2. Did I do that? Drug-Induced Acute Kidney Injury Krista Rieger, PharmD, BCPS PGY2 Internal Medicine Resident

3. Defining AKI: RIFLE Criteria Serum Creatinine (SCr)Urine Output (UOP) Risk ↑ SCr x 1.5 (or ↓ GFR > 25%)UOP ↓ to 0.5 mL/kg/hr x 6 hrs Injury ↑ SCr x 2 (or ↓ GFR > 50%)UOP ↓ to 0.5 mL/kg/hr x 12 hrs Failure ↑ SCr x 3 (or ↓ GFR > 75% or SCr ≥ 4 mg/dL) UOP ↓ to 0.3 mL/kg/hr x 24 hrs (or anuria x 12 hrs) Loss Persistent AKI = complete loss of renal function for >4 weeks ESRD End stage renal disease Clin Kidney J. 2013;6:8-14. Kidney Int. 2012;2(2):1-138.

4. Diagnosing types of AKI History & Physical – Medications – Time-course – Response to fluids Labs: – Urinalysis – Fractional excretion of sodium (FENa) Limitations – SCr – Blood urea nitrogen (BUN) – Urine output Postrenal Prerenal Intrinsic Ann Intern Med. 1978;89:47-50.

5. Acute glomerulonephritis Causes of AKI Liver failure Heart failure Decreased Effective Circulating Volume Decreased Cardiac Output Hypovolemia Prerenal Drug-induced Decreased renal blood flow Postrenal Nephrolithiasis Vascular Malignant Hypertension TTP/HUS Vasculitis Nephrotoxins Sepsis Ischemia Tubular damage Intrinsic Abbreviations: TTP = Thrombotic thrombocytopenic purpura; HUS = Hemolytic uremic syndrome

6. Acute glomerulonephritis Drug-Induced AKI Liver failure Heart failure Decreased Effective Circulating Volume Decreased Cardiac Output Hypovolemia Prerenal Drug-induced Decreased renal blood flow Postrenal Nephrolithiasis Vascular Malignant Hypertension TTP/HUS Vasculitis Nephrotoxins Sepsis Ischemia Tubular damage Intrinsic Abbreviations: TTP = Thrombotic thrombocytopenic purpura; HUS = Hemolytic uremic syndrome

7. Acute glomerulonephritis Intrinsic Liver failure Heart failure Decreased Effective Circulating Volume Decreased Cardiac Output Hypovolemia Prerenal Drug-induced Decreased renal blood flow Postrenal Nephrolithiasis Vascular Malignant Hypertension TTP/HUS Vasculitis Nephrotoxins Sepsis Ischemia Tubular damage Intrinsic Abbreviations: TTP = Thrombotic thrombocytopenic purpura; HUS = Hemolytic uremic syndrome

8. Intrinsic: Drug-induced AKI Nephrotoxins Acute tubular necrosis (ATN) Prolonged ischemia Aminoglycosides Amphotericin B Contrast Cisplatin Abbreviations: NSAIDs = Non-steroidal anti-inflammatory drugs; COX-2 = Cyclooxygenase 2

9. Intrinsic: Drug-induced AKI Nephrotoxins Acute tubular necrosis (ATN) Prolonged ischemia Aminoglycosides Amphotericin B Contrast Cisplatin Abbreviations: NSAIDs = Non-steroidal anti-inflammatory drugs; COX-2 = Cyclooxygenase 2

10. Intrinsic: Drug-induced AKI Nephrotoxins Acute tubular necrosis (ATN) Prolonged ischemia Aminoglycosides Amphotericin B Contrast Cisplatin Abbreviations: NSAIDs = Non-steroidal anti-inflammatory drugs; COX-2 = Cyclooxygenase 2

11. Intrinsically toxic drugIncidence Most toxic 1 Amphotericin B (Conventional)20 – 65 % 2Cisplatin10 – 30 % 3Aminoglycosides5 – 25 % 4 Least toxic Radiocontrast media0 – 10 % Drug-Induced Diseases. 2010: 853-71.

12. Drug-induced ATN: Characteristics Aminoglycosides - Incidence: 5-25% - Non-oliguric AKI - Urinary Mg-wasting - β2-microglobin urinary marker - Onset: 5-10 days Crit Care Med. 2008; 36(4): s216-23. Crit Care Med. 2010;38(6):s169-74. Drugs Aging. 2015;32:1-12. Drug-Induced Diseases. 2010: 853-71.

