Facing the Organ Shortage Crisis:
Business as Usual vs NonConventional Solutions?
Richard Perez MD
Division of Transplant Surgery
UC Davis Medical Center
Rationale for Transplantation
• Survival benefit vs dialysis
• Improvement in quality of life
• Economic benefit to health care
system
Merion, et al. JAMA 2005
Survival benefit with use of extended criteria donor
kidneys
Merion, et al. JAMA 2006
Our Goal
To make transplantation a
safe option for as many
patients as possible
Patients waiting for kidney
transplantation on
October 2, 2013
97,916
A National Crisis
Waiting list growing – 97,916 today
Transplant rate flat – 16,000+/yr x 8yrs
Transplantation - A victim of its own success:
UC Davis waiting list
California kidney wait list
18,219
2000
2005
2010
SRTR July 2012
UC Davis Kidney Transplantation
More transplants but the donor gap widens
Clinical J American Society of Nephrology 2009
Crisis Response
Business as usual
vs
non-conventional solutions?
Deceased Donor
Transplantation
Making the most of
every opportunity
Organ preservation method
matters
vs
Machine preservation may increase
availability of organs for transplantation
Hypothermic Pulsatile Pump Preservation:
Rationale
– Hypothermic conditions with decreased metabolism
– Simulates normal circulation
– Continuous provision of micro-nutrients
– Removal of toxic waste products and free radicals
– Pulsatile flow stimulates endothelial expression of
vasoprotective genes
Pulsatile Pump Preservation
• Rationale for initiation of pump preservation
– Improved early allograft function
– Lower DGF rates
– Able to exclude kidneys at high risk for primary nonfunction
– Particularly important in ECD and DCD kidneys
– Shorter hospital stay?
Improved graft survival with machine perfusion
Moers, et al. N Engl J Med 2012
Question
How does pulsatile perfusion
preservation impact long term
Extended Criteria Donor allograft
survival?
American Transplant Congress 2009
Machine preservation improves survival of
extended criteria donor kidneys
1.0
Pulsatile
Perfusion
.9
Proportion Survival
.8
.7
.6
Cold
Storage
.5
.4
.3
Patients at risk:
PP 60
45
CS 31
21
.2
.1
30
13
20
9
16
9
2
3
4
.0
0
1
Time after transplant (years)
p = 0.002, log-rank test
American Transplant Congress 2009
University of California, Davis Kidney and Pancreas Transplant Program
Options for Expanding the Deceased Donor Pool
•
•
•
•
•
•
•
Expanded Criteria Donors (ECD)
Donation after Circulatory Death (DCD)
Pediatric en-bloc kidneys (peds-en-bloc)
Dual Adult Kidneys
Donors with Acute Kidney Injury (AKI)
HCV positive donors
Hepatitis B core Ab positive donors
Making more organs available:
Extended Criteria Donors
Age > 60 years old
Or
Age 50 -60 years old + 2 factors below:
1. Death by stroke
2. History of hypertension
3. High serum creatinine
General evaluation of kidneys from extended criteria
donors
• All organ offers evaluated by txp surgeon
• History
– General health maintenance, lifestyle
– Presence of co-morbidities
– History of tobacco use
• Inspection of organs at time of procurement
• Biopsy results
• Pump flow and resistance
Selection of appropriate recipients of ECD or “nonconventional” kidneys
• Wait list management important to maintain a pool of patients eligible
for ECD kidneys
• Ensure appropriate patients in all blood groups
• For certain kidneys with limited renal mass consider allocation of
organ to patients with:
– Presumed lower metabolic needs
• Older age group
• Low BMI
– Low immunologic risk
• Primary transplants
• Non-sensitized patients
Extended Criteria vs Standard Criteria Donors:
2006-2011
84%
76%
SCD = Standard Criteria Donor
ECD = Expanded Criteria Donor
p = 0.012; Log rank test
SCD(n = 344)
ECD (n = 133)
Dual Transplantation of ECD Kidneys
• Offered to patients who will accept ECD
kidneys
• Donor > 55 yo
• Creat Cl 50 – 90 ml/min
• Must be able to tolerate longer surgical
procedure
• Standard immunosuppresion protocol
Dual kidney transplantation with single arterial and
venous anastomoses
Ex vivo vascular
reconstruction prior
to transplantation
D Nghiem, J Urol 2006
Dual adult donation equivalent to standard criteria donation
UCD graft survival (1996-2010)
Percentage Survival
100
90
Dual-ECD (n = 15)
SCD (n = 469)
80
ECD (n = 101)
70
60
50
40
30
20
p = 0.009, log-rank test
10
0
1
2
3
Time after Transplantation (years)
4
5
Hepatitis B Core Ab+ Kidneys
– Informed consent at time of listing
– Offered to patients are immunized (HbsAb+)
– All HbcAb+ donors are tested for viremia (HBV
DNA by PCR)
– Recipient prophylactic antiviral treatment:
•
•
Hepatitis B Immune Globulin pre-transplant.
