Biomarkers for the Prevention of Drug Induced AKI (D-AKI) Sandra Kane-Gill, PharmD, MSc, FCCM, FCCP Associate Professor, University of Pittsburgh Critical Care Medication Safety Pharmacist, UPMC
OBJECTIVE Propose the utility of novel biomarkers for the prevention of D-AKI Disclosures: None
WHAT ARE THE IDEAL CHARACTERISTICS OF A BIOMARKER FOR AKI PREVENTION?
CHARACTERISTICS OF BIOMARKERS FOR PREVENTION OF AKI/D-AKI IDEAL CHARACTERISTICS 1. Easily measured 2. Present at initiation of disease & earlier than other biomarkers 3. Detect to a greater degree than current biomarkers 4. Unaffected by other diseases/factors 5. Proportional response to severity CURRENT CHARACTERISTICS 1. Urine and serum 2. Major advantage 3.? Accuracy of detection 4. Affected by other diseases; varies by biomarker 5. Proportional to severity depends on biomarker
EVIDENCE FROM D-AKI LITERATURE Advantage Urine and serum Presents earlier than current biomarkers Detect to a greater degree Affected by other diseases Severity Example of Evidence NGAL: cisplatin induced nephrotoxicity; 4 of 6 studies positive; more favorable for urine than serum; similar results for KIM-1 NGAL: evaluated amphotericin induced AKI and compared NGAL to SCr; NGAL detected AKI 1.7-3.2 days sooner NGAL: higher for AKI-related to NSAIDs than hypovolemia and type 1 hepatorenal syndrome and lower than acute tubular necrosis NGAL: may be elevated in sepsis, malignancy, CKD, UTIs TIMP-2-IGFBP7: may be elevated in diabetes KIM-1 and NGAL: higher concentration more severe kidney damage TIMP-2-IGFBP7: moderate risk > 0.3 to 2.0 & high > 2.0; also on day one of nephrotoxin administration the biomarker value is higher >0.5 for patients who progress to Stage 2/3 AKI NGAL = Neutrophil gelatinase-associated lipocalin; KIM-1 = kidney injury molecule-; TIMP2-IGFBP-7 = tissue inhibitor of metalloproteinase-insulin like growth factor-binding protein Kane-Gill et al. Drug Saf 2017;40:1049
Kashani K, et al. Crit Care 2013;17:R25. Hoste E, et al. Nephrol Dial Transplant 2014;29:2054-61. Bihorac A, et al. Am J Resp Crit Care Med 2014;189:932-9. TIMP-2 IGFBP7 (NEPHROCHECK ) Sapphire study: Discovery and Validation Discovery: 340 proteins; AKI stage II and III in 12 h TIMP2 AUC 0.76; IGFBP7 AUC 0.79; TIMP2-IGFBP7 AUC 0.8 Validation Clinical variables (included SCr): AUC 0.81 Clinical variables + TIMP2-IGFBP7: AUC 0.87 Opal study: Established clinical cut-offs Low risk <0.3 negative predictive value 97% Moderate risk > 0.3-2.0: 4+ fold higher risk High risk >2.0: 10+ fold higher risk Topaz study Clinical adjudication of AKI (not KDIGO) TIMP2-IGFBP7 better association with clinicians than SCr 12% disagreement- biomarker more often agreed with majority (2 of 3 clinicians)
Kashani K, et al. Crit Care 2013;17:R25. Courtesy of Erin Frazee Baretto, PharmD. TIMP-2 IGFBP7 (NEPHROCHECK ) Cell-cycle arrest markers detected in urine Pause in replication to prevent damaged cells from dividing TIMP-2 and IGFBP7 released Kidney sustains an insult (e.g. hypoperfusion) G 1 Phase Mitosis S Phase (DNA Synthesis) G 2 Phase Detected in the urine, signal risk for cell damage and AKI
PREVAKI RANDOMIZED CONTROLLED TRIAL Single-center, randomized trial of 276 cardiac surgery patients with TIMP-2 IGFBP7 0.3 138 control patients 138 intervention patients Primary Endpoint: Any AKI at 72-h Any AKI: 72% Stage II/III: 45% Any AKI: 55% Stage II/III: 30% ACEI/ARB- significantly less Vancomycin, diuretics, contrast and overall nephrotoxins not significantly less KDIGO Bundle Avoid nephrotoxins Withhold ACEI/ARB Monitor SCr/UOP Glucose < 150 mg/dl Limit IV contrast Optimize volume status/hemodynamics Meersch M, et al. Intensive Care Med 2017;43:1551-61.
