Immunosuppression

A paired study comparing the efficacy of renal preservation by normothermic autologous blood perfusion and hypothermic pulsatile perfusion☆

The use of normothermic machine perfusion has been developed over the last few years for the preservation of abdominal and thoracic organs for transplantation. Recent studies suggest that normothermic machine perfusion (NMP) may provide a superior alternative to standard hypothermic perfusion and cold storage for kidneys procured from donation after circulatory death (DCD) donors. The use of NMP for renal grafts from DCD donors has been under investigation for the assessment and reconditioning of these grafts. Herein, we describe the principles of NMP, the current state of the technology in clinical and experimental practice and potential future applications.

Kidney transplantation is the treatment of choice for end-stage renal disease. Despite its superiority over dialysis, the persisting organ shortage remains a major drawback. Additional sources to increase the donor pool are grafts recovered from extended criteria donors (ECD) and donation after circulatory death (DCD). Although transplantation of marginal grafts demonstrates promising outcomes, increased rates of primary non-function, delayed graft function, and reduced graft survival have been reported. Cold ischemic injury, caused by static cold storage is a significant risk factor for poor outcome. Machine perfusion (MP) at various temperatures bears the potential to improve organ preservation, assessment, and repair. While hypothermic machine perfusion (HMP) is well established in clinical practice, modified HMP, subnormothermic machine perfusion (SMP), and normothermic machine perfusion (NMP) are novel emerging strategies with the potential to significantly improve the outcome of marginal kidney grafts. This review summarizes findings and recent advances from pre-clinical and clinical machine perfusion studies, organized by temperature, and discusses potential future developments for graft assessment and repair.

Normothermic machine perfusion (NMP) is an alternative strategy for preserving kidneys donated after cardiac death (DCD). The relative efficacy of prolonged NMP compared to hypothermic machine perfusion (HMP) in DCD kidneys with moderate ischemic injury is undetermined. This study compares NMP and HMP kidney preservation in a porcine DCD model.

Ten porcine kidneys underwent NMP or HMP preservation following 45 minutes of warm ischemia and 5 hours of cold ischemia. After 8 hours of machine preservation, hemodynamic stability, renal function, perfusate biomarkers, and histologic integrity were assessed in a simulated reperfusion model.

During simulated reperfusion, no differences were observed in oxygen consumption, urine production, creatinine clearance, fractional excretion of sodium, proteinuria, and perfusate levels of lactate dehydrogenase and aspartate aminotransferase. Resistance was no different after 30 minutes of simulated reperfusion. Histologically, NMP kidneys demonstrated increased vacuolization after preservation and greater loss of tubular integrity after simulated reperfusion. Perfusate levels of alkaline phosphatase (AP) and gamma glutamyltransferase (GGT) were higher in NMP kidneys during preservation, but upon simulated reperfusion, AP and GGT levels were higher in HMP-preserved kidneys. Peak AP and GGT during simulated reperfusion of HMP kidneys were over 14 times higher than peak AP and GGT during preservation of NMP kidneys.

NMP provided comparable preservation of renal function as HMP and minimized AP and GGT release upon reperfusion.

Cold storage of organs for preservation and transplantation is reaching its limits especially with extended criteria for heart beating donors and donation after cardiac death. We will discuss recent findings and perspectives in normothermic kidney preservation.

A literature review was performed from original articles and syntheses selected by the search engine PubMed. Keywords used were: cold ischemia; warm ischemia, normothermic, organ preservation, preconditioning, organ perfusion.

We identified several ways to improve kidney preservation: Ischemic normothermic preconditioning; Pharmacologic normothermic preconditioning; Ex vivo normothermic reperfusion; Remote ischemic transplantation preconditioning; Ischemic postconditioning.

In clinical practice, only uses of ECMO for organ preconditioning or ex vivo normothermic organ perfusion were used.

Promising experimental and clinical results make challenge cold preservation. The most suitable and physiological method seems to be a normothermic perfusion and conservation with autologous oxygenated blood using Extra Corporeal Membrane Oxygenation or Regional Normothermic Circulation.

la conservation hypothermique des greffons en transplantation a atteint ses limites en particulier pour les greffons à issu de donneurs à critères élargis et décédés après arrêt cardiaque. Les résultats et les perspectives récentes en conservation normothermique pour la préservation des greffons rénaux sont discutés dans cet article.

Une revue de la littérature a été réalisée à partir des articles originaux et des synthèses sélectionnés par le moteur de recherche PubMed à l’aide des mots-clés suivants: Ischemic normothermic preconditioning; Pharmacologic normothermic preconditioning; Ex vivo normothermic reperfusion; Remote ischemic transplantation preconditioning; Ischemic postconditioning.

Plusieurs techniques d’amélioration de la conservation des greffons rénaux ont été identifiées comme le préconditionnement ischémique normothermique, le préconditionnement normothermique pharmacologique, la reperfusion normothermique ex vivo et le postconditionnement ischémique. En pratiques cliniques, seules la circulation régionale normothermique pour le préconditionnement d’organes ou la perfusion normothermqique ex vivo des greffons ont été utilisées.

les résultats expérimentaux et cliniques de ces techniques semblent prometteurs qui pourraient concurrencer la conservation statique hypothermique. La méthode la plus appropriée et plus physiologique semble être la perfusion normothermique et la conservation avec sang autologue oxygéné par membrane extra-corporelle d’oxygénation ou Circulation Normothermique Régionale.

This pilot study compared the use of the Lifor Organ Preservation Medium (RTLF) at room temperature with hypothermic Belzer machine preservation solution (CMPS) and room in vitro temperature Belzer machine preservation solution (RTMPS) in a porcine model of uncontrolled donation after cardiac death (DCD). In this study, 5 porcine kidneys for each perfusate group were recovered under a DCD protocol. The kidneys were recovered, flushed, and placed onto a renal preservation system following standard perfusion procedures. The average flow rate for CMPS was 36.2 ± 7.2549 mL/min, RTMPS was 90.2 ± 9.7159 mL/min, and RTLF was 103.1 ± 5.1108 mL/min. The average intrarenal resistance for CMPS was 1.33 ± 0.1709 mm Hg/mL per minute, RTMPS was 0.84 ± 0.3586 and RTLF was 0.39 ± 0.04. All perfusion parameters were statistically significant (P < .05) at all time points for the CMPS when compared with both RTMPS and RTLF. All perfusion parameters for RTMPS and RTLF were equivalent for the first 12 hours; thereafter, RTLF became significantly better than RTMPS at 18 and 24 hours. It appears that both RTMPS and RTLF have equivalent perfusion characteristic for the initial 12 hours of perfusion, but LF continues to maintain a low resistance and high flow up to 24 hours. The results of this pilot study indicate that RTLF may represent a better alternative to pulsatile perfusion with CMPS and requires validation in an in vivo large animal transplant model.

Although organ preservation has relied upon hypothermia throughout the history of clinical transplantation, increasing reliance on suboptimal organs has recently focused attention on novel techniques that avoid the cumulative effects of preexisting organ damage and cold preservation. Normothermic preservation provides oxygen delivery at physiologic or near-physiologic temperature and allows maintenance of normal cellular metabolism. There is increasing evidence, mainly from experimental models, that this technique reduces preservation-related organ damage and that it has potential application particularly in the transplantation of marginal donor organs. The technical challenges and logistic constraints of what is an intrinsically more complex method have prevented introduction of normothermic preservation other than very limited clinical trials. However, the potential advantages of this technique are considerable, and it is likely that the technical problems will be overcome, allowing more widespread application into clinical practice.