Serum Soluble B Cell-Activating Factor Is a Non-Invasive Biomarker of Antibody-Mediated Rejection in Kidney Allograft With Satisfactory Risk Stratification Performance But Negligible Diagnostic Value

Shenghui Wu, Xiaojun Su, Qianyu Ye, Yongcheng Wei, Yifang Gao, Mingchuan Huang, Yanxu Chen, Jiali Wang, Qiang Zhang, Qian Fu, Jun Li, Chenglin Wu, Huiting Huang, Bowen Xu, Huanxi Zhang, Longshan Liu, Changxi Wang, Shenghui Wu, Xiaojun Su, Qianyu Ye, Yongcheng Wei, Yifang Gao, Mingchuan Huang, Yanxu Chen, Jiali Wang, Qiang Zhang, Qian Fu, Jun Li, Chenglin Wu, Huiting Huang, Bowen Xu, Huanxi Zhang, Longshan Liu, Changxi Wang

Abstract

Objectives: B cell-activating factor (BAFF), which is critical in the activation and differentiation of B cells, is a candidate diagnostic and predictive biomarker for antibody-mediated rejection (ABMR). We aimed to investigate the value of serum soluble BAFF (sBAFF) for the diagnosis and risk stratification of ABMR after kidney transplantation.

Methods: In the diagnostic study, sBAFF level among ABMR (n = 25), T cell-mediated rejection (TCMR) (n = 14), 4 other pathological lesions (n = 21), and stable allograft function group (n = 15) were compared. In the nested case-control study, kidney allograft recipients with de novo donor-specific antibody (DSA) or ABMR (n = 16) vs. stable allograft function (n = 7) were enrolled, and sBAFF was measured preoperatively, at D7, M1, M3, M6, M9, M12, M18 posttransplant and at allograft biopsy.

Results: There was no significant difference in sBAFF level at biopsy between ABMR and non-ABMR groups. Longitudinal study showed that the sBAFF levels decreased dramatically at D7 in both groups. The sBAFF level in the DSA group started to increase within M1, while in the stable group, it maintained a low level until M3 and M6. The sBAFF levels of the DSA group were significantly higher than that of the stable group at M1 [1,013.23 (633.97, 1,277.38) pg/ml vs. 462.69 (438.77, 586.48) pg/ml, P = 0.005], M3 [1,472.07 (912.79, 1,922.08) pg/ml vs. 561.63 (489.77, 630.00) pg/ml, P = 0.002], and M6 [1,217.95 (965.25, 1,321.43) pg/ml vs. 726.93 (604.77, 924.60) pg/ml, P = 0.027]. sBAFF levels at M3 had the best predictive value for the DSA/ABMR with the area under the receiver operating characteristic (AUROC) curve value of 0.908. The predictive performance of the maximum (max) change rate from D7 to the peak within M3 was also excellent (AUROC 0.949, P = 0.580).

Conclusion: We clarified by a diagnostic study that sBAFF is not a diagnostic biomarker for ABMR in kidney transplantation and revealed by a nested case-control study that sBAFF values at M3 posttransplant and dynamic changes in sBAFF within M3 posttransplant have a good predictive value for the DSA/ABMR. It provides a useful tool for early screening of low-risk patients with negative preoperative DSA for the risk of developing postoperative DSA in kidney allograft recipients.

Keywords: B cell-activating factor (BAFF); antibody-mediated allograft rejection; diagnostic; kidney transplantation; predictive.

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2022 Wu, Su, Ye, Wei, Gao, Huang, Chen, Wang, Zhang, Fu, Li, Wu, Huang, Xu, Zhang, Liu and Wang.

Figures

Figure 1
Figure 1
The flowchart of the diagnostic study. ABMR, antibody-mediated rejection; BAFF, B cell-activating factor.
Figure 2
Figure 2
Serum B cell-activating factor (BAFF) levels in kidney transplant recipients. (A) The BAFF levels of the antibody-mediated rejection (ABMR) group was comparable to that of the non-ABMR group [951.92 (566.09, 1,162.97) pg/ml vs. 734.77 (564.95, 1,020.04) pg/ml, P = 0.438]. The end points of the lower and upper line segments represent 5% and 95%, respectively. The lower and upper horizontal lines of the boxplot mean the first and the third quartile, respectively, while the mid one represents the median. The solid points were outliers (<5th percentile or >95th percentile). (B) No significant difference was observed in these groups [951.92 (568.15, 1,155.23) pg/ml vs. 862.32 (647.15, 1112.30) pg/ml vs. 773.09 (554.98, 1,297.68) pg/ml vs. 705.58 (580.18, 1,044.08) pg/ml vs. 55.10 (519.96, 696.14) pg/ml vs. 470.95 (415.30, 723.17) pg/ml vs. 812.46 (633.45, 965.26) pg/ml, P = 0.168].
Figure 3
Figure 3
The flowchart of the nested case-control study. ABMR, antibody-mediated rejection; DSA, donor-specific antibody; BAFF, B cell-activating factor.
Figure 4
Figure 4
The dynamic changes of serum B cell-activating factor (BAFF) levels and tacrolimus concentration in the donor-specific antibody (DSA) group and the stable group before the occurrence of DSA. (A) Dynamic changes of BAFF levels in the DSA group and the stable group. There were significant differences between the two groups at 1 month (P = 0.006), 3 months (P = 0.003), and 6 months (P = 0.033). (B) Dynamic changes of tacrolimus concentration in the DSA group and the stable group. There was no significant difference between the two groups at different time points [W1: 6.9 (6.2, 9.0) pg/L vs. 7.5 (5.5, 9.7) pg/L, P = 0.947; M1: 8.6 (7.9, 9.7) pg/L vs. 8.3 (8.2, 10.7) pg/L pg/L, P = 0.670; M3: 7.7 (6.8, 8.1) pg/L vs. 8.1 (7.8, 8.2) pg/L, P = 0.230; M6: 6.7 (5.4, 7.5) pg/L vs. 7.3 (6.7, 8.6) pg/L, P = 0.230; M9: 6.1 (5.6, 7.2) pg/L vs. 6.6 (5.5, 8.2) pg/L, P = 0.770; M12: 6.2 (4.4, 8.1) pg/L vs. 7.8 (7.2, 8.6) pg/L, P = 0.480; respectively].
Figure 5
Figure 5
The receiver operating characteristic (ROC) curves of soluble B cell-activating factor (sBAFF) levels at different time points in predicting the donor specific antibody (DSA). (A) The ROC curve of pretransplant sBAFF levels to predict the dnDSA. The pretransplant sBAFF levels had no predictive value for dnDSA. (B–D) The ROC curve of sBAFF levels at M1, M3 and M6 to predict the dnDSA. The sBAFF levels at M3 had the biggest AUC (0.908), with a good sensitivity (0.786) and specificity when the threshold was 839.28 pg/ml.
Figure 6
Figure 6
Kaplan–Meier curves depicting time to the occurrence of dnDSA from 1 month (m), 3 m, and 6 m after transplantation. The recipients were divided into two groups according to the cutoff calculated by the receiver operating characteristic (ROC). (A–C) High-level soluble B cell-activating factor (sBAFF) at 1 m, 3 m, and 6 m was a risk factor for the occurrence of the dnDSA.
Figure 7
Figure 7
The predictive performance of max change rate from the first week to the third month for the occurrence of donor-specific antibody (DSA). (A) The receiver operating characteristic (ROC) curve (if the max change rate is 38.65%, the Youden index is maximal). (B) The sensitivity, specificity, and Youden index were presented according to specific change rate threshold.

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Source: PubMed

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