract
Studies investigating the effect of rituximab in children with nephrotic syndrome (NS) due to focal segmental glomerulosclerosis (FSGS) have reported conflicting results, with some concluding that patients may require additional immunosuppressive therapy to achieve and/or maintain long-term remission. We report successful treatment of pediatric FSGS with rituximab infusions, followed by maintenance immunosuppression with mycophenolic acid (MPA) and a calcineurin inhibitor (CNI) in 1 patient with refractory steroid-resistant NS (SRNS), and one with frequently relapsing NS (FRNS). Case 1 is a patient with refractory SRNS due to FSGS. MPA and tacrolimus induced complete remission within 6 months following rituximab treatment. Remission was maintained for over 2 years, and the patient's kidney function and body height also returned to normal ranges within this time. Case 2 is a patient with FRNS due to FSGS, who was treated with rituximab followed by MPA and cyclosporine, which successfully prevented relapses for 18 months, that is, at the end point of the observation. Our case report demonstrates that rituximab and a combination of CNIs and MPA can be effective in achieving complete remission in pediatric refractory SRNS and sustaining remission in pediatric FSGS with FRNS and SRNS for several years. This treatment regimen has the advantage of eliminating the need for long-term high-dose steroid treatments, allowing 1 patient to achieve normal growth and recover from other adverse steroid effects.
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Affiliation(s)
- Cahyani Gita Ambarsari
- aDepartment of Child Health, Faculty of Medicine Universitas Indonesia − Cipto Mangunkusumo Hospital, Jakarta, Indonesia,bSchool of Medicine, University of Nottingham, Nottingham, UK,cPediatric Centre, Pondok Indah Bintaro Jaya Hospital, South Tangerang, Indonesia,*Cahyani Gita Ambarsari,
| | - Meilania Saraswati
- dDepartment of Pathology Anatomy, Faculty of Medicine Universitas Indonesia − Cipto Mangunkusumo Hospital, Jakarta, Indonesia
| | - Genta Syaifrin Laudza
- aDepartment of Child Health, Faculty of Medicine Universitas Indonesia − Cipto Mangunkusumo Hospital, Jakarta, Indonesia
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Mishra OP, Sidar M, Batra VV, Prasad R, Singh A, Abhinay A, Mishra A, Yadav AK. Desfechos de crianças com síndrome nefrótica idiopática córtico-resistente: um estudo observacional de centro único. J Bras Nefrol 2022. [DOI: 10.1590/2175-8239-jbn-2022-0073pt] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
RESUMO Introdução: A síndrome nefrótica idiopática córtico-resistente (SNICR) apresenta desfechos variáveis em crianças. O objetivo principal deste estudo foi avaliar a taxa de remissão cumulativa. Os objetivos secundários foram avaliar fatores que afetam status de remissão, sobrevida da função renal e efeitos adversos de medicamentos. Métodos: Foram incluídos 114 pacientes com SNCR. Utilizou-se protocolo de tratamento baseado em inibidores de calcineurina juntamente com prednisolona e inibidor da enzima conversora de angiotensina. Os pacientes foram acompanhados durante 5 anos. Resultados: A idade mediana foi 4,5 anos; 53,5% dos casos tinham entre 1 e 5 anos. 62 pacientes (54,4%) estavam em estágio inicial; 52 (45,6%) em estágio tardio da SNCR. A TFGecr mediana foi 83,5 mL/min/1,73 m2 na apresentação. Dos 110 pacientes, 63 (57,3%) alcançaram remissão [remissão completa 30 (27,3%), remissão parcial 33 (30%)], e 47 (42,7%) não apresentaram remissão. A sobrevida da função renal foi 87,3%; 14 casos (12,7%) progrediram para DRC (G3-8, G4-3, G5-1, G5D-2). A duração mediana do acompanhamento foi 36 meses (IIQ 24, 60). Idade no início, ciclosporina/tacrolimus, TFGecr e histopatologia (DLM/GESF) não afetaram a remissão. Igualmente, status de remissão, além da idade no início, protocolo de medicamentos e histopatologia não afetaram significativamente a função renal por 5 anos. Observou-se hipertensão, fácies cushingoide, baixa estatura, catarata e obesidade em 37,7; 29,8; 25,5; 17,5; e 0,7% dos casos, respectivamente. Conclusão: Aproximadamente metade dos casos alcançou remissão. Idade no início, uso de ciclosporina/tacrolimus e lesão histopatológica não afetaram o status de remissão nem a sobrevida da função renal a curto prazo na SNICR.
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Affiliation(s)
| | | | - Vineeta V. Batra
- G. B. Pant Institute of Post Graduate Medical Education & Research, India
| | | | | | | | - Akash Mishra
- Jawahar Lal Institute of Postgraduate Medical Education and Research, India
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21
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Morello W, Budelli S, Bernstein DA, Montemurro T, Montelatici E, Lavazza C, Ghio L, Edefonti A, Peruzzi L, Molino D, Benetti E, Gianoglio B, Mehmeti F, Catenacci L, Rotella J, Tamburello C, Moretta A, Lazzari L, Giordano R, Prati D, Montini G. First clinical application of cord blood mesenchymal stromal cells in children with multi-drug resistant nephrotic syndrome. STEM CELL RESEARCH & THERAPY 2022; 13:420. [PMID: 35986374 PMCID: PMC9389735 DOI: 10.1186/s13287-022-03112-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/23/2022] [Accepted: 08/03/2022] [Indexed: 12/02/2022]
Abstract
Background and objectives Children with multi-drug resistant idiopathic nephrotic syndrome (MDR-INS) usually progress to end-stage kidney disease with a consistent risk of disease recurrence after transplantation. New therapeutic options are needed for these patients. Mesenchymal stromal cells (MSCs) are multipotential non-hematopoietic cells with several immunomodulatory properties and growing clinical applications. Cord blood-derived MSC have peculiar anti-inflammatory and immunosuppressive properties. We aimed at assessing safety and efficacy of cord-blood-derived MSCs (CB-MSCs) in children with MDR-INS. Design, setting, participants Prospective, open-label, single arm phase I–II pilot study. Pediatric patients with MDR-INS, resistant to at least two lines of therapy, were enrolled. Allogenic CB-MSCs were administered intravenously on days 0, 14, and 21 at a dose of 1.5 × 106 cells/kg. Patients were followed for at least 12 months. The primary outcomes were safety and toxicity. The secondary outcome was remission at 12 months evaluated by urinary protein/urinary creatinine ratio (uPr/uCr). Circulating regulatory T cells (Tregs) were monitored. Results Eleven pediatric patients with MDR-INS (10 females, median age 13 years) resistant to a median of 3 previous lines of therapy were enrolled. All patients completed the CB-MSC infusion schedule. No patient experienced any infusion-related adverse event or toxicity. Nine patients were assessable for efficacy. At the 12 months follow-up after the treatment, the median uPr/uCr did not change significantly from baseline (8.13 vs. 9.07; p = 0.98), while 3 patients were in partial or complete remission. A lower baseline uPr/uCr was a predictor of remission (2.55 vs. 8.74; p = 0.0238). Tregs count was not associated with CB-MSCs therapy. Conclusions CB-MSCs are safe and may have a role in the immunosuppressive therapy of pediatric patients with MDR-INS. This preliminary experience paves the way toward further phase II studies addressing MSC efficacy in immune-mediated kidney diseases. Supplementary Information The online version contains supplementary material available at 10.1186/s13287-022-03112-7.
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22
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Lin J, Sun J. Rituximab May Have Positive Effect on Refractory Nephrotic Syndrome: A Meta-Analysis of Randomized Trials. COMPUTATIONAL AND MATHEMATICAL METHODS IN MEDICINE 2022; 2022:3008597. [PMID: 35813445 PMCID: PMC9262522 DOI: 10.1155/2022/3008597] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/24/2022] [Revised: 06/11/2022] [Accepted: 06/14/2022] [Indexed: 11/17/2022]
Abstract
Purpose This study was aimed at demonstrating the role of rituximab (RTX) on the influence of nephrotic syndrome (NS) and on urinary protein which was not significant. Methods The clinical randomized controlled trials were performed by eight databases. Meanwhile, the confidence interval (CI) of either relative risk or mean difference was set to 95%. Besides, the heterogeneity of the research results is tested by I 2. Results A total of 1658 references were found using the search method. This meta-analysis will be done by the ultimately eight different studies. Each study is described as random controlled trial. According to these eight studies, the remission of test group and control group was quite higher (OR: 1.60; 95% Cl: 1.17, 2.20; P < 0.01) than the control group, serum albumin (SMD: 4.19; 95% Cl: 1.49, 6.89; P < 0.01), and urine protein (SMD: 0.79; 95% Cl: -0.64, 2.22; P = 0.28). Despite the fact that the remission rate's funnel plot was asymmetrically distributed, Egger's test and Begg's test revealed no probable publish bias. Conclusion The results of this study suggest that rituximab (RTX) may be effective in RNS, as evidenced by remission rates and serum albumin. However, the effect on urinary protein was not significant. The clear evidence is missing in this literature. Therefore, large sample, multicenter, low risk of bias clinical studies, as well as basic medical research, is needed.
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Affiliation(s)
- Jingjing Lin
- Nephrology Department, First People's Hospital of Linping District, Hangzhou, China
| | - Jia Sun
- Nephrology Department, First People's Hospital of Linping District, Hangzhou, China
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PARMAKSIZ G. Tedavisi zor nefrotik sendromlu çocuklarda rituksimab tedavisi. CUKUROVA MEDICAL JOURNAL 2022. [DOI: 10.17826/cumj.1038641] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022] Open
Abstract
Amaç: Rituksimab (RTX), tedavisi zor nefrotik sendromlu (sık tekrarlayan, steroide bağımlı ve steroide dirençli) hastalar için kurtarma tedavisi olarak önerilmektedir. Amacımız zor nefrotik sendromlu çocuklarda RTX tedavisinin etkinliğini ve uzun dönem sonuçlarını değerlendirmek ve deneyimlerimizi paylaşmaktır.
Gereç ve Yöntem: RTX ile tedavi edilen zor nefrotik sendromlu çocukların tıbbi kayıtları geriye dönük olarak değerlendirildi. Oniki ayda nükssüz sağkalım oranı ve B hücre deplesyonun izlemi değerlendirildi.
