切换至 "中华医学电子期刊资源库"
高级检索
中华移植杂志(电子版)

中华移植杂志(电子版) ›› 2024, Vol. 18 ›› Issue (03) : 165 -170. doi: 10.3877/cma.j.issn.1674-3903.2024.03.004

论著

内皮粘蛋白抗体与肾移植术后抗体介导排斥反应和移植肾预后的研究
尚丽红1, 王志华1, 张文艳1, 朱琳茹1, 周华1,†()   
  1. 1. 030012　太原，山西省第二人民医院肾移植中心实验室
  • 收稿日期:2024-04-23 出版日期:2024-06-25
  • 通信作者: 周华
  • 基金资助:
    山西省卫生健康委员会重点攻关专项资助项目(2021XM24)

Pre-transplantation endomucin antibody is independently associated with ABMR and affects the prognosis of renal allografts

Lihong Shang1, Zhihua Wang1, Wenyan Zhang1, Linru Zhu1, Hua Zhou1,†()   

  1. 1. Laboratory of kidney transplantation center of Shangxi Second People′s Hospital, Taiyuan 030012, China
  • Received:2024-04-23 Published:2024-06-25
  • Corresponding author: Hua Zhou
全文 ( ) 下载PDF ( ) 导出引用
引用本文：

尚丽红, 王志华, 张文艳, 朱琳茹, 周华. 内皮粘蛋白抗体与肾移植术后抗体介导排斥反应和移植肾预后的研究[J]. 中华移植杂志(电子版), 2024, 18(03): 165-170.

Lihong Shang, Zhihua Wang, Wenyan Zhang, Linru Zhu, Hua Zhou. Pre-transplantation endomucin antibody is independently associated with ABMR and affects the prognosis of renal allografts[J]. Chinese Journal of Transplantation(Electronic Edition), 2024, 18(03): 165-170.

目的

探讨肾移植前内皮粘蛋白(EMCN)抗体与抗体介导排斥反应(ABMR)以及移植物预后的相关性。

方法

选择2021～2022年在山西省第二人民医院进行移植肾穿刺活检诊断为ABMR或高度怀疑为ABMR的受者作为病例组，以2022年行肾移植且移植肾功能稳定的受者作为对照组。最终病例组纳入18例受者，对照组纳入37例受者；另有9例受者移植肾穿刺活检诊断为非ABMR，纳入移植物预后分析。比较两组移植前EMCN抗体水平差异，利用受试者工作特征(ROC)曲线确定移植前EMCN抗体预测术后ABMR的最佳截断值，分析移植前EMCN抗体对移植肾存活和功能恶化的影响，通过单因素和多因素Cox比例风险模型分析ABMR发生的危险因素。

结果

病例组和对照组受者移植前EMCN抗体检测校正值分别为(0.87±0.64)和(0.41±0.31)，差异有统计学意义(t＝2.85，P<0.05)。移植前EMCN抗体水平对ABMR发生具有预测作用，ROC曲线下面积为0.7679(95%CI 0.64～0.90，P<0.05)。根据约登指数(0.41)确定截断值为0.4276，敏感度为70.59%，特异度为70.27%。移植前EMCN阳性受者和EMCN阴性受者移植肾存活率无统计学意义差异(P>0.05)，EMCN阳性受者经移植肾穿刺活检确诊或高度怀疑ABMR的比例高于EMCN阴性受者(41.4%和14.3%)，移植肾功能恶化比例亦高于EMCN阴性受者(48.3%和11.4%)(P均<0.05)。肾移植前EMCN抗体水平和HLA-DSA是术后发生ABMR的独立危险因素(HR＝5.50和5.56，95%CI 1.89～16.06和1.08～28.63)，供肾冷缺血时间越短ABMR风险越低(HR＝0.41，95%CI 0.25～0.70)。

结论

肾移植前EMCN抗体水平与术后ABMR和移植物功能恶化相关，对ABMR有预测作用，是ABMR发生的独立危险因素。

关键词: 肾移植, 内皮粘蛋白抗体, 抗体介导排斥反应, 人类白细胞抗原, 供者特异性抗体, 存活率
Objective

To investigate the association between pre-transplantation endomucin (EMCN) antibodies and antibody-mediated rejection (ABMR) and graft prognosis.

Methods

Patients diagnosed with ABMR by renal allograft biopsy in the Shangxi Second People′s Hospital from 2021 to 2022 were selected as the case group (n=18), and recipients who underwent renal transplantation in 2022 and had stable renal allograft function were selected as the control group (n=37). Another 9 recipients were diagnosed as non-ABMR by renal allograft biopsy and included in the graft prognosis analysis. The differences of EMCN antibodies before transplantation between the two groups were compared, the optimal cutoff value of EMCN antibodies before transplantation was determined using receiver operating characteristic (ROC) curves. The effect of EMCN antibodies before transplantation on renal allograft survival and functional deterioration was analyzed, and the risk factors for the occurrence of ABMR were analyzed by univariate and multivariate Cox proportional hazards models.

