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Uro-Coste C, Lambert C, Audard V, Couzi L, Caillard S, Büchler M, Del Bello A, Malvezzi P, Pernin V, Colosio C, Mesnard L, Bertrand D, Martinez F, Ducloux D, Poulain C, Thierry A, Danthu C, Greze C, Lanaret C, Moal V, Hertig A, Dantal J, Legendre C, Chatelet V, Sicard A, Gosset C, Maillard N, Duveau A, Petit C, Kamar N, Heng AE, Anglicheau D, Garrouste C. Prophylactic treatment of FSGS recurrence in patients who relapsed on a previous kidney graft. Nephrol Dial Transplant 2025; 40:475-483. [PMID: 38794882 PMCID: PMC11879060 DOI: 10.1093/ndt/gfae108] [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] [Subscribe] [Scholar Register] [Received: 09/07/2023] [Indexed: 05/26/2024] Open
Abstract
BACKGROUND Recurrence of focal segmental glomerulosclerosis (FSGS) is common after kidney transplantation and is classically associated with a significant decrease in graft survival. A major risk factor is a prior history of FSGS recurrence on a previous graft. This analysis reports the impact of a prophylactic treatment of FSGS recurrence in very high-risk patients who experienced a recurrence on a previous graft. METHODS We performed a retrospective multicentre observational study in 25 French transplantation centres. The inclusion criteria were patients aged more than 18 years who had undergone kidney transplant between 31 December 2004 and 31 December 2020, and who had a history of FSGS recurrence on a previous graft. RESULTS We identified 66 patients: 40 received prophylactic treatment (PT+), including intravenous cyclosporine and/or rituximab and/or plasmapheresis, and 26 did not receive any prophylactic treatment (PT-). The time to progression to end-stage kidney disease was similar between groups. The PT+ group was younger at FSGS diagnosis and at the time of kidney retransplantation and lost their previous graft faster. The overall recurrence rate was 72.7% (76.9% in the PT- group and 70.0% in the PT+ group, P = .54). At least partial remission was achieved in 87.5% of patients. The 5-year graft survival was 67.7% [95% confidence interval (CI) 53.4%-78.4%]: 65.1% (95% CI 48.7%-77.4%) in patients with FSGS recurrence vs 77.3% (95% CI 43.8%-92.3%) in patients without recurrence (P = .48). CONCLUSION Our study suggests that prophylactic treatment should not be used routinely in patients receiving a second transplantation after recurrence of FSGS on a previous graft. The recurrence rate is high regardless of the use of prophylactic treatment. However, the 5-year graft survival remains satisfactory.
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Affiliation(s)
| | - Céline Lambert
- Unité de Biostatistiques, DRCI, CHU Clermont-Ferrand, Clermont-Ferrand, France
| | - Vincent Audard
- Assistance Publique des Hôpitaux de Paris, Service de Néphrologie et Transplantation Centre de Référence Maladie Rare « Syndrome Néphrotique Idiopathique », Hôpitaux Universitaires Henri-Mondor, Univ Paris Est Créteil, INSERM, IMRB, Créteil, France
| | - Lionel Couzi
- Service de Néphrologie, Transplantation, Dialyse et Aphérèses, CHU de Bordeaux, Bordeaux, France
| | - Sophie Caillard
- Service de Néphrologie, University Hospital, Strasbourg, France
| | - Matthias Büchler
- Service de Néphrologie et Immunologie Clinique, CHRU de Tours, Tours, France
| | - Arnaud Del Bello
- Département de Néphrologie et Transplantation d'Organes, CHU Toulouse, INSERM U1043, IFR–BMT, Université Paul Sabatier, Toulouse, France
| | - Paolo Malvezzi
- Service de Néphrologie, Hémodialyse, Aphérèses et Transplantation Rénale, CHU Grenoble-Alpes, Grenoble, France
| | - Vincent Pernin
- Service de Néphrologie, Dialyse et Transplantation, Hôpital Lapeyronie, CHU Montpellier, Montpellier, France
| | | | - Laurent Mesnard
- Assistance Publique – Hôpitaux de Paris, Soins Intensifs Néphrologiques et Rein Aigu, APHP Sorbonne Université, Hôpital Tenon, Paris, France
| | | | - Frank Martinez
- Assistance Publique des Hôpitaux de Paris, Service de Néphrologie et Transplantation, Hôpital Universitaire Necker-Enfants Malades, Université de Paris, Paris, France
| | - Didier Ducloux
- Service de Néphrologie, Dialyse et Transplantation, CHU Besançon, Besançon, France
| | - Coralie Poulain
- Service de Néphrologie-Médecine Interne-Dialyse-Transplantation, CHU d'Amiens, Amiens, France
| | - Antoine Thierry
- Service de Néphrologie-Hémodialyse-Transplantation Rénale, CHU de Poitiers, Poitiers, France
| | - Clément Danthu
- Service de Néphrologie, Dialyse et Transplantation, CHU Limoges, Limoges, France
| | - Clarisse Greze
- Service de Néphrologie, CHU Clermont-Ferrand, Clermont-Ferrand, France
| | | | - Valérie Moal
- Aix Marseille Université, Assistance Publique Hôpitaux de Marseille, Hôpital Conception, Centre de Néphrologie et Transplantation Rénale, Marseille, France
| | | | - Jacques Dantal
- Institut de Transplantation Urologie Néphrologie (ITUN), Service de Néphrologie et Immunologie Clinique, CHU Nantes, Nantes, France
| | - Christophe Legendre
- Assistance Publique des Hôpitaux de Paris, Service de Néphrologie et Transplantation, Hôpital Universitaire Necker-Enfants Malades, Université de Paris, Paris, France
| | - Valérie Chatelet
- Centre Universitaire des Maladies Rénales, Centre Hospitalier Universitaire de Caen, Caen, France
| | - Antoine Sicard
- Service de Néphrologie, Dialyse et Transplantation, CHU Nice, Nice, France
| | - Clément Gosset
- Service de Néphrologie, Dialyse et Transplantation, CHU Nice, Nice, France
| | - Nicolas Maillard
- Service de Néphrologie et Transplantation, CHU Saint-Etienne, Saint-Etienne, France
| | - Agnès Duveau
- Service de Néphrologie, CHU Angers, Angers, France
| | - Clémence Petit
- Institut de Transplantation Urologie Néphrologie (ITUN), Service de Néphrologie et Immunologie Clinique, CHU Nantes, Nantes, France
| | - Nassim Kamar
- Département de Néphrologie et Transplantation d'Organes, CHU Toulouse, INSERM U1043, IFR–BMT, Université Paul Sabatier, Toulouse, France
| | | | - Dany Anglicheau
- Assistance Publique des Hôpitaux de Paris, Service de Néphrologie et Transplantation, Hôpital Universitaire Necker-Enfants Malades, Université de Paris, Paris, France
| | - Cyril Garrouste
- Service de Néphrologie, CHU Clermont-Ferrand, Clermont-Ferrand, France
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Ivanov D, Weber LT, Levtchenko E, Vakulenko L, Ivanova M, Zavalna I, Lagodych Y, Boiko N. Rituximab Administration to Treat Nephrotic Syndrome in Children: 2-Year Follow-Up. Biomedicines 2024; 12:2600. [PMID: 39595166 PMCID: PMC11592163 DOI: 10.3390/biomedicines12112600] [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: 10/15/2024] [Revised: 11/01/2024] [Accepted: 11/07/2024] [Indexed: 11/28/2024] Open
Abstract
BACKGROUND Steroid-sensitive nephrotic syndrome (SSNS) and steroid-resistant nephrotic syndrome (SRNS) significantly affect children's quality of life. There are frequent relapses in SSNS and progression in SRNS. IPNA guidelines suggest that monoclonal antibodies like rituximab (RTX) are promising treatments. OBJECTIVE This study aims to evaluate the long-term efficacy and safety of rituximab administration in children with SSNS, encompassing FRNS and SDNS, and SRNS over a two-year follow-up period, facilitating individualized management. METHODS We conducted an open-label, multicenter, randomized, and patient-oriented study (RICHNESS), involving children aged 3-18 with SRNS (18) and SSNS (11) undergoing 2 years continuous RTX therapy. The primary outcome was complete/partial remission (CR/PR), as defined by IPNA/KDIGO guidelines, at 6, 12, 18, and 24 months on RTX; secondary outcomes included adverse events. Key endpoints included the estimated glomerular filtration rate (eGFR), the albumin-to-creatinine ratio (ACR), CD20 levels, IgG levels, and the incidence of infections. Kidney biopsies were performed in 94% of SRNS patients. RTX was administered every 6-9 months, depending on CD20 levels, IgG levels, and the presence of infections. The eGFR and ACR were assessed every 6 months. RESULTS Some 31 children were selected for RTX treatment. Overall, 2 experienced severe allergic reactions, leading to their exclusion from the final analysis of 29 children. In the SSNS group, all children achieved and maintained complete remission within 2 years. Remission rates in the SRNS group ranged from 39% (RR 0.78; 95% CI: 16.4-61.4%, NNT 9) at the 6th month to 72% (RR 1.44; 95% CI: 51.5-92.9%) over the 2-year follow-up period due to continuous RTX therapy. The median duration of RTX use was 26.1 months, with a median cumulative dose of 1820 mg/m2. Adverse reactions and complications were presented by mild infusion-related reactions in 3 children (10.3%), severe allergic reactions in 2 children (6.2%), hypogammaglobulinemia in 7 children (24%), infections in 3 children (10.3%), severe destructive pneumonia in 1 child, recurrent respiratory infections in 2 children, and neutropenia in 1 child (3.44%). CONCLUSIONS RTX was tolerated well, and proved highly effective as a steroid-sparing agent, offering potential in terms of stopping relapses and minimizing steroid-related side effects. It also demonstrated efficacy in slowing progression in SRNS, indicating potential for use in ACR reduction and renal function restoration, but requires careful use given potential severe allergic reactions and infectious complications. Further studies should focus on long-term cost-effectiveness and deferred side effects.
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Affiliation(s)
- Dmytro Ivanov
- Institute of Postgraduate Education, Bogomolets National Medical University, 01601 Kyiv, Ukraine
| | - Lutz T. Weber
- German Society for Pediatric Nephrology, 10963 Berlin, Germany;
| | - Elena Levtchenko
- Emma Children Hospital Amsterdam, University Medical Centre, BA2 6HE Amsterdam, The Netherlands
| | - Liudmyla Vakulenko
- Department of Propaedeutics of Childhood Illnesses and Pediatrics 2, Dnipro State Medical University, 49489 Dnipro, Ukraine
| | - Mariia Ivanova
- European Institute of Oncology IRCCS, 20139 Milan, Italy;
| | - Iryna Zavalna
- Institute of Postgraduate Education, Bogomolets National Medical University, 01601 Kyiv, Ukraine
| | - Yelizaveta Lagodych
- Institute of Postgraduate Education, Bogomolets National Medical University, 01601 Kyiv, Ukraine
| | - Ninel Boiko
- Regional Children Hospital, 33027 Rivne, Ukraine
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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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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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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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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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Chan EYH, Yu EL, Angeletti A, Arslan Z, Basu B, Boyer O, Chan CY, Colucci M, Dorval G, Dossier C, Drovandi S, Ghiggeri GM, Gipson DS, Hamada R, Hogan J, Ishikura K, Kamei K, Kemper MJ, Ma ALT, Parekh RS, Radhakrishnan S, Saini P, Shen Q, Sinha R, Subun C, Teo S, Vivarelli M, Webb H, Xu H, Yap HK, Tullus K. Long-Term Efficacy and Safety of Repeated Rituximab to Maintain Remission in Idiopathic Childhood Nephrotic Syndrome: An International Study. J Am Soc Nephrol 2022; 33:1193-1207. [PMID: 35354600 PMCID: PMC9161790 DOI: 10.1681/asn.2021111472] [Citation(s) in RCA: 52] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Accepted: 03/14/2022] [Indexed: 11/03/2022] Open
Abstract
BACKGROUND Long-term outcomes after multiple courses of rituximab among children with frequently relapsing, steroid-dependent nephrotic syndrome (FRSDNS) are unknown. METHODS A retrospective cohort study at 16 pediatric nephrology centers from ten countries in Asia, Europe, and North America included children with FRSDNS who received two or more courses of rituximab. Primary outcomes were relapse-free survival and adverse events. RESULTS A total of 346 children (age, 9.8 years; IQR, 6.6-13.5 years; 73% boys) received 1149 courses of rituximab. A total of 145, 83, 50, 28, 22, and 18 children received two, three, four, five, six, and seven or more courses, respectively. Median (IQR) follow-up was 5.9 (4.3-7.7) years. Relapse-free survival differed by treatment courses (clustered log-rank test P<0.001). Compared with the first course (10.0 months; 95% CI, 9.0 to 10.7 months), relapse-free period and relapse risk progressively improved after subsequent courses (12.0-16.0 months; HRadj, 0.03-0.13; 95% CI, 0.01 to 0.18; P<0.001). The duration of B-cell depletion remained similar with repeated treatments (6.1 months; 95% CI, 6.0 to 6.3 months). Adverse events were mostly mild; the most common adverse events were hypogammaglobulinemia (50.9%), infection (4.5%), and neutropenia (3.7%). Side effects did not increase with more treatment courses nor a higher cumulative dose. Only 78 of the 353 episodes of hypogammaglobulinemia were clinically significant. Younger age at presentation (2.8 versus 3.3 years; P=0.05), age at first rituximab treatment (8.0 versus 10.0 years; P=0.01), and history of steroid resistance (28% versus 18%; P=0.01) were associated with significant hypogammaglobulinemia. All 53 infective episodes resolved, except for one patient with hepatitis B infection and another with EBV infection. There were 42 episodes of neutropenia, associated with history of steroid resistance (30% versus 20%; P=0.04). Upon last follow-up, 332 children (96%) had normal kidney function. CONCLUSIONS Children receiving repeated courses of rituximab for FRSDNS experience an improving clinical response. Side effects appear acceptable, but significant complications can occur. These findings support repeated rituximab use in FRSDNS.
