Perfusate Composition and Duration of Ex-Vivo Normothermic Perfusion in Kidney Transplantation: A Systematic Review

Abstract

Ex-vivo normothermic perfusion (EVNP) is an emerging strategy in kidney preservation that enables resuscitation and viability assessment under pseudo-physiological conditions prior to transplantation. The optimal perfusate composition and duration, however, remain undefined. A systematic literature search (Embase; Medline; Scopus; and BIOSIS Previews) was conducted. We identified 1,811 unique articles dating from January 1956 to July 2021, from which 24 studies were deemed eligible for qualitative analysis. The perfusate commonly used in clinical practice consisted of leukocyte-depleted, packed red blood cells suspended in Ringer’s lactate solution with Mannitol, dexamethasone, heparin, sodium bicarbonate and a specific nutrient solution supplemented with insulin, glucose, multivitamins and vasodilators. There is increasing support in preclinical studies for non-blood cell-based perfusates, including Steen solution, synthetic haem-based oxygen carriers and acellular perfusates with supraphysiological carbogen mixtures that support adequate oxygenation whilst also enabling gradual rewarming. Extended durations of perfusion (up to 24 h) were also feasible in animal models. Direct comparison between studies was not possible due to study heterogeneity. Current evidence demonstrates safety with the aforementioned widely used protocol, however, extracellular base solutions with adequate oxygenation, supplemented with nutrient and metabolic substrates, show promise by providing a suitable environment for prolonged preservation and resuscitation.Systematic Review Registration:https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021231381, identifier PROSPERO 2021 CRD42021231381

Effects of T3 Administration on Ex Vivo Rat Hearts Subjected to Normothermic Perfusion: Therapeutic Implications in Donor Heart Preservation and Repair

“…After removal of the organ, the disconnection from all autonomic and endocrine systems may cause deregulation of vascular tone which leads to impairment in microcirculation and tissue hypoxia which in turn results in tissue injury, edema and remodeling (viscous circle). Several pharmacological interventions aiming to induce vasodilation, reduce edema and enhance metabolism have been investigated as potential donor organ preservation modalities (24). Triiodothyronine has long been used for hemodynamic support and as replacement therapy along with other hormones for donor organ preservation and resuscitation (8)(9)(10)(11).…”

“…However, the use of red cells may not be suitable for prolonged periods of perfusion. There is now evidence that non cell solutions as Ringer’s lactate or Steen solution supplemented with nutrient and metabolic substrates may optimize normothermic perfusion ( 24 ). Along this line, the present study provides evidence that addition of high dose of T3 in K-H can preserve ex vivo rat hearts subjected to normothermic perfusion.…”

Cancer Metabolism and Ischemia-Reperfusion Injury: Two Sides of the Same Coin

“…EVNP involves the use of a perfusion solution that mimics the physiological environment to rewarm the graft at hand to a normothermic temperature range. This restores the metabolic processes and allows for the assessment of graft quality assessment prior to transplantation [ 22 , 23 ]. These solutions are not able to fully mitigate the effects of IRI but are able to reduce them significantly.…”

“…HIFs (hypoxia-inducible factors) are frequently overexpressed in cancer cells independently from a hypoxic environment. HIF1α mRNA was found elevated in pre-neoplastic breast, colon, and prostate lesions and remained elevated when cells were cultured in normoxic conditions, which further suggests that hypoxia is not necessary for HIF-1α activation in cancer cells [ 22 ]. The constitutive expression of both HIF-1α and HIF-2α can be due to different causes, that is overstimulation of the PI3K/Akt/mTOR pathway, mutations in oncogenes that affect the HIF gene transcription rate (e.g., p53, Bcl2, Myc, and Ras), or functional loss of the Von Hippel-Lindau (VHL) protein, responsible for HIF-1α degradation [ 38 ].…”

Breaking the limits of experimental pancreas transplantation: Working toward the clinical ideal graft

“…Normothermic organ preservation demands a physiological environment with appropriate oxygen, nutrition, and metabolic substrates to replace consumed cellular energy resources. Additionally, to reduce oxidative damage, the perfusate solution needs to stabilize electrolyte balance and cell fluid content to decrease edema and reduce free radical peroxide scavengers (24). In clinical practice, the most used perfusate solution contains a red cell-based solution enriched with nutrients and also containing physiological buffers and supplementary constituents.…”