Results

The corrected values of EMCN antibody before transplantation were (0.87±0.64) and (0.41±0.31) in the case group and the control group, respectively, and the difference was statistically significant (t=2.85, P<0.05). Pre-transplant EMCN antibody levels were predictive of ABMR development, with an area under the ROC curve of 0.7679 (95%CI 0.64-0.90, P<0.05). The cutoff value was determined to be 0.4276, with a sensitivity of 70.59% and a specificity of 70.27%. There was no significant difference in the survival rate of transplanted kidneys between EMCN-positive recipients and EMCN-negative recipients before transplantation (P>0.05). The proportion of EMCN-positive recipients with confirmed or highly suspected ABMR by renal allograft biopsy was higher than that of EMCN-negative recipients (41.4% and 14.3%), and the proportion of deteriorated renal allograft function was also higher than that of EMCN-negative recipients (48.3% and 11.4%) (P<0.05). EMCN antibody and HLA-DSA before renal transplantation were independent risk factors for ABMR after surgery (HR = 5.50 and 5.56, 95%CI 1.89-16.06 and 1.08-28.63), and the shorter the cold ischemia time of the donor kidney, the lower the risk of ABMR (HR=0.41, 95%CI 0.25-0.70).

Conclusion

Pre-transplantation EMCN antibody is associated with ABMR and graft function deterioration after renal transplantation, and has a predictive effect on ABMR, and is an independent risk factor for the ABMR.

