Editorial
Annals of Clinical Biochemistry
Drug dosing and estimates of kidney function
Michael P Bosomworth1 and Jonathan AT Sandoe2
Serum (or plasma) creatinine, creatinine clearance
(CrCl), estimated creatinine clearance (eCrCl) and esti-
mated glomerular filtration rate (eGFR) are used to
assess kidney function in order to detect and manage
kidney disease and to optimize the dosing of renally
excreted medicines.
Despite improvements in assay performance follow-
ing the introduction of isotope dilution mass spectrom-
etry (IDMS)-traceable creatinine methods, including
enzymatic methods, serum creatinine results can still
vary by  13% between laboratories at levels of
85 mmol/L.1 In addition to methodological issues,
there are other limitations to serum creatinine as a
measure of kidney function. For example, serum cre-
atinine can vary by about 10% depending upon meat
intake;2 creatinine is secreted in the proximal tubule
and at low urine flow rates can be reabsorbed;2 extra-
renal excretion of creatinine can also occur.3 Creatinine
is not an ideal filtration marker.
CrCl is calculated using methods that do not meas-
ure the ‘true’ creatinine, but which estimate its concen-
tration in blood and a timed urine collection. To avoid
collecting a timed urine, numerous equations and
nomograms have been devised to estimate CrCl from
serum creatinine. In estimating CrCl, it is assumed that
creatinine excretion is constant and equal to creatinine
production, which itself is proportional to muscle mass
and can, in turn, be estimated from an individual’s age,
gender and weight. eCrCl will overestimate CrCl in
obese or oedematous patients and in those with reduced
creatinine production. eCrCl also assumes that serum
creatinine concentration is at steady state.
eCrCl is probably most commonly calculated using
the Cockcroft and Gault (C&G) equation first
described in 19764 using serum creatinine measured
with a kinetic Jaffe assay on a Technicon
Autoanalyser II. In principle, the technique used to
determine the patient’s serum creatinine should be the
same as the one used to derive the equation from which
50(6) 520–522
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the eCrCl (or eGFR) are calculated:2 this can clearly
not be the case with modern use of the C&G equation.
Other equations have now been proposed including the
Modification of Diet in Renal Disease (MDRD) study
and Chronic Kidney Disease Epidemiology (CKD-EPI)
collaboration equations5,6 that estimate GFR normal-
ized to a body surface area (BSA) of 1.73 m2. All equa-
tions are valid only for the population in which they
were derived and some have been produced for more
specific purposes, e.g. the Wright formula for cancer
patients.7 Wright et al.7 recognized that such equations
were also serum creatinine method dependent.
The C&G equation has been and is used in pharma-
cokinetic studies.8 It is therefore included in drug
dosage information despite the fact that the serum cre-
atinine method used to derive it is no longer available
and despite the fact that IDMS-traceable creatinine
assays tend to give lower results and therefore a
higher eCrCl than the earlier non-IDMS traceable cre-
atinine assays.9
In 2005, the Department of Health10 recommended
the use of the MDRD equation to detect chronic
kidney disease (CKD) in the UK. Since then eGFR
has been routinely reported and the relative merits of
using eGFR and the C&G eCrCl to guide drug dosing
have been debated in the literature. On occasions, art-
icles arguing for eGFR11 have appeared in the same
edition of the same journal as articles supporting the
continued use of the C&G eCrCl.12
In this edition of the Annals, Chin et al.13 compare
the performance of C&G, MDRD and CKD-EPI equa-
tions in predicting gentamicin clearance. The authors
1
Blood Sciences, Leeds General Infirmary, Leeds, UK
2
Microbiology, Leeds General Infirmary, Leeds, UK
Corresponding author:
Michael P Bosomworth, Blood Sciences, Leeds General Infirmary, Leeds
LS1 3EX, UK.
Email: mike.bosomworth@leedsth.nhs.uk
Bosomworth and Sandoe
conclude that both the CKD-EPI and C&G equations
provide reasonable estimates of gentamicin clearance in
most situations but that body size should be accommo-
dated when using estimating equations at extremes of
body size. This is consistent with published guidance.14
It is clear that creatinine and its derivative equations
are affected strongly by muscle mass.15 Yet, how many
laboratories are capable of reporting BSA-adjusted
eGFRs and how many clinicians will perform this cal-
culation themselves in the frail or the obese?
What does this mean in clinical practice? Drug dosing
can clearly be heavily influenced by the serum creatinine
method and the equation used to estimate CrCl/GFR.
This is especially true in the frail or the obese. Accurate
dosing of gentamicin is important to optimize antimicro-
bial activity and minimize risks of harm. This is compli-
cated by the multitude of different ways in which
gentamicin is used clinically (e.g. different dosing regi-
mens for endocarditis, gram-negative sepsis and surgical
prophylaxis). Extended-interval gentamicin dosing
(EIGD) regimens are in common use; a region wide
‘Yorkshire Hartford Gentamicin Regimen’ (http://
nww.lhp.leedsth.nhs.uk/common/guidelines/
detail.aspx?id ¼ 1944), for example, uses the C&G (total
body weight version) to initially assess suitability for
EIGD. Beyond this initial assessment, CrCl calculators
do not have a role, as therapeutic drug monitoring is
used to modify dose. The importance of weight and
obesity in gentamicin dosing are not well appreciated.
Gentamicin does not distribute well into adipose tissue,
so an obese patient might be given a larger dose than is
ideal if their actual (total) body weight is used in dosing.
Approximately, 10% of drugs are cleared entirely by
renal pathways16 and for some drugs, e.g. carboplatin,
blood concentrations are not monitored so dosage is
determined using measured and/or estimated GFR.17
For patients to receive the correct dose of a renally
cleared drug, where eCrCl/eGFR is used to guide
dosing, laboratories responsibilities extend beyond
merely supplying serum creatinine results and an
eGFR. Laboratories should be properly engaged with
colleagues prescribing drugs to ensure that the most
appropriate equation is used to calculate the eCrCl or
eGFR including an assessment as to whether body
weight/surface area adjustments are appropriate.
Serum creatinine is an excellent example of why we
must be engaged with our users to ensure that the
number we generate is understood and used appropri-
ately whether to detect/monitor CKD or acute kidney
injury or to ensure that a patient receives the correct
dose of a renally cleared drug. Only if we do so, can we
play our part in ensuring that we achieve optimum
patient outcomes. Chin et al. should be commended
for their meticulous validation of estimating equations
in the clinical context of drug dosing.
521
Acknowledgements
The authors thank Dr E. J. Lamb for his advice during
writing.
Declaration of conflicting interests
None declared.
Funding
This research received no specific grant from any funding
agency in the public, commercial, or not-for-profit sectors.
Ethical approval
Not applicable.
Guarantor
MPB.
Contributorship
MPB and JATS wrote the editorial.
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