Determinants and Outcomes of Accelerated Arteriosclerosis

Abstract

Rationale: The role of circulating antibodies in addition to traditional cardiovascular risk factors in the development of accelerated arteriosclerosis and their long-term clinical consequences have not been demonstrated. Objective: We investigated the role of circulating antibodies in accelerated arteriosclerosis and the role of immune-associated arteriosclerosis in graft and patient survival and the occurrence of major adverse cardiovascular events. Methods and Results: This was an observational prospective cohort study that included 1065 kidney transplant patients (principal cohort, n=744; validation cohort, n=321) between 2004 and 2010. Participants were assessed for traditional cardiovascular risk factors and circulating anti–human leukocyte antigen (HLA) antibodies. All patients underwent allograft biopsies to assess arteriosclerotic lesions and endothelial activation, endarteritis, and complement deposition. In the principal cohort, 250 (33.6%) patients had severe arteriosclerosis (luminal narrowing >25% via fibrointimal arterial thickening). Circulating donor-specific anti-HLA antibodies were significantly associated with severe allograft arteriosclerosis (hazard ratio, 2.9; P <0.0001), independently of traditional risk factors. Patients with severe arteriosclerosis and anti-HLA antibodies (n=91, 12.2%) demonstrated allograft endothelial activation, endarteritis, and complement deposition. High levels of anti-HLA antibodies and their complement binding capacity were associated with increased severity of arteriosclerosis. Patients with antibody-associated severe arteriosclerosis had decreased allograft survival and increased mortality ( P <0.0001); they exhibited a 2.5- and 4.1-fold increased risk of major adverse cardiovascular events compared with patients who had severe arteriosclerosis without antibodies and patients with minimal arteriosclerosis, respectively ( P <0.0005). Circulating donor-specific anti-HLA antibodies were significantly associated with occurrence of major adverse cardiovascular events (hazard ratio, 2.4; P =0.0004), independently of traditional risk factors. Conclusions: Circulating antibodies are major determinants of severe arteriosclerosis and major adverse cardiovascular events, independent of traditional cardiovascular risk factors.

The Banff 2015 Kidney Meeting Report: Current Challenges in Rejection Classification and Prospects for Adopting Molecular Pathology

“…Note that the extent of i‐IFTA is not analogous to the Banff total inflammation score, the latter representing the sum of inflammation in scarred and nonscarred areas of the cortex. Consequently, it was decided to modify the Banff 2007 criteria by adding a statement (Table 3, category 4), reflecting findings that lesions of transplant arteriopathy may represent chronic active ABMR 42 as well as TCMR—also shown in experimental studies 43—and that chronic active TCMR may also be manifest in the tubulointerstitial compartment.…”

Immunobiology of Allograft Human Leukocyte Antigens in the New Microenvironment

“…One of the forms of sHLA-I consists of sHLA HC monomers associated with β2m; the other has a molecular weight indicative of HLA antigen/antibody complexes. Rhynes, et al [134] also noticed the presence of this sHLA-Iin one of the patients who had rejected the allograft. The molecular weight of one of the isolated sHLA forms was higher than the usual molecular weight (near 1,000,000 daltons), which was attributed to the presence of sHLA/antibody complexes in allograft recipients.…”

“…Levels of sHLA in allograft recipients that increased, post-transplantation, from a detectable pre-transplant level, and the persistence of sHLA at a high level as long as the liver allograft functioned confirmed the post-transplantation shedding of sHLA by allografts. Rhynes, et al [134] observed that the serum sHLA levels were low pre-transplant but increased substantially during the initial 10 days post-transplantation in liver (n = 9) and heart (n = 12) allograft recipients. In renal transplant patients, the increase in sHLA-I was noticed prior to or during 16 of 20 (80%) biopsy-proven rejections and in 9 of 11 (83%) after episodes of infection (bacterial, viral, and fungal).…”

Histopathological findings in transplanted kidneys

“…DSA may also promote arteriosclerosis, as judged by progression of severity in allografts from patients with DSA. Loupy et al recently suggested that circulating antibodies are major determinants of severe arteriosclerosis and major adverse cardiovascular events, independent of traditional cardiovascular risk factors [41].…”