PREVAKI RANDOMIZED CONTROLLED TRIAL Single-center, randomized trial of 276 cardiac surgery patients with TIMP-2 IGFBP7 0.3 138 control patients 138 intervention patients Primary Endpoint: Any AKI at 72-h Any AKI: 72% Stage II/III: 45% Any AKI: 55% Stage II/III: 30% KDIGO Bundle Avoid nephrotoxins Monitor SCr/UOP Limit IV contrast Withhold ACEI/ARB Glucose < 150 mg/dl Optimize volume status/hemodynamics We already do this Meersch M, et al. Intensive Care Med 2017;43:1551-61.
BIGPAK RANDOMIZED CONTROLLED TRIAL Single-center, randomized trial of 121 major elective noncardiac surgery patients with 1 risk factor for AKI- screened If TIMP-2 IGFBP7 0.3 randomized 61 control patients 60 intervention patients Primary Endpoint: Any AKI at 7 days Any AKI: 48% Stage II/III: 20% Any AKI: 32% Stage II/III: 7% 35% (n=21) patients had a recommendation for nephrotoxic drug management by nephrologist and 76% changes accepted KDIGO Bundle Avoid nephrotoxins Optimize fluid status Maintain perfusion pressure Nephrology consult Gocze I et al. Annals of Surgery 2017; epub ahead of print.
NEPHROCHECK RAPID RESPONSE TEAM Clinical Stratification Low Risk High Risk Very High Risk Monitor & prevent TIMP-2 IGFBP7 nephrology consult Ronco C, et al. Nephrol Dial Transplant 2017;32:408-13. Rizo-Topete L et al. 2017;43:82-88 Laboratory Stratification 0.3 > 0.3 to 2.0 > 2.0 Monitor, non-invasive tests, optimize fluid status and perfusion, avoid nephrotoxins, informal nephrology consult Consult Neph., d/c nephrotoxins, optimize perfusion with fluids and vasopressors, consider dialysis
WHAT IS THE THEME? Know your AKI rates Also, need an understanding of causes Identify patients at risk for AKI Hypervigilance Surveillance-discussion on each patient Ensuring best practices
MANAGING NEPHROTOXINS EARLY WARNING AND HYPERVIGILANCE
KINETICS OF URINARY BIOMARKERS(KIM-1, NGAL) AND VANCOMYCIN EXPOSURE Biomarker AUC-ROC 95% CI SCr Day 0 0.447 0.222-0.673 SCr Day 1 0.676 0.461-0.892 SCr Day 2 0.782 0.582-0.981 SCr Day 3 0.799 0.617-0.981 ukim-1 Day 0 0.769 0.629-0.910 ukim-1 Day 1 0.724 0.556-0.892 ukim-1 Day 2 0.849 0.75-0.948 ukim-1 Day3 0.781 0.658-0.904 ungal Day 0 0.703 0.575-0.831 ungal Day 1 0.733 0.59-0.877 ungal Day 2 0.824 0.7260.922 ungal Day 3 0.812 0.698-0.927 ukim-1 and ungal 0.852 0.754-0.996 Pang HM et al. Eur Rev Med Pharmaocol SCI 2017;21:4203 NGAL = Neutrophil gelatinaseassociated lipocalin; KIM-1 = kidney injury molecule-; AUC-ROC= area under the receiver operating characteristic curve
BIOMARKER(TIMP2-IGFBP7)KINETICS AND VANCOMYCIN EXPOSURE Ostermann M et al. Crit Care Med 2018: epub ahead of print
HYPERVIGILANCE/SURVEILLANCE PREVENTION IN PEDIATRIC, NON-ICU PATIENTS Development and refinement of a predictive AKI trigger with the goal of reducing AKI severity Knowledge for alert 3 nephrotoxins on the same day IV aminoglycoside for 3 days Recent: vancomycin for 3 days Pharmacist managed alert -outside of workflow and advice provided to practitioner Evidence of AKI Pediatric RIFLE criteria; no urine evaluation Risk: ecrcl decrease by 25% Injury: ecrcl decrease by 50% Failure: ecrcl decrease by 75% 1-yr: 42% decrease in AKI intensity with a reduction in days in AKI per 100 exposure days 3-yr: Results sustained with a 31% AKI intensity decrease and a 64% AKI rate decrease Goldstein SL et al. Pediatrics 2013;132:e756 Kirkendall ES et al. Appl Clin Inform 2014;5:313 Goldstien SL Kidney Int 2016;90:212
CHANGE SERUM CREATININE TO BIOMARKER MONITORING Adults? ICU patients? We already monitor serum creatinine regularly Alert 3 nephrotoxins Pharmacists evaluate alert -repeat, patient already has AKI Pharmacists order biomarker test and inform physician Pharmacists aid in interpretation and makes medication management recommendations QI- evaluate medication recommendations made, AKI severity, days of AKI and AKI incidence Frazee E, Voils S, Kane-Gill SL. Pharmacotherapy (in press).