13. ATN: Aminoglycosides Proximal tubule ( - ) AMG (+) Lysosomes ( - ) AMG (+) Interfere with cell functioning Cell necrosis * * * * * * Crit Care Med. 2010;38(6):s169-74. Drug-Induced Diseases. 2010: 853-71.

14. Drug-induced ATN: Prevention Aminoglycosides - Therapeutic drug monitoring (TDM) ◦ Target troughs < 1 mcg/mL - Extended-interval or once-daily dosing: ◦ Uptake in nephron saturable ◦ Similar efficacy and lower cost ◦ Not shown to ↓nephrotoxicity Crit Care Med. 2008; 36(4): s216-23. Crit Care Med. 2010;38(6):s169-74. Drugs Aging. 2015;32:1-12. Drug-Induced Diseases. 2010: 853-71.

15. Drug-induced ATN: Characteristics Amphotericin B - Incidence: 20-65% - Electrolyte abnormalities: ◦ Na, K, & Mg-wasting ◦ Metabolic acidosis - Onset: 7 days (median) Crit Care Med. 2008; 36(4): s216-23. Crit Care Med. 2010;38(6):s169-74. Drugs Aging. 2015;32:1-12. Drug-Induced Diseases. 2010: 853-71.

16. ATN: Amphotericin B Distal tubule Amphotericin B * * * * * * Cell necrosis * * Vasoconstriction Renal artery Crit Care Med. 2010;38(6):s169-74. Drug-Induced Diseases. 2010: 853-71.

17. Drug-induced ATN: Prevention Amphotericin B - Lipid/Liposomal formulations: ◦ ie, Abelcet®, AmBisome® - Sodium loading: ◦ Normal saline bolus before dose ◦ Always with conventional formulation Crit Care Med. 2008; 36(4): s216-23. Crit Care Med. 2010;38(6):s169-74. Drugs Aging. 2015;32:1-12. Drug-Induced Diseases. 2010: 853-71.

18. Drug-induced ATN: Characteristics Contrast - Incidence: 0-10% ◦ Up to 40-50% with chronic kidney disease - Onset: 1-3 days ◦ Peaks at days 3-5 Crit Care Med. 2008; 36(4): s216-23. Crit Care Med. 2010;38(6):s169-74. Drugs Aging. 2015;32:1-12. Drug-Induced Diseases. 2010: 853-71.

19. Vasoconstriction ATN: Contrast Proximal tubule Contrast Lysosomes Contrast Release of vasoconstrictors Crit Care Med. 2010;38(6):s169-74. Drug-Induced Diseases. 2010: 853-71. * * * * * * Cellular necrosis

20. Drug-induced ATN: Prevention Contrast - IV hydration before and after - Lower osmolality formulations - Administer low volume - N-acetylcysteine ◦ PO BID the day before and of contrast Crit Care Med. 2008; 36(4): s216-23. Crit Care Med. 2010;38(6):s169-74. Drugs Aging. 2015;32:1-12. Drug-Induced Diseases. 2010: 853-71.

21. Drug-induced ATN: Characteristics Cisplatin - Incidence: 10-30% - Significant electrolyte wasting (K, Mg) - Onset: 1-10 days ◦ Remains elevated up to 3 weeks Crit Care Med. 2008; 36(4): s216-23. Crit Care Med. 2010;38(6):s169-74. Drugs Aging. 2015;32:1-12. Drug-Induced Diseases. 2010: 853-71.

22. ATN: Cisplatin Proximal tubule Cisplatin Mitochondria * * * * * Cellular necrosis ** * * * * * ** * Crit Care Med. 2010;38(6):s169-74. Drug-Induced Diseases. 2010: 853-71.

23. Drug-induced ATN: Prevention Cisplatin - Aggressive IV hydration ◦ Sometimes with electrolytes - Co-administered with mannitol - Dose minimization when possible - Consider carboplatin Crit Care Med. 2008; 36(4): s216-23. Crit Care Med. 2010;38(6):s169-74. Drug-Induced Diseases. 2010: 853-71. NCCN. Head and neck. 2014.

24. ATN: Pharmacist Role Management – Consider alternative agent – Minimize concomitant nephrotoxins Specific Drugs Pearls – Aminoglycosides – TDM (target low troughs) – Amphotericin – hydration and electrolytes – Contrast – check MAR for hydration – Cisplatin – monitor renal function before cycle Crit Care Med. 2008; 36(4): s216-23. Crit Care Med. 2010;38(6):s169-74. Drug-Induced Diseases. 2010: 853-71. NCCN. Head and neck. 2014.