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

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1.0

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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