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32 SECTION II Investigation of Renal Disease
Table 3-2 Comparison of creatinine, urea, and cystatin C as filtration markers. ELISA, Enzyme-linked immunosorbent assay; GFR, glomerular
filtration rate; IDMS, isotope-dilution–mass spectroscopy; PENIA, particle-enhanced nephelometric immunoassay; PETIA, particle-enhanced turbidimetric
immunoassay. (Modified with permission from reference 2.)
filtered across the glomerulus and secreted by the tubules. Several creatinine excretion from age, gender, weight, and other variables.4
medications, such as cimetidine and trimethoprim, competitively Deviations from these expected values can give some indication of
inhibit creatinine secretion and reduce creatinine clearance. These errors in timing or completeness of urine collection. Creatinine
medications thus lead to a rise in the serum creatinine concentration clearance systematically overestimates GFR because of tubular cre-
without an effect on GFR (Table 3-3). atinine secretion. In the past the amount of creatinine excreted by
In addition, creatinine is contained in intestinal secretions and tubular secretion at normal levels of GFR was thought to be relatively
can be degraded by bacteria. If GFR is reduced, the amount of cre- small (10% to 15%), but with newer, more accurate assays for low
atinine eliminated through this extrarenal route is increased. Anti- values of serum creatinine, this difference may be substantially
biotics can raise serum creatinine concentration by destroying greater. At low values of GFR, the amount of creatinine excreted by
intestinal flora, thereby interfering with extrarenal elimination, as tubular secretion may exceed the amount filtered.2
well as by reducing the GFR. The rise in serum creatinine concentra-
tion after inhibition of tubular secretion and extrarenal elimination
is greater in patients with a reduced GFR. Clinically, it can be difficult Creatinine Assay
to distinguish a rise in serum creatinine concentration caused by Historically, the most common assay for measurement of serum
inhibition of creatinine secretion or extrarenal elimination from a creatinine was the alkaline picrate (Jaffe) assay that generates a color
decline in GFR. However, processes other than a decrease in GFR reaction. Chromogens other than creatinine are known to interfere
should be suspected if serum urea concentration remains unchanged with the assay, giving rise to errors of up to approximately 20%
despite a significant change in serum creatinine concentration in a in normal individuals. Modern enzymatic assays do not detect non-
patient with an initially reduced GFR. creatinine chromogens and yield lower serum levels than with the
Creatinine clearance is usually computed from the creatinine alkaline picrate assays. Until recently, calibration of assays to adjust
excretion in a 24-hour urine collection and single measurement of for this interference was not standardized across laboratories, thereby
serum creatinine in the steady state. Creatinine excretion rates vary limiting the estimation of GFR from serum creatinine concentra-
with age, gender, and race and are approximately 20 to 25 mg/kg/day tions, especially at higher GFR.
and 15 to 20 mg/kg/day in a complete collection in healthy young To address the heterogeneity in creatinine assays, fresh-
men and women, respectively. Equations are available to estimate the frozen serum pools with known creatinine levels traceable to an
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CHAPTER 3 Assessment of Renal Function 33
Table 3-3 Factors affecting serum creatinine concentration. (Modified from reference 3.)
isotope-dilution–mass spectrometry (IDMS) reference are available The Cockcroft-Gault formula has three main limitations. First,
for instrument manufacturers to standardize creatinine measure- it is not precise, in particular in the GFR range above 60 ml/min.
ments.5 Use of standardized assays is recommended.6 Standardiza- Second, it estimates creatinine clearance rather than GFR and thus
tion will reduce, but not completely eliminate, the error in estimating is expected to overestimate GFR, while normal values for creatinine
GFR at higher levels (Table 3-3). secretion are not well known. Third, the formula was derived by
older assay methods for serum creatinine, which cannot be cali-
brated to newer assay methods, which would be expected to lead to
Estimated Glomerular Filtration Rate a systematic bias in estimating creatinine clearance.