Entecavir starting POD 1
– Continuation of Entecavir depends on results of
donor HBV DNA and recipient quantitative HBsAb
titer
Deceased Donors with
Acute Kidney Injury
Deceased Donors with AKI:
UC Davis Experience
• AKI group: n= 83
• Control group: n= 620
• Outcome measures:
- rate of DGF (dialysis during 1st week post-txp)
- renal allograft function
- acute rejection in the first year post-transplant
- patient and graft survival
Santhanakrishnan, et al. Amer Transplant Congress 2013
Donor Demographics 2005-2012
AKI (n = 83)
No-AKI (n=620) p value
Donor age (years)
Cold ischemic time (hours)
42 ± 14.4
40 ± 16.4
0.18
23.6 ± 7.46
19.8 ± 9.81
<0.001
Donor Terminal Creat (mg/dl)
3.2 ± 1.37
0.98 ± 0.39
<0.001
26 ± 9.3
105 ± 79.3
<0.001
26.5
18.4
0.08
76
38
<0.001
3.5
18
0.005
Donor e-GFR (mg/min)
Expanded Criteria Donor (%)
Imported graft (%)
Donation Circulatory Death (%)
Santhanakrishnan, et al. Amer Transplant Congress 2013
Recipients of AKI kidneys were older
and less sensitized
AKI (n = 83)
No-AKI (n = 620) p value
Recipient age (years)
57 ± 13.6
54 ± 12.8
0.024
Years on dialysis (mean ±
SD)
PRA at Transplant (%)
3.8 ± 3.11
3.8 ± 2.74
0.9
7 ± 20.4
17 ± 30
<0.001
Santhanakrishnan, et al. Amer Transplant Congress 2013
More Delayed Graft Function in Recipients
of Kidneys with Acute Injury
AKI (n = 83)
p
value
Delayed Graft Function
30 (36%)
No-AKI (n =
620)
124 (20%)
Graft Failure within 90 days
2 (2.4%)
28 (4.5%)
0.6
0 (0%)
10 (1.6%)
0.6
3 (3.6%)
33 (5.3%)
0.79
Recipient Death - 90 days
Acute Rejection within 1st yr
0.001
Santhanakrishnan, et al. Amer Transplant Congress 2013
Excellent survival of allografts with acute renal injury
Donors with AKI (n = 83)
Donors without AKI (n = 620)
1 year graft survival
was 95.9% (AKI) vs
93.3% (control) p =
0.38
P = 0.38; Log rank test
Santhanakrishnan, et al. Amer Transplant Congress 2013
Excellent patient survival of allografts with acute
kidney injury vs donors with normal function
Donors with AKI (n = 83)
Donors without AKI (n = 620)
Pt survival at 1 yr –
98.2 (AKI) vs 96.4%
Pt survival at 3 yr –
89.9% (AKI) vs 92.1%
P = 0.68; Log rank test
Santhanakrishnan, et al. Amer Transplant Congress 2013
Slower recovery of AKI kidneys
p=.03
p=.4
e-GFR (ml/min)
p=.7
p=.017
p<.001
AKI (n = 83)
No-AKI (n = 608)
Santhanakrishnan, et al. Amer Transplant Congress 2013
Kidneys from Small Pediatric Donors
Study Patient Cohort
• Recipients of deceased donor kidneys from
small pediatric donors (<20kg) from June
2007 to November 2012
Results
• 146 patients received kidneys from donors
<20kg
• 89% imported from distant OPOs
• 88% transplanted en bloc
• 55% donors age <6 months old
• 35% donors weighed <5kg
• 34% donors after circulatory death
Graft survival of kidneys from small pediatric
donors
93%
Patients
76
89%
36
24
Addressing the organ shortage crisis:
Importing kidneys that require further
assessment
UC Davis Region 5
U.S.
