Renal Function-Based Dose Adjustments - Adult - Inpatient/Ambulatory Consensus Care Model Population/Problem: This document describes renal function evaluation in adults who are receiving medications that require dose adjustment to maximize outcomes and prevent toxicity. This includes patients receiving intermittent hemodialysis or peritoneal dialysis. Excluded populations are those with cystic fibrosis and those receiving extracorporeal continuous renal replacement therapy modalities [(e.g. continuous venovenous hemofiltration (CVVH), continuous venovenous hemodialysis (CVVHD), continuous venovenous hemodiafiltration (CVVHDF), slow-continuous ultrafiltration (SCUF), sustained low-efficiency dialysis (SLED), or extended daily dialysis (EDD)]. Renal function evaluation in adults is intended to facilitate renal dosing modifications that maximize outcomes by establishing and maintaining therapeutic drug concentrations while minimizing toxicity that may result from excessive accumulation of the drug or its metabolites. Renal dosing modifications further simplify and lengthen dosing intervals as appropriate to minimize errors and optimize medication use. Intended Users: Physicians, Advanced Practice Providers, Pharmacists, Nurses Copyright © 2020 University of Wisconsin Hospitals and Clinics Authority. All Rights Reserved. Printed with Permission Contact: CCKM@uwhealth.org Last Revised: 08/2020 Effective 12/15/2020. Contact CCKM@uwhealth.org for previous versions Definitions: 1. Abbreviations • 𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴 = Adjusted body weight in kilograms (as indicated)1 = �0.4 × �𝑇𝑇𝐴𝐴𝐴𝐴(𝑘𝑘𝑘𝑘)− 𝐼𝐼𝐴𝐴𝐴𝐴(𝑘𝑘𝑘𝑘)�� + 𝐼𝐼𝐴𝐴𝐴𝐴(𝑘𝑘𝑘𝑘) • 𝑎𝑎𝑘𝑘𝑎𝑎 = Age in years • BMI = Body Mass Index2 = 𝑇𝑇𝑇𝑇𝑇𝑇 [𝐻𝐻𝐻𝐻(𝑚𝑚)]2 • 𝐻𝐻𝐻𝐻 = Height of the patient; see the unit in parentheticals to follow • 𝐼𝐼𝐴𝐴𝐴𝐴 = Ideal Body Weight o Ideal body weight (IBW) for Males3,4 = 50 𝑘𝑘𝑘𝑘 + [(2.3 𝑘𝑘𝑘𝑘) × (𝐻𝐻𝐻𝐻(𝑖𝑖𝑖𝑖)− 60)] o Ideal body weight (IBW) for Females3,4 = 45.5 𝑘𝑘𝑘𝑘 + [(2.3 𝑘𝑘𝑘𝑘) × (𝐻𝐻𝐻𝐻(𝑖𝑖𝑖𝑖)− 60)] • (𝑖𝑖𝑖𝑖) = Inches; record the patient-specific value at left in terms of inches • (𝑘𝑘𝑘𝑘)= Kilograms; record the patient-specific value at left in terms of kilograms • (𝑚𝑚) = Meters; record the patient-specific value at left in terms of meters • 𝑀𝑀𝐴𝐴𝑀𝑀 { = Maximum; use the larger of the two values in brackets (separated by a comma) in the equation • �𝑚𝑚𝑚𝑚 𝑑𝑑𝑑𝑑 � = Milligrams per deciliter; record the patient-specific value at left in terms of milligrams per deciliter • (𝑚𝑚𝑖𝑖𝑖𝑖) = Minutes; record the value at left in terms of minutes • 𝑀𝑀𝐼𝐼𝑀𝑀 { = Minimum; use the smaller of the two values in brackets (separated by a comma) in the equation • (𝑚𝑚𝑚𝑚) = Milliliters; record the value at left in terms of milliliters • 𝑆𝑆𝑆𝑆𝑆𝑆 = Serum Creatinine; the measured serum creatinine in milligrams per deciliter (as indicated) • 𝑇𝑇𝐴𝐴𝐴𝐴 = Total (or “Actual”) Body Weight; the measured patient weight in kilograms (as indicated) • 𝑈𝑈𝑆𝑆𝑆𝑆= Urine Creatinine; the measured urine creatinine in milligrams per deciliter (as indicated) 2. Glomerular Filtration Rate (GFR)5 • The volume of blood that passes through the glomeruli each minute which is considered the best overall index of kidney function 3. Estimated Glomerular Filtration Rate (eGFR)6-9 • An estimate of glomerular filtration rate that is normalized to body surface area 4. Estimated Creatinine Clearance (CrCl)10-12 • An estimate of glomerular filtration rate based upon the estimated volume of blood plasma that is cleared of creatinine per unit time using serum creatinine 5. Measured Creatinine Clearance13,14 • An estimate of glomerular filtration rate based upon the calculated volume of blood plasma that is cleared of creatine per unit time using serum and urine creatinine levels 6. Hemodialysis14-17 • The extracorporeal process of removing uremic retention products using a semipermeable membrane • High permeability dialysis membranes o Membranes whose in vitro ultrafiltration coefficient (KUf) is greater than 8 mL/hr/mmHg o Include both high-flux and high-efficiency membranes o Routinely used in standard hemodialysis technology 7. Peritoneal Dialysis17 • A dialysis technique utilizing peritoneum to filter blood and remove uremic retention products • CAPD: Continuous Ambulatory Peritoneal Dialysis o Requires manual exchanges of dialysis fluid every 4-6 hours • CCPD: Continuous Cyclic Peritoneal Dialysis o A cycler machine is utilized to perform dialysis exchanges 3-4 times per night during sleep Copyright © 2020 University of Wisconsin Hospitals and Clinics Authority. All Rights Reserved. Printed with Permission Contact: CCKM@uwhealth.org Last Revised: 08/2020 Effective 