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

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