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

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

Nov 21, 2023 306 likes •861 views

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

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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

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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

Disclosures

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Jeff Gray, PhD

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The Smarter People Who Have Received the Jeff Gray Award

NGAL TIMP2-IGBP7 IL-18

Father of Critical Care Nephrology = Everything

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

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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?

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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

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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

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Fluid Balance Time Maintenance/ Homeostasis Removal/ Recovery

R E S U C I T A T I O N

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2nd 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
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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

The Dilemma and Decision

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Poor Management Strategy

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

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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?
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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

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Fluid Balance Time Maintenance/ Homeostasis

The AKI Fluid Epidemiology Paradigm

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  • 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)

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Percent Fluid Overload Calculation

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

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  • Lesser % FO at CVVH (D) initiation

was associated with improved

  • utcome (p=0.03)
  • Lesser % FO at CVVH (D) initiation

was also associated with improved

  • utcome when sample was adjusted

for severity of illness (p=0.03; multiple regression analysis)

M e a n + S E M e a n

  • S

E M e a n

O U T C O M E % F O a t C V V H In itia tio n

5 1 1 5 2 2 5 3 3 5 4 4 5 D e a t h S u r v i v a l

p = . 3

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The Evolution of Idea to Practice Paradigm

Single center study Registry Randomized Trial

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

  • Mi

Michael Somers rs

  • Mi

Michelle Baum

  • Pa

Pat Br Brophy

  • Jor

Jordan Symon

  • ns
  • Ti

Tim Bu Bunchman

  • Ri

Rick Ha Hackbarth

  • Ma

Mark rk Benfield

  • Da

Davi vid As Askenazi

  • Mi

Michael Za Zappitelli

  • Ja

James For

  • rtenberry
  • Joh

John Mahan

  • De

Deepa Chand

  • Fr

Francisco Fl Flores

  • Ke

Kevin Mc McBry ryde

  • St

Steven Alexander

  • An

Annabelle Chua

  • Do

Douglas Bl Blowey

  • Sc

Scott Su Sutherland

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  • 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
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  • 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
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High NTMx-exposure Criteria

Patient receiving 3 or more nephrotoxic medications (NTMx) concomitantly*

  • r

On an aminoglycoside for 3 or more days

*IV radiology contrast, amphotericin, or cidofovir in previous week is counted for the week following administration

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

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Measure 2011* 2012 2013 2014 2015* Aggregate Annualized Non-Critically Ill Patient Days (Actual Count) 97,065 (26,133) 91,363 90,627 99,076 109,968 (27,492) 334,691 Census Days Annualized Number Of Patient Exposures (Actual Count) 1,129 (304) 969 837 960 692 (173) 3,243 Patient Exposures Annualized Number Of Patients With AKI (Actual Count) 271 (73) 168 141 159 116 (29) 575 Patients With AKI 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.

Adverse Events Avoided

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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

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Before AKI Hospital DC 6 months post-AKI eGFR (ml/min/1.73m2) <90 0/100 22/92 (5<60) 18/77 (2< 60) 90-150 100/100 70/92 50/77 >150 0/100 0/92 9/77 CystatinC eGFR (ml/min/1.73m2) N/A N/A 80+23 Urine protein/creat >0.2 0/15 N/A 27/34

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NINJA Cost Savings to the Healthcare System for 1000 Patients

CKD Stagec Pre-NINJA AKI (n=282)a Ages (years)d 3, 10, 15 Post-NINJA AKI (n=211)b Ages (years)d 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

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NINJA Cost Savings to the Healthcare System for 1000 Patients

Goldstein, Lazear, Dynan: submitted

No NINJA $18,794,678 NINJA $7,350,000 Screening $256,680 TOTAL SAVINGS $11,187,998

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The Evolving AKI Paradigm

Early Recognition Early Treatment Early Recovery SCr/UOP Biomarkers Renal Angina + Biomarkers

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“Early” Recognition

Acute Myocardial Infarction (AMI)

Clinical Signs/Symptoms Classic Risk Factors Ancillary Tests Biomarkers

Early Recognition Early Treatment

(Thrombolytics, PCI)

Early Recovery Courtesy: Derek Wheeler

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AKI versus AMI

Period Acute Myocardial Infarction Acute Kidney Injury 1960s LDH Serum creatinine 1970s CPK, myoglobin Serum creatinine 1980s CK-MB Serum creatinine 1990s Troponin T Serum creatinine 2000s Troponin I Serum creatinine

Delayed Functional Marker Supportive Care High Mortality Need early damage markers for better treatment

  • f AKI

Early Damage Markers Multiple Therapies 50% ↓ Mortality

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How, and In Whom, Do We Apply AKI Biomarkers?

  • AKI does not have a specific symptom set to prompt evaluation
  • Medical school aphorism: “There are only three reasons that

people go to a doctor”

  • Fever
  • Bleeding
  • Pain
  • AKI is not specifically associated with any of these, simply put,

“AKI doesn’t hurt”

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Renal angina – birth of AKI risk stratification

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The problem with angina Heart attack Kidney attack PAIN NO PAIN

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Calculating Renal Angina Index

Risk Level Description Risk Score Moderate ICU status 1 High History of Transplantation 3 Very High Mechanical ventilation + Inotropy 5

Injury (Creatinine) Injury (Fluid Overload) Injury Score No ↓eCrCl / No ↑[SCr] < 5% 1 0<x<25% ↓eCrCl / 0-33% ↑[SCr] >5 % 2 25%-50% ↓eCrCl / 33-100% ↑[SCr] >10 % 4 >50% ↓eCrCl / >100% ↑[SCr] >15 % 8

= Renal Angina Index Score Angina rules in > 8

X

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The RAI Works Across Multiple Cohorts

CCHMC Cohort 1 CCHMC Cohort 2 Montreal Cohort 1 Montreal Cohort 2 AKI-CHERUB AWARE RAI (+), n (%) 51 (35) 145 (68) 18 (15) 38 (35) 52 (33.3) 213 (19) Day-3 severe AKI, n (%) 28 (19) 29 (13) 12 (10) 11 (10) 15 (10) 133 (13) PPV, % (95%CI) 40 (27-55) 18 (15-19) 39 (17-64) 26 (13-43) 20 (11-32) 54 (45-62) NPV, % (95%CI) 92 (85-97) 97 (90-99) 95 (89-98) 99 (92-100) 98 (93-100) 94 (92-95) AUC, (95%CI) 0.77 (0.68-0.86) 0.80 (0.75-0.86) 0.74 (0.59-0.88) 0.81 (0.71-0.91) 0.80 (0.58-1.00) 0.80 (0.76-0.84)

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Where We are Heading

Funded by P50 DK096418-06

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Research Support

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Tim Bunchman Steve Alexander

A Pictorial History of Pediatric AKI Clinical Research

Prasad Devarajan

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LONDON ADQI 2012 LONDON AKI & CRRT 2018

Ravi Mehta: International Man of Mystery