Tools
Renal Failure Drug Dose Adjustments
Definition/Introduction
The effects of many drugs are altered in renal impairment, particularly when a drug is renally cleared. Drug doses should be altered based on the predicted reduction in the clearance of the drug. Patient factors, such as the degree of renal disease and patient size, also influence the decision to adjust drug doses. In addition, drug factors, including the drug excretion and the therapeutic index, must be considered when adjusting doses. Accurate estimation of renal function is crucial for determining appropriate doses of renally excreted drugs.
Renal disease can alter drug concentrations and effects in the body, occasionally reducing effects but more commonly escalating their effects and thus causing potential toxicity. Most of these changes are predictable and may be prevented by altering drug doses in accordance with established guidelines.
Renal disease primarily affects drug dosing in 3 ways:
- Patient susceptibility: Patients with renal impairment may be more vulnerable to a specific drug effect.
- Pharmacodynamic change: The effect of a drug may be increased or decreased in patients with renal disease.
- Pharmacokinetic changes: When given at usual doses, some drugs have higher steady-state concentrations in patients with renal impairment.
Chronic kidney disease (CKD) is a type of kidney disorder characterized by a gradual decline in kidney function that occurs over several months to years.[1] Although various organs contribute to drug metabolism and excretion, the liver is the primary site for metabolism, and the kidneys are primarily responsible for excretion.
CKD is defined as a glomerular filtration rate (GFR) lower than 60 mL/min or albumin higher than 30 mg/g of creatinine, accompanied by abnormalities of kidney structure or function for more than 3 months. End-stage renal disease is a GFR of less than 15 mL/min.
Renal impairment modifies the effects of many medications, occasionally diminishing them but more typically enhancing or even multiplying them, thus leading to accumulation and potential toxicity. Many of these alterations can be and should be predicted and subsequently alleviated by adjusting drug doses.
In summary, the medication dose should be decreased equivalently to the calculated reduction of drug clearance.
Issues of Concern
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Issues of Concern
CKD is classified into 6 stages. Determining whether a patient has renal insufficiency (CKD stages 2 through 5) and identifying the specific stage are crucial because the kidneys excrete almost half of all drugs or their metabolites, and 30% of all adverse effects of medication are attributed to either a renal cause or a renal effect.[2] CKD affects a significant proportion of the general population, especially hospitalized patients. According to the NHANES study, the prevalence of renal insufficiency with a GFR below 60 mL/min is 11% to 13%, and about 20% of hospitalized patients have impaired renal function.[3]
In patients with renal impairment, the dosing of renally cleared drugs has to be adjusted based on the patient's actual GFR. In the past, this adjustment was made using the Cockcroft-Gault equation or by measuring creatinine clearance.[4] Previously, the Modification of Diet in Renal Disease (MDRD) formula was also used. However, the Chronic Kidney Disease-Epidemiology Collaborative Group (CKD-EPI) creatinine-based formula has largely replaced these older methods.
The CKD-EPI task force has also developed complex equations incorporating serum creatinine and cystatin C, using a population comprising healthy individuals and CKD patients, which are preferred when estimating GFRs in multi-ethnic populations due to their reduced bias.[5] A recent review by Inker et al presented new equations using cystatin C and creatinine without race, demonstrating an improved correlation between measured and calculated GFR. These complex equations can be found in this study and supplementary materials.[6]
The use of race as a qualitative factor to estimate muscle mass was previously supported, but the trend is toward removing race from GFR calculations. The current CKD-EPI formulas have gone through several iterations. Although some experts may prefer eGFR equations using cystatin or both cystatin and creatinine, in practice, cystatin is not widely measured. Therefore, the National Kidney Foundation (NKF) and the American Society of Nephrology (ASN) Task Force recommend using the CKD-EPI creatinine-based equation.[7] This formula uses serum creatinine, age, and constant values. For estimated GFR, this formula has been adopted by most major laboratories, including national laboratories.
