Kidney Transplantation in Infants and Small Children

1. 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

2. Disclosure InformationBlanche 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

3. 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

4. Incident ESRD rates, by agefigure 6.1, per million population, adjusted for gender & race(2001 USRDS ADR)

5. 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

6. Renal dysplasia/hypoplasia

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

8. Posterior Urethral Valves

10. 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

11. Etiology of Kidney Disease in 207 Infants

12. Treatment Options for ESRD • Dialysis • Peritoneal • Hemodialysis • Kidney transplantation

13. 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

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

15. 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

16. 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

17. Transplant Nephrologist is key Transplant Surgeon is key

18. 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

19. Transplant the patient under the best possible conditions Optimize medical management pretransplant

22. 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

23. 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

26. Technically Challenging

27. 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

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

29. 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

30. Adult kidney into small infant

31. > 900 Pediatric Kidney Transplants

32. Comparison of Pediatric Renal Txs 1984-2006

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

38. 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

39. Trends in Height Z Scores after Kidney Transplant 2004 NAPRTCS Annual Data Report

40. 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

41. The Bad Infection Rates are Up in Young Pediatric Kidney Transplant Recipients

42. 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.

43. 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

44. Cause-specific hospitalization rates in months 6-24 by selected characteristics at month 6 post-transplant (%) Dharnidharka et al, AJT 4:384, 2004

45. 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

47. The Bad: ConclusionsInfection 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

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

49. 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

50. 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