Drug dosing in patients with chronic kidney disease

1. How can chronic kidney disease (CKD) alter the pharmacokinetic behavior of most drugs?

CKD directly and indirectly affects the pharmacokinetic properties of most drugs. Alterations of drug pharmacokinetics in patients with kidney failure are based on changes in absorption, distribution, metabolism, and elimination.

2. How can changes in absorption resulting from CKD alter the pharmacokinetic behavior of drugs?

• Alkaline saliva. As CKD progresses, saliva becomes more alkaline. This compromises absorption of drugs that need an acid milieu (e.g., iron supplements) and contributes to a higher gastric pH.

• Nausea and vomiting may reduce drug ingestion and absorption.

• Volume overload states: Edema of the gastrointestinal tract limits absorption.

• Drug interactions: Many drugs used in the management of CKD limit drug absorption by forming nonabsorbable complexes (e.g., iron, phosphate-binding agents).

• Gastrointestinal neuropathy: Uremia may delay gastric emptying time, particularly in patients with diabetes.

3. How can changes in distribution from CKD alter the pharmacokinetic behavior of drugs?

The volume of distribution (V _D ) represents the ratio of administered dose to the resulting plasma drug concentration. The calculated V _D is a theoretic representation of the size of the anatomic space occupied by the drug if it were present throughout the body in the same concentration as that in the plasma. Drugs with a large V _D , such as digoxin, are distributed widely throughout the tissues and are present in relatively small amounts in the blood. In patients with CKD, changes in drug distribution may arise from either fluid retention or reductions in the extent of protein binding in tissue and plasma. CKD has very limited effects on drugs with large volume distribution. Conversely, drugs that are less lipid soluble and highly protein bound will tend to have a lower V _D because they are more restricted to the vascular compartment. Kidney impairment and hemodialysis has a significant effect on drugs with small V _D . For example, in critically ill patients with CKD, for a drug like vancomycin with a small V _D , higher than recommended loading and daily doses are needed to rapidly achieve therapeutic serum concentrations.

Malnutrition and proteinuria reduce the amount of protein available for protein binding, and uremic stage may alter the affinity of many drugs to albumin. Thus the concentration of free drug will increase in these settings, which can result in increased free fraction and potential adverse drug reactions. Therapeutic drug monitoring (TDM) for free or unbound drug concentrations in patients with kidney insufficiency or heavy proteinuria (e.g., free phenytoin levels) is an important consideration.

4. How can changes in metabolism as a result of CKD alter the pharmacokinetic behavior of drugs?

Even drugs without or with only minimal kidney elimination can have altered pharmacokinetics in advanced CKD. CKD may increase, decrease, or have no effect on nonkidney clearance. Some drugs are metabolized to active metabolites that are insignificant with normal kidney function but accumulate in CKD. For example, morphine metabolizes to 6- and 3-morphine-gluconate with respiratory depression and seizure properties. In CKD the clearance of the parent compound (morphine) is not significantly affected; however, morphine metabolizes to 6- and 3-morphine-gluconate, which accumulate and place patients at risk for serious adverse drug reactions. Therefore it is recommended that morphine be used cautiously in patients with CKD or avoided completely if high doses or a prolonged use is indicated.

5. How can changes in elimination as a result of CKD alter the pharmacokinetic behavior of drugs?

A reduction in the glomerular filtration rate (GFR) will generally lead to an increased half-life of a drug that is eliminated primarily by the kidney. Clearance is a measure of the efficiency of the kidney at excreting a specific compound. The clearance of a drug is the amount of plasma from which the drug is completely removed from over unit time. For example, a furosemide clearance of 20 mL/min means that every minute enough furosemide is excreted in the urine to completely clear out all of the furosemide from 20 mL of plasma.

6. What characteristics determine whether a drug is removed by dialysis?

• Molecular weight. As a general rule, smaller molecular weight substances pass through the dialyzer membrane much more easily than larger weight molecules. In general, free drug molecules with a molecular weight of less than 500 Daltons (D) are removed efficiently by hemodialysis.

• Protein binding. Decreased protein binding may increase the amount of free drug available for removal during dialysis. In the setting of an overdose, the amount of ingested drug may exceed the normal protein-binding capacity. This would allow removal of the excess drug by hemodialysis, even though dialysis has a minimal effect when the drug is used at normal doses.

• V _D . Drugs with large volumes of distribution are not removed effectively by dialysis. Lipid-soluble drugs usually have large volumes of distribution, making significant removal of the drug difficult because the plasma volume is rapidly replenished from other tissues (e.g., cyclosporine and digoxin).

• Water solubility. Drugs with high water solubility will be dialyzed to a greater extent than those with high lipid solubility.

• Dialyzer membrane. The pore size, surface area, and geometry are the primary factors in determining whether a dialysis membrane will clear a specific drug. Historically, standard dialysis membranes did not effectively remove vancomycin (molecular weight, 3300 D) given its size. Currently, high-flux membranes that remove larger-molecular-weight molecules have become standard of care in dialysis practice. Therefore vancomycin and many other antibiotics are removed by these membranes. Dosing of these medications should be held until after dialysis on those days.

• Blood and dialysate flow rates. Increased flow rates during hemodialysis will increase drug clearance. Patients who cannot tolerate standard blood flow rates will require less replacement dosing of a drug after hemodialysis.

7. How is kidney function assessed for drug dosing determination?

The best way is to estimate the GFR. The gold standard is measurement of the clearance of inulin; however, this is cumbersome and impractical for clinical use. Measurement of the 24-hour creatinine clearance (CrCl) is no longer recommended for similar reasoning. This has led to the development of equations to estimate GFR such as the Cockcroft-Gault (CG) and Modification of Diet in Renal Disease (MDRD) study. These equations use serum creatinine as one of the variables and both generally provide similar dosing recommendations. Adverse events such as drug accumulations are relatively uncommon when the GFR remains >50 mL/min.

It is still important to consider potential analytic interferences in these calculations based on the concurrent drug therapy. Some drugs may artifactually increase or decrease the measured serum creatinine concentration without directly influencing GFR. Drugs that inhibit the tubular secretion of creatinine will raise the serum level (e.g., trimethoprim, cimetidine, and probenecid).

8. What the best method to estimate kidney function for drug dosing in CKD?

Most approved drugs advice to use CG method by the way to estimated kidney function for medication dosage adjustment in patients with kidney disease. Recently, it has been questioned that other methods of estimating kidney function perhaps are more accurate than CG method for estimating kidney function. It is important to remember that CG formula, MDRD, and Chronic Kidney Disease-Epidemiology (CKD-EPI) Collaboration equation are only an “estimation” and “approximation” of kidney function. Neither of these methods provides accurate “measurement” or “calculation” of kidney function. In addition, there are many other changes in the kidney that might affect drug handling than just filtration rate such tubular function and organic acid accumulations. Health care providers should also consider drug safety and efficacy for dosage adjustment. In general, a number of recent studies comparing the equations for their influence on drug dosage adjustment have shown that the MDRD perhaps is a better method with a greater concordance with measured GFR compared with other methods.