Key words: Kidney transplantation, Endomucin antibody, Antibody-mediated rejection, Human leukocyte antigen, Donor specific antibody, Survival rate
表1 两组肾移植受者基本特征
特征 病例组(n＝18) 对照组(n＝37) t/χ2/Z值 P值
受者年龄(岁，±s) 37±11 38±13 －0.43 >0.05
受者性别(例，男/女) 14/4 24/13 0.95 >0.05
供者年龄(岁，±s) 51±13 47±15 0.84 >0.05
供者性别(例，男/女) 14/4 34/3 2.17 >0.05
供肾类型(例)     4.27  
公民逝世后器官捐献 16 37   >0.05
亲属活体捐献 2 0   >0.05
供肾冷缺血时间(h，±s) 5.25±1.87 5.97±0.16 －1.55 <0.05
原发病(例)     5.87 >0.05
慢性肾小球肾炎 11 27    
IgA肾病 1 4    
移植肾衰竭 2 2    
高血压肾病 0 1    
多囊肾 1 0    
膜性肾病 0 1    
其他 3 2    
免疫诱导药物(例)        
IL-2受体拮抗剂 9 19 0.01 >0.05
抗胸腺细胞球蛋白 11 35 9.92 <0.05
免疫抑制剂(例)     4.27  
环孢素 2 0   >0.05
他克莫司 16 37   >0.05
非HLA抗体检测距离移植时间[月，M(Min-Max)] 2.5(0～20) 3(0～19) 0.75 >0.05
图1 肾移植前EMCN抗体预测术后ABMR的受试者工作特征曲线注：EMCN.内皮粘蛋白；ABMR.抗体介导排斥反应；AUC.曲线下面积
图2 肾移植前EMCN抗体阳性组和阴性组受者生存曲线注：EMCN.内皮粘蛋白
表2 肾移植前EMCN抗体阳性组和阴性组受者移植肾存活和功能情况
特征 EMCN阳性组(n＝29) EMCN阴性组(n＝35) t/χ2/Z值 P值
移植肾穿刺活检确诊或高度怀疑ABMR[例(%)] 12(41.4) 5(14.3) 5.97 <0.05
移植肾失功[例(%)] 5(17.2) 4(11.4) 0.44 >0.05
受者死亡[例(%)] 3(10.3) 2(5.7) 0.47 >0.05
术后随访时间[月，M(Min-Max)] 15(1～52) 15(2～31) 1.12 >0.05
HLA-DSA阳性 7(24.1) 4(11.4) 1.80 >0.05
基线eGFR[mL·min－1·(1.73 m2)－1，±s] 72.0±29.8 61.6±23.0 1.14 >0.05
术后移植物功能恶化[例(%)] 14(48.3) 4(11.4) 10.65 <0.05
移植肾功能恶化距离术后时间[月，M(Min-Max)] 11(1～25) 12(1～30) 0.09 >0.05
表3 肾移植术后发生ABMR危险因素的Cox比例风险回归分析(n＝55)
变量 单因素分析 多因素分析
HR 95%CI P值 HR 95%CI P值
肾移植前EMCN抗体水平 5.18 2.29～11.74 <0.05 5.50 1.89～16.06 <0.05
HLA-DSA 4.34 1.50～12.58 <0.05 5.56 1.08～28.63 <0.05
移植时受者年龄(岁) 0.99 0.96～1.04 >0.05 1.03 0.96～1.09 >0.05
受者性别 1.55 0.50～4.74 >0.05 0.79 0.18～3.51 >0.05
使用ATG进行免疫诱导治疗 0.33 0.12～0.97 <0.05 0.69 0.15～3.11 >0.05
供肾冷缺血时间(h) 0.68 0.52～0.90 <0.05 0.41 0.25～0.70 <0.05
1
Senev A, Coemans M, Lerut E, et al. Histological picture of antibody-mediated rejection without donor-specific anti-HLA antibodies: clinical presentation and implications for outcome[J]. Am J Transplant, 2019，19(3)：763-780.
2
Sablik KA, Clahsen-van Groningen MC, Looman CWN, et al. Chronic-active antibody-mediated rejection with or without donor-specific antibodies has similar histomorphology and clinical outcome - a retrospective study[J]. Transpl Int, 2018，31(8)：900-908.
3
Delville M, Lamarthée B, Pagie S, et al. Early acute microvascular kidney transplant rejection in the absence of anti-HLA antibodies is associated with preformed IgG antibodies against diverse glomerular endothelial cell antigens[J]. J Am Soc Nephrol, 2019，30(4)：692-709.
4
Callemeyn J, Lerut E, de Loor H, et al. Transcriptional changes in kidney allografts with histology of antibody-mediated rejection without anti-HLA donor-specific antibodies[J]. J Am Soc Nephrol, 2020，31(9)：2168-2183.
5
Sorohan BM, Baston C, Tacu D, et al. Non-HLA antibodies in kidney transplantation: immunity and genetic insights[J]. Biomedicines, 2022，10(7)：1506.
6
Park-Windhol C, Ng YS, Yang J, et al. Endomucin inhibits VEGF-induced endothelial cell migration, growth, and morphogenesis by modulating VEGFR2 signaling[J]. Sci Rep, 2017，7(1): 17138.
7
Butler CL, Hickey MJ, Jiang N, et al. Discovery of non-HLA antibodies associated with cardiac allograft rejection and development and validation of a non-HLA antigen multiplex panel: From bench to bedside[J]. Am J Transplant, 2020，20(10)：2768-2780.
8
Loupy A, Haas M, Roufosse C, et al. The Banff 2019 Kidney Meeting Report (I): Updates on and clarification of criteria for T cell- and antibody-mediated rejection[J]. Am J Transplant, 2020，20(9)：2318-2331.
9
Senev A, Ray B, Lerut E, et al. The pre-transplant non-HLA antibody burden associates with the development of histology of antibody-mediated rejection after kidney transplantation[J]. Front Immunol, 2022，13：809059.
10
