Prescribing in renal disease Randall Faull, Senior Consultant Nephrologist, Royal Adelaide Hospital, and Associate Professor of Medicine, University of Adelaide, and Lisa Lee, Renal Pharmacist, Royal Adelaide Hospital Serum creatinine The appropriate prescribing of many drugs
The serum creatinine concentration has important limitations when used for estimating renal function. depends on knowledge of the patient's total
1. There is an inverse relationship between serum creatinine
renal function, which is proportional to their
and renal function. A doubling of serum creatinine represents
body mass. The Cockcroft-Gault method of
a halving of GFR. A person's serum creatinine can rise from
calculating creatinine clearance takes into account
60 to 120 micromol/L and so still be in the normal range
the patient's weight. The recently introduced
(typically 50 to 120 micromol/L), yet the renal function has
estimated glomerular filtration rate, which is now routinely reported with biochemistry test
2. Renal function declines steadily with age in adults, but this is
results, is useful for screening for renal disease,
not reflected in the serum creatinine, which remains steady
but is unsuitable for calculating doses as it does
or may only increase slightly with age (in the absence of overt renal disease, where it may rise more obviously). An
not take into account the patient's size. Both
80-year-old will have approximately half of the renal function
are unreliable at extremes of weight. The list
of a 20-year-old, despite both having the same serum
of medications that need dosage adjustment according to renal function is long, but includes
3. Renal function has an approximately linear relationship
commonly prescribed drugs such as antivirals,
with lean body mass. In the presence of the same serum
hypoglycaemic drugs (metformin, sulfonylureas,
creatinine, a 120 kg person will have twice the renal function
insulin), spironolactone and allopurinol.
of a 60 kg person because they have bigger kidneys.
4. Women have a lower muscle mass than men of equivalent
Key words: creatinine clearance, drug therapy, glomerular
weight and age. A woman's serum creatinine represents
approximately 0.85 of the renal function of a man with the
These limitations are particularly relevant and must be
The clearance of many drugs and their metabolites depends on
addressed when attempting to measure renal function for the
adequate renal function. Renal clearance is especially important
for some drugs where the gap between efficacy and toxicity is
narrow. Doses of these drugs need careful adjustment if they are prescribed for patients with impaired renal function. Some
The serum creatinine concentration represents a balance
drugs also have the potential to cause renal toxicity. This is
between its production in the body (from muscle) and its
particularly likely to occur in patients who already have some
excretion by the kidneys. From this can be derived an
degree of renal impairment, although other factors can increase
estimation of the creatinine clearance by the kidneys, in
millilitres per minute (mL/min) or millilitres per second (mL/sec). This is the notional volume of serum that is cleared
Estimating renal function
of creatinine in those times. The creatinine clearance is the
An accurate estimation of renal function, or glomerular filtration
'poor man's' equivalent of the formal measurements of GFR,
rate (GFR), requires sophisticated techniques that are unsuitable
but for most clinical purposes is an adequate measurement of
for routine or repeated use. In practice, the serum creatinine
concentration is used for day-to-day assessment of renal
Direct determination of creatinine clearance requires
function. It has limitations, but it remains a robust and practical
simultaneous measurement of the concentration of creatinine in
parameter for most clinical situations.
the serum and in a timed urine specimen (usually 24 hours).
| VOLUME 30 | NUMBER 1| FEBRUARY 2007 17
Timed urine collections are labour-intensive and notoriously
renal disease such as urinary abnormalities and hypertension.
unreliable. As a result many equations for estimating creatinine
It has similar limitations as the Cockcroft-Gault equation2,
clearance have been derived that only need measurement of
including that it is not validated in Aboriginal and Torres Strait
serum creatinine. The most widely recognised of these is the
Cockcroft-Gault formula, which relies on patient age, weight, gender and serum creatinine.
