肾移植术后中远期急性排斥反应临床研究

doi:10.3877/cma.j.issn.1674-3903.2022.01.005

目的

探讨肾移植术后中远期移植肾急性排斥反应(AR)发生影响因素及移植肾生存情况。

方法

回顾性分析浙江大学医学院附属第一医院肾脏病中心2018年1月至2019年12月因血清肌酐水平升高而接受移植肾病理活检并确诊移植肾AR受者临床资料，共纳入43例受者，其中急性抗体排斥反应组17例，急性T细胞排斥反应组26例；同时纳入同期(2周内)肾移植且移植肾功能正常的39例受者为对照组。正态分布计量资料比较采用配对t检验或单因素方差分析。计数资料比较采用χ²检验或Fisher确切概率法。采用Kaplan-Meier进行生存分析，并采用log-rank进行比较。P<0.05为差异有统计学意义。

结果

急性抗体排斥反应组HLA-A错配2个比例(4/17)高于对照组(1/39)，差异有统计学意义(P＝0.026)。急性抗体排斥反应组和急性T细胞排斥反应组AR发生时和末次血清肌酐和估算肾小球滤过率(eGFR)均高于AR发生前(P均<0.05)；急性抗体排斥反应组和急性T细胞排斥反应组AR发生时和末次血清肌酐和eGFR均高于对照组(P均<0.05)；急性抗体排斥反应组进入慢性肾脏病(CKD)-4期受者比例低于急性T细胞排斥反应组(χ²＝5.73，P<0.05)；急性T细胞排斥反应组进入CKD-4期受者比例以及急性抗体排斥反应组移植肾失功比例均高于对照组(χ²＝17.727和9.882，P均<0.05)。AR发生时急性抗体排斥反应组和急性T细胞排斥反应组受者均接受PRA检测，前者PRA-Ⅰ和PRA-Ⅱ阳性比例分别为41.2%(7/17)和88.2%(15/17)，均高于后者[11.5%(3/26)和26.9%(7/26)]，差异均有统计学意义(P＝0.042，P<0.001)。急性抗体排斥反应组、急性T细胞排斥反应组及对照组术后分别有13、24和38例受者应用他克莫司。发生AR时，急性抗体排斥反应组他克莫司血药浓度[(3.72±0.76)ng/mL]与急性T细胞排斥反应组[(3.37±0.86)ng/mL]均低于对照组[(5.73±1.25)ng/mL]，差异均有统计学意义(P均<0.05)；急性抗体排斥反应组与急性T细胞排斥反应组他克莫司血药浓度均低于发生AR前[(6.27±1.18)和(6.33±1.63)ng/mL]，差异均有统计学意义(t＝7.120和6.216，P均<0.05)。急性抗体排斥反应组4例受者应用以环孢素为基础的免疫抑制方案，其中3例术后33、36和55个月环孢素血浓度分别为112.4、138.3和7.0 ng/mL，均低于要求血药浓度。急性T细胞排斥反应组2例应用环孢素受者术后16和177个月环孢素血药浓度分别为43.2和24.6 ng/mL，均低于要求血药浓度。随访至2021年6月30日，急性抗体排斥反应组移植肾生存率低于对照组(χ²＝8.738，P<0.05)。

结论

HLA-A位点错配及他克莫司低血药浓度是肾移植术后中远期诱发AR的重要原因。急性抗体介导排斥反应是移植肾生存重要影响因素。

关键词: 肾移植, 急性抗体介导排斥反应, 急性T细胞介导排斥反应, 他克莫司

Objective

To investigate the influence factors of allograft acute rejection (AR) at the metaphase and long-term after kidney transplantation and the postoperative survival of allograft.

Methods

The clinical data were retrospectively analysed in 43 recipients who accepted kidney transplantation were more than 1 years and were diagnosed with AR by allograft renal biopsy during January 2018 to December 2019. Seventeen of them with acute antibody-mediated rejection were as acute antibody rejection group, 26 of them with acute T cell-mediated rejection were as acute T cell rejection group, and 39 recipients who got kidney transplantation during the same period (in 2 weeks) were matched as control group. Paired sample t test or one-way ANOVA was used to compare the measurement data conforming to normal distribution among multiple groups. Chi-square test or Fisher exact probability was used for comparison between counting data groups. Kaplan-Meier was used for survival analysis and log-rank was used for comparison. A P<0.05 was considered statistically significant.

