Renal Failure-Measuring the Glomerular Filtration Rate

Abstract

Chronic renal disease is common, and its prevalence is rising. Its main causes are hypertension and diabetes mellitus. An abnormally low glomerular filtration rate (GFR) often escapes medical notice in the earliest, most treatable stage, so that an increasing number of patients progress to end-stage renal failure. Early recognition of low GFR would thus be an important clinical advance.
The authors selectively review the literature retrieved by a PubMed search on the topic and also present their own clinical and laboratory data.
Chronic renal failure can be detected early by direct measurement of the GFR with the aid of an exogenous filtration marker. Such techniques are costly and time-consuming and are therefore indicated only for patients at special risk. Chronic renal disease can also be diagnosed early with the aid of the endogenous filtration markers creatinine and cystatin C, which serve as indicators of a low GFR. The serum levels of these two substances are not taken as measures of GFR in themselves, but are rather entered into predictive equations for the estimation of GFR. Cystatin C-based equations seem to be more sensitive indicators of low GFR than creatinine-based equations.
Creatinine- and cystatin C-based equations for the estimation of GFR are valuable tools for the early diagnosis of chronic renal disease and for disease staging according to the US National Kidney Foundation criteria.

Full text

MEDICINE
REVIEW ARTICLE
Renal Failure—Measuring the
Glomerular Filtration Rate
Christian Thomas, Lothar Thomas
SUMMARY
Background: Chronic renal disease is common, and its
prevalence is rising. Its main causes are hypertension and
diabetes mellitus. An abnormally low glomerular filtration
rate (GFR) often escapes medical notice in the earliest,
most treatable stage, so that an increasing number of
patients progress to end-stage renal failure. Early
recognition of low GFR would thus be an important
clinical advance.
Methods: The authors selectively review the literature
retrieved by a PubMed search on the topic and also
present their own clinical and laboratory data.
Results: Chronic renal failure can be detected early by
direct measurement of the GFR with the aid of an
exogenous filtration marker. Such techniques are costly
and time-consuming and are therefore indicated only for
patients at special risk. Chronic renal disease can also be
diagnosed early with the aid of the endogenous filtration
markers creat inine and cystatin C, which serve as
indicators of a low GFR. The se rum levels of these two
substances are not taken as measures of GFR in themselves,
but are rather entered into predictive equations for the
estimation of GFR. Cystatin C-based equations seem to be
more sensitive indicators of low GFR than creatinine-based
equations.
Conclusions: Creatinine- and cystatin C-based equations
for the estimation of GFR are valuable tools for the early
diagnosis of chronic renal disease and for disease staging
according to the US National Kidney Foundation criteria.
Key words: renal failure, chronic disease, nephropathy,
hypertension, diabetes mellitus
Cite this as: Dtsch Arztebl Int 2009; 106(51–52): 849–54
DOI: 10.3238/arztebl.2009.0849
C
hronic renal disease (CRD) is defined as a glo-
merular filtration rate (GFR) of <60 (mL × min
–1
per 1.73 m
2
body surface area) for at least three months,
whatever the cause and regardless of the presence of
kidney damage (1). Patients in whom signs of damage
are found on diagnostic imaging or renal biopsy and
those with albuminuria also have nephropathy, even if
their GFR is >60. Patients without signs of kidney
damage whose GFR is >60 are highly unlikely to be
nephropathic (2). CRD is classified into five stages
according to the GFR (Table 1) (1). In the USA (3)
approximately 10% of adults are estimated to be in an
early stage of impaired renal function, of whom 40%
have a GFR <60 and 60% show elevated albumin
excretion (>30 mg/g creatinine) (e1). According to a
European study (4), the prevalence of CRD stage 4 and
5 is 1% in hospital patients under the age of 30 years
and 12% in those over 80 years of age.
Persons with impaired renal function are at greater
risk of cardiovascular morbidity and mortality (5), and
the prevalence is considerably higher in older people
(6). The latter generally display an annual GFR
decrease of <1 (7), but a yearly drop of >3, regardless
of baseline GFR, has proved to be an independent risk
factor for increased mortality (8).
