Automatic eGFR reporting — its role in screening for kidney disease and drug-dosing decisions

• Glomerular filtration rate (GFR) is the best measure of kidney function — using serum creatinine concentration alone is unreliable and insensitive.
• GFR can be:
• • measured as the urinary clearance of a filtration marker from a timed urine collection (e.g. 24-hour creatinine clearance)
  • estimated from the Cockcroft–Gault equation, based on serum creatinine concentration, age, gender and body weight
  • estimated from the Modified Diet in Renal Disease (MDRD) equation, based on serum creatinine, age, gender and race (if African–American) and adjusted to the average body surface area for adults.
• Dosing recommendations for drugs cleared by the kidney are mainly based on creatinine clearance calculated by the Cockcroft–Gault equation or from a direct measurement of GFR.
• Most pathology laboratories now automatically report an estimated GFR (eGFR) from the MDRD equation with all requests for serum creatinine concentration. This is possible because the equation does not need a measure of body weight or height.
• Reporting of MDRD eGFR helps to identify chronic kidney disease early, and may signal when drug dosage adjustments are necessary.
• For most drugs prescribed in primary care and for most patients of average age and body size, dosage adjustments based on MDRD eGFR should be similar to those based on creatinine clearance. However, there are important exceptions and limited evidence comparing use of the MDRD or Cockcroft–Gault equation to guide dosage adjustments.
• For dosage adjustments in people at both extremes of body size, use creatinine clearance or recalculate MDRD eGFR to account for the patient's actual body surface area.
• Based on limited evidence, MDRD eGFR should not replace creatinine clearance for determining dosage adjustments for:
• • critical-dose drugs that have a narrow therapeutic index
  • patients who may be sensitive to small differences in drug dosages (particularly hospitalised, frail or elderly people).
• GFR is one of many determinants of the clinical response to drugs.

Serum creatinine concentration is not a sensitive indicator of kidney function — it is influenced by a range of other factors, including age, gender, ethnicity, muscle mass, diet, drugs and certain disease states.1–3 Consequently, serum creatinine concentration alone is unreliable for identifying impaired kidney function or chronic kidney disease.1

Glomerular filtration rate (GFR) more accurately determines kidney function.3 Normal GFR values are related to age, gender and body size.3 A patient's GFR may reflect impaired kidney function while their serum creatinine concentration is in the normal range (this often occurs in older people).2,4–6

Measuring and estimating GFR

GFR can be measured directly from the urinary clearance of a filtration marker (e.g. 24-hour creatinine clearance).3However, this method is often impractical and prone to error.3 Numerous equations have been developed that estimate GFR and avoid the need for a timed urine collection.3

The Cockcroft–Gault equation (Box 1), which calculates creatinine clearance (mL/min) as a surrogate for GFR, is one of the most widely used equations. It provides an estimate of GFR based on serum creatinine concentration, age, gender and body weight.

The MDRD equation (Box 1) was developed more recently. It provides an estimate of GFR based on serum creatinine concentration, age, gender and race (if African–American) and is adjusted to average adult body surface area (1.73 m2). MDRD eGFR values are expressed as mL/min/1.73 m2.

In August 2005 a working group representing Australian nephrology, pathology and biochemistry organisations recommended that pathology laboratories automatically report MDRD eGFR with all requests for serum creatinine concentration in adults.4* This is now occurring in most laboratories and has made the early identification of chronic kidney disease easier.4,7

The MDRD equation has several advantages as a screening tool. Because it does not require a measurement of body weight or height, pathology laboratories can estimate GFR using information that is routinely acquired. In people with chronic kidney disease, the MDRD equation appears to predict GFR more accurately than the Cockcroft–Gault equation, particularly for values < 60 mL/min/1.73 m2.4,8 However, both equations have similar limitations (seeLimitations to use of the Cockcroft–Gault or MDRD equation).