from Serum Creatinine Importantly, before standardization of creatinine assays, the
Again, GFR can be estimated from serum creatinine by equations Cockcroft-Gault formula was widely used to assess pharmacokinetic
that use age, gender, race, and body size as surrogates for creatinine properties of drugs in patients with impaired kidney function. The
generation.1 Despite substantial advances in the accuracy of estimat- accuracy of drug dosing recommendations based on the Cockcroft-
ing equations based on creatinine during the past several years, GFR Gault formula using creatinine values from modern assays remains
estimates remain imprecise, and no equation is likely to overcome controversial. One study suggested that drug dosage adjustment
the limitations of creatinine as a filtration marker. None of the equa- guided by the Cockcroft-Gault formula is slightly less accurate than
tions is expected to work as well in patients with extreme levels for adjustments based on more accurate estimating equations.8
creatinine generation, such as amputees, large or small individuals,
patients with muscle-wasting conditions, or people with high or low Modification of Diet in Renal Disease Study
levels of dietary meat intake (Table 3-3). Because of differences The Modification of Diet in Renal Disease (MDRD) study equation
among racial and ethnic groups according to muscle mass and diet, uses age, gender, and race (African American vs. Caucasian or other)
equations developed in one racial or ethnic group are unlikely to be and standardized serum creatinine to estimate GFR9 (Box 3-1). It
accurate in multiethnic populations. As discussed later, further was derived from a study population with chronic kidney disease
improvements will probably require additional filtration markers. (CKD) and underestimates the measured GFR in populations with
higher levels of GFR (Fig. 3-2). It has not been validated in children
Cockcroft-Gault Formula or pregnant women. The MDRD study equation had greater preci-
The Cockcroft-Gault formula estimates creatinine clearance from sion and greater overall accuracy than the Cockcroft-Gault formula.
age, gender, and body weight, in addition to serum creatinine (Box Modifications of the MDRD have now been reported in racial and
3-1).7 An adjustment factor for women is based on a theoretical ethnic populations other than African American and Caucasian,
assumption of 15% lower creatinine generation because of lower including those in China, Japan, Thailand, and South Africa.10,11 In
muscle mass. Comparison to normal values for creatinine clearance general, these modifications improve the accuracy of the MDRD
requires computation of BSA and adjustment to 1.73 m2. Because of equation in the study population but do not generalize well to other
the inclusion of a term for “weight” in the numerator, this formula populations.
systematically overestimates creatinine clearance in edematous or Organizations in several countries now recommend GFR esti-
obese patients. mates (eGFR) as the primary method of clinical assessment of
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34 SECTION II Investigation of Renal Disease
where κ is 0.7 for females and 0.9 for males, α is −0.329 for females and −0.411 for males, min indicates the minimum of Scr/κ or 1,
and max indicates the maximum of Scr/κ or 1.
Female ≤ 0.7 → GFR = 144 × (Scr / 0.7)−0.329 × (0.993)Age × 1.157 (if black)
where min indicates the minimum of Scys/0.8 or 1, and max indicates the maximum of Scys/0.8 or 1.
where κ is 0.7 for females and 0.9 for males; α is −0.248 for females and −0.207 for males; min indicates the minimum of Scr/κ or 1,
or of Scys/0.8 or 1; and max indicates the maximum of Scr/κ or 1, or of Scys/0.8 or 1.
Female ≤0.7 ≤ 0.8 → GFR = 130 × (Scr / 0.7)−0.248 × (Scys / 0.8)−0.375 × 0.995Age × 1.08 (if black)
Box 3-1 Equations for estimating glomerular filtration rate. Age in years; weight in kg; Scr, serum creatinine; Scys, serum cystatin C. The Modification
of Diet in Renal Disease (MDRD) study and Chronic Kidney Disease Epidemiology (CKD-EPI) equation calculator can also be found online at http://www.
kidney.org/professionals/kdoqi/gfr_calculator.cfm.