Bulgular: Çalışmaya 8'i steroide bağımlı (SBNS), 6'sı sık tekrarlayan (STNS) ve 6'sı steroide dirençli nefrotik sendromlu (SDNS) 20 çocuk dahil edildi. RTX tedavisi alan STNS/SBNS hastalarının tedavi öncesi ve sonrası 1 yıllık ortalama nüks sayısı karşılaştırıldı. Ortalama nüks sayısı 2 (1-4)’den 0 (0-1) kez/yıla geriledi. RTX tedavisi sonrası ortalama takip süresi 23 ay (12-59) ve 8 hastada nüks gelişti. RTX tedavisi sonrası nüks eden 5 hastaya, tekrarlayan dozlarda RTX uygulandı. Bu hastalarda, CD19+B hücreleri remisyon sırasında yeniden ortaya çıkarken, hafıza B hücrelerinin deplesyonu devam etti.
Sonuç: RTX tedavisi, STNS/SBNS hastalarında remisyon süresini uzattı, ancak SDNS hastalarında etkisiz kaldı. Bu hastalarda remisyonun idamesi için RTX dozunun tekrarlanabileceği ve tekrarlama dozlarının zamanlamasında en iyi hafıza B hücre sayısının yardımcı olabileceği saptandı.
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Meeuwisse C, Morgan CJ, Samuel S, Alexander RT, Rodriguez-Lopez S. Rituximab Use for the Treatment of Childhood Nephrotic Syndrome by Canadian Pediatric Nephrologists: A National Survey. Can J Kidney Health Dis 2022; 9:20543581221079959. [PMID: 35300066 PMCID: PMC8922210 DOI: 10.1177/20543581221079959] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Accepted: 01/04/2022] [Indexed: 11/23/2022] Open
Abstract
Background: There is known practice variation in the treatment of frequently relapsing, steroid-dependent, and steroid-resistant nephrotic syndrome in children. Rituximab is an emerging therapy for difficult-to-treat nephrotic syndrome; however, there are no clear treatment guidelines. We therefore hypothesized that a wide variety of approaches to this therapy exist. Objective: To evaluate when and how rituximab is used for the treatment of childhood nephrotic syndrome in Canada. Design and setting: An online survey was used. Participants: Canadian pediatric nephrologists. Methods: A cross-sectional survey was distributed across Canada through the Canadian Association of Pediatric Nephrologists (CAPN) to evaluate rituximab treatment practices. Results: Of a total of 20 responses, 19 (95%) use rituximab in the treatment of nephrotic syndrome, usually as a third or fourth agent. For the number of rituximab doses, the majority (68%) uses 2 doses each time they use it. Eighteen respondents (90%) measure B cells when using this medication, mostly monthly (50%) or every 3 months (39%). Respondents were administered additional doses of rituximab prophylactically (74%) or at first relapse (47%). Long-term drug safety and drug funding were identified as the main barriers to rituximab use. Limitations: This survey represents the practice styles of physicians in a single country, and there is a nonresponse bias of 63%. Also, associations were not calculated. Conclusions: Among Canadian pediatric nephrologists, rituximab use for nephrotic syndrome appears to be increasing, but significant practice variations remain, including approaches to B-cell monitoring. It is reserved mostly for second-line and third-line use due to cost, funding issues, and residual uncertainty regarding long-term safety. Understanding these critical areas of practice uncertainty is a first step to optimize treatment of nephrotic syndrome in children.
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Affiliation(s)
- Cory Meeuwisse
- Department of Pediatrics, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Canada
| | - Catherine J. Morgan
- Division of Nephrology, Department of Pediatrics, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Canada
| | - Susan Samuel
- Section of Nephrology, Department of Pediatrics, Cumming School of Medicine, University of Calgary, AB, Canada
| | - R Todd Alexander
- Division of Nephrology, Department of Pediatrics, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Canada
| | - Sara Rodriguez-Lopez
- Division of Nephrology, Department of Pediatrics, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Canada
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Bazargani B, Noparast Z, Khedmat L, Fahimi D, Esfahani ST, Moghtaderi M, Abbasi A, Afshin A, Mojtahedi SY. Efficacy of rituximab therapy in children with nephrotic syndrome: a 10-year experience from an Iranian pediatric hospital. BMC Pediatr 2022; 22:36. [PMID: 35022016 PMCID: PMC8753871 DOI: 10.1186/s12887-022-03109-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/13/2021] [Accepted: 01/05/2022] [Indexed: 11/10/2022] Open
Abstract
Abstract
Background
There are controversy results in the optimal management of children with steroid-dependent and steroid-resistant nephrotic syndrome (SDNS, SRNS). This study aimed to determine the efficacy and safety of rituximab (RTX) in these pediatric patients.
Methods
Medical records of 1–18-year-old Iranian children with SDNS (n = 26) and SRNS (n = 22) with a follow-up for at least 24 months were included from 2009 to 2019. The short- and long-term responses to RTX were respectively evaluated to determine the random protein-to-creatinine ratio after 6 and 24 months and classified as complete (CR) and partial (PR) remission or no response.
Results
Male patients (n = 26) were slightly predominate. The median age of patients at the time of RTX therapy was 8.6 ± 4.01 years. At the end of the 6-month follow-up, CR and PR occurred in 23 (47.9%) and 12 (25%) patients, respectively. Of 23 patients with CR, 18 (69.2%) and 5(22.7%) had SDNS and SRNS, respectively (p < 0.005). However, only 18 (37.5%) of patients after 24 months had been in CR. No significant difference in the CR rate was found between the two groups. RTX was more effective when administered during the proteinuria-free period (p = 0.001).
Conclusion
In the short term, RTX significantly was efficient in inducing complete or PR in SDNS and SRNS patients. However, the favorable response rate in a long-term follow-up was insignificantly lower between the two groups.
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Haddad M, Kale A, Butani L. Intravenous cyclophosphamide induces remission in children with difficult to treat steroid resistant nephrotic syndrome from minimal change disease. BMC Nephrol 2021; 22:395. [PMID: 34839817 PMCID: PMC8628458 DOI: 10.1186/s12882-021-02605-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2021] [Accepted: 11/08/2021] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Steroid resistant nephrotic syndrome (SRNS), while uncommon in children, is associated with significant morbidity. Calcineurin inhibitors (CNIs) remain the first line recommended therapy for children with non-genetic forms of SRNS, but some children fail to respond to them. Intravenous (IV) cyclophosphamide (CTX) has been shown to be effective in Asian-Indian children with difficult to treat SRNS (SRNS-DTT). Our study evaluated the outcome of IV CTX treatment in North American children with SRNS-DTT. METHODS Retrospective review of the medical records of children with SRNS-DTT treated with IV CTX from January 2000 to July 2019 at our center. Data abstracted included demographics, histopathology on renal biopsy, prior and concomitant use of other immunosuppressive agents and serial clinical/laboratory data. Primary outcome measure was attainment of complete remission (CR). RESULTS Eight children with SRNS-DTT received monthly doses (median 6; range 4-6) of IV CTX. Four (50%) went into CR, 1 achieved partial remission and 3 did not respond. Three of the 4 responders had minimal change disease (MCD). Excluding the 1 child who responded after the 4th infusion, the median time to CR was 6.5 (range 0.5-8) months after completion of IV CTX infusions. Three remain in CR at a median of 8.5 years (range: 3.7-10.5 years) after completion of CTX; one child relapsed and became steroid-dependent. No infections or life-threatening complications related to IV CTX were observed. CONCLUSIONS IV CXT can induce long term remission in North-American children with MCD who have SRNS-DTT.
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Affiliation(s)
- Maha Haddad
- Section of Pediatric Nephrology, University of California Davis, 2516 Stockton Blvd, Sacramento, CA, 95817, USA
| | - Arundhati Kale
- Section of Pediatric Nephrology, University of California Davis, 2516 Stockton Blvd, Sacramento, CA, 95817, USA
| | - Lavjay Butani
- Section of Pediatric Nephrology, University of California Davis, 2516 Stockton Blvd, Sacramento, CA, 95817, USA.
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Chang D, Gong M, Liu C, Zhang Q, Hu Z, Li Z. Efficacy and safety of rituximab for childhood refractory nephrotic syndrome: A meta-analysis of randomized controlled trials. Med Clin (Barc) 2021; 157:418-426. [PMID: 33070945 DOI: 10.1016/j.medcli.2020.07.039] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2020] [Revised: 07/03/2020] [Accepted: 07/09/2020] [Indexed: 10/23/2022]
Abstract
BACKGROUND Idiopathic nephrotic syndrome is the most common glomerular disease in children, but there are still some difficulties in treating childhood steroid-dependent or steroid-resistant nephrotic syndrome (SDNS/SRNS). Rituximab (RTX) might be an effective and safe choice. METHODS Studies were searched from PubMed, Web of Science, Cochrane library and some Chinese databases up to April 2020. Only randomized controlled trials (RCT) were included. RESULTS Of 1383 screened articles, 6 RCTs with 334 participants were included. RTX was better than the control group at improving relapse-free rate in the short term [RR (risk ratio) (95% CI (confidence interval)), 1.84(1.41, 2.39)]. As for long-term, RTX did not show significant improvement [RR (95% CI), 4.43(.57, 34.67)]; but in subgroup analysis, RTX was still better than conventional drugs and tacrolimus [RR (95% CI), 9.91(1.95, 50.52) and 1.42(1.15, 1.75), respectively]. And there was a difference between the two groups of prednisolone dose after treatment [MD (mean difference) (95% CI), -.22(-.36, -.09) mg/kg/d)]. However, RTX did not significantly improve serum albumin and creatinine [MD (95% CI), 3.46(-1.40, 8.32)g/L and -3.66(-11.79, 4.48)μmol/L, respectively]. No significant differences between the RTX and the control group were found in total adverse events (AEs) or serious AEs. CONCLUSION Childhood SDNS/SRNS patients appear to benefit from RTX in relapse-free rate and dose of prednisolone use. Also, RTX did not significantly increase the incidence of AEs. But RTX did not show improvements in biological indicators, more studies are required to explain the effect of RTX.
