Long-term follow-up after rituximab for steroid-dependent idiopathic nephrotic syndrome

Kemper, Markus J.; Gellermann, Jutta; Habbig, Sandra; Krmar, Rafael T.; Dittrich, Katalin; Jungraithmayr, Therese; Pape, Lars; Patzer, Ludwig; Billing, Heiko; Weber, Lutz T.; Pöhl, Martin; Rosenthal, Katrin; Rosahl, Anne; Mueller-Wiefel, Dirk E.; Dötsch, Jörg

doi:10.1093/ndt/gfr548

Cited by 115 publications

(96 citation statements)

References 29 publications

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“…26 The pathogenic role of B lymphocytes would also explain why MCD or FSGS may occasionally occur in patients with other B cell-mediated diseases 27 and why NS remission achieved by rituximab associates with circulating B-cell depletion. [8][9][10][11][12][13][14]26 In patients in this study, persistence of remission after B lymphocyte reappearance in the circulation could actually be the result of a complete and definitive disruption of the potential autoreactive clone(s). This is in line with the evidence that in IMN, persistent remission achieved by rituximab therapy is paralleled by depletion of nephritogenic autoantibodies, even after re-emergence of B lymphocytes in the circulation.…”

Section: Discussionmentioning

confidence: 76%

“…7 Subsequent uncontrolled observations found some effect of rituximab in patients with steroid-dependent or frequently relapsing MCD, [8][9][10][11] suggesting that B-cell immunity could play a key role in the pathophysiology of the disease. Controlled studies in support of this hypothesis, however, have been both scanty and almost confined to children 12,13 or to patients with MCD who were evaluated in the context of a retrospective, observational design.…”

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confidence: 99%

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Rituximab in Steroid-Dependent or Frequently Relapsing Idiopathic Nephrotic Syndrome

Ruggenenti

Ruggiero

Cravedi

et al. 2014

Journal of the American Society of Nephrology

204

183

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The outcome of steroid-dependent or frequently relapsing nephrotic syndrome of minimal change disease (MCD), mesangial proliferative GN (MesGN), or FSGS may be poor and with major treatment toxicity. This academic, multicenter, off-on trial (ClinicalTrials.gov #NCT00981838) primarily evaluated the effects of rituximab therapy followed by immunosuppression withdrawal on disease recurrence in 10 children and 20 adults with MCD/MesGN (n=22) or FSGS who had suffered $2 recurrences over the previous year and were in steroidinduced remission for $1 month. Participants received one dose (n=28) or two doses of rituximab (375 mg/m 2 intravenously). At 1 year, all patients were in remission: 18 were treatment-free and 15 never relapsed. Compared with the year before rituximab treatment, total relapses decreased from 88 to 22 and the per-patient median number of relapses decreased from 2.5 (interquartile range [IQR], 2-4) to 0.5 (IQR, 0-1; P,0.001) during 1 year of follow-up. Reduction was significant across subgroups (children, adults, MCD/MesGN, and FSGS; P,0.01). After rituximab, the per-patient steroid maintenance median dose decreased from 0.27 mg/kg (IQR, 0.19-0.60) to 0 mg/kg (IQR, 0-0.23) (P,0.001), and the median cumulative dose to achieve relapse remission decreased from 19.5 mg/kg (IQR, 13.0-29.2) to 0.5 mg/kg (IQR, 0-9.4) (P,0.001). Furthermore, the mean estimated GFR increased from 111.3625.7 to 121.8629.2 ml/min per 1.73 m 2 (P=0.01), with the largest increases in children and in FSGS subgroups. The mean height z score slope stabilized in children (P,0.01). Treatment was well tolerated. Rituximab effectively and safely prevented recurrences and reduced the need for immunosuppression in steroiddependent or frequently relapsing nephrotic syndrome, and halted disease-associated growth deficit in children.

