2012. Minimize adverse events and nephrotoxicity

10/1/2012 NephroPharmacology 2012 Gary R. Matzke PharmD FCP, FCCP, FASN, FNAP Professor of Pharmacy and Medicine Virginia Commonwealth University Ri...
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NephroPharmacology 2012

Gary R. Matzke PharmD FCP, FCCP, FASN, FNAP Professor of Pharmacy and Medicine Virginia Commonwealth University Richmond, Virginia

Minimize adverse events and nephrotoxicity  Aminoglycosides and other anti-infective

agents  Gabapentin and other anticonvulsants  Opioid analgesics

Optimize efficacy  Aminoglycosides and other anti-infective

agents 

Reduce health care costs

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Cefazolin: bleeding, seizures, tremors, thrombocytopenia Cefepime: seizures Imipenem: CNS toxicity, seizures Cefotetan: bleeding complications, prolonged PTT Ceftriaxone: Bleeding complications Penicillin: CNS toxicity, lethargy, seizures Acyclovir, ganciclovir: seizures, confusion, renal damage Ketorolac: nephropathy, acute renal failure Nitrofurantoin: peripheral neuropathy Fluoroquinolones: Torsades de Pointes, Achilles tendonitis with rupture, hepatitis



Cefazolin in HD patients  Marx MA, et al. Cefazolin as empiric therapy in hemodialysis-related

infections: efficacy and blood concentrations. Am J Kidney Dis 1998;32:410414.

Vancomycin in CKD, HD, AKI patients  Macias WL, Mueller BA, Scarim SK. Vancomycin pharmacokinetics in acute

renal failure: preservation of nonrenal clearance. Clin Pharmacol Ther 1991; 50: 688–694  Li J, Udy AA, Kirkpatrick CM et al. Improving vancomycin prescription in

critical illness through a drug use evaluation process: a weight-based dosing intervention study. Int J Antimicrob Agents. 2012 Jan;39(1):69-72

Beta Lactams in CRRT patients  Seyler L, et al.Recommended b-lactam regimens are inadequate in septic

patients treated with continuous renal replacement therapy. Crit care 2011;15:R137

Therapeutics in Kidney Disease J Clinical Pharmacology January 2012

Renal Function Effects on Drug Disposition Characteristics



The conference generated 37 recommendations for clinical practice, 32 recommendations for future research directions, and 24 recommendations for regulatory agencies (US Food and Drug Administration and European Medicines Agency) to enhance the quality of pharmacokinetic and pharmacodynamic information available to clinicians. Kidney International (2011) 80, 1122–1137

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Glomerular filtration rate (GFR) should be the standard measure to evaluate kidney function for staging of CKD and drug dosing purposes Clinicians should use the most accurate method/tool to assess kidney function for the individual patient (i.e., eCLcr or eGFR or mGFR) Timed clearances of creatinine and urea may be of value for patients with AKI Metrics to determine the most accurate eGFR methodology-measures of bias, precision, and accuracy should be published



Serum Creatinine Assay Bias Miller WG et al Arch Pathol Lab Med 2005;129:297-304

Effect of Creatinine Measurement Imprecision on eGFR Myers GL et al Clin Chem 2006;52:5-18



KDIGO Recommendations Assessment for CKD Patients • In drug development, measure GFR with an inert tracer (e.g. inulin, iohexol, iothalamate) to determine PK alterations due to kidney dysfunction. • In patients with impaired kidney function, use the most accurate estimate of GFR available to determine dosing. Ann Intern Med. 2012;156(11):785-795 Ann Pharmacother 2012 online 28Aug 2012 doi:10.1345/aph.1Q757

Original Article

Estimating Glomerular Filtration Rate from Serum Creatinine and Cystatin C Lesley A. Inker, M.D., Christopher H. Schmid, Ph.D., Hocine Tighiouart, M.S., John H. Eckfeldt, M.D., Ph.D., Harold I. Feldman, M.D., Tom Greene, Ph.D., John W. Kusek, Ph.D., Jane Manzi, Ph.D., Frederick Van Lente, Ph.D., Yaping Lucy Zhang, M.S., Josef Coresh, M.D., Ph.D., Andrew S. Levey, M.D., for the CKD-EPI Investigators

• This study presents an equation for estimating the glomerular filtration rate that uses both creatinine and cystatin C. • It performs better than equations with either marker alone and is potentially useful for confirming chronic kidney disease. N Engl J Med Volume 367(1):20-29 July 5, 2012

Performance of Three Equations for Estimating Glomerular Filtration Rate (GFR).

