Drug Dosing Consideration in Patients With Acute and Chronic Kidney Disease

A Clinical Update From Kidney Disease: Improving Global Outcomes (KDIGO)

Gary R Matzke; George R Aronoff; Arthur J Atkinson Jr; William M Bennett; Brian S Decker; Kai-Uwe Eckardt; Thomas Golper; Darren W Grabe; Bertram Kasiske; Frieder Keller; Jan T Kielstein; Ravindra Mehta; Bruce A Mueller; Deborah A Pasko; Franz Schaefer; Domenic A Sica; Lesley A Inker; Jason G Umans; Patrick Murray

Disclosures

Kidney Int. 2011;80(11):1122-1137. 

In This Article

Drug Dosing Considerations for HD Patients

The optimization of pharmacotherapy for patients receiving intermittent HD is critically dependent on the availability of reliable information from well-designed PK studies. The artificial kidney is an ideal eliminating 'organ' because, in contrast to renal or hepatic routes of drug elimination, blood flow to the dialyzer, drug concentrations in blood entering and leaving the dialyzer, and recovery of eliminated drug can all be measured.[109]

PK and PD Data

Although many hemodialyzers have been introduced in the past 10 years, and more than 100 different ones were available in the United States in 2011, the effect of HD on the disposition of a drug is rarely evaluated more than once. Thus, most of the literature, especially for older medications, probably represents an underestimation of the impact of HD on its disposition.[110]

The impact of HD on a patient's drug therapy is dependent on several factors, including the drug characteristics, the dialysis prescription, and the clinical situation for which dialysis is performed. Drug-related factors include the molecular weight or size, degree of protein binding, and distribution volume.[2,62] The vast majority of dialysis filters in use until the mid 1990s were composed of cellulose, cellulose acetate, or regenerated cellulose (cuprophane); and they were generally impermeable to drugs with molecular weights >1000 Daltons.[109] The HD procedure prescription can dramatically affect the dialysis clearance of a medication.[111] The primary factors that vary between patients are the composition of the dialysis filter, the filter surface area, the blood, dialysate and ultrafiltration rates, and whether or not the dialysis unit reuses the dialysis filter. Dialysis membranes in the twenty-first century are predominantly composed of semisynthetic or synthetic materials (for example, polysulfone, polymethylmethacrylate, or polyacrylonitrile). High-flux dialysis membranes have the larger pore sizes and this allows the passage of most solutes, including drugs that have a molecular weight of ≤20,000 Daltons.[109,110]

The impact of HD is not strictly limited to dialysis clearance. There is evidence that some drugs adhere to the dialyzer membrane, and recent findings suggest that the nonrenal clearance (metabolism) of some agents is altered by HD. A single 4-h session of HD increased the nonrenal clearance of erythromycin in patients with end-stage renal disease by 27% as soon as 2 h after HD.[112] This was presumably secondary to the removal of uremic solutes that accumulate during the interdialytic period and inhibited CYP450 3A4 and drug transporters. A subsequent study of midazolam in subjects with end-stage renal disease implicated transporters (human organic anion-transporting polypeptide and/or intestinal P-glycoprotein) as the likely drug disposition bottleneck in uremia rather than CYP3A4.[56] Should CLNR actually increase during HD, this would lead to an overestimation of CLD.

Assessment of the Impact of HD

The most common method for assessing the effect of HD is to calculate the dialyzer clearance (CLD) of the drug; CLD b from blood can be calculated as CLD b=Q b[(A b−Vb)/A b], where Q b is blood flow through the dialyzer, A b is the concentration of drug in blood going into the dialyzer, and V b is the blood concentration of drug leaving the dialyzer.[113–117] This equation, which has been termed the 'A-V difference method,' is only valid if the drug concentrations are measured in whole blood and if the drug rapidly and completely distributes into red blood cells. Because drug concentrations are generally determined in plasma, the previous equation is usually modified to CLD p=Q p [(A p−Vp)/A p] where p represents plasma and Q p is plasma flow, which equals Q b (1−hematocrit). This equation tends to underestimate HD clearance for drugs that readily partition into and out of erythrocytes. In addition, venous plasma concentrations may be artificially high if extensive ultrafiltration is performed and thus CLD p will be low if plasma water is removed from the blood at a faster rate than drug.

Because of the above limitations, the recovery clearance approach remains the benchmark for the determination of dialyzer clearance and it can be calculated as:[2,115,116] CLD r=R/AUC0−t where R is the total amount of drug recovered unchanged in the dialysate and AUC0−t is the area under the predialyzer plasma concentration–time curve during the period of time that the dialysate was collected. To determine the AUC0−t, a minimum of three to four plasma concentrations should be obtained during dialysis.

The HD clearance values reported in the literature may vary significantly depending on which of these methods were used to calculate CLD. The principal reason for this is that for most medications we do not know the degree and rapidity with which the drug crosses the red blood cell membrane.[2,110,113] Because the CLDr method incorporates no assumption of the degree of red blood cell permeability, it can be reliably used as the benchmark value. The primary limitation of this calculation is that the concentrations of the drug in the dialysate may be below the sensitivity limits of the assay. A continuing clinical problem is that PK results obtained with one dialyzer are generally not representative of the performance of another dialyzer.[2,110] Thus, there is a critical need to characterize CLD estimates made with one dialyzer in a way that results can be readily extrapolated to a different dialyzer.[118] Therapeutic drug monitoring, including measurement of the dialyzer clearance, should be utilized for drugs with a narrow therapeutic range, for example, aminoglycosides and vancomycin. Finally, drug dosage recommendations derived from studies conducted before 2000 likely represent an underestimate of the impact of HD and dosages may need to be empirically increased by 25–50% (Table 6).

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