Assessment of Kidney Function

Assessment of kidney function - UpToDate 07/04/2024 19:05
Official reprint from UpToDate®

www.uptodate.com © 2024 UpToDate, Inc. and/or its affiliates. All Rights Reserved.
Assessment of kidney function

authors: Lesley A Inker, MD, MS, Ronald D Perrone, MD
section editor: Richard H Sterns, MD
deputy editor: John P Forman, MD, MSc
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Mar 2024.

This topic last updated: Mar 14, 2023.
INTRODUCTION
Patients with kidney disease may have a variety of different clinical presentations. Some
have symptoms that are directly referable to the kidney (gross hematuria, flank pain) or to
extrarenal symptoms (edema, hypertension, signs of uremia). Many patients, however, are
asymptomatic and are noted on routine examination to have an elevated serum creatinine
concentration or an abnormal urinalysis.
Once kidney disease is discovered, the presence or degree of kidney function impairment,
kidney damage, and rapidity of progression are assessed, and the underlying disorder is
diagnosed. Although the history and physical examination can be helpful, the most useful
information is initially obtained from estimation of the glomerular filtration rate (GFR),
assessment of albuminuria (or proteinuria), and examination of the urinary sediment.
The kidney performs many functions, including elimination of nitrogenous wastes;

regulation of fluid, electrolyte, acid-base, and mineral balance; control of blood pressure;
and synthesis and secretion of erythropoietin and other hormones. The GFR is considered
the best overall measure of the kidney's ability to carry out these various functions, and
therefore estimation of the GFR is used clinically to assess the degree of kidney
impairment and to follow the course of the disease. However, the GFR provides no
information on the cause of the kidney disease. This is achieved by the urinalysis,
measurement of urinary protein excretion, kidney imaging, and, if necessary, kidney
https://www.uptodate.com/contents/assessment-of-kidney-function…result&selectedTitle=1%7E150&usage_type=default&display_rank=1 Página 1 de 44
biopsy.
This topic will provide an overview of the issues concerning assessment of the GFR in the
patient with chronic kidney disease (CKD). The utility of the urinalysis, radiologic studies,
and kidney biopsy are discussed separately, as is the general approach to the patient with
kidney disease:
● (See "Urinalysis in the diagnosis of kidney disease".)

● (See "Radiologic assessment of kidney disease".)
● (See "The kidney biopsy".)
● (See "Diagnostic approach to adult patients with subacute kidney injury in an
outpatient setting".)
OVERVIEW OF KIDNEY FUNCTION
Prior to discussing the evaluation of glomerular filtration rate (GFR), it is helpful to first
briefly review normal kidney physiology. The kidney performs a number of essential
processes:
● It participates in the maintenance of the constant extracellular environment that is

required for adequate functioning of the cells. This is achieved by excretion of some
of the waste products of metabolism (such as urea, creatinine, and uric acid) and by
specifically adjusting the urinary excretion of water and electrolytes to match net
intake and endogenous production ( table 1 and table 2). The kidney is able to
regulate individually the excretion of water and solutes such as sodium, potassium,
and hydrogen, largely by changes in tubular reabsorption or secretion.
● It secretes hormones that participate in the regulation of systemic and renal

hemodynamics (renin, prostaglandins, and bradykinin), red blood cell production
(erythropoietin), and calcium, phosphorus, and bone metabolism (1,25-
dihydroxyvitamin D3 or calcitriol).
In the patient with kidney disease, some or all of these functions may be diminished or
entirely absent. As an example, patients with nephrogenic diabetes insipidus have a
decreased urinary concentrating ability, but other functions are entirely normal. By
comparison, all kidney functions may be significantly impaired in the patient with end-
stage kidney disease, thereby resulting in the retention of uremic toxins, marked
abnormalities in fluid and electrolyte balance, and anemia and bone disease.
GLOMERULAR FILTRATION RATE
Normal GFR — The glomerular filtration rate (GFR) is equal to the sum of the filtration
rates in all of the functioning nephrons. The filtering units of the kidney, the glomeruli,
filter approximately 180 liters per day (125 mL/min) of plasma. The normal value for GFR
depends upon age, sex, and body size, and is approximately 140 to 173 liters per day/1.73
m2 (90 to 120 mL/min/1.73 m2 ), with considerable variation even among healthy
individuals [1-5].
Significance of a declining GFR — In patients with kidney disease, a fall in glomerular

