1

Long term outcome after renal transplantation

Influence of donor & recipient risk Influence of donor & recipient risk factors and the choice of factors and the choice of

immunosuppressionimmunosuppression

TH Mathew, SP McDonald & GR Russ

ANZDATA Registry & Renal Unit,

The Queen Elizabeth Hospital Adelaide. September, 2001

Source of data – ANZDATA & ANZOD

• Australia & New Zealand Dialysis & Transplant (ANZDATA) Registry – A voluntary registry documenting the outcome of all

dialysis & transplant patients in Aus & NZ since 1965– 100% reporting and follow-up of ~24,000 patients

• Australia & New Zealand Organ Donor (ANZOD)Registry– Has acquired donor information since 1988

• Registries co-located

Long term outcome in renal transplantation

• The short term (1yr) outcome has improved substantially in recent times

• The long term outcome beyond 5 yrs has been little studied

• This study aims to assess the influence of various factors on long term graft (& patient outcome)

• All data is from ANZDATA and ANZOD Registries.

Australia CD1. One year survival 1975-99

30

40

50

60

70

80

90

100

75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99

% s

urv

iva

l

Graft

Patient

Predictive patient & donor characteristics significantly affecting 1yr survival on multivariate

analysis (0n 1993-8 cohort) – Briganti et al

• Donor age p=0.000• HLA mismatches p=0.000• Vascular disease p=0.002• Time on dialysis p=0.004• Year of transplant

p=0.008• Allograft source p=0.044

Long term outcome in renal transplantation

• The short term (1yr) outcome has improved substantially in recent times

• The long term outcome in CD1 & LD1 recipients beyond 5 yrs has been little studied

• This study aims to assess the influence of various factors on long term graft (& patient outcome)

Australia primary patient & graft (CD & LD) survival 1970-94. n = 7623 grafts

0

20

40

60

80

100

0 2 4 6 8 10 12 14 16 18 20 22 24

% s

urvi

val

PatientGraft

Australia primary graft (CD & LD) survival 1970-94. n = 7623 grafts. The decay is exponential.

y = 84.395e-0.065x

R2 = 0.9993

10

20

30

40

50

60

70

80

90

100

2 4 6 8 10 12 14 16 18 20 22 24

% s

urv

ival

Graft

Expon.(Graft)

Australia primary graft survival 1970-94. n = 7623 grafts

0

20

40

60

80

100

% g

raft

su

rviv

als

Graft

Graft (+censor)

1.8%/yr

2.7%/yr

5 Yr+ survival for primary grafts (n= 4353) Australia (1970-94)

0

20

40

60

80

100

5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20

% s

urv

ival

Patient

Graft

4.3%/yr

3.2%/yr

Patient survival after 5 yrs (Aus CD1 & LD1) by selected time periods – the death rate has declined

50

60

70

80

90

100

5 6 7 8 9 10 11 12 13 14 15Years

% S

urv

ival

1970-74 (440)

1975-84 (1266)

1985-89 (1231)

1990-94 (1415)

~3.3-3.7%/yr

The death rate/100 patient years for primary renal grafts beyond 5 yrs is reducing in recent years

4.56

3.61 3.38

0

1

2

3

4

5

Dea

th r

ate

1970-84 1985-89 1990-94

Death rate/100 patient years >5yrs post graftAustralia CD1 & LD1 by period

2.25

1.06

0.540.71

1.42

0.650.49

0.340.5

1.92

0.850.82

0

0.5

1

1.5

2

2.5

Cardio-Vasc Malignancy Infection Other

Dea

th R

ate

1970-84

1985-89

1990-94

Graft survival beyond 5 yrs (Aus CD1 & LD1). The decline is the same in each selected time period

40

50

60

70

80

90

100

5 6 7 8 9 10 11 12 13 14 15

Years

% s

urv

ival

1970-74 (440)

1975-84 (1266)

1985-89 (1231)

1990-94 (1415)

40

50

60

70

80

90

100

5 6 7 8 9 10 11 12 13 14 15

Years

% s

urv

ival

1970-74 (440)

1975-84 (1266)

1985-89 (1231)

1990-94 (1415)

4.8%/yr

Death censored graft fail rate/100 graft/yrs > 5yrs post has increased 33% since 1984

CD1& LD1 Australia

6.63

2.69

6.38

3.35

2

3

4

5

6

7

8

Graft fail rate Death censored graft fail rate

Ra

te/1

00

pt

yrs

1970-84 (1706)

1985-94 (2644)