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Affiliation(s)
- Eugene Yu-hin Chan
- Paediatric Nephrology Centre, Hong Kong Children’s Hospital, Hong Kong SAR
- Department of Paediatrics and Adolescent Medicine, University of Hong Kong, Hong Kong SAR
- Department of Paediatric Nephrology, Great Ormond Street Hospital for Children, National Health Service Trust, London, United Kingdom
| | - Ellen L.M. Yu
- Clinical Research Center, Princess Margaret Hospital, Hong Kong SAR
| | - Andrea Angeletti
- Nephrology, Dialysis and Transplantation, IRCCS Istituto Giannina Gaslini, Genoa, Italy
- Laboratory of Molecular Nephrology, IRCCS Istituto Giannina Gaslini, Genova, Italy
| | - Zainab Arslan
- Department of Paediatric Nephrology, Great Ormond Street Hospital for Children, National Health Service Trust, London, United Kingdom
| | - Biswanath Basu
- Division of Pediatric Nephrology, Nilratan Sircar Medical College and Hospital, Kolkata, India
| | - Olivia Boyer
- Pediatric Nephrology, Reference Center for Nephrotic Syndrome in Children and Adults, Necker-Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Institut Imagine, Institut National de la Santé et de la Recherche Médicale (INSERM) U1163, Université Paris Cité, Paris, France
| | - Chang-Yien Chan
- Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
- Khoo Teck Puat – National University Children’s Medical Institute, National University Health System, Singapore
| | - Manuela Colucci
- Renal Diseases Research Unit, Genetics and Rare Diseases Research Division, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
| | - Guillaume Dorval
- Pediatric Nephrology, Reference Center for Nephrotic Syndrome in Children and Adults, Necker-Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Institut Imagine, Institut National de la Santé et de la Recherche Médicale (INSERM) U1163, Université Paris Cité, Paris, France
| | - Claire Dossier
- Pediatric Nephrology Department, Robert Debré Hospital, APHP, Paris, France
| | - Stefania Drovandi
- Nephrology, Dialysis and Transplantation, IRCCS Istituto Giannina Gaslini, Genoa, Italy
| | - Gian Marco Ghiggeri
- Nephrology, Dialysis and Transplantation, IRCCS Istituto Giannina Gaslini, Genoa, Italy
| | - Debbie S. Gipson
- Division of Nephrology, Department of Pediatrics, University of Michigan, CS Mott Children’s Hospital, Ann Arbor, Michigan
| | - Riku Hamada
- Department of Nephrology and Rheumatology, Tokyo Metropolitan Children’s Medical Center, Tokyo, Japan
| | - Julien Hogan
- Department of Pediatric Nephrology, Robert-Debré Hospital, Reference Center for Nephrotic Syndrome in Children and Adults, Centre de Référence Syndrome Néphrotique de l’Enfant et de l’Adulte (CMR SNI), AP-HP, Université Paris Cité, Paris, France
| | - Kenji Ishikura
- Department of Pediatrics, Kitasato University School of Medicine, Tokyo, Japan
- Department of Pediatrics, Kitasato University Hospital, Tokyo, Japan
| | - Koichi Kamei
- Division of Nephrology and Rheumatology, National Center for Child Health and Development, Tokyo, Japan
| | - Markus J. Kemper
- Department of Pediatrics, Asklepios Medical School, Hamburg, Germany
| | - Alison Lap-tak Ma
- Paediatric Nephrology Centre, Hong Kong Children’s Hospital, Hong Kong SAR
- Department of Paediatrics and Adolescent Medicine, University of Hong Kong, Hong Kong SAR
| | - Rulan S. Parekh
- Division of Pediatric Nephrology, Hospital for Sick Children, Toronto, Ontario, Canada
| | - Seetha Radhakrishnan
- Division of Pediatric Nephrology, Hospital for Sick Children, Toronto, Ontario, Canada
| | - Priya Saini
- Division of Pediatric Nephrology, Hospital for Sick Children, Toronto, Ontario, Canada
| | - Qian Shen
- Children’s Hospital of Fudan University, National Children’s Medical Center, Shanghai, China
| | - Rajiv Sinha
- Pediatric Nephrology Unit, Institute of Child Health, Kolkata, India
| | - Chantida Subun
- Department of Paediatric Nephrology, Great Ormond Street Hospital for Children, National Health Service Trust, London, United Kingdom
| | - Sharon Teo
- Khoo Teck Puat – National University Children’s Medical Institute, National University Health System, Singapore
| | - Marina Vivarelli
- Division of Nephrology, Department of Pediatric Subspecialties, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
| | - Hazel Webb
- Department of Paediatric Nephrology, Great Ormond Street Hospital for Children, National Health Service Trust, London, United Kingdom
| | - Hong Xu
- Children’s Hospital of Fudan University, National Children’s Medical Center, Shanghai, China
| | - Hui Kim Yap
- Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
- Khoo Teck Puat – National University Children’s Medical Institute, National University Health System, Singapore
| | - Kjell Tullus
- Department of Paediatric Nephrology, Great Ormond Street Hospital for Children, National Health Service Trust, London, United Kingdom
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8
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Zhong E, Ghadiri S, Pai A, Marin JG, Barbour SJ. Rituximab for Adults With Multi-Drug Resistant Focal Segmental Glomerulosclerosis: A Case Series and Review of the Literature. Can J Kidney Health Dis 2022; 9:20543581221090010. [PMID: 35465258 PMCID: PMC9021507 DOI: 10.1177/20543581221090010] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Accepted: 01/13/2022] [Indexed: 12/03/2022] Open
Abstract
Background: Adults with primary focal segmental glomerulosclerosis (FSGS) are frequently resistant to multiple immunosuppressive agents, which is associated with ongoing complications of nephrotic syndrome and a high risk of progression to end-stage renal disease (ESRD). Rituximab, a monoclonal antibody against the B cell CD20 antigen, has shown some preliminary evidence in treating nephrotic syndrome. Objectives: Describe the usage and the efficacy of rituximab for adults with FSGS in British Columbia (BC) (Canada) and perform a literature review of multi-immunosuppressive drug resistant FSGS in adult patients treated with rituximab to estimate the overall response rate. Design: Case series report and a literature review. Patients: For the case-series, all BC patients who received rituximab for a diagnosis of primary FSGS were included. The literature review included all cases of immunosuppressive-resistant FSGS patients treated with rituximab. We excluded transplant and pediatric patients in both groups. Methods: We describe all cases of adults with native-kidney FSGS resistant to conventional immunosuppressive medications from our provincial health database who were treated with rituximab from 2014 to 2018. A review of the existing literature was performed via PubMed, MEDLINE, and Embase using the following keywords: rituximab, focal segmental glomerulosclerosis, and FSGS up to August 2019. Results: We characterize four immunosuppressive-resistant FSGS patients who were treated with rituximab as part of our provincial program, all of whom showed a response to rituximab with a sustained remission. We found 29 specific cases in the literature of adults with native-kidney FSGS treated with rituximab after being resistant to other immunosuppressive medications, of whom 15 cases showed a response to rituximab. This has increased the total response rate from 15/29 (52%) to 19/33 (58%). Limitations: Literature on this topic is coming predominantly from case series. Prospective trials are needed to confirm efficacy, tolerability, and duration of remission. Conclusions: Due to the low number of currently reported cases and variable response rates, these four cases provide critical data to generate a more accurate understanding of the role of rituximab in adults with resistant FSGS. Adding these results to the confirmed literature cases of multiple-immunosuppressive-resistant FSGS patients treated with rituximab results in a total remission rate of 19/33 cases.
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Affiliation(s)
- Ellia Zhong
- The University of British Columbia, Vancouver, Canada
| | | | - Alexander Pai
- The University of British Columbia, Vancouver, Canada
| | - Judith G Marin
- The University of British Columbia, Vancouver, Canada.,BC Provincial Renal Agency, Vancouver, Canada
| | - Sean J Barbour
- BC Provincial Renal Agency, Vancouver, Canada.,Division of Nephrology, The University of British Columbia, Vancouver, Canada.,Centre for Health Evaluation and Outcome Sciences, St. Paul's Hospital, Vancouver, BC, Canada
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9
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Zotta F, Vivarelli M, Emma F. Update on the treatment of steroid-sensitive nephrotic syndrome. Pediatr Nephrol 2022; 37:303-314. [PMID: 33665752 DOI: 10.1007/s00467-021-04983-3] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2020] [Revised: 01/13/2021] [Accepted: 02/02/2021] [Indexed: 02/07/2023]
Abstract
Steroid-sensitive nephrotic syndrome (SSNS) is a rare condition that develops primarily in preadolescent children after the age of 1 year. Since the 1950s, oral corticosteroids have been the mainstay of treatment of all children presenting with nephrotic syndrome, with most patients responding within 4 weeks to an oral course of prednisone (PDN). However, corticosteroids have important side effects and 60-80 % of patients relapse, developing frequently relapsing or steroid-dependent forms. For these reasons, many patients require second-line steroid-sparing immunosuppressive medications that have considerably improved relapse-free survival, while avoiding many PDN-related toxicities. Since most patients will eventually heal from their disease with a normal kidney function, the morbidity of SSNS is primarily related to side effects of drugs that are used to maintain prolonged remission. Therefore, treatment is essentially based on balancing the use of different drugs to achieve permanent remission with the lowest cumulative number of side effects. Treatment choice is based on the severity of SSNS, on patient age, and on drug tolerability. This review provides an update of currently available therapeutic strategies for SSNS.
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Affiliation(s)
- Federica Zotta
- Department of Pediatric Subspecialties, Division of Nephrology, Bambino Gesù Children's Hospital - IRCCS, Piazza S. Onofrio 4, 00165, Rome, Italy
| | - Marina Vivarelli
- Department of Pediatric Subspecialties, Division of Nephrology, Bambino Gesù Children's Hospital - IRCCS, Piazza S. Onofrio 4, 00165, Rome, Italy
| | - Francesco Emma
- Department of Pediatric Subspecialties, Division of Nephrology, Bambino Gesù Children's Hospital - IRCCS, Piazza S. Onofrio 4, 00165, Rome, Italy.
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10
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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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11
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da Silva Filha R, Burini K, Pires LG, Brant Pinheiro SV, Simões E Silva AC. Idiopathic Nephrotic Syndrome in Pediatrics: An Up-to-date. Curr Pediatr Rev 2022; 18:251-264. [PMID: 35289253 DOI: 10.2174/1573396318666220314142713] [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: 09/13/2021] [Revised: 10/31/2021] [Accepted: 12/12/2021] [Indexed: 11/22/2022]
Abstract
BACKGROUND Idiopathic or Primary Nephrotic Syndrome (INS) is a common glomerular disease in pediatric population, characterized by proteinuria, edema and hypoalbuminemia with variable findings in renal histopathology. OBJECTIVE This review aims to summarize current data on the etiopathogenesis diagnosis, protocols of treatment and potential therapeutic advances in INS. METHODS This narrative review searched for articles on histopathology, physiopathology, genetic causes, diagnosis and treatment of INS in pediatric patients. The databases evaluated were PubMed and Scopus. RESULTS INS is caused by an alteration in the permeability of the glomerular filtration barrier with unknown etiology. There are several gaps in the etiopathogenesis, response to treatment and clinical course of INS that justify further investigation. Novel advances include the recent understanding of the role of podocytes in INS and the identification of genes associated with the disease. The role of immune system cells and molecules has also been investigated. The diagnosis relies on clinical findings, laboratory exams and renal histology for selected cases. The treatment is primarily based on steroids administration. In case of failure, other medications should be tried. Recent studies have also searched for novel biomarkers for diagnosis and alternative therapeutic approaches. CONCLUSION The therapeutic response to corticosteroids still remains the main predictive factor for the prognosis of the disease. Genetic and pharmacogenomics tools may allow the identification of cases not responsive to immunosuppressive medications.
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Affiliation(s)
- Roberta da Silva Filha
- Faculty of Medicine, Interdisciplinary Laboratory of Medical Investigation, Federal University of Minas Gerais (UFMG), Belo Horizonte, MG, Brazil
| | - Kassia Burini
- Faculty of Medicine, Interdisciplinary Laboratory of Medical Investigation, Federal University of Minas Gerais (UFMG), Belo Horizonte, MG, Brazil
| | - Laura Gregório Pires
- Faculty of Medicine, Interdisciplinary Laboratory of Medical Investigation, Federal University of Minas Gerais (UFMG), Belo Horizonte, MG, Brazil
| | | | - Ana Cristina Simões E Silva
- Faculty of Medicine, Interdisciplinary Laboratory of Medical Investigation, Federal University of Minas Gerais (UFMG), Belo Horizonte, MG, Brazil.,Department of Pediatrics, Unit of Pediatric Nephrology, Faculty of Medicine, UFMG, Belo Horizonte, MG, Brazil
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12
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UK experience of ofatumumab in recurrence of focal segmental glomerulosclerosis post-kidney transplant. Pediatr Nephrol 2022; 37:199-207. [PMID: 34383125 PMCID: PMC8674165 DOI: 10.1007/s00467-021-05248-9] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2019] [Revised: 07/23/2021] [Accepted: 07/23/2021] [Indexed: 12/03/2022]
Abstract
BACKGROUND Steroid-resistant nephrotic syndrome (SRNS), commonly caused by focal segmental glomerulosclerosis (FSGS), is associated with progression to stage 5 chronic kidney disease, requirement for kidney replacement therapy and a risk of disease recurrence post-kidney transplantation. Ofatumumab (OFA) is a fully humanised monoclonal antibody to CD20, with similar mechanisms of action to rituximab (RTX). METHODS We report a case series of seven UK patients (five paediatric, two adult), all of whom developed FSGS recurrence after kidney transplantation and received OFA as part of their therapeutic intervention. All also received concomitant plasmapheresis. The 2-year outcome of these seven patients is reported, describing clinical course, kidney function and proteinuria. RESULTS Four patients (all paediatric) achieved complete urinary remission with minimal proteinuria 12 months post-treatment. Three of those four also had normal graft function. Two patients showed partial remission-brief improvement to non-nephrotic proteinuria (197 mg/mmol) in one patient, maintained improvement in kidney function (estimated glomerular filtration rate 76 ml/min/1.73 m2) in the other. One patient did not demonstrate any response. CONCLUSIONS OFA may represent a useful addition to therapeutic options in the management of FSGS recurrence post-transplantation, including where RTX has shown no benefit. Concomitant plasmapheresis in all patients prevents any definitive conclusion that OFA was the beneficial intervention.
