Normothermic Kidney Perfusion · ** P
Transcript of Normothermic Kidney Perfusion · ** P
![Page 1: Normothermic Kidney Perfusion · ** P](https://reader033.fdocuments.us/reader033/viewer/2022050212/5f5e3c8ab9626f1108028002/html5/thumbnails/1.jpg)
Sarah Hosgood
University of Cambridge
14th November 2015
Normothermic Kidney Perfusion
![Page 2: Normothermic Kidney Perfusion · ** P](https://reader033.fdocuments.us/reader033/viewer/2022050212/5f5e3c8ab9626f1108028002/html5/thumbnails/2.jpg)
Refrigeration
Cooling: to Cell Metabolism
• Anaerobic metabolism
• ATP depleted
•
Physiological
Maintains cellular metabolism
• Oxygenation
• Aerobic metabolism
• ATP regenerated
• Pre-transplant assessment
• Pre-transplant therapies
Preservation: Warm or Cold
Static Cold Storage
Hypothermic Machine
Perfusion
Ex-vivo Normothermic
Perfusion (EVNP)
![Page 3: Normothermic Kidney Perfusion · ** P](https://reader033.fdocuments.us/reader033/viewer/2022050212/5f5e3c8ab9626f1108028002/html5/thumbnails/3.jpg)
Flow probe
Centrifugal Pump
Pressure line
Oxygenator/heater
Infusion Pumps
Arterial
Venous
Urine collection
Venous
Reservoir
Ex-Vivo Normothermic Perfusion Circuit
![Page 4: Normothermic Kidney Perfusion · ** P](https://reader033.fdocuments.us/reader033/viewer/2022050212/5f5e3c8ab9626f1108028002/html5/thumbnails/4.jpg)
Infusion fluids
Urine collection bag
Organ chamber
Venous reservoir
Oxygenator
Centrifugal pump
Isolated Organ Perfusion System
![Page 5: Normothermic Kidney Perfusion · ** P](https://reader033.fdocuments.us/reader033/viewer/2022050212/5f5e3c8ab9626f1108028002/html5/thumbnails/5.jpg)
EVNP in Renal Transplantation
Resuscitation to improve early graft function
Pilot series of EVNP (n=36)
Pre-transplant quality and viability assessment
EVNP discarded human kidneys series (n=92)
Pre-transplant therapies and allograft modulation
Noble gases/ nanoparticles
![Page 6: Normothermic Kidney Perfusion · ** P](https://reader033.fdocuments.us/reader033/viewer/2022050212/5f5e3c8ab9626f1108028002/html5/thumbnails/6.jpg)
Aim: To determine the feasibility, safety and efficacy of
normothermic perfusion in marginal donor kidney transplantation
vs
n=36 n=47
ECD 23 all ECD
DCD 8
SCD 5
Pilot Clinical Study
![Page 7: Normothermic Kidney Perfusion · ** P](https://reader033.fdocuments.us/reader033/viewer/2022050212/5f5e3c8ab9626f1108028002/html5/thumbnails/7.jpg)
Back-table prep
- in ice
Recipient Anaesthetised Dissection Transplant bed
Kidney
cold flushed
EVNP 60 min
EVNP Human Pilot Study Protocol
![Page 8: Normothermic Kidney Perfusion · ** P](https://reader033.fdocuments.us/reader033/viewer/2022050212/5f5e3c8ab9626f1108028002/html5/thumbnails/8.jpg)
• 1 unit cross-matched packed red cells + 250 ml crystalloid
• Mean arterial pressure 75 mmHg
• 34-37oC
• TPN (no lipid); Dexamethasone; PGI2
• Co-amoxiclav
• No leucocytes/ little complement
A period of ‘Ideal Perfusion”
EVNP Perfusate
![Page 9: Normothermic Kidney Perfusion · ** P](https://reader033.fdocuments.us/reader033/viewer/2022050212/5f5e3c8ab9626f1108028002/html5/thumbnails/9.jpg)