The GFR is considered the best marker for renal
function (1). The early stages of renal function impair-
ment are clinically silent and are diagnosed only by
measuring GFR by means of external filtration markers
(measured GFR, mGFR) (9). Once GFR has decreased
to <60, functional impairments can be detected by
determining internal filtration markers and calculating
the estimated GFR (eGFR) (10). The complications of
CRD increase with decreasing GFR and may progress
from gradual reduction in renal function to end-stage
renal failure. The goal of GFR determination is to
detect CRD early in order to slow its progress.
The determination of mGFR and eGFR is indicated
●
as an isolated measurement to assess renal func-
tion at a particular point in time, e.g., in patients
with high prevalence of GFR <60;
●
to evaluate the progression of CRD;
●
to assess the efficacy of function-preserving treat-
ment measures.
GFR can be determined using exogenous and endo-
genous markers of filtration (Box 1). Measurements
employing exogenous filtration markers (mGFR) yield
Laboratoriumsmedizin, Krankenhaus Nordwest, Frankfurt am Main: Prof. Dr.
med. Lothar Thomas
The Prostate Centre at VGH, Vancouver BC: Dr. med. Christian Thomas
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MEDICINE
reliable results and represent the gold standard.
However, they are costly, time-consuming, and labor-
intensive, can be performed only in specialized labora-
tories, and are therefore indicated primarily in patients
displaying nephrological symptoms. Simpler, but less
precise, is estimation of GFR (eGFR) by means of the
endogenous filtration markers creatinine and cystatin
C.The aim of this review is to depict the methods used
to determine GFR and—by sifting the nephrological,
internal medical and clinical chemistry literature avail-
able in PubMed—ascertain their reliability in the detec-
tion and monitoring of CRD.
Measuring GFR by means of exogenous
filtration markers (mGFR)
The clearance of various markers of filtration, such as
inulin,
51
Cr-EDTA, iohexol, iothalamate, and
99m
Tc-diethylenetriaminepentaacetic acid (DTPA), is
determined. The GFR is either expressed in absolute
terms as mL × min
–1
or standardized to 1.73 m
2
, the
body surface area of a person weighing 70 kg. The unit
of measurement is: mL × min
–1
× (1.73 m
2
)
–1
. Age- and
gender-specific reference values for GFR can be found
in Table 2 (11). The reduction in GFR correlates with
the extent of functional impairment of the nephrons and
thus with the degree of renal failure. A patient whose
GFR falls below 15 usually requires dialysis. Never -
theless, in certain cases GFR is insensitive to the loss of
functioning nephrons. In the early stage of diabetes-
related kidney disease, for instance, characterized by
microalbuminuria, the renal hypertrophy and hyperper-
fusion mean that GFR is normal or raised; thus, deter-
mination of GFR is of no value in the diagnosis of
incipient diabetic nephropathy (e2). The different
methods for mGFR do not show full agreement: at GFR
values >80, GFR
iohexol
gives lower readings than
GFR
EDTA
, but below this threshold GFR
EDTA
is lower
than GFR
iohexol
(13).
Measuring GFR by means of endogenous
filtration markers (eGFR)
Internal markers of filtration such as creatinine and cys-
tatin C are endogenous substances that are almost com-
pletely filtered out by the glomeruli. Increasing serum
levels of these parameters indicate decreasing GFR. It
is recommended that whenever creatinine is determined
the eGFR should be calculated and reported along with
the serum value (14). Equations frequently used to
ascertain eGFR based upon creatinine and cystatin C
are presented in Box 2.
Serum creatinine
Determination of creatinine in serum is the method
most frequently used to evaluate renal function. Creati-
nine derives from the muscular metabolism of creatine
and phosphocreatine. As such, the synthesis of creati-
nine at a daily rate of approximately 20 mg/kg body
weight reflects muscle mass and varies little from day
to day.
