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Clinical Indicators of Renal Allograft LossClinical Indicators of Renal Allograft Loss

Lawrence Y.C. Agodoa, MD FACPJon J. Snyder, MSBertram L. Kasiske, MDAllan J. Collins, MD FACP

United States Renal Data System

Department of Health and Human ServicesNational Institutes of HealthNational Institute of Diabetes and Digestive and Kidney Diseases

DEPARTMENT OF HEALTH & HUMAN SERVICESPublic Health Service National Institutes of Health

National Institute of Diabetes and Digestive and Kidney Diseases Bethesda, Maryland 20892

National Institute of Diabetes and Digestive and Kidney Diseases

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Time Trends in Transplants in the USTime Trends in Transplants in the US

0

2000

4000

6000

8000

10000

12000

14000

Year of Transplant

No

. o

f T

ran

sp

lan

ts

Total Cadaveric Living Live Unrel

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Renal Allograft Survival Probabilities, US; adjusted for age, gender, race and primary diseaseRenal Allograft Survival Probabilities, US; adjusted for age, gender, race and primary disease

93.5 96.3

88.293.8

83.890.3

77.1

85.4

64.6

76.3

34.6

52

0102030405060708090

100

Su

rviv

al P

rob

abil

itie

s

90 -day 1 year 2 - year 3 - year 5 - year 10 - year

Donor source

Cadaver Living

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Causes of Renal Allograft LossCauses of Renal Allograft Loss

Acute – Mechanical- Immune mediated

Early - Immune mediated- Non-immune

Late - Non-immune

I M M U N O L O G I C

NON- IMMUNOLOGIC

Clinical Indicators

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Study ObjectivesStudy Objectives

Determine how various clinical indicators affect graft survival in the cadaveric and living donor transplant recipients.

Three outcomes were considered: Graft failure (including death) Death-censored graft failure (graft loss without death) Death with functioning graft

Due to factors unique to cadaveric vs. living donor recipients, cadaveric transplant recipients are analyzed separately from recipients of living donor transplants.

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Analytical MethodsAnalytical Methods

The effects of various factors on graft failure, death-censored graft failure, and death with function were analyzed for the living donor and cadaveric donor populations using Cox proportional hazards models.

The results include: Trends in first-year graft survival Trends in conditional half-lives. Overall survival curves Relative risks associated with each covariate.

All results are adjusted for all other covariates.

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PopulationPopulation

All first, renal-only transplants in the United States from 1995 to 2001 with known recipient age and known donor type:

N=76,467 Living Donor

Transplants: 28,469 Cadaveric Donor

Transplants: 47,998

Follow-up through 9/30/2002.

37%

17%

63%

16%

11%

25%

26%

5%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Parent

Child

Identical Twin/2 Hap. Sib.

Other Sibling

Unknown

Distant/Unrelated

Cadaveric

Living

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Trends in First-Year Graft SurvivalTrends in First-Year Graft Survival

80%

82%

84%

86%

88%

90%

92%

94%

96%

98%

100%

80%

82%

84%

86%

88%

90%

92%

94%

96%

98%

100%

Cadaveric Living

Death-Censored Graft Failure Death with FunctionGraft Failure

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Trends in Conditional* Half-LivesTrends in Conditional* Half-Lives

0

10

20

30

40

50

60

70

Ye

ars

Pa

st F

irst

Ye

ar

0

10

20

30

40

50

60

70

Ye

ars

Pa

st F

irst

Ye

ar

Cadaveric Living

Death-Censored Graft Failure Death with FunctionGraft Failure

*Conditional on 1 year graft survival

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Estimated Graft Survival 1995-2001Estimated Graft Survival 1995-2001

50%

60%

70%

80%

90%

100%

0 12 24 36 48 60 72

Months

50%

60%

70%

80%

90%

100%

0 12 24 36 48 60 72

Months

Cadaveric Living

Death-Censored Graft Failure Death with FunctionGraft Failure

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Clinical IndicatorsClinical Indicators

Factors Associated with both cadaveric and living donor transplants

Factors associated with cadaveric transplants

Factors associated with living donor transplants

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Clinical Indicators: Recipient AgeClinical Indicators: Recipient Age

0.00

0.50

1.00

1.50

2.00

2.50

3.00

0-17 18-34

35-49

50-64

65+

Recipient Age (ref: 18-34)

