Transplant Kidneys SoonerTransplant Kidneys SoonerDiscard Kidneys LessDiscard Kidneys Less

Francis L. Delmonico, M.D., F.A.C.S.Francis L. Delmonico, M.D., F.A.C.S.

Professor of Surgery,Professor of Surgery,

Harvard Medical SchoolHarvard Medical School

Director, Renal TransplantationDirector, Renal TransplantationMassachusetts General Massachusetts General Hospital Hospital

Medical Director,Medical Director,

New England Organ BankNew England Organ Bank

New England Organ BankNew England Organ Bank

For the year 2000:For the year 2000:

15 % of donors15 % of donors

> 60 years of age> 60 years of age

Discarded: Discarded: 45%45%

New England Organ BankNew England Organ Bank

YearYear < 60< 60 years years > 60 > 60

19981998 29/28529/285 discarded discarded 20/45 20/45

1999 1999 25/27925/279 discarded discarded 21/39 21/39

20002000 47/28947/289 discarded discarded 20/45 20/45____________ ______________101/853101/853 61/129 61/129 11%11% 47% 47%

Discard Rates after Recovery Discard Rates after Recovery of Cadaveric Kidneysof Cadaveric Kidneys

11%

12% 12% 12%

14%

15%

10%

11%

12%

13%

14%

15%

1995 1996 1997 1998 1999 2000*

SRTR analyses of data supplied by OPTN contractor through November 30, 2000SRTR analyses of data supplied by OPTN contractor through November 30, 2000

0

2,000

4,000

6,000

8,000

10,000

1989 1991 1993 1995 1997 1999

Organ Donors UNOSDonorscadaverliving

Recover organs from Recover organs from marginal donormarginal donor

OPO incentivesOPO incentives OPO disincentives OPO disincentives

legal and ethical extensive clinical testinglegal and ethical extensive clinical testing

responsibility responsibility fewer organs fewer organs recoveredrecovered

more organs more organs discardeddiscarded

meet HCFAmeet HCFA difficult to place difficult to place

performance performance cost per organ cost per organ increasedincreased

standards standards organ acquisition fee organ acquisition fee increasedincreased

disappointing to disappointing to staff staff

disappointing to disappointing to familiesfamilies

HCFA Performance StandardsHCFA Performance Standards

Analysis of performance over 24 month periodAnalysis of performance over 24 month perioddivided by two to yield average "annual" resultsdivided by two to yield average "annual" results

Donors / million populationDonors / million populationKidneys recovered / million populationKidneys recovered / million populationKidneys transplanted / million populationKidneys transplanted / million populationExtrarenal organs recovered / million populationExtrarenal organs recovered / million populationExtrarenal organs transplanted / million pop.Extrarenal organs transplanted / million pop.

OPO must achieve > 75% of the national mean OPO must achieve > 75% of the national mean for at least three of the five standardsfor at least three of the five standards

Transplant organs from Transplant organs from marginal donormarginal donor

Center incentivesCenter incentives Center Center disincentivesdisincentives

increase number delayed graft functionincrease number delayed graft function of transplantsof transplants increased increased

rejection rejection longer longer hospital stayhospital stay

assure financial worse long-term outcome assure financial worse long-term outcome stability recipient informed stability recipient informed consentconsent

worse center-specific worse center-specific resultsresults

attract managed managed care disapproval attract managed managed care disapproval care providerscare providers criticism of public criticism of public

presspress

0

10

20

30

40

50

60

Pe

rce

nt

1990 1994 1999

UNOS Kidney Donors

ParentOffspringSiblingRelativeUnrelated

Terasaki, et alTerasaki, et alN Engl J Med 1995N Engl J Med 1995

Effect of DGF

0 1 2 3 4 5 6 7 8 9 10

Id Sib1-haplo SibUnrelatedCadaver

1009080706050403020100

Perc

en

t S

urv

ival

Years Post transplant

2,1293,1402,071

34,572

39.216.116.710.2

n T1/2Relationship

Graft Survival Rates for LRD and LURD grafts

82

64

47

Cecka, M.UNOS

1994-1999

The New England Journal of Medicine -- August 10, 2000 -- Vol. 343, No. 6

Nondirected Donation of Kidneys from Living DonorsArthur J. Matas, M.D., Catherine A. Garvey, R.N., Cheryl L. Jacobs, L.I.C.S.W., M.S.W.

Jeffrey P. Kahn, Ph.D., M.P.H.

