Australian Prescriber Vol. 24 No. 1 2001
`
`3. Withdrawing patients from antidepressants. Drug Ther Bull 1999;37:
`49-52.
`4. Delgado PL. Approaches to the enhancement of patient adherence to
`antidepressant medication treatment. J Clin Psychiatry 2000;61 Suppl
`2:6-9.
`5. Haddad P. Do antidepressants have any potential to cause addiction?
`J Psychopharmacol 1999;13:300-7.
`6. Thompson C. Discontinuation of antidepressant therapy: Emerging
`complications and their relevance. J Clin Psychiatry 1998;59:541-8.
`7. Writing Group for Therapeutic Guidelines: Psychotropic. Therapeutic
`Guidelines: Psychotropic. Version 4. Melbourne: Therapeutic Guidelines
`Limited; 2000.
`
`Self-test questions
`
`The following statements are either true or false
`(answers on page 23)
`5. When changing from one antidepressant to another
`it can be difficult to differentiate discontinuation
`symptoms from adverse effects of the new medication.
`6. After a patient has recovered from depression, the
`antidepressant dose is usually tapered off.
`
`A B N O R M A L L A B O R A T O R Y R E S U L T S
`
`Creatinine clearance and the
`assessment of renal function
`
`Brian J. Nankivell, Department of Renal Medicine, Westmead Hospital, Sydney
`
`SYNOPSIS
`The selection of the most appropriate measurement of
`renal function depends on the clinical question being
`asked, the accuracy required and the inconvenience to the
`patient. Serum creatinine and calculated creatinine
`clearance yield a reasonable estimation of renal function
`with minimal cost and inconvenience. A urinary creatinine
`clearance is more accurate if the urine collection is complete.
`Isotopic measurement of glomerular filtration rate can be
`used when greater accuracy is required, when renal
`function is poor or muscle mass is significantly outside the
`normal range. Glomerular filtration rate should be
`corrected for body surface area and interpreted in the
`context of physiological effects such as pregnancy and
`blood pressure.
`Index words: glomerular filtration, kidney.
`(Aust Prescr 2001;24:15–7)
`
`Introduction
`Estimation of renal function is important in a number of
`clinical situations (Table 1), including assessing renal damage
`and monitoring the progression of renal disease. Renal function
`should also be calculated if a potentially toxic drug is mainly
`cleared by renal excretion. The dose of the drug may need to
`be adjusted if renal function is abnormal.
`
`Renal function and glomerular filtration
`rate
`The glomerulus is a high-pressure filtration system, composed
`of a specialised capillary network. It generates an ultrafiltrate
`that is free of blood and significant amounts of blood proteins.
`Renal damage or alterations in glomerular function affect the
`
`kidneys’ ability to remove metabolic substances from the
`blood into the urine.
`Glomerular filtration rate (GFR) is the rate (volume per unit of
`time) at which ultrafiltrate is formed by the glomerulus.
`Approximately 120 mL are formed per minute. The GFR is a
`direct measure of renal function. It is reduced before the onset
`of symptoms of renal failure and is related to the severity of the
`structural abnormalities in chronic renal disease. The GFR can
`
`Table 1
`Indications for renal function testing
`
`Test
`Serum creatinine
`
`Setting
`Screening for renal
`disease
`
`Calculated GFR/
`creatinine
`clearance
`
`Monitoring renal
`function
`
`Initial evaluation of
`renal disease
`
`Monitoring of renal
`disease
`
`Isotopic GFR
`
`Accurate GFR
`
`Low levels of GFR
`
`Altered muscle mass
`
`GFR = Glomerular filtration rate
`
`Clinical indication
`Hypertension
`Urine abnormalities
`Potential renal diseases
`(e.g. diabetes)
`Non-specific symptoms
`(e.g. tiredness)
`Chronic renal disease
`Transplantation
`Drug toxicity
`
`Glomerulonephritis
`Proteinuria
`Chronic renal failure
`Chemotherapy dosing
`Glomerulonephritis
`Chronic renal failure
`
`Monitoring therapy in
`glomerulonephritis
`Deciding when to start
`dialysis
`Chronic renal failure
`Body builder
`Chemotherapy dose in
`wasted patient
`
`15
`
`Mylan v. Janssen (IPR2020-00440) Ex. 1043, p. 001
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`

`

`Australian Prescriber Vol. 24 No. 1 2001
`
`predict the signs and symptoms of uraemia, especially when it
`falls to below 10–15 mL/min. Unfortunately it is not an ideal
`index, being difficult to measure directly, and is sometimes
`insensitive for detecting renal disease.
