Kidney Transplantation in Infants and Small Children

Blanche Chavers, M.D.Professor of Pediatrics

University of Minnesota Amplatz Children’s Hospital

The Good, The Bad, and the Ugly

Disclosure Information

Blanche Chavers, MD

• I have no financial relationship to disclose

• I will not discuss off label use and/or investigational use of drugs in my presentation

How is ESRD Defined and How Common is it in US Children?

• End stage renal disease - GFR < 15 mL/min/1.73 m2

• 1% of new US ESRD patients

• 1.5% of prevalent US ESRD patients

• On average, 7000 US children receive ESRD treatment each year

Incident ESRD rates, by agefigure 6.1, per million population, adjusted for gender & race

(2001 USRDS ADR)

0.0

5.0

10.0

15.0

20.0

25.0

30.0

35.0

1990

1991

1992

1993

1994

1995

1996

1997

1998

1999

2000

2001

2002

2003

2004

2005

2006

2007

Rate

Per

Mill

ion

Popu

lati

on

Ages 0-4Ages 5-9Ages 10-14Ages 15-19

Incidence of Pediatric End-Stage Renal Incidence of Pediatric End-Stage Renal Disease by RaceDisease by Race

(per million age adjusted population per year, 2008 USRDS ADR)(per million age adjusted population per year, 2008 USRDS ADR)

• Black 24

• Native American 19

• Asian/Pacific Islander 15

• White 13

Renal dysplasia/hypoplasia

Intrauterine bladder outlet obstruction associated with• renal dysplasia• hypoplasia of abdominal musculature

Prune-belly syndrome

Posterior Urethral Valves

FINNISH-TYPE CONGENITAL NEPHROTIC SYNDROME(NPHS1)

Onset of proteinuria occurs in utero

Massive proteinuria edema malnutrition hypothyroidism hypercoagulability infection

With supportive care only: ESRD by 2-3 yrs, highmorbidity/mortality from infection, thrombosis

Excellent survival, QOL with BNx @ 4-6 mos, aggressivenutrition, transplant @ 8-10 kgs

42234

6891011

1826

4262

0 10 20 30 40 50 60 70

Unknown

Anatomic

Jeune's

Steroid res neph s

Hypoxia at birth

Drash

Glomerulonephritis

Hemolytic Uremic S

Polycystic

Cortical Necrosis

Oxalosis

Cong Nephrotic Synd

Obstructive Uropathy

Hypoplasia

Number

Etiology of Kidney Disease in 207 Infants

Treatment Options for ESRD

• Dialysis– Peritoneal– Hemodialysis

• Kidney transplantation

Benefits of transplantation• Improved patient survival

Special issues in 0-5 year olds

• Improved growth and development

• Improved quality of life

• Avoidance of dialysis complications

• ESRD unresponsive to medical management

• Progressive growth failure

• Developmental delay

• Progressive renal osteodystrophy

• Failure to thrive

Indications for Kidney Transplantation in Children

• Active malignancy or less than 12 months post treatment for malignancy

• Human immunodeficiency viral infection

• Positive current T cell crossmatch

• Nonadherence with medical management

Contraindications for Kidney Transplantation in Children

Timing of the Transplant

• Optimal age for kidney transplant in the infant with ESRD remains controversial

• University of Minnesota minimum requirements are 6 months of age and

• 8 - 10 kg in body size

Transplant Surgeon is key

Transplant Nephrologist is key

Pediatric Transplant Team• Pediatric Nephrologist• Surgeon • Anesthesiologist• Urologist• Pediatric Intensivist• Neurologist• Psychiatrist / Psychologist • Dialysis and Transplant Ward Nurses • Transplant Nurse Coordinator • Dietitian• Social Worker• Transplant Pharmacist• Child Family Life Specialist• Occupational/Physical and Speech Therapists

Transplant the patient under the best possible conditions

Optimize medical management pretransplant

Optimize medical management pre transplant

– Early referral and evaluation at transplant center

– Screen for infections

– Ensure up-to-date immunizations including influenza

– Correct urological abnormalities pretransplant

– Optimize dialysis treatment and encourage compliance with treatment regimen

– Correct malnutrition, anemia, acidosis, renal osteodystrophy, growth failure

Optimize medical management pre transplant

– Correct hypercoagulable state

– Pretransplant nephrectomy of native kidneys as indicated

– Document patency of the aorta and inferior vena cava

– Identify potential living donors or list for deceased donor transplantation

– Screen for antileukocyte antibodies in potential deceased donor recipients

– Provide psychosocial support to child and family

Technically Challenging

• Adult-sized kidney• Big Kidney: Hemodynamics

– Blood flow– Blood pressure– Blood volume

Very Big Kidney-->Infant & Small Child

Note: The kidney will shrink to size and GROW with child

Special issues in 0-5 year olds: Risks -Graft thrombosis

Consequences of Hypovolemia

Hypovolemia Hypotension

Acute tubular necrosis Renal hypoperfusion

Graft thrombosis/infarction

Protecting intravascular volume followingkidney transplantation

• Vigorous volume-expansion prior to establishing circulation to transplant

• Replace all urine output (cc for cc) for initial 48-72 hours

• Maintain: CVP 8-12BP 90th-95th% tile for ageHR within normal range

• “Third-space” fluid losses are common in first 24-72 hours after intraperitoneal transplant (bowel manipulation results in bowel wall edema)