Transplant rate
21%*
10%
12%
Imported kidneys
64.4%
24.6%
21.8%
Dialysis in 1st week
21.2%
27.8%
23.6%
Waitlist mortality
3.0%*
5.0%
6.0%
Graft survival (1 yr)
92.86%
92.04%
SRTR July 2012
University of California, Davis Kidney and Pancreas Transplant Program
Demographic Data II
Year of
Transplantation
Total # of
DDTx
# of NCDTx
% of NCDTx
2005
49
7
14%
2006
70
20
29%
2007
77
36
47%
2008
79
37
47%
2009
97
53
55%
2010
129
81
63%
2011
213
143
67%
2012 (partial)
142
107
75%
Total
856
484
57%
p < 0.001, Chi-squared test
University of California, Davis Kidney and Pancreas Transplant Program
Demographic Data: 1/2005-7/2012
Non-Conventional Deceased
Donors
n
% of total
DDTx
% of NCDDTx
Expanded Criteria Donors
151
18%
31%
Donors with Circulatory Death
151
18%
31%
Pediatric en-bloc donors
115
13%
24%
Dual-kidney adult donors
19
2%
4%
120
14%
25%
HCV Donors
22
3%
4.5%
HBcAb positive Donors
64
7.5%
13%
484
57%
*>100% due to
dual classification
Donors with Acute Kidney Injury
Total
University of California, Davis Kidney and Pancreas Transplant Program
Delayed Graft and 90 Day Complications
N
DGF
90 Day Graft
Failure
90 Day
Surgical
Complications
SCD
412
1.0
(reference)
1.0
(reference)
1.0
(reference)
ECD
151
2.7
(1.73-4.29)
2.2
(0.98-5.08)
1.4
(0.85 -2.22)
DCD
103
3.4
(2.07-5.62)
2.2
(0.87-5.76)
1.3
(0.71-2.21)
Peds-enbloc
114
1.7
(0.98-2.87)
1.7
(0.63-4.59)
1.7
(1.03-2.86)
AKI
75
3.3
(1.90-5.80)
0.8
(0.19-3.80)
0.7
(0.30-1.44)
Hazard Ratio (95% Confidence Interval)
University of California, Davis Kidney and Pancreas Transplant Program
Patient and Graft Survival, 3 yr eGFR
N
SCD
ECD
DCD
peds-en-bloc
HCV+
Hep BcAb+
AKI/SCD
412
151
103
114
22
64
75
1 yr pt
survival
99%
97%
96%
96%
100%
100%
99%
1 yr graft
survival
95%
88%
91%
89%
96%
97%
93%
*p-value is for eGFR for group vs SCD
5 yr pt
survival
91%
84%
89%
92%
100%
92%
89%
5 yr graft
survival
82%
75%
85%
87%
86%
74%
86%
3 yr e-GFR
ml/min
67 ± 24.7
52 ± 18.8
66 ± 29.7
112 ± 40.8
60 ± 22.5
54 ± 19.9
74 ± 47.2
p Value*
.002
1.0
<.001
1.0
University of California, Davis Kidney and Pancreas Transplant Program
Graft Survival 2005 – 2012
by Type of Donor
SCD/AKI (n = 75)
DCD (n = 103)
Pediatric en-bloc (n = 114)
Living Donors (n = 366)
SCD (n = 412)
ECD (n = 151)
p < 0.001, log-rank test for trend (ECD)
University of California, Davis Kidney and Pancreas Transplant Program
Estimated-GFR
p<.001
e-GFR (ml/min)
110
100
90
80
70
60
50
40
30
20
10
0
by Type of Deceased-Donor
p=.04
p<.001
p=.2
p=.9
p<.001
NCD (n = 484)
Conv (n = 372)
437 vs
404
429 vs
398
426 vs
392
291 vs
338
165 vs
249
111 vs
194
University of California, Davis Kidney and Pancreas Transplant Program
Conclusions
1. The use of non-conventional donors (NCDD) is a viable option for
expanding the deceased donor pool
2. Delayed graft function or slow graft function is more common with NCDD
3. Surgical complications are greater at 90 days with the pediatric en bloc
4. The long term outcome with NCDD transplants is comparable to SCD
outcomes at 3 years.
New technologies for deceased
donor transplantation?
Normothermic perfusion for organ
preservation/pre-conditioning
•
•
•
•
•
Maintain body temperature
Oxygenation
Support aerobic metabolism
Normal physiologic function
Advantages
–
–
–
–
Restore ATP (energy source)
Regeneration and repair processes initiated
Able to assess organ function
Minimize cold ischemia injury
Hosgood / Nicholson, Transplantation 2011
Normothermic Machine Perfusion:
“ECMO for the kidney”
Normothermic Perfusion:
Future Directions
• Routine assessment of high risk/marginal organs
• Normothermic perfusion as a means to intervene and
optimize organ function pre-transplant
– Pharmacologic
– Gene therapy
– Stem cells
• Development of “Organ Repair Centers”
The Future of Transplantation:
Organ Assessment at Regional Repair
Centers
♦
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UC Davis
♦ ♦
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♦
♦
♦
♦
♦ - Donor Hospitals
- Organ Repair Center
The Future of Transplantation:
Organ Reconditioning at Regional Repair
Centers
♦
♦
UC Davis
♦♦
♦
♦
♦
♦♦♦
♦
♦
♦♦
- Organ Repair Center
♦ - Transplant Center
Normothermic kidney perfusion at UC Davis!
April 18, 2013
Making the most of every opportunity in
deceased donor transplantation
• Why?
– There is a survival advantage with
deceased donor renal transplantation
– Improvement in quality of life
Going the extra mile!
• In the face of the organ shortage crisis, we
cannot continue in “business as usual” mode
• Expansion of donor pool by identifying new
organ sources
• “Non-conventional” organ sources
– More resources necessary up front
– Slower recovery of the kidney and management
of patient expectations
• Newer technologies needed