Advantages of replacing hydroxyethyl starch in University of Wisconsin solution with hyperbranched polyglycerol for cold kidney perfusion.

BACKGROUND: Efficient and effective perfusion during organ procurement is required for the best prevention of donor organ injury preceding transplantation. However, current organ preservation solutions, including hydroxyethyl starch (HES)-based University of Wisconsin (UW) solution, do not always yield the best outcomes. Our previous study demonstrated that replacing HES with hyperbranched polyglycerol (HPG) reduced donor heart injury during cold storage. The current research was designed to examine the advantages of HPG-based solution for cold kidney perfusion. METHODS: Perfusion efficiency of HPG versus UW solution was tested using mouse kidneys at 4°C. The blood washout was evaluated by using a semiquantitative scoring system and tissue damage by histologic analysis. The interaction of HPG or UW solution with human red blood cells (RBCs) was examined by measuring RBC sedimentation and aggregation. RESULTS: The lower viscosity of HPG solution was correlated with faster and more efficient perfusion through donor kidneys as compared with UW. HPG solution was also more effective than UW in removing RBCs from the kidney and was associated with less tissue damage to donor kidneys. In vitro UW solution caused significant RBC sedimentation and hyperaggregation, whereas HPG showed minimal impact on RBC sedimentation and prevented RBC aggregation. CONCLUSIONS: This experimental study demonstrated that compared with UW, HPG solution was more efficient and effective in the removal of the blood from donor kidneys and offered better protection from donor tissue damage, suggesting that the HPG solution is a promising candidate to supplant standard UW solution for donor kidney perfusion in transplantation.

Comparison of reversal activity and mechanism of action of UHRA, andexanet, and PER977 on heparin and oral FXa inhibitors.

Anticoagulants such as unfractionated heparin (UFH), low-molecular-weight heparins (LMWHs), fondaparinux, and direct oral anticoagulants (DOACs) targeting thrombin (IIa) or factor Xa (FXa) are widely used in prevention and treatment of thromboembolic disorders. However, anticoagulant-associated bleeding is a concern that demands monitoring and neutralization. Protamine, the UFH antidote, has limitations, while there is no antidote available for certain direct FXa inhibitors. Improved antidotes in development include UHRA (Universal Heparin Reversal Agent) for all heparin anticoagulants; andexanet alfa (andexanet), a recombinant antidote for both direct FXa inhibitors and LMWHs; and ciraparantag (PER977), a small-molecule antidote for UFH, LMWHs, and certain DOACs. The binding affinities of these antidotes for their presumed anticoagulant targets have not been compared. Here, isothermal titration calorimetry (ITC) was used to determine the affinity of each antidote for its putative targets. Clotting and chromogenic FXa assays were used to characterize neutralization activity, and electron microscopy was used to visualize the effect of each antidote on clot morphology in the absence or presence of anticoagulant. ITC confirmed binding of UHRA to all heparins, and binding of andexanet to edoxaban and rivaroxaban, and to the antithrombin-enoxaparin complex. PER977 was found to bind heparins weakly, but not the direct FXa inhibitors studied. For UHRA and andexanet, an affinity at or below the micromolar level was found to correlate with neutralization activity, while no reversal activity was observed for the PER977/anticoagulant systems. Standard metrics of clot structure were found to correlate weakly with PER977's activity. This is the first study comparing 3 antidotes in development, with each exerting activity through a distinct mechanism.