In-situ v Normothermic Regional Perfusion for Abdominal Organs ANGEL RUIZ M.D. DONATION AND TRANSPLNAT COORDINATION UNIT MEDICAL DIRECTION HOSPITAL CLÍNIC DE BARCELONA
Introduction Donation after circulatory death (cdcd or udcd) has become a significant source of organ donors Warm ischemic damage increases the risk of primary non-function and a suboptimal long-term graft function Normothermic regional perfusion (NRP) has been proposed as an alternative to super-rapid recovery (SRR) to minimize the impact of warm ischemia and improve functional restoration and organ outcome
Warm Ischemia and DCD
SUPER-RAPID RECOVERY Direct In situ Perfusion IN SITU PERFUSIÓN Doble baloon & triple lumen catheter Doble baloon & triple lumen catheter Venous Dreinage
REGIONAL PRESERVATION (nrp or hrp) Normothermic Recirculation 1-4h (6h) with Pump maintenance > 1.2-1.7 L/m 2 Continuous gasometric and ionic control (every 30 min) Hepatic and renal biochemical Control Hemogram Control Reheparinization (1,5 mg/kg/90min)
- Survival: In situ Perfusion 1year 71,8% - 5 years 50% CP Bypass 1year 87,3% - 5 years 76,1%
P = 0.03 P = 0.36 P = 0.01
30 min CA 30 min CA + 30 min NRP
Compare results of cdcd liver transplants performed in Spain with post-mortem NRP with those achieved with super rapid recovery, the current standard for cdcd. Prospective cohort study including all potential cdcd liver donors evaluated in Spain and the liver transplants that resulted between 06/2012 and 12/2016, with follow-up ending 12/2017 Recovery method determined by individual donor hospitals: NRP with pre-mortem cannulation NRP with post-mortem cannulation Super rapid recovery
342 potential cdcd liver donors evaluated & transplanted during study period: NRP: 152 (44%) Transplanted: 95 SRR: 190 (56%) Transplanted: 117 REASONS FOR DISCARDING cdcd LIVERS NRP (N=57/152) SRR (N=73/190) Poor macroscopic aspect at recovery 32 (21%) 51 (27%) Technical failure of NRP 6 (3,9%) -- Technical/logistical problem(s) associated with recovery 4 (2,6%) 11 (6%) Prolonged warm ischemic time 4 (2,6%) 7 (4%) Altered laboratory value(s) 4 (2,6%) 2 (1%) Anatomical problem(s) associated with the graft 2 (2,6%) 1 (0.5%) Pathological biopsy 2 (1,4%) 1 (0.5%) Previously undiagnosed cancer 2 (1,4%) 0 Active untreated infection 1 (0,7%) 0
DONOR- AND GRAFT-RELATED CHARACTERISTICS Raw Analysis IPTW Analysis NRP SRR P value SD* NRP SRR SD* (N=95) (N=117) Age (y) 57 [45-65] 56 [47-64] 0 796-0 050 58 [44-65] 56 [46-64] -0 068 Sex male 63 (66 3%) 77 (65 8%) 0 939 0 011 61 (62 0%) 79 (69 0%) -0 148 Cause of death CVA 42 (44 2%) 49 (41 9%) 0 733 0 047 39 (39 7%) 48 (41 2%) -0 031 Anoxic brain injury 38 (40 0%) 47 (40 2%) 0 980-0 004 48 (48 2%) 48 (42 0%) 0 125 Traumatic brain injury 8 (8 4%) 13 (11 1%) 0 514-0 091 7 (7 4%) 13 (11 0%) -0 126 Other 7 (7 4%) 8 (6 8%) 0 881 0 021 5 (4 7%) 7 (5 7%) -0 048 ICU stay (days) 7 [4-12] 7 [5-11] 0 460-0 033 7 [5-13] 7 [5-11] 0 117 Total WIT (min) 18 [13-23] 22 [19-26] <0.001-0 515 20 [15-30] 21 [17-25] 0 092 Functional WIT (min) 12 [9-16] 15 [12-20] <0.001-0 541 14 [11-20] 13 [11-19] 0 102 CIT (min) 315 [265-365] 340 [285-383] 0 141-0 075 315 [280-375] 340 [287-390] 0 074 Preservation UW or IGL-1 37 (38 9%) 15 (12 8%) <0 001 0 625 23 (23 6%) 27 (23 6%) 0 000 solution HTK 1 (1 1%) 27 (23 1%) <0 001-0 719 11 (11 4%) 15 (13 4%) -0 062 Celsior 57 (60 0%) 75 (64 1%) 0 540-0 085 64 (65 0%) 72 (62 9%) 0 043 *Bold-marked figures are greater in absolute value than 0 15.