12/15/2020. Contact CCKM@uwhealth.org for previous versions Recommendations: 1. Estimate the renal clearance of medications based on the patient’s estimated creatinine clearance and/or dialysis modality.18-23 UW Health GRADE Moderate quality evidence, strong recommendation 1.1. The Cockcroft-Gault equation using total (actual) body weight should be used for estimating creatinine clearance in patients with BMI between 18 and 30 kg/m2.10,14,15,24 (Table 1; Appendix A) UW Health GRADE Moderate quality evidence, conditional recommendation 1.1.1. Creatinine clearance often exceeds true GFR due to creatinine secretion.10,12 1.1.2. Within HealthLink CrCl is calculated for adults by default using the Cockcroft-Gault equation with total (actual) body weight. Calculators are available to calculate CrCl using other equations and weights. 1.2. The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) Creatinine equation (2009) or the Modification of Diet in Renal Disease (MDRD) equation may be used to calculate eGFR in patients with estimated clearance rate <60 mL/min/1.73 m2. The CKD-EPI Creatinine equation should be used to calculate eGFR in patients with estimate clearance rate ≥60 mL/min/1.73 m2.5- 9 (Table 1; Appendix A) UW Health GRADE Moderate quality evidence, conditional recommendation 1.2.1. In general, eGFR equations provide a more accurate estimate of true GFR than creatinine clearance equations and measured creatinine clearance7-9,14,15 1.2.2. Within HealthLink eGFR is calculated using the CKD-EPI Creatinine (2009) equation with respect to sex, but not race. For Black patients, the reported value should be multiplied by 1.159. 1.3. The National Institute of Diabetes and Kidney Diseases and The National Kidney Disease Educational Program recommend dosing based on either CrCl or eGFR.22 1.4. CrCl and eGFR are NOT interchangeable.9 The equation chosen to estimate renal function should be selected based upon the renal function estimate used in the medication dosing adjustment recommendations (Table 1). UW Health GRADE Low quality evidence, conditional recommendation 2. Estimate renal function in obese patients with a BMI ≥30 kg/m2 using predictive equations that take higher body weight into account:11,12 UW Health GRADE Moderate quality evidence, conditional recommendation 2.1. Either the Salazar-Corcoran equation or the Cockcroft-Gault equation (using adjusted body weight) can be used to estimate renal function in obese patients with a BMI ≥30 kg/m2.11,12 (Table 1; Appendix A) 2.2. Obese patients have variable amounts of body fat versus muscle mass which makes estimating creatinine clearance even more challenging in this population. No one equation consistently demonstrates maximal precision or minimal bias.12,25-27 2.3. Using total body weight in the Cockcroft-Gault equation will overestimate creatinine clearance, whereas using ideal body weight will underestimate clearance in the obese patient. The Salazar- Corcoran equation is more complex and estimates fat-free mass. If a precise estimate of creatinine clearance is required to improve efficacy or prevent toxicity, then a measured creatinine clearance is recommended.27 2.4. These recommendations do not address dosing modifications that may be warranted based on obesity (BMI >30 kg/m2) outside of the appropriate equations for estimating creatinine clearance. 3. Regularly evaluate renal function and adjust medication doses based on estimated renal function when clinically appropriate in patients with mild to severe renal impairment and end-stage renal disease including those receiving dialysis as indicated by evidence-based dosing recommendations detailed in the drug-specific Lexicomp Drug Monograph.28 UW Health GRADE Moderate quality evidence, conditional recommendation 3.1. Dose modifications are not limited to adjustments based on declining renal function. Dose adjustments should be made as renal function improves, including adjusting doses for normal renal function. 3.2. Drugs that are listed as “no renal dose adjustment necessary” may require further investigation in the event of suspected adverse effects that may be due to drug accumulation in specific patients. Copyright © 2020 University of Wisconsin Hospitals and Clinics Authority. All Rights Reserved. Printed with Permission Contact: CCKM@uwhealth.org Last Revised: 08/2020 Effective 12/15/2020. Contact CCKM@uwhealth.org for previous versions 3.3. Medication dose adjustment for patients on renal replacement therapy (HD/PD) must be made based on type of replacement modality, not on reported serum creatinine or estimation of creatinine clearance/eGFR. 4. Consistently assess the applicability and accuracy of plasma/serum creatinine-based equations in the context of the individual patient.14,15,18 UW Health GRADE Moderate quality evidence, strong recommendation 4.1. In patients with renal impairment, plasma/serum creatinine-based equations are used routinely to estimate renal function in place of more accurate exogenous markers such as inulin or iothalamate.14,15 4.1.1. Equations used to calculate creatinine clearance and estimated glomerular filtration rate represent approximations and are meant to provide a basis for clinical evaluation of the patient. 