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来那度胺联合地塞米松治疗伴单克隆免疫球蛋白沉积的增生性肾小球肾炎
周后安, 陈菁菁, 李曼娜, 王霞, 曾彩虹, 黄湘华, 陈朝红, 程震
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来那度胺联合地塞米松治疗伴单克隆免疫球蛋白沉积的增生性肾小球肾炎
Lenalidomide plus dexamethasone for proliferative glomerulonephritis with monoclonal immunoglobulin deposits
目的 评估来那度胺（lenalidomide）联合地塞米松（dexamethasone）方案（LD方案）治疗伴单克隆免疫球蛋白（Ig）沉积的增生性肾小球肾炎（proliferative glomerulonephritis with monoclonal Ig deposits，PGNMID）的疗效及安全性。方法 回顾性分析2010年1月至2019年10月于东部战区总医院采用LD方案治疗的PGNMID患者的临床病理资料。结果 于东部战区总医院行肾活检并接受LD方案治疗≥3个月的患者共6例。随访6~19个月，肾脏缓解3例，缓解率为50%（3/6）。所有患者肾脏病理光镜：膜增生性肾小球肾炎。免疫荧光：单一κ型IgG3沉积于系膜区和血管袢。在服用LD方案前，6例患者的中位尿蛋白量7.76（1.27，14.57）g/24 h，中位血肌酐118.5（70.7，289.1）μmol/L，中位血白蛋白34.5（22.4，37.5）g/L。5例血清游离κ、λ轻链浓度升高，但血清游离轻链比值均正常。2例血补体C3下降。6例行骨髓流式细胞学检查，2例单克隆浆细胞升高，所占比例分别为0.7%和0.5%。1例患者血M蛋白阳性，为κ型IgG3。末次随访时，6例患者的中位尿蛋白量3.33（0.33，11.23）g/24 h，中位血肌酐108.7（80.4，160.9）μmol/L，中位血白蛋白35.9（24.5，45.6）g/L。5例血清游离轻链浓度升高患者中，4例浓度较服药前下降。2例补体C3下降的患者升高至正常浓度，另2例患者补体C3略有下降。随访期间，1例患者的血M蛋白阳性未见转阴。所有患者血清游离轻链比值均正常。不良反应有贫血、中性粒细胞减少、四肢麻木感和上呼吸道感染。结论 本文首次报道LD方案用于治疗PGNMID可能有效，但需进一步关注来那度胺的血液系统不良反应。
Objective To evaluate the efficacy and safety of lenalidomide plus dexamethasone (LD) in patients with proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID). Methods The clinicopathological data of PGNMID patients who were treated with LD protocol from January 2010 to October 2019 were retrospectively analyzed. Results All of 6 patients received LD treatment for≥3 months after renal biopsy in Jinling Hospital. During the follow-up period of 6 to 19 months, 3 patients achieved renal remission, and the renal remission rate was 50%(3/6). Light microscopy showed membranoproliferative glomerulonephritis and immunofluorescence showed single kappa type IgG3 was deposited in the mesangial region and the vascular loop. Before taking LD scheme, the median urinary protein were 7.76(1.27, 14.57) g/24 h, the median serum creatinine was 118.5(70.7, 289.1) μmol/L, and the median albumin was 34.5(22.4, 37.5) g/L. The concentration of serum free kappa and lambda light chain was increased in 5 patients, but the serum free light chain ratio was normal. Hypocomplementemia was detected in two cases. Six patients underwent bone marrow flow cytometry, and 2 patients had elevated monoclonal plasma cells, accounting for 0.7% and 0.5%, respectively. Immunofixation electrophoresis suggested that 1 patient had positive serum M protein for kappa type IgG3. At the last follow-up, median urine protein was 3.33(0.33, 11.23) g/24 h, median serum creatinine was 108.7(80.4, 160.9) μmol/L, and median albumin was 35.9(24.5, 45.6) g/L. The concentration of serum free light chain in 4 patients from 5 patients with elevated serum free light chain was lower than that before taking the drug. Decreased level of serum complement in two cases returned to normal after treatment. The M spike did not turn negative during the follow-up in one patient. Adverse events included anemia, neutropenia, limb numbness and upper respiratory tract infection. Conclusion This study reports for the first time that LD protocol may be effective in treating PGNMID, but more attention should be paid to the hematological adverse events of lenalidomide.
