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Facing the Organ Shortage Crisis: Business as Usual vs Non-Conventional 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. - PowerPoint PPT Presentation
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Facing the Organ Shortage Crisis: Business as Usual vs Non-Conventional Solutions?
Richard Perez MDDivision 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 todayTransplant rate flat – 16,000+/yr x 8yrs
Transplantation - A victim of its own success:UC Davis waiting list
20052000 2010
SRTR July 2012
California kidney wait list18,219
UC Davis Kidney TransplantationMore 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
Machine preservation may increase availability of organs for transplantation
vs
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 non-
function – 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
p = 0.002, log-rank test
Time after transplant (years)
43210
Prop
ortio
n Su
rviv
al
1.0
.9
.8
.7
.6
.5
.4
.3
.2
.1
.0
Machine preservation improves survival of extended criteria donor kidneys
Patients at risk:PP 60 45 30 20 16CS 31 21 13 9 9
Pulsatile Perfusion
ColdStorage
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 oldOr
Age 50 -60 years old + 2 factors below:1. Death by stroke2. History of hypertension3. 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 “non-conventional” 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
SCD(n = 344)
ECD (n = 133)
p = 0.012; Log rank test
84%
76%
SCD = Standard Criteria Donor
ECD = Expanded Criteria Donor
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
D Nghiem, J Urol 2006
Ex vivo vascular reconstruction priorto transplantation
Time after Transplantation (years)
Per
cent
age
Surv
ival
100
90
80
70
60
50
40
30
20
10
0
Dual adult donation equivalent to standard criteria donation UCD graft survival (1996-2010)
1 2 3 4 5
SCD (n = 469)ECD (n = 101)
Dual-ECD (n = 15)
p = 0.009, log-rank test
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 2005-2012AKI (n = 83) No-AKI (n=620) p value
Donor age (years) 42 ± 14.4 40 ± 16.4 0.18
Cold ischemic time (hours) 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
Donor e-GFR (mg/min) 26 ± 9.3 105 ± 79.3 <0.001
Expanded Criteria Donor (%) 26.5 18.4 0.08
Imported graft (%) 76 38 <0.001
Donation Circulatory Death (%) 3.5 18 0.005
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) 3.8 ± 3.11 3.8 ± 2.74 0.9
PRA at Transplant (%) 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) No-AKI (n = 620)
p value
Delayed Graft Function 30 (36%) 124 (20%) 0.001
Graft Failure within 90 days 2 (2.4%) 28 (4.5%) 0.6
Recipient Death - 90 days 0 (0%) 10 (1.6%) 0.6
Acute Rejection within 1st yr 3 (3.6%) 33 (5.3%) 0.79
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)
P = 0.38; Log rank test
1 year graft survival was 95.9% (AKI) vs 93.3% (control) p = 0.38
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)
P = 0.68; Log rank test
Pt survival at 1 yr – 98.2 (AKI) vs 96.4%Pt survival at 3 yr –89.9% (AKI) vs 92.1%
Santhanakrishnan, et al. Amer Transplant Congress 2013
Slower recovery of AKI kidneys
e-GF
R (m
l/min
)
7 days
30 days
90 days1 ye
ar
2 years
AKI (n = 83)
No-AKI (n = 608)
p<.001
p=.7
p=.017
p=.03p=.4
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% 89%
Patients 76 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 IIYear 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: 1/2005-7/2012Non-Conventional Deceased
Donorsn % 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%
Donors with Acute Kidney Injury 120 14% 25%HCV Donors 22 3% 4.5%HBcAb positive Donors 64 7.5% 13%
Total 484 57% *>100% due to dual classification
University of California, Davis Kidney and Pancreas Transplant Program
Delayed Graft and 90 Day Complications N DGF 90 Day Graft
Failure90 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-en-bloc
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
N 1 yr pt survival
1 yr graft survival
5 yr pt survival
5 yr graft survival
3 yr e-GFR ml/min
p Value*
SCD 412 99% 95% 91% 82% 67 ± 24.7 ECD 151 97% 88% 84% 75% 52 ± 18.8 .002 DCD 103 96% 91% 89% 85% 66 ± 29.7 1.0
peds-en-bloc 114 96% 89% 92% 87% 112 ± 40.8 <.001 HCV+ 22 100% 96% 100% 86% 60 ± 22.5
Hep BcAb+ 64 100% 97% 92% 74% 54 ± 19.9 AKI/SCD 75 99% 93% 89% 86% 74 ± 47.2 1.0
Patient and Graft Survival, 3 yr eGFR
*p-value is for eGFR for group vs SCD
University of California, Davis Kidney and Pancreas Transplant Program
Graft Survival 2005 – 2012by Type of Donor
Living Donors (n = 366)
DCD (n = 103)Pediatric en-bloc (n = 114)
SCD (n = 412)
ECD (n = 151)
p < 0.001, log-rank test for trend (ECD)
SCD/AKI (n = 75)
University of California, Davis Kidney and Pancreas Transplant Program
Estimated-GFRby Type of Deceased-Donor
0102030405060708090
100110
e-GF
R (m
l/min
)
7 days
30 days
90 days
1 year
2 years
NCD (n = 484)
Conv (n = 372)
3 years
p<.001
p<.001p<.001
p=.04p=.2
p=.9
437 vs404 165 vs
249111 vs194
426 vs392
291 vs338
429 vs398
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
♦ ♦
♦
♦ - Donor Hospitals
UC Davis
♦
♦
♦ ♦♦
♦
♦
- Organ Repair Center
♦
The Future of Transplantation:Organ Reconditioning at Regional Repair
Centers
♦
♦♦
♦ ♦♦♦
♦
♦
♦ ♦
♦♦♦
♦ - Transplant Center
UC Davis
- Organ Repair 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