Interpreting MDRD eGFR

Chronic kidney disease may be present in people who have an MDRD eGFR < 60 mL/min/1.73 m2 and/or evidence of kidney damage (e.g. proteinuria) for at least 3 months.2,9 Clinical action plans for each stage of chronic kidney disease are available from the Kidney Health Australia Chronic Kidney Disease (CKD) Management in General Practice Handbook. Kidney Health Australia also provides an eGFR calculator on this website and educational resources for health professionals on interpreting MDRD eGFR values.

Because the MDRD equation is adjusted for average adult body surface area, it does not provide an estimate of the patient's actual GFR.5 If clinicians require an estimate of actual kidney function, the MDRD eGFR value needs to be recalculated using the patient's actual body surface area (see Box 1). This is particularly important for patients at both extremes of body size.4

The MDRD equation was developed using data from people with chronic kidney disease, and its use may underestimate GFR in those with normal kidney function.3,4 However, knowing when values are 60–90 mL/min/1.73 m2 could be important in some clinical situations, such as providing an early warning of declining kidney function and for monitoring trends over time.2,7 The working group thus recommended that pathology laboratories report precise values up to 90 mL/min/1.73 m2, and higher values as '> 90 mL/min/1.73 m2'.7

Glomerular filtration rate declines with age.7 For people aged 70 years and over, stable MDRD eGFR values from 45–59 mL/min/1.73 m2, in the absence of other signs of kidney damage, may not be associated with complications of chronic kidney disease.2,7 However, these values are a sign of impaired kidney function that could affect the clearance of drugs by the kidney.

There are certain populations or clinical settings in which the Cockcroft–Gault or MDRD equation is inappropriate for estimating kidney function, or where their use requires careful interpretation. This is mainly because both equations derive from serum creatinine concentration, which is influenced by many factors (see Glomerular filtration rate is the best measure of kidney function).

The Cockcroft–Gault and MDRD equations are less accurate at higher levels of kidney function.3,4,8 Both equations may also be unreliable or imprecise in:

• people with exceptional dietary intake (e.g. vegetarian diet, high-protein diet, or taking creatine or amino acid supplements)
• people at both extremes of body size
• people with diseases or conditions affecting skeletal muscle, e.g. cachexia, sarcopenia, paraplegia, high muscle mass, or amputees
• certain populations for which the equations are not validated (e.g. children, Aboriginal and Torres Strait Islander peoples)
• people dependent on dialysis or with acute changes in kidney function (e.g. acute kidney failure).2,3,5,10

The MDRD equation can be corrected to give a more accurate result in people of African–American race (Box 1). It may overestimate GFR in Chinese people with severe kidney disease, and a modified equation may be required for this racial group.11,12 Other measures of kidney function (e.g. timed urine collection) are options for non-Caucasian groups, but these are also imprecise and less practical.7 Until validation studies are available, automatic eGFR reports must be interpreted with caution in Aboriginal and Torres Strait Islander peoples and other racial groups.2,7

Most pathology laboratories in Australia are standardising creatinine assays to the international reference method (isotope dilution mass spectrometry, or IDMS).7 This will improve the accuracy of serum creatinine concentration measurements. However, unlike the MDRD equation, the Cockcroft–Gault equation has not yet been modified to account for the restandardisation of creatinine assays.7 This could result in creatinine clearance calculations being overestimated by the Cockcroft–Gault equation.13,14 The impact of this change is as yet unknown, but for many situations may not be clinically important.14

Most drug-dosing recommendations are based on creatinine clearance calculated by the Cockcroft–Gault equation or from a direct measurement of GFR. At present it is not known which method of estimating kidney function — the MDRD or Cockcroft–Gault equation — best determines the dosage adjustments required for drugs cleared by the kidney.

Automatically reported eGFR values may signal the need for drug dosage adjustments, and are a better screen than serum creatinine concentration (see Glomerular filtration rate is the best measure of kidney function).2,5,7,10 However, there is limited evidence comparing the use of the MDRD or Cockcroft–Gault equation to guide dosage adjustments. More studies are needed to determine the preferred method for estimating kidney function for this purpose and whether this differs for different drugs.