As of March 31, 2000, 98 persons had contacted us for information on nondirected donation. 18 of these persons have been evaluated, and 20 are being evaluated or are about to be evaluated; the other 60 persons have not pursued donation. Of the 18 persons who have been evaluated, 6 have been accepted as donors (the transplantation has been performed in 4 cases and scheduled in 2), the evaluation of 1 person is being reviewed, and 11 persons have not been accepted as donors because of medical or psychosocial factors.

The donors for our first four nondirected transplantations have remained anonymous. We elected to admit each donor under an alias.

With the use of organs from living related donors, both the donor and the recipient are usually admitted on the day of surgery. For our nondirected donations, the donors and recipients (each accompanied by family members) were admitted to different parts of the hospital to maintain anonymity.

The operations in the donors and the recipients were performed simultaneously with the use of standard open techniques. The transplanted kidneys functioned immediately. Neither the donors nor the recipients had complications.

High Survival Rates of Kidney Transplants High Survival Rates of Kidney Transplants from Spousal and Living Unrelated Donorsfrom Spousal and Living Unrelated Donors

Paul I. Terasaki, J. Michael Cecka, Paul I. Terasaki, J. Michael Cecka, David W. Gjertson, Steven David W. Gjertson, Steven

TakemotoTakemoto

N Engl J Med 1995; 333: 333N Engl J Med 1995; 333: 333 - - 66

Conclusion:Conclusion:

Spouses are an important source Spouses are an important source of living-donor kidney grafts because, of living-donor kidney grafts because,

despite poor HLA matching, despite poor HLA matching, the graft-survival rate is similar the graft-survival rate is similar

to that of parental-donor kidneys. to that of parental-donor kidneys. This high rate of survival attributed to fact This high rate of survival attributed to fact

kidneys were uniformly healthy.kidneys were uniformly healthy.

Brain dead Brain dead LURD LURD

Cytokine stormCytokine storm none none

CIT CIT 20 hrs 20 hrs < 1 < 1

hourhour

INJURYINJURY

DGF DGF 25%25% < 1% < 1%

00

1010

2020

3030

4040

5050

6060

1212 2424 3636 4848 7272

Cold Ischemia Time (hrs)Cold Ischemia Time (hrs)

Per

cen

t D

GF

Per

cen

t D

GF

The Effect of Cold Ischemia Time on DGFThe Effect of Cold Ischemia Time on DGF

CeckaCeckaUNOSUNOS

1994-981994-98

5,03218,915

9,924

1,282

120

Effect of dialysis within first week of transplant upon outcome

68

79

89

5365

83

0

20

40

60

80

100

3 month 1 year 3 year 5 year

noyes

1999UNOS3m 1 yr96 – 973yr 5 yr89 - 97

CIT may not affect outcomeCIT may not affect outcome

but it may affect rate of discardbut it may affect rate of discard

especially especially

of the marginal donor kidneyof the marginal donor kidney

because well known to affect DGFbecause well known to affect DGF

centers have compelling reasonscenters have compelling reasons

to avoid DGFto avoid DGF

00

1010

2020

3030

4040

5050

6060

7070

1212 2424 3636 4848 7272

Cold Ischemia Time (hrs)Cold Ischemia Time (hrs)

Per

cen

t D

GF

Per

cen

t D

GF 19-30

51-65

Cold Ischemia Time and Donor AgeCold Ischemia Time and Donor Age

Donor age (yrs)

CeckaCeckaUNOSUNOS

1994-981994-98

10

15

20

25

30

356 Match

0 MM

> 0 MM

CIT by Age, Mismatch, Sharing, DGFCIT by Age, Mismatch, Sharing, DGF

No DGFNo DGF DGFDGF

From Dolly Tyan : Crystal City Conference March 28, 2001From Dolly Tyan : Crystal City Conference March 28, 2001

Years PosttransplantYears Posttransplant

Perc

en

t G

raft

Su

rviv

al

Perc

en

t G

raft

Su

rviv

al

(LoG

)(L

oG

)Effect of CIT on Older Donor KidneysEffect of CIT on Older Donor Kidneys

UNOSUNOS1994-991994-99

1010

100100

00 11 22 33 44 55 66 77 88 99 1010

0-240-2425-3625-3637-4837-48

CIT(hrs)CIT(hrs)

