Cold Machine Perfusion versus Static Cold Storage for SCD, ECD
and DCD Kidneys
Session 6: Devices for Kidney Flushing, Transport and Preservation
William Irish, PhD
CTI Clinical Trial and Consulting Services
September 9, 2011
Disclosure
• Consultant: Y’s Therapeutics
Outline• Delayed graft function
– Incidence and clinical impact
– Risk factors – role of ischemia time
• Kidney preservation
– Preservation solutions
– Storage modalities – cold storage vs. machine perfusion
– Outcomes
– Cost-effectiveness
• Sources of variability
• Unanswered questions/unresolved issues
• Approaching resolution
Delayed Graft Function by Donor Status
0.0
10.0
20.0
30.0
40.0
50.0
19
91
19
92
19
93
19
94
19
95
19
96
19
97
19
98
19
99
20
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20
01
20
02
20
03
20
04
20
05
20
06
20
07
20
08
Pe
rce
nt
DG
F
Year of Transplant
U.S. Renal Data System, USRDS 2010 Annual Data Report: Atlas of Chronic Kidney Disease
and End-Stage Renal Disease in the United States, National Institutes of Health, National
Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, 2010.
ECD deceased donors
Donation after cardiac death
All deceased donors
SCD deceased donors
Living donors
Clinical Impact of Delayed Graft Function
Endpoint With DGF(N=203)
No DGF(N=298)
% AR by 6 months post-transplantOdds Ratio* (95% CI)
33.5
1.9 (1.2 –2.8)
20.1
1.0
AR, Graft failure or death**Hazard rate ratio* (95% CI) 2.1 (1.5 –3.1) 1.0
Graft failure**Hazard rate ratio* (95% CI) 3.1 (1.5 –6.5) 1.0
* Adjusted for MMF vs. no MMF, Europe vs. North America and ANTILFA vs. placebo
** Excludes patients who failed within the first 7 days post-transplant
Danovich G and Irish W for the DGF Study Group. Program and Abstract from the American
Society of Nephrology 2000, October 11-16, Toronto, Canada
Clinical Impact of Delayed Graft Function continued
Yarlagadda et al. Nephol Dial Transplant 24: 1039-1047, 2009
Systematic Review and Meta Analysis
Endpoint Number of Studies
Follow-up Relative Risk (RR)
95% CI for RR
Acute Rejection N=11 1 yr 1.38 1.29 – 1.47
Graft Loss:
Overall N=21 3.5 yrs 1.42 1.24 – 1.63
Excluding AR N=5 3.2 yrs 1.34 1.17 – 1.54
Pooled estimates using random effects model
Clinical Impact of Delayed Graft Function by Donor Type
Source: UNOS/OPTN data as of April 29, 2011
0.0
0.1
0.2
0.3
0.4
0.5
Years Post-Transplant
0 1 2 3 4 5
ECD DGF %
Yes Yes 5.3
Yes No 9.6
No Yes 19.4
No No 65.7
Hazard
s o
f G
raft
Failu
re
Continuous Variables0 10 20 30 40 50 60 70 80 90 100
Peak PRA (%)0 60
Duration Dialysis (days)0 1000 2000 3000 4000 5000 6000 7000 8000
Duration Dialysis Squared8000 7000 6000 5000 4000 3000 1000
Recipient BMI (kg/m2)0 5 10 15 20 25 30 35 40 45
HLA Mismatch0 4
1 5
CIT (hours)0 5 10 15 20 25 30 35 40 45
WIT (minutes)0 30 60 90
Donor Terminal Creatinine (mg/dL)0 0.5 1 1.5 2 2.5 3 3.5 4
Donor Age (years)0 10 25 40 55
Donor Weight (kg)200 160 120 80 40 0
Donor Weight Squared0 60 80 100 120 140 160 180 200
Total Points0 50 100 150 200 250 300 350
Risk of DGF0.10 0.20 0.50 0.70 0.90
Points
6Donor Cause of Death-Cardiovascular
6Donor Cause of Death-Anoxia
6Donor History of Hypertension
27Donation after Cardiac Death
6Recipient Pre-transplant Transfusion
8Recipient Diabetes
5Previous Transplant
9Male Recipient
6Black Recipient
PointsCategorical Variables
Comprehensive Risk Model to Predict Risk of DGF
Irish et al. Am J Transplant 2010;10(10):2279-2286
Cold Ischemia Time and Probabilityof Delayed Graft Function
0
0.05
0.1
0.15
0.2
0.25
0.3
0.35
0.4
0.45
10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30
Pre
dic
ted
Pro
bab
ility
of
DG
F
CIT (Hours)
CIT Odds of DGF
Odds Ratio
30 hours 0.642 1.492
20 hours 0.430 1.0Slope = 0.0084 risk of DGF per 1 hr increase in CIT
Irish et al. Am J Transplant 2010;10(10):2279-2286
Potential Role of Warm Ischemia Timeas a Risk Factor for DGF
Jochmans et al. Ann Surg 2010; 252:756-764
Warm ischemia time*
Adjusted# OR (95% CI) p value
Per 10 minute interval
3.40 (1.87-6.17) <0.001
*Time from circulatory arrest until start of cold perfusion and grouped by 10 minute
intervals with <10 minutes as reference
# Adjusted for donor - and recipient characteristics and type of preservation method
(machine perfusion versus static cold storage)
Warm ischemic time associated with DCD transplants
Kidney Preservation Modalities
LifePort™ Kidney Transporter
for hypothermic machine perfusion
Static Cold Storage1:
US: 80%
Eurotransplant: 100%
1Hartono C, Suthanthiran M Nat Rev Nephr 2009; 5:433-434
Static Cold Storage
Solution Description
University of Wisconsin (UW) solution
- Widely used for preservation of kidney, pancreas and liver transplanted organs since the late 1980s.
