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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 Introduction
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 Creatinine clearance
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 Antiviral drugs
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 References
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 Spironolactone
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 http://www.nephrologypharmacy.com/pub_dialysis.html 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

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