Abstract 2581: Serum Matrix Metalloprotease-1 Concentrations Predict Rejection-Free Outcome in Cardiac Transplant Recipients
Acute allograft rejection is a severe complication in cardiac transplantation. Graft rejection is diagnosed by histological analysis of myocardial biopsies; and no serological marker of rejection is in common use. Acute rejection events are associated with upregulation of growth factors and cytokines including TGF-β and bFGF, which in turn modulate expression of the collagenase matrix metalloprotease (MMP)-1. Therefore, this study analyzed MMP-1 serum concentrations in heart transplant recipients. Myocardial biopsies and serum samples were obtained from recipients (n=141) at 1, 2, 3, 4, 6, 8, 12 and 24 weeks post-transplant. Immunosuppression comprised cyclosporine A (CyA; n=67), tacrolimus (TAC) with mycophenolate mofetil and steroids (n=28), CyA with azathioprine and steroids (n=26) or CyA with everolimus (EVL) and steroids (n=20). Rejection was defined histologically using ISHLT guidelines. Serum MMP-1 concentrations were measured by ELISA. Rejection was diagnosed in 132 of 834 biopsies (grade 1A/B: n=23/73; grade 2: n=10; grade 3A/B: n=17/9). Mean pre-transplant serum MMP-1 levels were not significantly different between patients. At week 1 (p=0.048), week 2 (p=0.026) and week 3 (p=0.033) following transplantation, MMP-1 serum concentrations significantly elevated in patients with rejection episodes compared to patients with rejection-free outcome. In receiver operating characteristic curve analysis, mean week 1 and 2 MMP-1 serum levels significantly predicted rejection (p<0.002, AUC=0.754, CI=1.042–1.110). At a cut-off level of ≥ 5 ng/mL MMP-1 had a sensitivity of 90% and a specificity of 71% to predict rejection. Eighty-five percent of patients with initial MMP-1 serum concentrations ≤ 4 ng/mL were free from rejection. MMP-1 serum concentrations ≤ 4 ng/mL correlated with EVL (p<0.001), whereas concentrations ≥ 5 ng/mL correlated with CyA and TAC therapy (p<0.001). Serum MMP-1 is a sensitive, specific, and easily measurable marker of efficient immunosuppression; and its serum concentrations ≤ 4 ng/mL predict rejection-free outcome in cardiac transplant recipients.