World Kidney Day 2016: Kidney Disease & Children World Kidney Day 2016: Kidney Disease & Children. Act Early to Prevent It!

World Kidney Day 2016: Kidney Disease & Children World Kidney Day 2016: Kidney Disease & Children. Act Early to Prevent It! Kidney disease affects millions of people worldwide, including many children who may be at risk at an early age. It is therefore crucial that we encourage and facilitate education, early detection and a healthy life style in children, to fight the increase of preventable kidney diseases and to treat children with inborn and acquired disorders of the kidneys worldwide.

Pediatric Kidney Disease – An Update Edited by the ASPN Clinical Affairs Committee

Kidney Transplant Mini Michael, MD, MMed (Clin Epi) Texas Children’s Hospital, Baylor College of Medicine Jodi M. Smith, MD, MPH Seattle Children’s Hospital, University of Washington School of Medicine

Transplant: Objectives Introduction Epidemiology Immunosuppression Outcome: graft and patient survival Unresolved issues in Pediatric Renal Transplantation (RTx) Global Inequalities in Access to Pediatric RTx Summary and future

Transplant: Introduction Renal transplant is the optimal treatment for children with end-stage renal disease (ESRD) Incidence of ESRD in children varies throughout the world United States: ~14.8 cases per million Japan: ~ 4 cases per million Europe: ~ 8.3 cases per million but varies greatly among countries Developing world: Limited data Available estimates range from 3.4 pmcp (per million children population) in Turkey to a high of 35 pmcp in Kuwait Higher incidence in US may be due to earlier initiation of renal replacement therapy

Transplant: Epidemiology NAPRTCS (North American Pediatric Renal Trials and Collaborative Studies) Annual Report 2014: Gender: Males 59% Race: White 59%, Black 17% and Hispanics 17% Age at transplant: age groups in years: 0-1: 5%; 2-5: 15%; 6-12: 32%; 13-17: 39% and >18 : 8% Most common primary diagnosis: Aplastic/hypoplastic/dysplastic kidneys (in 15.8%) Obstructive uropathy (in 15.3%) Focal segmental glomerulosclerosis (FSGS) is the third most common (11.7%) and continues to be the most prevalent acquired renal disease. Based on NKF data 712 renal transplants performed in children <18 yrs in 2014 (470 DD RTx and 242 LD RTx)

Transplant: Epidemiology - Donor Type 50% of all transplants have involved a deceased donor (DD) source, 40% came from a parent and 10% from other living donors (LD) Advantages of living donor renal transplant Pre-emptive transplantation Fewer rejection episodes Incidence of delayed graft function is lower Better graft survival Better graft function

Transplant: Advantages Improved growth and development Improved patient survival Improved quality of life Cost effective

Transplant: Immunosuppression Three general approaches: To deplete circulating lymphocytes by destroying them To use an inhibitor of lymphocyte activation (cyclosporine or tacrolimus) To use various metabolic inhibitors (azathioprine, mycophenolate mofetil [MMF]) to interfere with lymphocyte proliferation essential for amplification of the response

Transplant: Site of Action of Immunosuppressive Drugs Figure 2. Stages of T cell activation: multiple targets for immunosuppressive agentsSignal 1: Stimulation of T cell receptor (TCR) results in calcineurin activation, a process inhibited by cyclosporin (CyA) and tacrolimus. Calcineurin dephosphorylates NFAT (nuclear factor of activated T cells) enabling it to enter nucleus and bind to interleukin-2 promotor. Corticosteroids inhibit cytokine gene transcription in lymphocytes and antigen-presenting cells by several mechanisms. Signal 2: Costimulatory signals are necessary to optimise T cell interleukin-2 gene transcription, prevent T cell anergy, and inhibit T cell apoptosis. Experimental agents but not current immunosuppressive agents interrupt these intracellular signals. Signal 3: Interleukin-2 receptor stimulation induces cell to enter cell cycle and proliferate. Signal 3 may be blocked by interleukin-2 receptor antibodies or by sirolimus, which inhibits second messenger signals induced by interleukin-2 receptor ligation. Following progression into cell cycle, azathioprine and mycophenolate mofetil (MMF) interrupt DNA replication by inhibiting purine synthesis. The Lancet. Vol 353. March 27, 1999

Transplant: Graft and Patient Survival Both graft & patient survival significantly better in LD vs. DD recipients In both donor types, improved graft and patient survival in most recent transplant era (2005-2013) as compared to older eras NAPTRCS 2014

Transplant: Major Issues Medication non-adherence Major cause of rejection and graft failure Adolescents with poor social support more affected Recurrence of FSGS post-transplant Results in graft failure in >60% Limited prevention/treatment options High PRA: Major focus of new kidney allocation system Recipients with CPRA of >80% receive additional priority points Recipients with CPRA of 98, 99 and 100% receive local, regional, and national priority, respectively Transplant in small children

Transplant: Global inequalities to access Pediatric RTx performed in >60 countries worldwide but may cover no more than 10 % of global needs In US, pediatric RTx incidence rate was >10 pmarp (per million age related population) in 2012 In developing world, incidence rates of pediatric RTx depend on country income <1–2 pmarp in Pakistan, Arab countries, and South Africa <4 pmarp in Brazil Suggests a limited number of ESRD children have access to transplant Access to pediatric RTx varies substantially within same country Transplant outcome is generally poorer in low-income countries Harambat J et al: Inequalities in access to pediatric ESRD care: a global health challengw; Pediatr Nephrol. 2015 Dec 1 Rizvi et al: Pediatric Kidney Transplantation in the Developing World; AJT 2013; 13: 2441–2449

Transplant: Summary Renal transplant is the optimal treatment for children with ESRD Living donor RTx has superior graft and patient survival Non-adherence is a major cause of graft failure Adolescents with poor social support more affected Major challenge is to reduce the inequality gap in access to optimal care for children with ESRD especially renal transplant worldwide World Kidney Day 2016, dedicated to children, will help to deliver this message to governments, health-policy makers, the medical community, and the public at large

Happy World Kidney Day 2016! Your pediatric nephrology community continues to work hard to improve clinical care, foster education, and advance the science regarding kidney disease in children! We appreciate your support and all you do for children’s health care!