• Colloid (albumin) is often necessary to maintain adequate BP and CVP

Adult kidney into small infant

> 900 Pediatric Kidney Transplants

Comparison of Pediatric Renal Txs 1984-2006

Age (yrs) <1 1-5 6-10 11-17 Total

Nation 105 2618 2806 8589 14,118

U of MN 36 146 94 179 450

% U of MN 34 6 3 2 3

Trends in Pediatric Kidney Transplantation 1996-2006

The Good

Impact of ESRD on Growth

»0-1 years: -2.21

»2-5 years: -2.26

»6-12 years: -2.00

»13-17 years: -1.41 2008 NAPRTCS Annual Report

Younger subjects have greater height deficits at transplantation

Trends in Height Z Scores after Kidney Transplant

2004 NAPRTCS Annual Data Report

The Good: Conclusions

• Compared to chronic dialysis, kidney transplantation leads to improved patient survival

• Children aged 0-5 years have the best long-term (5 year) graft survival rates of all kidney transplant recipients

• Improvement in linear growth after transplant is associated with age < 6 years

Infection Rates are Up in Young Pediatric Kidney Transplant Recipients

The Bad

Incident dialysis patients & first-time, kidney-only transplant patients, with Medicare as primary payor; unadjusted. Infectious hospitalizations represent inpatient claims with a principal diagnosis code for infection.

Infectious hospitalization rates in pediatric vs. adult ESRD patients,

by modality: any infection

Figure 8.23, 2004 USRDS ADR

Admissions for infection (overall), by age, gender, and time on ESRD: transplant

0-4 5-9 10-14 15-190

10

20

30

40

50

60

70

80

< 1 year 1 to < 2 years 2 to <5 years 5+ years

Male Female

Age Gender

Adm

issi

ons

per 1

00 p

atie

nt y

ears

at r

isk

Figure 6.17, incident & prevalent transplant patients, 1997–1999 combined, 2001 USRDS ADR

Viral Bacterial

Age at transplant

0-1 years 27.1 25.3

2-5 years 24.5 23.0

6-12 years 14.6 13.3

> 12 years 10.0 11.6

Cause-specific hospitalization rates in months 6-24 by selected characteristics at month 6 post-

transplant (%)

Dharnidharka et al, AJT 4:384, 2004

Prevention of infection after transplant

– Screening of donor and recipient for infections before transplant» CMV, EBV, HIV, Hepatitis A/B/C

– Pretransplant serology

– Ensuring up-to-date immunizations including influenza

– Prophylaxis» Antiviral: ganciclovir, valganciclovir» Antibacterial» Antifungal

The Bad: Conclusions Infection after kidney transplantation• Largest cause of death in pediatric first kidney

transplant recipients -Infection 28.9% (NAPRTCS 2008 ADR)

• The smallest children have the greatest number of infections after kidney transplantation

• Immunizations help prevent vaccine preventable infection posttransplant

• Co-infection is common

PTLD Rates are Unacceptable in Young Pediatric Kidney

Transplant Recipients

The Ugly

Posttransplant Lymphoproliferative Disorder (PTLD)

• 4 -5 x more common in children after kidney transplant than adults

• Usually caused by proliferation of Epstein Barr virus (EBV) infected B cells

• Symptoms– Infectious mononucleosis– Lymphoid hyperplasia– Invasive malignant lymphoma

QuickTime™ and aTIFF (Uncompressed) decompressor

are needed to see this picture.

Posttransplant lymphoproliferative disorders after renal transplantation in the United States in era of

modern immunosuppression

• Patient characteristics– Data obtained from the USRDS

– 25,127 Medicare patients aged 1-98 years, transplanted between 1996 and 2000, 80% with grafts from deceased donors

– 344 (1.4%) developed PTLD (non Hodgkin lymphoma) within the first 3 years of transplant. Mean time to onset was 12 months. 27% mortality

– The incidence in pediatric patients (< 20 years) was 5.8%

Caillard, et al Transplantation 80:1233, 2005

3

Posttransplant lymphoproliferative disorders after renal transplantation

Caillard, et al Transplantation 80:1233, 2005

Posttransplant lymphoproliferative disorders after renal transplantation

Caillard, et al Transplantation 80:1233, 2005

Incidence of PTLD in Pediatric Renal Transplant Recipients Receiving Basiliximab, Calcineurin

Inhibitor, Sirolimus and Steroids

• 7% incidence in 274 recipients

• Rate varied by age – 12% in 0-5 years

– 7% in 6-10 years

– 3% in 11-17 years

– 0% in > 17 years

McDonald, et al AJT 8:984, 2008

Malignancy Prevention in Pediatric Kidney Transplant Recipients

• Pretransplant serology on donor and recipient

• Viral load monitoring in high risk patients– EBV seronegative recipient– Children < 1 year at transplant– Children tested after receiving blood products that might transiently

confer EBV positivity

• Reduce immunosuppression if positive

• Monitor uric acid, LDH, CT scans

The Ugly: Conclusions Malignancy in Pediatric Kidney

Transplant Recipients• Third largest cause of death in first kidney transplant recipients

– Malignancy 10.6%

• Highest rates are seen in the young

• Mean 3-year posttransplant malignancy rates have increased– 1987-1990 1.05%– 1991-1994 1.4%– 1995-1998 2.93%– ≥ 1999 3.0%

2008 NAPRTCS ADR

Conclusions: Pediatric Kidney Transplantation in

Infants and Small Children• Young children have excellent long-term outcomes after

kidney transplantation

• Improvement in linear growth after transplant is associated with age < 6 years

• Infectious complications of immunosuppression are highest in young children

• Highest rates of PTLD are seen in young kidney transplant recipients age ≤ 5 years

Acknowledgements

Katherine TabakaJerry VincentJensina Ericksen