Ex-vivo Normothermic Perfusion
![Page 10: Normothermic Kidney Perfusion · ** P](https://reader033.fdocuments.us/reader033/viewer/2022050212/5f5e3c8ab9626f1108028002/html5/thumbnails/10.jpg)
EVNP CS P value
N=36 n=47
First CIT (hr) 10.6 ± 3.9 11.8 ± 3.8 0.240
EVNP (min) 63 ±16 -
Second CIT (min) 26 ± 20 -
Anastomosis (min) 26 ± 6 31 ± 4 0.060
Total ischaemia (hr) 12.9 ± 4.5 12.3 ± 3.7 0.614
Ischaemic Times
![Page 11: Normothermic Kidney Perfusion · ** P](https://reader033.fdocuments.us/reader033/viewer/2022050212/5f5e3c8ab9626f1108028002/html5/thumbnails/11.jpg)
• Basiliximab (20mg days 0 & 4)
• Tacrolimus (7-10 ng/ml)
• MMF 0.5g bd
• Prednisolone 20mg 5mg 6/52
Immunosuppression
![Page 12: Normothermic Kidney Perfusion · ** P](https://reader033.fdocuments.us/reader033/viewer/2022050212/5f5e3c8ab9626f1108028002/html5/thumbnails/12.jpg)
0
5
10
15
20
25
30
35
40
45
50
EVNP CS
IF
DGF
Results: Early Graft Function
Number of
patients
DGF: 4/36 vs 17/47
(11%) (36%)
P=0.011
Requirement
for dialysis in
first 7 days
![Page 13: Normothermic Kidney Perfusion · ** P](https://reader033.fdocuments.us/reader033/viewer/2022050212/5f5e3c8ab9626f1108028002/html5/thumbnails/13.jpg)
0
5
10
15
20
25
30
35
40
45
50
EVNP CS
No AR
AR
Number of
patients
AR: 6/36 vs 9/47
(17%) (19%)
P=0.755
Results: Acute rejection
![Page 14: Normothermic Kidney Perfusion · ** P](https://reader033.fdocuments.us/reader033/viewer/2022050212/5f5e3c8ab9626f1108028002/html5/thumbnails/14.jpg)
EVNP CS P value Graft survival 95. 7% 94.3% 0.510 Patient survival 100% 94.3% 1.000
Renal Function
![Page 15: Normothermic Kidney Perfusion · ** P](https://reader033.fdocuments.us/reader033/viewer/2022050212/5f5e3c8ab9626f1108028002/html5/thumbnails/15.jpg)
n=36
Arterial thrombosis 0
Venous thrombosis 0
Renal artery stenosis 0
Ureteric stenosis 1
Infection 0
EVNP: Complications
![Page 16: Normothermic Kidney Perfusion · ** P](https://reader033.fdocuments.us/reader033/viewer/2022050212/5f5e3c8ab9626f1108028002/html5/thumbnails/16.jpg)
EVNP (n=36 kidneys)
• Feasible and straightforward
• Appears to be safe
• May improve early graft function
in marginal donor kidneys
Summary
![Page 17: Normothermic Kidney Perfusion · ** P](https://reader033.fdocuments.us/reader033/viewer/2022050212/5f5e3c8ab9626f1108028002/html5/thumbnails/17.jpg)
0
2
4
6
8
10
12
14
18h CS NP
AT
P:A
DP
ra
tio
ATP : ADP Ratio
**
** P <0.05
Pre CS 18h CS NP
0
5
10
15
20
25
30
35
40
Ex
pre
ssio
n o
f 7
0K
D H
SP
70
vo
lum
e d
ensi
ty (
mm
2)
HSP 70
**
** P <0.05
Reconditioning
![Page 18: Normothermic Kidney Perfusion · ** P](https://reader033.fdocuments.us/reader033/viewer/2022050212/5f5e3c8ab9626f1108028002/html5/thumbnails/18.jpg)
0.0
20.0
40.0
60.0
80.0
100.0
120.0
5 10 15 30 60 90 120 150 180
ml/
min
/10
0g
Reperfusion time (minutes)
Mean Renal Blood Flow
Experimental Evidence
![Page 19: Normothermic Kidney Perfusion · ** P](https://reader033.fdocuments.us/reader033/viewer/2022050212/5f5e3c8ab9626f1108028002/html5/thumbnails/19.jpg)
