Colucci Manuela, Carsetti Rita, Cascioli Simona, Casiraghi Federica, Perna Annalisa, Ravà Lucilla, Ruggiero Barbara, Emma Francesco, Vivarelli Marina
Division of Nephrology and Dialysis,
Immunology Unit, Immunology and Pharmacotherapy Area.
J Am Soc Nephrol. 2016 Jun;27(6):1811-22. doi: 10.1681/ASN.2015050523. Epub 2015 Nov 13.
The pathogenesis of nephrotic syndrome is unclear. However, the efficacy of rituximab, a B cell-depleting antibody, in nephrotic syndrome suggests a pathogenic role of B cells. In this retrospective study, we determined by flow cytometry levels of B and T cell subpopulations before and after rituximab infusion in 28 pediatric patients with frequently relapsing or steroid-dependent nephrotic syndrome. At baseline, patients had lower median percentages of transitional and mature B cells than age-matched healthy controls (P<0.001). Rituximab induced full depletion of B cells (<1% of lymphocytes). At 1 year, most patients exhibited complete total and mature B cell recovery, whereas memory B cell subsets remained significantly depleted. Total T cell concentration did not change with rituximab, whereas the CD4(+)/CD8(+) T cell ratio tended to increase. Fourteen patients relapsed within 24 months, with a median follow-up of 11.2 months (interquartile range, 8-17.7 months). We observed no difference at baseline between nonrelapsing and relapsing patients in several clinical parameters and cell subset concentrations. Reconstitution of all memory B cell subpopulations, number of immunosuppressive drugs, and dose of tacrolimus during the last 4 months of follow-up were predictive of relapse in univariate Cox regression analysis. However, only delayed reconstitution of switched memory B cells, independent of immunosuppressive treatment, was protective against relapse in multivariate (P<0.01) and receiver operator characteristic (P<0.01 for percentage of lymphocytes; P=0.02 for absolute count) analyses. Evaluation of switched memory B cell recovery after rituximab may be useful for predicting relapse in patients with nephrotic syndrome.
肾病综合征的发病机制尚不清楚。然而，利妥昔单抗（一种B细胞清除抗体）在肾病综合征中的疗效提示B细胞具有致病作用。在这项回顾性研究中，我们通过流式细胞术测定了28例频繁复发或激素依赖型肾病综合征儿科患者在输注利妥昔单抗前后B细胞和T细胞亚群的水平。在基线时，患者过渡性和成熟B细胞的中位百分比低于年龄匹配的健康对照（P<0.001）。利妥昔单抗诱导B细胞完全清除（<1%的淋巴细胞）。在1年时，大多数患者的总B细胞和成熟B细胞完全恢复，而记忆B细胞亚群仍显著减少。总T细胞浓度在使用利妥昔单抗后未发生变化，而CD4(+)/CD8(+)T细胞比值有升高趋势。14例患者在24个月内复发，中位随访时间为11.2个月（四分位间距，8 - 17.7个月）。我们观察到在几个临床参数和细胞亚群浓度方面，非复发患者和复发患者在基线时没有差异。在单变量Cox回归分析中，随访最后4个月所有记忆B细胞亚群的重建、免疫抑制药物数量和他克莫司剂量可预测复发。然而，在多变量（P<0.01）和受试者工作特征分析（淋巴细胞百分比P<0.01；绝对计数P = 0.02）中，只有转换记忆B细胞的延迟重建（与免疫抑制治疗无关）对预防复发有保护作用。评估利妥昔单抗治疗后转换记忆B细胞的恢复情况可能有助于预测肾病综合征患者的复发。
