Normothermic machine perfusion of donor livers without the need for human blood products

Abstract

Normothermic machine perfusion (NMP) enables viability assessment of donor livers prior to transplantation. NMP is frequently performed by using human blood products including red blood cells (RBCs) and fresh frozen plasma (FFP). Our aim was to examine the efficacy of a novel machine perfusion solution based on polymerized bovine hemoglobin‐based oxygen carrier (HBOC)‐201. Twenty‐four livers declined for transplantation were transported by using static cold storage. Upon arrival, livers underwent NMP for 6 hours using pressure‐controlled portal and arterial perfusion. A total of 12 livers were perfused using a solution based on RBCs and FFPs (historical cohort), 6 livers with HBOC‐201 and FFPs, and another 6 livers with HBOC‐201 and gelofusine, a gelatin‐based colloid solution. Compared with RBC + FFP perfused livers, livers perfused with HBOC‐201 had significantly higher hepatic adenosine triphosphate content, cumulative bile production, and portal and arterial flows. Biliary secretion of bicarbonate, bilirubin, bile salts, and phospholipids was similar in all 3 groups. The alanine aminotransferase concentration in perfusate was lower in the HBOC‐201–perfused groups. In conclusion, NMP of human donor livers can be performed effectively using HBOC‐201 and gelofusine, eliminating the need for human blood products. Perfusing livers with HBOC‐201 is at least similar to perfusion with RBCs and FFP. Some of the biomarkers of liver function and injury even suggest a possible superiority of an HBOC‐201–based perfusion solution and opens a perspective for further optimization of machine perfusion techniques. Liver Transplantation 24 528–538 2018 AASLD.

Synthetic hemoglobin-based oxygen carriers are an acceptable alternative for packed red blood cells in normothermic kidney perfusion

“…42 The preconditioning effects achieved through active replenishment of ATP stores may help renal grafts mitigate the injurious effects of reperfusion. 27 We recorded sustained ATP production in the HBOC group following the first hour of perfusion, which was associated with a consistent increase in renal energy charge throughout the perfusion. 44 Because of lower oxygen affinity and lessened viscosity of an HBOC-201 solution (Hemopure units are 1 × 10 −8 the size of an RBC) compared to a red cell-based solution, the former is able to deliver significantly higher oxygen levels, thereby achieving a superior cellular ATP content within perfused tissues.…”

“…[20][21][22][23] Organs undergoing ex vivo perfusion at normothermic temperatures require adequate oxygen delivery to meet metabolic demand. [26][27][28] The promise of these agents lies in their long shelf half-life, ease of use, easy accessibility, and negligible infectious risks. [26][27][28] The promise of these agents lies in their long shelf half-life, ease of use, easy accessibility, and negligible infectious risks.…”

Pretransplant sequential hypo- and normothermic machine perfusion of suboptimal livers donated after circulatory death using a hemoglobin-based oxygen carrier perfusion solution

“…9,10 In preclinical studies using human donor livers, it was previously shown that a short period of DHOPE prior to NMP results in increased ATP concentrations, less hepatobiliary injury and improved function during the NMP phase, compared to direct end-ischemic NMP. 14,16,17 Based on the presumed complementary effect of (D)HOPE and NMP we have combined these two techniques in a clinical machine perfusion protocol using an HBOC-201-based solution. A perfusion fluid based on human red blood cells (RBC) is frequently used for NMP.…”

“…For the application of this combined machine perfusion protocol we have developed a perfusion fluid that can be used at various temperatures and eliminates the use of a third party human blood product. 14 Our group reported higher ATP concentration, and cumulative bile production in discarded human livers undergoing NMP with an HBOC-201-based solution, compared to perfusion with an RBC-based perfusion fluid 16. Perfusion solutions based on RBC, which are mostly used for NMP, cannot be used at low temperatures due to increasing lipid membrane stiffness and the risk of hemolysis.…”

“…In the cold, the affinity of HBOC-201 for oxygen increases, similar to that of human Hb in erythrocytes, but is still less.HBOC-201 has previously been used in experimental and preclinical studies on ex-situ liver machine perfusion, but not in clinical practice 14,16,17. While during hypothermic machine perfusion, oxygen can be dissolved in the perfusion solution, during NMP an oxygen carrier is necessary.…”