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13
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Del Vecchio L, Allinovi M, Rocco P, Brando B. Rituximab Therapy for Adults with Nephrotic Syndromes: Standard Schedules or B Cell-Targeted Therapy? J Clin Med 2021; 10:5847. [PMID: 34945143 PMCID: PMC8709396 DOI: 10.3390/jcm10245847] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Revised: 12/01/2021] [Accepted: 12/08/2021] [Indexed: 12/12/2022] Open
Abstract
Rituximab is a chimeric anti-CD20 monoclonal antibody. It acts mainly through complement-dependent cytotoxicity on B cells expressing the CD20 marker. In this review, we analyse the efficacy and possible pitfalls of rituximab to treat nephrotic syndromes by taking into account pharmacological considerations and CD19 marker testing utility. Despite the fact that the drug has been in use for years, efficacy and treatment schedules in adults with nephrotic syndrome are still a matter of debate. Clinical trials have proven the efficacy and safety of rituximab in idiopathic membranous nephropathy. Data from observational studies also showed the efficacy of rituximab in minimal change disease and focal segmental glomerulosclerosis. Rituximab use is now widely recommended by new Kidney Disease Improved Outcome (KDIGO) guidelines in membranous nephropathy and in frequent-relapsing, steroid-dependent minimal change disease or focal segmental glomerulosclerosis. However, rituximab response has a large interindividual variability. One reason could be that rituximab is lost in the urine at a higher extent in patients with nonselective nephrotic proteinuria, exposing patients to different rituximab plasma levels. Moreover, the association between CD19+ levels and clinical response or relapses is not always present, making the use of this marker in clinical practice complex. High resolution flow cytometry has increased the capability of detecting residual CD19+ B cells. Moreover, it can identify specific B-cell subsets (including IgG-switched memory B cells), which can repopulate at different rates. Its wider use could become a useful tool for better understanding reasons of rituximab failure or avoiding unnecessary retreatments.
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Affiliation(s)
- Lucia Del Vecchio
- Department of Nephrology and Dialysis, Sant’Anna Hospital, ASST Lariana, 22042 Como, Italy
| | - Marco Allinovi
- Nephrology, Dialysis and Transplantation Unit, Careggi University Hospital, 50134 Florence, Italy;
| | - Paolo Rocco
- Department of Pharmaceutical Sciences, Università degli Studi di Milano, Via G. Colombo, 71-20133 Milan, Italy;
| | - Bruno Brando
- Haematology Laboratory and Transfusion Centre, Legnano General Hospital (Milan), 20025 Milan, Italy;
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14
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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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15
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Lanaret C, Anglicheau D, Audard V, Büchler M, Caillard S, Couzi L, Malvezzi P, Mesnard L, Bertrand D, Martinez F, Pernin V, Ducloux D, Poulain C, Thierry A, Del Bello A, Rerolle JP, Greze C, Uro-Coste C, Aniort J, Lambert C, Bouvier N, Schvartz B, Maillard N, Sayegh J, Oniszczuk J, Morin MP, Legendre C, Kamar N, Heng AE, Garrouste C. Rituximab for recurrence of primary focal segmental glomerulosclerosis after kidney transplantation: Results of a nationwide study. Am J Transplant 2021; 21:3021-3033. [PMID: 33512779 DOI: 10.1111/ajt.16504] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2020] [Revised: 01/15/2021] [Accepted: 01/15/2021] [Indexed: 01/25/2023]
Abstract
Rituximab (RTX) therapy for primary focal segmental glomerulosclerosis recurrence after kidney transplantation (KT) has been extensively debated. We aimed to assess the benefit of adding RTX to plasmapheresis (PP), corticosteroids, and calcineurin inhibitors (standard of care, SOC). We identified 148 adult patients who received KT in 12/2004-12/2018 at 21 French centers: 109 received SOC (Group 1, G1), and 39 received immediate RTX along with SOC (Group 2, G2). In G1, RTX was introduced after 28 days of SOC in the event of failure (G1a, n = 19) or PP withdrawal (G1b, n = 12). Complete remission (CR) was achieved in 46.6% of patients, and partial remission (PR) was achieved in 33.1%. The 10-year graft survival rates were 64.7% and 17.9% in responders and nonresponders, respectively. Propensity score analysis showed no difference in CR+PR rates between G1 (82.6%) and G2 (71.8%) (p = .08). Following the addition of RTX (G1a), 26.3% of patients had CR, and 31.6% had PR. The incidence of severe infections was similar between patients treated with and without RTX. In multivariable analysis, infection episodes were associated with hypogammaglobulinemia <5 g/L. RTX could be used in cases of SOC failure or remission for early discontinuation of PP without increasing the risk of infection.
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Affiliation(s)
- Camille Lanaret
- Department of Nephrology, Clermont-Ferrand University Hospital, Clermont-Ferrand, France
| | - Dany Anglicheau
- Assistance Publique des Hôpitaux de Paris, Service de Néphrologie et Transplantation, Hôpital Universitaire Necker-Enfants Malades, Université de Paris, Paris, France
| | - Vincent Audard
- Assistance Publique des Hôpitaux de Paris (AP-HP, Service de Néphrologie et Transplantation Centre de Référence Maladie Rare «Syndrome Néphrotique Idiopathique», Hôpitaux Universitaires Henri-Mondor, Univ Paris Est Créteil, INSERM, IMRB, Créteil, France
| | - Mathias Büchler
- Service de Néphrologie et Immunologie Clinique, CHRU de Tours, Tours, France
| | - Sophie Caillard
- Service de Néphrologie, University Hospital, Strasbourg, France
| | - Lionel Couzi
- Service de Néphrologie, Transplantation, Dialyse et Aphérèses, CHU de Bordeaux, Bordeaux, France
| | - Paolo Malvezzi
- Service de Néphrologie, Hémodialyse, Aphérèses et Transplantation Rénale, CHU Grenoble-Alpes, Grenoble, France
| | - Laurent Mesnard
- Assistance Publique des Hôpitaux de Paris, Hôpital Universitaire Tenon, Urgences Néphrologiques et Transplantation Rénale, Université de Paris, Paris, France
| | | | - Franck Martinez
- Assistance Publique des Hôpitaux de Paris, Service de Néphrologie et Transplantation, Hôpital Universitaire Necker-Enfants Malades, Université de Paris, Paris, France
| | - Vincent Pernin
- Service de Néphrologie, Dialyse et Transplantation, Hôpital Lapeyronie, CHU Montpellier, Montpellier, France
| | - Didier Ducloux
- Service de Néphrologie, Dialyse et Transplantation, CHU Besançon, Besançon, France
| | - Coralie Poulain
- Service de Néphrologie-Médecine Interne-Dialyse-Transplantation, CHU d'Amiens, Amiens, France
| | - Antoine Thierry
- Service de Néphrologie-Hémodialyse-Transplantation Rénale, CHU de Poitiers, Poitiers, France
| | - Arnaud Del Bello
- Département de Néphrologie et Transplantation d'Organes, CHU Toulouse, INSERM U1043, IFR-BMT, Université Paul Sabatier, Toulouse, France
| | - Jean P Rerolle
- Service de Néphrologie, Dialyse et Transplantation, CHU Limoges, Limoges, France
| | - Clarisse Greze
- Assistance Publique des Hôpitaux de Paris, Service de Néphrologie, Hôpital Universitaire Bichat-Claude-Bernard, Université de Paris, Paris, France
| | - Charlotte Uro-Coste
- Department of Nephrology, Clermont-Ferrand University Hospital, Clermont-Ferrand, France
| | - Julien Aniort
- Department of Nephrology, Clermont-Ferrand University Hospital, Clermont-Ferrand, France
| | - Céline Lambert
- Unité de Biostatistiques (DRCI, CHU Clermont-Ferrand, Clermont-Ferrand, France
| | - Nicolas Bouvier
- Service de Néphrologie et Transplantation, CHU Caen, Caen, France
| | | | - Nicolas Maillard
- Service de Néphrologie et Transplantation, CHU Saint-Etienne, Saint-Etienne, France
| | - Johnny Sayegh
- Service de Néphrologie-Dialyse-Transplantation, CHU Angers, Angers, France
| | - Julie Oniszczuk
- Assistance Publique des Hôpitaux de Paris (AP-HP, Service de Néphrologie et Transplantation Centre de Référence Maladie Rare «Syndrome Néphrotique Idiopathique», Hôpitaux Universitaires Henri-Mondor, Univ Paris Est Créteil, INSERM, IMRB, Créteil, France
| | | | - Christophe Legendre
- Assistance Publique des Hôpitaux de Paris, Service de Néphrologie et Transplantation, Hôpital Universitaire Necker-Enfants Malades, Université de Paris, Paris, France
| | - Nassim Kamar
- Département de Néphrologie et Transplantation d'Organes, CHU Toulouse, INSERM U1043, IFR-BMT, Université Paul Sabatier, Toulouse, France
| | - Anne E Heng
- Department of Nephrology, Clermont-Ferrand University Hospital, Clermont-Ferrand, France
| | - Cyril Garrouste
- Department of Nephrology, Clermont-Ferrand University Hospital, Clermont-Ferrand, France
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16
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Liu S, Gui C, Lu Z, Li H, Fu Z, Deng Y. The Efficacy and Safety of Rituximab for Childhood Steroid-Dependent Nephrotic Syndrome: A Systematic Review and Meta-Analysis. Front Pediatr 2021; 9:728010. [PMID: 34490171 PMCID: PMC8417896 DOI: 10.3389/fped.2021.728010] [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: 06/20/2021] [Accepted: 07/22/2021] [Indexed: 11/13/2022] Open
Abstract
Objectives: Rituximab (RTX), a possible alternative treatment option, is recognized as a new therapeutic hope for the treatment of steroid-dependent nephrotic syndrome (SDNS) in children. However, the efficacy and safety of RTX in the treatment of childhood SDNS are still controversial. The objective of this study was to evaluate the efficacy and safety of RTX treatment in children with SDNS. Study Design: Six randomized controlled trials (RCTs) and one retrospective comparative control study data from studies, performed before January 2021 were collected, from PubMed, Cochrane Library, Embase, and Web of Science. The studies evaluating the efficacy and safety of RTX in childhood SDNS were included. Results: Six RCTs and one retrospective comparative control study were included in our analysis. Compared with the control group, the RTX treatment group achieved a higher complete remission rate (OR = 5.21; 95% CI, 3.18-8.54; p < 0.00001), and we found significant differences between the two groups on serum albumin level (MD = 0.88; 95% CI, 0.43-1.33; p = 0.0001) and estimated glomerular filtration rate (MD = 6.43; 95% CI, 2.68-10.19; p = 0.0008). However, RTX treatment did not significantly lower serum creatinine levels nor did it significantly reduce the occurrence of proteinuria. In addition, we found no advantages with RTX on treatment safety. Conclusions: RTX has shown satisfactory characteristics in terms of efficacy and may be a promising treatment method for SDNS in children. However, the long-term effects have not been fully evaluated and should be further studied through randomized clinical trials.
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Affiliation(s)
| | | | | | | | | | - Yueyi Deng
- Department of Nephrology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
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17
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Schijvens AM, van der Weerd L, van Wijk JAE, Bouts AHM, Keijzer-Veen MG, Dorresteijn EM, Schreuder MF. Practice variations in the management of childhood nephrotic syndrome in the Netherlands. Eur J Pediatr 2021; 180:1885-1894. [PMID: 33532891 PMCID: PMC8105198 DOI: 10.1007/s00431-021-03958-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Revised: 01/13/2021] [Accepted: 01/18/2021] [Indexed: 11/29/2022]
Abstract
Nephrotic syndrome in childhood is a common entity in the field of pediatric nephrology. The optimal treatment of children with nephrotic syndrome is often debated. Previously conducted studies have shown significant variability in nephrotic syndrome management, especially in the choice of steroid-sparing drugs. In the Netherlands, a practice guideline on the management of childhood nephrotic syndrome has been available since 2010. The aim of this study was to identify practice variations and opportunities to improve clinical practice of childhood nephrotic syndrome in the Netherlands. A digital structured survey among Dutch pediatricians and pediatric nephrologists was performed, including questions regarding the initial treatment, relapse treatment, kidney biopsy, additional immunosuppressive treatment, and supportive care. Among the 51 responses, uniformity was seen in the management of a first presentation and first relapse. Wide variation was found in the tapering of steroids after alternate day dosing. Most pediatricians and pediatric nephrologists (83%) would perform a kidney biopsy in case of steroid-resistant nephrotic syndrome, whereas for frequent relapsing and steroid-dependent nephrotic syndrome this was 22% and 41%, respectively. Variation was reported in the steroid-sparing treatment. Finally, significant differences were present in the supportive treatment of nephrotic syndrome.Conclusion: Substantial variation was present in the management of nephrotic syndrome in the Netherlands. Differences were identified in steroid tapering, use of steroid coverage during stress, choice of steroid-sparing agents, and biopsy practice. To promote guideline adherence and reduce practice variation, factors driving this variation should be assessed and resolved. What is Known: • National and international guidelines are available to guide the management of childhood nephrotic syndrome. • Several aspects of the management of childhood nephrotic syndrome, including the choice of steroid-sparing drugs and biopsy practice, are controversial and often debated among physicians. What is New: • Significant practice variation is present in the management of childhood nephrotic syndrome in the Netherlands, especially in the treatment of FRNS, SDNS, and SRNS. • The recommendation on the steroid treatment of a first episode of nephrotic syndrome in the KDIGO guideline leaves room for interpretation and is likely the cause of substantial differences in steroid-tapering practices among Dutch pediatricians and pediatric nephrologists.
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Affiliation(s)
- Anne M. Schijvens
- Department of Pediatric Nephrology, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Amalia Children’s Hospital, 804, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands
| | - Lucie van der Weerd
- Department of Pediatric Nephrology, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Amalia Children’s Hospital, 804, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands
| | - Joanna A. E. van Wijk
- Department of Pediatric Nephrology, Amsterdam University Medical Center, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
| | - Antonia H. M. Bouts
- Department of Pediatric Nephrology, Amsterdam University Medical Center, Emma Children’s Hospital, Amsterdam, The Netherlands
| | - Mandy G. Keijzer-Veen
- Department of Pediatric Nephrology, University Medical Center Utrecht, Wilhelmina Children’s Hospital, Utrecht, The Netherlands
| | - Eiske M. Dorresteijn
- Department of Pediatric Nephrology, Erasmus MC - Sophia Children’s Hospital, Rotterdam, The Netherlands
| | - Michiel F. Schreuder
- Department of Pediatric Nephrology, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Amalia Children’s Hospital, 804, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands
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18
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Chan EYH, Tullus K. Rituximab in children with steroid sensitive nephrotic syndrome: in quest of the optimal regimen. Pediatr Nephrol 2021; 36:1397-1405. [PMID: 32577808 DOI: 10.1007/s00467-020-04609-0] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2020] [Revised: 05/02/2020] [Accepted: 05/11/2020] [Indexed: 10/24/2022]
Abstract
Rituximab has emerged as an effective and important therapy in children with complicated frequently relapsing and steroid-dependent nephrotic syndrome to induce long-term disease remission and avoid steroid toxicities. The optimal rituximab regimen is not totally well defined, and there are many varying practices worldwide. We will in this review describe how patient factors, rituximab dose, and use of maintenance immunosuppression affect treatment outcomes. Specifically, low-dose rituximab without concomitant immunosuppression is associated with shorter relapse-free duration while other regimens have comparable outcomes. Patients with more severe disease generally have worse response to rituximab. Although rituximab appears to be generally safe, there are growing concerns of chronic hypogammaglobulinemia and impaired immunity especially in young children. Reliable prognostications and biomarkers for guiding subsequent treatments to avoid excessive treatments are yet to be identified. In this review, we will outline the, as we see it, best approach of rituximab in childhood steroid sensitive nephrotic syndrome at the present state of knowledge.