Re

lativ

e R

isk

0.00

0.50

1.00

1.50

2.00

2.50

3.00

0-17 18-34

35-49

50-64

65+

Recipient Age (ref: 18-34)R

ela

tiv

e R

isk

Cadaveric Living

Death-Censored Graft Failure Death with FunctionGraft Failure

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Clinical Indicators: Recipient GenderClinical Indicators: Recipient Gender

1.0

1

0.9

7

1.0

60.70

1.00

1.30

Male (reference: Female)

Re

lativ

e R

isk

Cadaveric Living

Death-Censored Graft Failure Death with FunctionGraft Failure

0.9

0

0.7

8

1.1

5

0.70

1.00

1.30

Male (reference: Female)

Re

lativ

e R

isk*

*

*

*

* p< 0.05

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Clinical Indicators: Recipient RaceClinical Indicators: Recipient Race

1.1

2

0.7

2

0.8

8

1.3

2

0.7

9

0.8

6

0.8

6

0.6

2

0.8

90.20

1.00

1.80

Bla

ck

Asia

n

Oth

er

Bla

ck

Asia

n

Oth

er

Bla

ck

Asia

n

Oth

er

Race (reference: White)

Re

lative

Ris

k

Cadaveric Living

Death-Censored Graft Failure Death with FunctionGraft Failure

0.9

0

0.6

4

1.1

5

0.9

5

0.5

9

1.3

1

0.8

6

0.6

9

0.8

0

0.20

1.00

1.80

Bla

ck

Asia

n

Oth

er

Bla

ck

Asia

n

Oth

er

Bla

ck

Asia

n

Oth

er

Race (reference: White)R

ela

tive

Ris

k

*

**

*

* ** * *

*

* p<0.05

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Clinical Indicators: Recipient Hispanic EthnicityClinical Indicators: Recipient Hispanic Ethnicity

0.7

4

0.8

3

0.6

30.50

1.00

1.50

Hisapanic (ref: Non-Hispanic)

Re

lativ

e R

isk

Cadaveric Living

Death-Censored Graft Failure Death with FunctionGraft Failure

0.7

8

0.8

4

0.6

5

0.50

1.00

1.50

Hispanic (ref: Non-Hispanic)

Re

lativ

e R

isk

**

**

**

* P < 0.05

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Clinical Indicators:Primary Cause of Renal FailureClinical Indicators:Primary Cause of Renal Failure

1.2

6

1.1

3

0.7

8

1.0

1

0.9

1.0

5

0.8

0.8

7

2.0

2

1.3

5

0.8

2

1.3

6

0.00

0.50

1.00

1.50

2.00

2.50

Dia

be

tes

Hyp

erte

nsio

n

CK

DO

the

r

Dia

be

tes

Hyp

erte

nsio

n

CK

DO

the

r

Dia

be

tes

Hyp

erte

nsio

n

CK

D

Oth

er

PCOD (reference: GN)

Re

lative

Ris

k

Cadaveric Living

Death-Censored Graft Failure Death with FunctionGraft Failure

1.1

5

1.0

8

0.7

4

0.8

8

0.7

3

0.9

9

0.6

1

0.7

4

2.3

7

1.4

9

1.1

6

1.4

0.00

0.50

1.00

1.50

2.00

2.50

3.00

Dia

be

tes

Hyp

erte

nsio

nC

KD

Oth

er

Dia

be

tes

Hyp

erte

nsio

nC

KD

Oth

er

Dia

be

tes

Hyp

erte

nsio

nC

KD

Oth

er

PCOD (reference: GN)R

ela

tive

Ris

k

*** * **

*

***

* ** * **

*

* *

* p < 0.05

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Clinical Indicators:Pre-transplant Serology: HepatitisClinical Indicators:Pre-transplant Serology: Hepatitis

0.9

9

1.3

4

0.9

6

1.3

5

1.0

5

1.3

4

0.20

1.00

1.80

He

p. B

+

He

p. C

+

He

p. B

+

He

p. C

+

He

p. B

+

He

p. C

+

Pretransplant Serology

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isk

Cadaveric Living

Death-Censored Graft Failure Death with FunctionGraft Failure

0.9

7

1.3

8

1.0

3

1.4

6

0.9

2

1.3

5

0.20

1.00

1.80

He

p. B

+

He

p. C

+

He

p. B

+

He

p. C

+

He

p. B

+

He

p. C

+

Pretransplant SerologyR

ela

tive

Ris

k

* * ** * *

* p < 0.05

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Clinical Indicators: Recipient EducationClinical Indicators: Recipient Education

0.9

1

0.8

6

0.9

70.70

1.00

1.30

College+ (reference: <College)