4.2. These equations are intended for patients with stable renal function and are less accurate for patients with changing renal function.7,8,10,11,18,26 4.2.1. Additional factors must be evaluated in patients with changing renal function such as urine output and medication efficacy and toxicity.18 5. Obtain a measured creatinine clearance in patients with renal impairment when estimated creatinine clearance may be inaccurate.14,15,24 UW Health GRADE Low quality evidence, conditional recommendation 5.1. Calculated clearances using serum creatinine may be inaccurate in patients with low creatinine, hypoalbuminemia, hypermetabolic conditions, decreased muscle mass (as seen in cirrhosis, spinal cord injury, anorexia, malnutrition, debilitation).14,15 5.2. Renal function using predictive equations may be overestimated in situations associated with rapidly rising serum creatinine, which includes all cases of acute kidney injury (AKI) such as hepato-renal syndrome, ischemic injury, or drug-induced nephrotoxicity. 5.3. Proper urine collection is challenging because all the urine needs to be collected and any deviation from collecting for 24 hours will affect creatinine estimation. 5.4. Mixed data exists on the accuracy and usefulness of urine collections shorter than 24 hours. Some studies indicate that a 2-hour urine measurement is sufficient; another indicates that a minimum of 8 hours is required and yet others indicate 24-hour measurement is required. 29-34 5.5. Measured creatinine clearance may overestimate the true GFR in patients with advanced chronic kidney disease (CKD) due to increased creatinine secretion.13,14 6. Asses medication regimens and adjust administration schedules as appropriate for patients receiving dialysis.21 UW Health GRADE Low quality evidence, strong recommendation 6.1. To accommodate the administration of drugs that are removed by hemodialysis, administer the scheduled dose after hemodialysis (HD) is complete.21 UW Health GRADE Low quality evidence, strong recommendation 6.1.1. For example, a drug listed as “every 24 hours/once daily/three times per week post hemodialysis” could be scheduled for 1600 or later depending on the end of the dialysis session. 6.1.2. A drug listed as “every 12 hours post hemodialysis” could be scheduled at 1200 and 2400 if morning HD is anticipated, or at 0600 and 1800 if afternoon HD is anticipated. 6.1.3. If the HD schedule is altered, then a dose may need to be administered after the patient returns from HD and with subsequent administrations adjusted accordingly. 6.1.4. If the schedule is “every 6 hours” or “every 8 hours,” no special scheduling needs to be done as the time is frequent enough that scheduling around HD is not necessary. 6.1.5. Anti-hypertensive medications may be held before HD to allow for greater ultrafiltrate removal without precipitating hypotension during the procedure. The decision to hold or give an antihypertensive medication prior to HD should be individualized to the patient. 6.2. When high permeability membranes are used for hemodialysis, consider that more drug may be required compared to cases in which conventional filters are used.16 UW Health GRADE Low quality evidence, conditional recommendation 6.2.1. Hemodialysis dosing information has been obtained primarily from studies conducted under conditions where conventional dialysis membranes have been used. Copyright © 2020 University of Wisconsin Hospitals and Clinics Authority. All Rights Reserved. Printed with Permission Contact: CCKM@uwhealth.org Last Revised: 08/2020 Effective 12/15/2020. Contact CCKM@uwhealth.org for previous versions 6.2.2. Drug removal from plasma is often enhanced with the use of high permeability membranes as compared to conventional membranes, especially in drugs with higher molecular weight. 6.2.3. Individualized therapeutic drug monitoring may be necessary in these instances; the clinician is referred to the primary literature for further details. 7. All of the above recommendations must be utilized in conjunction with clinical evaluation and adjustments must be made to account for the individual patient. 