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Affiliation(s)
- Eugene Yu-Hin Chan
- Department of Paediatric Nephrology, Great Ormond Street Hospital for Children NHS Trust, London, UK.
- Paediatric Nephrology Centre, Hong Kong Children's Hospital, Kowloon, Hong Kong.
| | - Kjell Tullus
- Department of Paediatric Nephrology, Great Ormond Street Hospital for Children NHS Trust, London, UK
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19
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Laroche C, Lemieux D, Sylvestre P, Lapeyraque AL, Flahault A. Younger children treated with rituximab for nephrotic syndrome are at higher risk of adverse events. Nephrol Dial Transplant 2021; 36:gfab013. [PMID: 33538834 DOI: 10.1093/ndt/gfab013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Indexed: 11/12/2022] Open
Affiliation(s)
- Camille Laroche
- University of Montreal, Montreal, Quebec, Canada
- Division of Nephrology, Department of Pediatrics, Sainte-Justine University Hospital, Montreal, Quebec, Canada
| | - Dominique Lemieux
- University of Montreal, Montreal, Quebec, Canada
- Department of Pharmacy, Sainte-Justine University Hospital, Montreal, Quebec, Canada
| | | | - Anne-Laure Lapeyraque
- University of Montreal, Montreal, Quebec, Canada
- Division of Nephrology, Department of Pediatrics, Sainte-Justine University Hospital, Montreal, Quebec, Canada
- Sainte-Justine University Hospital Research Center, Montreal, Quebec, Canada
| | - Adrien Flahault
- University of Montreal, Montreal, Quebec, Canada
- Sainte-Justine University Hospital Research Center, Montreal, Quebec, Canada
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20
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McAtee CL, Lubega J, Underbrink K, Curry K, Msaouel P, Barrow M, Muscal E, Lotze T, Srivaths P, Forbes LR, Allen C, Bernhardt MB. Association of Rituximab Use With Adverse Events in Children, Adolescents, and Young Adults. JAMA Netw Open 2021; 4:e2036321. [PMID: 33533931 PMCID: PMC7859842 DOI: 10.1001/jamanetworkopen.2020.36321] [Citation(s) in RCA: 51] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
IMPORTANCE Rituximab is among the most frequently used immunotherapies in pediatrics. Few studies have reported long-term adverse events associated with its use for children. OBJECTIVE To describe the use of rituximab and to assess whether its use is associated with short- or long-term adverse events, infections, or time to immune reconstitution in a diverse group of young people. DESIGN, SETTING, AND PARTICIPANTS This retrospective cohort study included 468 patients aged younger than 21 years who received rituximab for diverse indications between October 1, 2010, and December 31, 2017, at Texas Children's Hospital, a large pediatric referral hospital. Patterns of adverse events, infections, and immune recovery are described. Data analyses were conducted from December 2019 to June 2020. EXPOSURE One or more doses of rituximab. MAIN OUTCOMES AND MEASURES Adverse drug events (eg, anaphylaxis), incidence of mild and severe infections, and time to recovery of B lymphocyte subset counts and immunoglobulin levels. Survival models and logistic regression analyses and were used to identify associated risk factors of infectious and noninfectious adverse drug events. RESULTS We identified 468 patients receiving at least 1 dose of rituximab. The total follow-up time was 11 713 person-months. Of the 468 patients, 293 (62.6%) were female, the median (interquartile range) age at receipt of dose was 14.3 (9.9-16.8) years, and 209 (44.7%) were self-reported White Hispanic. Adverse events associated with rituximab infusion occurred in 72 patients (15.4%), and anaphylaxis occurred in 17 patients (3.6%). Long-term adverse events, such as prolonged neutropenia and leukoencephalopathy, were absent. Infections occurred in 224 patients (47.9%); 84 patients (17.9%) had severe infections, and 3 patients (0.6%) had lethal infections. Concurrent use of intravenous chemotherapy, treatment of systemic lupus erythematosus, neutropenia, and use of intravenous immunoglobulin were associated with increased risk of infection. Among 135 patients (28.8%) followed up to B cell count recovery, CD19+ or CD20+ cell numbers normalized in a median of 9.0 months (interquartile range, 5.9-14.4 months) following rituximab use; 48 of 95 patients (51%) evaluated beyond a year had low-for-age B cell counts. Recovery of CD27+ memory B cell number occurred in a median of 15.7 months (interquartile range, 6.0-22.7 months). Among patients with normal baseline values, low immunoglobulin G (IgG) levels developed in 67 of 289 patients (23.2%) and low IgM levels in 118 of 255 patients (40.8%); of these patients evaluated beyond 12 months from rituximab, 16 of 117 (13.7%) had persistently low IgG and 37 (33.9%) of 109 had persistently low IgM. CONCLUSIONS AND RELEVANCE Rituximab is well tolerated among young people and is associated with few serious adverse events, but infections are common, corresponding to a prolonged period of B cell count recovery often lasting for longer than a year. Further examination of strategies to prevent infections following rituximab should be pursued.
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Affiliation(s)
- Casey Lee McAtee
- Section of Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, Texas
| | - Joseph Lubega
- Section of Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, Texas
| | - Kristen Underbrink
- Section of Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, Texas
| | - Kristen Curry
- Department of Pharmacy, Texas Children’s Hospital, Houston
| | - Pavlos Msaouel
- Department of Genitourinary Medical Oncology, Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston
| | - Martha Barrow
- Section of Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, Texas
| | - Eyal Muscal
- Section of Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, Texas
| | - Timothy Lotze
- Section of Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, Texas
| | - Poyyapakkam Srivaths
- Section of Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, Texas
| | - Lisa R. Forbes
- Section of Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, Texas
| | - Carl Allen
- Section of Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, Texas
| | - M. Brooke Bernhardt
- Section of Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, Texas
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21
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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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22
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Basu B, Preussler S, Sander A, Mahapatra TKS, Schaefer F. Randomized clinical trial to compare efficacy and safety of repeated courses of rituximab to single-course rituximab followed by maintenance mycophenolate-mofetil in children with steroid dependent nephrotic syndrome. BMC Nephrol 2020; 21:520. [PMID: 33256621 PMCID: PMC7706288 DOI: 10.1186/s12882-020-02153-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2020] [Accepted: 11/05/2020] [Indexed: 11/19/2022] Open
Abstract
Background Approximately 30% of children with idiopathic nephrotic syndrome develop a complicated course with frequent relapses or steroid dependency. Rituximab, a B cell depleting monoclonal antibody, is a safe and effective alternative to steroids or other immunosuppressants for achieving and maintaining remission in this population at short term. Despite the good initial response relapses inevitably occur after regeneration of B lymphocytes, necessitating either repeat courses of rituximab or addition of another steroid-sparing immunosuppressant. Methods This is a prospective, single-center, open-label, two-parallel-arm randomized controlled phase III study among children with steroid dependent nephrotic syndrome who are maintained in remission with oral steroids. One hundred children will be randomized to either Rituximab and maintenance Mycophenolate mofetil (A) or repeated courses of prophylactic Rituximab only (B). In arm A, mycophenolate mofetil (1200 mg/m2 per day) will be started 3 months after Rituximab administration. In arm B, Rituximab infusions will be administered at 0, 8 and 16 months if B cell count normalize at the given time points. Prednisolone will be discontinued in both groups 2 weeks following first course of rituximab. Primary aim is to evaluate the difference in 24-month relapse-free survival. Main secondary endpoints are cumulative prednisolone dose, frequency of relapses and changes in anthropometry. Circulating B lymphocyte populations will be studied as biomarkers or predictors of rituximab responsiveness and adverse events will be analysed. Discussion The study will provide evidence as to the comparative safety and efficacy of two alternative steroid-sparing therapeutic options in children suffering from steroid dependent nephrotic syndrome. The two-year study design will address the long-term results obtained with the alternative treatment protocols. Trial registration This trial was prospectively registered to the Clinicaltrial.gov (NCT03899103 dated 02/04/2019; https://clinicaltrials.gov/) and Clinical Trials Registry of India (CTRI/2019/04/018517 dated 09/04/2019).
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Affiliation(s)
- Biswanath Basu
- Division of Pediatric Nephrology, Department of Pediatrics, Nilratan Sircar Medical College & Hospital, Kolkata, West Bengal, 700014, India.
| | - Stella Preussler
- Institute of Medical Biometry and Informatics, University of Heidelberg, Im Neuenheimer Feld 130.3, 69120, Heidelberg, Germany
| | - Anja Sander
- Institute of Medical Biometry and Informatics, University of Heidelberg, Im Neuenheimer Feld 130.3, 69120, Heidelberg, Germany
| | - T K S Mahapatra
- Department of Pediatrics, Nilratan Sircar Medical College & Hospital, Kolkata, West Bengal, 700014, India
| | - Franz Schaefer
- Division of Pediatric Nephrology, Center for Pediatrics and Adolescent Medicine, University of Heidelberg, Im Neuenheimer Feld 430, 69120, Heidelberg, Germany.
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23
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Kari JA, Alhasan KA, Albanna AS, Safdar OY, Shalaby MA, Böckenhauer D, El-Desoky SM. Rituximab versus cyclophosphamide as first steroid-sparing agent in childhood frequently relapsing and steroid-dependent nephrotic syndrome. Pediatr Nephrol 2020; 35:1445-1453. [PMID: 32337638 DOI: 10.1007/s00467-020-04570-y] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2020] [Revised: 03/20/2020] [Accepted: 04/06/2020] [Indexed: 01/22/2023]
Abstract
BACKGROUND Approximately 50% of children with steroid-sensitive nephrotic syndrome (SSNS) will suffer from frequent relapses or steroid dependency, prompting the use of so-called steroid-sparing drugs. In this pilot study, we compare the efficacy and safety of rituximab to oral cyclophosphamide as first-line steroid-sparing medications. METHODS A prospective open-label non-randomized study of children with frequent relapsing or steroid-dependant SSNS. Exclusion criteria were steroid-resistant disease, prescription of immunosuppressive agents other than prednisolone or levamisole, evidence of impaired kidney function, leucopenia, or active infection. The recruited children were allocated either to the oral cyclophosphamide (3 mg/kg/day for 8 weeks) or intravenous rituximab treatment (two doses of 375 mg/m2/dose, 2 weeks apart) and were monitored for relapses and side effects for 12 months. RESULTS Forty-six subjects were included from two centers; 27 received cyclophosphamide and 19 received rituximab. One-year relapse-free survival was reached in 17 (58.6%) patients treated with cyclophosphamide compared to 16 (84.2%) with rituximab (adjusted HR 0.36; 95% CI 0.09-1.45; p = 0.151). The mean interval to relapse was 6.9 months in the cyclophosphamide group (N = 10) and 6.3 months in the rituximab group (N = 3). Both treatments were associated with a significant (p < 0.001) reduction in prescribed dose of oral alternate-day steroid from 1.02 to 0.36 mg/kg (cyclophosphamide) and 0.86 to 0.08 mg/kg (rituximab). Importantly, a significantly (p = 0.003) higher percentage of patients achieved complete withdrawal of steroid within 3 months of commencing study treatment in the rituximab (73.7%) versus cyclophosphamide (29.6%) group. Transient leucopenia was the most frequent adverse effect observed in the cyclophosphamide group (18.5%) and one patient (3.4%) had acute hepatotoxicity besides severe leucopenia and neutropenia in the 7th week of treatment with complete recovery with the withdrawal of cyclophosphamide and maintenance of remission. A minor infusion-related reaction in the form of a generalized macular skin rash was observed in one patient (5%) in the rituximab group. CONCLUSIONS Rituximab is non-inferior to cyclophosphamide and safe as a first-line steroid-sparing agent in children with SSNS. A larger multicenter study is required to assess superiority over cyclophosphamide. Graphical abstract.
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Affiliation(s)
- Jameela A Kari
- Faculty of Medicine, King Abduaziz University, PO Box 80215, Jeddah, 21589, Kingdom of Saudi Arabia. .,Paediatric Nephrology Center of Excellence, Department of Pediatrics, King Abdulaziz University, PO Box 80215, Jeddah, 21589, Kingdom of Saudi Arabia.
| | - Khalid A Alhasan
- Pediatrics Department, College of Medicine, King Saud University, Riyadh, Kingdom of Saudi Arabia
| | - Amr S Albanna
- King Abdullah International Medical Research Center, King Saud Bin Abdulaziz University for Health Sciences, Jeddah, Kingdom of Saudi Arabia
| | - Osama Y Safdar
- Faculty of Medicine, King Abduaziz University, PO Box 80215, Jeddah, 21589, Kingdom of Saudi Arabia.,Paediatric Nephrology Center of Excellence, Department of Pediatrics, King Abdulaziz University, PO Box 80215, Jeddah, 21589, Kingdom of Saudi Arabia
| | - Mohamed A Shalaby
- Faculty of Medicine, King Abduaziz University, PO Box 80215, Jeddah, 21589, Kingdom of Saudi Arabia.,Paediatric Nephrology Center of Excellence, Department of Pediatrics, King Abdulaziz University, PO Box 80215, Jeddah, 21589, Kingdom of Saudi Arabia
| | - Detlef Böckenhauer
- Department of Renal Medicine, University College London, London, UK.,Renal Unit, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
| | - Sherif M El-Desoky
- Faculty of Medicine, King Abduaziz University, PO Box 80215, Jeddah, 21589, Kingdom of Saudi Arabia.,Paediatric Nephrology Center of Excellence, Department of Pediatrics, King Abdulaziz University, PO Box 80215, Jeddah, 21589, Kingdom of Saudi Arabia
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24
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Hansrivijit P, Cheungpasitporn W, Thongprayoon C, Ghahramani N. Rituximab therapy for focal segmental glomerulosclerosis and minimal change disease in adults: a systematic review and meta-analysis. BMC Nephrol 2020; 21:134. [PMID: 32293308 PMCID: PMC7160971 DOI: 10.1186/s12882-020-01797-7] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2019] [Accepted: 04/06/2020] [Indexed: 12/12/2022] Open
Abstract
Background Use of rituximab (RTX) for focal segmental glomerulosclerosis (FSGS) and minimal change disease (MCD) is widely described in children. Clinical evidence in adults is limited. The objective of this study was to determine the treatment outcomes of RTX in adults with FSGS and MCD. Methods Ovid MEDLINE, SCOPUS, and Cochrane Database of Systematic Reviews were searched up to September 2019. Out of 699 studies, we included 16 studies describing the treatment outcomes of rituximab in adult patients with FSGS or MCD. Results were reported in remission rate and relapse rate. Serious adverse events were also reported. Results A total of 16 studies were included in our review and analysis. All studies were observational studies and included a total of 221 patients (23.1% FSGS, 76.9% MCD). Mean follow-up duration was 26.3 ± 12.8 months. From the analysis of five studies with FSGS patients (n = 51), the overall remission rate and relapse rate of RTX therapy was 53.6% (95% CI, 15.8–87.6%) and 47.3% (95% CI, 25.4–70.2%), respectively. Complete remission occurred in 42.9%. In contrast, from the analysis of 11 studies with MCD patients (n = 170), the overall remission rate and relapse rate of RTX therapy was 80.3% (95% CI, 68.5–88.5%) and 35.9% (95% CI, 25.1–48.4), respectively. Complete remission occurred in 74.7%. Subgroup analyses showed that overall remission and relapse were not different after adjusted for study year and RTX dose for both FSGS and MCD. Incidence of serious adverse events was 0.092 events/year. Conclusions Rituximab may be considered as an additional treatment to the standard therapy for adult patients with FSGS and MCD. Remissions and relapses are similar between FSGS and MCD. Serious adverse effects of rituximab were uncommon. We encourage further randomized controlled trials to confirm the efficacy of rituximab therapy in these patients.
