Twenty‐four–hour normothermic perfusion of discarded human kidneys with urine recirculation

Transportable normothermic kidney perfusion for 24 hours or longer could enable viability assessment of marginal grafts, increased organ use, and improved transplant logistics. Eleven clinically declined kidneys were perfused normothermically, with 6 being from donors after brain death (median cold ischemia time 33 ± 36.9 hours) and 5 being from donors after circulatory death (36.2 ± 38.3 hours). Three kidneys were perfused using Ringer’s lactate to replace excreted urine volume, and 8 kidneys were perfused using urine recirculation to maintain perfusate volume without fluid replenishment. In all cases, normothermic perfusion either maintained or slightly improved the histopathologically assessed tubular condition, and there was effective urine production in kidneys from both donors after brain death and donors after circulatory death (2367 ± 1798 mL vs 744.4 ± 198.4 mL, respectively; P = .44). Biomarkers, neutrophil gelatinase–associated lipocalin, and kidney injury molecule‐1 were successfully detected and quantified in the perfusate. All kidneys with urine recirculation were readily perfused for 24 hours (n = 8) and exhibited physiological perfusate sodium levels (140.7 ± 1.2 mmol/L), while kidneys without urine recirculation (n = 3) achieved a reduced normothermic perfusion time of 7.7 ± 1.5 hours and significantly higher perfusate sodium levels (159.6 ± 4.63 mmol/:, P < .01). Normothermic machine perfusion of human kidneys for 24 hours appears to be feasible, and urine recirculation was found to facilitate the maintenance of perfusate volume and homeostasis.

[1]  M. Nicholson,et al.  The conditioning effect of ex vivo normothermic perfusion in an experimental kidney model. , 2013, The Journal of surgical research.

[2]  B. Ross,et al.  The influence of renal function on lactate and glucose metabolism. , 1984, The Biochemical journal.

[3]  K. Saeb‐Parsy,et al.  Successful Transplantation of Human Kidneys Deemed Untransplantable but Resuscitated by Ex Vivo Normothermic Machine Perfusion , 2016, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[4]  P. Clavien,et al.  Short, Cool, and Well Oxygenated – HOPE for Kidney Transplantation in a Rodent Model , 2016, Annals of surgery.

[5]  B. Dimitrov,et al.  Long-Term Outcome of Renal Transplantation from Older Donors , 2006 .

[6]  Jean-Paul Squifflet,et al.  Machine perfusion or cold storage in deceased-donor kidney transplantation. , 2009, The New England journal of medicine.

[7]  M. Nicholson,et al.  Ex vivo normothermic perfusion for quality assessment of marginal donor kidney transplants , 2015, The British journal of surgery.

[8]  N. Heaton,et al.  A randomized trial of normothermic preservation in liver transplantation , 2018, Nature.

[9]  M. Kon,et al.  Repair of Damaged Organs in Vitro , 2005, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[10]  J. Bonventre,et al.  Kidney Injury Molecule-1 (KIM-1): a novel biomarker for human renal proximal tubule injury. , 2002, Kidney international.

[11]  M L Nicholson,et al.  Renal Transplantation After Ex Vivo Normothermic Perfusion: The First Clinical Study , 2013, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[12]  M. Nicholson,et al.  An Assessment of Urinary Biomarkers in a Series of Declined Human Kidneys Measured During Ex Vivo Normothermic Kidney Perfusion , 2017, Transplantation.

[13]  N. Heaton,et al.  Liver Transplantation After Ex Vivo Normothermic Machine Preservation: A Phase 1 (First‐in‐Man) Clinical Trial , 2016, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[14]  M. Nicholson,et al.  A pilot study assessing the feasibility of a short period of normothermic preservation in an experimental model of non heart beating donor kidneys. , 2011, The Journal of surgical research.

[15]  M. Nicholson,et al.  Carbon Monoxide Protects Against Ischemia-Reperfusion Injury in an Experimental Model of Controlled Nonheartbeating Donor Kidney , 2008, Transplantation.

[16]  M. Nicholson,et al.  First in Man Renal Transplantation After Ex Vivo Normothermic Perfusion , 2011, Transplantation.

[17]  C. Haisch,et al.  Overcoming severe renal ischemia: the role of ex vivo warm perfusion. , 2002, Transplantation.

[18]  I. Mucsi,et al.  Continuous Normothermic Ex Vivo Kidney Perfusion Is Superior to Brief Normothermic Perfusion Following Static Cold Storage in Donation After Circulatory Death Pig Kidney Transplantation , 2017, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[19]  I. Mucsi,et al.  Continuous Normothermic Ex Vivo Kidney Perfusion Improves Graft Function in Donation After Circulatory Death Pig Kidney Transplantation , 2017, Transplantation.

[20]  Jean‐Paul Squifflet,et al.  Machine perfusion versus cold storage for preservation of kidneys from expanded criteria donors after brain death , 2011, Transplant international : official journal of the European Society for Organ Transplantation.

[21]  I. Mucsi,et al.  Normothermic Ex Vivo Kidney Perfusion Following Static Cold Storage—Brief, Intermediate, or Prolonged Perfusion for Optimal Renal Graft Reconditioning? , 2017, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[22]  Haiqun Lin,et al.  Associations of Perfusate Biomarkers and Pump Parameters With Delayed Graft Function and Deceased Donor Kidney Allograft Function , 2016, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[23]  C. Haisch,et al.  NOS: The Underlying Mechanism Preserving Vascular Integrity and During Ex Vivo Warm Kidney Perfusion , 2003, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[24]  C. Pollock,et al.  Glucose handling by the kidney. , 2011, Kidney international. Supplement.

[25]  I. Mucsi,et al.  Eight-Hour Continuous Normothermic Ex Vivo Kidney Perfusion Is a Safe Preservation Technique for Kidney Transplantation: A New Opportunity for the Storage, Assessment, and Repair of Kidney Grafts , 2016, Transplantation.

[26]  Joseph V Bonventre,et al.  Kidney injury molecule-1 is a phosphatidylserine receptor that confers a phagocytic phenotype on epithelial cells. , 2008, The Journal of clinical investigation.

[27]  M. Allison,et al.  Observations on the ex situ perfusion of livers for transplantation , 2018, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[28]  Rinaldo Bellomo,et al.  Bench-to-bedside review: Lactate and the kidney , 2002, Critical care.

[29]  M. Stumvoll,et al.  Renal substrate exchange and gluconeogenesis in normal postabsorptive humans. , 2002, American journal of physiology. Endocrinology and metabolism.

[30]  T. Minor,et al.  Controlled Rewarming after Hypothermia: Adding a New Principle to Renal Preservation , 2015, Clinical and translational science.

[31]  M. Nicholson,et al.  The use of ex-vivo normothermic perfusion for the resuscitation and assessment of human kidneys discarded because of inadequate in situ perfusion , 2015, Journal of Translational Medicine.

[32]  M. Nicholson,et al.  Hydrogen sulphide ameliorates ischaemia–reperfusion injury in an experimental model of non‐heart‐beating donor kidney transplantation , 2010, The British journal of surgery.

[33]  Darius Bagli,et al.  Normothermic Ex Vivo Kidney Perfusion for the Preservation of Kidney Grafts prior to Transplantation , 2015, Journal of visualized experiments : JoVE.