Re

lativ

e R

isk

Cadaveric Living

Death-Censored Graft Failure Death with FunctionGraft Failure

0.8

2

0.8

2

0.8

3

0.70

1.00

1.30

College+ (reference: <College)

Re

lativ

e R

isk

** * * *

* p < 0.05

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Clinical Indicators: Recipient EmploymentClinical Indicators: Recipient Employment

0.8

7

0.9

3

0.8

00.60

1.00

1.40

Able to Work (ref: Unable)

Re

lativ

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isk

Cadaveric Living

Death-Censored Graft Failure Death with FunctionGraft Failure

0.8

2

0.8

4

0.7

7

0.60

1.00

1.40

Able to Work (ref: Unable)

Re

lativ

e R

isk

**

* * * *

* p < 0.05

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Clinical Indicators: Prior Dialysis TimeClinical Indicators: Prior Dialysis Time

0.20

0.40

0.60

0.80

1.00

1.20

1.40

1.60

1.80

Pre

em

ptive

<1

1-<

2

2-<

3

3+

Prior Dialysis Time (ref: <1)

Re

lativ

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isk

Cadaveric Living

Death-Censored Graft Failure Death with FunctionGraft Failure

0.20

0.40

0.60

0.80

1.00

1.20

1.40

1.60

1.80

Pre

em

ptive

<1

1-<

2

2-<

3

3+

Prior Dialysis Time (ref: <1)R

ela

tive

Ris

k

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Clinical Indicators: Donor Age Clinical Indicators: Donor Age

0.000.200.400.600.801.001.201.401.601.802.00

0-17 18-34

35-49

50-64

65+

Donor Age (ref: 18-34)

Re

lativ

e R

isk

0.00

0.20

0.40

0.60

0.80

1.00

1.20

1.40

1.60

1.80

2.00

<35 35-49 50-64 65+

Donor Age (ref: <35)R

ela

tiv

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isk

Cadaveric Living

Death-Censored Graft Failure Death with FunctionGraft Failure

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Clinical Indicators: Donor GenderClinical Indicators: Donor Gender

1.0

4

1.1

0

0.9

70.60

1.00

1.40

Male (reference: Female)

Re

lativ

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isk

Cadaveric Living

Death-Censored Graft Failure Death with FunctionGraft Failure

1.1

3

1.2

7

0.9

5

0.60

1.00

1.40

Male (reference: Female)

Re

lativ

e R

isk

**

*

*

* p<0.05

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Clinical Indicators: Donor RaceClinical Indicators: Donor Race

1.2

4

0.9

9

1.2

6

1.3

2

0.9

9

1.2

7

1.1

1

0.9

8

1.2

2

0.20

1.00

1.80

Bla

ck

Asia

n

Oth

er

Bla

ck

Asia

n

Oth

er

Bla

ck

Asia

n

Oth

er

Race (reference: White)

Re

lative

Ris

k

Cadaveric Living

Death-Censored Graft Failure Death with FunctionGraft Failure

1.5

0

1.1

3

1.0

0

1.7

8

1.1

8

0.9

4

0.9

9

1.1

1

1.1

4

0.00

0.50

1.00

1.50

2.00

2.50

Bla

ck

Asia

n

Oth

er

Bla

ck

Asia

n

Oth

er

Bla

ck

Asia

n

Oth

er

Race (reference: White)R

ela

tive

Ris

k

** *

*

* **

* p<0.05

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Clinical Indicators: HLA MismatchesClinical Indicators: HLA Mismatches

0.40

0.60

0.80

1.00

1.20

1.40

1.60

0 1 2 3 4 5 6

Mismatches (ref: 3)

Re

lativ

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isk

Cadaveric Living

Death-Censored Graft Failure Death with FunctionGraft Failure

0.40

0.60

0.80

1.00

1.20

1.40

1.60

0 1 2 3 4 5 6

Mismatches (ref: 3)R

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tive

Ris

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Clinical Indicators:Recipient Body Mass Index (BMI)Clinical Indicators:Recipient Body Mass Index (BMI)

0.60

0.80

1.00

1.20

1.40

<18.5 18.5-24.9

25.0-29.9

30.0-34.9

35.0+

BMI (ref: 18.5-24.9)

Re

lativ

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isk

Cadaveric Living

Death-Censored Graft Failure Death with FunctionGraft Failure

0.60

0.80

1.00

1.20

1.40

<18.5 18.5-24.9

25.0-29.9

30.0-34.9

35.0+

BMI (ref: 18.5-24.9)R

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tive

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Clinical Indicators: PRAClinical Indicators: PRA