肾小球肾炎 / 免疫球蛋白类 / 地塞米松 / 增生性肾小球肾炎 / 来那度胺 / 治疗结果 / 药物相关性不良反应 {{custom_keyword}} /
Glomerulonephritis / Immunoglobulins / Dexamethasone / Proliferative glomerulonephritis / Lenalidomide / Treatment outcome / Drug-related adverse reactions {{custom_keyword}} /
杨克魁 , {{custom_editor}}
表1 根据eGFR水平调整来那度胺剂量 |
| eGFR水平 | 来那度胺 | 地塞米松（第1、8、15、22天） |
|---|---|---|
| eGFR≥60 | 25 mg/d | 40 mg |
| 30≤eGFR<60 | 10 mg/d | 40 mg |
| eGFR<30 | 7.5 mg/d | 40 mg |
| 注：eGFR：估算的肾小球滤过率，单位为ml·min-1·(1.73 m2)-1 |
表2 6例伴单克隆免疫球蛋白沉积的增生性肾小球肾炎患者的一般资料 |
| 项目 | 患者1 | 患者2 | 患者3 | 患者4 | 患者5 | 患者6 |
|---|---|---|---|---|---|---|
| 性别 | 男 | 男 | 男 | 男 | 女 | 女 |
| 确诊年龄(岁) | 40 | 62 | 51 | 61 | 48 | 38 |
| 肾脏沉积类型 | IgG3-κ | IgG3-κ | IgG3-κ | IgG3-κ | IgG3-κ | IgG3-κ |
| Scr(μmol/L) | 152.9 | 108.7 | 129.1 | 289.1 | 107.8 | 70.7 |
| ALB (g/L) | 36.4 | 37.3 | 32.7 | 27.1 | 22.4 | 37.5 |
| eGFR | 49 | 63 | 65 | 19 | 62 | 93 |
| 尿蛋白量 (g/24 h) | 4.31 | 2.44 | 14.57 | 11.22 | 14.46 | 1.27 |
| 血清C3(g/L) | 0.881 | 0.765 | 1.070 | 0.500 | 0.993 | 0.894 |
| 血清C4(g/L) | 0.129 | 0.264 | 0.215 | 0.242 | 0.187 | 0.219 |
| 血清游离κ(mg/L) | 14.1 | 25.4 | 20.1 | 66.2 | 23.8 | 21.8 |
| 血清游离λ(mg/L) | 13.5 | 36.2 | 32.5 | 74.0 | 48.2 | 39.8 |
| 血清游离κ/λ比值 | 1.04 | 0.70 | 0.62 | 0.89 | 0.49 | 0.55 |
| 血M蛋白 | - | - | - | - | - | IgG-κ |
| 单克隆浆细胞(%) | 0.7 | - | 0.5 | - | - | - |
| 注：Scr：血肌酐；ALB：血白蛋白；eGFR：估算的肾小球滤过率，单位为ml·min-1·(1.73 m2)-1；-：阴性 |
表3 6例伴单克隆免疫球蛋白沉积的增生性肾小球肾炎患者的肾脏病理表现 |
| 项目 | 患者1 | 患者2 | 患者3 | 患者4 | 患者5 | 患者6 |
|---|---|---|---|---|---|---|
| IgG | 2+ | 1+ | 1+ | 3+ | 2+ | 3+ |
| IgG亚型 | IgG3(2+) | IgG3(2+) | IgG3(2+) | IgG3(2+) | IgG3(2+) | IgG3(2+) |
| κ | 2+ | 2+ | 1+ | 3+ | 2+ | 2+ |
| λ | - | ± | - | 1+ | - | ± |
| 病理类型 | MPGN | MPGN | MPGN | MPGN | MPGN | MPGN |
| 新月体比例(%) | 10.8 | 0 | 0 | 13.3 | 0 | 6.1 |
| 硬化球比例(%) | 18.9 | 62.9 | 0 | 60.0 | 30.3 | 9.1 |
| 节段硬化比例(%) | 2.7 | 0 | 0 | 13.3 | 0 | 3.0 |
| 肾间质纤维化 | ± | 1+ | 1+ | ± | ± | 1+ |
| 注：MPGN：膜增生性肾小球肾炎 |
表4 6例伴单克隆免疫球蛋白沉积的增生性肾小球肾炎患者治疗方案疗效 |
| 项目 | 患者1 | 患者2 | 患者3 | 患者4 | 患者5 | 患者6 |
|---|---|---|---|---|---|---|
| 初始治疗方案 | LD | LD | LD | P+Tw | BD | TD |
| 更换原因 | 无效 | 停药复发 | 四肢麻木 | |||
| 目前治疗方案 | LD | LD | LD | LD | LD | LD |
| 来那度胺治疗剂量(mg/d） | 10.0 | 25.0 | 25.0 | 7.5 | 25.0 | 25.0 |
| 末次随访肾脏缓解 | CR | CR | NR | CR→PR | PR→PD | PD |
| 开始缓解时间(月） | 6 | 5 | 3 | 6 |
| 注：LD：来那度胺+地塞米松；P+Tw：泼尼松+雷公藤；BD：硼替佐米+地塞米松；CR：肾脏完全缓解；PR：肾脏部分缓解；NR：肾脏无效；PD：肾脏进展 |
表5 6例患者治疗期间出现的不良反应（例） |
| 不良反应 | 1级 | 2级 | 3级 | 4级 | 总计 |
|---|---|---|---|---|---|
| 贫血 | - | 1 | 3 | 1 | 5 |
| 中性粒细胞减少 | 1 | 1 | 1 | 1 | 4 |
| 血小板减少 | - | - | - | 1 | 1 |
| 血肌酐一过性升高 | 4 | - | - | - | 4 |
| 皮肤干燥、瘙痒 | - | 2 | - | - | 2 |