filtration rate (GFR) implies either progression of the underlying disease or the
development of a superimposed and often reversible problem, such as decreased kidney
perfusion due to volume depletion. In addition, the level of GFR has prognostic
implications in patients with chronic kidney disease (CKD), and such patients are staged, in
part, according to GFR. These issues are discussed in detail separately. (See "Diagnostic
approach to adult patients with subacute kidney injury in an outpatient setting" and
"Definition and staging of chronic kidney disease in adults".)
There is not an exact correlation between the loss of kidney mass (ie, nephron loss) and
the loss of GFR. The kidney adapts to the loss of some nephrons by compensatory
hyperfiltration in the remaining, normal nephrons. Thus, an individual who has lost one-
half of total kidney mass will not necessarily have one-half the normal amount of GFR.
These concepts have important consequences:
● A stable GFR does not necessarily imply stable disease. Signs of disease progression
other than a change in GFR must be investigated, including increased activity of the
urine sediment, a rise in protein excretion, or an elevation in blood pressure.
● Similarly, an increase in GFR may indicate improvement in the kidney disease or may
imply a counterproductive increase in filtration (hyperfiltration) due to hemodynamic
factors. (See "Secondary factors and progression of chronic kidney disease".)
● Some patients who have true underlying kidney disease may go unrecognized
because they have a normal GFR.
ASSESSMENT OF GFR
The true glomerular filtration rate (GFR) cannot be measured directly in humans. Rather, it
is determined from clearance measurements or serum levels of filtration markers, which
are exogenous or endogenous solutes that are mainly eliminated by glomerular filtration.
Urinary clearance equals the rate of urinary excretion of the marker divided by its plasma
concentration. Plasma clearance is the amount of marker eliminated from plasma per unit
time factored by its plasma concentration. The gold standard method, which is
recommended in selected circumstances, is urinary or plasma clearance of an exogenous
filtration marker. (See 'Measurement of GFR (selected settings)' below.)
However, in most clinical settings, blood levels of endogenous filtration markers are used
to estimate GFR (eGFR). Creatinine, which is widely available and frequently measured, is
the most commonly used endogenous marker ( algorithm 1). (See 'eGFR from creatinine
(primary approach)' below.)
Cystatin C is another endogenous filtration marker. It is less commonly available