The GFR is estimated using various formulas, and it is calculated as follows:
- The Cockroft-Gault formula
GFR = [(140−age) × weight]/[(72 × SCr) × 0.85 (if female)]
- The MDRD equation
186 × (SCr/88.4) × (Age) × (0.742 if female) × (1.210 if black)
- CKD-EPI equation
eGFR = 142 × min(SCr/κ,1)α × max(SCr/κ,1)−1.200 × 0.9938Age × 1.012 (if female)
Abbreviations/unitsSCr is serum creatinine in mg/dLκ = 0.7 for females and 0.9 for malesα = −0.329 for females and −0.411 for malesmin = the minimum of S/κ or 1, andmax = the maximum of S/κ or 1
Classification of CKD Based on GFR
- Stage 1: GFR 120 to 90 mL/min (GFR is normal, but mild abnormalities, such as proteinuria, indicate possible underlying renal pathology)
- Stage 2: GFR 89 to 60 mL/min (mild renal insufficiency)
- Stage 3a: GFR 59 to 45 mL/min (intermediate renal insufficiency)
- Stage 3b: GFR 44 to 30 mL/min (moderate renal insufficiency)
- Stage 4: GFR 29 to 15 mL/min (severe renal insufficiency)
- Stage 5: GFR 14 to 0 mL/min (preterminal, requires renal replacement therapy)
The units of drug dosing are typically expressed as the amount of drug administered per unit of time. Dose adjustment is typically crude for most drugs in many circumstances, such as doubling or halving doses. In most cases, having the means to establish when the drug dose should be doubled or halved is crucial, whereas a 20% alteration in dose is typically impractical and unnecessary. However, there are many drugs for which minor changes in dose or concentration may cause a significant effect, commonly called a narrow therapeutic index. The therapeutic index is calculated using the following formula:
- The therapeutic index = minimum toxic dose / minimum effective dose
Clinical Significance
Factors and conditions that may worsen the renal injury and thus should be either avoided or resolved include the following:
- Nephrotoxic drugs, such as nonsteroidal anti-inflammatory drugs, aminoglycosides, and iodinated contrast
- Uncontrolled diabetes
- Systemic hypertension
- Proteinuria
- Dehydration
- Smoking
- Hyperlipidemia
- Hyperphosphatemia
Nursing, Allied Health, and Interprofessional Team Interventions
Based on several studies, 34% to 53% of the drugs requiring adjustment were not considered in physicians' instructions.[8][9] There are various explanations for the inadequacy of medication dose regulation. The most frequent reason is that physicians often underestimate the impact of mild and intermediate renal insufficiency or that they have inadequate knowledge of the medications that require dose adjustment in renal insufficiency. Although the serum creatinine level is a widely used value in everyday practice, this is a late biomarker of decreased renal function (rising only after significant loss of renal function), thus leading to underestimating renal impairment, especially among older patients.
Another possible explanation is that physicians do not calculate the creatinine clearance using one of the three existing formulas due to insufficient time, which leads to underestimating the necessity of adjusting medication dosage.[10] The Food and Drug Administration and European Medicines Agency have particular guidelines about pharmacokinetics regarding patients with impaired renal function that should be followed when developing new drugs.[11][12] Physicians should consider the potential adverse effects, drug interactions, and treatment failures or discontinuations due to nephrotoxicity before administering any drug.
Effective communication between physicians, pharmacists, and nurses is essential for safe and appropriate drug administration in patients with renal impairment.
References
Stevens LA, Nolin TD, Richardson MM, Feldman HI, Lewis JB, Rodby R, Townsend R, Okparavero A, Zhang YL, Schmid CH, Levey AS, Chronic Kidney Disease Epidemiology Collaboration. Comparison of drug dosing recommendations based on measured GFR and kidney function estimating equations. American journal of kidney diseases : the official journal of the National Kidney Foundation. 2009 Jul:54(1):33-42. doi: 10.1053/j.ajkd.2009.03.008. Epub 2009 May 17 [PubMed PMID: 19446939]