7.1. Factors to consider include but are not limited to age, body weight, drug interactions, hepatic function, clinical response, and concurrent disease states. Table 1. Renal Function Estimation Equation SelectionA,B A Equations are described in Appendix A B All listed equations are serum creatinine-based and may overestimate renal function in advanced CKD, cirrhosis, spinal cord injury, anorexia, malnutrition, debilitation, obesity, and rapidly rising creatinine (including AKI)12,14,15,24-27 C Equation may generally underestimate true renal function7,8 Disclaimer Consensus care models assist clinicians by providing a framework for the evaluation and treatment of patients. This guideline outlines the preferred approach for most patients. It is not intended to replace a clinician’s judgment or to establish a protocol for all patients. It is understood that some patients will not fit the clinical condition contemplated by a guideline and that a guideline will rarely establish the only appropriate approach to a problem. Renal Dosing in terms of CrCl BMI <30kg/m2 Cockcroft-Gault equation using TBW BMI ≥30kg/m2 Salazar-Corcoran equation OR Cockcroft-Gault equation using AdjBW Renal Dosing in terms of GFR or eGFR eGFR <60 mL/min/1.73 m2 CKD-EPI Creatinine equation (2009) OR MDRD equationC eGFR ≥60 mL/min/1.73 m2 CKD-EPI Creatinine equation (2009) Copyright © 2020 University of Wisconsin Hospitals and Clinics Authority. All Rights Reserved. Printed with Permission Contact: CCKM@uwhealth.org Last Revised: 08/2020 Effective 12/15/2020. Contact CCKM@uwhealth.org for previous versions Contact for Changes: Name: Philip Trapskin, PharmD, BCPS - Pharmacy Phone Number: (608) 263-1328 Email Address: ptrapskin@uwhealth.org Guideline Authors: Mikala Hillis, PharmD - Pharmacy Sara Shull, PharmD, MBA, BCPS Reviewers: Tripti Singh, MD - Nephrology Laura Maursetter, MD - Nephrology Jason Bergsbaken, PharmD - Pharmacy Jeff Fish, PharmD, BCPS - Pharmacy Kimberly Holdener, PharmD - Pharmacy Mary Mably, RPh, BCOP - Pharmacy Marie H. Pietruszka, PharmD, BCPS, AAHIVP - Pharmacy Anne Rose, PharmD - Pharmacy Lucas Schulz, PharmD, BCIDP - Pharmacy Martha Starzewski, PharmD, BCPS - Pharmacy Philip Trapskin, PharmD, BCPS - Pharmacy Committee Approvals: Pharmacy and Therapeutics Committee: August 2020 Copyright © 2020 University of Wisconsin Hospitals and Clinics Authority. All Rights Reserved. Printed with Permission Contact: CCKM@uwhealth.org Last Revised: 08/2020 Effective 12/15/2020. Contact CCKM@uwhealth.org for previous versions Table 2. GRADE Ranking of Evidence High We are confident that the effect in the study reflects the actual effect. Moderate We are quite confident that the effect in the study is close to the true effect, but it is also possible it is substantially different. Low The true effect may differ significantly from the estimate. Very Low The true effect is likely to be substantially different from the estimated effect. Table 3. GRADE Ratings for Recommendations for or Against Practice Strong (S) Generally, should be performed (i.e., the net benefit of the treatment is clear, patient values and circumstances are unlikely to affect the decision.) Conditional (C) May be reasonable to perform (i.e., may be conditional upon patient values and preferences, the resources available, or the setting in which the intervention will be implemented.) Copyright © 2020 University of Wisconsin Hospitals and Clinics Authority. All Rights Reserved. Printed with Permission Contact: CCKM@uwhealth.org Last Revised: 08/2020 Effective 12/15/2020. Contact CCKM@uwhealth.org for previous versions Collateral Tools & Resources The following collateral tools and resources support staff execution and performance of the evidence- based model recommendations in everyday clinical practice. Delegation Protocols • Parenteral Nutrition Support – Developing, Ordering, and Monitoring Parenteral nutrition Support Care – Adult/Pediatric/Neonatal – Inpatient/Ambulatory [6] • Renal Function-Based Dose Adjustment – Adult – Inpatient/Ambulatory [8] o Drugs that can be dose adjusted per protocol based on renal function are listed within the Lexicomp drug monograph and specifically identified • Antimicrobial Dosing Based on Pharmacokinetic and Pharmacodynamic Principles – Adult – Inpatient/Emergency Department [9] • Medication Therapeutic Interchange – Adult/Pediatric – Inpatient/Ambulatory/Emergency Department [13] • Non-Thoracic Solid Organ Transplant Antiviral Prophylaxis – Adult – Inpatient [17] • Anemia Management in Pre-Dialysis Chronic Kidney Disease