Malheiro J, Tafulo S, Dias L, et al. Deleterious effect of anti-angiotensin Ⅱ type 1 receptor antibodies detected pretransplant on kidney graft outcomes is both proper and synergistic with donor-specific anti-HLA antibodies[J]. Nephrology (Carlton), 2019，24(3)：347-356.
11
Betjes MGH, Roelen DL, van Agteren M, et al. Causes of kidney graft failure in a cohort of recipients with a very long-time follow-up after transplantation[J]. Front Med (Lausanne), 2022，9：842419.
12
Crespo M, Llinàs-Mallol L, Redondo-Pachón D, et al. Non-HLA antibodies and epitope mismatches in kidney transplant recipients with histological antibody-mediated rejection[J]. Front Immunol, 2021，12：703457.
13
Kamburova EG, Gruijters ML, Kardol-Hoefnagel T, et al. Antibodies against ARHGDIB are associated with long-term kidney graft loss[J]. Am J Transplant, 2019，19(12)：3335-3344.
14
Yu S, Huh HJ, Lee KW, et al. Pre-transplant angiotensin Ⅱ type 1 receptor antibodies and anti-endothelial cell antibodies predict graft function and allograft rejection in a low-risk kidney transplantation setting[J]. Ann Lab Med, 2020，40(5)：398-408.
15
Zhang Q, Reed EF. The importance of non-HLA antibodies in transplantation[J]. Nat Rev Nephrol, 2016，12(8)：484-495.
16
Butler CL, Valenzuela NM, Thomas KA, et al. Not all antibodies are created equal: factors that influence antibody mediated rejection[J]. J Immunol Res, 2017，2017：7903471.
17
尚丽红，武小桐，李宁，等. 非HLA抗体检测方法研究进展[J/CD]. 中华移植杂志：电子版，2024，18(1)：60-64.
18
Fichtner A, Süsal C, Höcker B, et al. Association of non-HLA antibodies against endothelial targets and donor-specific HLA antibodies with antibody-mediated rejection and graft function in pediatric kidney transplant recipients[J]. Pediatr Nephrol, 2021，36(8)：2473-2484.
19
Kubes P, Kerfoot SM. Leukocyte recruitment in the microcirculation: the rolling paradigm revisited[J]. News Physiol Sci, 2001，16：76-80.
20
Zahr A, Alcaide P, Yang J, et al. Endomucin prevents leukocyte-endothelial cell adhesion and has a critical role under resting and inflammatory conditions[J]. Nat Commun, 2016，7：10363.
21
Hu Z, Cano I, Saint-Geniez M, et al. EMCN knockout leads to increased monocyte infiltration in kidney and albuminuria in mice[J]. FASEB J, 2022, 36(S1): R2538.
[1] 王冰, 孙海宁, 于秀淳, 周珂, 翟凯, 苗族康. 膝骨关节炎的活动衬垫型单髁置换疗效与假体生存率[J]. 中华关节外科杂志(电子版), 2024, 18(03): 337-345.
[2] 张少华, 林爱齐, 张玉, 董晓云, 刘红英. HLA和IL基因多态性及其与复发性自然流产的相关性[J]. 中华妇幼临床医学杂志(电子版), 2024, 20(03): 251-259.
[3] 孙姚承, 汤建军, 张伟元, 刘传磊. 阳性淋巴结比和阳性淋巴结对数比对结直肠癌患者预后价值的研究[J]. 中华普通外科学文献(电子版), 2024, 18(03): 204-208.
[4] 陆婷, 陈浩, 王雪静, 谭若芸, 彭宇竹. 肾移植术后一年发生代谢综合征的危险因素分析[J]. 中华移植杂志(电子版), 2024, 18(02): 98-103.
[5] 郭明星, 徐烨, 徐菀佚, 赵莹, 刘冉佳, 潘晨, 崔向丽. 2017—2022年中国105家医院肾移植术后门诊受者免疫抑制剂用药分析[J]. 中华移植杂志(电子版), 2024, 18(02): 104-109.
[6] 尚丽红, 武小桐, 李宁, 石韶华, 王志华, 朱琳茹, 周华. 非HLA抗体检测方法研究进展[J]. 中华移植杂志(电子版), 2024, 18(01): 60-64.
[7] 张心怡, 吕军好, 陈大进. 2023年肾移植领域研究进展[J]. 中华移植杂志(电子版), 2024, 18(01): 7-11.
[8] 吴小山, 任桂灵, 朱杰东, 史天陆, 马葵芬. 肾移植受者围手术期霉酚酸暴露量及不良反应分析[J]. 中华移植杂志(电子版), 2024, 18(01): 17-21.
[9] 赵丽, 蔡瑞明, 赵纪强, 林民专, 陈志勇, 彭娟. 肾移植术后新发泌尿系统恶性肿瘤二例并文献复习[J]. 中华移植杂志(电子版), 2024, 18(01): 35-39.
[10] 陆婷, 姜巧玲, 孙黎, 王雪静. 加速康复外科在肾移植围手术期应用的研究进展[J]. 中华移植杂志(电子版), 2024, 18(01): 55-59.
[11] 刘路浩, 张鹏, 陈荣鑫, 郭予和, 尹威, 徐璐, 李光辉, 方佳丽, 马俊杰, 陈正. 奈玛特韦/利托那韦治疗肾移植术后重型新型冠状病毒肺炎的临床效果分析[J]. 中华移植杂志(电子版), 2023, 17(06): 349-353.
[12] 李晓宇, 许昕, 谌诚, 张萌, 韩文科, 林健. 肾移植受者新型冠状病毒感染合并肺炎支原体感染临床特点及诊疗分析[J]. 中华移植杂志(电子版), 2023, 17(06): 354-357.
[13] 中华医学会器官移植学分会, 中国医师协会器官移植医师分会, 上海医药行业协会. 中国肝、肾移植受者霉酚酸类药物应用专家共识(2023版)[J]. 中华移植杂志(电子版), 2023, 17(05): 257-272.
[14] 彭雨诗, 苗芸, 严紫嫣. 宏基因组高通量测序诊断肾移植术后华支睾吸虫感染一例[J]. 中华移植杂志(电子版), 2023, 17(05): 297-299.
[15] 张秋玥, 程羽, 牛雨田, 唐茂芝, 张克勤, 张懿, 郭亚楠, 涂增. 肾移植与人体微生态的相关性研究进展[J]. 中华临床医师杂志(电子版), 2024, 18(02): 207-213.
阅读次数
全文


摘要

版权所有 中华医学会 中华医学电子音像出版社有限责任公司  京ICP备14006079号-1  网络出版服务许可证：(署)网出证(京)字第075号