`Tubular function
`Although glomeruli control the GFR, damage to the
`tubulointerstitium is also an important predictor of GFR and
`progression towards renal failure. Renal tubules make up 95%
`of the renal mass, do the bulk of the metabolic work and
`modify the ultrafiltrate into urine. They control a number of
`kidney functions including acid-base balance, sodium
`excretion, urine concentration or dilution, water balance,
`potassium excretion and small molecule metabolism (such as
`insulin clearance). Measurement of tubular function is
`impractical for daily clinical use, so we usually use the GFR
`to assess renal function.
`
`Normal range for GFR
`The GFR varies according to renal mass and correspondingly
`to body mass. GFR is conventionally corrected for body
`surface area (which equates with renal mass), which in normal
`humans is approximately 1.73m2 and represents an average
`value for normal young men and women. When the GFR is
`corrected for body surface area, a normal range can be derived
`to assess renal impairment.
`The normal corrected GFR is 80–120 mL/min/1.73m2,
`impaired renal function is 30–80 mL/min/1.73m2 and renal
`failure is less than 30 mL/min/1.73m2. The corrected GFR is
`approximately 8% lower in women than in men, and declines
`with age at an annual rate of 1 mL/min/1.73m2 from the age
`of 40.
`In addition to ageing there are a number of physiological and
`pathological conditions that can affect GFR, including pregnancy,
`hypertension, medications and renal disease. These conditions
`should be considered when interpreting a patient’s GFR.
`
`Measurement of GFR by renal clearance
`The GFR cannot be directly measured in humans, but can be
`estimated from urinary clearance of a substance (x), given by
`the equation:
`
`Urinary clearance (x) =
`
`Ux V
`Px
`
`where U is the urinary concentration of an ideal filtration
`marker of x, V is the urine flow rate and Px is the average
`plasma concentration of x.
`An ‘ideal filtration marker’ is a substance that is freely
`excreted by glomerular filtration, without tubular reabsorption
`or secretion. The clearance of ideal filtration markers can be
`shown mathematically to be an accurate estimate of GFR.
`The balance concept
`The plasma concentration of a substance in a steady state
`depends on the balance of the input (from either endogenous
`production or exogenous intake) and the clearance from the
`blood (by either excretion or metabolism). When an ideal
`
`16
`
`filtration marker is used (and there is no hepatic metabolism or
`non-renal clearance) and the input is constant (for example, by
`endogenous creatinine generation), then the plasma
`concentration is inversely proportional to the GFR.
`
`Methods to estimate GFR
`The GFR can be estimated from the serum concentration of
`filtration markers (such as creatinine or urea) or the renal
`clearance of these markers. Each method has its advantages
`and disadvantages in terms of accuracy, cost and convenience
`(Table 2).
`Serum creatinine or calculated creatinine clearance are the
`most convenient estimates of GFR, requiring only a single
`blood sample. Measured creatinine clearance requires a
`24-hour urinary collection while isotopic methods involve
`intravenous injection of a nuclear tracer, and two subsequent
`blood samples to estimate clearance. Both these methods are
`more expensive and less convenient to the patient. Selection of
`the most appropriate test depends on the clinical question, the
`required accuracy and cost (Table 2).
`Serum creatinine
`Serum creatinine is commonly used to screen for renal disease
`or to investigate urinary sediment abnormalities, hypertension
`or non-specific symptoms such as tiredness. It is also used to
`monitor renal function after transplantation, in chronic renal
`disease, and in patients with glomerulonephritis taking disease-
`modifying therapy. Serum creatinine can also be used to monitor
`the effects of nephrotoxic drugs such as gentamicin or anticancer
`drugs. Serum urea can be used to estimate renal function but is
`highly variable, less accurate and prone to errors.
`Serum creatinine is mainly produced by the metabolism of
`creatine in muscle, but also originates from dietary sources of
`creatinine such as cooked meat. Creatinine generation from
`the muscles is proportional to the total muscle mass and
`muscle catabolism. In people with a relatively low muscle
`mass, including children, women, the elderly, malnourished
`patients and cancer patients, the serum creatinine is lower for
`a given GFR. There is a danger of underestimating the amount
`of renal impairment in these patients, as their serum creatinine
`is also relatively lower. For example, the GFR may be reduced
`as low as 20–30 mL/min in a small elderly woman, while her
`serum creatinine remains in the upper range of normal.
`
`Table 2
`Assessment of renal function
`
`Method
`
`Accuracy
`
`Cost
`
`Convenience
`
`Serum creatinine
`Serum urea
`Calculated creatinine
`clearance
`Measured creatinine
`clearance
`Isotopic glomerular
`filtration rate
`
`**
`*
`
`***
`
`$
`$
`
`$
`
`** to ***
`
`$$
`
`****
`
`$$$
`
`***
`***
`
`***
`
`*
`
`*
`
`Mylan v. Janssen (IPR2020-00440) Ex. 1043, p. 002
`
`

`

`Creatinine is an imperfect filtration marker, because it is
`secreted by the tubular cells into the tubular lumen, especially
`if renal function is impaired. When the GFR is low, the serum
`creatinine and creatinine clearance overestimate the true GFR.