1.3

7

1.4

6

1.2

50.30

1.00

1.70

PRA > 50% (ref: <= 50%)

Re

lativ

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isk

Cadaveric Living

Death-Censored Graft Failure Death with FunctionGraft Failure

1.1

9

1.2

7

1.0

5

0.30

1.00

1.70

PRA > 50% (ref: <= 50%)

Re

lativ

e R

isk

**

*

* p<0.05

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Clinical Indicators: CMV MatchingClinical Indicators: CMV Matching

1.1

2

1.1

5

1.2

1

1.1

1

1.1

6

1.2

1.1

2

1.1

3

1.2

10.20

1.00

1.80

D-/R

+D

+/R

D+

/R-

D-/R

+

D+

/RD

+/R

-

D-/R

+

D+

/RD

+/R

-

CMV Matching (ref: D-/R-)

Re

lativ

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isk

Cadaveric Living

Death-Censored Graft Failure Death with FunctionGraft Failure

1.0

5

0.9

5

1.1

3

1.0

3

0.9

5 1

1.0

7

0.9

4

1.3

5

0.20

1.00

1.80

D-/R

+D

+/R

D+

/R-

D-/R

+

D+

/RD

+/R

-

D-/R

+

D+

/RD

+/R

-

CMV Matching (ref: D-/R-)R

ela

tive

Ris

k

* * * * * * * * *

* p<0.05

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Clinical IndicatorsClinical Indicators

Factors Associated with both cadaveric and living donor transplants

Factors associated with cadaveric transplants

Factors associated with living donor transplants

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Cadaveric-Specific Clinical Indicators: Donor Traumatic Cause of DeathCadaveric-Specific Clinical Indicators: Donor Traumatic Cause of Death

0.8

7

0.8

2

0.9

6

0.70

1.00

1.30

Trauma (ref: non-trauma)

Re

lativ

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isk

Death-Censored Graft Failure Death with FunctionGraft Failure

***

* p<0.05

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Cadaveric-Specific Clinical Indicators:Cold Ischemia TimeCadaveric-Specific Clinical Indicators:Cold Ischemia Time

0.60

0.80

1.00

1.20

1.40

0-12 13-24 25-36 37+

CIT (ref: 0-12 hours)

Re

lativ

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isk

Death-Censored Graft Failure Death with FunctionGraft Failure

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Cadaveric-Specific Clinical Indicators:Donor Co-morbid ConditionsCadaveric-Specific Clinical Indicators:Donor Co-morbid Conditions

1.0

9

1.2

3

1.1

5

1.3

9

1.0

4

1.0

4

0.50

1.00

1.50

Dia

be

tes

Hyp

erte

nsio

n

Dia

be

tes

Hyp

erte

nsio

n

Dia

be

tes

Hyp

erte

nsio

n

Donor History of:

Re

lativ

e R

isk

Death-Censored Graft Failure Death with FunctionGraft Failure

* **

* p<0.05

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Clinical IndicatorsClinical Indicators

Factors Associated with both cadaveric and living donor transplants

Factors associated with cadaveric transplants

Factors associated with living donor transplants

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Living Donor Clinical Indicators:Donor-Recipient RelationshipLiving Donor Clinical Indicators:Donor-Recipient Relationship

1.5

2

1.0

2

1.1

1

1.0

8

1.2

7

0.5

4

0.7

6

0.7

3

1.5

2

2.2

1.6

4

1.7

1

0.000.501.001.502.002.503.003.50

Pa

ren

t

Ch

ild

Oth

er S

iblin

g

Dista

nt/U

nre

late

d

Pa

ren

t

Ch

ild

Oth

er S

iblin

g

Dista

nt/U

nre

late

d

Pa

ren

t

Ch

ild

Oth

er S

iblin

g

Dista

nt/U

nre

late

d

Living Donor Type (reference: Identical Twin / 2 Haplotype Sibling)

Rel

ativ

e R

isk

Death-Censored Graft Failure Death with FunctionGraft Failure

**

**

* *

* p<0.05

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Clinical Indicators for transplant Outcome: Summary and ConclusionsClinical Indicators for transplant Outcome: Summary and Conclusions

Clinical Indicators that promote allograft loss include: Older age (recipient and donor) Race and ethnicity (recipient and donor) Education and employment status Primary Cause of Renal Disease Longer time on dialysis prior to transplant Hepatitis C and CMV positivity HLA mismatches