Kidney Transplantation in Infants and Small Children The Good, The Bad, and the Ugly Blanche Chavers, M.D. Professor of Pediatrics University of Minnesota Amplatz Children’s Hospital

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 age figure 6 Incident ESRD rates, by age figure 6.1, per million population, adjusted for gender & race (2001 USRDS ADR)

Incidence of Pediatric End-Stage Renal Disease by Race (per million age adjusted population per year, 2008 USRDS ADR) Black 24 Native American 19 Asian/Pacific Islander 15 White 13

Renal dysplasia/hypoplasia

Prune-belly syndrome Intrauterine bladder outlet obstruction associated with renal dysplasia hypoplasia of abdominal musculature

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, high morbidity/mortality from infection, thrombosis Excellent survival, QOL with BNx @ 4-6 mos, aggressive nutrition, transplant @ 8-10 kgs

Etiology of Kidney Disease in 207 Infants

Treatment Options for ESRD Dialysis Peritoneal Hemodialysis Kidney transplantation

Benefits of transplantation Special issues in 0-5 year olds Benefits of transplantation Improved patient survival Improved growth and development Improved quality of life Avoidance of dialysis complications

Indications for Kidney Transplantation in Children ESRD unresponsive to medical management Progressive growth failure Developmental delay Progressive renal osteodystrophy Failure to thrive

Contraindications 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

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

Very Big Kidney-->Infant & Small Child Special issues in 0-5 year olds: Risks -Graft thrombosis Very Big Kidney-->Infant & Small Child Adult-sized kidney Big Kidney: Hemodynamics Blood flow Blood pressure Blood volume Note: The kidney will shrink to size and GROW with child

Consequences of Hypovolemia Hypotension Renal hypoperfusion Acute tubular necrosis Graft thrombosis/infarction

Protecting intravascular volume following kidney transplantation Vigorous volume-expansion prior to establishing circulation to transplant Replace all urine output (cc for cc) for initial 48-72 hours Maintain: CVP 8-12 BP 90th-95th% tile for age HR 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

Trends in Pediatric Kidney Transplantation 1996-2006 The Good Trends in Pediatric Kidney Transplantation 1996-2006

Impact of ESRD on Growth Younger subjects have greater height deficits at transplantation 0-1 years: -2.21 2-5 years: -2.26 6-12 years: -2.00 13-17 years: -1.41 2008 NAPRTCS Annual Report

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 Infection Rates are Up in Young Pediatric Kidney Transplant Recipients

Infectious hospitalization rates in pediatric vs Infectious hospitalization rates in pediatric vs. adult ESRD patients, by modality: any infection Figure 8.23, 2004 USRDS ADR 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.

Admissions for infection (overall), by age, gender, and time on ESRD: transplant Figure 6.17, incident & prevalent transplant patients, 1997–1999 combined, 2001 USRDS ADR

Cause-specific hospitalization rates in months 6-24 by selected characteristics at month 6 post-transplant (%) 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 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

The Ugly PTLD Rates are Unacceptable in Young Pediatric Kidney Transplant Recipients

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

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

Posttransplant lymphoproliferative disorders after renal transplantation 3 Caillard, et al Transplantation 80:1233, 2005

Posttransplant lymphoproliferative disorders after renal transplantation Caillard, et al Transplantation 80:1233, 2005

7% incidence in 274 recipients Rate varied by age 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 Tabaka Jerry Vincent Jensina Ericksen