Characteristics and Clinical Significance of De Novo Donor-Specific Anti-HLA Antibodies after Kidney Transplantation

Abstract

Background: The association of de novo donor-specific anti-human leukocyte antigens (HLA) antibodies (DSA) and development of antibody-mediated rejection (AMR) in kidney transplant recipients (KTRs) is still undetermined.

Methods: We prospectively screened de novo DSA in 167 KTRs during 32 months after kidney transplantation (KT). Timing of DSA detection was at 3, 6, and 12 months post-transplant and annually thereafter and when clinically indicated. DSA levels were determined by Luminex assays and expressed as mean fluorescence intensity (MFI). We evaluated the incidence, characteristics of DSA, and association between DSA and tacrolimus trough levels or AMR.

Results: De novo DSA developed in 16 KTRs (9.6%) and acute AMR occurred more commonly in KTRs with de novo DSA compared to KTRs without de novo DSA (18.8% vs. 0%, P < 0.001). All de novo DSA were against class II antigens. The mean number of DSA was 1.8 ± 1.2 and the average MFI of DSA was 7,399 ± 5,470. Tacrolimus trough level during the first 0-2 months after KT was an independent predictor of DSA development (hazard ratio, 0.70; 95% confidence interval, 0.50-0.99; P = 0.043). No differences were found in the number of DSA, average MFI of DSA, and tacrolimus levels during the first year between de novo DSA-positive KTRs with AMR and those without AMR.

Conclusion: The results of our study suggest that monitoring of DSA and maintaining proper tacrolimus levels are essential to prevent AMR during the initial period after KT.

Keywords: Antibodies; Graft Rejection; Kidney Transplantation; Survival.

Fig. 1. Flow chart of patients. A total of 203 KTRs were enrolled. After excluding 31 patients with pre-transplant anti-HLA Ab and 5 patients with missing data regarding pre-transplant anti-HLA Ab, 167 KTRs were included in this study. Of 167 KTRs, 26 KTRs developed de novo anti-HLA Ab (16 were DSA and 10 were non-DSA).

KTRs = kidney transplant recipients, HLA = human leukocyte antigens, DSA = donor-specific anti-human leukocyte antigens antibodies, anti-HLA Ab = anti-human leukocyte antigens antibodies.

Fig. 2. Kaplan-Meier analysis for DSA development according to TAC trough levels after KT. (A) TAC trough levels at 0–2 months and DSA development after 1 day post-transplant, (B) TAC trough levels at 3–6 months and DSA development after 6 months post-transplant, (C) TAC trough levels at 7–12 months and DSA development after 12 months post-transplant. LL-TAC group for 0–2 months after KT showed significantly increased risk for the development of DSA compared to SL-TAC group (P = 0.021).

DSA = donor-specific anti-human leukocyte antigens antibodies, TAC = tacrolimus, KT = kidney transplantation, LL = low-level, SL = standard-level.

Fig. 3. The cumulative incidences of (A) AMR, (B) TCMR, and (C) death-censored allograft loss according to the presence of DSA. Acute AMR occurred more commonly in KTRs with de novo DSA compared to KTRs without de novo DSA (P < 0.001). No significant differences were found in the cumulative incidence of TCMR and death-censored allograft loss between groups.

AMR = antibody-mediated rejection, TCMR = T-cell medicated rejection, DSA = donor-specific anti-human leukocyte antigens antibodies, KTRs = kidney transplant recipients.