eGFR is not preferred for calculating drug doses Drug dosing should be based on the patient's actual GFR and
creatinine (140 – age) x lean body weight (kg) (x 0.85 for females)
not an adjusted GFR. While recognising that the Cockcroft-Gault
equation has limitations, it does at least take into account body size when estimating GFR, whereas the eGFR does not. Using
The accuracy of this formula for estimating creatinine clearance
the eGFR to calculate dosages would lead to overdosing of
is equivalent to that from a timed urine collection, so there is
small patients and underdosing of large patients. Overdosing
no good reason for using a 24-hour collection. Manufacturers'
increases the risk of toxicity of drugs with a narrow therapeutic
renal dosing recommendations for medications are based on
range, while underdosing reduces efficacy. The MDRD formula
Cockcroft-Gault estimates of renal function, so this formula is
used to calculate eGFR can be manipulated to adjust for a
also recommended when estimating creatinine clearance for the
patient's body surface area (if the patient's height and weight
purpose of calculating drug doses that vary according to renal
are known). A recently published observational analysis
suggests wide variation between the formulas.3 However, as
Clinicians should be aware of some important limitations of the
yet it is unknown whether the MDRD formula is superior to
Cockcroft-Gault estimation of renal function. It is:
Cockcroft-Gault for calculating drug doses. Prescribing for dialysis patients
■ unreliable in extremes of body size (that is, in severe
For the purpose of drug prescribing, patients on dialysis (haemodialysis or peritoneal dialysis) should be considered
■ imprecise and unreliable for rapidly changing renal function
to have a creatinine clearance/GFR of less than 10 mL/min.
(for example intensive care, acute renal failure).
Certain drugs are actively removed from the circulation during
What is estimated GFR?
dialysis, and this needs to be considered when deciding on the timing of administration as well as the dosage. Factors that
Australian pathology laboratories have started routinely
may reduce the extent to which a drug is dialysed include large
including an estimated GFR (eGFR) in all biochemistry reports
molecular size of the drug, high protein binding, large volume
that include serum creatinine. The reporting of serum creatinine
of distribution and high lipid solubility. In addition to these
has also been standardised to be in micromol/L (so the actual
parameters, the type of dialyser membrane may also affect
number is 1000 times that when reported as mmol/L).
drug clearance, as will blood and dialysate flow rates. If a drug
The formula used to calculate eGFR was derived as part of a
is known to be dialysed, patients having haemodialysis may be
large study of the effect of dietary protein restriction on the
instructed to take the drug after the dialysis session.
progression of renal failure. (This was the Modification of Diet in Renal Disease study, hence the MDRD formula.1) The advantage
Dose alteration in renal impairment
of this formula is that it does not require knowledge of the
Once renal impairment has been detected and creatinine
patient's height or weight as the eGFR is calculated using serum
clearance estimated, the need for dose alteration of renally
cleared drugs must be determined. Generally dose adjustment
It is crucial that clinicians realise that the eGFR is not estimating
is needed when the creatinine clearance is below 60 mL/min.
the patient's actual GFR, but is estimating an adjusted GFR –
People who have been taking a drug for many years may need
which assumes that the patient is of average body size. This
a dose adjustment as they age. Adjustments can be achieved by
explains how the number can be calculated without any
a reduction in dose, or an extension of the dosing interval, or
knowledge of the patient's actual size. Average body size
both. Knowledge of appropriate dosage adjustment is important
equates to a body surface area of 1.73 m2, and so the eGFR is
to ensure the drug is effective and that accumulation and further
reported as mL/min/1.73 m2. In practice, this means that while
kidney damage is avoided. There are various references to
one person who is twice the size of another, of the same age,
consult in Australia including the approved product information
gender and serum creatinine, will have twice the actual GFR, the
and the Australian Medicines Handbook. International references
include the Renal Drug Handbook and Drug prescribing in renal
The eGFR is primarily intended to be a screening tool for renal
failure.4 Table 1 lists some of the commonly prescribed drugs
disease in the community, in association with other signs of
that require dose alteration in renal impairment. | VOLUME 30 | NUMBER 1| FEBRUARY 2007 Table 1 Commonly prescribed drugs that require dose adjustment in renal impairment Examples
aminoglycosides (e.g. gentamicin), vancomycin, ceftazidime, cefepime, cephazolin, ciprofloxacin, fluconazole, piperacillin, carbapenems (e.g. meropenem), sulfamethoxazole
famciclovir, aciclovir, valaciclovir, valganciclovir, ganciclovir
low molecular weight heparins (e.g. enoxaparin)
If creatinine clearance is less than 30 mL/min:
– avoid potassium-sparing diuretics due to risk of hyperkalaemia
– thiazide diuretics have limited efficacy
morphine, codeine, pethidine (due to risk of accumulation of active or toxic metabolites)
amisulpride, gabapentin, lithium, levetiracetam, topiramate, vigabatrin
metformin, glibenclamide, glimepiride, insulin
myocardial infarction), with increasing age and with higher
Renal clearance is the major route of elimination for many
doses of metformin (generally above 2 g/day). The common
antivirals, including those used for treating herpes simplex,
adverse effect of nausea is also dose-related and more likely to
herpes zoster and cytomegalovirus infections (such as aciclovir,
occur in the presence of renal impairment.