TABLE 1
Classification of chronic renal failure, modified from (1)
GFR, glomerular filtration rate; GFR in mL × min
–1
× (1.73 m
2
)
–1
Stage
1
2
3
4
5
GFR
≥90
89 to 60
59 to 30
29 to 15
<15
Renal disease
With normal GFR
With mild functional
impairment
With moderate fail-
ure
With severe failure
With end-stage renal
failure
Measures
Confirm diagnosis,
inhibit progression
Inhibit progression
Confirm diagnosis, treat secondary
complications
Prepare for renal replacement
treatment
Institute renal replacement treatment
BOX 1
Methods for determination and estimation
of GFR and their evaluation
●
Clearance of exogenous substances
Inulin, iohexol,
51
Cr-EDTA,
125
I-iothalamate,
99m
Tc-diethylenetriaminepenta -
acetic acid (DTPA)
Evaluation: Precise and accurate, but costly, time-consuming, and labor-inten-
sive
●
Clearance of endogenous blood substances
–Serum creatinine
Evaluation: Insufficiently sensitive for detection of chronic renal disease (CRD)
–Creatinine clearance
Evaluation: No longer recommended due to errors in urine collection
Exception: Patients with highly abnormal muscle mass or vegetarian diet
(e8, e9)
–Serum cystatin C
Evaluation: More sensitive than serum creatinine for detection of GFR
reduction in the range 70 to 40; better than creatinine in children
●
Estimated GFR (eGFR)
–Creatinine-based and use of patient-specific data
– Counahan-Barratt equation
Evaluation: Only suitable for children, overestimates GFR by ca. 20% to 30%
– Cockcroft-Gault equation
Evaluation: Only suitable for adults, slightly overestimates GFR, well suited for
estimation of GFR changes during pharmacotherapy
– MDRD (Modification of Diet in Renal Disease) equation
Evaluation: Practicable in adults with CRD; not suitable for children
–Cystatin C-based eGFR
No patient-specific data required
Evaluation: In the range 70 to 40, estimates GFR more sensitively than
creatinine-based equations
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Creatinine synthesis is age-dependent. As measured
by urinary excretion, it decreases with increasing age,
falling from a mean 23.8 mg/kg body weight in men
aged 20 to 29 years to 9.8 mg/kg body weight in men
aged 90 to 99 years (e2). The essential reason is reduc-
tion in muscle mass.
When renal function is normal, creatinine is filtered
out by the glomeruli and 15% of it is secreted by the
tubuli (e3). There is a reciprocal non-linear relationship
between GFR and serum creatinine, such that a decrease
in GFR to around 40 often does not lead to an increase to
above the upper limit of normal (e4). If no previously
obtained values are available, a concentration within the
normal range cannot be interpreted as potentially showing
a decrease in GFR. In acute renal failure serum creatinine
rises within 2 days as a direct result of retention within
the body. In CRD the increase in serum is only 30% to
50% of what would be expected from the prevailing
GFR. The reason for this is that, depending on the extent
of GFR reduction, 16% to 66% of creatinine is eliminated
extraglomularly (e5). Tubular secretion and intestinal
elimination reach their maximum when GFR falls to
≤15. Noteworthy extra renal patient-related factors that
influence creatinine synthesis and thus the concentration
in serum include sex, age, ethnicity, muscle mass,
chronic illness, and the consumption of cooked meat.
Lack of standardization of methods also impacts
negatively on the validity of serum creatinine for
assessment of GFR. Medications such as cimetidine and
trimethoprim inhibit creatinine secretion and increase the
serum concentration without affecting GFR. It must also
be realized that serum creatinine is not suitable for
evaluation of rapid changes in GFR: The estimated GFR
is too high in swiftly decreasing renal function and too
low when function recovers.
Serum cystatin C
Cystatin C is a plasma protein with a molecular weight
of 13.4 kDa and belongs to the cysteine protease in-
hibitors. It is synthesized at a constant rate by all
nucleated cells, excreted into plasma, filtered by the
glomeruli, and reabsorbed and metabolized by the
proximal tubule cells. In the age group from 1 to 50
years, the serum concentration is independent of
muscle mass, sex, and age .
