Who should get a Biomarker Assessment? A focus on Biomarkers you may have at your hospital and risk scores

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1 Who should get a Biomarker Assessment? A focus on Biomarkers you may have at your hospital and risk scores Jay L. Koyner MD Section of Nephrology Department of Medicine University of Chicago

2 Disclosures Research funding from NIH, Astute, Bioporto, NxStage, Satellite Healthcare Consulting Fees from Astute Medical, Sphingotec, Pfizer, Baxter 2

3 Outline Serum Creatinine and Urine Output Sniffers and E-Alerts RCTs (alert alone, care bundles, consults) Electronic Medical Record Risk Prediction Furosemide Stress Test 3

4 Limitations /Unapproved use of TIMP2-IGFBP7: Those already with Stage 2/3 AKI (double / triple SCr) Patients under the age of 21 Ambulatory, non critically ill setting including: low risk / minor surgery in the hospital Non-critical emergency department Not approved for daily or serial measurement Not a substitute for serum creatinine or urine output Severe Proteinuria/ Albuminuria and bilirubinuria can interfere with test result Turnaround time is approximately 30 to 60 minutes Adapted from Vijayan et al. 2016

5 Revising the rules Age + BUN = Lasix Dose If you don t measure a biomarker (SCr, UOP, other), you can't find a AKI The delivery of good medical care is to do as much nothing as possible. 5

6 Daily Creatinine Checks Promote Earlier and Increased Detection of AKI Case of AKI Days of AKI per 100 at risk days First Day of AKI No Daily Check (n=124) Daily Check (n=103) P-value 15 (12) 21(20) ( ) 5.5 (4-7) (3-16) 5.5 (4-7)

7 Using UOP increases AKI rates and decreases risk: Quan et al NDT ,229 major, non-cardiac surgery from in Calgary Adding UOP to standard SCr based AKI definitions increased the AKI event rates from 8% to 60% Mortality (below) and LOS for a given stage lower in those with only UOP AKI vs only SCr AKI (adjusting hurt UOP). Relative Oliguria w/ SCr changes did worse than those without oliguria.

8 Intensive Urine Output Monitoring: Kellum et al. Retrospective Study 15,724 subjects (4049 with intense UOP) After adjusting UOP monitoring Improved AKI detection Improved survival in those w/ AKI Less fluid overload 8

9 Mizota et al: Intra-op UOP predicts post-op AKI Single center, retrospective 3560 major abdominal surgery Exclude intra-op diuretics UOP < 0.3 mg/kg/hr was associated with AKI aor 2.65( ) p<0.001 UOP of mg/kg/hr not associated with AKI

10 Albuminuria : Risk of AKI Grams et al. AJKD A Meta-analysis of the Association of Estimated GFR,Albuminuria, Age, Race, and Sex With AKI

11 James et al. AJKD Albuminuria and Diabetes: AKI

12 Albuminuria and AKI and LOS in Veteran Hospital post-cv surgery 5,968 VA patients undergoing CABG w/ egfr>60 Preop UACR associated with mortality, LOS and incidence and severity of AKI (Scr) Results held after adjusting for ACE/ARB, statin, age, gender, BP, DM, CHF, Charlson Co-morbid index

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14 Kashani et al: ICU Sniffer to Detect AKI 14

15 Wilson et al: RCT of Alerts but not linked to intervention 15

16 Selby et al: Linking e-alert with Care Bundle 2,297 patients with 2500 episodes of AKI Care bundle only completed in 12.2% in 24 hrs Less severe AKI with completion 3.9% vs 8.1%, p=0.01 Lower inpatient mortality 18% vs 23% p=0.05 Lower long term risk of death or RRT 16

17 Selby et al., JASN Multi-center step wedge cluster randomized trial AKI detection and alerting AKI care bundle assessment, investigation and management of AKI AKI education for health care workers 17

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21 Park et al. Linking E-Alert with Consults 21

22 Park et al. Linking E-Alert with Consults Patients receiving the alert (n=1309) were more likely to get an early consult 28% vs 7% Less likely to get Stage 2/3 AKI (27% vs 32%) AOR 0.75 ( ) P<0.001 More likely to recover (SCr w/in 20%)- 80% vs 56% AOR 1.70 ( ), p<