DonorDonorageage

19-4519-45

46-6546-65

2020

3030

4040

8080

6060

12,77312,7734,5004,500

609609

11.611.611.511.510.410.4

7,0567,0562,9302,930

445445

8.28.27.77.76.06.0

N T1/2N T1/2 N T1/2N T1/2

46-6546-6519-4519-45

50505252545456565858606062626464666668687070

1818 3030 4040 5050 6060 >60>60Donor AgeDonor Age

Perc

en

t >

18h

r C

ITP

erc

en

t >

18h

r C

ITCold Ischemia Time and Donor AgeCold Ischemia Time and Donor Age

CeckaCecka

Risk of Graft Loss

0

0.5

1

1.5

2

1 to 12 12--18 18-24 24-30 >30

Cold Ischemia Hours

Rela

tive

Ris

k

<55 0 MM

<55 1-6 MM

>55 0MM

>55 1-6 MM

Exhibit 5

From Held and Merion: Crystal City Conference March 28, 2001

1010

100100

00 11 22 33 44 55 66 77 88 99 1010

Years Post transplantYears Post transplant

Perc

en

t G

raft

Su

rviv

al

Perc

en

t G

raft

Su

rviv

al

(Log

)(L

og

)

1919--303031-4531-4546-5546-5556-6556-65>65>65

14178141781069910699

743474344248424812851285

12.712.711.111.1

9.09.06.76.75.45.4

555550504242323224242020

3030

4040

60608080

Effect of Donor Age on Graft SurvivalEffect of Donor Age on Graft Survival

AgAgee

Cecka, M.UNOS

1994-1999

7070606050504040303020201010

0055 1515 4545 5555 6565 >65>65

Donor Donor AgeAge

Tu

rnd

ow

n R

ate

(%)

Tu

rnd

ow

n R

ate

(%)

Turndown Rate for Donor QualityTurndown Rate for Donor Quality

CeckaCecka

1012141618202224262830

Loc<55

Loc55+

Reg<55

Reg55+

Natl<55

Natl55+

6 Match0 MM> 0 MM

Loc55+ Loc55+

cold cold ischemia ischemia timetime

Sharing of kidneys by ageSharing of kidneys by age

Kidney Cold Ischemia Kidney Cold Ischemia by Age, Mismatch, Sharingby Age, Mismatch, Sharing

From Dolly Tyan: Crystal City Conference March 28, 2001From Dolly Tyan: Crystal City Conference March 28, 2001

Current system of HLA matching Current system of HLA matching

as a basis of allocation priorityas a basis of allocation priority

affects preservation timeaffects preservation time

to determine HLAto determine HLA

to identify national matchto identify national match

or necessity of paybackor necessity of payback

to make contact with candidateto make contact with candidate

to determine candidate acceptableto determine candidate acceptable

to transport kidney 12 hours to transport kidney 12 hours

to transplant kidneyto transplant kidney

Why impose the duration of cold Why impose the duration of cold ischemia upon the cadaver kidney?ischemia upon the cadaver kidney?

To achieve 0 mm HLA matchingTo achieve 0 mm HLA matching

and the required paybackand the required payback

which has all of the ischemia and which has all of the ischemia and

none of the HLA match none of the HLA match

55

60

65

70

75

80

85

906 Ag

0 MM

> 0 MM

% 3

Yea

r S

urv

ival

% 3

Yea

r S

urv

ival

3 Year Kidney Graft Survival by Sharing, Age, Mismatch3 Year Kidney Graft Survival by Sharing, Age, Mismatch

< 55 years of age< 55 years of age 55 +55 +

From Dolly Tyan : Crystal City Conference March 28, 2001From Dolly Tyan : Crystal City Conference March 28, 2001

(1)(1) (7)(7)

(10)(10)

(65)(65)

(99)(99)

(data NS)(data NS)

Survival Benefit from Marginal KidneysSurvival Benefit from Marginal Kidneys

0.00

0.50

1.00

1.50

2.00

2.50

3.00

3.50

4.00

0 100 200 300 400 500 600 700

Marginal donor kidney (MDK) recipient

Ideal donor kidney (IDK) recipient

ERER

ES ES

Wait-listed dialysis (WLD) patient

Days since transplantation (Equal time from wait-listing)

Relative Risk (RR) of Death

Compared to WLD IDK MDK Time to Equal Risk (ER) 122d 185d Time to Equal Survival (ES) 256d 531d

Ojo et al. J Am Soc Nephrol 2001; 12: 589.Ojo et al. J Am Soc Nephrol 2001; 12: 589.