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Affiliation(s)
- Dan Chang
- Department of Nephrology, University of Electronic Science and Technology, Sichuan Academy of Sciences & Sichuan Provincial People's Hospital, Chengdu 610072, Sichuan China
| | - Minmin Gong
- Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Chaofan Liu
- Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Quan Zhang
- Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Ziwei Hu
- Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Zhuoguang Li
- Department of Endocrinology, Shenzhen Children's Hospital, Shenzhen 518038, China.
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Sinha R, Agrawal N, Xue Y, Chanchlani R, Pradhan S, Raina R, Marks SD. Use of rituximab in paediatric nephrology. Arch Dis Child 2021; 106:1058-1065. [PMID: 34112638 PMCID: PMC8543203 DOI: 10.1136/archdischild-2020-321211] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2020] [Revised: 02/27/2021] [Accepted: 03/10/2021] [Indexed: 11/03/2022]
Abstract
Rituximab is a chimeric monoclonal antibody capable of depleting B cell populations by targeting the CD20 antigen expressed on the cell surface. Its use in oncology, initially in B cell lymphoma and post-transplant lymphoproliferative disorders, predates its current utility in various fields of medicine wherein it has become one of the safest and most effective antibody-based therapies. It was subsequently found to be effective for rheumatological conditions such as rheumatoid arthritis and antineutrophil cytoplasmic antibody-associated vasculitis. Over the past decade, rituximab has generated a lot of interest in nephrology and has become an emerging or accepted therapy for multiple renal conditions, including systemic lupus erythematosus, lupus nephritis, vasculitis, nephrotic syndrome and in different scenarios before and after kidney transplantation. This review outlines its current use in paediatric nephrology practice, focusing on the knowledge required for general paediatricians who may be caring for children prescribed this medication and reviewing them on a shared care basis.
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Affiliation(s)
- Rajiv Sinha
- ICH, Institute of Child Health, Kolkata, India
| | - Nirav Agrawal
- Department of Nephrology, Akron Children's Hospital, Akron, Ohio, USA
| | - Yuanxin Xue
- Faculty of Health Sciences, McMaster University, Hamilton, Ontario, Canada
| | - Rahul Chanchlani
- Division of Pediatric Nephrology, Department of Pediatrics, McMaster University, Hamilton, Ontario, Canada
| | - Subal Pradhan
- Department of Pediatrics, Sardar Vallabhbhai Patel Post Graduate Institute of Paediatrics(SVPPGIP), Cuttack, Odisha, India
| | - Rupesh Raina
- Department of Nephrology, Akron Children's Hospital, Akron, Ohio, USA
| | - Stephen D Marks
- Department of Paediatric Nephrology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
- NIHR Great Ormond Street Hospital Biomedical Research Centre, University College London Great Ormond Street Institute of Child Health, London, UK
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Rovin BH, Adler SG, Barratt J, Bridoux F, Burdge KA, Chan TM, Cook HT, Fervenza FC, Gibson KL, Glassock RJ, Jayne DR, Jha V, Liew A, Liu ZH, Mejía-Vilet JM, Nester CM, Radhakrishnan J, Rave EM, Reich HN, Ronco P, Sanders JSF, Sethi S, Suzuki Y, Tang SC, Tesar V, Vivarelli M, Wetzels JF, Floege J. KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases. Kidney Int 2021; 100:S1-S276. [PMID: 34556256 DOI: 10.1016/j.kint.2021.05.021] [Citation(s) in RCA: 1104] [Impact Index Per Article: 276.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Accepted: 05/25/2021] [Indexed: 12/13/2022]
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30
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Guo HL, Li L, Xu ZY, Jing X, Xia Y, Qiu JC, Ji X, Chen F, Xu J, Zhao F. Steroid-resistant Nephrotic Syndrome in Children: A Mini-review on Genetic Mechanisms, Predictive Biomarkers and Pharmacotherapy Strategies. Curr Pharm Des 2021; 27:319-329. [PMID: 33138756 DOI: 10.2174/1381612826666201102104412] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2020] [Accepted: 08/11/2020] [Indexed: 11/22/2022]
Abstract
Steroid-resistant nephrotic syndrome (SRNS) constitutes the second most frequent cause of chronic kidney disease in childhood. The etiology of SRNS remains largely unknown and no standardized treatment exists. Recent advances in genomics have helped to build understanding of the molecular mechanisms and pathogenesis of the disease. The genetic polymorphisms in genes encoding proteins which are involved in the pharmacokinetics and pharmacodynamics of glucocorticoids (GCs) partially account for the different responses between patients with nephrotic syndrome. More importantly, single-gene causation in podocytes-associated proteins was found in approximately 30% of SRNS patients. Some potential biomarkers have been tested for their abilities to discriminate against pediatric patients who are sensitive to GCs treatment and patients who are resistant to the same therapy. This article reviews the recent findings on genetic mechanisms, predictive biomarkers and current therapies for SRNS with the goal to improve the management of children with this syndrome.
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Affiliation(s)
- Hong-Li Guo
- Department of Pharmacy, Children's Hospital of Nanjing Medical University, Nanjing 210008, China
| | - Ling Li
- School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Ze-Yue Xu
- School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Xia Jing
- Department of Pharmacy, Children's Hospital of Nanjing Medical University, Nanjing 210008, China
| | - Ying Xia
- Department of Pharmacy, Children's Hospital of Nanjing Medical University, Nanjing 210008, China
| | - Jin-Chun Qiu
- Department of Pharmacy, Children's Hospital of Nanjing Medical University, Nanjing 210008, China
| | - Xing Ji
- Department of Pharmacy, Children's Hospital of Nanjing Medical University, Nanjing 210008, China
| | - Feng Chen
- Department of Pharmacy, Children's Hospital of Nanjing Medical University, Nanjing 210008, China
| | - Jing Xu
- Department of Pharmacy, Children's Hospital of Nanjing Medical University, Nanjing 210008, China
| | - Fei Zhao
- Department of Nephrology, Children's Hospital of Nanjing Medical University, Nanjing, China
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31
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Gao X, Wang Y, Xu Z, Deng H, Yang H, Zhong F. Systematic Review and Meta-Analysis of Rituximab for Steroid-Dependent or Frequently Relapsing Nephrotic Syndrome in Children. Front Pediatr 2021; 9:626323. [PMID: 34368023 PMCID: PMC8339375 DOI: 10.3389/fped.2021.626323] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2020] [Accepted: 06/16/2021] [Indexed: 11/20/2022] Open
Abstract
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.
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Affiliation(s)
- Xia Gao
- Nephrology Department, Guangzhou Women and Children's Medical Center, Guangzhou, China
| | - Yan Wang
- Graduate School, Ningxia Medical University, Yinchuan, China.,Neonatology Department, Northwest Women and Children's Hospital, Xi'an, China
| | - Zichuan Xu
- Nephrology Department, Guangzhou Women and Children's Medical Center, Guangzhou, China
| | - Huiying Deng
- Nephrology Department, Guangzhou Women and Children's Medical Center, Guangzhou, China
| | - Huabin Yang
- Nephrology Department, Guangzhou Women and Children's Medical Center, Guangzhou, China
| | - Fu Zhong
- Nephrology Department, Guangzhou Women and Children's Medical Center, Guangzhou, China
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32
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Lee JM, Kronbichler A, Shin JI, Oh J. Current understandings in treating children with steroid-resistant nephrotic syndrome. Pediatr Nephrol 2021; 36:747-761. [PMID: 32086590 PMCID: PMC7910243 DOI: 10.1007/s00467-020-04476-9] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2019] [Revised: 12/22/2019] [Accepted: 01/07/2020] [Indexed: 12/27/2022]
Abstract
Steroid-resistant nephrotic syndrome (SRNS) remains a challenge for paediatric nephrologists. SRNS is viewed as a heterogeneous disease entity including immune-based and monogenic aetiologies. Because SRNS is rare, treatment strategies are individualized and vary among centres of expertise. Calcineurin inhibitors (CNI) have been effectively used to induce remission in patients with immune-based SRNS; however, there is still no consensus on treating children who become either CNI-dependent or CNI-resistant. Rituximab is a steroid-sparing agent for patients with steroid-sensitive nephrotic syndrome, but its efficacy in SRNS is controversial. Recently, several novel monoclonal antibodies are emerging as treatment option, but their efficacy remains to be seen. Non-immune therapies, such as angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers, have been proven efficacious in children with SRNS and are recommended as adjuvant agents. This review summarizes and discusses our current understandings in treating children with idiopathic SRNS.
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Affiliation(s)
- Jiwon M. Lee
- Department of Pediatrics, Chungnam National University Hospital, Daejeon, South Korea
| | - Andreas Kronbichler
- Department of Internal Medicine IV (Nephrology and Hypertension), Medical University Innsbruck, Innsbruck, Austria
| | - Jae Il Shin
- Department of Pediatrics, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, C.P.O. Box 8044, Seoul, 120-752 South Korea ,Division of Pediatric Nephrology, Severance Children’s Hospital, Seoul, South Korea ,Institute of Kidney Disease Research, Yonsei University College of Medicine, Seoul, South Korea
| | - Jun Oh
- Department of Pediatrics Nephrology, University Hamburg-Eppendorf, Martinistrasse, 52 20246, Hamburg, Germany.
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33
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Podestà MA, Ponticelli C. Autoimmunity in Focal Segmental Glomerulosclerosis: A Long-Standing Yet Elusive Association. Front Med (Lausanne) 2020; 7:604961. [PMID: 33330569 PMCID: PMC7715033 DOI: 10.3389/fmed.2020.604961] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Accepted: 10/26/2020] [Indexed: 01/17/2023] Open
Abstract
Focal segmental glomerulosclerosis (FSGS) is a histological term that describes a pathologic renal entity affecting both adults and children, with a wide array of possible underlying etiologies. Podocyte damage with scarring, the hallmark of this condition, leads to altered permeability of the glomerular barrier, which may result in massive proteinuria and relentless renal function deterioration. A definite cause of focal segmental glomerulosclerosis can be confirmed in a minority of cases, while most forms have been traditionally labeled as primary or idiopathic. Despite this definition, increasing evidence indicates that primary forms are a heterogenous group rather than a single disease entity: several circulating factors that may affect glomerular permeability have been proposed as potential culprits, and both humoral and cellular immunity have been implicated in the pathogenesis of the disease. Consistently, immunosuppressive drugs are considered as the cornerstone of treatment for primary focal segmental glomerulosclerosis, but response to these agents and long-term outcomes are highly variable. In this review we provide a summary of historical and recent advances on the pathogenesis of primary focal segmental glomerulosclerosis, focusing on implications for its differential diagnosis and treatment.