| 皮肤瘀斑 | 1 | - | - | - | 1 |
| 皮肤色素沉着 | 1 | - | - | - | 1 |
| 黑痣 | 1 | - | - | - | 1 |
| 乏力 | 3 | - | - | - | 3 |
| 手抖 | 2 | - | - | - | 2 |
| 四肢麻木感 | 1 | - | - | - | 1 |
| 上呼吸道感染感染 | - | 1 | - | - | 1 |
| 关节不适 | 1 | - | - | - | 1 |
| 恶心、纳差 | 1 | - | - | - | 1 |
| [1] |
Renal disease related to the deposition of monoclonal immunoglobulins containing both heavy and light chains can occur in type 1 cryoglobulinemia, Randall type light and heavy chain deposition disease (LHCDD), and immunotactoid glomerulonephritis. We report a novel phenotype of glomerular injury that does not conform to any of the previously described patterns of glomerular involvement by monoclonal gammopathy.Ten cases of unclassifiable proliferative glomerulonephritis manifesting glomerular monoclonal immunoglobulin G (IgG) deposits were identified retrospectively from the archives of the Renal Pathology Laboratory of Columbia University over the past 3 years (biopsy incidence 0.21%).The monoclonal immunoglobulins formed granular electron dense deposits in mesangial, subendothelial, and subepithelial sites, mimicking ordinary immune complex-mediated glomerulonephritis and producing a diffuse endocapillary proliferative or membranoproliferative glomerulonephritis. However, by immunofluorescence, the deposits were monoclonal, staining for a single light chain isotype and a single gamma subclass (including two IgG1kappa, one IgG1lambda, one IgG2lambda, four IgG3kappa, and one IgG3lambda). All cases stained for the three constant domains of the gamma heavy chain (CH1, CH2, and CH3), suggesting deposition of a nondeleted immunoglobulin molecule. Tissue fixation of complement was observed in 90% of cases, and 40% of patients had hypocomplementemia. Clinical presentations included renal insufficiency in 80% (mean serum creatinine 2.8 mg/dL, range 0.9 to 8.0), proteinuria in 100% (mean urine protein 5.8 g/day; range 1.9 to 13.0), nephrotic syndrome in 44%, and microhematuria in 60%. A monoclonal serum protein with the same heavy and light chain isotype as that of the glomerular deposits was identified in 50% of cases (including three IgGkappa and two IgGlambda); however, no patient had clinical or laboratory features of type 1 cryoglobulinemia. No patient had overt myeloma or lymphoma at presentation or over the course of follow-up (mean 12 months).Glomerular deposition of monoclonal IgG can produce a proliferative glomerulonephritis that mimics immune-complex glomerulonephritis by light and electron microscopy. Proper recognition of this entity requires confirmation of monoclonality by staining for the gamma heavy chain subclasses.
