目的：利妥昔单抗（Rituximab，RTX）是特发性膜性肾病（Idiopathic Membranous Nephropathy，IMN）的一线治疗手段之一。既往研究显示肥胖可能会加重IMN患者的24h尿蛋白水平和肾脏病理损伤。本研究拟观察合并肥胖的IMN患者接受RTX治疗的效果。

方法：本研究为单中心回顾性队列研究。纳入自2017年12月至2023年12月在我院曾接受RTX治疗的IMN患者。纳入标准如下：①书面签署知情同意书；②IMN的诊断经肾活检病理证实或存在血清学抗PLA2R抗体阳性；③肾脏方面符合肾病水平蛋白尿（尿蛋白≥3.5g/天）；④接受利妥昔单抗方案为第0天1g/次，第15天如CD19阳性B细胞计数>5/mm³, 予利妥昔单抗1g；如CD19阳性B细胞计数<5/mm³,不再应用利妥昔单抗；⑤自首次应用利妥昔单抗治疗后随访时间至少12个月。排除标准如下：①孕妇及哺乳期女性；②肾脏活检病理证实IMN合并肥胖相关肾病；③IMN合并重症感染；④IMN合并急性肾损伤。其中合并肥胖（身体质量指数即BMI大于或等于28kg/㎡）的患者为肥胖组，对照组为非肥胖患者。观察结局为RTX应用12个月后尿蛋白及血白蛋白的缓解情况，包括完全缓解（Complete Remission, CR，即尿蛋白小于0.3g/d且血清白蛋白水平正常），部分缓解（Patial Remission，PR，即24h尿蛋白水平较用药前下降大于或等于50%且血清白蛋白大于或等于30g/L）。上述条件均不满足的情况定义为未缓解（Non-Remission，NR）。采用单模型法Logistic回归分析控制混杂偏倚研究肥胖对观察结局的效应。

结果：本研究共纳入223例患者，肥胖组74例（BMI 32.04±3.82kg/㎡），对照组149例（BMI 24.60±2.17kg/㎡）。肥胖组中45例依靠肾活检病理诊断，其中6例（13.3%）可见膜性肾病合并肾小球肥大的表现。相较于对照组，肥胖组患者相对更年轻(平均年龄45.9±14.9岁vs. 55.3±12.9岁, p<0.001)，而性别比例大致相当(男 70.27% vs. 63.76%,p=0.334)；肥胖组患者用药前24h尿蛋白水平相对更高(10.18±5.35g/d vs. 7.51±3.52g/d, p<0.001)，但经过体重校正即24h尿蛋白/体重（g/kg）则不存在显著的组间差异（0.11±0.06 vs. 0.11±0.05，p=0.637），两组的血白蛋白水平(25.62±4.98g/L vs. 25.48±4.71g/L, p=0.832)及血肌酐水平(100.73±49.79μmol/L vs. 93.25±39.10μmol/L, p=0.222)大致相当；两组的肾脏病理梅奥慢性评分大致相当（2.13±1.77 vs. 2.19±1.41），即两组肾脏病理慢性病变程度大致相当；两组的抗PLA2R抗体水平未见显著差异(79.15 (IQR 35.25, 135.00) U/L vs. 90.00(IQR 36.90，244.00) U/L, P=0.270)。肥胖组患者治疗前血CD19⁺B细胞计数与对照组大致相当（253.0(IQR 144.0, 372.0)/μL vs.195.5(IQR 111.5, 347.3)/μL, P=0.103)。两组中初治患者的比例大致相当（25.68% vs. 33.56%，p=0.231）；合并高血压（64.86% vs. 57.72%，p=0.306）及糖尿病（28.38% vs. 30.20%，p=0.779）的比例也大致相当。两组患者除接受RTX治疗，其中一些还联合糖皮质激素和（或）传统免疫抑制剂（烷化剂、钙调磷酸酶抑制剂等）的治疗，相较于对照组，较少的肥胖组患者接受RTX单药治疗(p=0.012)。肥胖组中10例患者(13.51%)获得完全缓解，42例患者(56.76%)获得部分缓解。对照组中30例患者(20.13%)获得完全缓解，73例患者(48.99%)获得部分缓解。肥胖组和对照组的完全缓解率、部分缓解率和未缓解率无显著差异(p=0.425)，整体缓解率（完全缓解率与部分缓解率之和）亦不存在显著差异(p=0.861)。单模型法Logistic回归控制混杂偏倚后，肥胖与完全缓解率(单因素p=0.228，多因素p=0.266)及整体缓解率(单因素p=0.861,多因素p=0.860)均无显著相关。

结论：本研究条件下，肥胖与IMN患者完全缓解或者整体缓解均无显著相关性；鉴于本单中心回顾性研究存在局限性，结论尚需大型前瞻性研究证实。

Objectives: Rituximab (RTX) is one of the first-line treatment for Idiopathic Membranous Nephropathy (IMN). Previous studies have shown that obesity may aggravate urinary protein levels in patients with IMN. The aim is to observe the effect of RTX on IMN patients with obesity.

