3 Drug Therapy Individualization in Patients with Renal
and Liver Dysfunction
The liver and kidneys are the main organs involved in the processes of elimination
of drugs and their metabolites. Hence, proper dosage adjustment is of utmost
importance in patients with liver or kidney dysfunction. It would maximize thera-
peutic efficacy, minimize drug toxicity, and can have an important economic
impact on the health system.
It was shown that dosing errors and the risk of toxicity are common among
patients with chronic kidney disease (CKD).^12 CKD is defined as the presence of
kidney damage or a reduction in the glomerular filtration rate (GFR) for 3 months or
longer.^13 Incidence of CKD significantly increased over the last decade, either as
complication of hypertension and/or diabetes as two major causative factors of this
illness or because of increasing number of older population. Indeed, kidney func-
tion decreases with age, and older patients constitute the most rapidly expanding
patient group linked with CKD.^14 The degree of renal insufficiency and the severity
of kidney disease are generally reflected in the decline of glomerular filtration rate
(GFR). The evaluation of GFR is the most reliable index and surrogate marker of
overall kidney function. The Kidney Disease Outcomes Quality Initiative
(K/DOQI) of the National Kidney Foundation (NKF) established a classification
of CKD based on GFR that has been accepted and used worldwide (see footnote
12). The five stages of classification, along with a description of each stage, are
shown in Table 1.
GFR below 60 ml/min requires dosage adjustment for certain drugs. Direct
measurement of GFR using exogenous filtration markers is more accurate but the
most costly option. The estimation of creatinine clearance has been extensively
used even though creatinine is a crude index of kidney function. Several formulas
have been developed for estimating GFR based on serum creatinine clearance data,
all of which have advantages and/or limitations (Table 2 ). The most commonly
used are the Cockcroft-Gault and the 4-variable Modification of Diet in Renal
Disease (MDRD4) formulas. The NKF, however, is now recommending the
Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. Cock-
croft and Gault equation depends on serum creatinine concentrations and associated
measurements limitations, including tubular secretion of creatinine that results in
overestimation of GFR by up to 20 %. Despite these limitations, this equation
remains the most appropriate method to determine drug dosage individualization
based on kidney function. Many have considered that an advantage of this equation
for individual drug dose adjustment is that the body weight is considered (see
footnote 14). The abbreviated version of Modification of Diet in Renal Disease
(^12) Verbeeck and Musuamba ( 2009 ).
(^13) Hartmann et al. ( 2010 ).
(^14) Matzke et al. ( 2011 ).
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