TABLE 2
Reference values for GFR (11)
* (mL × min
–1
× [1,73 m
2
]
–1
)
Premature births
Neonates
Children (2 to 8 weeks)
Children (3 to 12 months)
Children/adolescents (1 to 20 years)
Adults (age group, years)
20–29
30–39
40–49
50–59
60–69
70–79
80–89
>0.5 mL × min
–1
× kg
–1
>10 mL × min
–1
× [m
2
]
–1
16.3 to 44.6 (mL × min
–1
× [1.73 m
2
]
–1
)
>70 (mL × min
–1
× [1.73 m
2
]
–1
)
>80 (mL × min
–1
× [1.73 m
2
]
–1
)
Men*
77–179
70–162
63–147
56–130
49–113
42–98
35–81
Women*
71–165
64–149
58–135
51–120
45–104
39–90
32–75
BOX 2
Creatinine- and cystatin C-based equations for calculation of eGFR
Children
Counahan-Barratt equation (e14) Creatinine-based
eGFR (mL × min
–1
) = 0.43 × height (cm) × (S
Cr
[mg/dL])
–1
Equation according to Cystatin C-based
Grubb et al. (24) eGFR (mL × min
–1
× [1.73 m
2
]
–1
) = 84.69 × (S
cystatin C
[mg × L
–1
])
–1.68
× 1.384 (in children <14 years)
Adults
Cockcroft-Gault equation (19) Creatinine-based
C
Cr
(mL × min
–1
) = (140 – age [years]) × (S
Cr
[mg × dL
–1
])
–1
× (BW [kg] × [72]
–1
)
Correction factor: for women × 0.85
MDRD equation (10) Creatinine-based
eGFR (mL × min
–1
× [1.73 m
2
]
–1
) = 175 × (S
Cr
standardized [mg × dL
–1
])
–1.154
× (age [years])
–0.203
Correction factor: for women × 0.742
f or blacks × 1.18
Equation according to Cystatin C-based
Hoek et al. (25) eGFR (mL × min
–1
× [1.73 m
2
]
–1
) = 80.35 × (S
cystatin C
[mg × L
–1
] – 4)
–1.68
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These properties show that cystatin C is a good
marker for assessment of renal function. Comparably
with serum creatinine, there is an inverse, non-linear
relationship between GFR and serum cystatin C. In
comparison with serum creatinine, the proportional
increase of cystatin C is higher when GFR falls to a
level between 70 and 40 (Figure) (17). Cystatin C rises
age-dependently from the age of 50 years and corre-
lates with the decrease in GFR.
Cystatin is not always a reliable marker of renal
function, as its synthesis is increased in smokers,
patients with hyperthyroidism, and those on glucocorti-
coid therapy and decreased in hypothyroidism (e6).
According to a meta-analysis, however, cystatin C is a
more reliable parameter than creatinine for detection of
CRD (18).
Creatinine-based eGFR
eGFR is determined by means of equations that take
account of empirically patient-related parameters and
thus permit more precise and accurate assessment of
GFR. All of the equations employed for estimating
GFR were developed using cross-sectional data from
patient collectives. The Cockcroft-Gault equation (19)
and the Modification of Diet in Renal Disease (MDRD)
equation (20) are recommended (Box 2). The former
incorporates age, body weight, sex, and serum creati-
nine concentration, while the latter considers age,
ethnicity, sex, and serum creatinine concentration. The
Counahan-Barratt equation is recommended for
children.
Cockcroft-Gault equation
The Cockcroft-Gault equation estimates creatinine
clearance in mL × min
–1
, but not GFR, and is not stan-
dardized to the body surface area of 1.73 m
2
. In relation
to GFR it systematically overestimates clearance
because tubular creatinine secretion is not taken into
account (19, 20). Because this equation includes body
weight, it is particularly recommended for the monitor-
ing of renal function during treatment with medications
that influence kidney performance.
MDRD equation
The MDRD equation includes age, sex, and ethnicity to
take account of differences among population sub-
groups. Therefore reductions in GFR are detected ear-
lier than with serum creatinine.
Because the MDRD equation was developed exclu -
sively using data from patients with CRD, a GFR of
>60 should be reported not as an absolute value but as
eGFR >60 mL = (mL × min
–1
× [1.73 m
2
]
–1
) (20, 21).