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Affiliation(s)
- Panupong Hansrivijit
- Department of Internal Medicine, University of Pittsburgh Medical Center Pinnacle, 504 S. Front St, Suite 3C, Harrisburg, PA, 17104, USA.
| | - Wisit Cheungpasitporn
- Division of Nephrology, University of Mississippi Medical Center, Jackson, MS, 39216, USA
| | - Charat Thongprayoon
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, 55905, USA
| | - Nasrollah Ghahramani
- Division of Nephrology, Department of Medicine, Penn State University College of Medicine, Hershey, PA, 17033, USA
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25
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Girişgen İ, Yüksel S, Pekal Y. Rituximab experience in children with nephrotic syndrome: what have we observed differently. TURK PEDIATRI ARSIVI 2020; 55:60-66. [PMID: 32231451 PMCID: PMC7096562 DOI: 10.14744/turkpediatriars.2019.76148] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 05/17/2019] [Accepted: 11/28/2019] [Indexed: 11/20/2022]
Abstract
AIM We aimed to evaluate the efficacy of rituximab therapy in children with nephrotic syndromes and to share our experiences. MATERIAL AND METHODS Twelve children with nephrotic syndrome (four with steroid-dependent, eight with steroid-resistant nephrotic syndrome) who were treated with rituximab were retrospectively evaluated in terms of clinical and laboratory data and CD19-20 levels. All patients received rituximab (375 mg/m2) once weekly for 4 weeks. A proteinuria-free period under steroid therapy was not sought prior to initiating rituximab therapy. RESULTS The overall remission rates in patients with steroid-dependent and steroid-resistant nephrotic syndrome were 100% and 27%. Focal segmental glomerulosclerosis was diagnosed in six patients and the remission rate was 33% in this population. CD19 cell depletion was observed in 10 of the 12 children. Seven of the 10 patients with CD19 depletion achieved remission, whereas the other three had persistent nephrotic proteinuria despite CD19 depletion. Two patients without CD19 depletion never achieved remission. Relapse occurred in three of the seven patients associated with increased CD19. CONCLUSION We observed that rituximab could be given without waiting for a proteinuria-free period under steroid therapy. Our result suggest that administering four weekly doses of rituximab increases the likelihood of remission, considering the amount of drug lost in the urine of children with nephrotic proteinuria. However, our findings must be confirmed with dose-comparison studies conducted with larger populations and an evaluation of long-term adverse effects. Some patients did not achieve remission despite B cell depletion, which suggests that B cell depletion is necessary but insufficient for remission in nephrotic syndromes.
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Affiliation(s)
- İlknur Girişgen
- Division of Pediatric Nephrology, Department of Pediatrics, Pamukkale University Faculty of Medicine, Denizli, Turkey
| | - Selçuk Yüksel
- Division of Pediatric Nephrology, Department of Pediatrics, Pamukkale University Faculty of Medicine, Denizli, Turkey
| | - Yücel Pekal
- Department of Pediatrics, Pamukkale University Faculty of Medicine, Denizli, Turkey
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26
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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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27
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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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28
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Chan EYH, Webb H, Yu E, Ghiggeri GM, Kemper MJ, Ma ALT, Yamamura T, Sinha A, Bagga A, Hogan J, Dossier C, Vivarelli M, Liu ID, Kamei K, Ishikura K, Saini P, Tullus K. Both the rituximab dose and maintenance immunosuppression in steroid-dependent/frequently-relapsing nephrotic syndrome have important effects on outcomes. Kidney Int 2019; 97:393-401. [PMID: 31874801 DOI: 10.1016/j.kint.2019.09.033] [Citation(s) in RCA: 69] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2019] [Revised: 08/21/2019] [Accepted: 09/26/2019] [Indexed: 12/15/2022]
Abstract
Rituximab is an effective treatment for steroid-dependent/ frequently-relapsing nephrotic syndrome (SDFRNS) in children. However, the optimal rituximab regimen remains unknown. To help determine this we conducted an international, multicenter retrospective study at 11 tertiary pediatric nephrology centers in Asia, Europe and North America of children 1-18 years of age with complicated SDFRNS receiving rituximab between 2005-2016 for 18 or more months follow-up. The effect of rituximab prescribed at three dosing levels: low (375mg/m2), medium (750mg/m2) and high (1125-1500mg/m2), with or without maintenance immunosuppression (defined as concurrent use of corticosteroids, mycophenolate motile or calcineurin inhibition at first relapse or for at least six months following the rituximab treatment) was examined. Among the 511 children (median age 11.5 year, 67% boys), 191, 208 and 112 received low, medium and high dose rituximab, respectively. Within this total cohort of 511 children, 283 (55%) received maintenance immunosuppression. Renal biopsies were performed in 317 children indicating the predominant histology was minimal change disease (74%). Without maintenance immunosuppression, low-dose rituximab had a shorter relapse-free period and a higher relapse risk (8.5 months) than medium (12.7 months; adjusted hazard ratio, 0.62) and high dose (14.3 months; adjusted hazard ratio, 0.50; all significant). With maintenance immunosuppression, the relapse-free survival in low-dose rituximab (14 months) was similar to medium (10.9 months; adjusted hazard ratio, 1.23) and high dose (12.0 months; adjusted hazard ratio, 0.92; all non-significant). Most adverse events were mild. Thus, children receiving low-dose rituximab without maintenance immunosuppression had the shortest relapse-free survival. Hence, both rituximab dose and maintenance immunosuppression have important effects on the treatment outcomes.
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Affiliation(s)
- Eugene Yu-Hin Chan
- Department of Paediatric Nephrology, Great Ormond Street Hospital for Children National Health Service Trust, London, UK; Paediatric Nephrology Centre, Department of Paediatrics, Princess Margaret Hospital, Hong Kong; Paediatric Nephrology Centre, Department of Paediatrics, Hong Kong Children's Hospital, Hong Kong
| | - Hazel Webb
- Department of Paediatric Nephrology, Great Ormond Street Hospital for Children National Health Service Trust, London, UK
| | - Ellen Yu
- Clinical Research Centre, Princess Margaret Hospital, Hong Kong
| | - Gian Marco Ghiggeri
- Division of Nephrology, Dialysis and Transplantation and Laboratory on Molecular Nephrology, Istituto G. Gaslini, Genoa, Italy
| | - Markus J Kemper
- Department of Pediatrics, Asklepios Medical School, Hamburg, Germany
| | - Alison Lap-Tak Ma
- Paediatric Nephrology Centre, Department of Paediatrics, Princess Margaret Hospital, Hong Kong; Paediatric Nephrology Centre, Department of Paediatrics, Hong Kong Children's Hospital, Hong Kong
| | - Tomohiko Yamamura
- Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Aditi Sinha
- Department of Pediatrics, Indian Council of Medical Research Center for Advanced Research in Nephrology, All India Institute of Medical Sciences, New Delhi, India
| | - Arvind Bagga
- Department of Pediatrics, Indian Council of Medical Research Center for Advanced Research in Nephrology, All India Institute of Medical Sciences, New Delhi, India
| | - Julien Hogan
- Service de néphrologie pédiatrique, Hôpital Robert-debré, Paris, France
| | - Claire Dossier
- Service de néphrologie pédiatrique, Hôpital Robert-debré, Paris, France
| | - Marina Vivarelli
- Division of Nephrology and Dialysis, Department of Pediatric Subspecialties, Ospedale Pediatrico "Bambino Gesù" Istituto di Ricovero e Cura a Carettere Scientifico, Rome, Italy
| | - Isaac Desheng Liu
- Department of Paediatric Medicine, Khoo Teck Puat-National University Children's Medical Institute, National University Health System, Singapore
| | - Koichi Kamei
- Division of Nephrology and Rheumatology, National Center for Child Health and Development, Tokyo, Japan
| | - Kenji Ishikura
- Division of Nephrology and Rheumatology, National Center for Child Health and Development, Tokyo, Japan; Department of Pediatrics, Kitasato University School of Medicine, Kanagawa, Japan
| | - Priya Saini
- Division of Pediatric Nephrology, Hospital for Sick Children, Toronto, Ontario, Canada
| | - Kjell Tullus
- Department of Paediatric Nephrology, Great Ormond Street Hospital for Children National Health Service Trust, London, UK.
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29
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Topaloğlu R, Gülhan B, Çelegen K, İnözü M, Hayran M, Düzova A, Ozaltin F. Rituximab for Children With Difficult-to-Treat Nephrotic Syndrome: Its Effects on Disease Progression and Growth. Front Pediatr 2019; 7:313. [PMID: 31417883 PMCID: PMC6682627 DOI: 10.3389/fped.2019.00313] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2019] [Accepted: 07/11/2019] [Indexed: 12/20/2022] Open
Abstract
Background: Since the early 2000s rituximab (RTX) has been thought of as an alternative treatment for steroid-sensitive nephrotic syndrome (SSNS) and steroid-resistant nephrotic syndrome (SRNS). Objective: This study aimed to determine the effects of RTX treatment on disease outcome and growth in pediatric SSNS and SRNS patients. Materials and Methods: The medical records of pediatric SSNS and SRNS patients that began RTX treatment at the mean age of 10.8 ± 5.1 years between 2009 and 2017 were retrospectively reviewed. Additionally, the effect of RTX on growth was evaluated based on patient height, weight, and BMI z scores. Results: The study included 41 children, of which 21 had SSNS and 20 had SRNS. Mean age at diagnosis of NS was 5.8 ± 4.7 years. Mean duration of post-RTX treatment follow-up was 2.3 ± 1.6 years. Among the SSNS patients, 6 and 11 patients were steroid free and calcineurin inhibitor free at the last follow-up visit, respectively. The 1-year cumulative steroid and calcineurin inhibitor doses both decreased after RTX treatment, as compared to before RTX (P = 0.001 and P = 0.015, respectively). The median height z-score at the time of RTX initiation was -1.2 and the median height z-score at the last follow-up visit was -0.6 (P = 0.044). The median BMI z-score decreased from 1.6 (IQR; 0.9-3.0) at the time RTX was initiated to 1.1 IQR; [(-0.7)-2.5] at the last follow-up visit (P = 0.007). At the last follow-up visit 4 SRNS patients had complete remission and 4 had partial remission. The 1-year cumulative steroid dosage in the SRNS patients decreased significantly after RTX, as compared to before RTX (P = 0.001). The median height z-score at the time of RTX initiation was -0.8 and the median height z-score at the last follow-up visit was -0.7 (P = 0.81). The median BMI z-score decreased from 0.3 at the time RTX was initiated to -0.1 at the last follow-up visit (P = 0.11). Conclusion: RTX has a more positive effect on disease outcome and growth in SSNS patients than in those with SRNS.
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Affiliation(s)
- Rezan Topaloğlu
- Division of Pediatric Nephrology, Department of Pediatrics, School of Medicine, Hacettepe University, Ankara, Turkey
| | - Bora Gülhan
- Division of Pediatric Nephrology, Department of Pediatrics, School of Medicine, Hacettepe University, Ankara, Turkey
| | - Kübra Çelegen
- Division of Pediatric Nephrology, Department of Pediatrics, School of Medicine, Hacettepe University, Ankara, Turkey
| | - Mihriban İnözü
- Division of Pediatric Nephrology, Department of Pediatrics, School of Medicine, Hacettepe University, Ankara, Turkey
| | - Mutlu Hayran
- Department of Preventive Oncology, School of Medicine, Hacettepe University, Ankara, Turkey
| | - Ali Düzova
- Division of Pediatric Nephrology, Department of Pediatrics, School of Medicine, Hacettepe University, Ankara, Turkey
| | - Fatih Ozaltin
- Division of Pediatric Nephrology, Department of Pediatrics, School of Medicine, Hacettepe University, Ankara, Turkey
- Nephrogenetics Laboratory, School of Medicine, Hacettepe University, Ankara, Turkey
- Center for Biobanking and Genomics, School of Medicine, Hacettepe University, Ankara, Turkey
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30
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Nishiwaki H, Oikawa M, Kajitani H, Komukai D, Inoue Y, Koiwa F. Disseminated Intravascular Coagulation-like Reaction after Rituximab Infusion in a Patient with Nephrotic Syndrome. Intern Med 2019; 58:2057-2061. [PMID: 30918180 PMCID: PMC6702004 DOI: 10.2169/internalmedicine.2236-18] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
Several case series have suggested that rituximab is efficacious in adult patients with minimal change disease. We herein report a case of disseminated intravascular coagulation-like reaction after rituximab infusion in a patient with nephrotic syndrome. A 58-year-old Japanese man with minimal change disease diagnosed 15 years earlier was started on rituximab to prevent relapse of nephrotic syndrome when he presented to our clinic with low albuminemia, massive proteinuria, and leg edema. Eleven days after rituximab infusion, he presented with abdominal pain, appetite loss, and tarry stool. A laboratory examination revealed severe thrombocytopenia and coagulopathy, and upper gastrointestinal endoscopy revealed multiple hemorrhagic ulcers in his esophagus and stomach. The patient died two days later. Physicians should consider disseminated intravascular coagulation-like reaction when encountering cases with thrombocytopenia after rituximab infusion for any disease.
