Drug Therapy in Renal Failure

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174 Drug Therapy in Renal Failure

The incidence of acute kidney injury or insufficiency (AKI) in the intensive care unit (ICU) ranges from 5.9% to 25%, depending on how AKI is defined.1 Renal replacement therapy is required for 4.3% of all critically ill patients and up to 72.5% of patients with AKI.2 In-hospital mortality in ICU patients ranges from 5% to 10% in those with no renal dysfunction, 9% to 27% at risk of renal dysfunction, 11% to 30% with AKI, and 26% to 40% with overt kidney failure.3 Critically ill patients with chronic kidney disease (CKD) have poorer outcomes than patients with normal renal function on admission, and the presence of CKD is a significant predictor of hospital mortality in Acute Physiology, Age, and Chronic Health Evaluation (APACHE) III score tools.4,5 Renal insufficiency, whether acute or chronic, alters the absorption, distribution, metabolism, and elimination of many pharmacotherapeutic agents used in the treatment of critically ill patients. In this chapter, the drugs affected are tabulated, and the mechanisms responsible for the changes in disposition are discussed. A general construct for the individualization of drug therapy in patients with CKD or AKI is presented, along with dosage guidelines for the most commonly used ICU medications. Finally, the influence of continuous and intermittent renal replacement therapy on drug clearance is discussed, and dosage guidelines are tabulated for selected drugs for patients with severe CKD or AKI.

image Quantitation of Renal Function

Accurate assessment of renal function in critically ill patients is imperative. Serial estimates or measurements of renal function routinely are recommended to guide individualization of drug dosage regimens to optimize clinical outcomes. The calculation of creatinine clearance (CLcr) from a timed urine collection with creatinine measurement in serum and urine has been the standard clinical measure of renal function for decades. Urine is difficult to collect accurately in the ICU. Furthermore, many commonly used medications interfere with measurement of creatinine, especially when colorimetric assay methods such as the Jaffé method are used. Thus, measurement of CLcr by this approach is not always the best way to assess glomerular filtration rate (GFR).6,7 The administration of radioactive (125I iothalamate, 51Cr-EDTA, or technetium-99m DTPA) or nonradioactive (aminoglycosides, iohexol, iothalamate, and inulin) markers of GFR, although scientifically sound, is clinically impractical because intravenous (IV) or subcutaneous (SQ) administration of the marker and the collection of multiple timed blood and urine collections make the procedures expensive and difficult to perform.

Estimation of CLcr or GFR requires only routinely collected laboratory and demographic data and is inexpensive and clinically feasible. The Cockcroft and Gault (C-G) method for estimation of CLcr8 and the Modification of Diet in Renal Disease (MDRD) method for estimation of GFR9 correlate well with CLcr and GFR measurements in individuals with stable renal function.9 These methods lose their predictive performance, however, in patients with liver disease,1012 unstable renal function,6,13,14 estimated GFR above 60 mL/min,15 or obesity.16,17 In critically ill patients with AKI, both MDRD and C-G overestimate estimated GFR by 33% and 80%, respectively.18 Finally, although several methods for CLcr estimation in patients with unstable renal function have been proposed,7 as well as equations for “adjusted” weights (for use in the C-G equation) in the obese,16,17 the accuracy of these methods has not been rigorously assessed, and at present their use cannot be recommended.

There is considerable controversy at this time regarding whether the C-G or MDRD equation should be utilized to guide drug dosing adjustments in patients with CKD. The MDRD equation was developed to estimate GFR in patients with CKD.15 However, renal dosing recommendations for currently approved drugs are predominantly (>95%) based on relationships between drug clearance and CLcr estimated by the C-G equation.19 The literature now suggests that the two equations cannot be utilized interchangeably, as several studies have shown that the use of the MDRD equation results in discordant dosing recommendations (compared to dosing based on C-G) in up to 40% of patients.1921 Complicating these comparisons even further is another problem: several versions of the MDRD equation (and most recently, an equation called Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI]) have been reported since the publication of the original formula.22 As such, clinicians should continue to utilize CLcr estimated by C-G for drug dosing.23

image Altered Drug Disposition in Critically Ill Patients with Renal Insufficiency

Effect On Drug Distribution

The volume of distribution of several drugs is increased significantly in patients with AKI or severe CKD.25,2830 Increases may result from fluid overload, decreased protein binding, or altered tissue binding (Table 174-1). The volume of distribution of only a few drugs is decreased in patients with CKD, and the mechanism proposed for this change is a reduction in tissue binding. Digoxin and pindolol are two prime examples, and for both of these drugs, a significant relationship exists between the decrease in distribution volume and CLcr.29,30

Effect On Drug Metabolism

Preliminary human data suggest a differential effect of CKD on cytochrome P450 (CYP) enzyme activity: the activities of CYP2C19 and CYP3A4 are reduced, whereas the activities of CYP2D6 and CYP2E1 are not affected.29,30 This differential effect on individual enzymes may help explain some of the conflicting data regarding changes in drug metabolism in the presence of severe CKD.