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CHAPTER 3 Assessment of Renal Function 35
levels (Fig. 3-2). The CKD-EPI is also more accurate across a wide
60 range of characteristics, including age, gender, race, body mass
Underestimate
index, and presence or absence of diabetes or history of organ trans-
30 plantation. As with the MDRD, modifications of the CKD-EPI equa-
tions in Japan improve accuracy in these study populations.11
0 The CKD-EPI creatinine equation now allows reporting of eGFR
across the entire range of values, without substantial bias. It is cur-
Overestimate
-30
rently reported by the two major nationwide laboratories in the
United States, as well as by laboratories in France. The 2012 Kidney
Disease: Improving Global Outcomes (KDIGO) guidelines recom-
-60
mend that clinical laboratories report eGFR in all adults using
CKD-EPI creatinine equations, or using other equations if shown to
-90 be superior to CKD-EPI equation in that population.13
30 60 90 120 150
Estimated GFR (ml/min/1.73 m2)
UREA
Measured-Estimated GFR (ml/min/1.73 m2)
90
60 The serum urea level has limited value as an index of GFR, in view
Underestimate
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36 SECTION II Investigation of Renal Disease
proximal tubular cells, where it is almost completely catabolized, reference material for standardization of cystatin C, but international
with the remainder eliminated in the urine largely intact.15 Some standardization of the assay is still in process.19 The assays are con-
evidence suggests the existence of tubular secretion as well as extra- siderably more expensive than those for creatinine determination.
renal elimination, the latter estimated at 15% to 21% of renal
clearance.16
Because cystatin C is not excreted in the urine, it is difficult to Estimated Glomerular Filtration Rate
study its generation and renal handling. Thus, understanding from Serum Cystatin C
non-GFR determinants of cystatin C relies on epidemiologic associa- Numerous studies have found that serum cystatin C levels are a
tions. Some suggest that inflammation, adiposity, thyroid diseases, better estimate of GFR than serum creatinine concentration because
certain malignant neoplasms, and use of glucocorticoids may cystatin C is less affected than creatinine by age, gender, or race.
increase cystatin C levels. Two studies found that key factors leading However, cystatin C or equations based on cystatin C are not more
to higher cystatin C levels after adjustment for creatinine clearance accurate than creatinine-based estimating equations, due to varia-
or measured GFR were older age, male gender, fat mass, white race, tion in non-GFR determinants of serum cystatin C.20 Several studies,
diabetes, higher C-reactive protein level, increased white blood cell though, have demonstrated that equations combining both these
count, and lower serum albumin level.17,18 Therefore factors other filtration markers with age, gender, and race appear to be more
than GFR must be considered in interpreting cystatin C levels. precise than equations using either marker alone, probably because
of smaller effects of the non-GFR determinants of both markers
when used in combination. The 2012 CKD-EPI cystatin C and
Cystatin C Assay creatinine–cystatin C equations (see Box 3-1) are expressed for use
Available assays to analyze cystatin C all can result in different values. with standardized serum creatinine and cystatin C and are recom-
The International Federation of Clinical Chemists (IFCC) made a mended by the 2012 KDIGO guidelines (Fig. 3-3).20 The equation
15
10
0
<15 15–29 30–59 60–89 90–120 >120
–5 Estimated GFR (ml/min/1.73 m2)
60
eGFRcr
eGFRcys
50 eGFRcr,cys
40
1 - P30
30
20
10
0
<15 15–29 30–59 60–89 90–120 >120
Estimated GFR (ml/min/1.73 m2)
Figure 3-3 Performance of three equations for estimating GFR. GFR was estimated using the Chronic Kidney Disease Epidemiology estimating equa-
tions. Top, Median difference between measured GFR and estimated glomerular filtration rate (eGFR). The bias is similar with the equation using creatinine
alone (eGFRcr), that using cystatin C alone (eGFRcys), and the combined creatinine–cystatin C equation (eGFRcr,cys). Bottom, Accuracy of the three equations
according to percentage of estimates greater than 30% of measured GFR (1 − P30). I bars indicate 95% CI. (Modified from reference 20.)
