State of Pediatric Kidney State of Pediatric Kidney TransplantationTransplantation

Vikas Dharnidharka, MD, MPHMedical Director, Pediatric Kidney

TransplantationUniversity of Florida

ObjectivesObjectives

• To understand unique aspects of pediatrickidney transplantation

• To review the state of pediatric kidney transplantation in the USA

• To inform you about our current initiatives and research at our center

Common aspects in adult and pediatric Common aspects in adult and pediatric kidney transplantkidney transplant

• Transplant offers a survival advantage over the long-term and better quality of life

• Work up of donor and recipient mostly the same

• Allocations also through UNOS• Most surgical aspects are similar, though not

all• Medications used are identical• Many complication issues are similar

Unique aspectsUnique aspects• Smaller volumes per center than in adults (10-30/year versus

50-300/year)• Therefore, pediatricians need multicenter data• Very different primary causes of end-stage renal disease• Allocation issues for pediatrics• Surgical issues• Drug metabolism issues• Work up differences• Vaccinations• Graft and patient survival results• Complications and outcomes:

– Growth– Infections– Post-transplant lymphoproliferative disease (PTLD)

Data SourcesData Sources

• United Network of Organ Sharing (UNOS) and Scientific Registry of Transplant Recipients (SRTR)

• North American Pediatric Kidney Transplant Cooperative Studies (NAPRTCS)

• Stanford University• University of Florida and Shands Transplant

Center

Primary Diagnosis by AgePrimary Diagnosis by Age

0102030405060708090

100

0-1 2-5 6-12 >12Patient Age (Years)

Perc

ent

FSGS GN Other Structural

Compare to adults, where diabetes and hypertension are the two leading causes of ESRD

AllocationAllocation

• Pediatric recipients need to live longer with their transplant

• May need multiple transplants over their lifetimes• UNOS always had preferential schemes for pediatric

kidney, but prior systems did not work• October 2005: new system

– Deceased donors <35 years age, relative priority to pediatric patients after 0 antigen mismatch, highly sensitized patients PRA > 80%, or kidney plus other organ combined transplant

Drop in waiting time

Jump in proportion of deceased donors

Surgical issuesSurgical issues• Thrombosis rate by recipient age group

– < 2 years of age 9.0% – 2-5 years: 5.5% – 6-12 years: 4.4% – > 12 years: 3.5% (P=0.01)

• Thrombosis rate by donor age group– < 5 years age 8.3% – 5-10 years: 4.5% – > 10 years: 3.2% (P<0.001)

• Practice changed: avoid small kidneys to small recipients; perform en bloc instead (superior results)

Singh et al, Transplantation, 1997Dharnidharka. AJT, 2006

Day 30 Maintenance MedicationsDay 30 Maintenance MedicationsPrednisone CyclosporineTacrolimus AzathioprineMMF Sirolimus

Perc

ent

0

20

40

60

80

100

Transplant Year

1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007

Recent drop in chronic steroid use

Drug metabolism in pediatricsDrug metabolism in pediatrics

• Immunosuppressive agents are metabolized much faster in very young children

• CsA may need to be given three times a day, not twice

• Sirolimus may need to be given twice daily, not once a day

• MMF marrow toxicity can be worse in absence of concomitant steroids

Filler et al, Schachter et al

Causes of Graft Failure 1987Causes of Graft Failure 1987--20042004

Cause of Index Subsequent TotalGraft Failure n=2123 n=291 n=2414Chronic Rejection 571 (33%) 101 (35%) 811 (34%)Acute Rejection 277 (13%) 39 (13%) 316 (13%)Thrombosis 220 (10%) 36 (12%) 256 (11%)Death 199 (9%) 22 (8%) 221 (9%)Recurrence 138 ( 7%) 28 (10%) 166 ( 7%)Other 718 (34%) 65 (22%) 644 (27%)

NAPRTCS, 2002

1987-19901991-19941995-19981999-20022003-2007

Perc

ent R

ejec

tion

0

20

40

60

80

100

Months from Transplant

0 12 24 36 48

0

20

40

60

80

100

Time to First Rejection for Index TransplantsTime to First Rejection for Index Transplants

Living Donor

Slope identical after red line

1987-19901991-19941995-19981999-20022003-2007

Perc

ent R

ejec

tion

0

20

40

60

80

100

Months from Transplant

0 12 24 36 48

0

20

40

60

80

100

Time to First Rejection for Index TransplantsTime to First Rejection for Index Transplants

Deceased Donor

Slope not as identical, especially for recent cohort

Graft SurvivalGraft Survival

Living Donor (1987-1995)Living Donor (1996-2007)Deceased Donor (1987-1995)Deceased Donor (1996-2007)