Cause of graft failure rate The loss from ‘chronic rejection’ is increased in

recent times

3.943.04

2.542.33

0.810.36

0

2

4

6

8

1970-84 (1706) 1985-94 (2644)

graf

ts fa

il/10

0 pt

/yrs

Other

Ch Rejection

Death

Predictive characteristics favoring primary graft survival beyond 5yrs

Significant factors on univariate analysis

• Donor source LD p=0.0002• Donor age <50yr p=0.0002• Donor not ‘marginal’ p=0.002• Donor death trauma p=0.02• Recipient never smoked p=0.0001• Not on CsA at 2 & 5yrs. P=0.0004

Predictive characteristics favoring primary graft survival beyond 5yrs

Non –significant factors on univariate analysis

• Donor hypertensive• Donor oliguric• Donor terminal creatinine >120umol/l • Donor smoked• CsA dose >5mg/kg/d• Primary renal disease• Use of Ab for rejection in 1st 6m• Delayed graft function >7d

Effect of donor source on graft outcome >5yrs (Aus CD1 1985-94 – 2646 grafts)

50

60

70

80

90

100

5 6 7 8 9 10 11 12Years

% S

urvi

val

Cadaver

Live Donor

p <0.0002

5.4%/yr

4%/yr

Effect of donor age on graft outcome >5yrs (Aus CD1 1985-94 – 2646 grafts)

40

50

60

70

80

90

100

5 6 7 8 9 10 11 12 13 14Years

% g

raft

su

rviv

al

Donor <50yrs

Donor >50yrs

p <0.0002

5.4%/yr

4.7%/yr

Effect of recipient smoking on graft outcome >5yrs (Aus CD1 1985-94 – 2646 grafts)

50

60

70

80

90

100

5 6 7 8 9 10Years

% g

raft

sur

viva

l

Never (751)Former (304)Current (142)

p <0.0001 (former v never)

7.8%/yr

7%/yr

5.4%/yr

Graft survival on CsA is reduced >5yrs (Aus CD1 & LD1 n=4009)

50

60

70

80

90

100

5 6 7 8 9 10 11 12 13 14

% g

raft

su

rviv

al

On CsA

No CsA

3.8%/yr

5.3%/yr

p <0.0000

Graft survival (death censored) 5yrs +CsA & no CsA (Aus CD1 & LD1)

50

60

70

80

90

100

5 6 7 8 9 10 11 12 13 14

% s

urv

iva

lss

On CsA

No CsA

3.4%/yr

2.1%/yr

p <0.0000

Predictive characteristics favoring primary graft survival beyond 5yrs

Significant factors on univariate analysis

• Donor source LD* p=0.0002• Donor age <50yr* p=0.0002• Donor not ‘marginal’ p=0.002• Recipient never smoked* p=0.0001• Donor death trauma p=0.02• Not on CsA at 2 & 5yrs* p=0.0004

* Retained significance on multivariant analysis

Multivariate analysis of factors affecting death censored primary graft outcome >5yrs

Significant factorsHR (CI)

• On CsA 1.9 (1.4-2.6)• Recipient smoking 1.86 (1.3-2.6)• Recipient <20yrs 1.55 (1.1-2.1)• Donor Age >50yrs 1.51 (1.2-2.0)• Recipient >50yrs 0.61 (0.5-0.8)• Live donor 0.67 (0.4-1.00)

Multivariate analysis of factors affecting death censored primary graft outcome >5yrs

Non -Significant factors

• Mismatch on HLA• Marginal donor status• Vascular disease at entry• Year of transplant• Cause of donor death

The effect of CsA on long term graft (death censored) outcome

• Is statistically and clinically significant : - – 10% difference over ten yrs– Most evident in those with S Cr <140umol/L at 1 yr

• Not accounted for by – donor source or quality– vascular disease pre entry

• The patients on CsA had– worse matching (-)– more recipients >50yrs (+)– more marginal donors (-)– more smokers (-)

(all marginally significant)

European Multicenter trial (Transpl Proc 25:527, 1993)

Data redrawn with 5yr survival adjusted to 100%. (ITT)

60

70

80

90

100

5yrs 6 7 8 9 10

% s

urv

iva

l

CsA (n=117)

Aza/Pred (n=115)

4%/yr

2.2%/yr

Conclusions on graft loss beyond 5 years

• Grafts fail after 5 years through1. Death. The death rate is currently decreasing & now

accounts for 48% of losses2. Graft failure. The rate of loss is increasing due to an

increase in ‘chronic rejection’ & ‘other’ causes

• Increased risk of late graft loss (death censored) with– Continuing exposure to CsA, donor age >50yrs,

recipient age <20yrs, recipient smoking

• Decreased risk of late graft loss (death censored) with– Recipients >50yrs, live donors