Controlled Oxygenated Rewarming Compensates for Cold Storage–induced Dysfunction in Kidney Grafts

Abstract

Background. Normothermic machine perfusion (NMP) provides a promising strategy for preservation and conditioning of marginal organ grafts. However, at present, high logistic effort limits normothermic renal perfusion to a short, postponed machine perfusion at site of the recipient transplant center. Thus, organ preservation during transportation still takes place under hypothermic conditions, leading to significantly reduced efficacy of NMP. Recently, it was shown that gentle and controlled warming up of cold stored kidneys compensates for hypothermic induced damage in comparison to end ischemic NMP. This study aims to compare controlled oxygenated rewarming (COR) with continuous upfront normothermic perfusion in a porcine model of transplantation. Methods. Following exposure to 30 min of warm ischemia, kidneys (n = 6/group) were removed and either cold stored for 8 h (cold storage [CS]), cold stored for 6 h with subsequent controlled rewarming up to 35 °C for 2 h (COR), or directly subjected to 8 h of continuous NMP. Kidney function was evaluated using a preclinical autotransplant model with follow-up for 7 d. Results. NMP and COR both improved renal function in comparison to CS and displayed similar serum creatinine and urea levels during follow-up. COR resulted in less tenascin C expression in the tissue compared with CS, indicating reduced proinflammatory upregulation in the graft by gentle rewarming. Conclusions. COR seems to be a potential alternative in clinical application of NMP, thereby providing logistic ease and usability.

Preservation of Mitochondrial Coupling and Renal Function by Controlled Oxygenated Rewarming of Porcine Kidney Grafts

“…The latter observation is in line with previous reports, indicating controlled oxygenated rewarming to mitigate rewarming injury upon reperfusion in vitro [ 11 ], in vivo [ 10 ], and in clinical kidney transplantation [ 13 ].…”

“…In contrast to cell culture experiments, which do not allow for functional evaluation of the whole organ, our model strictly mimics the clinical ex vivo graft perfusion and provides functional data on early reperfusion outcome at the whole organ level. Although no long term evaluation of graft function has been possible in the present study, nor could interferences of whole blood with the post-ischemic tissue be accounted for, close similarities of functional data after COR could be found between the present study and earlier investigations in vivo [ 10 ]. Apart from this, the primary goal of the present study, i.e., to decipher the mechanistic role of early mitochondrial dysfunction, triggered upon abrupt warm reperfusion after cold storage and its prevention by controlled oxygenated rewarming could be sensibly addressed by the used model.…”

“…In line with these observations, main parts of organ preservation injury substantiate not during cold storage but upon and in consequence of abrupt rewarming [ 8 , 9 ]. Hence, significant alleviation of functional impairment of kidney grafts after transplantation could be achieved by modifying the rise in temperature during reoxygenation using a controlled oxygenated rewarming (COR) protocol subsequent to cold storage by thermoregulated machine perfusion [ 10 , 11 ]. The use of an incremental temperature rise instead of an abrupt return to normothermia improved post-ischemic recovery of discarded human donor livers [ 12 ] and resulted in superior results after experimental [ 10 ] and clinical [ 13 ] kidney transplantation.…”

“…Hence, significant alleviation of functional impairment of kidney grafts after transplantation could be achieved by modifying the rise in temperature during reoxygenation using a controlled oxygenated rewarming (COR) protocol subsequent to cold storage by thermoregulated machine perfusion [ 10 , 11 ]. The use of an incremental temperature rise instead of an abrupt return to normothermia improved post-ischemic recovery of discarded human donor livers [ 12 ] and resulted in superior results after experimental [ 10 ] and clinical [ 13 ] kidney transplantation. COR was also found to be operative in significantly reducing the initiation of the mitochondrial apoptotic pathway upon reperfusion along, with a better preservation of mitochondrial content of NAD+ [ 14 ].…”

Advances in Hypothermic and Normothermic Perfusion in Kidney Transplantation

“…More recently, a porcine auto-transplantation model demonstrated that while 8h of NMP improves renal function compared to SCS, a similar improvement in renal function is observed when cold-stored kidneys are subjected to 2 h of COR [49]. The authors speculate that this may be a useful application given the current requirement for hypothermic storage in the logistics of organ transport.…”