Defining the optimal duration for normothermic regional perfusion in the kidney donor: A porcine preclinical study

Abstract

Kidneys from donation after circulatory death (DCD) are highly sensitive to ischemia-reperfusion injury and thus require careful reconditioning, such as normothermic regional perfusion (NRP). However, the optimal NRP protocol remains to be characterized. NRP was modeled in a DCD porcine model (30 minutes of cardiac arrest) for 2, 4, or 6 hours compared to a control group (No-NRP); kidneys were machine-preserved and allotransplanted. NRP appeared to permit recovery from warm ischemia, possibly due to an increased expression of HIF1α-dependent survival pathway. At 2 hours, blood levels of ischemic injury biomarkers increased: creatinine, lactate/pyruvate ratio, LDH, AST, NGAL, KIM-1, CD40 ligand, and soluble-tissue-factor. All these markers then decreased with time; however, AST, NGAL, and KIM-1 increased again at 6 hours. Hemoglobin and platelets decreased at 6 hours, after which the procedure became difficult to maintain. Regarding inflammation, active tissue-factor, cleaved PAR-2 and MCP-1 increased by 4-6 hours, but not TNF-α and iNOS. Compared to No-NRP, NRP kidneys showed lower resistance during hypothermic machine perfusion (HMP), likely associated with pe-NRP eNOS activation. Kidneys transplanted after 4 and 6 hours of NRP showed better function and outcome, compared to No-NRP. In conclusion, our results confirm the mechanistic benefits of NRP and highlight 4 hours as its optimal duration, after which injury markers appear.

The future of organ perfusion and re‐conditioning

“…During HMP, NRP kidneys showed clearly lower intrarenal resistance. Kidneys transplanted after 4 and 6 h of NRP displayed better function than the control group .…”

Preclinical Modeling of DCD Class III Donation: Paving the Way for the Increased Use of This Challenging Donor Type

“…Once circulatory arrest is determined, there is a 5min no touch period before death is declared and organs can be procured. Further management considerations such as normothermic regional circulation [8] are currently being discussed.…”

Normothermic Regional Perfusion in Solid Organ Transplantation

“…During warm ischemia, ATP degradation leads to the progressive accumulation of xanthine and hypoxanthine, important sources of superoxide radical at organ reperfusion [3]. A period of post-ischemic NRP in DCD donors is useful to restore cellular energy substrates [4], reduce levels of nucleotide degradation products [5], improve the concentrations of endogenous antioxidants [6], and even stimulate processes of cellular repair prior to graft recovery [7] (Figure 1). An experimental study demonstrates that by blocking the A2 receptors of adenosine, the beneficial effects of NRP are abolished, indicating that NRP mediates its effect, at least in part, through adenosine as a form of ischemic preconditioning [8].…”

“…Hepatic transaminases should remain stable throughout NRP; levels >3× the upper limit of normal at baseline and/or >4× the upper limit of normal at the end of NRP may be considered relative contraindications for recovery of the liver and pancreas [10,11]. In general, NRP is run for a minimum of 1 hour and a maximum of 4 hours to allow adequate reconditioning of the abdominal organs and recovery of energy substrates without provoking additional end-organ injury [4,5,7,8,13,14].…”