For most drugs prescribed in primary care and for most patients of average age and body size, it is considered that dosage adjustments based on MDRD eGFR should be similar to those recommended by creatinine clearance.3,7,15An automatic eGFR report may therefore be used in these settings to guide dosing decisions when no other measure of GFR is known or accessible (see Calculating creatinine clearance using the Cockroft–Gault equation).7

It is important to be aware of some exceptions. In a patient whose body size substantially differs from average, basing drug dosages on automatically reported eGFR values — which assume that a patient is of average height and build — can lead to significant under-dosing in larger people or overdosing in smaller people.5,10,16 To assist drug-dosing decisions in these patients, use creatinine clearance or recalculate MDRD eGFR based on actual body surface area (see Box 1).4,10,15

It is also important to consider that kidney function measured or estimated by GFR is just one of many factors that may influence the response to drugs.

For guidance on drug dosage adjustments for patients with renal impairment, refer to the approved product information or a drug information resource such as the Australian Medicines Handbook.

Use creatinine clearance for critical-dose drugs and certain patients

Dosage adjustments of drugs cleared by the kidney should be guided by creatinine clearance calculated by the Cockcroft–Gault equation, or from a direct measurement of GFR, for:

• critical-dose drugs that have a narrow therapeutic index (Table 1)
• patients who may be sensitive to small differences in drug dosages (particularly hospitalised, frail or elderly people).

It is important in these settings to base drug-dosing decisions on the Cockcroft–Gault equation (as used in most published recommendations to guide dosing in renal impairment) until the MDRD equation has been validated for this purpose.7,15 Monitoring of drug levels and/or clinical response should be used in conjunction with creatinine clearance calculations to guide dosage adjustments.7,15

Small adjustments in the dosage of a critical-dose drug can lead to toxicity or loss of therapeutic effect. Certain patients, particularly the hospitalised, frail or elderly, may be susceptible to adverse outcomes when the dosage of any drug changes. Because of this, differences in dosing recommendations between the MDRD and Cockcroft–Gault equation may be clinically significant for these critical-dose drugs and patients.

In elderly people, estimates of GFR from the MDRD equation have been found to be higher than those determined by the Cockcroft–Gault equation.18–21 Using MDRD eGFR instead of calculating creatinine clearance could lead to higher dosing recommendations in elderly patients. The Cockcroft–Gault equation should be used for elderly patients to adjust dosages of drugs cleared by the kidney, until there are more studies comparing the two estimates of GFR. Drug response should be closely monitored if MDRD eGFR has been used for dosage adjustments.

There is some evidence to suggest that the MDRD and Cockcroft–Gault equation are not interchangeable for critical-dose drugs. Even when the MDRD equation is corrected for a patient's actual body surface area, dosing recommendations have differed from those based on the Cockcroft–Gault equation.22–24

One study found that dosages of antibiotics would have differed in 25% of a sample of hospitalised patients with chronic kidney disease (n = 409) if MDRD eGFR† was used rather than the Cockcroft–Gault‡ equation.23 Another study of hospitalised elderly patients (n = 1067) found significant differences in dosages of enoxaparin in 15% of patients and of gentamicin in 37% of patients when MDRD eGFR† was used instead of the Cockcroft–Gault‡equation.22

Calculating creatinine clearance using the Cockcroft–Gault equation

Kidney function calculators based on the Cockcroft–Gault equation are available in most general practice prescribing software packages (e.g. Medical Director) and electronic versions of the Australian Medicines Handbook (go to 'Calculators') and Therapeutic Guidelines: Antibiotic (go to Appendix 2.6). Calculators for ideal body weight are also provided in these sources, or use the formulas in the print edition of the Australian Medicines Handbook (see 'Prescribing in renal impairment').

Ensure that ideal body weight is used in the Cockcroft–Gault equation for people who are overweight or obese.6,25Using actual body weight overestimates kidney function, which may lead to overdosing.

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