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 <i>de novo</i> 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 (<i>n</i>=205). Overall, 103 (50%) patients had preexisting DSA and 102 (50%) had <i>de novo</i> DSA. Compared with patients with preexisting DSA ABMR, patients with <i>de novo</i> DSA ABMR displayed increased proteinuria, more transplant glomerulopathy lesions, and lower glomerulitis, but similar levels of peritubular capillaritis and C4d deposition. <i>De novo</i> DSA ABMR was characterized by increased expression of IFN<i>γ</i>-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 <i>de novo</i> DSA ABMR (63% versus 34% at 8 years after rejection, respectively; <i>P</i><0.001). After adjusting for clinical, histologic, and immunologic characteristics and treatment, we identified <i>de novo</i> DSA ABMR (hazard ratio [HR], 1.82 compared with preexisting DSA ABMR; 95% confidence interval [95% CI], 1.07 to 3.08; <i>P</i>=0.03); low eGFR (<30 ml/min per 1.73 m²) at diagnosis (HR, 3.27; 95% CI, 1.48 to 7.23; <i>P</i><0.001); ≥0.30 g/g urine protein-to-creatinine ratio (HR, 2.44; 95% CI, 1.47 to 4.09; <i>P</i><0.001); and presence of cg lesions (HR, 2.25; 95% CI, 1.34 to 3.79; <i>P</i>=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 <i>de novo</i> DSA.