RCT of EVNP in DCD kidney Transplantation
CS Tx 1h NP
3 Centres
Cambridge, Newcastle and Guy’s
Primary Outcome Measure
Delayed graft function – Dialysis in first 7 days
Number of patients
Total sample size = 400 patients across the 3 centres
Tx CS
![Page 20: Normothermic Kidney Perfusion · ** P](https://reader033.fdocuments.us/reader033/viewer/2022050212/5f5e3c8ab9626f1108028002/html5/thumbnails/20.jpg)
Degree of injury does not necessarily correlate (inversely) with
viability
What is required is a measure of the potential for recovery from injury
- Restoration of function ex-vivo
EVNP: Viability/Quality Assessment of Discarded Human Kidneys
![Page 21: Normothermic Kidney Perfusion · ** P](https://reader033.fdocuments.us/reader033/viewer/2022050212/5f5e3c8ab9626f1108028002/html5/thumbnails/21.jpg)
October 2012 – May 2014
92 Kidneys Declined for Transplantation
Reasons for Decline
Poor Flush 20
Malignancy 18
PMH 11
Donor Age 11
Technical/Anatomical 12
HMP Parameters 8
Histology 6
Prolonged Ischaemia 5
No suitable recipient 1
Demographics (n= 74)
DBD 33
DCD 41
Donor Age (y) 60 ± 15 (31 – 78)
CIT (h) 28.7 ± 13.8 (8.2 – 76.5)
WIT (min) 13.3 ± 3.3 (9 – 20)
Declined Human Kidneys
![Page 22: Normothermic Kidney Perfusion · ** P](https://reader033.fdocuments.us/reader033/viewer/2022050212/5f5e3c8ab9626f1108028002/html5/thumbnails/22.jpg)
EVNP for pre-transplant quality assessment
Declined Kidneys from DCD aged 42 years
Right Kidney: Arrival
Left Kidney: Arrival
5 min EVNP
5 min EVNP
60 min EVNP
60 min EVNP
![Page 23: Normothermic Kidney Perfusion · ** P](https://reader033.fdocuments.us/reader033/viewer/2022050212/5f5e3c8ab9626f1108028002/html5/thumbnails/23.jpg)
Each kidney assessed after 60 minutes of EVNP
1. Visual assessment
1. Measurement of renal blood flow
2. Total urine output
Quality Assessment Score
![Page 24: Normothermic Kidney Perfusion · ** P](https://reader033.fdocuments.us/reader033/viewer/2022050212/5f5e3c8ab9626f1108028002/html5/thumbnails/24.jpg)
Score I: Excellent perfusion (Pink and evenly perfused)
Score II: Moderate perfusion (Pink/purple and patchy appearance)
Score III: Poor perfusion (Global mottled purple appearance)
Score I Score II Score III
n = 27 n = 31 n = 16
Grading: Macroscopic Assessment
![Page 25: Normothermic Kidney Perfusion · ** P](https://reader033.fdocuments.us/reader033/viewer/2022050212/5f5e3c8ab9626f1108028002/html5/thumbnails/25.jpg)
Area Sensitivity Specificity Threshold
RBF 0.892 88% (CI 62 - 99%)
72% (CI 59 - 83%)
< 63ml/min/100g
U/O 0.876 94% (CI 68 - 100%)
81% (CI (69 - 90%)
< 50ml
EVNP Assessment Score Macroscopic Score 1, 2, 3 = 1 - 3 RBF <63ml/min/100g = 1 U/O <50ml = 1 Total scores range from 1 to 5
Perfusion Parameter Thresholds
![Page 26: Normothermic Kidney Perfusion · ** P](https://reader033.fdocuments.us/reader033/viewer/2022050212/5f5e3c8ab9626f1108028002/html5/thumbnails/26.jpg)
Declined kidneys (n=92)
•18 suspected malignancies (excluded)