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Sinha R, Banerjee S, Mukherjee A, Pradhan S, Akhtar S. Early Use of Rituximab in Calcineurin Inhibitor-Refractory and Steroid-Resistant Nephrotic Syndrome. Kidney Int Rep 2020; 5:2354-2357. [PMID: 33305130 PMCID: PMC7710833 DOI: 10.1016/j.ekir.2020.09.021] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2020] [Revised: 09/14/2020] [Accepted: 09/15/2020] [Indexed: 12/04/2022] Open
Affiliation(s)
- Rajiv Sinha
- Division of Pediatric Nephrology, Institute of Child Health, Kolkata, India
- Division of Pediatric Nephrology, AMRI Hospital, Mukundapur, Kolkata, India
- Division of Pediatric Nephrology, Apollo Gleneagles Hospital, Kolkata, India
| | - Sushmita Banerjee
- Division of Pediatric Nephrology, Institute of Child Health, Kolkata, India
- Division of Pediatric Nephrology, Calcutta Medical Research Institute, Kolkata, India
| | - Anwesha Mukherjee
- Division of Pediatric Nephrology, Institute of Child Health, Kolkata, India
| | - Subal Pradhan
- Division of Pediatric Nephrology, SVPPGIP and Srirama Chandra Bhanja Medical College, Cuttack, Odisha, India
| | - Shakil Akhtar
- Division of Pediatric Nephrology, Institute of Child Health, Kolkata, India
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35
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Zhong H, Li HY, Zhou T, Zhong Z. Clinical efficacy and safety of rituximab with membranous nephropathy: a meta-analysis. Arch Med Sci 2020; 19:411-419. [PMID: 37034519 PMCID: PMC10074182 DOI: 10.5114/aoms.2020.99899] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2019] [Accepted: 08/02/2019] [Indexed: 02/05/2023] Open
Abstract
INTRODUCTION Membranous nephropathy (MN) is an organ-specific autoimmune disease, and its prevalence is increasing. B lymphocytes activated by T cells produce antibodies. CD19+/CD20+ plasma cells may contribute to autoantibody and alloantibody production. Rituximab has been effective in treating MN in many clinical trials. Thus, we conducted a meta-analysis to explore the clinical efficacy and safety of rituximab with MN. MATERIAL AND METHODS We searched Embase, PubMed, Cochrane Library and ClinicalTrials.gov without language or publication date limitations. Studies were classified in high-risk, medium-risk and low-risk groups based on baseline proteinuria. Follow-up periods and different administrations of rituximab were also compared. Complete remission (CR) and partial remission (PR) were assessed to measure the efficacy of rituximab, and adverse effects were also extracted. Dichotomous data were expressed by the odds ratio (OR), and the 95% confidence intervals (95% CI) were used for the recruited studies. RESULTS Fourteen articles, including 17 studies, were included in this meta-analysis. The pooled OR of overall PR and CR remission rate was 0.58 (95% CI: 0.53-0.63; p = 0.003). No studies belonged to the low-risk group. The overall PR and CR remission rate in the medium-risk group was 0.56 (95% CI: 0.36-0.73; p = 0.57). The pooled OR of overall PR and CR remission rate in the high-risk group was 0.59 (95% CI: 0.53-0.65; p = 0.03). At the 12-month follow-up, the pooled OR of overall PR and CR remission rate was 0.51 (95% CI: 0.43-0.59; p = 0.72). At the 24-month follow-up, the pooled OR of overall PR and CR remission rate was 0.71 (95% CI: 0.48-0.86; p = 0.07). The pooled OR of efficacy of rituximab at 375 mg/m2 × 4 was 0.63 (95% CI: 0.55-0.70; p = 0.001). Rituximab was tolerated in MN, and most adverse effects were mild. The pooled OR of infusion reaction rate of rituximab was 0.25 (95% CI: 0.13-0.44; p = 0.01) in MN. The pooled OR of cardiovascular-related event rate of rituximab in MN was 0.04 (95% CI: 0.02-0.11). The pooled OR of infection rate of rituximab in MN was 0.06 (95% CI: 0.03-0.12; p < 0.00001). CONCLUSIONS Rituximab is safe and effective in MN and a promising alternative treatment. More randomized control trials and studies on the role of MN are expected.
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Affiliation(s)
- Hongzhen Zhong
- Department of Nephrology, the Second Affiliated Hospital of Shantou University Medical College, Shantou, China
| | - Hong-Yan Li
- Department of Nephrology, Huadu District People’s Hospital of Guangzhou, Southern Medical University, Guangzhou, China
| | - Tianbiao Zhou
- Department of Nephrology, the Second Affiliated Hospital of Shantou University Medical College, Shantou, China
| | - Zhiqing Zhong
- Department of Nephrology, the Second Affiliated Hospital of Shantou University Medical College, Shantou, China
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Trautmann A, Vivarelli M, Samuel S, Gipson D, Sinha A, Schaefer F, Hui NK, Boyer O, Saleem MA, Feltran L, Müller-Deile J, Becker JU, Cano F, Xu H, Lim YN, Smoyer W, Anochie I, Nakanishi K, Hodson E, Haffner D. IPNA clinical practice recommendations for the diagnosis and management of children with steroid-resistant nephrotic syndrome. Pediatr Nephrol 2020; 35:1529-1561. [PMID: 32382828 PMCID: PMC7316686 DOI: 10.1007/s00467-020-04519-1] [Citation(s) in RCA: 206] [Impact Index Per Article: 41.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2019] [Revised: 02/07/2020] [Accepted: 02/21/2020] [Indexed: 02/06/2023]
Abstract
Idiopathic nephrotic syndrome newly affects 1-3 per 100,000 children per year. Approximately 85% of cases show complete remission of proteinuria following glucocorticoid treatment. Patients who do not achieve complete remission within 4-6 weeks of glucocorticoid treatment have steroid-resistant nephrotic syndrome (SRNS). In 10-30% of steroid-resistant patients, mutations in podocyte-associated genes can be detected, whereas an undefined circulating factor of immune origin is assumed in the remaining ones. Diagnosis and management of SRNS is a great challenge due to its heterogeneous etiology, frequent lack of remission by further immunosuppressive treatment, and severe complications including the development of end-stage kidney disease and recurrence after renal transplantation. A team of experts including pediatric nephrologists and renal geneticists from the International Pediatric Nephrology Association (IPNA), a renal pathologist, and an adult nephrologist have now developed comprehensive clinical practice recommendations on the diagnosis and management of SRNS in children. The team performed a systematic literature review on 9 clinically relevant PICO (Patient or Population covered, Intervention, Comparator, Outcome) questions, formulated recommendations and formally graded them at a consensus meeting, with input from patient representatives and a dietician acting as external advisors and a voting panel of pediatric nephrologists. Research recommendations are also given.
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Affiliation(s)
- Agnes Trautmann
- Division of Pediatric Nephrology, Center for Pediatrics and Adolescent Medicine, Heidelberg, Germany
| | - Marina Vivarelli
- Department of Pediatric Subspecialties, Division of Nephrology and Dialysis, Bambino Gesù Pediatric Hospital and Research Center, Rome, Italy
| | - Susan Samuel
- Department of Pediatrics, Section of Pediatric Nephrology, Alberta Children's Hospital, University of Calgary, Calgary, Canada
| | - Debbie Gipson
- Division of Nephrology, University of Michigan, Ann Arbor, MI, USA
| | - Aditi Sinha
- Department of Pediatrics, Division of Nephrology, All India Institute of Medical Sciences, New Delhi, India
| | - Franz Schaefer
- Division of Pediatric Nephrology, Center for Pediatrics and Adolescent Medicine, Heidelberg, Germany
| | - Ng Kar Hui
- Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Olivia Boyer
- Laboratory of Hereditary Kidney Diseases, Imagine Institute, INSERM U1163, Paris Descartes University, Paris, France
- Department of Pediatric Nephrology, Reference Center for Idiopathic Nephrotic Syndrome in Children and Adults, Necker Hospital, APHP, 75015, Paris, France
| | - Moin A Saleem
- Department of Pediatric Nephrology, Bristol Royal Hospital for Children, University of Bristol, Bristol, UK
| | - Luciana Feltran
- Hospital Samaritano and HRim/UNIFESP, Federal University of São Paulo, São Paulo, Brazil
| | | | - Jan Ulrich Becker
- Institute of Pathology, University Hospital of Cologne, Cologne, Germany
| | - Francisco Cano
- Department of Nephrology, Luis Calvo Mackenna Children's Hospital, University of Chile, Santiago, Chile
| | - Hong Xu
- Department of Nephrology, Children's Hospital of Fudan University, Shanghai, China
| | - Yam Ngo Lim
- Department of Pediatrics, Prince Court Medical Centre, Kuala Lumpur, Malaysia
| | - William Smoyer
- The Research Institute at Nationwide Children's Hospital, The Ohio State University, Columbus, OH, USA
| | - Ifeoma Anochie
- Department of Paediatrics, University of Port Harcourt Teaching Hospital, Port Harcourt, Rivers State, Nigeria
| | - Koichi Nakanishi
- Department of Child Health and Welfare (Pediatrics), Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan
| | - Elisabeth Hodson
- Cochrane Kidney and Transplant, Centre for Kidney Research, The Children's Hospital at Westmead and the Sydney School of Public Health, University of Sydney, Sydney, Australia
| | - Dieter Haffner
- Department of Paediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School Children's Hospital, Hannover, Germany.
- Department of Paediatric Kidney, Liver and Metabolic Diseases, Paediatric Research Center, Hannover Medical School, Carl-Neuberg-Str. 1, 30625, Hannover, Germany.
- Center for Rare Diseases, Hannover Medical School Children's Hospital, Hannover, Germany.
