Antibody-Mediated Rejection Due to Preexisting versus De Novo Donor-Specific Antibodies in Kidney Allograft Recipients

Abstract

Antibody-mediated rejection (ABMR) can occur in patients with preexisting anti-HLA donor-specific antibodies (DSA) or in patients who develop de novo DSA. However, how these processes compare in terms of allograft injury and outcome has not been addressed. From a cohort of 771 kidney biopsy specimens from two North American and five European centers, we performed a systematic assessment of clinical and biologic parameters, histopathology, circulating DSA, and allograft gene expression for all patients with ABMR (n=205). Overall, 103 (50%) patients had preexisting DSA and 102 (50%) had de novo DSA. Compared with patients with preexisting DSA ABMR, patients with de novo DSA ABMR displayed increased proteinuria, more transplant glomerulopathy lesions, and lower glomerulitis, but similar levels of peritubular capillaritis and C4d deposition. De novo DSA ABMR was characterized by increased expression of IFNγ-inducible, natural killer cell, and T cell transcripts, but less expression of AKI transcripts compared with preexisting DSA ABMR. The preexisting DSA ABMR had superior graft survival compared with the de novo DSA ABMR (63% versus 34% at 8 years after rejection, respectively; P<0.001). After adjusting for clinical, histologic, and immunologic characteristics and treatment, we identified de novo DSA ABMR (hazard ratio [HR], 1.82 compared with preexisting DSA ABMR; 95% confidence interval [95% CI], 1.07 to 3.08; P=0.03); low eGFR (<30 ml/min per 1.73 m²) at diagnosis (HR, 3.27; 95% CI, 1.48 to 7.23; P<0.001); ≥0.30 g/g urine protein-to-creatinine ratio (HR, 2.44; 95% CI, 1.47 to 4.09; P<0.001); and presence of cg lesions (HR, 2.25; 95% CI, 1.34 to 3.79; P=0.002) as the main independent determinants of allograft loss. Our findings support the transplant of kidneys into highly sensitized patients and should encourage efforts to monitor patients for de novo DSA.

Keywords: antibody-mediated rejection; donor-specific anti-HLA antibody; kidney transplantation; microscope; molecular; transplant outcomes.

Figure 1.

Early occurence of preexisting anti-HLA DSA ABMR and superior graft survival compared with de novo anti-HLA DSA ABMR. (A) Cumulative incidence of onset ABMR according to the DSA characteristics (preexisting DSA versus de novo DSA). (B) Probability of graft survival on the basis of DSA characteristics. (C) Probability of graft survival according to the DSA characteristics and the presence or absence of cg lesions. cg+ve, cg-positive; cg-ve, cg-negative.

Figure 2.

Preexisting DSA ABMR and de novo DSA ABMR landscapes. (A) Expression of preexisting DSA ABMR transcripts in kidney allografts. (B) Expression of de novo DSA ABMR transcripts in kidney allografts. Dots represent individual probe sets on the microarray. The association strength (x-axis) is compared with fold change (y-axis) defined by ABMR versus all other biopsies of the control set (i.e., without ABMR). NK, natural killer cell.

Figure 3.

Molecular biopsy scores according to DSA characteristics. Data are on the basis of 666 kidney allograft biopsies assessed for intragraft gene expression of the PBTs ([A] endothelial DSA-selective transcripts, [B] macrophage-inducible transcripts, [C] natural killer cell [NK] transcripts, [D] IFNγ production and inducing transcripts, [E] T cell transcripts, [F] injury–repair response transcripts) according to circulating anti-HLA DSA and ABMR status (reference set without ABMR, preexisting DSA ABMR, and de novo DSA ABMR). The T bars indicate SEM and DSA denotes anti-HLA DSA.

Figure 4.

Integrated immunohistomolecular phenotype of kidney allograft injury on the basis of 666 kidney allografts. Variables considered in this analysis are (1) histologic (glomerulitis, capillaritis, endarteritis, transplant glomerulopathy, interstitial inflammation, tubulitis, and percentage of C4d complement fraction deposition in peritubular capillaries); (2) molecular with intragraft expression of the PBTs (DSA transcripts, natural killer cell transcript burden [NK transcripts], macrophage-inducible transcripts, IFNγ production and inducing transcripts [IFNγ transcripts], T cell transcripts, and injury-repair response-associated transcripts); and (3) immunologic (circulating anti-HLA DSA). (A) Individual overview of histologic and gene expression profiles according to unsupervised cluster analysis. Each variable in an individual patient is colored according to the threshold for each parameter (0–3 with higher score including more severe injuries, transcripts expression level, or DSA). (B) Unsupervised principal component analysis segregating three distinct patterns (individuals factor map) with the variables factor map showing the contribution of each parameter in segregating the three patterns.