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CHAPTER 3 Assessment of Renal Function 37
using cystatin C without creatinine does not appear to require speci- Current estimating equations will be less accurate in people with
fication of race. Also, in patients with reduced muscle mass (e.g., factors affecting serum creatinine concentration other than GFR (see
neuromuscular or liver disease, low body mass index) or in patients Table 3-3). In these patients, more accurate GFR estimates require
with diabetes, cystatin C may result in more accurate GFR estimates additional testing, such as measurement with an endogenous filtra-
than creatinine. tion marker (e.g., cystatin C, β2M, βTP), a timed urine creatinine
Some studies show that a lower eGFR based on serum cystatin C clearance measurement, or clearance measurement using an exoge-
is a better predictor of the risk of cardiovascular disease and total nous marker.
mortality than is a lower eGFR based on serum creatinine concentra-
tion.21 Whether this is caused by its superiority as a filtration marker
or the confounding by non-GFR determinants of cystatin C and Acute Kidney Injury
creatinine remains to be determined. In the future, GFR estimating In the nonsteady state, there is a lag before the rise in serum level
equations using the combination of serum cystatin C and creatinine because of the time required for retention of an endogenous filtration
may be useful as a confirmatory test for CKD. However, this is fea- marker (Fig. 3-4). Conversely, after recovery of GFR, there is a lag
sible only after standardization, widespread availability, and cost before the excretion of the retained marker. During this time, neither
reductions of cystatin C assays, as well as further investigation of the serum level nor the GFR estimated from the serum level accu-
non-GFR determinants of serum cystatin C. rately reflects the measured GFR. Nonetheless, a change in the eGFR
in the nonsteady state can be a useful indication of the magnitude
and direction of the change in measured GFR. If the eGFR is decreas-
OTHER FILTRATION MARKERS ing, the decline in eGFR is less than the decline in measured GFR.
Conversely, if the eGFR is increasing, the rise in eGFR is greater
β2-Microglobulin (β2M) and β-trace protein (βTP) are two other than the rise in measured GFR. The more rapid the change in eGFR,
low-molecular-weight serum proteins being evaluated as filtration the greater is the change in measured GFR. When eGFR reaches a
markers for estimating GFR and for their role in prognosis. However, new steady state, it more accurately reflects measured GFR. In
β2M and βTP are not recommended for use at this time. An 11.8-kd patients with acute kidney injury, serum cystatin C appears to
subunit of major histocompatibility complex (MHC) class I mole- increase more rapidly than serum creatinine.30 More data are required
cules, β2M is present on all nucleated cells and plays a central role in to establish whether changes in serum cystatin C are a more sensitive
cellular immunology. βTP, also known as lipocalin prostaglandin indicator of rapidly changing kidney function than changes in serum
D2 synthase, is a 168–amino acid glycoprotein of 23 to 29 kd. As creatinine.
with cystatin C, β2M and βTP are freely filtered by the glomerulus
and extensively reabsorbed and degraded by the proximal tubule,
with only small amounts excreted in the urine under normal
conditions.