Per

cent

Gra

ft S

urvi

val

30

40

50

60

70

80

90

100

Years From Transplant

0 1 2 3 4 5 6 7

30

40

50

60

70

80

90

100

Worse graft survival in adolescents, also true for living donor

FSGS and Graft SurvivalFSGS and Graft Survival

Baum, KI, 2001

Loss of living donor advantage in FSGS

Patient SurvivalPatient Survival

Living Donor (1987-1995)Living Donor (1996-2007)Deceased Donor (1987-1995)Deceased Donor (1996-2007)

Per

cent

Pat

ient

Sur

viva

l

70

80

90

100

Years from transplant

0 1 2 3 4 5 6 7

70

80

90

100

CreatinineCreatinine ClearanceClearance

0-1 years2-5 years6-12 years>12 years

Cal

cula

ted

clea

renc

e

50

60

70

80

90

100

110

120

Years from Transplant

0 1 2 3 4 5 6 7

0-1 years2-5 years6-12 years>12 years

Cal

cula

ted

clea

renc

e

50

60

70

80

90

100

110

120

Years from Transplant

0 1 2 3 4 5 6 7

Living Donor Deceased Donor

0-1 years2-5 years6-12 years>12 years

Hei

ght Z

Sco

re

-2.5

-2.0

-1.5

-1.0

-0.5

Years from Transplant

0 1 2 3 4 5 6

-2.5

-2.0

-1.5

-1.0

-0.5

HEIGHT Z SCORE

Standardized Score (mean + SE)By Age at Transplant

Infections as ComplicationsInfections as Complications

0

5

10

15

20

25

30

35

1-6 Months 6-24 Months 1-6 Months 6-24 Months

RejectionViralAll Infection

Dharnidharka, AJT, 20041987 2000

%

Causes of DeathCauses of DeathTotal Living Donor Deceased Donor

N %

Functio-inggraft N %

Function-inggraft N %

Function-inggraft

All deceased patients 546 100.0 256 242 100.0 119 304 100.0 137

Cause of Death

Infection,Viral 44 8.1 23 24 9.9 13 20 6.6 10

Infection,Bacterial 69 12.6 34 33 13.6 15 36 11.8 19

Infection, Not Specified 43 7.9 14 22 9.1 7 21 6.9 7

Cancer/malignancy 58 10.6 40 32 13.2 23 26 8.6 17

Cardiopulmonary 84 15.4 39 30 12.4 15 54 17.8 24

Hemorrhage 33 6.0 12 9 3.7 2 24 7.9 10

Recurrence 10 1.8 1 4 1.7 1 6 2.0 0

Dialysis-relatedComplications 16 2.9 0 8 3.3 0 8 2.6 0

Other 136 24.9 67 61 25.2 33 75 24.7 34

Unknown 53 9.7 26 19 7.9 10 34 11.2 16

Infections together = 28.6%, plus malignancies = 39.2%These likely represent overimmunosuppression complications

• Big recent increase in number of recommended vaccines• Variable response to immunizations in ESRD• Increased risk with live virus vaccines post-transplantation• Fully immunize prior to transplantation as far as possible

PTLDPTLDTime to LPD by Era of Transplant

Era of transplant 1987-19921993-19971998-20022003-2006

Per

cent

with

LP

D

0

5

10

15

20

Months from transplant

0 12 24 36 48 60 72 84

•PTLD rate in pediatric kidney transplantation: rose from < 1 to > 3% over the years•PTLD rate in adult kidney transplantation: stayed < 1%•Highest risk factor is EBV donor/recipient mismatch (D+/R-)•Get EBV donor and recipient serology pre-transplant!

SteroidSteroid--free resultsfree results

Better growth

Better GFR

Sarwal, Transplantation, 2003

CCTPTCCTPT• Cooperative Clinical Trials in Pediatric

Transplantation• NIH grant mechanism for multi-center transplant

clinical trials and mechanistic studies, in children• Started in 1994

– IN01 (1994-1999): completed, presented and published– SW01 (1999-2004): completed and presented– SNS01 (2004-2009): data will be presented in 2 months

• Latest:– CTOT-2: looking at post-transplant donor specific antibody

production and pre-emptive rituximab– CTOT-C: just funded

University of Florida Pediatric Kidney University of Florida Pediatric Kidney Transplant ProgramTransplant Program

• Continuously active since early 1970s• We are the only CCTPT participating center in

Florida• We are an above-average volume center, historically

13-15 transplants/year• We offer a steroid-free protocol as standard of care• Short waiting times• Have patients from throughout the state, work with

all groups