Patients – Adult – Ambulatory [20] • Therapeutic Medication Blood Concentration Monitoring – Adult/Pediatric/Neonatal – Inpatient/Emergency Department [31] • Anemia Management in Abdominal Transplant Recipients – Adult – Ambulatory [32] • Pharmacist Management of Electronic Medication Orders – Adult/Pediatric/Neonatal – Inpatient/Ambulatory/Emergency Department [74] • Perioperative Antimicrobial Prophylaxis Adjustment – Adult/Pediatric – Inpatient/Ambulatory/Emergency Department [75] • Non-Thoracic Solid Organ Transplant Rejection Antimicrobial Prophylaxis – Adult – Ambulatory [76] • Lung Transplant Program Pharmacotherapy – Adult – Ambulatory [81] • Heart Failure Medication Titration – Adult – Ambulatory [82] • Diabetes Medication Titration in Primary Care – Adult – Ambulatory [87] • Diabetes Medication Titration in Endocrine Diabetes Clinic/Health and Education Department – Adult – Ambulatory [88] • Antihypertensive Medication Titration in Primary Care – Adult – Ambulatory [99] • Transplant Management of Intravenous Iron Therapy – Adult – Ambulatory [106] • Hepatitis B Prophylaxis for Non-Thoracic Solid Organ Transplant – Adult – Inpatient [118] • Post-Hematopoietic Stem Cell Transplant (HSCT) Immunosuppressive Therapy – Adult – Ambulatory [125] • Vancomycin Dosing and Monitoring – Adult – Inpatient/Emergency Department [129] • Enoxaparin Dosing and Monitoring for Therapeutic Use – Pediatric – Inpatient [134] • Pre-exposure Prophylaxis (PrEP) for HIV Prevention – Adult – Ambulatory [146] • Management of Direct Oral Anticoagulants in Anticoagulation Clinic – Adult – Ambulatory [152] • Primary Care Expanded Antihypertensive Medication Management – Adult – Ambulatory [164] • Medication Therapeutic Interchange – Adult – Ambulatory [182] • Heart Failure Medication Titration in Cardiology Clinic – Adult – Ambulatory [197] • Vancomycin Dosing and Monitoring – Adult – Ambulatory [220] • Antiseizure Medication Management – Adult – Ambulatory [225] Copyright © 2020 University of Wisconsin Hospitals and Clinics Authority. All Rights Reserved. Printed with Permission Contact: CCKM@uwhealth.org Last Revised: 08/2020 Effective 12/15/2020. Contact CCKM@uwhealth.org for previous versions References 1. Bauer LA, Edwards WA, Dellinger EP, Simonowitz DA. Influence of weight on aminoglycoside pharmacokinetics in normal weight and morbidly obese patients. European journal of clinical pharmacology. 1983;24(5):643-647. 2. Gadzik J. "How much should I weigh?"--Quetelet's equation, upper weight limits, and BMI prime. Connecticut medicine. 2006;70(2):81-88. 3. Pai MP, Paloucek FP. The origin of the "ideal" body weight equations. The Annals of pharmacotherapy. 2000;34(9):1066-1069. 4. McCarron MM, Devine BJ. Clinical Pharmacy: Case Studies: Case Number 25 Gentamicin Therapy. Drug Intelligence & Clinical Pharmacy. 1974;8(11):650-655. 5. Stevens LA, Coresh J, Greene T, Levey AS. Assessing kidney function--measured and estimated glomerular filtration rate. The New England journal of medicine. 2006;354(23):2473-2483. 6. Klahr S, Levey AS, Beck GJ, et al. The effects of dietary protein restriction and blood-pressure control on the progression of chronic renal disease. Modification of Diet in Renal Disease Study Group. The New England journal of medicine. 1994;330(13):877-884. 7. Levey AS, Greene T, Beck GJ, et al. Dietary protein restriction and the progression of chronic renal disease: what have all of the results of the MDRD study shown? Modification of Diet in Renal Disease Study group. Journal of the American Society of Nephrology : JASN. 1999;10(11):2426-2439. 8. Levey AS, Stevens LA, Schmid CH, et al. A new equation to estimate glomerular filtration rate. Annals of internal medicine. 2009;150(9):604-612. 9. Stevens LA, Manzi J, Levey AS, et al. Impact of creatinine calibration on performance of GFR estimating equations in a pooled individual patient database. American journal of kidney diseases : the official journal of the National Kidney Foundation. 2007;50(1):21-35. 10. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 1976;16(1):31- 41. 11. Salazar DE, Corcoran GB. Predicting creatinine clearance and renal drug clearance in obese patients from estimated fat-free body mass. The American journal of medicine. 1988;84(6):1053-1060. 12. Spinler SA, Nawarskas JJ, Boyce EG, Connors JE, Charland SL, Goldfarb S. Predictive performance of ten equations for estimating creatinine clearance in cardiac patients. Iohexol Cooperative Study Group. The Annals of pharmacotherapy. 1998;32(12):1275-1283. 