23 Forni: Systematic Review of Ward Based AKI prediction scores 23

24 ICE-AKI: Clinical Prediction Rule and E-AKI alerts Forni et al Controlled before and after study n=30,295 2 non-specialty English Hospitals Clinical Prediction Rule flagged at risk patients Alerts generated for those with AKI Primary outcome was change in HA-AKI rates 2 nd outcomes mortality, AKI progression 24

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26 Points Scored AMBER at risk: advise to be reviewed/consider: (score above 5) Search for underlying cause: eg. If sepsis suspected send blood cultures Assess fluid status & consider fluid bolus & re-assess, fluid balance chart, daily weights Review drug chart & consider stopping potential nephrotoxins Urine dip Age (years) < Respiratory Rate <20 20 AVPU Score Alert Other CKD Stage 3a-5 Heart failure Diabetes Liver disease Table A. Acute kidney injury prediction score (APS) AVPU scale best response (alert, vocal, pain, unresponsive), CKD chronic kidney disease (egfr <60mls/min), Respiratory rates - breaths/minute. Y Y Y Y RED AKI (Stage): 1, 6 & 24 hour advice & tasks to be considered & submitted Care bundle triggered immediately KDIGO criteria 1 hour: Search for underlying cause of admission eg. If sepsis suspected send blood cultures, IV antibiotics. Fluid bolus & re-assess, fluid balance chart, daily weights Review drug chart & stop potential nephrotoxins Urine dip 6 hour: Re-review fluid status, consider escalation of care 24 hour: Where appropriate consider imaging renal tract Consider other specific blood tests: autoimmune, CK. If not improving for discussion with Nephrology 26

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28 Multicenter prospective cohort UCSD (573pt) Mayo (1300pts) Predicting KDIGO Stage 1 5 Sens-63%, Spec-85% 28

29 Flechet et al. AKI-123 Risk Prediction Large multicenter EPaNIC database 2,121 development, 2,367 validation Data from before, upon ICU admit and Day 1 AUCs 0.75 for Stage 1+ prior to ICU 0.83 for Stage 2+ on Day 1 Outperformed NGAL

30 Koyner ESTOP-AKI 2.0 Retrospective Single Center Observational cohort study of all admitted adults at the University of Chicago from November 2008 to January 2016 (121,000 admits) Excluded if No documented SCr during admission Prior ICD coding for ESRD / CKD4-5 Had an initial SCr 3.0 mg/dl on admission Developed Stage 2 AKI prior to reaching the Wards or ICU Required RRT within 48 hours of their first SCr Used a Gradient Boosting Machine (gbm) model to predict the probability of AKI using all the predictor variables 30

31 Demographics Vital signs Vital sign trends Laboratory values Laboratory value trends Interventions Medications Transfusions Nurse Documentation Diagnostics Location Length of stay Prior cardiac arrest Urinary Bag LVAD What s in the model.. Age, Sex, Race Temperature (C ), Heart Rate, Respiratory Rate, Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP), Pulse Pressure Index (PPI), AVPU, O2 Saturation, FiO2, SpO2/FiO2 ratio Highest value in the last 24 hours of Heart Rate, Respiratory Rate, and AVPU Lowest value in last 24 hours of SBP, DBP, and O2 Saturation Slope over the last 24 hours of Heart Rate, SBP, and DBP Basic Metabolic Panel [BMP]: Sodium, Potassium, Bicarbonate (CO2), Anion Gap, Glucose, Calcium, Blood Urea Nitrogen (BUN), Serum Creatinine (SCr), BUN/SCr ratio, Phosphate Liver Function Test [LFT]: Total Protein, Albumin, Total Bilirubin, AST (SGOT), Alkaline Phosphatase Complete Blood Count [CBC]: White Blood Cells (WBC), Hemoglobin, Platelet Count Other labs: Lactate, Troponin, ph, Ketones Change from last collected value of SCr, BUN, BUN/SCr ratio, CO2, Sodium and Anion Gap IV bolus (0.9% Sodium Chloride, Lactated Ringers), Albumin (5% or 25%), Using Ventilator, Using BiPAP, Using CPAP, Using HFNC IV Diuretics, PO Diuretics, IV Antibiotics, PO Antibiotics, Nephrotoxic Medications*, Vasopressors, Inotropes, Insulin, PO Hypoglycemics, Lactulose, Proton Pump Inhibitors (PPIs) Red Blood Cell (RBC) transfusion, Fresh Frozen Plasma (FFP) transfusion, Platelet transfusion, Cryoprecipitate transfusion Morse Fall Scale, Braden Scale: Activity, Friction and Shear, Mobility, Moisture, Nutrition, Sensory Perception EKG, TTE, Chest X-ray, Abdomen X-ray, CT Scan w/contrast, CT Scan w/o contrast, Blood Culture Order Current location, Prior ICU stay, Prior OR stay Hours since first vital signs Prior cardiac arrest Urine Output, Foley catheter placed LVAD