- Key additives: adenosine (5mmol/L) and allopurinol (1mmol/L)- Estimated cost per liter = $282.00
Histidine-tryptophanketogluatarate (HTK)
- Used successfully in liver, kidney, pancreas and heart organ solution
- Key additives: histidine (198 mmol/L), ketoglutarate (1 mmol/L) and tryptophan (2 mmol/L)
- Estimated cost per liter = $181.00
Clinical Trials Comparing UW and HTK Solutionsin Deceased Donor Kidney Transplantation
Design/Population
DGF/Graft Survival ResultsAdditional
Results/CommentsHTK UW
1 - Multicenter, randomized study - Donor: deceased, DBD, kidney-
only or kidney + heart (UW: n=168; HTK: n=174)
- Transplant: Kidney-only (UW: n=297; HTK: n=314)
DGF: 33% (95% CI: 28-39%)GSR at:
1 yr = 83%3 yrs = 73%
DGF: 33% (95% CI:28-39%) GSR at:
1 yr = 81%3 yrs = 68%:
- Adjusted Odds ratio for DGF (UW vs. HTK) = 0.918; p=0.64
- Potential survival advantage with HTK vs. UW in recipients with IGF
2 - Single-center, randomized study
- Donor: multiple organ donors- Transplant: Kidney-only or
Kidney-Pancreas (UW: n=27; HTK: n=24)
DGF:50% (95% CI:29-71%)GSR at:
1 yr = 79%
DGF:63% (95% CI:42-81%)GSR at:
1 yr = 78%
- Insufficient sample size
- Long-term GS not presented
- Renal function comparable at 1 yr post-transplant
1. de Boer et al. Transpll Int. 1999;12(6):447-53.
2. Klaus et al. Transplant Proc 2007; 39(2):353-54.
Prolonged Cold Ischemia Time: UW versus HTK in Deceased Donor Kidney Transplantation
Study Solution Donor Age (yrs)
CIT (hrs)
WIT(min)
DGF %(95% CI)
Additional Results
1 HTK (n=40) 42±13 27±3 33±11 50 (34-66) - CrCL (min/L) at 1-yr:HTK = 43UW = 54
- Improved GS at 1-yr with UW
UW (n=67) 39±15 27±3 31±10 24 (14-36)
2 HTK (n=31) 33±19 31±6 38±18 16 (5-34) - Adjusted OR (UW vs. HTK) = 3.8; p=0.028
- Improved GS at 1-yr with HTK
UW (n=38) 31±14 29±6 29±9 56 (39-72)
3 HTK (n=33) - - 27 (13-45)
UW (n=34) - - 26 (13-44)
1. Roels et al. Transplantation. 1998; 66(12): 1660-64
2. Agarwal et al. Transplantation 2006; 81(3): 480-82
3. Lynch et al. Am J Transplant 2008; 8: 567-73
Impact of HTK on Long-term Graft Survival Following Deceased Donor Kidney Transplantation
Stewart et al. Am J Transplant 2009; 9:1048-54
What Does the Evidence Suggest?
• Results are mixed: no clear evidence to discriminate either preservation method
• Conflicting results, due in part, to:– Insufficient sample size– Non-randomized comparisons subject to:
Confounding by indication Selection and reporting biases Differential center-effects Changing patient management practices
• Prospective, randomized, adequately powered studies are still needed; especially in “at-risk” study populations (e.g., ECD, prolonged CIT)
Machine Pulsatile Perfusion
Taylor and Baicu. Cryobiology 2010; 60(3S): S20-S35
Sung et al. Am J Transplant 2008; 8(Part 2): 922-34
Influence of Machine Perfusion on Risk of DGF: Meta-analysis Results#
Wight et al Clin Transplant 2003; 17:293-307
RR* 95% CI P value
All studies (n=15) 0.804 0.672-0.961 0.017
Donation after cardiac death (n=3) 0.847 0.653-1.098 0.210
Donation after brain death (n=5) 0.718 0.572-0.903 0.005
Second transplant (n=5) 0.863 0.667-1.116 0.260
Ischemia time >24 hours (n=5) 0.690 0.540-0.870 0.002
*Relative risk (MP vs. CS) of DGF (DerSimonian and Laird random effects model)
# Included studies in which kidney pairs were allocated between the two preservation methods
Clinical Trial Comparing Static versus Active Perfusion in Deceased Donor Kidney Transplantation
Moers C et al N Engl J Med 2009; 360:7-19
Design/Population
Early Graft Function/Graft Survival Results Additional
Results/CommentsCS(n=336)
MP(n=336)
- Multicenter, donor-match, randomized study
- Donor: deceased, DBD or DCD, 16 years or older, kidney-pair
- Transplant: No restrictions
DGF:26.5% (95% CI:
21.9-31.6%)PNF:
4.8% (95% CI:2.8-7.7%)GSR at:
1 yr = 90%
Functional DGF*: 30.1% (95% CI: 25.2-35.3%)
DGF:20.8% (95%
CI:16.6-25.5%) PNF:
2.1% (95% CI:0.9-4.3%)GSR at:
1 yr = 94%Functional DGF: 22.9% (95% CI: 18.5-27.8%)
- Adjusted Odds ratio for DGF (MP vs. CS) = 0.57; p=0.01
- Potential graft survival advantage with MP vs. CS (Adjusted hazard ratio [MP vs. CS] =0.52; p=0.03)
- Total of 42 kidneys excluded post-storage and prior to analysis
*Defined as the absence of a decrease in the serum creatinine level of at least 10% per day for at least 3 consecutive days
in the first week after transplantation. This category did not include patients in whom acute rejection, CNI toxicity, or both
developed in the first week.
