AKI Biomarker Science is for Smarter People: I'm Just a Guy Trying - PowerPoint PPT Presentation

AKI Biomarker Science is for Smarter People: I'm Just a Guy Trying to Figure Out the In Whom and The When Stuart L. Goldstein, MD Professor of Pediatrics University of Cincinnati College of Medicine Director, Center for Acute Care Nephrology Nephrology and Hypertension The Heart Institute Cincinnati Children’s Hospital Medical Center Jeff Gray, PhD Memorial Translating to Management in AKI Award Presentation

Disclosures Baxter Healthcare Grant Support/Expert Panel/Consultant Baxter had no input into or control over the content of this presentation I mention CRRT as part of this presentation Bioporto Grant Support/Consultant BioPorto had no input into or control over the content of this presentation I mention NGAL as part of this presentation MediBeacon Consultant, Director of Clinical Development, Shareholder MediBeacon had no input into or control over the content of this presentation The topic of this presentation is not relevant to my work with MediBeacon La Jolla Pharmaceuticals, Akebia, Medtronic, Reata, CHF Solutions, Fresenius, Renibus Consultant The topic of this presentation is not relevant to my work with these entities

Jeff Gray, PhD

The Smarter People Who Have Received the Jeff Gray Award TIMP2-IGBP7 IL-18 Father of Critical Care NGAL Nephrology = Everything

So, Umm, What Have I Done in Comparison to These AKI Biomarker Luminaries?

A Career of Asking Questions As A Control Freak (AKA – As A Nephrologist) • Do patients really need to be THAT edematous before starting renal replacement therapy in the ICU? • Do we have to accept nephrotoxic medication associated AKI as part of the cost of doing business in a tertiary care center? • Now that we know these fancy proteins detect kidney stress/damage prior to a change in kidney function, would it be helpful to identify the patients in which they add clinical value?

The Clinical Biomarkers I’ve Looked At • Fluid Overload • High Nephrotoxic Medication Burden • Renal Angina A Translational Research Career Refining Risk Assessment for Poor Outcomes in Children with AKI

Standard Medical Fluid Prescription Training • “Maintenance Fluids” • Based on insensible losses + obligate losses + additional losses • Fluids in pathological situations • Dehydration • SIADH • Diabetes insipidus • Fluid composition and rates are taught in great detail • Yet, kidney function is usually normal in these instances, so accumulation rarely occurs

R E S U C Maintenance/ Fluid I Homeostasis Balance T A Removal/ T I Recovery O N Time

2 nd Phase of Fluid Therapy in Critical Illness • Maintenance of fluid balance homeostasis and/or prevention of worsening fluid overload • Assess patient’s needs for all fluids (nutrition, medications, blood products) and associated daily volumes • Assess patient’s ability to maintain fluid balance • UOP • Stool losses • Chest tubes • Assess patient’s current fluid accumulation status

The Dilemma and Decision If the patient with AKI cannot tolerate the needed fluid volumes without developing worsening fluid overload A. Fluid restrict B. Diuretics C.Consider renal replacement therapy to maintain fluid homeostasis

Poor Management Strategy I don’t need some nephrologist to tell me 2#$%@^#$%$% what to do!!!! #^@^#%w*%&w &^% Hellooo, there’s a patient here, and I can hear you

Fluid Is a Drug • An MD has to write an order for it • An RN has to take off the order • The Pharmacy has to send it • How to Dose It? • Depends on fluid therapy phase • Response to the need for fluid vs. a non-fluid related symptom • Not all hypotension needs fluid • Has the patient already been overdosed?

Goldilocks Paradigm Too Little Too Much Fluid Dose Meter *The Michelin Manufacturing Corporation provided no funding and had no input into the content of this presentation

The AKI Fluid Epidemiology Paradigm Maintenance/ Fluid Homeostasis Balance Time

• 22 pt (12 male/10 female) received 23 courses (3028 hrs) of CVVH (n=10) or CVVHD (n=12) over study period. • Overall survival was 41% (9/22). • Survival in septic patients was 45% (5/11). • PRISM scores at ICU admission and CVVH initiation were 13.5 +/- 5.7 and 15.7 +/- 9.0, respectively (p=NS). • Conditions leading to CVVH (D) • Sepsis (11) • Cardiogenic shock (4) • Hypovolemic ATN (2) • End Stage Heart Disease (2) • Hepatic necrosis, viral pneumonia, bowel obstruction and End-Stage Lung Disease (1 each)

Percent Fluid Overload Calculation % FO at CRRT initiation = [ ICU Admit Weight ] * 100% Fluid In - Fluid Out Fluid In = Total Input from ICU admit to CRRT initiation Fluid Out = Total Output from ICU admit to CRRT initiation