CASE: A.B. 74 y.o. male admitted for septic shock due to a urinary tract infection (UTI) PMH: Alcoholic cirrhosis, stroke with hemiparesis and urethrocutaneous fistula with recurrent UTIs Fluids, vasopressors, cultures were drawn Starting piperacillin/tazobactam, gentamicin, vancomycin Renal assessment Serum creatinine (SCr) 0.8 mg/dl (egfr 92 ml/min) Urine output (UOP) 20 ml/h x 4h (0.25 ml/kg/hr)
WHAT STATEMENT BEST CHARACTERIZES THE USE OF TIMP-2 * IGFBP7 IN A.B.? A. TIMP-2 - IGFBP7 is not indicated for use in A.B. given his baseline risk for AKI B. TIMP-2 - IGFBP7 is indicated in A.B. to estimate GFR for renally-dosed medications C. TIMP-2 - IGFBP7 is indicated in A.B. and a level >2.0 would justify holding gentamicin and/or other nephrotoxins D. TIMP-2 - IGFBP7 is indicated in A.B and requires daily monitoring to optimize medication use
CASE: A.B. Clinical Stratification Low Risk High Risk Very High Risk TIMP-2 _ IGFBP7 Laboratory Stratification 0.3 > 0.3 to 2.0 > 2.0 Follow SCr/UOP, consider volume replacement, nephrotoxic antibiotics benefit > risk, reevaluate in 12-hours Follow SCr/UOP, urinalysis, evaluate fluid status and perfusion, critically determine whether gentamicin or vancomycin or this antibiotic combination is needed Consult nephrology, antibiotic combination risk > benefit, consider fluids and vasopressors, more closely monitor and adjust doses
OPERATIONAL ISSUES FOR IMPLEMENTING ALERT AND BIOMARKER Factors Stakeholder Support Institutional Approval Alert Development Engaging the Patient Care Team Education Cost Considerations Considerations Determining the high risk, target patient population for this intervention requires communication and support from stakeholders and key thought leaders Institutional approvals may be necessary?use a commercially available biomarker or biomarkers in development?outcome evaluation of biomarker Wait in the queue Use clinical decision support external to, but works with EMR- Theradoc Revise knowledge to reduce noise Efforts/workload of physicians, pharmacists, nurses and laboratory services need to be considered for rapid ordering of a biomarker test. Education for the team members regarding ordering and interpreting the biomarker test results More to come. Frazee E, Voils S, Kane-Gill SL. Pharmacotherapy (in press).
COST OF AKI 30000 25000 20000 $60,000 $50,000 $40,000 $30,000 $20,000 $10,000 Cost of AKI in CTICU patients 15000 10000 5000 0 Total Costs Incremental Costs $0 BigpAK - One ICU day LOS reduction in intervention about a $2400 (US) savings Averting or reducing AKI severity in one patient could result in cost savings Budget impact models and economic evaluations are needed Dasta JF et al. Nephrol Dial Transplant 2008;23:1970-4 Collister D et al. Clin J Am Soc Nephrol 2017: 12:1733 Gocze I et al. Annals of Surgery 2017; epub ahead of print
Biomarkers for the Prevention of Drug Induced AKI (D-AKI) Sandra Kane-Gill, PharmD, MSc, FCCM, FCCP Associate Professor, University of Pittsburgh Critical Care Medication Safety Pharmacist, UPMC