Rituximab in refractory nephrotic syndrome | SpringerLink

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Abstract. The aim of this study was to establish the efficacy and safety of rituximab in refractory nephrotic syndrome (NS). Members of the International Paediatric ...
Pediatr Nephrol (2010) 25:461–468 DOI 10.1007/s00467-009-1376-6

ORIGINAL ARTICLE

Rituximab in refractory nephrotic syndrome Agnieszka Prytuła & Kazumoto Iijima & Koichi Kamei & Denis Geary & Errol Gottlich & Abdul Majeed & Mark Taylor & Stephen D. Marks & Shamir Tuchman & Roberta Camilla & Milos Ognjanovic & Guido Filler & Graham Smith & Kjell Tullus

Received: 16 September 2009 / Revised: 19 October 2009 / Accepted: 20 October 2009 / Published online: 23 December 2009 # IPNA 2009

Abstract The aim of this study was to establish the efficacy and safety of rituximab in refractory nephrotic syndrome (NS). Members of the International Paediatric Nephrology Association were asked to retrospectively fill in a questionnaire with details on the use of rituximab in their centres. We divided the data into three groups: group 1, patients with steroid-dependent and frequently relapsing NS; group 2, with steroid-resistant NS; group 3, with post-transplant recurrence of NS. Seventy questionnaires from 25 centres

described the outcome of 28, 27 and 15 patients in groups 1, 2 and 3, respectively. Of these, 82% of patients in group 1, 44% of patients in group 2 and 60% of patients in group 3 had a good initial response. Side effects were observed in 27% of the patients, and these were mostly acute reactions. We present a large multicentre series of children with refractory NS. Children in group 1 showed the best response. The good initial response in group 3 can be biased by the accompanying treatments that were administered at the same

A. Prytuła : S. D. Marks : K. Tullus (*) Department of Paediatric Nephrology, Great Ormond Street Hospital–NHS Trust, London, UK e-mail: [email protected]

M. Taylor Birmingham Children’s Hospital, Birmingham, UK

K. Iijima Division of Child Health and Development, Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan K. Iijima : K. Kamei Department of Nephrology, National Center for Child Health and Development, Tokyo, Japan D. Geary Division of Nephrology, The Hospital for Sick Children, Toronto, Canada

S. Tuchman Division of Pediatric Nephrology, The Children’s Hospital of Philadelphia, Philadelphia, USA R. Camilla Nephrology, Dialysis and Transplantation, Regina Margherita Children’s Hospital, Torino, Italy M. Ognjanovic Newcastle Children and Young People’s Kidney Team, Royal Victoria Infirmary, Newcastle upon Tyne, UK

E. Gottlich Morningside Children’s Kidney Treatment Centre, Sandton, South Africa

G. Filler Children’s Hospital, London Health Science Centre, Department of Paediatrics, University of Western Ontario, London, Canada

A. Majeed Paediatric Nephrology Unit, Dubai Hospital, Dubai, United Arab Emirates

G. Smith Children’s Kidney Centre, University Hospital of Wales, Cardiff, UK

462

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time as rituximab. Controlled prospective trials are required to establish the value of rituximab in idiopathic NS.

The aim of this study was to further assess the efficacy and safety of rituximab in refractory NS.

Keywords Pediatric . Nephrotic syndrome . Remission . Renal transplantation

Patients and methods

Abbreviations ACE-I angiotensin converting enzyme inhibitors CI calcineurin inhibitors FRNS frequently relapsing nephrotic syndrome FSGS focal and segmental glomerulosclerosis MCNS minimal change nephrotic syndrome MMF mycophenolate mofetil NS nephrotic syndrome PML progressive multifocal leukoencephalopathy PTLD post-transplant lymphoproliferative disorders SDNS steroid-dependent nephrotic syndrome SLE systemic lupus erythematosus SRNS steroid-resistant nephrotic syndrome

Introduction Most children with idiopathic nephrotic syndrome (NS) will respond well to steroid therapy. They enter remission and will later experience a limited number of relapses before finally outgrowing the condition. However, a number of children with NS will experience a more complicated course with frequent relapses or will develop steroid dependency [1, 2]. In addition, some children do not respond to steroids and are subsequently diagnosed as having steroid-resistant nephrotic syndrome (SRNS) [3]. The management of steroid-dependent NS (SDNS), frequently relapsing NS (FRNS) and SRNS can be very challenging. The aim is to reduce corticosteroid toxicity or to overcome steroid resistance. Various treatment options, including alkylating drugs (cyclophosphamide, chlorambucil), vinca alkaloids (e.g. vincristine), antiproliferative immunosuppressants [e.g. mycophenolate mofetil (MMF), calcineurin inhibitors (CI) cyclosporin A and tacrolimus], immunomodulating drugs (levamisole), angiotensin converting enzyme inhibitors (ACE-I) and plasma exchange, are used [1, 4]. Many of these treatments have significant side effects and are not always effective. During the past few years there have been a number of reports on the successful treatment of FRNS/SDNS, SRNS and post-transplant recurrence of NS with the anti-CD20 monoclonal antibody, rituximab [5–10]. Although these reports are encouraging, most of them are only isolated case reports, and there is clearly a risk for publication bias where the efficacy of rituximab is overestimated.

Questionnaire We contacted all IPNA (International Pediatric Nephrology Association) members and asked them to retrospectively fill in an anonymised questionnaire on all patients with childhood onset idiopathic NS who had been treated with rituximab. We explicitly asked for information on children who did not respond to this treatment in an attempt to reduce publication bias. We collected details on patients’ age, clinical and pathological diagnosis, previous and current treatments as well as data on individual and total rituximab dose, side effects, the initial response, the duration of response, biochemical parameters (such as proteinuria and serum albumin levels) and CD19 cell count. Personal data were not disclosed. In December 2008, we re-contacted the treating physicians by e-mail with the aim of collecting additional data on the duration of clinical response to rituximab in patients who had an ongoing remission while the data collection was being completed. Definitions Idiopathic NS is NS of unknown etiology for which relapse is defined as the recurrence of oedema and proteinuria with urinary dipstick proteinuria of ≥2+. Frequent relapses (FR) were defined as the recurrence of proteinuria at least twice within 6 months or at least four times within the last 12 months. Children were defined as steroid dependent (SD) when they relapsed while still on a weaning course of prednisolone, or within 14 days of discontinuing steroids. Steroid resistance (SR) denotes a lack of remission after 4 weeks of corticosteroid therapy [1]. Assessment of response Our approach to assessing the clinical response was to evaluate proteinuria and serum albumin after rituximab treatment. We classified the response into four stages: 1. no proteinuria, normal serum albumin 2. mild proteinuria, serum albumin >30 g/l 3. ongoing significant proteinuria, serum albumin 20– 30 g/l 4. no change in proteinuria and serum albumin.

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Stages 1 and 2 were regarded as a good clinical response, whereas stages 3 and 4 were regarded as a poor clinical response. Depletion of CD19+ following rituximab treatment was defined as a CD19+ count