•35 kidneys scored (1 - 2)
•25 kidneys scored (3 – 4)
•14 kidneys scored (5)
• 262 Unused kidneys (2013 – 2014)
81% suitable for transplantation
Potential extra transplants last year
= 170
Declined Kidney Series
![Page 27: Normothermic Kidney Perfusion · ** P](https://reader033.fdocuments.us/reader033/viewer/2022050212/5f5e3c8ab9626f1108028002/html5/thumbnails/27.jpg)
QUALITY ASSESSMENT SCORE
EVNP Clinical Series
![Page 28: Normothermic Kidney Perfusion · ** P](https://reader033.fdocuments.us/reader033/viewer/2022050212/5f5e3c8ab9626f1108028002/html5/thumbnails/28.jpg)
Score 1 – 2 n = 26
Score 3 – 4 n = 10
P value
Donor Age (y) 56.3 ± 11.4 57.3 ± 19.6 0.462
M : F 8 : 18 6 : 4 0.140
ECD 18 5 0.440
DCD 4 4 0.179
SCD 4 1 1.000
Score 1 – 2 Score 3 - 4 P value
Recipient Age (y) 55.9 ± 12.5 61.2 ± 10.4 0.261
M : F 18 : 8 6 : 4 0.700
Pre Dialysis 6 1 0.645
HD 14 4 0.711
PD 6 5 0.224
Demographics
![Page 29: Normothermic Kidney Perfusion · ** P](https://reader033.fdocuments.us/reader033/viewer/2022050212/5f5e3c8ab9626f1108028002/html5/thumbnails/29.jpg)
Score 1 – 2 n = 26
Score 3 – 4 n = 10
P value
WIT (min) 13.8 ± 2.8 11.3 ± 2.1 0.196
CIT 1 (h) 10.7 ± 4.9 12.3 ± 3.4 0.332
EVNP (min) 65.2 ± 9.9 51.5 ± 13.9 0.002*
CIT 2 (h) 23.4 ± 17.2 33.3 ± 15.0 0.120
Anastomosis (min)
29.5 ± 7.4 26.5 ± 6.7 0.266
Demographics
![Page 30: Normothermic Kidney Perfusion · ** P](https://reader033.fdocuments.us/reader033/viewer/2022050212/5f5e3c8ab9626f1108028002/html5/thumbnails/30.jpg)
Score 1 -2 n = 26
Score 3 – 4 n = 10
P value
PNF 0 0
DGF 1 3 0.056
SGF <10% Cr fall 5 3 0.149
Acute Rejection 3 4 0.076
0
100
200
300
400
500
600
700
800
Pre 1 2 3 4 5 6 7
Cr
(µ
mo
l/L
)
Post-transplant (Days)
Serum Creatinine Levels
Score 1-2
Score 3-4
P = 0.032
*
Outcome
![Page 31: Normothermic Kidney Perfusion · ** P](https://reader033.fdocuments.us/reader033/viewer/2022050212/5f5e3c8ab9626f1108028002/html5/thumbnails/31.jpg)
Score 1 – 2 n = 26
Score 3 – 4 n = 10
P value
Complications 0 0
Patient Survival 100% 100% 1.000
Graft Survival 96.2% 100% 1.000
0
50
100
150
200
250
300
Score 1-2 Score 3-4
Cr
()µ
mo
l/L
)
Serum Creatinine (12 months)
P = 0.018
0
10
20
30
40
50
60
70
80
Score 1-2 Score 3-4
eG
FR
(m
l)
eGFR (12 months)
P = 0.047
Graph Function
![Page 32: Normothermic Kidney Perfusion · ** P](https://reader033.fdocuments.us/reader033/viewer/2022050212/5f5e3c8ab9626f1108028002/html5/thumbnails/32.jpg)
Ischaemia Reperfusion Injury Directly administered to the kidney during EVNP
Transplantation Therapies
Nature Reviews Gastroenterology & Hepatology 10, 79-89 (February 2013)
Therapies
![Page 33: Normothermic Kidney Perfusion · ** P](https://reader033.fdocuments.us/reader033/viewer/2022050212/5f5e3c8ab9626f1108028002/html5/thumbnails/33.jpg)
Mechanisms of Tissue Protection • TNFα mediated ICAM/VCAM
expression • Inhibition of NFκB activity • HIF1α dependent (EPO/VEGF)*
• Anti-apoptotic signalling
*Ma D et al JASN 2009;20:713 Zhao H et al Am J Transplant 2013;13:2006
Irani Y et al. Nephron Extra. 2011;1:272.