Impact of Machine Perfusion on Risk of DGF by Donor Risk Category
Moers C et al N Engl J Med 2009; 360:7-19
Clinical Trial Comparing Static versus Active Perfusion in DCD Kidney Transplantation
Watson et al Am J Transplant 2010; 10:1991-1999
Design/Population
Early Graft Function/Graft Survival Results Additional
Results/CommentsCS(n=45)
MP(n=45)
- Multicenter, donor-match, randomized study
- Donor: deceased, DCD, adult, kidney-pair
- Transplant: Adults, negative X-match, no previous non-renal transplants
DGF: 56% (95% CI:40- 70%)No PNFCRR5 < 30%: 31/45GSR at:1 yr = 98%
DGF: 58% (95% CI:42- 72%)PNF: 1 case reportedCRR5 < 30%:33/45GSR at:1 yr = 93%
- Trial stopped early for futility
- acute rejection rate at 1 year was 9% in the MP group and 22% in the CS group (p = 0.1)
- eGFR was similar in both groups at 3 and 12 months following transplantation
- Total of 6 kidneys randomized did not undergo perfusion; none excluded from analysis
Unanswered Questions
Does Machine Perfusion Make a Difference Following DCD Only in Older Recipients?
Odds ratio for DGF
Comparison Unadjusted Adjusted
MP versus CS 0.80; P=0.001-
MP versus CS-Age >60 yrs -
0.76; P=0.02
• OPTN database analysis; N=6,057 DCD recipients transplanted between 1993-2008
• Mean follow up: 2.2±2.6 years
Cantafio et al Clin Transplant 2011; DOI: 10.1111/j.1399-0012.2011.01477.x
Does Preservation Modality Affect Outcomes Following Transplantation of ECD Kidneys?
Matsuoka Am J Transplant 2006; 6:1473-1478;
UNOS database analysis of ECD kidneys transplanted between 2000 and 2003
Cold Storage(n=3,706)
Pulsatile Perfusion(n=912)
P-value
DGF (%) 37.1 25.8 <0.001
PNF (%) 3.2 2.6 0.37
AR (%):
Initial hospital stay 7.5 6.8 0.46
At 6 months 16.4 16.0 0.80
At 1 year 18.9 19.0 0.96
Does Preservation Modality AffectLong-Term Graft Survival?
Results of a Meta-analysis
Wight et al Clin Transplant 2003; 17:293-307
CS – cold storage; DBD – donation after brain death; DCD –
donation after cardiac death; MP – machine perfusion
DBD
DCD
MP CS
What About Cost-Effectiveness?
Garfield et al. Transplant Proceedings 2009; 41:3531-36
• Modeling inputs based mostly on the European Machine Preservation Trial
• Assumes a higher utilization of machine perfusion (80%) for ECD kidneys
than for SCD kidneys (20%)
• Cost drivers: DGF, dialysis, acquisition cost, transplant hospitalization,
transplant maintenance
• Primary clinical endpoint (utility) is graft survival at one-year post-transplant
Approaching Resolution
Sources of Variability• Definitions of DGF1
– Lack of a standardized definition
– Dialysis-dependent: requirement within 7-10 days
– Creatinine-dependent: increase/insufficient reduction within 3 days
• Study design– Randomized vs. non-randomized
comparison
– Insufficient sample size
• Center effects– Kidney discard rate
– Staff resources and experience
– Patient management strategies
• Donor type– SCD vs. ECD
– DBD vs. DCD
• Organ treatment– Variable cold ischemia time
– Warm ischemia time (sp. uncontrolled DCD) not adequately studied
• Early exposure to calcineurin inhibitors
1Yarlagadda SG et al Nephrol Dial Transplant 2008; 23:2995-3003
Accounting for Variability
• How it:
– Affects outcome
– Choice of preservation modality
– Type of donor organ
