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

Abstract

contributed equally to this work.Abbreviations: ADP, adenosine diphosphate; AMP, adenosine monophosphate; ATP, adenosine triphosphate; CIT, cold ischemia time; DBD, donation after brain death; DCD, donation after circulatory death; FENa, fractional excretion of sodium; HBOC, hemoglobin-based oxygen carrier; HMP, hypothermic machine perfusion; NEDS, New England Donor Services; NEVKP, normothermic ex vivo kidney perfusion; NMP, normothermic machine perfusion; PRBC, packed red blood cells; QAS, quality assessment score; SCS, static cold storage; WIT, warm ischemia time.Normothermic machine perfusion presents a novel platform for pretransplant assessment and reconditioning of kidney grafts. Maintaining the metabolic activity of a preserved graft at physiologic levels requires an adequate oxygen supply, typically delivered by crystalloid solutions supplemented with red blood cells. In this study, we explored the feasibility of using a synthetic hemoglobin-based oxygen carrier (HBOC) in human kidney normothermic perfusion. Fourteen discarded human kidneys were perfused for 6 hours at a mean temperature of 37°C using a pressurecontrolled system. Kidneys were perfused with a perfusion solution supplemented with either HBOC (n = 7) or packed red blood cells (PRBC) (n = 7) to increase oxygencarrying capacity. Renal artery resistance, oxygen extraction, metabolic activity, energy stores, and histological features were evaluated. Throughout perfusion, kidneys from both groups exhibited comparable behavior regarding vascular flow (P = .66), oxygen consumption (P = .88), and reconstitution of tissue adenosine triphosphate (P = .057). Lactic acid levels were significantly higher in kidneys perfused with PRBC (P = .007). Histological findings were comparable between groups, and there was no evidence of histological damage caused by the HBOC. This feasibility experiment demonstrates that a HBOC solution can offer a logistically more convenient off-theshelf alternative to PRBC in normothermic machine perfusion of human kidneys. K E Y W O R D Sbasic (laboratory) research/science, kidney transplantation/nephrology, organ perfusion and preservation, organ procurement and allocation, tissue/organ engineering, translational research/science | 2815 ABURAWI et Al.

Normothermic kidney perfusion: An overview of protocols and strategies

“…It has an oxygen carrying capacity similar to that of human hemoglobin at normothermic temperatures and releases oxygen to tissues more readily than corpuscular hemoglobin 11 . Hemopure has been used for NMP in a series of experimental porcine and human kidneys that demonstrated equivalence in comparison to RBCs 12 . Nonetheless, Hemopure has not been widely tested and difficulties in supply limit its use.…”

“…A number of essential ingredients are needed to provide volume to the perfusate and metabolic support during NMP (Table 1). In brief, the protocols list the following ingredients: crystalloid‐ or colloid‐based solution with or without supplementation of albumin to maintain volume and prevent cellular edema, mannitol to increase osmolarity and enhance renal blood flow, vasodilators such as epoptrestenol sodium, a synthetic prostacyclin 18 , verapamil, a calcium channel blocking agent, 19 or sodium nitroprusside, 18 and corticosteroids to reduce inflammation 12,17,20 …”

Metabolic needs of the kidney graft undergoing normothermic machine perfusion

“…Longer perfusions that aim at repair and rejuvenation come with the additional need for anabolic factors such as essential amino-acids and vitamins. Current protocols are all based on continuous perfusion with red blood cells or an alternate oxygen carrier, an isotonic or/and colloid solution such as albumin, and glucose and amino acids (2)(3)(4)(5)(10)(11)(12)(13) as energy source (14). A detailed overview of the published protocols (including the perfusate composition) is provided in TABLE 1.…”

Kidney Perfusion as an Organ Quality Assessment Tool—Are We Counting Our Chickens Before They Have Hatched?

“…Normothermic preservation mandates an oxygenated perfusate and the use of an oxygen carrier. Although this oxygen carrier is usually red blood cells, acellular perfusates are under investigation, making use of hemoglobin-based oxygen carriers [46]. At normothermia and in the presence of oxygen, cellular metabolism resumes, and therefore it is likely that assessing both organ injury as well as residual function can take place during normothermic organ perfusion [28].…”