4 5 • Lesser % FO at CVVH (D) initiation 4 0 was associated with improved 3 5 outcome (p=0.03) 3 0 p = 0 . 0 3 2 5 • Lesser % FO at CVVH (D) initiation 2 0 was also associated with improved n tio itia outcome when sample was adjusted 1 5 In H V for severity of illness (p=0.03; multiple 1 0 V t C a regression analysis) O 5 F % M e a n + S E M e a n - S E 0 D e a t h S u r v i v a l M e a n O U T C O M E

The Evolution of Idea to Practice Paradigm Registry Single center study Randomized Trial

Prospective Pediatric CRRT (ppCRRT ) Registry: Phase 1 Design • Collected prospective data from 13 pediatric centers treating 15 to 20 patients annually (370 patients over 5 years) • Each center follows own institutional practice • Patient selection • Initiation and termination • Anti-coagulation protocols • Convection versus diffusion versus hemodiafiltration • Fluid composition

• Fluid overload independently associated with mortality • OR 8.5 for mortality at >20% FO (95% CI 2.8-25.7)

The ppCRRT Registry Co-Investigators • Mi Michael Somers rs • Ja James For ortenberry • Mi Michelle Baum • Joh John Mahan • Pa Pat Br Brophy • De Deepa Chand • Jor Jordan Symon ons • Fr Francisco Fl Flores • Ti Tim Bu Bunchman • Ke Kevin Mc McBry ryde • Ri Rick Ha Hackbarth • St Steven Alexander • Ma Mark rk Benfield • An Annabelle Chua • Da Davi vid As Askenazi • Do Douglas Bl Blowey • Mi Michael Za Zappitelli • Sc Scott Su Sutherland

• Patients receiving IV AG > 5 days • Primary renal diagnoses excluded • One year of study • 557 children • 95% > 3 months of age • AKI occurred in 19-33% of patients based on AKI definition • SCr measured at least q4 days only 50% of the time

• 350 non-critically ill children with AKI by pRIFLE • 350 matched children without AKI • 38 potential NTMx • Compared NTMx exposure rate between AKI vs. non- AKI patients • 86% exposed to at least 1 NTMx • Patients with AKI had 1.7 OR for exposure to a NTMx • PPV for AKI doubles for patient with 3+ NTMx

High NTMx-exposure Criteria Patient receiving 3 or more nephrotoxic medications (NTMx) concomitantly* or On an aminoglycoside for 3 or more days *IV radiology contrast, amphotericin, or cidofovir in previous week is counted for the week following administration

Initial AKI prevalence rates 10-fold higher than CAUTI rates and 3-fold higher than CLBSI rates at CCHMC

Adverse Events Avoided 2011 * 2012 2015 * Measure 2013 2014 Aggregate Annualized Non-Critically Ill Patient Days 97,065 91,363 90,627 99,076 109,968 334,691 Census Days (26,133) (27,492) (Actual Count) Annualized Number Of Patient Exposures 1,129 969 837 960 692 3,243 Patient Exposures (Actual Count) (304) (173) Annualized Number Of Patients With AKI 271 168 141 159 116 575 Patients With AKI (Actual Count) (73) (29) Patient Exposures Avoided N/A 108 200 219 106 633 Avoided Exposures Patients With AKI Avoided N/A 105 113 134 46 398 Avoided AKI Events * Data presented for partial year. Annualized values represent if data were extrapolated to full time period. Study period in 2011 (Sept – Dec), in 2015 (January – March). All aggregate data are actual count.

Dissemination of NINJA • Disseminate NINJA implementation at nine pediatric hospitals • Measure the impact of NINJA on NTMx-AKI in participating hospitals • Assess the association between context measures, including network participation, and reduction in NTMx-AKI by individual hospitals across the network

Before AKI Hospital DC 6 months post-AKI eGFR (ml/min/1.73m 2 ) 22/92 18/77 <90 0/100 (5<60) (2< 60) 90-150 100/100 70/92 50/77 >150 0/100 0/92 9/77 CystatinC eGFR N/A N/A 80+23 (ml/min/1.73m 2 ) Urine protein/creat >0.2 0/15 N/A 27/34

NINJA Cost Savings to the Healthcare System for 1000 Patients Pre-NINJA Ages (years) d Post-NINJA AKI Ages (years) d CKD Stage c AKI (n=282) a 3, 10, 15 (n=211) b 3, 10, 15 1 (GFR <90) n= 75 n=19, 37, 19 n = 56 n=14, 28, 14 2 (GFR 60-89) n= 68 n=17, 34, 17 n = 51 n=13, 25, 13 3 (GFR 30-59) n= 8 n=2 ,4, 2 n = 6 n=2, 3, 1 Goldstein, Lazear, Dynan: submitted

NINJA Cost Savings to the Healthcare System for 1000 Patients No NINJA $18,794,678 NINJA $7,350,000 Screening $256,680 TOTAL SAVINGS $11,187,998 Goldstein, Lazear, Dynan: submitted