famciclovir, valganciclovir and ganciclovir). In patients with
No definitive guidelines exist on reducing the dose of metformin
renal impairment, renal clearance of these drugs is reduced and
in renal impairment, and lactic acidosis has been reported
the elimination half-life is significantly prolonged. As a result,
with doses as low as 500 mg/day.5 Ideally, metformin should
normal doses will accumulate and may lead to neurological
be avoided in patients with a creatinine clearance of less than
signs such as dizziness, confusion, hallucinations, somnolence
30 mL/min and should be used with caution, at a reduced
and convulsions, as well as more rarely, tremor, ataxia,
maximum daily dose of 1 g, in patients with a creatinine
dysarthria, seizures and encephalopathy. These adverse effects
clearance of 30–60 mL/min. For those patients with a creatinine
are dose-related and reversible on stopping the drug. They are
clearance of 60–90 mL/min, the recommended maximum daily
especially problematic in elderly patients or patients taking
dose is 2 g. Metformin should also be withheld temporarily
other neurotoxic medications. If essential, it may be possible to
in patients undergoing surgery, suffering from dehydration,
reintroduce the drug at a lower dose.
trauma or serious infections, or undergoing procedures likely to affect renal function (for example, contrast studies). Hypoglycaemic drugs Renal function needs to be considered when prescribing three
of the major groups of hypoglycaemic drugs – biguanides
Long-acting sulfonylureas such as glibenclamide and
(metformin), sulfonylureas and insulin.
glimepiride are associated with a higher risk of hypoglycaemia in comparison to short-acting sulfonylureas.
In patients with renal impairment and/or advanced age, the
Metformin has been associated with rare but potentially fatal
risk of hypoglycaemia is increased. These drugs are
lactic acidosis. This is thought to result from accumulation of
inherently long-acting as well as having metabolites that
metformin when renal impairment reduces renal clearance.
are excreted renally. Shorter-acting sulfonylureas such as
The risk of lactic acidosis is potentially enhanced in conditions
gliclazide or glipizide are a safer choice in patients with
where tissue hypoperfusion and hypoxaemia are a problem
renal impairment. They should be started at a low dose and
(for example in cardiac or respiratory failure, or following a
| VOLUME 30 | NUMBER 1| FEBRUARY 2007 19
can be determined using the Cockcroft-Gault equation. The role
Renal elimination accounts for up to half of the clearance of
of the MDRD equation (expressed as eGFR on biochemistry
insulin, so as renal failure progresses, less insulin is excreted,
reporting) is currently as a screening tool for kidney disease.
so smaller doses are required. Patients with diabetes and
renal impairment can also have unrecognised gastroparesis
1. Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D.
which may disconnect absorption of ingested food from the
A more accurate method to estimate glomerular filtration
time of the insulin injection. This can lead to erratic glucose
rate from serum creatinine: a new prediction equation.
regulation that may be complicated by frequent episodes of
Modification of Diet in Renal Disease Study Group.
2. Mathew TH. The Australasian Creatinine Consensus Working
Group. Chronic kidney disease and automatic reporting of estimated glomerular filtration rate: a position statement.
Since the publication of the Randomized Aldactone Evaluation
Study6 in 1999, the use of spironolactone, in conjunction with
3. Wargo KA, Eiland EH 3rd, Hamm W, English TM,
an angiotensin-converting enzyme (ACE) inhibitor, has increased.