Expected Lifetime (years)

7.57.7

8.3

14.4

0

2

4

6

8

10

12

14

16

WaitlistedDialysis Patient

CAD Donor >= 60 yrs

Other MarginalDonors

"Ideal" CAD Donor

Expected Lifetime According to Donor CharacteristicsExpected Lifetime According to Donor Characteristics

SRTR 2001SRTR 2001

The Crystal City kidney work group proposal:The Crystal City kidney work group proposal:

• Allocate older donor kidneys Allocate older donor kidneys >> 60 years of age 60 years of age to a pre-informed group of patients to a pre-informed group of patients based upon waiting time only. based upon waiting time only. • Identify the recipients before organ procurement. Identify the recipients before organ procurement.

• Develop a standard UNOS policy Develop a standard UNOS policy whereby a local OPO could adopt whereby a local OPO could adopt the preferential allocation of 60 year old kidneys the preferential allocation of 60 year old kidneys upon UNOS notification upon UNOS notification of local OPO approval. of local OPO approval.

• Allocation would occur at the level of the OPO Allocation would occur at the level of the OPO except for the identification of a except for the identification of a 6 antigen matched recipient nationally.6 antigen matched recipient nationally.

The Crystal City kidney work group goals:The Crystal City kidney work group goals:

•Increase utilization of older donor kidneys Increase utilization of older donor kidneys by increasing procurement rates by increasing procurement rates and decreasing discard rates;and decreasing discard rates;

•  Improve patient outcomes Improve patient outcomes by decreasing cold ischemia times by decreasing cold ischemia times and delayed graft function;and delayed graft function;

thusthus

•Decrease hospitalization Decrease hospitalization (length of stay) and costs.(length of stay) and costs.

Not all DGF is the same;Not all DGF is the same;

data do not reveal adverse affectdata do not reveal adverse affect

upon outcome at the CIT of 24 hours;upon outcome at the CIT of 24 hours;

benefit of CIT of 4 hours;benefit of CIT of 4 hours;

Why impose the duration of cold Why impose the duration of cold

ischemia upon the cadaver kidney?ischemia upon the cadaver kidney?

Factors by Cecka Factors by Cecka

that increase DGF:that increase DGF:

CIT > 24 hoursCIT > 24 hours

PRA > 50 %PRA > 50 %

Donor > 50 years of ageDonor > 50 years of age

Dialysis > 3 yearsDialysis > 3 years

HLA MismatchesHLA Mismatches

0055

101015152020252530303535

00 11 22 33 44 55 66

Perc

en

t of

Kid

neys

Perc

en

t of

Kid

neys

Zero MM (23.5 hr)Zero MM (23.5 hr)

Contralateral (19.9 hr)Contralateral (19.9 hr)Other MM (21.7 hr)Other MM (21.7 hr)

100100

HLA Matching and Cold HLA Matching and Cold IschemiaIschemia

in 4,000 Kidney Pairsin 4,000 Kidney Pairs

UNOS 1987-1999UNOS 1987-1999

URREAURREA HLA Matching: HLA Matching:

Number of HLA mismatchesNumber of HLA mismatches

Cumulative Cumulative Frequency Frequency

Percent Percent

MismatchMismatch

0 0 4825 4825 13.97 13.97 48254825

1 1 1074 1074 3.11 3.11 5899 5899

17.0817.08

2 2 3955 3955 11.45 11.45 9854 9854

28.5328.53

3 3 7630 7630 22.09 22.09 17484 17484

50.6250.62

4 4 8198 8198 23.74 23.74 25682 25682

74.3674.36

5 5 5833 5833 16.89 16.89 31515 31515

91.2491.24

6 6 3024 3024 8.76 8.76 34539 34539 100100

URREAURREA PRA: PRA:

Cumulative Cumulative Frequency Frequency Percent Percent

PRAPRA

0-9 0-9 31611 31611 85.2385.23

10-79 10-79 2940 2940 7.937.93

80+ 80+ 505 505 1.361.36

Unknown Unknown 2032 2032 5.485.48________ ________

37088 37088 100.00100.00

Degree of HLA MatchDegree of HLA Match

Points are assigned based on # of mm Points are assigned based on # of mm between transplant candidate’s between transplant candidate’s antigens and donor’s antigens.antigens and donor’s antigens.

7 points7 points if there are no B or DR mm; if there are no B or DR mm;

5 points5 points if there is one B or DR mm; and if there is one B or DR mm; and

2 points2 points if there is a total of 2 if there is a total of 2

mismatches at the B and DR loci. mismatches at the B and DR loci.