Inker LA et al. N Engl J Med 2012;367:20-29



Creatinine Equation (CKD-EPI 2009), Cystatin C Equation (CKD-EPI 2012), and Creatinine– Cystatin C Equation (CKD-EPI 2012) for Estimating GFR, Expressed for Specified Sex, Serum Creatinine Level, and Serum Cystatin C Level.

Inker LA et al. N Engl J Med 2012;367:20-29

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Erratic gastrointestinal absorption due to gut hypoperfusion, gut barrier injury, or postoperative ileus. Variations in the extracellular fluid volume as a response to trauma, the resuscitation fluid load and/or as a consequence of continuous renal replacement therapy. Altered drug metabolism due to the systemic inflammatory response or liver and or kidney dysfunction as a component of MODS. Drug-drug pharmacokinetic and or pharmacodynamic interactions as the result of polypharmacy Heintz BH et al Pharmacother 2009;29(562–577 Seyler L et al Critical Care 2011;15:R137

Antibiotic Class

Vd (L/kg)

Increased Vd with Fluid Shifts?

Plasma T1/2 (hrs)

Protein Binding

Altered CL in Critically Ill?

TDM Required?

Aminoglycos ides








0.5-2 (except ceftriaxone





1 (except ertapenem 4 hrs)






4-6 (vancomycin) 80-160 (teicoplanin)

30% to 55% (vancomy cin) 90% (teicoplani n)

Yes, to ensure plasma Cmin >15 mg/mL

Yes, to Varies ensure with high Cmax renal No function



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Fluid administration is frequently necessary to stabilize ICU patients. Fluid overload has however been associated with an increased risk of mortality especially in those with AKI. The distribution volume of many drugs has been noted to be increased by 25-50% in critically ill patients esp. those with AKI. Fluid accumulation may mask severity of underlying renal injury Clinical impact -- one needs to start with higher loading doses and then adjust based on organ function Schrier RW Clin J Am Soc Nephrol 2010;5:733-9 Koyner JL & Murray PT Blood Purif 2010:29: 52-68 Roberts JA & Lipman J Crit Care Med 2009;37:840-51

Sodium and water over load may be an inevitable consequence of the resuscitation process.

Septic patients in the ICU gain as much as 12.5 L of body water during the first two days of resuscitation.

It may take up to 3 weeks for patients to excrete this excess load. Plank et al, Ann Surg 1998

Adjusted RR for death with %FO >10% at dialysis initiation: 2.07 (95% CI 1.27-3.37) Adjusted RR for death with %FO >10% at dialysis cessation: 2.52 (95% CI 1.55-4.08)

Bouchard et al Kidney Int. 2009 Aug;76(4):422-7. Epub 2009 May 13.



Fluid Accumulation has consequences: Underestimation of Severity of AKI Macedo E, et al Crit Care. 2010;14(3):R82. Epub 2010 May 6.

The volume of distribution is often dramatically increased in the presence of AKI and thus larger loading doses may need to be administered Therapeutic drug monitoring should be utilized if serum drug concentrations can be obtained in a clinically relevant time frame Trends in renal function indices such as serum creatinine and urine output along with volume status should be utilized to guide drug dosing A patient-centered team approach that includes an ICU pharmacist was recommended



Prevalence of the Stages of Chronic Kidney Disease in the U.S.


Glomerular Filtration Rate



≥90b (≥0.87)



60-89 (0.58-0.86)



30-59 (0.29-0.57)



15-29 (0.14-0.28)