Therapies: Argon and Xenon
![Page 34: Normothermic Kidney Perfusion · ** P](https://reader033.fdocuments.us/reader033/viewer/2022050212/5f5e3c8ab9626f1108028002/html5/thumbnails/34.jpg)
17h CS 1h EVNP
10m WIT
1: Argon 70% (n = 5) 2: Control 95%O2 (n = 5) 3: Nitrogen 70% (n = 6)
Reperfusion 3h
Effects of Argon Post-treatment on Renal Ischaemia-reperfusion Injury
![Page 35: Normothermic Kidney Perfusion · ** P](https://reader033.fdocuments.us/reader033/viewer/2022050212/5f5e3c8ab9626f1108028002/html5/thumbnails/35.jpg)
0
10
20
30
40
50
60
70
Argon Control NitrogenRB
F (
ml/
min
/10
0g
)
EVNP Mean Renal Blood Flow
P = 0.020
0,0
10,0
20,0
30,0
40,0
50,0
60,0
0 5 10 15 20 25 30 35 40 45 50 55 60
RB
F (
ml/
min
/10
0g
)
Mean Renal Blood Flow - EVNP Argon
Control
Nitrogen
EVNP Results
![Page 36: Normothermic Kidney Perfusion · ** P](https://reader033.fdocuments.us/reader033/viewer/2022050212/5f5e3c8ab9626f1108028002/html5/thumbnails/36.jpg)
0
50
100
150
200
250
300
350
400
Argon Control NitrogenRB
F (
ml/
min
/10
0g
)
EVNP Total Urine Output
P = 0.030
0
2
4
6
8
10
Argon Control NitrogenCr
Cl
(ml/
min
/10
0g
) EVNP Creatinine Clearance
P = 0.040
EVNP Results
![Page 37: Normothermic Kidney Perfusion · ** P](https://reader033.fdocuments.us/reader033/viewer/2022050212/5f5e3c8ab9626f1108028002/html5/thumbnails/37.jpg)
0
10
20
30
40
50
60
Argon Control NitrogenRB
F (
ml/
min
/10
0g
)
Mean Renal Blood Flow
P = 0.055
0,00
20,00
40,00
60,00
80,00
100,00
0 5 10 15 30 60 90 120 150 180
RB
F (
ml/
min
/10
0g
) Renal Blood Flow
ArgonControlNitrogen
Reperfusion
![Page 38: Normothermic Kidney Perfusion · ** P](https://reader033.fdocuments.us/reader033/viewer/2022050212/5f5e3c8ab9626f1108028002/html5/thumbnails/38.jpg)
0
100
200
300
400
500
600
Argon Control Nitrogen
Ur
ine
Ou
tpu
t (m
l)
Total Urine Output
P = 0.008
0
2
4
6
8
10
Argon Control Nitrogen
Cr
CL
(m
l/m
in/1
00
g).
h
AUC Creatinine Clearance
P = 0.016
Reperfusion
![Page 39: Normothermic Kidney Perfusion · ** P](https://reader033.fdocuments.us/reader033/viewer/2022050212/5f5e3c8ab9626f1108028002/html5/thumbnails/39.jpg)
Therapeutics and Allograft Modulation during EVNP
CD31 (green) Nanoparticles (red) Overlay
Nanoparticles
![Page 40: Normothermic Kidney Perfusion · ** P](https://reader033.fdocuments.us/reader033/viewer/2022050212/5f5e3c8ab9626f1108028002/html5/thumbnails/40.jpg)
Resuscitation
Viability/
Quality
Therapies
Ex-vivo Normothermic
Perfusion
Optimise early graft function
Increased use of
marginal kidneys
Stem cells
Gene therapy
Small molecules
Potential Roles for EVNP
![Page 41: Normothermic Kidney Perfusion · ** P](https://reader033.fdocuments.us/reader033/viewer/2022050212/5f5e3c8ab9626f1108028002/html5/thumbnails/41.jpg)
The ice age is ending