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Affiliation(s)
- Hiroki Nishiwaki
- Division of Nephrology, Department of Medicine, Showa University Fujigaoka Hospital, Japan
| | - Megumi Oikawa
- Division of Nephrology, Department of Medicine, Showa University Fujigaoka Hospital, Japan
| | - Hideto Kajitani
- Division of Nephrology, Department of Medicine, Showa University Fujigaoka Hospital, Japan
| | - Daisuke Komukai
- Division of Nephrology, Department of Medicine, Showa University Fujigaoka Hospital, Japan
- Division of Nephrology, Kawasaki-Saiwai Hospital, Japan
| | - Yoshihiko Inoue
- Division of Nephrology, Department of Medicine, Showa University Fujigaoka Hospital, Japan
| | - Fumihiko Koiwa
- Division of Nephrology, Department of Medicine, Showa University Fujigaoka Hospital, Japan
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31
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Guimarães FTL, Ferreira RN, Brito-Melo GEA, Rocha-Vieira E, Pereira WDF, Pinheiro SVB, Miranda AS, Simões E Silva AC. Pediatric Patients With Steroid-Sensitive Nephrotic Syndrome Have Higher Expression of T Regulatory Lymphocytes in Comparison to Steroid-Resistant Disease. Front Pediatr 2019; 7:114. [PMID: 31001501 PMCID: PMC6455073 DOI: 10.3389/fped.2019.00114] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2018] [Accepted: 03/08/2019] [Indexed: 12/13/2022] Open
Abstract
Background and Aim: Idiopathic nephrotic syndrome (INS) is classified according to the response to drug therapy in steroid-sensitive (SS), steroid-dependent (SD), and steroid-resistant (SR) categories. Previous studies showed changes in inflammatory activity of subpopulations of lymphocytes in INS. This study aimed to compare SS and SR patients in regard to subpopulations of leukocytes, profile of regulatory lymphocytes, and migratory activity of lymphocyte subpopulations. Results obtained in INS patients were also compared to age and sex-matched healthy controls. Methods: This is a cross-sectional study including SS patients (n = 30), SR patients (n = 14), and controls (n = 10). Peripheral blood samples were withdrawn for ex-vivo leukocyte flow cytometry analysis. Results: Percentage of B-lymphocytes and natural killer (NK) cells were significantly reduced in SR patients when compared to controls, while the percentage of NKT cells were decreased in SS patients in comparison to controls. Percentages of CD4+ expressing FoxP3 and CTLA4 were significantly higher in SS patients in comparison to SR patients and controls. The expression of integrin CD18 on the surface of T lymphocytes (CD3+) was reduced in SS patients if compared to controls. Conclusion: This study found that SS INS patients have higher levels of regulatory T-lymphocytes and lower expression of adhesion molecules than SR patients.
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Affiliation(s)
- Fabio Tadeu Lourenço Guimarães
- Centro Integrado de Pós-Graduação e Pesquisa em Saúde - CIPq, Universidade Federal dos Vales do Jequitinhonha e Mucuri (UFVJM), Diamantina, Brazil
| | - Rodrigo Novaes Ferreira
- Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Brazil
| | - Gustavo Eustáquio Alvim Brito-Melo
- Centro Integrado de Pós-Graduação e Pesquisa em Saúde - CIPq, Universidade Federal dos Vales do Jequitinhonha e Mucuri (UFVJM), Diamantina, Brazil
| | - Etel Rocha-Vieira
- Centro Integrado de Pós-Graduação e Pesquisa em Saúde - CIPq, Universidade Federal dos Vales do Jequitinhonha e Mucuri (UFVJM), Diamantina, Brazil
| | - Wagner de Fátima Pereira
- Centro Integrado de Pós-Graduação e Pesquisa em Saúde - CIPq, Universidade Federal dos Vales do Jequitinhonha e Mucuri (UFVJM), Diamantina, Brazil
| | - Sérgio Veloso Brant Pinheiro
- Unidade de Nefrologia Pediátrica, Departamento de Pediatria, Faculdade de Medicina, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Brazil
| | - Aline Silva Miranda
- Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Brazil.,Laboratório Interdisciplinar de Investigação Médica, Faculdade de Medicina, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Brazil
| | - Ana Cristina Simões E Silva
- Unidade de Nefrologia Pediátrica, Departamento de Pediatria, Faculdade de Medicina, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Brazil.,Laboratório Interdisciplinar de Investigação Médica, Faculdade de Medicina, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Brazil
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32
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Kallash M, Smoyer WE, Mahan JD. Rituximab Use in the Management of Childhood Nephrotic Syndrome. Front Pediatr 2019; 7:178. [PMID: 31134169 PMCID: PMC6524616 DOI: 10.3389/fped.2019.00178] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2019] [Accepted: 04/17/2019] [Indexed: 12/19/2022] Open
Abstract
Childhood nephrotic syndrome is a challenging and often persistent renal disorder, and its incidence varies between different ethnicities and regions. Corticosteroids have been the main treatment for decades and are effective in most children with idiopathic NS, although 10-15% of these children become steroid resistant. Furthermore, some initially steroid sensitive children follow a steroid dependent or frequently relapsing course and are therefore at increased risk for developing steroid toxicity. In such children, alternative immunosuppressive medications are used to induce and/or maintain remission of NS. One such drug, rituximab, is a monoclonal antibody directed against the B lymphocyte CD20 marker which induces depletion of B cells, and has shown promising results in the management of NS in children. In this review, we summarize recent studies on the efficacy and safety of rituximab in the different types of childhood nephrotic syndrome, the known and potential mechanisms of action of rituximab, its possible complications and side effects, and the available and potential biomarkers of rituximab activity.
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Affiliation(s)
- Mahmoud Kallash
- Division of Nephrology, Nationwide Children's Hospital, The Ohio State University College of Medicine, Columbus, OH, United States
| | - William E Smoyer
- Division of Nephrology, Nationwide Children's Hospital, The Ohio State University College of Medicine, Columbus, OH, United States
| | - John D Mahan
- Division of Nephrology, Nationwide Children's Hospital, The Ohio State University College of Medicine, Columbus, OH, United States
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33
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Tullus K, Webb H, Bagga A. Management of steroid-resistant nephrotic syndrome in children and adolescents. THE LANCET CHILD & ADOLESCENT HEALTH 2018; 2:880-890. [PMID: 30342869 DOI: 10.1016/s2352-4642(18)30283-9] [Citation(s) in RCA: 90] [Impact Index Per Article: 12.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/07/2018] [Revised: 08/18/2018] [Accepted: 08/21/2018] [Indexed: 02/08/2023]
Abstract
More than 85% of children and adolescents (majority between 1-12 years old) with idiopathic nephrotic syndrome show complete remission of proteinuria following daily treatment with corticosteroids. Patients who do not show remission after 4 weeks' treatment with daily prednisolone are considered to have steroid-resistant nephrotic syndrome (SRNS). Renal histology in most patients shows presence of focal segmental glomerulosclerosis, minimal change disease, and (rarely) mesangioproliferative glomerulonephritis. A third of patients with SRNS show mutations in one of the key podocyte genes. The remaining cases of SRNS are probably caused by an undefined circulating factor. Treatment with calcineurin inhibitors (ciclosporin and tacrolimus) is the standard of care for patients with non-genetic SRNS, and approximately 70% of patients achieve a complete or partial remission and show satisfactory long-term outcome. Additional treatment with drugs that inhibit the renin-angiotensin axis is recommended for hypertension and for reducing remaining proteinuria. Patients with SRNS who do not respond to treatment with calcineurin inhibitors or other immunosuppressive drugs can show declining kidney function and are at risk for end-stage renal failure. Approximately a third of those who undergo renal transplantation show recurrent focal segmental glomerulosclerosis in the allograft and often respond to combined treatment with plasma exchange, rituximab, and intensified immunosuppression.
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Affiliation(s)
- Kjell Tullus
- Nephrology Unit, Great Ormond Street Hospital for Children, Great Ormond Street, London, UK.
| | - Hazel Webb
- Nephrology Unit, Great Ormond Street Hospital for Children, Great Ormond Street, London, UK
| | - Arvind Bagga
- Division of Nephrology, Indian Council of Medical Research Advanced Center for Research in Nephrology, All India Institute of Medical Sciences, New Delhi, India
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Liu Y, Shi Y, Ren R, Xie J, Wang W, Chen N. Advanced therapeutics in focal and segmental glomerulosclerosis. Nephrology (Carlton) 2018; 23 Suppl 4:57-61. [PMID: 30298667 DOI: 10.1111/nep.13463] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/10/2018] [Indexed: 11/30/2022]
Affiliation(s)
- Yunzi Liu
- Department of Nephrology; Ruijin Hospital, Institute of Nephrology, Shanghai Jiao Tong University School of Medicine; Shanghai China
| | - Yifan Shi
- Department of Nephrology; Ruijin Hospital, Institute of Nephrology, Shanghai Jiao Tong University School of Medicine; Shanghai China
| | - Rong Ren
- Department of Nephrology; Ruijin Hospital, Institute of Nephrology, Shanghai Jiao Tong University School of Medicine; Shanghai China
| | - Jingyuan Xie
- Department of Nephrology; Ruijin Hospital, Institute of Nephrology, Shanghai Jiao Tong University School of Medicine; Shanghai China
| | - Weiming Wang
- Department of Nephrology; Ruijin Hospital, Institute of Nephrology, Shanghai Jiao Tong University School of Medicine; Shanghai China
| | - Nan Chen
- Department of Nephrology; Ruijin Hospital, Institute of Nephrology, Shanghai Jiao Tong University School of Medicine; Shanghai China
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Jellouli M, Charfi R, Maalej B, Mahfoud A, Trabelsi S, Gargah T. Rituximab in The Management of Pediatric Steroid-Resistant Nephrotic Syndrome: A Systematic Review. J Pediatr 2018; 197:191-197.e1. [PMID: 29680473 DOI: 10.1016/j.jpeds.2018.01.008] [Citation(s) in RCA: 14] [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: 09/25/2017] [Revised: 12/14/2017] [Accepted: 01/02/2018] [Indexed: 12/13/2022]
Abstract
OBJECTIVES To evaluate the efficacy and safety of rituximab in children with steroid-resistant nephrotic syndrome. STUDY DESIGN A systematic review evaluating the efficacy and safety of rituximab in children with steroid-resistant nephrotic syndrome was performed. Data from studies, performed before April 2017 were collected, from MEDLINE, Cochrane Library, Scopus, and Web of Science. Study eligibility criteria included clinical trials and observational studies with a minimal sample size of 5 patients, regarding treatment with rituximab in children with steroid-resistant nephrotic syndrome. Independent extraction of articles by 2 investigators using predefined data fields was performed. RESULTS We included 7 case series and 1 open-label randomized controlled trial. Among them, 3 studies were multicenter. A total of 226 patients were included. Mean age at onset was 5.6 ± 1.1 years. Mean number of rituximab administrations was 3.1 ± 1.1 infusions per patient. Remission was observed in 89 patients (46.4%). Remission was seen in 40.8% patients with initial steroid-resistant nephrotic syndrome and 52.8% patients with late steroid-resistant nephrotic syndrome. Good initial response to rituximab therapy was observed in 63.2% patients with minimal change nephrotic syndrome, 39.2% patients with focal and segmental glomerulosclerosis, 1 patient had diffuse mesangial hypercellularity, and 1 patient had IgM nephropathy. Sustained remission ranged from 18% to 93.7%. Five serious adverse events were observed. CONCLUSIONS Rituximab exhibited a satisfactory profile regarding efficacy and safety indicating that this agent is a promising therapy for steroid-resistant nephrotic syndrome and should be further investigated by randomized clinical trials.
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Affiliation(s)
- Manel Jellouli
- Department of Pediatric Nephrology, Charles Nicolle Hospital, Faculty of Medicine of Tunis, Tunis El Manar University, Tunis, Tunisia.
| | - Rim Charfi
- Department of Clinical Pharmacology, National Center of Pharmacovigilance, Faculty of Medicine of Tunis, Clinical and Experimental Pharmacology Laboratory LR16SP02, Tunis El Manar University, Tunis, Tunisia
| | - Bayen Maalej
- Department of Pediatrics, Pediatric Emergency and Intensive Care, Hedi Chaker Hospital, Sfax, Tunisia
| | - Abdelmajid Mahfoud
- Department of Pediatrics, Pediatric Emergency and Intensive Care, Hedi Chaker Hospital, Sfax, Tunisia
| | - Sameh Trabelsi
- Department of Clinical Pharmacology, National Center of Pharmacovigilance, Faculty of Medicine of Tunis, Clinical and Experimental Pharmacology Laboratory LR16SP02, Tunis El Manar University, Tunis, Tunisia
| | - Tahar Gargah
- Department of Pediatric Nephrology, Charles Nicolle Hospital, Faculty of Medicine of Tunis, Tunis El Manar University, Tunis, Tunisia
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Rituximab in steroid-sensitive nephrotic syndrome: lessons from clinical trials. Pediatr Nephrol 2018; 33:1449-1455. [PMID: 28717938 PMCID: PMC6061657 DOI: 10.1007/s00467-017-3746-9] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2017] [Revised: 06/23/2017] [Accepted: 06/23/2017] [Indexed: 01/31/2023]
Abstract
Idiopathic nephrotic syndrome is the most common chronic glomerular disease in children. A total of 80-90% of patients with childhood idiopathic nephrotic syndrome achieve remission with steroid therapy [steroid-sensitive nephrotic syndrome (SSNS)]. However, approximately 50% of children with SSNS develop frequently relapsing nephrotic syndrome (FRNS) or steroid-dependent nephrotic syndrome (SDNS). Children with FRNS or SDNS are usually treated with immunosuppressive agents, but 10-20% of children receiving immunosuppressive agents still show frequent relapses or steroid dependence during or after treatment, defined as complicated FRNS or SDNS. Rituximab, a chimeric anti-CD20 monoclonal antibody that was originally developed to treat patients with B-cell non-Hodgkin's lymphoma, is currently used for treating SSNS. In this review we highlight recent studies, mainly randomized controlled trials of rituximab for SSNS, including complicated and uncomplicated forms of FRNS or SDNS in children. We also discuss the effects of these studies on the management of patients suffering from these conditions.