More recently individuals without CRD have also been
FIGURE
Proportional increase in serum creatinine (blue) and serum cystatin C (yellow) with
decreasing glomerular filtration rate (GFR)
BOX 3
Advantages of cystatin C-based
eGFR over creatinine-based eGFR
(examples)
Patient category Advantage
Children (e23) Children have low levels of
creatinine and determina -
tion is unreliable in the
low er range of measure-
ment
The elderly (e15) Owing to physiological re-
duction in renal function
and decrease in muscle
mass, cystatin C correlates
better than creatinine with
inulin clearance
Myasthenics, Because of the lower
leg amputees, muscle mass, creatinine
paraplegics (e16) synthesis is low and
creatinine- based eGFR is
late to detect renal failure
Diabetics (e17) Early stages of renal failure
are detected more reliably
with cystatin C based than
with creatinine-based
eGFR
Liver cirrhosis (18) Creatinine methods are
slow to detect the decrease
in GFR because creatinine
metabolism in the liver is
reduced
Cytostatic treatment (e19) The nephrotoxicity of cis-
platin is dose-dependent
and a reduction in GFR is
detected earlier by cystatin
C-based than by creatinine-
based eGFR
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studied. The diagnostic reliability of the MDRD
equation for estimation of GFR can be summarized as
follows:
●
The eGFR can be 6% too high in CRD (11,
e7–e9), and may be 29% too low in individuals
without CRD (e10, e11).
●
In 90% of cases in the MDRD study group the
eGFR was within ±30% of the mGFR (21). For a
GFR of 60 (mL × min
–1
× [1.73 m
2
]
–1
) this would
mean a range of 42 to 78 (mL × min
–1
× [1.73
m
2
]
–1
). This degree of accuracy is considered ac-
ceptable provided eGFR is determined again after
3 months (22).
●
The MDRD equation over-stages patients in CRD
stages 2 and 3, but correctly classifies those in
stages 4 and 5 (4).
This overestimation of GFR by the MDRD equation
is important for the monitoring of CRD. Patients in
stage 3 are expected to exhibit an annual decrease in
GFR of 1.4 to 3.9. In a comparison of mGFR and
eGFR, however, 41.8% of patients showed a decrease
in eGFR that was less than that in mGFR by ≥2. Thus
monitoring of CRD by eGFR must be viewed critically
(23).
Any patient with eGFR <60 very probably has CRD.
Young patients with eGFR as low as this may have a
true GFR that is 29% higher, but will still probably
have impaired renal function (22). In such cases dem-
onstration of, for example, albuminuria is required for
the diagnosis of renal damage (1).
To ensure comparability of eGFR among labora-
tories it is important to use kinetic methods such as the
Jaffé reaction or enzymatic techniques to determine
creatinine. To this end calibrators and controls of the
tests carried out must be based on highly specific pro-
cedures for creatinine determination and specific ref -
erence materials (21).
Cystatin C-based eGFR
All that is needed for calculation of eGFR is the serum
concentration of cystatin C. This method is particularly
indicated in children (e12, e13), because the MDRD
equation cannot be used in this age group (e9), and in
the elderly (6). For children the equation according to
Grubb (24) has proved more reliable than the
Counahan-Barratt equation, and for adults the equation
according to Hoek (25) is more sensitive than the
MDRD equation (Box 2). In older age groups the
physiological decrease in GFR from year to year is reg-
istered more sensitively with cystatin C-based eGFR
than with the MDRD equation (6), and a drop of >3 is
associated with a higher subsequent risk of mortality
(8). Further indications for cystatin C-based determi-
nation of eGFR are listed in Box 3.
Conclusion
Serum creatinine and establishment of eGFR with the
MDRD equation are important basic investigations for
the diagnosis of CRD. The determination of cystatin C
and reporting of cystatin C-based eGFR offers advantages,
but on grounds of cost (determination of cystatin C is
20 to 30 times more expensive than that of creatinine) it
should be reserved for certain categories of patients.
Conflict of interest statement
The authors declare that no conflict of interest exists according to the guide-
lines of the International Committee of Medical Journal Editors.
Manuscript received on 5 March 2009, revised version accepted on 14 July
2009.
Translated from the original German by David Roseveare.
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KEY MESSAGES
●
The diagnostic sensitivity of serum creatinine
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●
In addition to measurement of serum creatinine the
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●
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●
Reductions in GFR are detected earlier by means of
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●
When a reduction in eGFR is found, direct measurement
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Corresponding author:
Prof. Dr. med. Lothar Thomas
Laboratoriumsmedizin
Krankenhaus Nordwest
Steinbacher Hohl 2–26
60488 Frankfurt am Main, Germany
th-books@t-online.de
@
For e-references please refer to:
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I
REVIEW ARTICLE
Renal Failure—Measuring the
Glomerular Filtration Rate
Christian Thomas, Lothar Thomas
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