RECIPIENT- AND TRANSPLANT-RELATED CHARACTERISTICS Raw Analysis IPTW Analysis NRP SRR P value SD* NRP SRR SD* (N=95) (N=117) Age (y) 56 [52-61] 59 [53-63] 0 119-0 294 58 [52-60] 58 [52-62] -0 092 Sex male 74 (77 9%) 99 (84 6%) 0 209-0 173 82 (82 6%) 92 (79 9%) 0 069 Laboratory MELD score 15 [11-19] 13 [9-18] 0 182 0 170 15 [10-17] 14 [9-21] 0 009 High-volume transplant center 4 69 (72 6%) 88 (75 2%) 0 670-0 059 73 (74 0%) 85 (73 8%) 0 004 Transplant indication Cirrhosis 53 (55 8%) 75 (64 1%) 0 218-0 170 66 (66.9%) 72 (62 5%) 0 094 Hepatocellular carcinoma 35 (36 8%) 38 (32 5%) 0 506 0 092 28 (28 4%) 39 (33 7%) -0 116 Re-transplantation or 2 (2 1%) 2 (1 7%) 0 833 0 029 2 (1 9%) 2 (2 1%) -0 011 fulminant liver failure Other 5 (5 3%) 2 (1 7%) 0 150 0 195 3 (2 8%) 2 (1 7%) 0 070 *Bold-marked figures are greater in absolute value than 0 15. 4 Defined as >50 liver transplants per year.
POST-TRANSPLANTATION COMPLICATIONS AND OUTCOMES NRP (N=95) SRR (N=117) Raw Analysis IPTW Analysis Risk Estimates [95% CI] P value Risk Estimates [95% CI] P value Early allograft dysfunction 21 (22%) 32 (27%) 0 75 [0 40-1 42] 0 381 0 97 [0 53-1 80] 0 931 Primary non-function 2 (2%) 3 (3%) 0 82 [0 13-4 99] 0 827 0 24 [0 04-1 56] 0 135 Hepatic artery thrombosis 4 (4%) 3 (3%) 1 67 [0 36-7 65] 0 509 0 79 [0 16-3 85] 0 770 All biliary complications 8 (8%) 36 (31%) 0 21 [0 09-0 47] <0 001 0 14 [0 06-0 35] <0 001 ITBL* 2 (2%) 15 (13%) 0 15 [0 03-0 66] 0 012 0 11 [0 02-0 57] 0 008 Retransplantation 5 (5%) 11 (9%) 0 54 [0 18-1 60] 0 263 0 24 [0 07-0 78] 0 018 Patient death 7 (7%) 20 (17%) 0 44 [0 19-1 05] 0 064 0 53 [0 23-1 22] 0 135 Graft loss 11 (12%) 28 (24%) 0 49 [0 24-0 98] 0 043 0 39 [0 20-0 78] 0 008 *Ischemic-type Biliary Lesions.
Graft Survival P = 0.008
RECENT SERIES DESCRIBING cdcd LIVER TRANSPLANTATION PERFORMED BY EXPERIENCED GROUPS Center, period N Donor age (y) Functional WIT (min) CIT (min) All biliary complications ITBL 1-year patient survival 1-year graft survival Washington University in St. Louis, 2005-49 28 [8-60] 12 [1-25] 318 [174-618] 20% 8% 96% 94% 2014 Indiana University, 2011-2015 30 31 [9-55] 11 [7-26] 294 [201-354] 23% 0 88% 88% Toronto General Hospital & Oschner Clinic 85 1 36 (15) 21(8) total 306 (72) 17% 4% 98% 96% Foundation, 2009-2013 Oschner Clinic Foundation, 2010-2016 100 1 38 (15) 20 (8) 2 304 (92) 25% 3% 93% 92% Kings College, 2001-2010 167 49 [range 16 (5) total 420 (12) 20% 2% >90% >90% 0-85] Mayo Clinics Florida, Rochester, & Arizona, 316 32 (11) 19 (8) total 324 (120) 18% 8% 92% 86% 2002-2016 155 56 (5) 20 (9) total 318 (84) 30% 12% 91% 87% University Hospital Birmingham, 2005-2015 222 45 [27-52] 17 [14-21] 414 [342-492] 27% 11% ~92% ~85% 93 67 [64-71] 18 [14-21] 426 [348-480] 33% 12% ~88% ~80% Spanish multicenter, 2012-2016 117 56 [47-64] 15 [12-20] 340 [285-383] 31% 13% 88% 83% 1 Include some of the same patients. 2 Starting from SBP <80 mmhg instead of <55-60 mmhg. 3 Using post-mortem NRP. 95 3 57 [45-65] 12 [9-16] 315 [265-365] 8% 2% 93% 88%
Clinical Outcomes of MP in DCD LT Group Period Graft type N CIT (h) PNF (%) ITBL (%) 6-mo. graft survival (%) University Hospital Zurich 2012-2014 cdcd (dwit 31-40 ) 25 3.1 (2.4-4.4) 0 0 90 University Medical Center Groningen 2014 cdcd (dwit 23-43 ) 10 5.5 (5.1-6.3) 0 10 100 Italian multicenter 2015-2016 udcd (dwit 98-145 ) 4 5 (3.5-6.2) 0 0 100 UK multicenter 2013 University of Cambridge 2015-2016 Toronto General Hospital 2015 University of Alberta, Edmonton Queen Elizabeth Hospital, Birmingham 2015 2014-??? DBD cdcd (dwit 14-31 ) DBD cdcd (dwit 17-160 ) DBD cdcd (dwit 28-30 ) DBD cdcd (dwit 16-23 ) DBD cdcd (dwit 19-109 ) * One graft lost during MP due to twisting of the portal vein. 16 4 3 9 8 2 6 3 1 4 NR 0 0 100 7.1 (3.7-14.6) 8 25 83 NR 0 0 NR 3.1 (1.6-4.9) 0 0 90 * 7.0 (6.5-7.9) 0 0 100