13. Proulx NL, Akbari A, Garg AX, Rostom A, Jaffey J, Clark HD. Measured creatinine clearance from timed urine collections substantially overestimates glomerular filtration rate in patients with liver cirrhosis: a systematic review and individual patient meta-analysis. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. 2005;20(8):1617-1622. 14. KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney Int Suppl. 2012;3:1-150. 15. Khwaja A. KDIGO clinical practice guidelines for acute kidney injury. Nephron Clinical practice. 2012;120(4):c179-184. 16. Ronco C, Clark WR. Haemodialysis membranes. Nature Reviews Nephrology. 2018;14(6):394-410. 17. KDOQI Clinical Practice Guideline for Hemodialysis Adequacy: 2015 update. American journal of kidney diseases : the official journal of the National Kidney Foundation. 2015;66(5):884-930. 18. Tucker GT. Measurement of the renal clearance of drugs. British journal of clinical pharmacology. 1981;12(6):761-770. 19. Perrone RD, Madias NE, Levey AS. Serum creatinine as an index of renal function: new insights into old concepts. Clinical chemistry. 1992;38(10):1933-1953. 20. Naud J, Nolin TD, Leblond FA, Pichette V. Current understanding of drug disposition in kidney disease. Journal of clinical pharmacology. 2012;52(1 Suppl):10s-22s. 21. Lam YW, Banerji S, Hatfield C, Talbert RL. Principles of drug administration in renal insufficiency. Clinical pharmacokinetics. 1997;32(1):30-57. 22. National Institute of Diabetes and Digestive and Kidney Diseases. CKD and Drug Dosing: Information for Providers 2020; https://www.niddk.nih.gov/health-information/professionals/advanced-search/ckd-drug- dosing-providers. 23. Lexi-Drugs. https://online.lexi.com/lco/action/home/switch. Accessed June 4, 2020. 24. Bauman W, Spungen A. Body Composition in Aging: Adverse Changes in Able-Bodied Persons and in Those with Spinal Cord Injury. Topics in Spinal Cord Injury Rehabilitation. 2001;6(3):22-36. 25. Winter MA, Guhr KN, Berg GM. Impact of various body weights and serum creatinine concentrations on the bias and accuracy of the Cockcroft-Gault equation. Pharmacotherapy. 2012;32(7):604-612. 26. Wilhelm SM, Kale-Pradhan PB. Estimating creatinine clearance: a meta-analysis. Pharmacotherapy. 2011;31(7):658-664. Copyright © 2020 University of Wisconsin Hospitals and Clinics Authority. All Rights Reserved. Printed with Permission Contact: CCKM@uwhealth.org Last Revised: 08/2020 Effective 12/15/2020. Contact CCKM@uwhealth.org for previous versions 27. Demirovic JA, Pai AB, Pai MP. Estimation of creatinine clearance in morbidly obese patients. American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists. 2009;66(7):642-648. 28. Hassan Y, Al-Ramahi RJ, Aziz NA, Ghazali R. Impact of a renal drug dosing service on dose adjustment in hospitalized patients with chronic kidney disease. The Annals of pharmacotherapy. 2009;43(10):1598-1605. 29. Baumann TJ, Staddon JE, Horst HM, Bivins BA. Minimum urine collection periods for accurate determination of creatinine clearance in critically ill patients. Clinical pharmacy. 1987;6(5):393-398. 30. Cherry RA, Eachempati SR, Hydo L, Barie PS. Accuracy of short-duration creatinine clearance determinations in predicting 24-hour creatinine clearance in critically ill and injured patients. The Journal of trauma. 2002;53(2):267-271. 31. Herrera-Gutiérrez ME, Seller-Pérez G, Banderas-Bravo E, Muñoz-Bono J, Lebrón-Gallardo M, Fernandez- Ortega JF. Replacement of 24-h creatinine clearance by 2-h creatinine clearance in intensive care unit patients: a single-center study. Intensive care medicine. 2007;33(11):1900-1906. 32. O'Connell MB, Wong MO, Bannick-Mohrland SD, Dwinell AM. Accuracy of 2- and 8-hour urine collections for measuring creatinine clearance in the hospitalized elderly. Pharmacotherapy. 1993;13(2):135-142. 33. Sladen RN, Endo E, Harrison T. Two-hour versus 22-hour creatinine clearance in critically ill patients. Anesthesiology. 1987;67(6):1013-1016. 34. Wilson RF, Soullier G. The validity of two-hour creatinine clearance studies in critically ill patients. Critical care medicine. 