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Girimaji N, Bharati J, Nada R, Rathi M, Kohli HS, Ramachandran R. Rituximab in treatment of collapsing FSGS-A case series. Nephrology (Carlton) 2020; 26:134-141. [PMID: 32662534 DOI: 10.1111/nep.13757] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2020] [Revised: 07/03/2020] [Accepted: 07/06/2020] [Indexed: 01/16/2023]
Abstract
BACKGROUND Collapsing focal segmental glomerulosclerosis (cFSGS) is an aggressive glomerular disease presenting as a nephrotic syndrome that has lower rates of remission with conventional immunosuppressive therapy and rapidly progresses to end-stage-renal-disease (ESRD). We report eight cases of HIV-negative cFSGS treated with rituximab. METHODS The current report is a retrospective case series of cFSGS treated with rituximab from January 2011 to March 2020, at varying phases of the disease. RESULTS Eight out of the 70 cFSGS patients received rituximab. The median age of patients was 30 years (IQR 24.25-37.5); five patients were males. The median serum creatinine, mean serum albumin and median 24 hours urinary protein at presentation was 0.9 (IQR 0.66-1.27) mg/dL, 2.95 ± 1.15 g/dL, 4.87 (IQR 1.64-5.75) g/day, respectively. Two patients were steroid-resistant, one steroid and tacrolimus dependent, one steroid and cyclosporine dependent, two steroids and tacrolimus resistant, one steroid, tacrolimus, cyclophosphamide, mycophenolate mofetil resistant and one steroid-resistant and tacrolimus dependent before rituximab therapy. Rituximab was given either as targeted therapy (after an initial dose of 375 mg/m2 ; patients having CD-19 levels >5/μL or >1% at 1 month received additional low-dose [100 mg] of rituximab), or weekly regimen. Five patients received CD-19 targeted rituximab; three received weekly doses of 375 mg/m2 , cumulative doses being 820 ± 228.03 mg, and 1800 ± 721.11 mg, respectively. At the end of median follow-up of 15 months, five (62.5%) patients were in remission (three partial, two complete remissions), two (25%) were resistant to therapy; one (12.5%) progressed to ESRD. CONCLUSION Rituximab is reasonably safe and achieves/maintains remission in 60% of cFSGS cases.
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Affiliation(s)
- Niveditha Girimaji
- Department of Nephrology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Joyita Bharati
- Department of Nephrology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Ritambhra Nada
- Department of Histopathology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Manish Rathi
- Department of Nephrology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Harbir Singh Kohli
- Department of Nephrology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Raja Ramachandran
- Department of Nephrology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
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Mason AE, Sen ES, Bierzynska A, Colby E, Afzal M, Dorval G, Koziell AB, Williams M, Boyer O, Welsh GI, Saleem MA, on behalf of the UK RaDaR/NephroS Study. Response to First Course of Intensified Immunosuppression in Genetically Stratified Steroid Resistant Nephrotic Syndrome. Clin J Am Soc Nephrol 2020; 15:983-994. [PMID: 32317330 PMCID: PMC7341765 DOI: 10.2215/cjn.13371019] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2019] [Accepted: 03/18/2020] [Indexed: 12/20/2022]
Abstract
BACKGROUND AND OBJECTIVES Intensified immunosuppression in steroid-resistant nephrotic syndrome is broadly applied, with disparate outcomes. This review of patients from the United Kingdom National Study of Nephrotic Syndrome cohort aimed to improve disease stratification by determining, in comprehensively genetically screened patients with steroid-resistant nephrotic syndrome, if there is an association between response to initial intensified immunosuppression and disease progression and/or post-transplant recurrence. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Pediatric patients with steroid-resistant nephrotic syndrome were recruited via the UK National Registry of Rare Kidney Diseases. All patients were whole-genome sequenced, whole-exome sequenced, or steroid-resistant nephrotic syndrome gene-panel sequenced. Complete response or partial response within 6 months of starting intensified immunosuppression was ascertained using laboratory data. Response to intensified immunosuppression and outcomes were analyzed according to genetic testing results, pattern of steroid resistance, and first biopsy findings. RESULTS Of 271 patients, 178 (92 males, median onset age 4.7 years) received intensified immunosuppression with response available. A total of 4% of patients with monogenic disease showed complete response, compared with 25% of genetic-testing-negative patients (P=0.02). None of the former recurred post-transplantation. In genetic-testing-negative patients, 97% with complete response to first intensified immunosuppression did not progress, whereas 44% of nonresponders developed kidney failure with 73% recurrence post-transplant. Secondary steroid resistance had a higher complete response rate than primary/presumed resistance (43% versus 23%; P=0.001). The highest complete response rate in secondary steroid resistance was to rituximab (64%). Biopsy results showed no correlation with intensified immunosuppression response or outcome. CONCLUSIONS Patients with monogenic steroid-resistant nephrotic syndrome had a poor therapeutic response and no post-transplant recurrence. In genetic-testing-negative patients, there was an association between response to first intensified immunosuppression and long-term outcome. Patients with complete response rarely progressed to kidney failure, whereas nonresponders had poor kidney survival and a high post-transplant recurrence rate. Patients with secondary steroid resistance were more likely to respond, particularly to rituximab.
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Affiliation(s)
- Anna E. Mason
- Bristol Renal, Translational Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom
| | - Ethan S. Sen
- Bristol Renal, Translational Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom
| | - Agnieszka Bierzynska
- Bristol Renal, Translational Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom
| | - Elizabeth Colby
- Bristol Renal, Translational Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom
| | - Maryam Afzal
- Bristol Renal, Translational Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom
| | - Guillaume Dorval
- Department of Pediatric Nephrology, Reference Center for Hereditary Kidney Diseases, Necker Hospital, Assistance Publique—Hôpitaux de Paris, Paris, France
| | - Ania B. Koziell
- Division of Transplantation Immunology and Mucosal Biology, Department of Experimental Immunobiology, Faculty of Life Sciences and Medicine, King’s College London, London, United Kingdom
| | - Maggie Williams
- Bristol Genetics Laboratory, Pathology Sciences, Southmead Hospital, Bristol, United Kingdom
| | - Olivia Boyer
- Department of Pediatric Nephrology, Reference Center for Hereditary Kidney Diseases, Necker Hospital, Assistance Publique—Hôpitaux de Paris, Paris, France
| | - Gavin I. Welsh
- Bristol Renal, Translational Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom
| | - Moin A. Saleem
- Bristol Renal, Translational Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom
| | - on behalf of the UK RaDaR/NephroS Study
- Bristol Renal, Translational Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom
- Department of Pediatric Nephrology, Reference Center for Hereditary Kidney Diseases, Necker Hospital, Assistance Publique—Hôpitaux de Paris, Paris, France
- Division of Transplantation Immunology and Mucosal Biology, Department of Experimental Immunobiology, Faculty of Life Sciences and Medicine, King’s College London, London, United Kingdom
- Bristol Genetics Laboratory, Pathology Sciences, Southmead Hospital, Bristol, United Kingdom
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Low-dose ofatumumab for multidrug-resistant nephrotic syndrome in children: a randomized placebo-controlled trial. Pediatr Nephrol 2020; 35:997-1003. [PMID: 31993781 DOI: 10.1007/s00467-020-04481-y] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2019] [Revised: 01/10/2020] [Accepted: 01/13/2020] [Indexed: 10/25/2022]
Abstract
BACKGROUND Children with multidrug-resistant nephrotic syndrome (MRNS) are exposed to drug toxicity (steroids/calcineurin inhibitors (CNI)/mycophenolate mofetil (MMF)) and have an increased risk of kidney disease progression. In small case series, the fully humanized anti-CD20 antibody ofatumumab (OFA) induced remission in children with MRNS when at high dose (10,300 mg/1.73 m2) and partial remission at standard dose (1000 mg/1.73 m2). METHODS This double-blind randomized placebo-controlled trial tested the efficacy of single infusion OFA in children with proven MRNS and initial chronic renal failure (eGFR [median/range] 119/38-155 ml/min/1.73 m2 in Placebo arm vs. 65/19-103 ml/min/1.73 m2 Intervention). Children who had been resistant to a combination of CNI and steroids, with or without MMF or rituximab, were randomized to receive single infusion OFA (1500 mg/1.73 m2) (Intervention arm) or normal saline (Placebo arm). We assessed complete or partial remission of proteinuria after 3 months (primary outcome), and after 6 and 12 months (secondary outcomes), as well as progression to end-stage kidney disease. RESULTS After 13 of the planned 50 children (25%) were randomized, the data safety and monitoring board recommended study termination for futility. All 13 children remained nephrotic. Renal function worsened in 5 children (2 in Intervention arm, 3 in Placebo arm) who required renal replacement therapy during the study period. Circulating CD20 was reduced following OFA infusion and remained low for > 3 months. CONCLUSIONS OFA given in one single infusion of 1500 mg/1.73 m2 doses does not induce remission in MRNS. Regimens based on higher OFA doses should be tested in clinical trials. TRIAL REGISTRATION https://clinicaltrials.gov: NCT02394106.
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The efficacy of rituximab in the treatment of refractory nephrotic syndrome: a meta-analysis. Int Urol Nephrol 2020; 52:1093-1101. [PMID: 32297182 DOI: 10.1007/s11255-020-02460-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2019] [Accepted: 03/31/2020] [Indexed: 10/24/2022]
Abstract
OBJECTIVE The evidence from epidemiological research on whether the efficacy of rituximab in treatment of refractory nephrotic syndrome (NS) is better than other agents is inconsistent. This meta-analysis aimed to assess the efficacy of rituximab in the treatment of NS compared with other immunosuppressive agents. METHODS Relevant literatures were identified and evaluated for quality before October 2019 through multiple search strategies on PubMed and EMBASE. Statistical evidence of the symmetry of the funnel plot obtained from Begg's test was indicated by Egger's linear regression and a sensitivity analysis identified heterogeneity. A fixed- or a random-effects model was applied to calculate the pooled SMDs and RRs. RESULTS A total of 12 studies, involving 383 patients and 354 controls, were included. Compared with other agents, rituximab significantly improved complete remission both in children and adults [Overall: RR = 1.313, 95% CI = 1.170-1.475, P < 0.001; Adult: RR = 1.359, 95% CI = 1.053-1.753, P = 0.019 Children: RR = 1.354, 95% CI = 1.072-1.709, P < 0.001], and dramatically decreased the relapse rate in children [Overall: RR = 0.349, 95% CI = 0.166-0.732, P < 0.001; Children: RR = 0.286, 95% CI = 0.176-0.463, P < 0.001]. CONCLUSIONS Rituximab might be a promising treatment for refractory NS. Compared with other agents, rituximab significantly improves the complete remission and decreased the relapse rate. However, to confirm the efficacy of rituximab in the treatment of refractory NS, more high-quality, large sample, and multicenter randomized controlled trials are needed.
