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 patientswithABMR (n=205).Overall, 103 (50%) patients hadpreexistingDSAand 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 andC4d deposition. De novoDSAABMRwas characterized by increased expression of IFNg-inducible, natural killer cell, and T cell transcripts, but less expression of AKI transcripts comparedwith preexistingDSAABMR. The preexistingDSAABMR 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 comparedwith preexistingDSAABMR; 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.