Reduction of nonrenal clearance of several drugs reported in patients with severe CKD supports the premise that alterations in hepatic cytochrome P450 enzyme expression and/or activity is responsible (Table 174-2).25,2830 Prediction of the effect of CKD on metabolism of a particular drug is difficult even for drugs within the same pharmacologic class.29,30 Patients with CKD exhibit reductions in nonrenal clearance and alterations in bioavailability of predominantly hepatically metabolized drugs which are generally proportional to the reductions in GFR.

TABLE 174-2 Effect of End-Stage Renal Disease on Nonrenal Clearance of Selected Drugs Used in the ICU

Decreased    
Acyclovir Erythromycin Nitrendipine
Aztreonam Imipenem Procainamide
Bufuralol Isoniazid Propranolol
Cefotaxime Ketorolac Quinapril
Ceftriaxone Metoclopramide Vancomycin
Cilastatin Morphine Verapamil
Ciprofloxacin Nicardipine Warfarin
Doripenem Nimodipine  
Increased    
Bumetanide Fosinopril Phenytoin
Cefpiramide Nifedipine Sulfadimidine
Unchanged    
Acetaminophen Insulin Nisoldipine
Chloramphenicol Lidocaine Pentobarbital
Clonidine Metoprolol Theophylline

Data from references 25, 2830.

Critically ill patients with AKI have been noted to have higher residual nonrenal clearance for three drugs—imipenem, meropenem, and vancomycin—than patients with CKD who have similar CLcr.31 This difference may be the result of less exposure to or accumulation of uremic waste products that alter hepatic function. Because patients with AKI may have a higher nonrenal clearance than patients with CKD, the resultant plasma concentrations will be lower than expected and possibly subtherapeutic if classic CKD-derived dosage guidelines are followed. Thus for these agents, initial dosing should be adjusted upward, and only after 7 to 10 days of persistent AKI do the dosing guidelines derived from CKD subjects likely become applicable.

Effect On Renal Excretion

Renal clearance is the composite of GFR, renal tubular secretion, and reabsorption: renal clearance = (GFR × fu) + (renal tubular secretion − renal reabsorption), where fu is the fraction of the drug unbound to plasma proteins. An acute or chronic progressive reduction in GFR decreases renal clearance; historically, drug dosage guidelines for patients with AKI or CKD have been based on this phenomenon. The contribution of a reduction in renal clearance to the degree of change in the total body clearance of a drug is highly dependent, however, on the fraction of the dose eliminated unchanged by the normal kidney, the intrarenal pathways for drug elimination and transport, and the degree of functional impairment of each of these pathways.29,30

Drug elimination by GFR occurs by diffusion, but renal tubular secretion and renal reabsorption are bidirectional processes that involve carrier-mediated renal transport systems and passive diffusion. The important renal transport systems involved in the renal tubular excretion of multiple compounds include the organic anionic (i.e., ampicillin, cefazolin, and furosemide), organic cationic (i.e., famotidine, trimethoprim, and dopamine), nucleoside (i.e., zidovudine), and P-glycoprotein transporters (i.e., digoxin and steroids).32,33 Accordingly, the clearance of drugs that are extensively renally secreted (renal clearance > 300 mL/min) may be reduced significantly by drug interactions (i.e., probenecid with β-lactam antibiotics) and/or impaired function of one or more of the renal transporter systems. For example, AKI due to ischemia or toxicants results in a significant impairment in the function of renal solute carrier (SLC) 22A organic ion transporters, compounding the effects of decreased GFR on drug clearance.34

image Strategies for Drug Therapy Individualization

Secondary references such as the American Hospital Formulary Service Drug Information,35 Drug Prescribing in Renal Failure by Aronoff and colleagues,36 and Goodman and Gilman’s The Pharmacological Basis of Therapeutics37 are excellent sources from which one can acquire information on the pharmacokinetic characteristics of drugs in subjects with normal renal as well as impaired renal function. However, these references often do not provide the explicit relationships of kinetic parameters with CLcr or GFR. In addition, since the references employ different definitions of renal impairment and utilize varying methodologies for deriving recommendations, drug dosing recommendations occasionally differ significantly.38 This section provides a practical approach for drug dosage individualization in critically ill patients with AKI or CKD and patients receiving continuous renal replacement therapy (CRRT) or intermittent hemodialysis (IHD). Basic pharmacokinetic principles (see Chapter 169) combined with the disposition properties of a particular drug and a quantitative measure of the patient’s degree of renal function enable the clinician to design an individualized therapeutic regimen.

If the relationship of a drug’s total body clearance with CLcr