Pediatric AKI and Application of Biomarkers

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1 Pediatric AKI and Application of Biomarkers Arnold O. Beckman Conference Michael Zappitelli MD, MSc Most AKI is ATN and multifactorial Glomerular Tubular Vascular Interstitial Child AKI disease model Community AKI? Surgery Emergency Wards Day Hospitals AKI? PICU AKI Increased outcome risk Mortality?Long Term CKD Non ICU AKI?Severity?Risk Factors Short/Long term impact? 1

2 Overview 1. Pediatric AKI common and associated with poor outcomes 2. Opportunities for AKI biomarkers in children 3. Review of some published pediatric AKI biomarker data 4. Future directions 1. Pediatric AKI common and associated with poor outcomes 2. Opportunities for AKI biomarkers in children 3. Review of some published pediatric AKI biomarker data 4. Future directions Overview Definition in children Acute SCr rise Acute UO drop KDIGO Refining timing of rise 2

3 Incidence of RRT AKI ~1% ~1-3% ~6% 5-6% 1-2% ~4% RRT AKI Mortality high everywhere 50-60% 40-45% 25-50% 42-67% 52-77% 33-65% 40% 64% 36% 11% AKI child populations At risk Pre operative cardiac Sx Clinical data collection ICU Admission Aminoglycoside start Chemotherapy start Blood collection Urine collection Follow up 3

4 Incidence: PICU full cohort studies Turkey N=189 No severe CKD Creat USA N=3396 No severe CKD Creat ~40% ~10% Kayaz et al, Acta Pediatr, 2012 Schneider et al, Ped Crit Care, 2010 Incidence: PICU partial cohort studies Canada N= hours Creat USA ~18% N=150 Vent and/or Vaso, Foley Alkandari et Creat al, Crit + Urine Care, 2011 ~80% Ackan-Arikan, Ped Crit Care, 2007 Plotz et al, Intens Care Med, 2008 ~60% Netherlands North India N=189 N=486 Vent >24 4 hours, days NO Creat severe + Admx Urine AKI ~20% South Creat India N=215 >48 hours Creat + Urine Mehta, et al, Ind Ped, 2012 ~30% Krishnamoorthy, et al, Ind J Ped, 2012 AKI OCCURS EARLY IN THE ICU Confirmed in several other larger epidemiologic cohort studies 4

5 Does a 50% SCr rise really matter? In repeated studies last 5 years: AKI independently associated with PICU mortality Length of stay Duration Confirmed: of mechanical several ventilation retrospective and prospective PICU studies Graded AKI response: associated with: Stage 1 worse than 2 worse than 3 PICU LOS Hospital LOS Longer ventilation Difficult to REALLY know if independent of illness severity Incidence: Cardiac 2 Canadian studies (646) Morgan, j Ped, 2012 Zappitelli, KI, Hungarian study (1510) Toth, Card Anethes, US studies (1594) Manrique, Ped Anesth, 2009 Li, Crit Care Med, 2011 Aydin, Ann Thorac Surg, 2012 Blinder, J Thor Card Surg, Indian study (124) Sethi, Clin Exp Nephrol, 2011 Day of Occurrence of AKI Number of patients Adults Children 0 Day 1 Day 2 Day 3 Day 4 Day 5 + First Day from surgery that AKI first appeared 5

6 Does a 50% SCr rise really matter? Neonatal cardiac Does a 50% SCr rise really matter? TRIBE-AKI, multi-centre cardiac: Li et al, CCM 2011 Infant cardiac surgery Mammen group, Pediatr Nephrol, 2013 AKIN Stage 3: Longer Longer stay PICU stay Prolonged Mortality ventilation Cardiac surgery setting Zappitelli, Pediatr Nephrol,

7 Cardiopulmonary bypass time and risk of AKI Patients developing acute kidney injury 80% 70% 60% 50% 40% 30% 20% 10% Adj OR: 1 Adj OR: 2.14 (0.97, 4.72) Adj OR: 2.47 (1.08, 5.65) Adj OR: 3.20 (1.38, 7.44) Adj OR: 7.57 (2.62, 21.92) 0% >180 Bypass time (minutes) Adjusted for age, RACHS 1 score and site AKI (or recognition) may be increasing Comparison of the incidences of general pediatric admissions and ARF cases according to year Vachvanichsanong et al, Pediatrics, 2006 THAILAND Community acquired AKI in children Prospective observation cohort of children admitted to the Texas Children's Hospital ED Jan Apr 2009 Serum creatinine an urine ordered? Consent obtained? Included: n=252 Only 27% had baseline SCr available 7% had AKI defined by prifle criteria 7

8 What do we know about non ICU AKI? 5% 25% Incidence: Nephrotoxins Aminoglycosides 5 days N=557 Increasing numbers ( 3) of NTM used Increases risk for AKI in non ICU children Moffett & Goldstein, CJASN, 2011 Zappitelli et al, NDT, 2011 Confirmed MCH prospective study (n~160) 40% Does a 50% SCr rise really matter? Houston AG cohort ( 5days): AKI associated with longer LOS & costs Zappitelli et al, NDT,

9 Acute renal damage with cancer therapy Chemotherapies Cisplatin, Ifosfamide, CsA? Stem cell transplant Myeloablation, Irradiation, Post-immunosuppresion, GVHD? Infection Sepsis, ABx Kidney attack TTP TLS Acute renal damage with cancer therapy AKI post stem-cell transplant: ~20%, wide range Acute renal damage with cancer therapy 11/11/12 9