Phillippe HM. Comparison of the modification of diet in
In this trial, the addition of spironolactone significantly improved
renal disease and Cockcroft-Gault equations for
morbidity and mortality in patients with advanced heart failure.
antimicrobial dosage adjustments. Ann Pharmacother
However, almost immediately following this publication came
4. Aronoff GR, Berns JS, Brier ME, Golper TA, Morrison G,
reports of an increase in hospital admissions (and subsequent
Singer I, et al. Drug prescribing in renal failure: dosing
guidelines for adults. 4th ed. Philadelphia: American College
Hyperkalaemia is a particular problem for patients with renal
of Physicians–American Society of Internal Medicine; 1999.
impairment and its risk is heightened by advanced age, doses
5. Nisbet JC, Sturtevant JM, Prins JB. Metformin and serious
of spironolactone exceeding 25 mg/day, dehydration, diabetes
adverse effects. Med J Aust 2004;180:53-4.
mellitus, and simultaneous treatment with non-steroidal
6. Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A,
et al. The effect of spironolactone on morbidity and mortality
anti-inflammatory drugs, ACE inhibitors or angiotensin receptor
in patients with severe heart failure: Randomized Aldactone
antagonists. Prescribers are urged to frequently monitor serum
Evaluation Study Investigators. N Engl J Med 1999;341:709-17.
potassium, creatinine and urea when starting spironolactone for
7. Juurlink DN, Mamdani MM, Lee DS, Kopp A, Austin PC,
heart failure, and to consider avoiding its use in patients with a
Laupacis A, et al. Rates of hyperkalemia after publication of
creatinine clearance of less than 30 mL/min.
the Randomized Aldactone Evaluation Study. N Engl J Med 2004;351:543-51. Allopurinol Further reading
Allopurinol is used in the management of gout to lower serum
Nankivell BJ. Creatinine clearance and the assessment of renal
and urinary uric acid concentrations. As allopurinol, and its
active principal metabolite oxypurinol, are mainly excreted in
Johnson CA, Simmons WD. 2006 Dialysis of drugs. Wisconsin:
the urine, they accumulate in patients with poor renal function
so the dose should be reduced. The manufacturers recommend
starting treatment with a maximum dose of 100 mg/day
and increasing it only if the serum or urinary urate is not
Stevens LA, Coresh J, Greene T, Levey AS. Assessing kidney
function – measured and estimated glomerular filtration rate.
Hypersensitivity reactions to allopurinol are characterised by
fever, chills, leucopenia, eosinophilia, arthralgia, rash, pruritis,
The Renal Drug Handbook. 2nd ed. Ashley C, Currie A, editors.
nausea and vomiting. The frequency of this reaction is thought
Oxford: Radcliffe Medical Press; 2004.
to be increased in patients with renal impairment, and in those
Conflict of interest: none declared
who are concomitantly taking allopurinol and a thiazide diuretic. Caution is advised when using this combination in renal
Self-test questions The following statements are either true or false Conclusion
Adjusting the dose of renally cleared drugs is important when
3. Estimates of glomerular filtration rate are unreliable if the
prescribing for patients with renal impairment. There are many
creatinine clearance is rapidly changing.
drugs that require dose adjustment according to renal function.
4. Renal impairment increases the risk of lactic acidosis in
Estimation of creatinine clearance and hence renal function
| VOLUME 30 | NUMBER 1| FEBRUARY 2007
CLIENT NAME 1223 Street Name City, State, Zip 777-777-77777 [email protected] EDUCATION____________________________________________________________________ University of Chicago Graduate School of Business Chicago, IL 1991 - 1993 Dean’s List United States Military Academy West Point, NY 1980 - 1984 Presidential & Senatorial Nomine
The Citric Acid (Krebs, TCA) Cycle Step 1: Condensation In step 1 of the Krebs cycle, the two-carbon compound, acetyl-S-CoA , participates in a condensation reaction with the four-carbon compound, oxaloacetate , to produce citrate : • This reacion is moderately exergonic . Thermodynamically, the equilibrium is in favor of the products. Thus, this is considered to be the