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Continuous Normothermic Ex Vivo Kidney Perfusion Improves Graft Function in Donation After Circulatory Death Pig Kidney Transplantation

Kaths, J. Moritz MD, MSc; Echeverri, Juan MD; Chun, Yi Min MSc; Cen, Jun Yu BSc; Goldaracena, Nicolas MD; Linares, Ivan MD; Dingwell, Luke S. BSc; Yip, Paul M. PhD; John, Rohan MD; Bagli, Darius MD, MSc; Mucsi, Istvan MD, PhD; Ghanekar, Anand MD, PhD; Grant, David R. MD; Robinson, Lisa A. MD; Selzner, Markus MD

doi: 10.1097/TP.0000000000001343
Original Basic Science-General

Background: Donation after circulatory death (DCD) is current clinical practice to increase the donor pool. Deleterious effects on renal graft function are described for hypothermic preservation. Therefore, current research focuses on investigating alternative preservation techniques, such as normothermic perfusion.

Methods: We compared continuous pressure-controlled normothermic ex vivo kidney perfusion (NEVKP) with static cold storage (SCS) in a porcine model of DCD autotransplantation. After 30 minutes of warm ischemia, right kidneys were removed from 30-kg Yorkshire pigs and preserved with 8-hour NEVKP or in 4°C histidine-tryptophan-ketoglutarate solution (SCS), followed by kidney autotransplantation.

Results: Throughout NEVKP, electrolytes and pH values were maintained. Intrarenal resistance decreased over the course of perfusion (0 hour, 1.6 ± 0.51 mm per minute vs 7 hours, 0.34 ± 0.05 mm Hg/mL per minute, P = 0.005). Perfusate lactate concentration also decreased (0 hour, 10.5 ± 0.8 vs 7 hours, 1.4 ± 0.3 mmol/L, P < 0.001). Cellular injury markers lactate dehydrogenase and aspartate aminotransferase were persistently low (lactate dehydrogenase < 100 U/L, below analyzer range; aspartate aminotransferase 0 hour, 15.6 ± 9.3 U/L vs 7 hours, 24.8 ± 14.6 U/L, P = 0.298). After autotransplantation, renal grafts preserved with NEVKP demonstrated lower serum creatinine on days 1 to 7 (P < 0.05) and lower peak values (NEVKP, 5.5 ± 1.7 mg/dL vs SCS, 11.1 ± 2.1 mg/dL, P = 0.002). The creatinine clearance on day 4 was increased in NEVKP-preserved kidneys (NEVKP, 39 ± 6.4 vs SCS, 18 ± 10.6 mL/min; P = 0.012). Serum neutrophil gelatinase-associated lipocalin at day 3 was lower in the NEVKP group (1267 ± 372 vs 2697 ± 1145 ng/mL, P = 0.029).

Conclusions: Continuous pressure-controlled NEVKP improves renal function in DCD kidney transplantation. Normothermic ex vivo kidney perfusion might help to decrease posttransplant delayed graft function rates and to increase the donor pool.

The authors demonstrate the feasibility and safety of a continuous pressure-controlled normothermic ex vivo kidney perfusion technique in a DCD model. It provides a physiologic environment during graft preservation and results in significantly superior outcomes when compared to static cold storage.

1 Multi Organ Transplant Program, Department of Surgery, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada.

2 Division of Nephrology, The Hospital for Sick Children, Toronto, Ontario, Canada.

3 Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada.

4 Department of General, Visceral, and Transplant Surgery, University Medical Center, Johannes Gutenberg University Mainz, Mainz, Germany.

5 Laboratory Medicine & Pathobiology, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada.

6 Departments of Surgery (Urology) and Physiology, The Hospital for Sick Children, Toronto, Ontario, Canada.

7 Developmental and Stem Cell Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.

8 Multi Organ Transplant Program, Department of Medicine, University of Toronto, Toronto, Ontario, Canada.

9 Transplant and Regenerative Medicine Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.

Received 29 March 2016. Revision received 11 May 2016.

Accepted 17 May 2016.

The authors declare no funding or conflicts of interest.

L.R. and M.S. share senior authorship.

J.M.K., J.E., D.B., I.M., A.G., D.G., L.R., and M.S. participated in research design. J.M.K., D.G., L.R., and M.S. participated in writing the article. J.M.K., J.E., Y.-M.C., D.C., N.G., I.L., and L.D. participated in performing the experiments. J.M.K., P.Y., and R.J. participated in data analysis.

Correspondence: Markus Selzner, MD, University of Toronto, General Surgery & Multi-Organ Transplant Program Toronto General Hospital, University Health Network 585 University Avenue, 11 PMB 178 Toronto, ON, Canada M5G 2N2. (markus.selzner@uhn.ca); Lisa A. Robinson, MD, FRCP(C), Division of Nephrology, The Hospital for Sick Children 555 University Avenue, Room 5265 Toronto, ON, Canada M5G 1X8. (lisa.robinson@sickkids.ca).

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