90 CA + 4 h CS 90 CA + 60 NRP + 4 h NMP
I declare to have NO CONFLICT OF INTERESTS with any Company
Review of the outcome of kidney transplantation from cdcd in Hospital Clínic de Barcelona that currently employs both techniques, normothermic regional perfusion and super-rapid recovery cdcd Acceptance criteria: Age 85yr Kidney, 65yr Liver No absolute Contraindication for Donation Functional Warm Isquemia Time Liver < 30 minutes Kidneys < 90 minutes
Transplant characteristics NRP (24) SRR (64) p Patient age 55.1 9.9 34-69 63.4 8.6 32-77 0.0002 Patient gender (M/F) 14/10 40/24 NS 1 st Tx 2 nd Tx 3 rd Tx 20 4 0 49 12 3 NS Donor age 52.6 11.3 21-65 67.1 9.4 49 84 <0.0001 Donor gender 18/6 32/32 0.0350 Immunosuppression: ATG + TACRO + mtori + PRED ATG + TACRO + MPA + PRED BASIL + TACRO + MPA + PRED 17 (70.8%) 7 (29.2%) 0 38 (59.4%) 21 (32.8%) 5 (7.8%) 0.0350* * CNI+mTOR vs CNI+MPA
Transplant characteristics NRP (24) SRR (64) p Functional warm ischemia (min) 14.1 3.5 11-21 25.1.4 7.8 11-47 p<0.0001 Total warm ischemia (min) 17.5 3.4 13-23 28.4 8.3 13-48 p<0.0001 Cold ischemia (hr) 12.6 4.5 1.5 20.4 14.8 5.6 5.3 28.1 0.0911 Pulsatile perfusion machine 11/24 (45.8%) 34/64 (53.1%) 0.0809
Renal function recovery NRP (24) SRR (64) p PNF 1/24 (4.2%) 1/64 (1.5%) 0.46 DGF (%) 8/23 (34.7%) 26/63 (41.3) 0.586 DGF (days) 10.7 13.0 1-34 11.7 9.3 1-40 0.761
Renal function recovery 3 months creatinine 1 yr creatinine 2 years serum creatinine 2 2 2 mg/dl 1 p=0.2192 mg/dl 1 p=0.0008 mg/dl 1 p=0.0085 0 NRP SRR 0 NRP SRR 0 NRP SRR 1.58 ± 0.14 (=23) 1.78 ± 0.08 (n=63) 1.23 ± 0.08 (n=19) 1.78 ± 0.092 (n=46) 1.24 ± 0.13 (n=15) 1.80 ± 0.14 (n=18)
Renal function recovery 3 months nadir creatinine days to nadir creatinine 2 40 mg/dl 1 p=0.4978 post-transplant days 30 20 10 p=0.077 0 NRP SRR 0 NRP SRR 1.53 ± 0.15 (n=23) 1.64 ± 0.08 (n=42) 19.7 ± 4.5 (n=22) 29.8 ± 3.0 (n=57)
Acute rejection NRP (24) SRR (64) Acute rejection 1yr 4/23 (17.4%) 8/63 (12.7%) Borderline rejection 3/23 (13.0%) 6/63 (9.5) AMR 1/4 (25%) 6/8 (75%)
Patient survival % survival 100 80 60 40 95.3% 86.5% 20 p=0.26 NRP (24) SRR (64) 0 0 6 12 18 24 Post-transplant months
Death-censored graft survival Death-censored graft survival Excluding PNF 100 98.4% 94.0% 100 100% 95.0% 80 80 % survival 60 40 % survival 60 40 20 p=0.13 SRR (64) NRP (24) 0 0 6 12 18 24 20 p=0.12 SRR (63) NRP (23) 0 0 6 12 18 24 Post-transplant months Post-transplant months
Conclusions The use of post-mortem NRP appears to: In liver transplantation Reduce postoperative biliary complications, Ischemic-type biliary lesions, and graft loss. Allow for successful transplantation of livers, udcd and cdcd, even from cdcd donors of advanced age. In Kidney transplantation No differences in DGF incidence and immediate renal function recovery between NRP and SRR Comparable short-term survival rates Better mid and long-term renal function for NRP donor grafts In Pancreas and Heart transplantation Be a valid methodology to obtain valid organs Better graft survival rates
Thank You for your Attention aruiz@clinic.cat