1980;8(5):281-284. Copyright © 2020 University of Wisconsin Hospitals and Clinics Authority. All Rights Reserved. Printed with Permission Contact: CCKM@uwhealth.org Last Revised: 08/2020 Effective 12/15/2020. Contact CCKM@uwhealth.org for previous versions Appendix A. Equations for Renal Function Estimation Estimated Creatinine Clearance Equations Cockcroft-Gault equation using total (actual) body weight1 CrCl Males mL/min = �(140−𝑎𝑎𝑚𝑚𝑎𝑎) × 𝑇𝑇𝑇𝑇𝑇𝑇(𝑘𝑘𝑚𝑚) 𝑆𝑆𝑆𝑆𝑆𝑆�𝑚𝑚𝑚𝑚𝑑𝑑𝑑𝑑 � × 72 � CrCl Females mL/min = � (140−𝑎𝑎𝑚𝑚𝑎𝑎) × 𝑇𝑇𝑇𝑇𝑇𝑇(𝑘𝑘𝑚𝑚) 𝑆𝑆𝑆𝑆𝑆𝑆�𝑚𝑚𝑚𝑚𝑑𝑑𝑑𝑑 � × 72 � × 0.85 Cockcroft-Gault equation using adjusted body weight2 CrCl Males mL/min = �(140−𝑎𝑎𝑚𝑚𝑎𝑎) × 𝐴𝐴𝑑𝑑𝐴𝐴𝑇𝑇𝑇𝑇(𝑘𝑘𝑚𝑚) 𝑆𝑆𝑆𝑆𝑆𝑆�𝑚𝑚𝑚𝑚𝑑𝑑𝑑𝑑 � × 72 � CrCl Females mL/min = � (140−𝑎𝑎𝑚𝑚𝑎𝑎) × 𝐴𝐴𝑑𝑑𝐴𝐴𝑇𝑇𝑇𝑇(𝑘𝑘𝑚𝑚) 𝑆𝑆𝑆𝑆𝑆𝑆�𝑚𝑚𝑚𝑚𝑑𝑑𝑑𝑑 � × 72 � × 0.85 Salazar-Corcoran equation3 CrCl Males mL/min = �(137−𝑎𝑎𝑚𝑚𝑎𝑎) × �0.285 × 𝑇𝑇𝑇𝑇𝑇𝑇(𝑘𝑘𝑚𝑚)� + (12.1 ×𝐻𝐻𝐻𝐻(𝑚𝑚) 2) 𝑆𝑆𝑆𝑆𝑆𝑆�𝑚𝑚𝑚𝑚𝑑𝑑𝑑𝑑 � × 51 � CrCl Females mL/min = �(146−𝑎𝑎𝑚𝑚𝑎𝑎) × �0.287 × 𝑇𝑇𝑇𝑇𝑇𝑇(𝑘𝑘𝑚𝑚)� + (9.74 × 𝐻𝐻𝐻𝐻(𝑚𝑚) 2) 𝑆𝑆𝑆𝑆𝑆𝑆�𝑚𝑚𝑚𝑚𝑑𝑑𝑑𝑑 � × 60 � Estimated Glomerular Filtration Rate Equations CKD-EPI Creatinine equation (2009)4 eGFR Males mL/min/1.73m2 = 141 × �𝑀𝑀𝐼𝐼𝑀𝑀 � 𝑆𝑆𝑆𝑆𝑆𝑆�𝑚𝑚𝑚𝑚𝑑𝑑𝑑𝑑 � 0.9 , 1�� −0.411 × �𝑀𝑀𝐴𝐴𝑀𝑀 � 𝑆𝑆𝑆𝑆𝑆𝑆�𝑚𝑚𝑚𝑚𝑑𝑑𝑑𝑑 � 0.9 , 1�� −1.209 × 0.993 𝑎𝑎𝑚𝑚𝑎𝑎 [× 1.159 𝑖𝑖𝑖𝑖 𝐴𝐴𝐵𝐵𝑎𝑎𝐵𝐵𝑘𝑘 𝑆𝑆𝑎𝑎𝐵𝐵𝑎𝑎] eGFR Females mL/min/1.73m2 = 141 × �𝑀𝑀𝐼𝐼𝑀𝑀 � 𝑆𝑆𝑆𝑆𝑆𝑆�𝑚𝑚𝑚𝑚𝑑𝑑𝑑𝑑 � 0.7 , 1�� −0.329 × �𝑀𝑀𝐴𝐴𝑀𝑀 � 𝑆𝑆𝑆𝑆𝑆𝑆�𝑚𝑚𝑚𝑚𝑑𝑑𝑑𝑑 � 0.7 , 1�� −1.209 × 0.993 𝑎𝑎𝑚𝑚𝑎𝑎 × 1.018 [× 1.159 𝑖𝑖𝑖𝑖 𝐴𝐴𝐵𝐵𝑎𝑎𝐵𝐵𝑘𝑘 𝑆𝑆𝑎𝑎𝐵𝐵𝑎𝑎] MDRD equation5,6 eGFR Males mL/min/1.73m2 = 186 × �𝑆𝑆𝑆𝑆𝑆𝑆 �𝑚𝑚𝑚𝑚 𝑑𝑑𝑑𝑑 �� −1.154 × (𝑎𝑎𝑘𝑘𝑎𝑎)−0.203 [× 1.212 𝑖𝑖𝑖𝑖 𝐴𝐴𝐵𝐵𝑎𝑎𝐵𝐵𝑘𝑘 𝑆𝑆𝑎𝑎𝐵𝐵𝑎𝑎] eGFR Females mL/min/1.73m2 = 186 × �𝑆𝑆𝑆𝑆𝑆𝑆 �𝑚𝑚𝑚𝑚 𝑑𝑑𝑑𝑑 �� −1.154 × (𝑎𝑎𝑘𝑘𝑎𝑎)−0.203 × 0.742 [× 1.212 𝑖𝑖𝑖𝑖 𝐴𝐴𝐵𝐵𝑎𝑎𝐵𝐵𝑘𝑘 𝑆𝑆𝑎𝑎𝐵𝐵𝑎𝑎] Copyright © 2020 University of Wisconsin Hospitals and Clinics Authority. All Rights Reserved. Printed with Permission Contact: CCKM@uwhealth.org Last Revised: 08/2020 Effective 12/15/2020. Contact CCKM@uwhealth.org for previous versions Measured Creatinine Clearance Equation7,8 CrCl mL/min = � 𝑈𝑈𝑆𝑆𝑆𝑆�𝑚𝑚𝑚𝑚𝑑𝑑𝑑𝑑 � × (𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑎𝑎𝑐𝑐𝐻𝐻𝑎𝑎𝑑𝑑 𝑢𝑢𝑆𝑆𝑢𝑢𝑢𝑢𝑎𝑎 𝑣𝑣𝑐𝑐𝑐𝑐𝑢𝑢𝑚𝑚𝑎𝑎)(𝑚𝑚𝑑𝑑) 𝑆𝑆𝑆𝑆𝑆𝑆�𝑚𝑚𝑚𝑚𝑑𝑑𝑑𝑑 � × (𝑢𝑢𝑆𝑆𝑢𝑢𝑢𝑢𝑎𝑎 𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑎𝑎𝑐𝑐𝐻𝐻𝑢𝑢𝑐𝑐𝑢𝑢 𝐻𝐻𝑢𝑢𝑚𝑚𝑎𝑎)(𝑚𝑚𝑢𝑢𝑢𝑢) � Copyright © 2020 University of Wisconsin Hospitals and Clinics Authority. All Rights Reserved. Printed with Permission Contact: CCKM@uwhealth.org Last Revised: 08/2020 Effective 12/15/2020. Contact CCKM@uwhealth.org for previous versions Appendix A References 1. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 1976;16(1):31-41. 2. Spinler SA, Nawarskas JJ, Boyce EG, Connors JE, Charland SL, Goldfarb S. Predictive performance of ten equations for estimating creatinine clearance in cardiac patients. Iohexol Cooperative Study Group. The Annals of pharmacotherapy. 1998;32(12):1275-1283. 3. Salazar DE, Corcoran GB. Predicting creatinine clearance and renal drug clearance in obese patients from estimated fat-free body mass. The American journal of medicine. 1988;84(6):1053-1060. 4. Levey AS, Stevens LA, Schmid CH, et al. A new equation to estimate glomerular filtration rate. Annals of internal medicine. 2009;150(9):604-612. 5. Klahr S, Levey AS, Beck GJ, et al. The effects of dietary protein restriction and blood-pressure control on the progression of chronic renal disease. Modification of Diet in Renal Disease Study Group. The New England journal of medicine. 1994;330(13):877-884. 6. Levey AS, Greene T, Beck GJ, et al. Dietary protein restriction and the progression of chronic renal disease: what have all of the results of the MDRD study shown? Modification of Diet in Renal Disease Study group. Journal of the American Society of Nephrology : JASN. 1999;10(11):2426-2439. 7. KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney Int Suppl. 2012;3:1-150. 8. Proulx NL, Akbari A, Garg AX, Rostom A, Jaffey J, Clark HD. Measured creatinine clearance from timed urine collections substantially overestimates glomerular filtration rate in patients with liver cirrhosis: a systematic review and individual patient meta-analysis. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. 2005;20(8):1617-1622. Copyright © 2020 University of Wisconsin Hospitals and Clinics Authority. All Rights Reserved. Printed with Permission Contact: CCKM@uwhealth.org Last Revised: 08/2020 Effective 12/15/2020. Contact CCKM@uwhealth.org for previous versions Appendix B. Selecting Appropriate Dosing Weight for Antimicrobial Medications From: Renal Function-Based Dose Adjustments – Adult – Inpatient/Ambulatory – Consensus Care Model Contact for Content: Lucas Schulz, PharmD, BCPS (AQ-ID); 608-890-8617; LSchulz2@uwhealth.org Definitions and Equations: • TBW = Total body weight (also called “Actual Body Weight”) • IBW = ideal body weight o IBW in kg (male) = 50 𝑘𝑘𝑘𝑘 + 2.3 × [𝐻𝐻𝑎𝑎𝑖𝑖𝑘𝑘ℎ𝐻𝐻 (𝑖𝑖𝑖𝑖𝐵𝐵ℎ𝑎𝑎𝑒𝑒)− 60] o IBW in kg (female) = 45.5 𝑘𝑘𝑘𝑘 + 2.3 × [𝐻𝐻𝑎𝑎𝑖𝑖𝑘𝑘ℎ𝐻𝐻 (𝑖𝑖𝑖𝑖𝐵𝐵ℎ𝑎𝑎𝑒𝑒)− 60] • AdjBW = adjusted body weight o AdjBW in kg = 𝐼𝐼𝐴𝐴𝐴𝐴(𝑘𝑘𝑘𝑘) + 0.4 × [𝐴𝐴𝐴𝐴𝐴𝐴(𝑘𝑘𝑘𝑘)− 𝐼𝐼𝐴𝐴𝐴𝐴(𝑘𝑘𝑘𝑘)] Appendix B: Selecting appropriate dosing weight for antimicrobial dosing (all recommendations are UW Health GRADE Low-moderate quality evidence, conditional recommendation) If patient TBW less than IBW, use this column If patient is non- obese and TBW is greater than IBW, use this column