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Introduction: Long term outcomes of proteasome inhibitor (PI) based treatment for antibody-mediated rejection (AMR) and mixed-acute rejection (MAR) remain to be defined. Additionally, prognostic factors that determine allograft survival post-rejection have not been clearly defined in the literature with a homogenous treatment population. Therefore, the primary outcome of this study was to evaluate clinical responses to PI-based therapy for four rejection phenotypes (i.e. early AMR, early MAR, late AMR, late MAR) and to determine factors that predict allograft survival. Methods: Renal transplant recipients with first-time AMR treated with PI-based therapy between January 2005 to June 2015 at the University of Cincinnati and The Christ Hospital were evaluated. Patient demographic, immunosuppression, and laboratory information was obtained from an IRB-approved prospective database and electronic medical records. Categorical variables were compared with either the Kruskal Wallis test or ?2 test. Continuous variables were compared with the Wilcoxon signed-rank test, Mann-Whitney U test, or the Kruskal Wallis test. Univariate and multivariate logistic regression models were generated to determine risk factors for death-censored graft failure 3 years post-rejection.Results: 108 patients were analyzed with early AMR (n = 40), early MAR (n = 9), late AMR (n = 20), or late MAR (n = 39). Histopathologic improvement assessed using Banff component scoring was similar across the groups (early AMR 50.0% vs. early MAR 66.7% vs. late AMR 64.2% vs. late MAR 76.3%, p=0.25). Median percent reduction in immunodominant DSA (iDSA) was significantly different across the rejection phenotypes (early AMR 79.6% vs. early MAR 54.7% vs. late AMR 23.4% vs. late AMR 21.1%, p < 0.001). Death-censored graft survival (DCGS) was significantly different at 3-years post-rejection (early AMR 88.3% vs. early MAR 77.8% vs. late AMR 56.7% vs. late MAR 54.9%, p=0.02). Patients who achieved a > 50% reduction in iDSA 14 days post-rejection were less likely to experience allograft failure (OR 0.12, 95% Confidence Interval [CI] 0.02 – 0.52, p = 0.01).Conclusion: To summarize, PI-based therapy reduced tubular and microvascular inflammation, improved renal function at 90 days in early but not late AMR and MAR, and reduced iDSA levels. Different phenotypes of rejection yielded varying therapeutic responses. Ultimately, iDSA reduction was an important influence in allograft survival after both AMR and MAR. Effective treatments for both AMR and MAR continue to represent an unmet clinical need within solid organ transplantation and warrant additional study and drug development. |
