B Cell Reconstitution after Rituximab Treatment in Idiopathic Nephrotic Syndrome

Colucci, Manuela; Carsetti, Rita; Cascioli, Simona; Casiraghi, Federica; Perna, Annalisa; Ravà, Lucilla; Ruggiero, Barbara; Emma, Francesco; Vivarelli, Marina

doi:10.1681/asn.2015050523

Cited by 170 publications

(182 citation statements)

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“…A recent study of 28 pediatric patients with frequently relapsing steroid-sensitive nephrotic syndrome showed that delayed reconstitution of switched memory B cells after rituximab treatment was protective against relapse (25). In contrast, the 22 patients in our study represented a difficult spectrum of nephrotic syndrome, where rituximab was indicated because of treatment refractoriness or CNI toxicity with evidence of increasing glomerulosclerosis on repeat renal biopsy.…”

Section: Discussionmentioning

confidence: 54%

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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Section: Discussionmentioning

confidence: 54%

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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“…Though its overall safety profile is reassuring (56), rituximab use in children is not without rare serious side effects: fulminant myocarditis, pulmonary fibrosis, fatal Pneumocystis jirovecii infections, severe ulcerative colitis, and severe allergic reactions (reviewed in Avner et al [11]). We have shown that, in children with frequently relapsing NS or steroid-dependent NS, rituximab infusion determines a prolonged depletion of memory B cells (33), and have observed long-term hypogammaglobulinemia in a few patients. Therefore, prospective long-term studies are necessary to evaluate the effect of repeated infusions on immune competence in the pediatric setting.…”

Section: Nonsteroidal Immunosuppressive Drugsmentioning

confidence: 93%

“…Moreover, after rituximab infusion, some patients maintain prolonged remission despite reconstitution of B cells (32). Regarding this aspect, we have recently shown that after rituximab-induced B cell depletion in children with frequently relapsing nephrotic syndrome or steroid-dependent nephrotic syndrome, the reconstitution of memory B cells predicts relapse (33). Targeting B cells may affect costimulatory pathways involved in T cell activation, and this may well be one of the mechanisms involved in the effectiveness of CD20-depleting agents, such as rituximab and the newer humanized anti-CD20 monoclonal antibody, ofatumumab (34).…”

Section: Pathogenesismentioning

confidence: 99%

Minimal Change Disease

Vivarelli

Massella

Ruggiero

et al. 2016

CJASN

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Minimal change disease (MCD) is a major cause of idiopathic nephrotic syndrome (NS), characterized by intense proteinuria leading to edema and intravascular volume depletion. In adults, it accounts for approximately 15% of patients with idiopathic NS, reaching a much higher percentage at younger ages, up to 70%-90% in children >1 year of age. In the pediatric setting, a renal biopsy is usually not performed if presentation is typical and the patient responds to therapy with oral prednisone at conventional doses. Therefore, in this setting steroid-sensitive NS can be considered synonymous with MCD. The pathologic hallmark of disease is absence of visible alterations by light microscopy and effacement of foot processes by electron microscopy. Although the cause is unknown and it is likely that different subgroups of disease recognize a different pathogenesis, immunologic dysregulation and modifications of the podocyte are thought to synergize in altering the integrity of the glomerular basement membrane and therefore determining proteinuria. The mainstay of therapy is prednisone, but steroid-sensitive forms frequently relapse and this leads to a percentage of patients requiring second-line steroid-sparing immunosuppression. The outcome is variable, but forms of MCD that respond to steroids usually do not lead to chronic renal damage, whereas forms that are unresponsive to steroids may subsequently reveal themselves as FSGS. However, in a substantial number of patients the disease is recurrent and requires long-term immunosuppression, with significant morbidity because of side effects. Recent therapeutic advances, such as the use of anti-CD20 antibodies, have provided long-term remission off-therapy and suggest new hypotheses for disease pathogenesis.

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“…Clinically, it has been shown that there is no clear relationship between the duration of the response to rituximab and the timing of recovery of B cells. It is this gap in knowledge that Colucci et al 10 address in their important paper in this issue of the Journal of the American Society of Nephrology. Colucci et al 10 studied 28 children with presumed MCD on the basis of a history of frequently relapsing or steroid-dependent disease.…”

mentioning

confidence: 98%

“…It is this gap in knowledge that Colucci et al 10 address in their important paper in this issue of the Journal of the American Society of Nephrology. Colucci et al 10 studied 28 children with presumed MCD on the basis of a history of frequently relapsing or steroid-dependent disease. In line with standard clinical practice in pediatric nephrology, the diagnosis of MCD was made on the basis of responsiveness to steroids and not on the basis of a kidney biopsy.…”

mentioning

confidence: 98%