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Roccatello D, Sciascia S, Rossi D, Alpa M, Naretto C, Radin M, Barreca A, Fenoglio R, Baldovino S, Menegatti E. High-Dose Rituximab Ineffective for Focal Segmental Glomerulosclerosis: A Long-Term Observation Study. Am J Nephrol 2017; 46:108-113. [PMID: 28700988 DOI: 10.1159/000477944] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2017] [Accepted: 05/30/2017] [Indexed: 11/19/2022]
Abstract
BACKGROUND A beneficial effect of rituximab (RTX) on focal segmental glomerulosclerosis (FSGS) in pediatric patients or in transplant recipients has been reported in isolated cases. However, the use of RTX in adult patients with idiopathic FSGS needs further investigation. METHODS Eight patients who had biopsy-proven FSGS (63.9 ± 14.0, range 40-81 years, 4 women, 4 men) with major risk factors precluding corticosteroids or conventional immunosuppression were treated with a high dose of RTX (8 weekly doses of 375 mg/m2) and prospectively followed up for at least 2 years (29.1 ± 8.8 months, range 24-42 months). RESULTS RTX failed to improve proteinuria in 7 out of 8 patients, who had persistent nephrotic proteinuria. In one case, a rapidly deteriorating renal function was also observed. Only one patient showed an improvement in renal function and a remarkable reduction in proteinuria. There were no differences in clinical or laboratory characteristics or in the CD20 B lymphocyte count after RTX between the responder and the 7 nonresponder patients. CONCLUSIONS Only a minority (1 of 8) in our series of adult patients with FSGS showed positive effects of high doses of RTX. Future studies are warranted to investigate more promising therapeutic options in the management of FSGS.
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Affiliation(s)
- Dario Roccatello
- Center of Research of Immunopathology and Rare Diseases - Coordinating Center of the Network for Rare Diseases of Piedmont and Aosta Valley, Department of Clinical and Biological Sciences, University of Turin, Turin, Italy
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Van Horebeek I, Knops N, Van Dyck M, Levtchenko E, Mekahli D. Rituximab in children with steroid-dependent nephrotic syndrome: experience of a tertiary center and review of the literature. Acta Clin Belg 2017; 72:147-155. [PMID: 27409338 DOI: 10.1080/17843286.2016.1208955] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
OBJECTIVES Rituximab (RTX) is a new treatment option in children with difficult-to-treat steroid-dependent nephrotic syndrome (SDNS). We evaluated the experience of our tertiary center and reviewed the current literature. METHODS This is a retrospective single-center study evaluating the efficacy and safety of RTX in children with difficult-to-treat SDNS. Age at diagnosis, type and duration of immunosuppression, age at administration, dose of RTX, possible adverse events, number of relapses, duration of remission, and B-cell count after administration of RTX were analyzed. RESULTS Nine children with a median age at diagnosis of nephrotic syndrome of 4.75 (range 1.33-11.33) years and a median age at administration of RTX of 16.08 (range 3.33-19.25) years were included. Before administration of RTX they had a median number of relapses per year of 1.70 (range 0.82-4.80). At last follow-up (median 2.75 years, range 0.58-3.92), a reduction in the number of relapses per year to 0.26 (range 0-2.18) was noted, despite cessation or lowering the dose of immunosuppressive therapy. Four patients achieved complete remission after the first administration of RTX, four more patients after subsequent doses of RTX. No severe adverse events were noted. CONCLUSION RTX was an effective and safe therapeutic option in our cohort of children with difficult-to-treat SDNS, resulting in a significant reduction of yearly relapses in the absence of severe adverse events and facilitating the reduction of other immunosuppressive medication.
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Affiliation(s)
- Ilse Van Horebeek
- Department of Pediatric Nephrology, University Hospitals Leuven, Leuven, Belgium
| | - Noël Knops
- Department of Pediatric Nephrology, University Hospitals Leuven, Leuven, Belgium
| | - Maria Van Dyck
- Department of Pediatric Nephrology, University Hospitals Leuven, Leuven, Belgium
| | - Elena Levtchenko
- Department of Pediatric Nephrology, University Hospitals Leuven, Leuven, Belgium
| | - Djalila Mekahli
- Department of Pediatric Nephrology, University Hospitals Leuven, Leuven, Belgium
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Rituximab for Recurrence of Primary Focal Segmental Glomerulosclerosis After Kidney Transplantation: Clinical Outcomes. Transplantation 2017; 101:649-656. [PMID: 27043407 DOI: 10.1097/tp.0000000000001160] [Citation(s) in RCA: 51] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
BACKGROUND Rituximab has shown encouraging results for the treatment of kidney transplantation recipients with focal segmental glomerulosclerosis (FSGS) recurrence. However, the correct, opportune, and safe use of rituximab for this indication remains to be determined. METHODS This multicenter retrospective study reports on 19 new cases aged 35 (15-66) years who developed FSGS recurrence at 12 (1.5-27) days posttransplantation. Initial treatment consisted of plasma exchanges (PE), high doses of calcineurin inhibitors, and steroids. Rituximab was introduced either immediately (N = 6) or after failure of the initial treatment (N = 10) or failed attempted weaning from PE (N = 3). RESULTS Overall, we observed 9 of 19 complete remissions and 3 of 19 partial remissions. Estimated glomerular filtration rates (Modification of Diet in Renal Disease 4) were significantly higher in the responding patients than in nonresponding patients at month (M)12, M36, and M60. Overall, kidney survival at 5 years was 77.4% (95% range, 41.9-92.7). The 5-year graft survival rates in the responding patients and the nonresponding patients were 100% and 36.5%, respectively (P = 0.01). A further course of rituximab was required for 4 patients as a result of FSGS relapse, with good results. During the first year after renal transplantation, 14 patients developed severe infections (16 bacterial, 4 viral, 1 parasitic). CONCLUSIONS In kidney transplantation recipients with recurrent FSGS, rituximab therapy may be a recommended treatment for cases that have failed either the initial treatment or weaning from PE.
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Nourbakhsh N, Mak RH. Steroid-resistant nephrotic syndrome: past and current perspectives. PEDIATRIC HEALTH MEDICINE AND THERAPEUTICS 2017; 8:29-37. [PMID: 29388620 PMCID: PMC5774596 DOI: 10.2147/phmt.s100803] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
Patients with steroid-resistant nephrotic syndrome (SRNS) represent a challenging subset of patients with nephrotic syndrome who often fail standard immunosuppression and have a higher likelihood of progressing to end-stage renal disease. Appropriate treatment of SRNS requires an adequate understanding of the historical treatment, renal histopathology, and genetics associated with the disease. The aim of this review is to present a comprehensive appraisal of the history, role of renal biopsy, genetics, and treatment of SRNS.
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Affiliation(s)
- Noureddin Nourbakhsh
- Division of Pediatric Nephrology, Rady Children's Hospital San Diego, University of California, San Diego, La Jolla, CA, USA
| | - Robert H Mak
- Division of Pediatric Nephrology, Rady Children's Hospital San Diego, University of California, San Diego, La Jolla, CA, USA
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Iijima K, Sako M, Nozu K. Rituximab for nephrotic syndrome in children. Clin Exp Nephrol 2017; 21:193-202. [PMID: 27422620 PMCID: PMC5388729 DOI: 10.1007/s10157-016-1313-5] [Citation(s) in RCA: 60] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2016] [Accepted: 07/11/2016] [Indexed: 12/31/2022]
Abstract
Idiopathic nephrotic syndrome is the most common chronic glomerular disease in children. At least 20 % of children with this syndrome show frequent relapses and/or steroid dependence during or after immunosuppressive therapies, a condition defined as complicated frequently relapsing/steroid-dependent nephrotic syndrome (FRNS/SDNS). Approximately 1-3 % of children with idiopathic nephrotic syndrome are resistant to steroids and all immunosuppressive agents, a condition defined as refractory steroid-resistant nephrotic syndrome (SRNS); these SRNS children have a high risk of end-stage renal failure. Rituximab, a chimeric anti-CD20 monoclonal antibody, has been shown to be effective for patients with complicated FRNS/SDNS and refractory SRNS. This review describes the recent results of rituximab treatment applied to pediatric nephrotic syndrome, as well as those of our recent study, a multicenter, double-blind, randomized, placebo-controlled trial of rituximab for childhood-onset complicated FRNS/SDNS (RCRNS01). The overall efficacy and safety of rituximab for this disease are discussed.
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Affiliation(s)
- Kazumoto Iijima
- Department of Pediatrics, Kobe University Graduate School of Medicine, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, 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
| | - Kandai Nozu
- Department of Pediatrics, Kobe University Graduate School of Medicine, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan
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Ravani P, Bonanni A, Ghiggeri GM. Randomised controlled trial comparing ofatumumab to rituximab in children with steroid-dependent and calcineurin inhibitor-dependent idiopathic nephrotic syndrome: study protocol. BMJ Open 2017; 7:e013319. [PMID: 28314744 PMCID: PMC5372102 DOI: 10.1136/bmjopen-2016-013319] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
INTRODUCTION Oral steroids induce remission in about 90% of children with idiopathic nephrotic syndrome (INS), which is characterised by severe proteinuria and hypoalbuminaemia. Some children become steroid-dependent (SD) and require addition of calcineurin inhibitors (CNI) to maintain remission. Since these oral agents are toxic, alternative interventions are needed for long-term treatment. The anti-CD20 antibody rituximab has shown promising steroid-sparing properties in clinical trials, but benefits are less convincing in complicated forms of SD-INS. Ofatumumab, a new anti-CD20 antibody with stronger affinity to CD20, may be superior to rituximab in maintaining oral steroid-free and CNI-free disease remission in children with SD-INS. METHODS AND ANALYSIS This open-label, two-parallel-arm, controlled, phase II randomised clinical trial will enrol children with SD-INS maintained in remission with oral steroids and CNI. Children will be randomised to either ofatumumab or rituximab infusion. After infusion of either antibody, steroids will be maintained for 30 days and then tapered off by 0.3 mg/kg/week until complete withdrawal. 1 week after complete steroid withdrawal, CNI will be decreased by 50% and withdrawn within 2 additional weeks. We will enrol 140 children to detect as significant at the 2-sided p value of 0.01 with a power of >0.8, a reduction in the risk of 1-year relapse (primary end point) of at least 0.3 (ie, from 0.65 to 0.35; (risk ratio 0.54)) in the ofatumumab arm when compared with the rituximab arm. We will compare the amount of steroids required to maintain complete disease remission at 6 and 24 months, relapse-free period, relapse rate per year as secondary end points. Circulating cell populations will be studied as biomarkers or predictors of the anti-CD20 response. ETHICS AND DISSEMINATION The trial received ethics approval from the local ethics board. We will publish study results and present them at international scientific meetings. TRIAL REGISTRATION NUMBERS NCT02394119; 2015-000624-28; Pre-results.
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Affiliation(s)
- Pietro Ravani
- Division of Nephrology, University of Calgary, Calgary, Alberta, Canada
| | - Alice Bonanni
- Division of Nephrology, Dialysis, Transplantation, Giannina Gaslini Children's Hospital, Genoa, Italy
- Laboratory on Pathophysiology of Uremia, Giannina Gaslini Children's Hospital, Genoa, Italy
| | - Gian Marco Ghiggeri
- Division of Nephrology, Dialysis, Transplantation, Giannina Gaslini Children's Hospital, Genoa, Italy
- Laboratory on Pathophysiology of Uremia, Giannina Gaslini Children's Hospital, Genoa, Italy
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Madanchi N, Bitzan M, Takano T. Rituximab in Minimal Change Disease: Mechanisms of Action and Hypotheses for Future Studies. Can J Kidney Health Dis 2017; 4:2054358117698667. [PMID: 28540057 PMCID: PMC5433659 DOI: 10.1177/2054358117698667] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2016] [Accepted: 11/23/2016] [Indexed: 12/13/2022] Open
Abstract
Treatment with rituximab, a monoclonal antibody against the B-lymphocyte surface protein CD20, leads to the depletion of B cells. Recently, rituximab was reported to effectively prevent relapses of glucocorticoid-dependent or frequently relapsing minimal change disease (MCD). MCD is thought to be T-cell mediated; how rituximab controls MCD is not understood. In this review, we summarize key clinical studies demonstrating the efficacy of rituximab in idiopathic nephrotic syndrome, mainly MCD. We then discuss immunological features of this disease and potential mechanisms of action of rituximab in its treatment based on what is known about the therapeutic action of rituximab in other immune-mediated disorders. We believe that studies aimed at understanding the mechanisms of action of rituximab in MCD will provide a novel approach to resolve the elusive immune pathophysiology of MCD.
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Affiliation(s)
- Nima Madanchi
- Division of Nephrology, Department of Medicine, McGill University Health Centre, Montreal, Quebec, Canada
| | - Martin Bitzan
- Division of Nephrology, Department of Pediatrics, Montreal Children's Hospital, McGill University Health Centre, Montreal, Quebec, Canada
| | - Tomoko Takano
- Division of Nephrology, Department of Medicine, McGill University Health Centre, Montreal, Quebec, Canada
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Kinetics of Rituximab Excretion into Urine and Peritoneal Fluid in Two Patients with Nephrotic Syndrome. Case Rep Nephrol 2017; 2017:1372859. [PMID: 28243475 PMCID: PMC5294364 DOI: 10.1155/2017/1372859] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2016] [Revised: 12/26/2016] [Accepted: 12/28/2016] [Indexed: 01/27/2023] Open
Abstract
Clinical observations suggest that treatment of Rituximab might be less effective in patients with nephrotic range proteinuria when compared to nonnephrotic patients. It is conceivable that the reason for this is that significant amounts of Rituximab might be lost in the urine in a nephrotic patient and that these patients require a repeated or higher dosage. However, this has not been systematically studied. In this case report we describe two different patients with nephrotic range proteinuria receiving Rituximab. The first patient received Rituximab for therapy resistant cryoglobulinemic membranoproliferative glomerulonephritis and the other for second line treatment of Felty's syndrome. We employed flow cytometry to determine the amount of Rituximab excretion in both urine and peritoneal fluid specimens in these patients following administration of Rituximab. We found that a significant amount of Rituximab is lost from the circulation by excretion into the urine. Furthermore we saw a close correlation of the excretion of Rituximab to the excretion of IgG molecules suggesting selectivity of proteinuria as the determining factor of Rituximab excretion. Further larger scale clinical studies could have the potential to evaluate an optimal cut-off value of IgG urinary loss before a possible administration of Rituximab therefore contributing to a more individualized treatment approach in patients with nonselective and nephrotic range proteinuria.