10 Zappitelli et al, ASN poster, 2012 SCr monitoring Rx's 11 days: 1/5 Rx days It is possible to DOUBLE SCr monitoring by ticking off a box! Routinely drawn SCr's per day of AG treatment Houston Montreal 1 SCr per day 16% 30% 1 SCr/2 days 26% 48% 1 SCr/3 days 41% 57% 1 SCr/4 days 48% 60% Overview 1. Pediatric AKI common and associated with poor outcomes 2. Opportunities for AKI biomarkers in children 3. Review of some published pediatric AKI biomarker data 4. Future directions AKI child populations At risk Pre operative cardiac Sx Clinical data collection ICU Admission Aminoglycoside start Chemotherapy start Blood collection Urine collection Follow up 10

11 TRIBE AKI cardiac surgery Early diagnosis Pre operative Consider clinical risk models Immediate post operative Consider pre op & intra op clinical risk models Prognosis At the time of AKI Severity of renal injury Pre operative AKI prediction: SCr, CysC, egfr Pre-op clinical model: Age, gender, RACHS-1, CPB time, study site. AKI AUC = 0.73 (0.67, 0.80) Stage 2+ AKI AUC = 0.79 (0.70, 0.87) Pre operative AKI prediction: CysC, egfr in children not predictive OR * * Pre op CysC egfr 0 Stage 1+ Stage 2+ 11

12 GFR in children not simple TRIBE AKI cardiac surgery Early diagnosis Pre operative Consider clinical risk models Immediate post operative Consider pre op & intra op clinical risk models Prognosis At the time of AKI Severity of renal injury Post operative AKI prediction: early SCr rise IL-18 ungal pngal 12

13 Post operative AKI prediction: NGAL & IL 18 IL-18 ungal pngal How have biomarkers been doing? Mishra et al, Lancet, 2005 Single centre, cardiac Parikh et al, JASN, 2012 Multi-centre, cardiac Post operative AKI prediction: NGAL & IL 18: added value 13

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16 Non cardiac PICU setting Much more challenging No pre-operative assessment Many patients arrive with AKI: mild, moderate or severe Many patients arrive with high SCr not all AKI. Biomarkers may help distinguish: but who to measure in? How have biomarkers been doing? Very high risk PICU: 80% AKI Zappitelli et al, CCM, 2007 Lower risk PICU: ~40% AKI Zappitelli et al, unpublished WHAT HAPPENED? Biomarker Day 1 2 ICU AKI AUC Urine NGAL 0.61 ( ) UrineIL ( ) Urine KIM ( ) 16

17 Nephrotoxicity 17

18 Nephrotoxicity Zappitelli et al, ASN poster, 2012 Children treated with Tobramycin Pi-GST on the 1 st day of AKI AUC = % CI Focus is on QUICK and SIMPLE assessment Intent is to have an index / threshold risk with HIGH NPV No Renal Angina: HIGHLY likely NOT to develop AKI Do NOT study biomarker performance Do NOT use biomarkers to predict AKI (future) Putting it to the test! At risk PICU day 1 RA yes or no? PICU day 3 Outcome: Sever AKI (St 2) 18

19 19

20 AKI scenarios At risk Improved biomarker performance Better performed clinical trials Improved AKI outcomes Pre operative cardiac Sx ICU Admission Aminoglycoside start Chemotherapy start Who do we measure biomarkers in? Everyone? When do we measure biomarkers? At ICU admission? After start of drug? 3 days after? How often do we measure biomarker? Every day? Every 12 hours? Cardiac surgery patients at risk for AKI Clinical/biomarker risk profile Low Risk High Risk Standard Care Preventive Rx Active Avoidance Remnant/ongoing Injury dipstick Long-term risk Need follow-up Preventive Rx DISCHARGE AKI Dipstick Treatment AKI Injury Severity Dipstick?Real AKI?Long-term risk?rrt need Overview 1. Pediatric AKI common and associated with poor outcomes 2. Opportunities for AKI biomarkers in children 3. Review of some published pediatric AKI biomarker data 4. Future directions 20

21 Long term follow up studies 21

22 COG LTFU guidelines V 3 Urinary tract References Old data Lack of prospective long term studies THANK YOU GST measurements Colleagues and Collaborators MCH co-investigators R. Gottesman A. Dancea C. Tchervenkov L. Lands U Alberta C. Morgan A. Joffee CHUSJ J Lacroix P Jouvet F Gauvin V Phan ABLE K. Schultz R. Rassekh L. Mitchell M. McBryde G. Cuvelier U Cincinnati P. Devarajan C. Krawczeski S. Goldstein M. Bennett LHSC, Ontario A. Garg Yale C. Parikh S. Coca Z. Wang Harvard J. Bonventre V. Sabissetti THANK YOU MCH Research Team A. Palijan, PhD M. Pizzi J. Caldwell J.A. Doucet, BNSc S. Segal M. Piccioni, MSc P. Lagos-Arevalo M. Harel-Sterling M. Verway, PhD(c) M. Haasz, MD O. Alkandari, MD B. Albright, MD Z. Al-Sani, MD Y. Kazzaz, MD J. Séguin, MD Z. Alismaili, MD 22

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