Methods: This study was a single-center retrospective cohort study. Patients with IMN who received RTX treatment at our hospital from December 2017 to December 2023 were included. The inclusion criteria were as follows: ① signed informed consent in person; ② diagnosis of IMN confirmed by renal biopsy pathology or positive serum anti-PLA2R antibody; ③ nephrotic-level proteinuria (urinary protein ≥ 3.5g/day); ④ received the rituximab regimen of 1g on day 0 and 1g on day 15 if CD19-positive B cell count was >5/mm3, otherwise no further rituximab was administered; ⑤ followed up for at least 12 months after the first application of rituximab. The exclusion criteria are as follows: ① Pregnant and lactating women; ② IMN combined with obesity-related nephropathy confirmed by renal biopsy pathology; ③ IMN combined with severe infection; ④ IMN combined with acute kidney injury. Among them, patients with obesity (BMI ≥ 28kg/㎡) were classified as the obesity group, and the non-obese patients were classified as the control group. The observation outcome was the remission of urinary protein and serum albumin 12 months after the first RTX application, including complete remission (CR, urinary protein < 0.3g/d and normal serum albumin level), partial remission (PR, 24-hour urinary protein level decreased by ≥ 50% compared to before medication and serum albumin ≥ 30g/L). The situation where none of the above conditions were met was defined as non-remission (NR). Logistic regression analysis with a single model was used to control for confounding bias and study the effect of obesity on the outcome of interest.

Results: A total of 223 patients were included in this study, with 74 in the obesity group (BMI 32.04 ± 3.82kg/㎡) and 149 in the control group (BMI 24.60 ± 2.17kg/㎡). Among the obesity group, 45 cases were diagnosed by renal biopsy pathology, and 6 cases (13.3%) showed membranous nephropathy combined with glomerular hypertrophy. Compared with the control group, patients in the obesity group were relatively younger (average age 45.9 ± 14.9 years vs. 55.3 ± 12.9 years, p < 0.001), while the gender ratio was roughly the same (male 70.27% vs. 63.76%, p = 0.334); the 24-hour urinary protein level before medication was relatively higher in the obesity group (10.18 ± 5.35g/d vs. 7.51 ± 3.52g/d, p < 0.001), but after adjusting for body weight, i.e., 24-hour urinary protein/body weight (g/kg), there was no significant difference between the groups (0.11 ± 0.06 vs. 0.11 ± 0.05, p = 0.637), and the serum albumin levels (25.62 ± 4.98g/L vs. 25.48 ± 4.71g/L, p = 0.832) and serum creatinine levels (100.73 ± 49.79μmol/L vs. 93.25 ± 39.10μmol/L, p = 0.222) were roughly the same in both groups; the Mayo chronic score of renal pathology was roughly the same in both groups (2.13 ± 1.77 vs. 2.19 ± 1.41), indicating that the degree of chronic lesions in renal pathology was roughly the same in both groups; there was no significant difference in the anti-PLA2R antibody levels between the two groups (79.15 (IQR 35.25, 135.00) U/L vs. 90.00 (IQR 36.90, 244.00) U/L, P = 0.270). Before treatment, the count of CD19+ B cells in the obese group was comparable to that in the control group (253.0 (IQR 144.0, 372.0)/μL vs. 195.5 (IQR 111.5, 347.3)/μL, P = 0.103). The proportion of patients who were newly diagnosed was similar in both groups (25.68% vs. 33.56%, p = 0.231); the proportion of patients with hypertension (64.86% vs. 57.72%, p = 0.306) or diabetes (28.38% vs. 30.20%, p = 0.779) was also comparable. Besides receiving RTX treatment, some patients in both groups were treated with glucocorticoids and/or conventional immunosuppressants (cyclophosphamide, calcineurin inhibitors, and mycophenolate mofetil). Compared with the control group, fewer patients in the obese group received RTX monotherapy (p = 0.012). In the obese group, 10 patients (13.51%) achieved complete remission, and 42 patients (56.76%) achieved partial remission. In the control group, 30 patients (20.13%) achieved complete remission, and 73 patients (48.99%) achieved partial remission. There was no significant difference in the complete remission rate, partial remission rate, and non-remission rate between the obese group and the control group (p = 0.425), and there was also no significant difference in the overall remission rate (the sum of the complete remission rate and the partial remission rate) (p = 0.861). After controlling for confounding bias using the single model method of Logistic regression, obesity was not significantly associated with the complete remission rate (univariate p = 0.228, multivariate p = 0.266) or the overall remission rate (univariate p = 0.861, multivariate p = 0.860).

Conclusion: Under the conditions of this study, obesity was not significantly associated with complete remission or overall remission in IMN patients. Given the limitations of this single-center retrospective study, the conclusion needs to be confirmed by large-scale prospective studies.