IMPROVING OUR UNDERSTANDING OF DRUG ASSOCIATED AKI Sandra Kane-Gill, PharmD, MS, FCCM, FCCP Associate Professor of Pharmacy, Critical Care Medicine, and Biomedical Informatics Center for Critical Care Nephrology

Prevalence of Drug Associated Acute Kidney Injury (AKI) 5,143 patients in 20 ICUs 20% (74/355) associated with drugs ICUs at 5 hospitals 25% (157/618) associated with drugs 26,269 critically ill patients in 54 hospitals in 23 countries 19% (328/1726) associated with drugs Brivet FG et al. Crit Care Med 1996;24:192 Mehta RL et al. Kid International 2004;66: Uchino S et al. JAMA 2005;294: rd -5 th

Understanding the Potential Risk Most Frequently Ordered Nephrotoxins Frequency of Orders Acetaminophen2751 Aspirin1935 Cefazolin1083 Furoseminde2085 Piperacillin/tazobactam1258 Vancomycin drugs commonly prescribed in ICU –23% were known nephrotoxins 83,970 orders for the 182 drugs in 1 year –18,180 orders or 22% were for a nephrotoxin Taber SS et al. Crit Care Clin 2006;

Drug Associated AKI: Consequences Approximately 50% of patients with drug associated AKI may show permanent damage 70% of patients with drug associated AKI have evidence of residual kidney damage Similar mortality rates and/or dialysis dependence to AKI of other etiologies Recurrent AKI episodes have worse outcomes Grunfeld JP et al. In: Diseases of the Kidney (eds Schrier RW et al) Menon S et a. J Pediatr 2014;165:522 Mehta RL et al. Kid Int 2004;66:1613 Harris DG et al. J Trauma Acute Care Surg 2014;76:1397

Will the risk factors or model of prediction for developing AKI be upheld in the elderly population? Will the risk factors (including nephrotoxins) or model of prediction for developing AKI be upheld in the elderly population?

Methods Data were obtained from the Medical Archival Repository System (MARS) International Classification Diseases, 9 th edition (ICD9) Diagnosis related group (DRG) Severity of illness (Acute Physiology Score III) Suspected sepsis (blood culture and antibiotic in 24h of each other) Hypotensive index Baseline serum creatinine Admission creatinine Reference creatinine GFR (mL/min/1.73 m2) = 175 × (Scr) × (Age) × (0.742 if female) × (1.212 if African American) (conventional units) eGFR of 75ml/min/1.73m 2 when baseline creatinine missing

Methods: Drugs Four sources containing drug toxicity information were searched and a list of drug related nephrotoxins was compiled Micromedex, UpToDate, Drug-Induced Diseases Textbook, recent publication on drug associated AKI Scoring system was developed to rank the drugs’ association with nephrotoxicity based on the frequency in drug information sources Drug considered a known nephrotoxin if found in three or four of the drug information sources (n=62) List of 62 categorized by common drug classes (n=8)

Methods Categorized patients by various age strata AKI classification according to KDIGO Risk factor assessment completed using a multivariate logistic regression model Impact of age Separate assessment by age group

Use of Nephrotoxins in Elderly (≥ 65y.o.) Critically Ill Patients

Multivariable Regression Analyses for AKI Patients Compared to Non-AKI Patients

Multivariable Regression Analyses for AKI Patients Compared to Non-AKI Patients by Age Strata

Comparison of AUC for Elderly vs Younger (with drugs)

Comparison of AUC for Elderly vs Younger (no drugs)

Improving our Understanding of Drug Associated AKI… Re-examination of known nephrotoxins in the ICU 62 medications know to cause AKI Evaluate the risks of developing drug associated AKI based on a combination of patient and drug factors Determine the combinations of drugs (proposed and known) that increase the risk for AKI

Cluster Randomized Trial Evaluating Stage-based Treatment for Acute Kidney Injury (CREST AKI) Specific Aim 1. To optimize the clinical performance of alerts generated by a clinical decision support system for the detection of AKI in patients that are 65 years and older. Specific Aim 2. To test whether a clinical decision support system coupled with an interdisciplinary team improves short and long-term outcomes for patients age 65 and older with AKI Specific Aim 3. To test the hypothesis that structured follow-up recommendations reduce long-term sequelae in 65 and older patients developing AKI.

Co-Investigators John Kellum, MD Ragi Marugan, MD Florentina Sileanu, MS Steven Handler, MD, PhD

QUESTIONS?