If patient is obese (BMI >30 kg/m2), use this column Antibiotics Aminoglycosides TBW IBW AdjBW1 Colistin IBW IBW2,3 Daptomycin IBW IBW4 Polymyxin B TBW AdjBW5-9 Trimethoprim/Sulfamethoxazole TBW AdjBW10 Vancomycin TBW TBW11,12 Antivirals Acyclovir TBW IBW IBW10 Ganciclovir TBW AdjBW10 Foscarnet TBW AdjBW 10; see footnote A Antifungals Liposomal amphotericin TBW TBW AdjBW 13; see footnote B Flucytosine IBW IBW14,15 Voriconazole TBW AdjBW16,17 Miscellaneous Bezlotoxumab TBW TBW TBW13 Ethambutol IBW IBW14 Pyrazinamide IBW IBW14,15 A Use TBW for the indication of ganciclovir-resistant cytomegalovirus B Consider IBW if risk of nephrotoxicity outweighs risk of infection Copyright © 2020 University of Wisconsin Hospitals and Clinics Authority. All Rights Reserved. Printed with Permission Contact: CCKM@uwhealth.org Last Revised: 08/2020 Effective 12/15/2020. Contact CCKM@uwhealth.org for previous versions Appendix B References 1. Bauer LA, Edwards WA, Dellinger EP, Simonowitz DA. Influence of weight on aminoglycoside pharmacokinetics in normal weight and morbidly obese patients. European journal of clinical pharmacology. 1983;24(5):643-647. 2. Garonzik SM, Li J, Thamlikitkul V, et al. Population pharmacokinetics of colistin methanesulfonate and formed colistin in critically ill patients from a multicenter study provide dosing suggestions for various categories of patients. Antimicrobial agents and chemotherapy. 2011;55(7):3284-3294. 3. Ortwine JK, Kaye KS, Li J, Pogue JM. Colistin: understanding and applying recent pharmacokinetic advances. Pharmacotherapy. 2015;35(1):11-16. 4. Ng JK, Schulz LT, Rose WE, et al. Daptomycin dosing based on ideal body weight versus actual body weight: comparison of clinical outcomes. Antimicrobial agents and chemotherapy. 2014;58(1):88-93. 5. Sandri AM, Landersdorfer CB, Jacob J, et al. Population pharmacokinetics of intravenous polymyxin B in critically ill patients: implications for selection of dosage regimens. Clin Infect Dis. 2013;57(4):524-531. 6. Pai MP. Polymyxin B dosing in obese and underweight adults. In: Clin Infect Dis. Vol 57. United States2013:1785. 7. Onufrak NJ, Rao GG, Forrest A, et al. Critical Need for Clarity in Polymyxin B Dosing. Antimicrob Agents Chemother. 2017;61(5). 8. Pogue JM, Ortwine JK, Kaye KS. Are there any ways around the exposure-limiting nephrotoxicity of the polymyxins? Int J Antimicrob Agents. 2016;48(6):622-626. 9. Pogue JM, Ortwine JK, Kaye KS. Clinical considerations for optimal use of the polymyxins: A focus on agent selection and dosing. Clin Microbiol Infect. 2017;23(4):229-233. 10. Polso AK, Lassiter JL, Nagel JL. Impact of hospital guideline for weight-based antimicrobial dosing in morbidly obese adults and comprehensive literature review. Journal of clinical pharmacy and therapeutics. 2014;39(6):584-608. 11. Rybak MJ, Lomaestro BM, Rotschafer JC, et al. Therapeutic monitoring of vancomycin in adults summary of consensus recommendations from the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, and the Society of Infectious Diseases Pharmacists. Pharmacotherapy. 2009;29(11):1275- 1279. 12. Srinivas NR. Influence of Morbidly Obesity on the Clinical Pharmacokinetics of Various Anti-Infective Drugs: Reappraisal Using Recent Case Studies-Issues, Dosing Implications, and Considerations. American journal of therapeutics. 2016. 13. Amsden JR, Slain D. Antifungal Dosing in Obesity: A Review of the Literature. Current Fungal Infection Reports. 2011;5(2):83. 14. Vermes A, Guchelaar HJ, Dankert J. Flucytosine: a review of its pharmacology, clinical indications, pharmacokinetics, toxicity and drug interactions. The Journal of antimicrobial chemotherapy. 2000;46(2):171- 179. 15. Tucker CE, Lockwood AM, Nguyen NH. Antibiotic dosing in obesity: the search for optimum dosing strategies. Clinical obesity. 2014;4(6):287-295. 16. Koselke E, Kraft S, Smith J, Nagel J. Evaluation of the effect of obesity on voriconazole serum concentrations. The Journal of antimicrobial chemotherapy. 2012;67(12):2957-2962. 17. Sebaaly JC, MacVane SH, Hassig TB. Voriconazole concentration monitoring at an academic medical center. American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists. 2016;73(5 Suppl 1):S14-21. Copyright © 2020 University of Wisconsin Hospitals and Clinics Authority. All Rights Reserved. Printed with Permission Contact: CCKM@uwhealth.org Last Revised: 08/2020 Effective 12/15/2020. Contact CCKM@uwhealth.org for previous versions Collateral Tools & Resources References Appendix A. Equations for Renal Function Estimation Appendix A References Appendix B. Selecting Appropriate Dosing Weight for Antimicrobial Medications