Lattanzio F, Corsonello A, Montesanto A, Abbatecola AM, Lofaro D, Passarino G, Fusco S, Corica F, Pedone C, Maggio M, Volpato S, Incalzi RA. Disentangling the Impact of Chronic Kidney Disease, Anemia, and Mobility Limitation on Mortality in Older Patients Discharged From Hospital. The journals of gerontology. Series A, Biological sciences and medical sciences. 2015 Sep:70(9):1120-7. doi: 10.1093/gerona/glv068. Epub 2015 May 19 [PubMed PMID: 25991829]
Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF 3rd, Feldman HI, Kusek JW, Eggers P, Van Lente F, Greene T, Coresh J, CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration). A new equation to estimate glomerular filtration rate. Annals of internal medicine. 2009 May 5:150(9):604-12 [PubMed PMID: 19414839]
Level 2 (mid-level) evidenceCockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 1976:16(1):31-41 [PubMed PMID: 1244564]
Hundemer GL, White CA, Norman PA, Knoll GA, Tangri N, Sood MM, Hiremath S, Burns KD, McCudden C, Akbari A. Performance of the 2021 Race-Free CKD-EPI Creatinine- and Cystatin C-Based Estimated GFR Equations Among Kidney Transplant Recipients. American journal of kidney diseases : the official journal of the National Kidney Foundation. 2022 Oct:80(4):462-472.e1. doi: 10.1053/j.ajkd.2022.03.014. Epub 2022 May 16 [PubMed PMID: 35588905]
Inker LA, Eneanya ND, Coresh J, Tighiouart H, Wang D, Sang Y, Crews DC, Doria A, Estrella MM, Froissart M, Grams ME, Greene T, Grubb A, Gudnason V, Gutiérrez OM, Kalil R, Karger AB, Mauer M, Navis G, Nelson RG, Poggio ED, Rodby R, Rossing P, Rule AD, Selvin E, Seegmiller JC, Shlipak MG, Torres VE, Yang W, Ballew SH, Couture SJ, Powe NR, Levey AS, Chronic Kidney Disease Epidemiology Collaboration. New Creatinine- and Cystatin C-Based Equations to Estimate GFR without Race. The New England journal of medicine. 2021 Nov 4:385(19):1737-1749. doi: 10.1056/NEJMoa2102953. Epub 2021 Sep 23 [PubMed PMID: 34554658]
Delgado C, Baweja M, Crews DC, Eneanya ND, Gadegbeku CA, Inker LA, Mendu ML, Miller WG, Moxey-Mims MM, Roberts GV, St Peter WL, Warfield C, Powe NR. A Unifying Approach for GFR Estimation: Recommendations of the NKF-ASN Task Force on Reassessing the Inclusion of Race in Diagnosing Kidney Disease. American journal of kidney diseases : the official journal of the National Kidney Foundation. 2022 Feb:79(2):268-288.e1. doi: 10.1053/j.ajkd.2021.08.003. Epub 2021 Sep 23 [PubMed PMID: 34563581]
Alahdal AM, Elberry AA. Evaluation of applying drug dose adjustment by physicians in patients with renal impairment. Saudi pharmaceutical journal : SPJ : the official publication of the Saudi Pharmaceutical Society. 2012 Jul:20(3):217-20. doi: 10.1016/j.jsps.2011.12.005. Epub 2011 Dec 24 [PubMed PMID: 23960796]
Salomon L, Deray G, Jaudon MC, Chebassier C, Bossi P, Launay-Vacher V, Diquet B, Ceza JM, Levu S, Brücker G, Ravaud P. Medication misuse in hospitalized patients with renal impairment. International journal for quality in health care : journal of the International Society for Quality in Health Care. 2003 Aug:15(4):331-5 [PubMed PMID: 12930048]
Level 2 (mid-level) evidenceMariani LH, Bomback AS, Canetta PA, Flessner MF, Helmuth M, Hladunewich MA, Hogan JJ, Kiryluk K, Nachman PH, Nast CC, Rheault MN, Rizk DV, Trachtman H, Wenderfer SE, Bowers C, Hill-Callahan P, Marasa M, Poulton CJ, Revell A, Vento S, Barisoni L, Cattran D, D'Agati V, Jennette JC, Klein JB, Laurin LP, Twombley K, Falk RJ, Gharavi AG, Gillespie BW, Gipson DS, Greenbaum LA, Holzman LB, Kretzler M, Robinson B, Smoyer WE, Guay-Woodford LM, CureGN Consortium. CureGN Study Rationale, Design, and Methods: Establishing a Large Prospective Observational Study of Glomerular Disease. American journal of kidney diseases : the official journal of the National Kidney Foundation. 2019 Feb:73(2):218-229. doi: 10.1053/j.ajkd.2018.07.020. Epub 2018 Nov 9 [PubMed PMID: 30420158]
Level 2 (mid-level) evidencePaglialunga S, Offman E, Ichhpurani N, Marbury TC, Morimoto BH. Update and trends on pharmacokinetic studies in patients with impaired renal function: practical insight into application of the FDA and EMA guidelines. Expert review of clinical pharmacology. 2017 Mar:10(3):273-283. doi: 10.1080/17512433.2017.1274651. Epub 2017 Jan 29 [PubMed PMID: 27998190]
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Level 3 (low-level) evidence