1. Acute Kidney Injury in Neonates Jordan M. Symons, MD University of Washington School of Medicine Seattle Children’s Hospital Seattle, WA - USA 8th International Conference On Paediatric Continuous Renal Replacement Therapy (pCRRT) 16th - 18th July 2015 Queen Elizabeth II Conference Centre, London, UK

2. AKI: Definition and Diagnosis Abrupt reduction in GFR Differential diagnosis includes: –Pre-renal Volume depletion; cardiac dysfunction –Renal Vascular; glomerular; tubular; interstitial –Post-renal Obstruction Complex, multi-factorial physiology

3. Neonatal AKI: Special Challenges Specific stresses unique to the neonate –Different renal physiology in newborn Risks associated with neonatal illness and its treatment –Low birth weight; fluid loss; infection; drugs Our ignorance of details in neonatal AKI –Do we really know which babies have AKI?

4. Neonatal Physiology with Implications for the Kidney

5. GFR is Low in the Newborn Transition to post- natal status favors flow to lungs High renal resistance at birth Even lower GFR in preterm infant

6. Delayed Renal Stabilization in Preterms Not in steady state

7. Tubular Function is Immature in the Newborn Immature isoforms of multiple channels Reduced function of Na/K ATPase Lower tubular surface area Diuresis is normal and expected after birth Risk for more tubular dysfunction with stress Na + Greater Sodium Losses

8. Neonatal Water Balance is Different Immature tubule Diminished aquaporin function Normal excretion ability Lower capacity to retain free water –Concentrating capacity improves with development Risk for greater water loss with illness, prematurity

9. Transepidermal Water Loss Preterm insensible loss is higher –Skin, respiratory tract –15x higher in preterm compared to term Highest immediately after birth Clinical maneuvers to limit water loss –Closed incubator –Humidification –Skin care

10. Water Loss by Gestational Age and Chronological Age Hartnoll, Sem Neonatol, 2003(8): 307-13

11. Neonatal Renal Risks from Clinical Conditions

12. Risk Factors for Neonatal AKI Very low birthweight Congenital Heart Dz Cardiac bypass ECMO The depressed or asphyxiated infant Renal anomalies (CAKUT) Hypotension or hypoperfusion Infection/sepsis Drugs Umbilical catheterization Multi-organ disease

13. Physiology IllnessInterventions Prematurity AKI

14. Neonatal AKI Epidemiology: What is the Scope of the Problem?

15. Neonatal AKI: Challenging to Define Often non-oliguric Unclear baseline Not steady state Less frequent labs Suboptimal markers Documentation issues Jetton & Askenazi, Clin Perinatol 2014

16. Neonatal AKI Incidence: Select Populations PopulationFindings Very Low Birth Wt 1 AKI: 41/229 (18%); hazard ratio (HR) for death = 9.3 (95% CI 5.1–21) Congenital Heart Dz 2 AKI: 225/430 (52%); odds ratio (OR) for death up with higher AKI stage (stage 2 OR=5.1 (95% CI 1.7–15.2); stage 3 OR=9.5 (95% CI 2.9–30.7)) ECMO 3 Higher AKI rate in non-survivors (19% vs 3.9%; P<0.0001); OR for death = 3.2 (P<0.0001) Perinatal depression 4 Higher level of AKI for infants with severe asphyxia (12/25) vs. moderate asphyxia (1/11) 1. Koralkar et al. Pediatr Res 20113. Askenazi et al. Pediatr Crit Care Med 2011 2. Blinder et al. J Thorac Cardiovasc Surg 20114. Kaur et al. Ann Trop Paediatr 2011;

17. Management of Established AKI: Pharmacotherapy Attempted Therapies Diuretics Mannitol Dopamine Fenoldopam Glucocorticoids Atrial natriuretic peptide N-acetylcysteine (other than contrast-induced AKI Definitive Therapies Hmmmm.....

18. Prophylaxis of Neonatal AKI Theophylline may protect asphyxiated infants against AKI: However: –Insufficient information on long-term renal or neurodevelopmental outcome –Different doses between trials –Toxicity remains unclear –Unsure of interaction/benefit with hypothermia Al-Wassia et al. J Perinatol 2013

19. Conservative Management of Established AKI: Traditional Approach Limit fluid intake Limit input of retained substances Augment losses (diuretics) Try not to mess up Wait and Hope

20. Renal Replacement Therapy for Neonatal AKI Askenazi et al. J Ped 2013

21. Acute Kidney Injury in Neonates: Summary Neonates are at special risk for AKI –Unique physiology –Clinical risks –Nature of our interventions Like older children and adults, AKI is a significant problem for the newborn –Morbidity and mortality Management remains a challenge –Meeting the challenge is why we are here!

22. Thank You for Your Attention and Thank You to the Organizers for a Scholarly and Dignified Conference