Systematic Histological Analysis of Thrombotic Microangiopathy in a Porcine Xeno-Kidney-Transplant-Model

Abstract

Introduction: Despite a variety of pharmacologic and transgenic interventions thrombotic microangiopathy is still a big challenge in porcine to human xenotransplantion. A detailed molecular analysis of histological patterns in xenokidneytransplant-models is necessary for a targeted anticoagulant therapy and a better understanding of the pathophysiology of human transplant associated thrombotic microangiopathy. Methods: Porcine kidneys were perfused with human whole blood (n=5). The histological alterations as well as the function of these kidneys were analysed in different intervention groups (application of antithrombin and activated Protein C (aPC), each n=5) and controls (perfusion with porcine whole blood, n=4). Microthrombi positive for fibrin (Fib+MT) and activated platelets (CD61+MT) were defined as lumen occlusion of more than 50% with fibrin and activated platelets. 100 glomeruli and preglomerular vessels per sample were analyzed. Results: Preglomerular CD61+MT were diminished in xenotransplants after application of aPC and antithrombin. Glomerular CD61+MT were increased in xenotransplants with and without intervention compared to controls. Only aPC, but not antithrombin was able to significantly diminish glomerular CD61+MT in xenotransplants. There were no differences in glomerular and preglomerular Fib+MT between both intervention groups. In total CD61+MT were more frequently observed than Fib+MT. Conclusion: Microthrombi in xenotransplants seem to be composed predominantly of platelets. In dependence on different antithrombotic interventions the number of microthrombi is diminished and the ratio of Fib+MT compared to CD61+MT is altered. Underlying mechanisms and the role of the vessel wall will be further investigated by gene expression analysis of pro- and antithrombotic factors. These data will be correlated with histological and laboratory data. These data will hopefully guide targeted antithrombotic interventions.