Results

The proportion of 2 mismatches at HLA-A sites in HLA match before operation (4/17) was more higher in acute antibody rejection group than that in control group (1/39), and the difference was statistically significant (P=0.026). Serum creatinine and estimated glomerular filtration rate (eGFR) at the onset and last time of AR were higher in acute antibody rejection group and acute T cell rejection group than those before AR (all P<0.05). Serum creatinine and eGFR at the onset and last time of AR in acute antibody rejection and acute T cell rejection group were higher than those in control group (all P<0.05). The proportion of chronic kidney disease (CKD)-4 recipients in acute antibody rejection group was lower than that in acute T cell rejection group (χ²=5.73, P<0.05). The proportion of CKD-4 recipients in acute T cell rejection group and the proportion of renal allograft failure in acute antibody rejection group were higher than those in control group (χ²=17. 727 and 9.882, all P<0.05). When AR happened, the rate of PRA-Ⅰ positive recipients [41.2% (7/17)] and the rate of PRA-Ⅱ positive recipients [88.2% (15/17)] in acute antibody rejection group were both higher than those in acute T cell rejection group [11.5% (3/26) and 26.9% (7/26), respectively], the difference had statistical significance (P=0.042, P<0.001). The serum concentration of tacrolimus was significantly decreased in the acute antibody rejection group (3.72±0.76) ng/mL and in the acute T cell rejection group (3.37±0. 86) ng/mL when the AR occurred, which were all lower than that of the control group (5.73±1.25) ng/mL, the difference had statistical significance (all P<0.05), and also lower than the serum concentration of tacrolimus before AR occurred, the difference had statistical significance (t=7.120 and 6.216, all P<0.05). There were 4 recipients in the acute T cell rejection group used cyclosporine, and the serum concentration of cyclosporine of 3 recipients among them was not up to the mark at 33 (112.4 ng/mL), 36 (138.3 ng/mL) and 55 (7.0 ng/mL) months after transplantation. The serum concentration of cyclosporine of 2 recipients who used cyclosporine in the acute T cell rejection group was 43.2 (16 months after transplantation) and 24.6 ng/mL (177 months after transplantation), which were not up to the mark. All the recipients were followed up until June 30, 2021, the survival rate of transplant kidney of the acute antibody rejection group was lower than the control group (χ²=8.738, P<0.05).

Conclusions

Mismatch at the HLA-A sites and the lower serum concentration of tacrolimus were the important factors for inducing AR in the metaphase and long-term after kidney transplantation. Acute antibody-mediated rejection was the important factor that affected the survival of transplant kidney.

Key words: Kidney transplantation, Acute antibody-mediated rejection, Acute T cell-mediated rejection, Tacrolimus

表1 急性抗体排斥反应组、急性T细胞排斥反应组及对照组肾移植受者一般资料比较

项目	急性抗体排斥反应组(n＝17)	急性T细胞排斥反应组(n＝26)	对照组(n＝39)
性别(例，男/女)	13/4	18/8	24/15
年龄(岁，±s)	35±14	41±15	42±13
亲属供肾[例(%)]	8(47.1)	10(38.5)	18(46.2)
肾移植术后时间(月，±s)	76±50	75±52	78±50
AR发生时间(月，±s)	65±52	60±50	-
HLA错配1个[例(%)]	0	5(19.2)	2( 5.1)
HLA错配2个[例(%)]	4 (23.5)	8(30.8)	7(17.9)
HLA错配3个[例(%)]	9 (52.9)	9(34.6)	21(53.8)
HLA错配4个[例(%)]	3 (17.6)	2( 7.7)	5(12.8)
HLA错配5个[例(%)]	0	2( 7.7)	4(10.3)
HLA错配6个[例(%)]	1( 5.9)	0	0
HLA-A错配0个[例(%)]	3(17.6)	10(38.5)	14(35.9)
HLA-A错配1个[例(%)]	10(58.8)	15(57.7)	24(61.5)
HLA-A错配2个[例(%)]	4(23.5)^a	1( 3.8)	1( 2.6)
HLA-B错配0个[例(%)]	2(11.8)	7(26.9)	5(12.8)
HLA-B错配1个[例(%)]	11(64.7)	15(57.7)	29(74.4)
HLA-B错配2个[例(%)]	4(23.5)	4(15.4)	10(25.6)
HLA-DR错配0个[例(%)]	2(11.8)	6(23.1)	6(15.4)
HLA-DR错配1个[例(%)]	12(70.6)	15(57.7)	23(58.9)
HLA-DR错配2个[例(%)]	3(17.6)	5(19.2)	10(25.6)
术前PRA-Ⅰ类阳性[例(%)]	0	0	1( 2.6)
术前PRA-Ⅱ类阳性[例(%)]	0	1( 3.8)	1( 2.6)