In NHANES-III analyses, the median (upper 99th percentile) Effect of a Sudden Decrease in Glomerular
levels of serum β2M and βTP for people age 20 to 39 without history
of hypertension or diabetes were 0.52 mg/l (0.81 mg/l) and 1.59 mg/l
Filtration Rate on Endogenous Marker
(2.80 mg/l), respectively, with levels lower in women than in men Acute GFR decline
and higher in non-Hispanic whites than in blacks and Mexicans;22
levels were higher in older people. Several studies found correlations
of serum β2M and βTP levels with directly measured GFR that were 120 GFR 120
better or similar to those observed with creatinine and that were 90 90
similar to cystatin C.23-26 In addition, studies have shown that β2M 60 60
and βTP are better predictors of adverse health outcomes than cre- Marker generation
atinine and are potentially as accurate as cystatin C in the general
population and in patients with CKD.23,27,28 However, some factors
may limit their use as a filtration marker; serum β2M concentration
Marker filtration Day Pmarker eGFR
may be increased in several malignancies and inflammatory and excretion 1.0 1.0 120
states, and corticosteroid administration may decrease serum βTP 1.5 1.6 79
concentration.28,29 2.0 1.8 69
2.5 1.9 65
3.0 2.0 60
CLINICAL APPLICATION OF ESTIMATED Cumulative marker
balance
GLOMERULAR FILTRATION RATE
Chronic Kidney Disease 2.0 2.0
Estimation of GFR is necessary for the detection, evaluation, and 1.5 1.5
management of patients with CKD. Current guidelines recommend 1.0 Plasma marker 1.0
testing of patients at increased risk of CKD for albuminuria, as a concentration
marker of kidney damage, or a reduced eGFR to assess kidney func- 0 1 2 3 4
tion and staging of disease severity by eGFR level. Use of serum Day
creatinine alone as an index of GFR is unsatisfactory and can lead
Figure 3-4 Sudden decrease in glomerular filtration rate. Graphs
to delays in detection of CKD and misclassification of the severity of show effect of acute GFR decline (top) on generation, filtration/excretion,
CKD. Use of estimating equations allows direct reporting of eGFR and balance of endogenous marker (middle) and concentration of plasma
by clinical laboratories whenever serum creatinine is measured. marker (bottom). (Modified from reference 1.)
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38 SECTION II Investigation of Renal Disease
MARKERS OF TUBULAR DAMAGE 12. Levey AS, Stevens LA, Schmid CH, et al. A new equation to estimate glo-
merular filtration rate. Ann Intern Med. 2009;150:604-612.
13. KDIGO 2012 clinical practice guideline for the evaluation and management
The urinary excretion of low-molecular-weight serum proteins may of chronic kidney disease. Kidney Int Suppl. 2013;3.
increase when proximal tubular reabsorption is impaired, which 14. Kottgen A, Selvin E, Stevens LA, et al. Serum cystatin C in the United States:
may serve as a marker of proximal tubular damage. Examples The Third National Health and Nutrition Examination Survey (NHANES
III). Am J Kidney Dis. 2008;51:385-394.
include cystatin C and β2M, as previously described, as well as
15. Tenstad O, Roald AB, Grubb A, Aukland K. Renal handling of radiolabelled
interleukin-18 (18,000 d), retinol-binding protein (21,000 d) and α1- human cystatin C in the rat. Scand J Clin Lab Investig. 1996;56:409-414.
macroglobulin (33,000 d). In contrast, other markers of tubular 16. Sjostrom P, Tidman M, Jones I. Determination of the production rate and
damage are produced in the kidney in response to injury, such as non-renal clearance of cystatin C and estimation of the glomerular filtration
N-acetyl-β-glucosaminidase (NAG) and urinary kidney injury mol- rate from the serum concentration of cystatin C in humans. Scand J Clin Lab
Investig. 2005;65:111-124.
ecule 1 (KIM-1). Increased excretion of neutrophil gelatinase– 17. Stevens LA, Schmid CH, Greene T, et al. Factors other than glomerular filtra-
associated lipocalin (NGAL), a 25,000-d protein in kidney disease, tion rate affect serum cystatin C levels. Kidney Int. 2009;75:652-660.
may reflect impaired reabsorption of filtered NGAL or increased 18. Knight EL, Verhave JC, Spiegelman D, et al. Factors influencing serum cys-
production by the kidney. These and other urinary markers of tatin C levels other than renal function and the impact on renal function
measurement. Kidney Int. 2004;65:1416-1421.
tubular damage under investigation are discussed further in
19. Grubb A, Blirup-Jensen S, Lindstrom V, et al. First certified reference mate-
Chapter 71. rial for cystatin C in human serum ERM-DA471/IFCC. Clin Chem Lab Med.
2010;48:1619-1621.
20. Inker LA, Schmid CH, Tighiouart H, et al. Estimating glomerular filtration
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