`Some drugs (such as cimetidine or trimethoprim) have the
`effect of reducing tubular secretion of creatinine. This increases
`the serum creatinine and decreases the measured creatinine
`clearance (Table 3). Paradoxically, when these drugs are used,
`a more accurate measurement of GFR is obtained as it is
`largely free from the error contributed by the physiological
`tubular secretion of creatinine.
`Calculated creatinine clearance
`As serum creatinine is so highly dependent on age, sex and
`body size, a number of corrections and formulae have been
`developed to estimate the muscle mass and assumed creatinine
`production. The most well-known formula is the Cockcroft-
`Gault formula, which is relatively simple to use and reasonably
`accurate. It is given as:
`
`Creatinine clearance
`(mL/min)
`
`=
`
`(140 – age [yrs]) x weight [kg]
`serum creatinine (micromol/L)
`
`Multiply result x 1.22 for male patients
`
`This is a good estimate of GFR, but it becomes inaccurate
`when a patient’s body mass is significantly outside the normal
`range (for example, morbid obesity or severe malnutrition) or
`when renal function is very impaired (i.e. GFR <20 mL/min).
`In these circumstances an isotopic method can be used if the
`GFR needs to be accurately measured.
`
`Creatinine clearance
`Creatinine clearance has been used for many decades to
`estimate GFR. It involves a 24-hour urine collection to measure
`creatinine excretion. As the same sample can be used to
`measure the protein excretion rate, creatinine clearance is
`often used for the initial evaluation of renal diseases, such as
`glomerulonephritis. It can also be used to monitor the
`progression of chronic renal failure, the response to therapy or
`to help decide when to start dialysis in patients with declining
`renal function.
`The major problem with measuring creatinine clearance is that
`the collection may be incomplete; often urine is passed into the
`toilet rather than into the collection bottles. This results in an
`underestimation of renal function, and has led some
`commentators to recommend alternative measures such as
`calculated creatinine clearance or an isotopic GFR. In hospital,
`especially when the patient is catheterised, creatinine clearance
`provides an accurate estimate of GFR. Overestimation of the
`GFR occurs at low levels of renal function, due to tubular
`secretion of creatinine. This can be corrected by collecting the
`urine while the patient is taking cimetidine or by averaging a
`urea and creatinine clearance in a single 24-hour collection. To
`accurately define the GFR at low levels of renal function, an
`isotopic GFR is recommended.
`
`Australian Prescriber Vol. 24 No. 1 2001
`
`Table 3
`Errors in measurement of renal function using
`creatinine
`
`Effects on
`creatinine
`clearance
`
`Effects on
`serum
`creatinine
`
`Assay interference
`
`ketosis
`
`hyperbilirubinaemia
`
`cephalosporin
`
`Nil
`
`Nil
`
`Nil
`
`Inhibition of tubular secretion of creatinine
`
`cimetidine or trimethoprim *
`
`Alteration of creatine/creatinine load
`
`eating cooked meat
`
`low protein diet
`
`body building
`
`muscle wasting
`
`Nil
`
`Nil
`
`Renal disease
`
`* becomes more accurate at low levels of GFR when increased
`tubular secretion of creatinine is blocked
`
`Isotopic GFR
`Isotopic GFR is the most accurate measurement of GFR,
`especially at low levels of renal function or with alterations of
`muscle mass. The most common isotopic marker is technetium
`99m DTPA, given as a single injection. Two plasma samples
`are taken at 1–3 hours after injection. The GFR is calculated
`from the plasma clearance of the isotope. Isotopic GFR can be
`used for monitoring renal function over time, or in chronic
`renal failure patients approaching dialysis. Patients are usually
`tested every two to five years, because of the cost and
`inconvenience of the procedure.
`
`Summary
`Renal function can be evaluated by measuring the GFR. As it
`is not easy to measure the GFR directly, the serum creatinine
`concentration is often used to assess renal function. Creatinine
`clearance provides a more accurate assessment and can be
`calculated from the serum creatinine or more exactly from the
`results of a 24-hour urine collection. Isotopic methods can be
`used if a very accurate measurement of the GFR is required.
`
`Self-test questions
`
`The following statements are either true or false
`(answers on page 23)
`
`In renal disease the creatinine clearance is increased.
`7.
`8. Cimetidine can increase the serum concentration of
`creatinine.
`
`17
`
`Mylan v. Janssen (IPR2020-00440) Ex. 1043, p. 003
`
`