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Monoclonal gammopathy of renal significance (MGRS) regroups renal disorders caused by a monoclonal immunoglobulin without overt hematological malignancy. MGRS includes tubular disorders, glomerular disorders with organized deposits, and glomerular disorders with non-organized deposits, such as proliferative glomerulonephritis with monoclonal IgG deposits. Since glomerular involvement related to monotypic IgA deposits is poorly described we performed retrospective analysis and defined clinico-biological characteristics, renal pathology, and outcome in 19 referred patients. This analysis allowed distinction between 2 types of glomerulopathies, α-heavy chain deposition disease (5 patients) and glomerulonephritis with monotypic IgA deposits (14 patients) suggestive of IgA-proliferative glomerulonephritis with monoclonal immunoglobulin deposits in 12 cases. Clinicopathologic characteristics of α-heavy chain deposition disease resemble those of the γ-heavy chain disease, except for a higher frequency of extra-capillary proliferation and extra-renal involvement. IgA-proliferative glomerulonephritis with monoclonal immunoglobulin deposits should be differentiated from diseases with polytypic IgA deposits, given distinct clinical, histological, and pathophysiological features. Similarly to IgG-proliferative glomerulonephritis with monoclonal immunoglobulin deposits, overt hematological malignancy was infrequent, but sensitive serum and bone marrow studies revealed a subtle plasma cell proliferation in most patients with IgA-proliferative glomerulonephritis with monoclonal immunoglobulin deposits. Anti-myeloma agents appeared to favorably influence renal prognosis. Thus, potential progression towards symptomatic IgA multiple myeloma suggests that careful hematological follow-up is mandatory. This series expands the spectrum of renal disease in MGRS.Copyright © 2016 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.
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单克隆免疫球蛋白及其不同成分主要由克隆性增殖B 细胞产生，可通过直接或间接损伤机制引起肾小球疾病。直接损伤机制包括增生性肾小球肾炎伴单克隆IgG 沉积、纤维性肾小球肾炎和免疫管状肾小球病，间接机制包括C3 肾病和血栓性微血管病。文章主要介绍这几类疾病的临床病理表现和治疗的最新进展。
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曾彩虹, 陈浩, 范芸, 等. 单克隆IgG沉积的增生性肾小球肾炎[J]. 肾脏病与透析肾移植杂志, 2012, 21(5): 401-407. DOI: 10.3969/j.issn.1006-298X.2012.05.001.
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Monoclonal gammopathy of renal significance (MGRS) regroups all renal disorders caused by a monoclonal immunoglobulin (MIg) secreted by a nonmalignant B-cell clone. By definition, patients with MGRS do not meet the criteria for overt multiple myeloma/B-cell proliferation, and the hematologic disorder is generally consistent with monoclonal gammopathy of undetermined significance (MGUS). However, MGRS is associated with high morbidity due to the severity of renal and sometimes systemic lesions induced by the MIg. Early recognition is crucial, as suppression of MIg secretion by chemotherapy often improves outcomes. The spectrum of renal diseases in MGRS is wide, including old entities such as AL amyloidosis and newly described lesions, particularly proliferative glomerulonephritis with monoclonal Ig deposits and C3 glomerulopathy with monoclonal gammopathy. Kidney biopsy is indicated in most cases to determine the exact lesion associated with MGRS and evaluate its severity. Diagnosis requires integration of morphologic alterations by light microscopy, immunofluorescence (IF), electron microscopy, and in some cases by IF staining for Ig isotypes, immunoelectron microscopy, and proteomic analysis. Complete hematologic workup with serum and urine protein electrophoresis, immunofixation, and serum-free light-chain assay is required. This review addresses the pathologic and clinical features of MGRS lesions, indications of renal biopsy, and a proposed algorithm for the hematologic workup.
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Multiple myeloma is the most frequent monoclonal gammopathy to involve the kidney; however, a growing number of kidney diseases associated with other monoclonal gammopathies are being recognized. Although many histopathologic patterns exist, they are all distinguished by the monoclonal immunoglobulin (or component) deposits. The hematologic disorder in these patients is more consistent with monoclonal gammopathy of undetermined significance (MGUS) than with multiple myeloma. Unfortunately, due to the limitations of the current diagnostic schema, they are frequently diagnosed as MGUS. Because treatment is not recommended for MGUS, appropriate therapy is commonly withheld. In addition to end-stage renal disease, the persistence of the monoclonal gammopathy is associated with high rates of recurrence after kidney transplantation. Preservation and restoration of kidney function are possible with successful treatment targeting the responsible clone. Achievement of hematologic complete response has been shown to prevent recurrence after kidney transplantation. There is a need for a term that properly conveys the pathologic nature of these diseases. We think the term monoclonal gammopathy of renal significance is most helpful to indicate a causal relationship between the monoclonal gammopathy and the renal damage and because the significance of the monoclonal gammopathy is no longer undetermined.
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李娟, 张明超, 梁丹丹, 等. 232例膜增生性肾小球肾炎的重新评估[J]. 肾脏病与透析肾移植杂志, 2018, 27(4): 301-305,325. DOI: 10.3969/j.issn.1006-298X.2018.04.001.