表1 急性抗体排斥反应组、急性T细胞排斥反应组及对照组肾移植受者一般资料比较

项目	急性抗体排斥反应组(n＝17)	急性T细胞排斥反应组(n＝26)	对照组(n＝39)
性别(例，男/女)	13/4	18/8	24/15
年龄(岁，±s)	35±14	41±15	42±13
亲属供肾[例(%)]	8(47.1)	10(38.5)	18(46.2)
肾移植术后时间(月，±s)	76±50	75±52	78±50
AR发生时间(月，±s)	65±52	60±50	-
HLA错配1个[例(%)]	0	5(19.2)	2( 5.1)
HLA错配2个[例(%)]	4 (23.5)	8(30.8)	7(17.9)
HLA错配3个[例(%)]	9 (52.9)	9(34.6)	21(53.8)
HLA错配4个[例(%)]	3 (17.6)	2( 7.7)	5(12.8)
HLA错配5个[例(%)]	0	2( 7.7)	4(10.3)
HLA错配6个[例(%)]	1( 5.9)	0	0
HLA-A错配0个[例(%)]	3(17.6)	10(38.5)	14(35.9)
HLA-A错配1个[例(%)]	10(58.8)	15(57.7)	24(61.5)
HLA-A错配2个[例(%)]	4(23.5)^a	1( 3.8)	1( 2.6)
HLA-B错配0个[例(%)]	2(11.8)	7(26.9)	5(12.8)
HLA-B错配1个[例(%)]	11(64.7)	15(57.7)	29(74.4)
HLA-B错配2个[例(%)]	4(23.5)	4(15.4)	10(25.6)
HLA-DR错配0个[例(%)]	2(11.8)	6(23.1)	6(15.4)
HLA-DR错配1个[例(%)]	12(70.6)	15(57.7)	23(58.9)
HLA-DR错配2个[例(%)]	3(17.6)	5(19.2)	10(25.6)
术前PRA-Ⅰ类阳性[例(%)]	0	0	1( 2.6)
术前PRA-Ⅱ类阳性[例(%)]	0	1( 3.8)	1( 2.6)

表2 急性抗体排斥反应组、急性T细胞排斥反应组及对照组肾移植受者排斥反应发生前后移植肾功能比较

项目	急性抗体排斥反应组(n＝17)	急性T细胞排斥反应组(n＝26)	对照组(n＝39)
AR发生前血清肌酐(μmol/L, ±s)	111± 34	105± 27	96±21
AR发生时血清肌酐(μmol/L, ±s)	242±160^ab	296±241^ab	98±22
末次血清肌酐(μmol/L, ±s)	276±256^ab	233±198^ab	97±22
AR发生前eGFR[mL·min^-1·(1.73 m²)^-1,±s]	76± 24	76± 25	79±18
AR发生时eGFR[mL·min^-1·(1.73 m²)^-1,±s]	38± 20^ab	37± 21^ab	76±18
末次eGFR[mL·min^-1·(1.73 m²)^-1,±s]	42± 28^ab	43± 27^ab	77±17
CKD-4期[例(%)]	1( 5.9)^c	10(38.5)^b	0
移植肾失功[例(%)]	4(23.5)^b	2( 7.7)	0

表2 急性抗体排斥反应组、急性T细胞排斥反应组及对照组肾移植受者排斥反应发生前后移植肾功能比较

项目	急性抗体排斥反应组(n＝17)	急性T细胞排斥反应组(n＝26)	对照组(n＝39)
AR发生前血清肌酐(μmol/L, ±s)	111± 34	105± 27	96±21
AR发生时血清肌酐(μmol/L, ±s)	242±160^ab	296±241^ab	98±22
末次血清肌酐(μmol/L, ±s)	276±256^ab	233±198^ab	97±22
AR发生前eGFR[mL·min^-1·(1.73 m²)^-1,±s]	76± 24	76± 25	79±18
AR发生时eGFR[mL·min^-1·(1.73 m²)^-1,±s]	38± 20^ab	37± 21^ab	76±18
末次eGFR[mL·min^-1·(1.73 m²)^-1,±s]	42± 28^ab	43± 27^ab	77±17
CKD-4期[例(%)]	1( 5.9)^c	10(38.5)^b	0
移植肾失功[例(%)]	4(23.5)^b	2( 7.7)	0

表3 急性抗体排斥反应组、急性T细胞排斥反应组和对照组肾移植受者他克莫司血药浓度比较(ng/mL，±s)

组别	例数	AR发生前	AR发生时
急性抗体排斥反应组	13	6.27±1.18	3.72±0.76^ab
急性T细胞排斥反应组	24	6.33±1.63	3.37±0.86^ab
对照组	38	5.99±0.86	5.73±1.25
F值	-	0.656	41.50
P值	-	>0.05	<0.05

表3 急性抗体排斥反应组、急性T细胞排斥反应组和对照组肾移植受者他克莫司血药浓度比较(ng/mL，±s)

组别	例数	AR发生前	AR发生时
急性抗体排斥反应组	13	6.27±1.18	3.72±0.76^ab
急性T细胞排斥反应组	24	6.33±1.63	3.37±0.86^ab
对照组	38	5.99±0.86	5.73±1.25
F值	-	0.656	41.50
P值	-	>0.05	<0.05

图1 急性抗体排斥反应组、急性T细胞排斥反应组和对照组移植肾生存曲线

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[13]	张修源, 吕军好, 陈大进. 2022年肾移植领域研究进展[J]. 中华移植杂志(电子版), 2023, 17(01): 32-35.
[14]	朱晨晨, 韩飞, 寿张飞. HCV阳性供肾移植单中心回顾性研究[J]. 中华移植杂志(电子版), 2023, 17(01): 47-53.
[15]	李娜, 王丹. 肾移植受者HCV感染研究进展[J]. 中华移植杂志(电子版), 2023, 17(01): 58-62.

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Clinical study on allograft acute rejection at metaphase and long-term after kidney transplantation

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Clinical study on allograft acute rejection at metaphase and long-term after kidney transplantation