Obstacles to CIT of < 4 - 6 hoursObstacles to CIT of < 4 - 6 hours

for cadaver donor recipient:for cadaver donor recipient:

Identifying recipient by HLA typing Identifying recipient by HLA typing

and T- cell crossmatching;and T- cell crossmatching;

Communication of organ centerCommunication of organ center

with tissue typing lab and transplant center;with tissue typing lab and transplant center;

Acceptance of kidney by transplant center:Acceptance of kidney by transplant center:finding the recipient finding the recipient

and evaluating to be medically suitableand evaluating to be medically suitable;;

scheduling and performing the transplant.scheduling and performing the transplant.

Hypothesis:Hypothesis:

If the unrelated living donor kidneyIf the unrelated living donor kidney

without the benefit of HLA matchingwithout the benefit of HLA matching

can achieve such a successful outcomecan achieve such a successful outcome

usually with < 1 hour CIT and <1% DGF usually with < 1 hour CIT and <1% DGF

the cadaver donor kidney with the cadaver donor kidney with

< 4 hours CIT, < 4 hours CIT,

reduced rate of DGF,reduced rate of DGF,

and improved regimen of immunosuppression,and improved regimen of immunosuppression,

would achieve a much improved outcomewould achieve a much improved outcome

for a majority of recipients.for a majority of recipients.

UNOS Region 1 kidney transplantsUNOS Region 1 kidney transplants 12.1.97 - 7.31.0012.1.97 - 7.31.00

1063 transplants1063 transplants

Kidneys allocated Kidneys allocated

by Region 1 planby Region 1 plan 54.1%54.1%

by special criteriaby special criteria 5.4%5.4%

0 mismatch Reg 10 mismatch Reg 1 3.1%3.1%

not used in Regionnot used in Region 19.7%19.7%discarded discarded 14.7%14.7%sent out of Regionsent out of Region 5.2%5.2%

exported mandatory shareexported mandatory share 17.7%17.7%

100%100%

0 1 2 3 4 5 6 7 8 9 10

Id Sib1-haplo SibUnrelatedCadaver

1009080706050403020100

Perc

en

t S

urv

ival

Years Post transplant

2,1293,1402,071

34,572

39.216.116.710.2

n T1/2Relationship

Graft Survival Rates for LRD and LURD grafts

82

64

47

Cecka, M.UNOS

1994-1999

Kusaka, M.; Pratschke, J.; Wilhelm, M.; ….Hancock, W.; Tilney, N. Kusaka, M.; Pratschke, J.; Wilhelm, M.; ….Hancock, W.; Tilney, N. Activation of inflammatory mediators in rat renal isografts Activation of inflammatory mediators in rat renal isografts

by donor brain death.by donor brain death. Transplantation 69: 405-10, 2000Transplantation 69: 405-10, 2000

Brain death triggers nonspecific inflammatory events. Brain death triggers nonspecific inflammatory events. In this study,changes in kidney isografts from BD donors In this study,changes in kidney isografts from BD donors compared to normal anesthetized, ventilated controls. compared to normal anesthetized, ventilated controls.

numbers of infiltrating polymorphonuclear leukocytes peaked at numbers of infiltrating polymorphonuclear leukocytes peaked at 24 hr in parallel with intragraft induction of P- and E-selectin, 24 hr in parallel with intragraft induction of P- and E-selectin, complement, and proinflammatory chemokines and cytokines. complement, and proinflammatory chemokines and cytokines.

At 5 days, isografts from BD donors infiltrated by host leukocyte At 5 days, isografts from BD donors infiltrated by host leukocyte populations assoc with up- regulation of products. In contrast, populations assoc with up- regulation of products. In contrast, those from control donors remained relatively normal.those from control donors remained relatively normal. Accelerated rejection of renal allografts from brain dead donors.Accelerated rejection of renal allografts from brain dead donors. Annals of Surgery 232: 263-271, 2000Annals of Surgery 232: 263-271, 2000

0

5

10

15

20

25

30

35

0 1 2 3 4 5 6HLA Mismatches

Perc

en

t

ShorterLonger

0 1 2 3Years Posttransplant

Perc

en

t G

raft

Su

rviv

al

ShorterShorterLongerLonger

3,1093,1093,1093,109

10.19.59.5

n T1/2

100

90

80

70

60

50

40

CIT

CITCIT

7875

HLA Matching and Graft Survival in Recipients ofPaired Cadaver Kidneys with Longer or Shorter CIT

Cecka, Clinical Transplants 1999 (p. Cecka, Clinical Transplants 1999 (p. 13)13)