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Nishikawa M, Shimada N, Kawazoe T, Sawaki R, Ikuta H, Kanzaki M, Fukuoka K, Fukushima M, Asano K. Long-term Successful Treatment of Rituximab for Steroid-resistant Minimal Change Nephrotic Syndrome and Idiopathic Thrombocytopenic Purpura. Intern Med 2020; 59:983-986. [PMID: 31866629 PMCID: PMC7184077 DOI: 10.2169/internalmedicine.3837-19] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2019] [Accepted: 11/04/2019] [Indexed: 01/19/2023] Open
Abstract
A 22-year-old woman had been diagnosed with idiopathic thrombocytopenic purpura (ITP) 5 years earlier. After undergoing splenectomy, she relapsed frequently following prednisolone tapering. She was complicated with minimal change nephrotic syndrome (MCNS) while taking 20 mg of prednisolone. Despite treatment with prednisolone, cyclosporin and low-density lipoprotein-apheresis, MCNS and ITP did not improve. We added rituximab in 4 weekly infusions of 375 mg/m2. MCNS and ITP were in complete remission. After administering rituximab once, all medicines were discontinued. No relapse had occurred by 50 months following the first rituximab administration. Rituximab affects steroid-resistant MCNS and ITP for a long time without complications.
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Affiliation(s)
- Mana Nishikawa
- Department of Nephrology, Kurashiki Central Hospital, Japan
| | | | | | - Ryo Sawaki
- Department of Nephrology, Kurashiki Central Hospital, Japan
| | - Haruka Ikuta
- Department of Nephrology, Kurashiki Central Hospital, Japan
| | - Motoko Kanzaki
- Department of Nephrology, Kurashiki Central Hospital, Japan
| | - Kosuke Fukuoka
- Department of Nephrology, Kurashiki Central Hospital, Japan
| | - Masaki Fukushima
- Department of Internal Medicine, Shigei Research Institute Hospital, Japan
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Zhao J, Liu Z. Treatment of nephrotic syndrome: going beyond immunosuppressive therapy. Pediatr Nephrol 2020; 35:569-579. [PMID: 30904930 DOI: 10.1007/s00467-019-04225-7] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2018] [Revised: 02/13/2019] [Accepted: 02/25/2019] [Indexed: 01/15/2023]
Abstract
It is indisputable that immunosuppressive therapy and pathological diagnosis of renal biopsy have greatly improved the prognosis of childhood nephrotic syndrome. Unfortunately, there is no "one-size-fits-all" approach for precise patient stratification and treatment when facing the huge challenges posed by steroid-resistant nephrotic syndrome (SRNS). But genomic medicine has brought a glimmer of light, and the cognition of SRNS has entered a new stage. Based on this, identification of single genetic variants of SRNS has recognized the key role of podocyte injury in its pathogenesis. Targeted treatment of podocyte injury is paramount, and immunosuppressant with podocyte-targeted therapy seems to be more suitable as the first choice for SRNS, that is, we need to pay attention to their additional non-immunosuppressive effects. In the same way, other effect factors of nephrotic syndrome and the related causes of immunosuppressive therapy resistance require us to select reasonable and targeted non-immunosuppressive therapies, instead of only blindly using steroids and immunosuppressants, which may be ineffective and bring significant side effects. This article provides a summary of the clinical value of identification of genetic variants in podocytes and non-immunosuppressive therapy for nephrotic syndrome in children.
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Affiliation(s)
- Jinghong Zhao
- Department of Nephrology, Institute of Nephrology of Chongqing and Kidney Center of PLA, Xinqiao Hospital, Third Military Medical University, Chongqing, China
| | - Zhihong Liu
- National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China.
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Different effects of rituximab on a native kidney and a post-transplant kidney with recurrence of focal segmental glomerulosclerosis. CEN Case Rep 2020; 9:195-199. [PMID: 31997159 DOI: 10.1007/s13730-020-00451-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2019] [Accepted: 01/18/2020] [Indexed: 11/27/2022] Open
Abstract
We present the case of a 29-year-old woman with focal segmental glomerulosclerosis (FSGS) who was treated with rituximab administration under different conditions for refractory nephrotic syndrome and posttransplant FSGS recurrence. At the age of 13 years, she developed FSGS, which followed a refractory clinical course, and eventually necessitated her to undergo plasmapheresis and receive rituximab at the age of 25 years. However, both therapies were ineffective, and she subsequently had progressive renal failure, for which dialysis was initiated at the age of 26 years. At the age of 28 years, she received a renal transplant from a living donor. However, nearly 1 year after the transplantation, nephrotic-range proteinuria was observed and FSGS recurrence was confirmed via biopsy of the transplanted kidney. Plasmapheresis resulted in complete remission, which was maintained by rituximab administration, and the patient followed a favorable course. To date, there have been no reports on the effect of rituximab on both the native kidney and post-transplant FSGS recurrence in the same patient. Interestingly, this case showed different responses to rituximab administration.
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Kamei K, Ishikura K, Sako M, Ito S, Nozu K, Iijima K. Rituximab therapy for refractory steroid-resistant nephrotic syndrome in children. Pediatr Nephrol 2020; 35:17-24. [PMID: 30564879 DOI: 10.1007/s00467-018-4166-1] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2018] [Revised: 11/30/2018] [Accepted: 12/03/2018] [Indexed: 12/24/2022]
Abstract
Patients with steroid-resistant nephrotic syndrome (SRNS) who develop resistance to immunosuppressive agents, defined as refractory SRNS, have poor renal outcomes. Although the chimeric anti-CD20 monoclonal antibody rituximab has shown efficacy for frequently relapsing nephrotic syndrome and steroid-dependent nephrotic syndrome, its efficacy for refractory SRNS remains uncertain due to limited data. According to previous case reports, 50.4% of patients with refractory SRNS showed clinical improvements after rituximab treatment. Remission rates in patients with initial steroid resistance and late steroid resistance were 43.9 and 57.7%, respectively, and 41.5 and 63.6% in patients with focal segmental glomerulosclerosis and minor glomerular abnormalities, respectively. However, various factors (race, disease severity, number of rituximab doses, concomitant treatments, and observation period) differed among these observational studies and their consensus may also have been affected by potential publication bias. Rituximab monotherapy may have some degree of efficacy and lead to satisfactory outcomes in a subset of patients with refractory SRNS. However, administration of concomitant treatments during rituximab-mediated B cell depletion, such as methylprednisolone pulse therapy, daily oral prednisolone therapy, and immunosuppressive agents, may lead to better outcomes in these patients. Large-scale, multi-center prospective studies are needed to evaluate the efficacy and safety of such regimens.
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Affiliation(s)
- Koichi Kamei
- Division of Nephrology and Rheumatology, National Center for Child Health and Development, 2-10-1, Okura, Setagaya-ku, Tokyo, 157-8535, Japan
| | - Kenji Ishikura
- Division of Nephrology and Rheumatology, National Center for Child Health and Development, 2-10-1, Okura, Setagaya-ku, Tokyo, 157-8535, Japan
| | - Mayumi Sako
- Division for Clinical Trials, Department of Clinical Research, Center for Clinical Research and Development, National Center for Child Health and Development, 2-10-1, Okura, Setagaya-ku, Tokyo, 157-8535, Japan
| | - Shuichi Ito
- Department of Pediatrics, Graduate School of Medicine, Yokohama City University, 3-9, Fukuura, Kanazawa-ku, Yokohama, Kanagawa, 236-0004, Japan
| | - Kandai Nozu
- Department of Pediatrics, Kobe University Graduate School of Medicine, 7-5-2, Kusunoki-cho, Chuo-ku, Kobe, Hyogo, 650-0017, Japan
| | - Kazumoto Iijima
- Department of Pediatrics, Kobe University Graduate School of Medicine, 7-5-2, Kusunoki-cho, Chuo-ku, Kobe, Hyogo, 650-0017, Japan.
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Wang M, Wang R, He X, Yu M, Xia Z, Gao C. Two Children With Novel TRPC6 Spontaneous Missense Mutations and Atypical Phenotype: A Case Report and Literature Review. Front Pediatr 2020; 8:269. [PMID: 32509715 PMCID: PMC7249804 DOI: 10.3389/fped.2020.00269] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2020] [Accepted: 04/29/2020] [Indexed: 01/21/2023] Open
Abstract
Background: The phenotypes of TRPC6 mutations have been reported mainly in familial and sporadic focal segmental glomerulosclerosis (FSGS), which can occur in both adults and children. Herein, we report on two children with novel TRPC6 spontaneous missense mutations associated with immune complex-mediated glomerulonephritis and minor glomerular abnormality (MGA) that showed to be resistant to corticosteroids and other immunosuppressants. Case Presentation: A 9-year-old girl presented with steroid-resistant nephrotic syndrome (SRNS), while another 11-year-old boy developed proteinuria at 7 years old. Treatment with a variety of immunosuppressants had no effect, and the renal biopsy showed immune complex-mediated glomerulonephritis and MGA. No members of their family were clinically affected. Genetic testing was performed in the two patients, revealing two novel spontaneous missense mutations in TRPC6-N110S and P112R. The girl developed end-stage renal disease (ESRD) 5 months after onset while the boy continued to have sub-nephrotic range proteinuria and normal creatinine. Conclusions: Two novel TRPC6 mutations were associated with the atypical phenotype-immune complex-mediated glomerulonephritis and MGA, rather than FSGS as previously reported. Their rates of disease progression are different. Genetic testing is helpful to identify the etiology and avoid the side effects brought on by immunosuppressants.
