Novel miRNA Profiling as a Biomarker to Predict Ischemic Cholangiopathy and Graft Loss in Donation after Circulatory Death (DCD) Liver Transplantation

Abstract

Research Question: What differences can be seen amongst donation after circulatory death (DCD) liver graft recipient whom develop ischemic cholangiopathy compared to DCD recipients who do not develop IC and donation after brain death recipients.

Background and Significance: The use of donation after circulatory death (DCD) liver grafts has emerged in the effort to address organ shortage through expanding criteria for donor selection. However, DCD liver transplantation has been associated with increased morbidity and graft loss vs. donation after brain death (DBD) liver grafts. Ischemic cholangiopathy (IC) is recognized as a major post-transplant complication that can occur following DCD liver transplantation, leading to graft dysfunction, potential graft loss, and in some cases, re-transplantation. Multiple mechanisms may contribute to cholangiocyte injury during DCD transplant, including ischemia and bile salt toxicity.

Materials and Methods: Our study investigated current literature surrounding the development and prevention of IC. Additionally, DCD with IC cohort was developed from the liver transplant recipient database. A cohort of DCD and DBD recipients who do not develop IC was used as controls. Clinical data was analyzed from the cohort groups. Lastly, a cohort of whether a change in RNA expression, including selective expression of circulating messenger RNAs (mRNA), associated with control of inflammatory markers and bile salt composition was evaluated between DCD recipients who develop IC compared with DCD and DBD recipients who did not develop IC.

Results: We first performed a literature review on the current knowledge surrounding the proposed mechanisms of cholangiocyte injury associated with IC and the clinical management of IC. We evaluated clinical data from our cohorts and found significant changes in creatinine and ALT levels prior to transplant (p<0.05). Next, we evaluated miRNA from blood samples of recipients at specific time points before and after transplantation within a cohort of DCD recipients with established IC. Blood samples were undergoing evaluation by the time of this writing and will be evaluated in future studies. We anticipated that DCD recipients with IC will demonstrate an miRNA profile characterized by elevated concentrations of inflammatory markers and downregulation of bicarbonate and glucose transporters.

Conclusion: Our review paper provided understanding of risk factors contributing to the development of IC may play an important role in optimizing transplant outcomes, including patient and graft selection, preventing the development of IC, improving long-term liver graft function, avoiding re-transplantation, and improving morbidity within DCD liver graft recipients. Additionally, our clinical analysis further supported other current studies and provided understanding for potential biomarkers for detection of development of IC.