BACKGROUND

The role of circulating antibodies and alloimmune response beyond traditional cardiovascular risk factors in the development of accelerated arteriosclerosis and its long-term clinical consequences is not demonstrated at a population level.

METHODS

Observational prospective cohort study, including 1.065 kidney transplant patients (principal n=744; external validation cohort, n=321) between 2004 and 2010. Participants were screened for traditional cardiovascular risk factors and the presence of circulating DSA. All patients underwent prospective protocol kidney allograft biopsies at 1 year post transplant. The role of immune-mediated arteriosclerosis in patient and kidney allograft survivals together with occurrence of major adverse cardiovascular events was determined. The results were replicated in an independent validation set.

RESULTS

Of the 744 patients from the principal cohort, 250 (33.6%) patients had severe arteriosclerosis at 1 year post-transplantation. The independent determinants of severe allograft arteriosclerosis were donor age (p<0.0001), donor diabetes mellitus (p=0.005), cold ischemia time (p=0.0121), recipient hypertension post-transplant (p=0.0332) and the presence of circulating DSA (p<0.0001). Patients with severe arteriosclerosis and circulating DSA (n=91, 12.2%) showed allograft microcirculation inflammation and C4d capillary deposition. Patients with severe arteriosclerosis and DSA had decreased allograft survival and increased mortality (7 years graft and patient survival of 76.9% and 80.8% respectively) as compared with patients with severe arteriosclerosis without DSA (92.7% and 93.2% respectively) and the patients with minimal arteriosclerosis (93.1% and 93.4% respectively, p<0.001 for both comparisons). Patients with severe arteriosclerosis and DSA exhibited a 2.5- and 4.1-fold-increased risk of major adverse cardiovascular events compared with patients with severe arteriosclerosis without DSA and patients with minimal arteriosclerosis, respectively (p<0.0005 for both comparisons), independently of traditional cardiovascular factors.

CONCLUSION

We demonstrated that circulating DSA are major determinants of severe arteriosclerosis independent of traditional cardiovascular risk factors. Antibody-mediated severe arteriosclerosis is associated with reduced kidney survival, increased patient death and occurrence of major adverse cardiovascular events.

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