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Affiliation(s)
- Meiqiu Wang
- Department of Pediatrics, Jinling Hospital, The First School of Clinical Medicine, Southern Medical University, Nanjing, China
| | - Ren Wang
- Department of Pediatrics, Jinling Hospital, Nanjing Medical University, Nanjing, China
| | - Xu He
- Department of Pediatrics, Jinling Hospital, Nanjing, China
| | - Min Yu
- Department of Pediatrics, Jinling Hospital, Nanjing Medical University, Nanjing, China.,Department of Neonatology, Taizhou People's Hospital, Taizhou, China
| | - Zhengkun Xia
- Department of Pediatrics, Jinling Hospital, Nanjing, China
| | - Chunlin Gao
- Department of Pediatrics, Jinling Hospital, Nanjing, China
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Liu ID, Willis NS, Craig JC, Hodson EM, Cochrane Kidney and Transplant Group. Interventions for idiopathic steroid-resistant nephrotic syndrome in children. Cochrane Database Syst Rev 2019; 2019:CD003594. [PMID: 31749142 PMCID: PMC6868353 DOI: 10.1002/14651858.cd003594.pub6] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND The majority of children who present with their first episode of nephrotic syndrome achieve remission with corticosteroid therapy. Children who fail to respond to corticosteroids in the first episode of nephrotic syndrome (initial resistance) or develop resistance after one or more responses to corticosteroids (delayed resistance) may be treated with immunosuppressive agents including calcineurin inhibitors (CNI) (cyclosporin or tacrolimus) and with non-immunosuppressive agents such as angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARB). However, response to these agents is limited so newer agents are being assessed for efficacy. This is an update of a review first published in 2004 and updated in 2006, 2010 and 2016. OBJECTIVES To evaluate the benefits and harms of different interventions used in children with idiopathic nephrotic syndrome, who do not achieve remission following four weeks or more of daily corticosteroid therapy. SEARCH METHODS We searched the Cochrane Kidney and Transplant Register of Studies to 17 September 2019 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov. SELECTION CRITERIA Randomised controlled trials (RCTs) and quasi-RCTs were included if they compared different immunosuppressive agents or non-immunosuppressive agents with placebo, prednisone or other agent given orally or parenterally in children aged three months to 18 years with steroid-resistant nephrotic syndrome (SRNS). Studies, which enrolled children and adults but in which paediatric data could not be separated from adult data, were also included. DATA COLLECTION AND ANALYSIS Two authors independently searched the literature, determined study eligibility, assessed risk of bias and extracted data. For dichotomous outcomes, results were expressed as risk ratios (RR) and 95% confidence intervals (CI). For continuous outcomes, results were expressed as mean difference (MD) and 95% CI. Data were pooled using the random effects model. The certainty of the evidence was assessed using the GRADE approach. MAIN RESULTS Twenty-five studies (1063 participants) were included. Fourteen studies were at low risk of bias for sequence generation and allocation concealment. Five and 19 studies were at low risk of performance and detection bias. Fourteen, 14 and 13 studies were at low risk of attrition bias, reporting bias and other bias respectively. Cyclosporin compared with placebo or no treatment may increase the number of participants who achieve complete remission (4 studies, 74 participants: RR 3.50, 95% CI 1.09 to 11.20) or complete or partial remission (4 studies, 74 children: RR 3.15, 95% CI 1.04 to 9.57) by 6 months (low certainty evidence). It is uncertain whether cyclosporin increases the likelihood of worsening hypertension or reduces the likelihood of end-stage kidney disease (very low certainty evidence). CNI compared with IV cyclophosphamide (CPA) may increase the number of participants with complete or partial remission at 3 to 6 months (2 studies, 156 children: RR 1.98, 95% CI 1.25 to 3.13) (low certainty evidence) and probably reduces the number with treatment failure (non response, serious infection, persistently elevated creatinine (1 study, 124 participants: RR 0.32, 95% CI 0.18 to 0.58) (moderate certainty evidence) with little or no increase in serious infections (1 study, 131 participants: RR 0.49, 95% CI 0.16 to 1.56) (moderate certainty evidence). Tacrolimus compared with cyclosporin may make little or no difference to the number who achieve complete or partial remission (2 studies, 58 participants: RR 1.05, 95% CI 0.87 to 1.25) (low certainty evidence) or in the number with worsening hypertension (2 studies, 58 participants: RR 0.41, 95% CI 0.08 to 2.15) (low certainty evidence). Cyclosporin compared with mycophenolate mofetil (MMF) and dexamethasone probably makes little or no difference to the number who achieve complete or partial remission (1 study, 138 participants: RR 2.14, 95% CI 0.87 to 5.24) (moderate certainty evidence) and makes little or no difference to the number dying (1 study, 138 participants: RR 2.14, 95% CI 0.87 to 5.24) or with 50% reduction in glomerular filtration rate (GFR) (1 study, 138 participants: RR 2.29, 95% CI 0.46 to 11.41) (low certainty evidence). Among children, who have achieved complete remission, tacrolimus compared with MMF may increase the number of children who maintain complete or partial response for 12 months (1 study, 60 children: RR 2.01, 95% CI 1.32 to 3.07) (low certainty evidence). Oral CPA with prednisone compared with prednisone alone may make little or no difference to the number who achieve complete remission (2 studies, 84 children: RR 1.06, 95% CI 0.61 to 1.87) (low certainty evidence). IV CPA compared with oral CPA (2 studies, 61 children: RR 1.58, 95% CI 0.65 to 3.85) and IV compared with oral CPA plus IV dexamethasone (1 study, 49 children: RR 1.13, 95% CI 0.65 to 1.96) may make little or no difference to the number who achieve complete remission (low certainty evidence). It is uncertain whether rituximab and cyclosporin compared with cyclosporin increases the likelihood of remission because the certainty of the evidence is very low. It is uncertain whether adalimumab or galactose compared with conservative therapy increases the likelihood of remission because the certainty of the evidence is very low. Two studies reported that ACEi may reduce proteinuria in children with SRNS. One study reported that the dual angiotensin II and endothelin Type A receptor antagonist, sparsentan, may reduce proteinuria more effectively than the angiotensin receptor blocker, irbesartan. AUTHORS' CONCLUSIONS To date RCTs have demonstrated that CNIs may increase the likelihood of complete or partial remission compared with placebo/no treatment or CPA. For other regimens assessed, it remains uncertain whether the interventions alter outcomes because the certainty of the evidence is low. Further adequately powered, well designed RCTs are needed to evaluate other regimens for children with idiopathic SRNS. Since SRNS represents a spectrum of diseases, future studies should enrol children from better defined groups of patients with SRNS.
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Affiliation(s)
- Isaac D Liu
- National University Health SystemDepartment of Paediatrics1E Kent Ridge Road, NUHS Tower Block, Level 12SingaporeSingapore119228
| | - Narelle S Willis
- The University of SydneySydney School of Public HealthSydneyNSWAustralia2006
- The Children's Hospital at WestmeadCochrane Kidney and Transplant, Centre for Kidney ResearchLocked Bag 4001WestmeadNSWAustralia2145
| | - Jonathan C Craig
- The Children's Hospital at WestmeadCochrane Kidney and Transplant, Centre for Kidney ResearchLocked Bag 4001WestmeadNSWAustralia2145
- Flinders UniversityCollege of Medicine and Public HealthAdelaideSAAustralia5001
| | - Elisabeth M Hodson
- The University of SydneySydney School of Public HealthSydneyNSWAustralia2006
- The Children's Hospital at WestmeadCochrane Kidney and Transplant, Centre for Kidney ResearchLocked Bag 4001WestmeadNSWAustralia2145
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47
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Bensimhon AR, Williams AE, Gbadegesin RA. Treatment of steroid-resistant nephrotic syndrome in the genomic era. Pediatr Nephrol 2019; 34:2279-2293. [PMID: 30280213 PMCID: PMC6445770 DOI: 10.1007/s00467-018-4093-1] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2018] [Revised: 09/13/2018] [Accepted: 09/18/2018] [Indexed: 12/25/2022]
Abstract
The pathogenesis of steroid-resistant nephrotic syndrome (SRNS) is not completely known. Recent advances in genomics have elucidated some of the molecular mechanisms and pathophysiology of the disease. More than 50 monogenic causes of SRNS have been identified; however, these genes are responsible for only a small fraction of SRNS in outbred populations. There are currently no guidelines for genetic testing in SRNS, but evidence from the literature suggests that testing should be guided by the genetic architecture of the disease in the population. Notably, most genetic forms of SRNS do not respond to current immunosuppressive therapies; however, a small subset of patients with monogenic SRNS will achieve partial or complete remission with specific immunomodulatory agents, presumably due to non-immunosuppressive effects of these agents. We suggest a pragmatic approach to the therapy of genetic SRNS, as there is no evidence-based algorithm for the management of the disease.
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Affiliation(s)
- Adam R. Bensimhon
- Department of Pediatrics, Division of Nephrology, Duke University Medical Center, Durham, NC 27710, USA
| | - Anna E. Williams
- Department of Pediatrics, Division of Nephrology, Duke University Medical Center, Durham, NC 27710, USA
| | - Rasheed A. Gbadegesin
- Department of Pediatrics, Division of Nephrology, Duke University Medical Center, Durham, NC 27710, USA,Department of Medicine, Division of Nephrology, Duke University Medical Center, Durham, NC 27710, USA,Duke Molecular Physiology Institute, Durham, NC, USA
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48
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Kaegi C, Wuest B, Schreiner J, Steiner UC, Vultaggio A, Matucci A, Crowley C, Boyman O. Systematic Review of Safety and Efficacy of Rituximab in Treating Immune-Mediated Disorders. Front Immunol 2019; 10:1990. [PMID: 31555262 PMCID: PMC6743223 DOI: 10.3389/fimmu.2019.01990] [Citation(s) in RCA: 126] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2019] [Accepted: 08/06/2019] [Indexed: 12/20/2022] Open
Abstract
Background: During the past years biologic agents (also termed biologicals or biologics) have become a crucial treatment option in immunological diseases. Numerous articles have been published on biologicals, which complicates the decision making process on the use of the most appropriate biologic for a given immune-mediated disease. This systematic review is the first of a series of articles assessing the safety and efficacy of B cell-targeting biologics for the treatment of immune-mediated diseases. Objective: To evaluate rituximab's safety and efficacy for the treatment of immune-mediated disorders compared to placebo, conventional treatment, or other biologics. Methods: The PRISMA checklist guided the reporting of the data. We searched the PubMed database between 4 October 2016 and 26 July 2018 concentrating on immune-mediated disorders. Results: The literature search identified 19,665 articles. After screening titles and abstracts against the inclusion and exclusion criteria and assessing full texts, 105 articles were finally included in a narrative synthesis. Conclusions: Rituximab is both safe and effective for the treatment of acquired angioedema with C1-inhibitor deficiency, ANCA-associated vasculitis, autoimmune hemolytic anemia, Behçet's disease, bullous pemphigoid, Castleman's disease, cryoglobulinemia, Goodpasture's disease, IgG4-related disease, immune thrombocytopenia, juvenile idiopathic arthritis, relapsing-remitting multiple sclerosis, myasthenia gravis, nephrotic syndrome, neuromyelitis optica, pemphigus, rheumatoid arthritis, spondyloarthropathy, and systemic sclerosis. Conversely, rituximab failed to show an effect for antiphospholipid syndrome, autoimmune hepatitis, IgA nephropathy, inflammatory myositis, primary-progressive multiple sclerosis, systemic lupus erythematosus, and ulcerative colitis. Finally, mixed results were reported for membranous nephropathy, primary Sjögren's syndrome and Graves' disease, therefore warranting better quality trials with larger patient numbers.