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33 Performance of the model without SCr, ΔSCr, BUN, ΔBUN, BUN/SCr and ΔBUN/SCr Outcome AUC (95% CI) Stage 1 AKI - 48hrs 0.71( ) Stage 2 AKI - 48hrs 0.85( ) Stage 3 AKI - 48hrs 0.91( ) Receipt of RRT (24 hours) 0.97( ) Receipt of RRT (48 hours) 0.96( ) Receipt of RRT (72 hours) 0.94( ) 33

34 Supplemental Figure 5. Variable importance plot for the complete model excluding SCr, ΔSCr, BUN, ΔBUN, BUN/SCr and ΔBUN/SCr Current Serum Phosphate Length of Stay Saturation po2/fio2 ratio Current Total 12 hour Urine Output Current FiO2 Current Serum Bicarbonate Lowest Systolic Pressure (24hrs) Braden Scale Score Current White Blood Cell Count Current Serum Calcium Current Total 24 hour Urine Output Number of Nephrotoxin Exposures (24hrs) Current Heart Rate Highest Heart Rate (24hrs) Current Patient Age Current Anion Gap Change in Systolic Pressure (24hr) Current Platelet Count Current Serum Glucose Lowest Diastolic Pressure (24hr)

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38 Furosemide Stress Test: 1mg/kg or 1.5 mg/kg in the setting of Early AKI 38

39 Furosemide Stress Test (FST) Results Outcome AUC (SE) P-value Chawla and Koyner et al. Crit Care 2013 Progress to AKIN (0.09) <0.001 RRT 0.86 (0.08) Inpatient Mortality 0.70 (0.09) Progress or Death 0.81 (0.06) <0.001

40 Doi et al: Furosemide Responsiveness Retrospective Cohort from Japan 95 patients 18 w/ Stage 3 AKI Variable dosing of furosemide 30mg(20-55) Ideal cutoff of 3.9ml/kg/hr is 232 ml in 2 hrs Improved prediction in those with elevated biomarkers 40

41 Blinder et al.: FST in Infants Post CT Surg. Infants (<1yr) on CPB Furosemide dose 8 and 24 hrs postop 0.8 mg/kg 1.2 mg/kg Responsiveness < 1ml/kg/hr Corrected for fluid balance AKI by SCr only AUC 0.74 at 2 hours 0.77 at 6 hours 41

42 Penk et al Journal of Thoracic and Cardiac Surgery Basu et al: FST in KIDS CV surgery 166 patients, 4 sites Retrospective identification of at risk patients (STS-EACS >3) Post-op furosemide AKI defined by KDIGO (33%, n=54) Lower 2 and 6-hr urines in those with AKI 2hr 6hr

43 Used the FST to determine risk for progressive AKI and only enrolled those who failed FST to early vs. standard RRT start FST Failed (n=118) FST Passed (n=44) P-value Baseline SCr 1.08(0.41) 1.09(0.36) 0.93 SCr at enrollment 2.0 (2-3) 2.0 (2-3) 0.43 Stage 3 AKI 52 (44%) 11 (25%) Receipt of RRT 103 (87.3%) 6 (13.6%) <0.001 Mortality 71 (60.2%) 15 (34.1%) Lumlertgul et al. Critical Care 2018

44 Conclusions Serum Creatinine and Urine output remains useful tools in improving outcomes in patients with AKI Risk Prediction models are getting more accurate and will soon be built into the EMR but their utility requires further investigation The FST seems to reliably identify those destined for severe AKI and performs even better when paired with biomarkers 44

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