肾移植术后供者特异性抗体针对性治疗单中心效果观察

Efficacy of individualized donor-specific antibody removal therapy after kidney transplantation at a single center

目的探讨供者特异性抗体(donor specific antibodies,DSA)针对性治疗的疗效和影响因素。方法回顾性观察分析2016年1月至2021年1月在海军军医大学第一附属医院接受肾移植手术、行DSA规律检测并发现阳性且接受以利妥昔单抗(rituximab,RTX)联合静脉注射丙种球蛋白(intravenous immune globulin,IVIG)为基础的DSA针对性治疗方案的34例受者的临床资料。分析预存DSA(preformed DSA,pfDSA)转阴率与DSA类别、治疗开始距离移植手术时间、DSA针对的HLA位点及DSA强度的相关性,治疗前后免疫显性DSA(immunodominant DSA,iDSA)水平及新生DSA(de novo DSA,dnDSA)阳性受者血肌酐水平变化情况。结果全部34例受者中,治疗后3个月完全转阴17例(50%),末次随访时转阴19例(55.9%)。对受者体内针对所有位点的78个DSA进行统计后发现,pfDSA及dnDSA的转阴率在治疗后3个月[62.9%(39/62)比37.5%(6/16)]及末次随访时[74.2%(46/62)比56.3%(9/16)]差异均没有统计学意义(P=0.067和0.219)。对于pfDSA,治疗3个月后,不同MFI强度的pfDSA转阴率差异明显[DSA弱阳性转阴率78.6%(33/42),DSA阳性及以上转阴率30%(6/20),P<0.001],而且是pfDSA能否转阴的独立影响因素(48.6%,95%CI:22.3%~66.8%,P=0.001)。末次随访时,不同治疗开始时间受者的pfDSA转阴率差异明显[术后30 d以内转阴率79.2%(42/53),术后30 d以上转阴率44.4%(4/9),P=0.042],不同DSA MFI强度受者的pfDSA转阴率亦差异明显[DSA弱阳性转阴率88.1%(37/42),DSA阳性及以上转阴率45%(9/20),P<0.001],而且两者都是pfDSA能否转阴的独立影响因素(34.8%,95%CI:3.2%~61.8%,P=0.008;43.1%,95%CI:18.5%~63.4%,P=0.001)。治疗后3个月免疫显性DSA(immunodominant DSA,iDSA)的平均荧光强度(mean fluorescence intensity,MFI)较治疗前下降幅度的均值为66.67%,末次随访时iDSA MFI下降幅度的均值为77.90%,差异有统计学意义(P=0.035)。9例dnDSA弱阳性及以上强度受者治疗前、治疗期间、治疗后3个月及末次随访时的血肌酐值分别为(110.2±26.9)μmol/L、(178.8±90.5)μmol/L、(153.9±72.8)μmol/L及(213.6±185.8)μmol/L。治疗期间血肌酐水平较治疗前明显上升(配对样本t检验,t=-2.794,P=0.023),治疗后3个月较治疗期间明显下降(配对样本t检验,t=3.430,P=0.009),而末次随访时较治疗后3个月再次上升(秩和检验,P=0.028)。结论接受以RTX+IVIG为基础的DSA针对性治疗后,pfDSA的转阴率与其强度及接受治疗的时间明显相关,治疗后DSA总体无明显反弹,dnDSA阳性受者的移植肾功能在治疗后短期内得到一定改善。

ObjectiveTo evaluate the efficacy of individualized removal therapeutic regimen for donor-specific antibodies(DSA)and examine its related influencing factors.MethodFrom January 2016 to January 2021,34 recipients of kidney transplant(KT)underwent regular DSA testing and the results were positive.DSA removal therapy based upon rituximab(RTX)plus intravenous immune globulin(IVIG)was offered.Correlation between DSA negative conversion rate and DSA types,time from start of treatment to transplantation,HLA loci targeted by DSA and DSA mean fluorescent intensity(MFI)were analyzed retrospectively.Changes of immunedominant DSA(iDSA)and serum creatinine in individuals with de novo DSA(dnDSA)before and after treatment were also examined.ResultsAt Month 3 post-treatment,antibodies turned negative in 17/34(50.0%)patients and DSA became negative in 19/34(55.9%)at the last follow-up.Then we identified 78 DSA from all patients.No significant difference existed in negative conversion rate of pfDSA and dnDSA at Month 3 post-treatment[62.9%(39/62)vs 37.5%(6/16)]and at the last follow-up[4.2%(46/62)vs 56.3%(9/16)](P=0.067,0.219).For pfDSA,negative conversion rate of pfDSA with different MFIs after 3-month treatment varied significantly[negative conversion rate of weak positive DSA was 78.6%(33/42)and positive and above DSA 30%(6/20),P<0.001].It was an independent related factor of whether or not pfDSA could turn negative(48.6%,95%CI:22.3%-66.8%,P=0.001).At the last follow-up,negative conversion rate of pfDSA differed markedly at different timepoints from start of treatment to transplantation[treated within 30 days post-operation was 79.2%(42/53)and over 30 days post-operation was 44.4%(4/9),P=0.042]and among different DSA MFI[88.1%(37/42)of weakly positive DSA and 45%(9/20)of positive and above DSA,P<0.001]and they were independent related factors for negative conversion of pfDSA(34.8%,95%CI:3.2%-61.8%,P=0.008;43.1%,95%CI:18.5%-63.4%,P=0.001).Mean decline rate in iDSA was 66.67%at Month 3 post-treatment and 77.90%at the last follow-up.The difference was statistically significant(P=0.035).Serum level of creatinine of 9 patients with dnDSA was(110.2±26.9)μmol/L pre-treatment,(178.8±90.5)μmol/L during treatment,(153.9±72.8)μmol/L at Month 3 post-treatment and(213.6±185.8)μmol/L at the last follow-up.Serum creatinine rose during treatment(t=-2.794,P=0.023),declined at Month 3 post-treatment(t=3.430,P=0.009)and spiked again at the last follow-up(P=0.028).ConclusionAfter DSA removal therapy based upon RTX plus IVIG,negative conversion rate of pfDSA is correlated with its MFI and time from start of treatment to transplantation.There is no significant rebound in DSA MFI and graft function of dnDSA patients improves immediately after treatment.