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Affiliation(s)
- Celine Kaegi
- Department of Immunology, University Hospital Zurich, Zurich, Switzerland
| | - Benjamin Wuest
- Department of Immunology, University Hospital Zurich, Zurich, Switzerland
| | - Jens Schreiner
- Department of Immunology, University Hospital Zurich, Zurich, Switzerland
| | - Urs C Steiner
- Department of Immunology, University Hospital Zurich, Zurich, Switzerland
| | - Alessandra Vultaggio
- Department of Biomedicine, Azienda Ospedaliero Universitaria Careggi, Florence, Italy
| | - Andrea Matucci
- Department of Biomedicine, Azienda Ospedaliero Universitaria Careggi, Florence, Italy
| | - Catherine Crowley
- Department of Immunology, University Hospital Zurich, Zurich, Switzerland
| | - Onur Boyman
- Department of Immunology, University Hospital Zurich, Zurich, Switzerland.,Faculty of Medicine, University of Zurich, Zurich, Switzerland
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49
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Colliou E, Karras A, Boffa JJ, Ribes D, Garrouste C, Quintrec ML, Daugas E, Huart A, Ducloux D, Hummel A, Ferrandiz I, Demoulin N, Jourde-Chiche N, Chauveau D, Audard V, Faguer S. Outcomes of Older Patients (≥60 years) with New-Onset Idiopathic Nephrotic Syndrome Receiving Immunosuppressive Regimen: A Multicentre Study of 116 Patients. J Clin Med 2019; 8:jcm8030298. [PMID: 30832362 PMCID: PMC6463053 DOI: 10.3390/jcm8030298] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2019] [Revised: 02/20/2019] [Accepted: 02/26/2019] [Indexed: 12/29/2022] Open
Abstract
Because of its rarity, renal presentation and outcomes of idiopathic nephrotic syndrome (INS; minimal changes disease or focal and segmental glomerulosclerosis) has poorly been described in elderly patients, precluding an individualized therapy procedure. Whether immunosuppressive regimens formerly designed in children and young adults are safe and efficient in elderly remains elusive. In a large multicentric retrospective study that included 116 patients with INS and onset ≥ 60 years of age, we showed that cumulative incidence of renal response was 95% after frontline therapy, with an age-dependent median time-to-response (60 days before 70 years of age at the onset vs. 120 days after; p = 0.03). Cumulative incidence of relapse was 90% at 7 years, with relapse occurring continuously over time. After a median follow-up of 34 months (IQR (12; 57)), 7 patients had died (6%) and 5 reached end-stage renal disease. Complications were highly prevalent: diabetes mellitus (23.3%), hypertension (24.1%), infection requiring hospitalization (21.6%) and acute kidney injury (9.5%). Thus, in older patients with INS and receiving steroids, renal response is delayed and relapse is the rule. Alternative immunosuppressive regimens, including B-cells depleting agents as frontline therapy, should be tested in this subset of patients to improve the mid- to long-term outcomes.
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Affiliation(s)
- Eloïse Colliou
- Département de Néphrologie et Transplantation d'Organes, Centre de Référence des Maladies Rénales Rares, Centre Hospitalier Universitaire de Toulouse, 31000 Toulouse, France.
| | - Alexandre Karras
- Service de Néphrologie, Hôpital Européen-Georges Pompidou, Assistance Publique des Hôpitaux de Paris, 75015 Paris, France.
| | - Jean-Jacques Boffa
- Service de Néphrologie, Hôpital Tenon, Assistance Publique des Hôpitaux de Paris, 75020 Paris, France.
| | - David Ribes
- Département de Néphrologie et Transplantation d'Organes, Centre de Référence des Maladies Rénales Rares, Centre Hospitalier Universitaire de Toulouse, 31000 Toulouse, France.
| | - Cyril Garrouste
- Service de Néphrologie et Transplantation Rénale, Centre Hospitalier Universitaire de Clermont-Ferrand, 63000 Clermont-Ferrand, France.
| | - Moglie Le Quintrec
- Service de Néphrologie et Transplantation Rénale, Centre Hospitalier Universitaire de Montpellier, 34000 Montpellier, France.
| | - Eric Daugas
- Service de Néphrologie et Transplantation Rénale, Hôpital Bichat, Assistance Publique des Hôpitaux de Paris, 75018 Paris, France.
| | - Antoine Huart
- Département de Néphrologie et Transplantation d'Organes, Centre de Référence des Maladies Rénales Rares, Centre Hospitalier Universitaire de Toulouse, 31000 Toulouse, France.
| | - Didier Ducloux
- Service de Néphrologie et Transplantation Rénale, Centre Hospitalier Universitaire de Besançon, 25000 Besançon, France.
| | - Aurélie Hummel
- Service de Néphrologie-Dialyse, Hôpital Necker, Assistance Publique des Hôpitaux de Paris, 75015 Paris, France.
| | - Inès Ferrandiz
- Département de Néphrologie et Transplantation d'Organes, Centre de Référence des Maladies Rénales Rares, Centre Hospitalier Universitaire de Toulouse, 31000 Toulouse, France.
| | - Nathalie Demoulin
- Département de Néphrologie, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, 1348 Louvain, Belgique.
| | - Noémie Jourde-Chiche
- Université d'Aix-Marseille C2VN, INSERM 1263, INRA 1260; AP-HM, Centre de Néphrologie et Transplantation rénale, 13000 Marseille, France.
| | - Dominique Chauveau
- Département de Néphrologie et Transplantation d'Organes, Centre de Référence des Maladies Rénales Rares, Centre Hospitalier Universitaire de Toulouse, 31000 Toulouse, France.
- Institut National de la Santé et de la Recherche Médicale, U1048 (Institut des Maladies Cardiovasculaires et Métaboliques-équipe 12), 31000 Toulouse, France.
| | - Vincent Audard
- Service de Néphrologie et Transplantation, Centre de Référence Maladie Rare Syndrome Néphrotique Idiopathique, Hôpital Mondor, Assistance Publique des Hôpitaux de Paris, Université Paris-Est Créteil (UPEC), INSERM U955, équipe 21, 94000 Créteil, France.
| | - Stanislas Faguer
- Département de Néphrologie et Transplantation d'Organes, Centre de Référence des Maladies Rénales Rares, Centre Hospitalier Universitaire de Toulouse, 31000 Toulouse, France.
- Institut National de la Santé et de la Recherche Médicale, U1048 (Institut des Maladies Cardiovasculaires et Métaboliques-équipe 12), 31000 Toulouse, France.
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50
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Fujinaga S, Nishino T, Umeda C, Tomii Y, Watanabe Y, Sakuraya K. Long-term outcomes after early treatment with rituximab for Japanese children with cyclosporine- and steroid-resistant nephrotic syndrome. Pediatr Nephrol 2019; 34:353-357. [PMID: 30426219 DOI: 10.1007/s00467-018-4145-6] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2018] [Revised: 10/25/2018] [Accepted: 11/07/2018] [Indexed: 01/11/2023]
Abstract
BACKGROUND Although rituximab (RTX) may be effective treatment in children with nephrotic syndrome who are resistant to cyclosporine A and steroid (CsA-SRNS), long-term outcomes after B cell depleting therapy remain unclear. CASE-DIAGNOSIS/TREATMENT We retrospectively reviewed the clinical courses (median follow-up, 5.1 years) of six CsA-SRNS children (three boys; median age at RTX, 4.2 years) unresponsive to oral cyclosporine combined with ≥ 2 courses of intravenous methylprednisolone pulses, who received RTX within 6 months after disease onset (median 11 weeks). After initial RTX treatment (median two doses of 375 mg/m2) followed by retreatment with intravenous methylprednisolone pulses and/or high-dose prednisolone, all patients achieved complete remission at a median of 158 days. Although 17 relapses occurred in five patients during follow-up, all but one patient became steroid sensitive. Severe neutropenia and hypogammaglobulinemia developed in two and four patients, respectively. However, no life-threatening infections were identified in the cohort. At last visit (median age, 11.3 years), all patients maintained complete remission without renal insufficiency. CONCLUSIONS Although late-onset adverse events should be considered, particularly for young patients, early RTX treatment may have positive outcomes in children with CsA-SRNS in the long term.
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Affiliation(s)
- Shuichiro Fujinaga
- Division of Nephrology, Saitama Children's Medical Center, 1-2 Shintoshin, Chuo-ku, Saitama city, Saitama, 330-8777, Japan.
| | - Tomohiko Nishino
- Division of Nephrology, Saitama Children's Medical Center, 1-2 Shintoshin, Chuo-ku, Saitama city, Saitama, 330-8777, Japan
| | - Chisato Umeda
- Division of Nephrology, Saitama Children's Medical Center, 1-2 Shintoshin, Chuo-ku, Saitama city, Saitama, 330-8777, Japan
| | - Yuji Tomii
- Division of Nephrology, Saitama Children's Medical Center, 1-2 Shintoshin, Chuo-ku, Saitama city, Saitama, 330-8777, Japan
| | - Yoshitaka Watanabe
- Division of Nephrology, Saitama Children's Medical Center, 1-2 Shintoshin, Chuo-ku, Saitama city, Saitama, 330-8777, Japan
| | - Koji Sakuraya
- Division of Nephrology, Saitama Children's Medical Center, 1-2 Shintoshin, Chuo-ku, Saitama city, Saitama, 330-8777, Japan
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