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Dysproteinemias that result in monoclonal glomerular deposits of IgG are relatively uncommon. Here, we report the largest series of proliferative glomerulonephritis with monoclonal IgG deposits, a form of renal involvement by monoclonal gammopathy that mimics immune-complex glomerulonephritis. We retrospectively identified 37 patients, most of whom were white (81%), female (62%), or older than 50 yr (65%). At presentation, 49% had nephrotic syndrome, 68% had renal insufficiency, and 77% had hematuria. In 30% of the patients, we identified a monoclonal serum protein with the same heavy- and light-chain isotypes as the glomerular deposits (mostly IgG1 or IgG2), but only one patient had myeloma. Histologic patterns were predominantly membranoproliferative (57%) or endocapillary proliferative (35%) with membranous features. Electron microscopy revealed granular, nonorganized deposits, and immunofluorescence demonstrated glomerular deposits that stained for a single light-chain isotype and a single heavy-chain subtype, most commonly IgG3kappa (53%). During an average of 30.3 mo of follow-up for 32 patients with available data, 38% had complete or partial recovery, 38% had persistent renal dysfunction, and 22% progressed to ESRD. Correlates of ESRD on univariate analysis were higher creatinine at biopsy, percentage of glomerulosclerosis, and degree of interstitial fibrosis but not immunomodulatory treatment or presence of a monoclonal spike. On multivariate analysis, higher percentage of glomerulosclerosis was the only independent predictor of ESRD. Only one patient lacking a monoclonal spike at presentation subsequently developed a monoclonal spike and no patient with a monoclonal spike at presentation subsequently developed a hematologic malignancy. We conclude that proliferative glomerulonephritis with monoclonal IgG deposits does not seem to be a precursor of myeloma in the vast majority of patients.
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The optimal treatment for the monoclonal gammopathies of renal significance is not known, but there is consensus among experts that treatment should be specific for the underlying clone. The majority of patients with proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID) do not have an identifiable clone, and prior studies have found poor renal outcomes for patients with PGNMID treated with a variety of regimens. Here we present a retrospective case series of 19 patients with PGNMID with a more uniform, clone-directed approach. A circulating paraprotein was detected in 37% of patients, and the overall clone detection rate was 32%. Treatment was directed at the underlying clone or, for patients without a detectable clone, empirically prescribed to target the hypothesized underlying clone. Of the 16 patients who underwent treatment, the overall renal response rate was 88%, and 38% of patients experienced complete renal response (proteinuria reduction to under 0.5 gm/24 hours) with initial treatment. All patients were End Stage Renal Disease-free at last follow-up (median 693 days after diagnosis), and treatment was well tolerated. Thus, a clone-directed approach may lead to novel, targeted treatment strategies that could significantly improve outcomes for patients with PGNMID.Copyright © 2018 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.
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周伟, 李娟, 黄湘华, 等. 沙利度胺联合地塞米松治疗伴单克隆IgG沉积的增生性肾小球肾炎[J]. 肾脏病与透析肾移植杂志, 2018, 27(2): 101-105,112. DOI: 10.3969/j.issn.1006-298X.2018.02.001.
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李新, 郭彩虹, 黄仲夏. 来那度胺在多发性骨髓瘤治疗中的应用[J]. 临床药物治疗杂志, 2013, 11(5): 36-40. DOI: 10.3969/j.issn.1672-3384.2013.05.009.
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We present a pooled update of two large, multicenter MM-009 and MM-010 placebo-controlled randomized phase III trials that included 704 patients and assessed lenalidomide plus dexamethasone versus dexamethasone plus placebo in patients with relapsed/refractory multiple myeloma (MM). Patients in both studies were randomized to receive 25 mg daily oral lenalidomide or identical placebo, plus 40 mg oral dexamethasone. In this pooled analysis, using data up to unblinding (June 2005 for MM-009 and August 2005 for MM-010), treatment with lenalidomide plus dexamethasone significantly improved overall response (60.6 vs 21.9%, P<0.001), complete response rate (15.0 vs 2.0%, P<0.001), time to progression (median of 13.4 vs 4.6 months, P<0.001) and duration of response (median of 15.8 months vs 7 months, P<0.001) compared with dexamethasone-placebo. At a median follow-up of 48 months for surviving patients, using data up to July 2008, a significant benefit in overall survival (median of 38.0 vs 31.6 months, P=0.045) was retained despite 47.6% of patients who were randomized to dexamethasone-placebo receiving lenalidomide-based treatment after disease progression or study unblinding. Low beta(2)-microglobulin and low bone marrow plasmacytosis were associated with longer survival. In conclusion, these data confirm the significant response and survival benefit with lenalidomide and dexamethasone.
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所有作者均声明不存在利益冲突
样本来自国家肾脏疾病临床研究中心生物样本库、江苏省重大疾病生物资源样本库
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