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Section: Discussionmentioning

confidence: 76%

mentioning

confidence: 99%

Rituximab in Steroid-Dependent or Frequently Relapsing Idiopathic Nephrotic Syndrome

Ruggenenti

Ruggiero

Cravedi

et al. 2014

Journal of the American Society of Nephrology

204

183

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“…Successive retrospective studies reported between 2008 and 2011 (17)(18)(19)(20)(21)(22)(23)(24)(25)(26) confirmed these potential benefits in uncontrolled small series of mixed populations with nephrotic syndrome. Although these studies could not assist in decision making because of their observational design, they were key to informing the design of subsequent clinical trials that have been completed in the last 5 years.…”

Section: Observational Datamentioning

confidence: 85%

Anti-CD20 Antibodies for Idiopathic Nephrotic Syndrome in Children

Ravani

Bonanni²,

Rossi³

et al. 2016

Clinical Journal of the American Society of Nephrology

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Rituximab, a chimeric anti-CD20 monoclonal antibody originally licensed for lymphoma, is emerging as a novel steroid-sparing agent for idiopathic nephrotic syndrome in children. The potential use of anti-CD20 monoclonal antibodies in idiopathic nephrotic syndrome has contributed to shifting the view of podocytopathies from T cellmediated to more complex immunomediated disorders that can benefit from targeting B cells and other mediators of the early immune response. Clinical data on the use of rituximab also have implications on disease management and classification. In this review, we present results of clinical studies that support rituximab as an effective steroid-sparing agent in steroid-dependent idiopathic nephrotic syndrome. Recent randomized controlled trials suggest that potential benefits of rituximab therapy in steroid-dependent forms of idiopathic nephrotic syndrome vary depending on whether children are dependent on steroids alone or on both steroids and calcineurin inhibitors, with greater probabilities to achieve drug-free remission in the former group. Multiple-drug dependence may identify a different disease state with different prognosis and treatment options. Insufficient data are available on optimal use of rituximab as a maintenance steroid-sparing agent in these steroid-sensitive forms of the disease, including how often and for how long rituximab infusions should be repeated to maximize expected benefits and minimize potential harms. Finally, one randomized controlled trial in children with steroid-resistant idiopathic nephrotic syndrome yielded negative results. New anti-CD20 antibodies are under study in this patient population.

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“…Subsequently, several other case series showed beneficial effect in patients with SDNS in terms of achieving complete remission or the ability to decrease immunosuppression (4)(5)(6)(7)(8)(9)(10)(11)(12).…”

Section: Introductionmentioning

confidence: 99%

T Lymphocyte Activation Markers as Predictors of Responsiveness to Rituximab among Patients with FSGS

Chan

Liu

Resontoc

et al. 2016

CJASN

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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%628.1% versus 78.9%616.4%; P=0.03). IFN-g + CD3 + and IL-2 + CD3 + were similarly decreased in responders compared with nonresponders (0.6%60.8% versus 7.5%66.1%; P=0.003 and 0.2%60.5% versus 4.0%64.7%; P,0.01, respectively). Recovery of all three activation subsets occurred 6 months postrituximab treatment (CD154 + CD4 + CD3 + , 74.8%617.2%; IFN-g + CD3 + , 7.1%67.7%; and IL-2 + CD3 + , 7.9%610.9%; 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-g + 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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Long-term follow-up after rituximab for steroid-dependent idiopathic nephrotic syndrome

Abstract: Rituximab is an effective treatment option in the short- and long-term control of treatment refractory SSNS. Further controlled studies are needed to address optimal patient selection, dose and safety of rituximab infusions.

Cited by 115 publications

References 29 publications

Rituximab in Steroid-Dependent or Frequently Relapsing Idiopathic Nephrotic Syndrome

Rituximab in Steroid-Dependent or Frequently Relapsing Idiopathic Nephrotic Syndrome

Anti-CD20 Antibodies for Idiopathic Nephrotic Syndrome in Children

T Lymphocyte Activation Markers as Predictors of Responsiveness to Rituximab among Patients with FSGS

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