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Takahashi Y, Ikezumi Y, Saitoh A. Rituximab protects podocytes and exerts anti-proteinuric effects in rat adriamycin-induced nephropathy independent of B-lymphocytes. Nephrology (Carlton) 2016; 22:49-57. [DOI: 10.1111/nep.12737] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2015] [Revised: 01/05/2016] [Accepted: 01/27/2016] [Indexed: 11/27/2022]
Affiliation(s)
- Yuichi Takahashi
- Department of Pediatrics; Niigata University Medical and Dental Hospital; Niigata Japan
| | - Yohei Ikezumi
- Department of Pediatrics; Niigata University Medical and Dental Hospital; Niigata Japan
| | - Akihiko Saitoh
- Department of Pediatrics; Niigata University Medical and Dental Hospital; Niigata Japan
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King C, Logan S, Smith SW, Hewins P. The efficacy of rituximab in adult frequently relapsing minimal change disease. Clin Kidney J 2016. [PMID: 28638601 PMCID: PMC5469552 DOI: 10.1093/ckj/sfw100] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
Background Corticosteroids are the basis of treatment for nephrotic syndrome due to minimal change disease (MCD), but 25% of patients have frequently relapsing nephrotic syndrome (FRNS) and 30% become steroid dependent. Prolonged use of conventional immunosuppressants causes significant toxicity. Rituximab (RTX) is now included in guidelines for childhood MCD. Evidence for use in adult MCD is limited. We describe a single-centre experience of RTX use in adult MCD. Methods Outcomes of all adult MCD patients treated with RTX for FRNS between 2008 and 2015 were retrospectively analysed. Results Thirteen patients received RTX; 11/13 had childhood-onset MCD. All had FRNS and 10 were steroid dependent. Eleven patients experienced one or more major treatment side effect from conventional therapy. At the time of RTX treatment, six patients were relapsing. All entered remission after RTX. The median length of follow-up after the first RTX treatment was 20 months (range 6–85). After RTX, the rate of relapse was reduced from 4 to 0.4/year (Wilcoxon signed rank P ≤ 0.05). Seven patients relapsed after RTX after a median of 10 months (range 1–11). All seven relapsing patients were successfully re-treated with RTX and none developed RTX-resistant nephrosis. The median number of courses of RTX per patient was 1 (range 1–5). The number of additional immunosuppressants, steroid dependency and antihypertensive agents were also reduced. At the last follow-up, two patients remained on low-dose steroids. No RTX-related adverse events were observed. Conclusion RTX is safe and effective in adults with FRNS due to MCD. The median rate of relapse is significantly reduced following RTX treatment and additional immunosuppressant exposure is minimized.
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Affiliation(s)
- Catherine King
- University Hospitals Birmingham, NHS Foundation Trust, Birmingham, UK
| | - Sarah Logan
- University Hospitals Birmingham, NHS Foundation Trust, Birmingham, UK
| | - Stuart W Smith
- University Hospitals Birmingham, NHS Foundation Trust, Birmingham, UK
| | - Peter Hewins
- University Hospitals Birmingham, NHS Foundation Trust, Birmingham, UK
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Chan CY, Liu ID, Resontoc LP, Ng KH, Chan YH, Lau PYW, Than M, Jordan SC, Lam KP, Yeo WS, Yap HK. T Lymphocyte Activation Markers as Predictors of Responsiveness to Rituximab among Patients with FSGS. Clin J Am Soc Nephrol 2016; 11:1360-1368. [PMID: 27269610 PMCID: PMC4974889 DOI: 10.2215/cjn.11941115] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2015] [Accepted: 04/05/2016] [Indexed: 12/13/2022]
Abstract
BACKGROUND AND OBJECTIVES Rituximab is used with variable success in difficult FSGS. Because B cell depletion significantly affects T cell function, we characterized T cell subsets in patients with FSGS to determine if an immunologic signature predictive of favorable response to rituximab could be identified. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Twenty-two consecutive patients with FSGS (median age =14.4 years old; range =6.2-25.0 years old) and age of onset of nephrotic syndrome 1-18 years old receiving rituximab for clinical indications between October of 2009 and February of 2014 were studied. Indications for rituximab were lack of sustained remission despite calcineurin inhibitors (CNIs) and mycophenolate in steroid-resistant patients and lack of steroid-sparing effect with cyclophosphamide and CNI or CNI toxicity in steroid-dependent patients. Exclusion criteria were infantile onset, known genetic mutations, and secondary causes. Rituximab (375 mg/m(2)) was given fortnightly up to a maximum of four doses. Immunologic subset monitoring was performed at baseline and regular intervals until relapse. Median follow-up duration postrituximab was 26.7 months (range =6.5-66.5 months). Baseline immunologic subsets were examined for association with rituximab response defined as resolution of proteinuria with discontinuation of prednisolone and CNI 3 months postrituximab. RESULTS Twelve patients (54.5%) responded to rituximab. Mitogen-stimulated CD154(+)CD4(+)CD3(+) subset before rituximab was significantly lower in FSGS responders compared with nonresponders (54.9%±28.1% versus 78.9%±16.4%; P=0.03). IFN-γ(+)CD3(+) and IL-2(+)CD3(+) were similarly decreased in responders compared with nonresponders (0.6%±0.8% versus 7.5%±6.1%; P=0.003 and 0.2%±0.5% versus 4.0%±4.7%; P<0.01, respectively). Recovery of all three activation subsets occurred 6 months postrituximab treatment (CD154(+)CD4(+)CD3(+), 74.8%±17.2%; IFN-γ(+)CD3(+), 7.1%±7.7%; and IL-2(+)CD3(+), 7.9%±10.9%; P<0.01). Receiver-operating characteristic analysis using optimal cutoff values showed that activated CD154(+)CD4(+)CD3(+) <83.3% (area under the curve [AUC], 0.81; 95% confidence interval [95% CI], 0.61 to 1.00), IFN-γ(+)CD3(+)<2.5% (AUC, 0.90; 95% CI, 0.75 to 1.00), and IL-2(+)CD3(+)<0.3% (AUC, 0.78; 95% CI, 0.57 to 0.98) were good predictors of rituximab response. CONCLUSIONS We have identified prognostic markers that define a subset of patients with FSGS bearing an immunologic signature representing hyporesponsiveness to T cell stimulation and therefore, who respond better to rituximab.
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Affiliation(s)
- Chang-Yien Chan
- Department of Paediatrics, Yong Loo Lin School of Medicine and
- Department of Paediatric Medicine, Khoo Teck Puat-National University Children’s Medical Institute, National University Health System, Singapore
| | - Isaac Desheng Liu
- Department of Paediatrics, Yong Loo Lin School of Medicine and
- Department of Paediatric Medicine, Khoo Teck Puat-National University Children’s Medical Institute, National University Health System, Singapore
| | - Lourdes Paula Resontoc
- Department of Paediatrics, Yong Loo Lin School of Medicine and
- Department of Paediatric Medicine, Khoo Teck Puat-National University Children’s Medical Institute, National University Health System, Singapore
| | - Kar-Hui Ng
- Department of Paediatrics, Yong Loo Lin School of Medicine and
- Department of Paediatric Medicine, Khoo Teck Puat-National University Children’s Medical Institute, National University Health System, Singapore
| | - Yiong-Huak Chan
- Biostatistics Unit, Medicine Dean's Office, National University of Singapore, Singapore
| | - Perry Yew-Weng Lau
- Department of Paediatrics, Yong Loo Lin School of Medicine and
- Department of Paediatric Medicine, Khoo Teck Puat-National University Children’s Medical Institute, National University Health System, Singapore
| | - Mya Than
- Department of Paediatrics, Yong Loo Lin School of Medicine and
- Department of Paediatric Medicine, Khoo Teck Puat-National University Children’s Medical Institute, National University Health System, Singapore
| | - Stanley C. Jordan
- Comprehensive Transplant Center, Cedars Sinai Medical Center, Los Angeles, California; and
| | - Kong-Peng Lam
- Department of Paediatrics, Yong Loo Lin School of Medicine and
- Immunology Group, Bioprocessing Technology Institute, Agency for Science, Technology and Research, Singapore
| | - Wee-Song Yeo
- Department of Paediatrics, Yong Loo Lin School of Medicine and
- Department of Paediatric Medicine, Khoo Teck Puat-National University Children’s Medical Institute, National University Health System, Singapore
| | - Hui-Kim Yap
- Department of Paediatrics, Yong Loo Lin School of Medicine and
- Department of Paediatric Medicine, Khoo Teck Puat-National University Children’s Medical Institute, National University Health System, Singapore
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Niu XL, Hao S, Wang P, Zhang W, Guo GM, Wu Y, Kuang XY, Zhu GH, Huang WY. Single dose of rituximab in children with steroid-dependent minimal change nephrotic syndrome. Biomed Rep 2016; 5:237-242. [PMID: 27446549 DOI: 10.3892/br.2016.711] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2016] [Accepted: 06/27/2016] [Indexed: 01/18/2023] Open
Abstract
Rituximab (RTX) can be used in children with nephrotic syndrome, particularly in those with steroid-dependent nephrotic syndrome (SDNS). However, at present there is no unified standard of how to use RTX, with regard to the amount of doses and frequency, in children with nephrotic syndrome. The study aimed to investigate the therapeutic efficacy of a single dose of RTX in children with steroid-dependent minimal change nephrotic syndrome (SD-MCNS). The patients with biopsy-proven minimal change disease (MCD) and clinical features of SDNS received a single dose of RTX (375 mg/m2). The toxicity and side effects of RTX were also observed. The study included 19 patients (10 males and 9 females). Follow-up of the patients was 1-50 months (28.1±16.6 months). B-cell depletion was achieved with RTX infusion (CD20<0.5%) and lasted 1-6 months (mean, 2.92±1.57 months). During follow-up, 10 patients remained in complete remission and did not relapse without administration of oral steroids or immunosuppressants for 4-50 months (mean, 30.1±12.6 months), despite recovery of the B-cell count. Nine patients relapsed in the process of reducing steroids, thus, treatment was maintained at a lower dosage (T=0, P<0.05) than prior to use of RTX. The number of relapses also decreased significantly (T=95, P<0.05). Five of the patients relapsed after stopping steroid for several months. At the end of follow-up, the efficacy of a single induction of RTX was 47.4% (9/19). There were no significant side effects associated with administration of RTX. In conclusion, RTX is a safe and effective alternative for children with SD-MCNS. RTX is an effective treatment for the rapid induction of remission and reduces relapse and steroid dependency. A single dose of RTX for children with SD-MCNS is recommended for rapid induction of remission, reduction of long-term steroid dosage, and decrease in the number of relapses, as it has few side effects.
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Affiliation(s)
- Xiao-Ling Niu
- Department of Nephrology and Rheumatology, Children's Hospital of Shanghai, Shanghai Jiaotong University, Shanghai 200062, P.R. China
| | - Sheng Hao
- Department of Nephrology and Rheumatology, Children's Hospital of Shanghai, Shanghai Jiaotong University, Shanghai 200062, P.R. China
| | - Ping Wang
- Department of Nephrology and Rheumatology, Children's Hospital of Shanghai, Shanghai Jiaotong University, Shanghai 200062, P.R. China
| | - Wei Zhang
- Department of Nephrology and Rheumatology, Children's Hospital of Shanghai, Shanghai Jiaotong University, Shanghai 200062, P.R. China
| | - Gui-Mei Guo
- Department of Nephrology and Rheumatology, Children's Hospital of Shanghai, Shanghai Jiaotong University, Shanghai 200062, P.R. China
| | - Ying Wu
- Department of Nephrology and Rheumatology, Children's Hospital of Shanghai, Shanghai Jiaotong University, Shanghai 200062, P.R. China
| | - Xin-Yu Kuang
- Department of Nephrology and Rheumatology, Children's Hospital of Shanghai, Shanghai Jiaotong University, Shanghai 200062, P.R. China
| | - Guang-Hua Zhu
- Department of Nephrology and Rheumatology, Children's Hospital of Shanghai, Shanghai Jiaotong University, Shanghai 200062, P.R. China
| | - Wen-Yan Huang
- Department of Nephrology and Rheumatology, Children's Hospital of Shanghai, Shanghai Jiaotong University, Shanghai 200062, P.R. China
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Cyclophosphamide and rituximab in frequently relapsing/steroid-dependent nephrotic syndrome. Pediatr Nephrol 2016; 31:589-94. [PMID: 26525199 DOI: 10.1007/s00467-015-3245-9] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2015] [Revised: 10/02/2015] [Accepted: 10/05/2015] [Indexed: 12/31/2022]
Abstract
BACKGROUND Steroid-sensitive nephrotic syndrome is the most common form of nephrotic syndrome in childhood, defined by the response to treatment with glucocorticoids with consequent remission. While most children eventually experience spontaneous resolution of the disease, some have a difficult course with frequent relapses or steroid dependence nephrotic syndrome (FRSDNS). The consequent steroid toxicity often prompts administration of other immunosuppressive drugs, traditionally cyclophosphamide. Recently, rituximab has been reported as effective in this disorder, but long-term experience is lacking. METHODS Retrospective note review of all children with FRSDNS treated with a first course of cyclophosphamide and/or rituximab in our center between December 2006 and April 2015. We reviewed time to first relapse after treatment, co-medications, and side effects. RESULTS A total of 102 children were treated with cyclophosphamide (79) and/or rituximab (42). Of these, 34 received cyclophosphamide prior to rituximab. Median time to first relapse was 7 months after cyclophosphamide and 14 months after rituximab. Documented side effects of cyclophosphamide included neutropenia, hair loss, and hemorrhagic cystitis (1). Rituximab was associated with an allergic reaction at infusion in two patients. CONCLUSIONS Rituximab was used in children with the most difficult to treat FRSDNS, yet was associated with longer remission time and less side effects than cyclophosphamide. A randomized controlled trial is needed to directly compare these drugs.
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Messina M, Gallo E, Mella A, Pagani F, Biancone L. Update on the treatment of focal segmental glomerulosclerosis in renal transplantation. World J Transplant 2016; 6:54-68. [PMID: 27011905 PMCID: PMC4801805 DOI: 10.5500/wjt.v6.i1.54] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2015] [Revised: 12/22/2015] [Accepted: 01/22/2016] [Indexed: 02/05/2023] Open
Abstract
Focal segmental glomerulosclerosis (FSGS) represents one of the most severe glomerular diseases, with frequent progression to end-stage renal disease and a high rate of recurrence in renal allografts (30%-50%). Recurrent FSGS portends a negative outcome, with the hazard ratio of graft failure being two-fold higher then that of other glomerulonephritis. Two patterns of clinical presentations are observed: Early recurrence, which is characterized by massive proteinuria within hours to days after implantation of the renal graft, and late recurrence, which occurs several months or years after the transplantation. Many clinical conditions have been recognized as risk factors for recurrence, including younger age, rapid progression of the disease to end-stage renal disease on native kidneys, and loss of previous renal allografts due to recurrence. However, much less is known about the incidence and risk factors of the so-called “de novo” type of FSGS, for which sufferers are transplanted patients without disease on native kidneys; but, rapid development of allograft failure is frequently observed. Management of both forms is challenging, and none of the approaches proposed to date have been demonstrated as consistently beneficial or effective. In the present review we report an update on the available therapeutic strategies for FSGS in renal transplantation within the context of a critical overview of the current literature.
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