compared with creatinine and is recommended as a confirmatory test. (See 'eGFR from
cystatin C' below.)
Blood concentrations of endogenous filtration markers, like creatinine and cystatin C, are
determined by GFR and other non-GFR physiologic determinants that cannot be easily
measured, including generation rate of the marker, tubular secretion and reabsorption of
the marker, or extrarenal elimination. GFR estimating equations incorporate known
demographic and clinical variables as observed surrogates for these unmeasured non-
GFR determinants. Estimation equations also appear to be reasonably accurate for
following changes in GFR over long periods of time [2,6]. These equations do not provide
accurate estimates of GFR in settings where the serum creatinine or cystatin C
concentrations are changing rapidly (eg, acute kidney injury).
There are limitations to GFR estimating equations. Surrogates are only able to capture
average relationships between the marker and its non-GFR determinants. Understanding
the limitations is helpful for optimal assessment of GFR across the range of individuals
and clinical scenarios [7].
We advise that, in some situations, eGFR calculated based upon the creatinine
concentration be confirmed by performing other tests ( algorithm 1) [8]. For
confirmation, we usually obtain an eGFR based on plasma concentrations of both
creatinine and cystatin C. If there is concern about the accuracy of cystatin C based
estimates, we measure the GFR using either an exogenous filtration marker or measure
the creatinine clearance with a timed urine collection. (See 'Confirmation of eGFR (when
needed)' below.)
Estimation of GFR
eGFR from creatinine (primary approach) — For estimating GFR (eGFR) in most clinical
situations, we and others recommend using the 2021 chronic kidney disease
epidemiology (CKD-EPI) creatinine equation (calculator 1) rather than other creatinine-
based estimating equations, such as the 2009 CKD-EPI equation, the Modification of Diet
in Renal Disease (MDRD) study equation, or the Cockcroft-Gault equation ( algorithm 1).
Importantly, the 2021 CKD-EPI equation does not include a term for race.
Our recommendations are consistent with those made by the American Society of
Nephrology (ASN) and National Kidney Foundation (NKF) [9]. Estimation of GFR in children
is presented separately. (See "Chronic kidney disease in children: Definition, epidemiology,
etiology, and course", section on 'Glomerular filtration rate'.)
Creatinine is derived from the metabolism of creatine in skeletal muscle and from dietary
intake of cooked meat. It is released into the circulation at a relatively constant rate. Mean
serum creatinine values differ between males and females (due to differences in muscle
mass and, therefore, creatinine generation) as well as other factors [10-12]. Such factors
are non-GFR determinants of the serum creatinine.
Estimated GFR calculated with any creatinine-based equation will therefore be less
accurate in people with more prominent non-GFR determinants of the serum creatinine
(eg, high or low muscle mass or creatine/creatinine intake, children, patients with
cirrhosis, serious chronic illness such as chronic heart failure, amputations or
neuromuscular disease, or those with a high-protein or vegetarian diet) [7]. (See
'Limitations of creatinine-based eGFR' below.)
The 2009 CKD-EPI equation was developed to provide an accurate estimate of GFR
among individuals with normal or only mildly reduced GFR (ie, above 60 mL/min per 1.73
m2) [13]. This equation was developed using data pooled from 10 studies and validated
against data derived from 16 additional studies, in which the gold standard was direct
measurement of GFR using external filtration markers (eg, iothalamate). The study
population included people with and without kidney disease who had a wide range of
GFRs. In the validation dataset, the 2009 CKD-EPI equation was as accurate as the MDRD
study equation among individuals with eGFR less than 60 mL/min per 1.73 m2 and
somewhat more accurate in those with higher GFRs ( figure 1).
These older equations include a term for race that, for any given creatinine value, results
in a higher eGFR for Black individuals as compared with other individuals [14]. The
rationale for using a race term in eGFR equations was based upon the empirical
observation that the association between creatinine and GFR differs in self-reported Black
people compared with others. This difference was thought to reflect biologic variations in
non-GFR determinants such as muscle mass or creatinine handling. Inclusion of the race
term led to unbiased estimates in both race groups.
The ongoing use of a race term in these equations is thought to no longer be appropriate
[15-19]. First, race is a social construct, and including the coefficient for race ignores the
substantial diversity within self-identified Black or African American patients. Second,
there are observations that the race term does not improve accuracy of eGFR based upon
creatinine when applied in all populations, such as African populations [20,21].
As a result of these concerns, the CKD-EPI group developed the 2021 CKD-EPI equation for
estimating GFR from serum creatinine without a term for race (calculator 1). The equation
was developed in the same dataset used for development of the 2009 CKD-EPI creatinine
equation and was validated in a new dataset composed of 4050 participants in 12 studies
[22]. Compared with the 2009 CKD-EPI creatinine equation, the 2021 equation is slightly
less accurate [22,23], but it is acceptable for clinical use in many circumstances.
In the overall dataset, the 2021 equation underestimated measured GFR (mGFR) in Black
individuals by 3.6 mL/min per 1.73 m2 but overestimated mGFR in other individuals by
approximately the same amount (3.9 mL/min per 1.73 m2) ( figure 2) [22]. Although
differences between mGFR and eGFR for this population were negligible, individual-level
differences between the mGFR and the eGFR can be clinically relevant. In addition,
differences between eGFR and mGFR can be large enough to affect chronic kidney disease
(CKD) staging.
As an example, in an analysis of 3223 participants from four prospective cohorts in the

United States, although the median difference between mGFR and eGFR was only 0.6
mL/min per 1.73 m2, individual-level differences were often large ( figure 3) [24]. At an
eGFR of 60 mL/min per 1.73 m2, 50 percent of mGFRs ranged from 52 to 67, 80 percent
from 45 to 76, and 95 percent from 36 to 87 mL/min per 1.73 m2. At an eGFR of 30 mL/min
per 1.73 m2, 50 percent of mGFRs ranged from 27 to 38, 80 percent from 23 to 44, and 95
percent from 17 to 54 mL/min per 1.73 m2. Among patients with eGFR of 45 to 59 mL/min
per 1.73 m2, 36 percent had mGFR greater than 60 whereas 20 percent had mGFR less
than 45 mL/min per 1.73 m2; among those with eGFR of 15 to 29 mL/min per 1.73 m2, 30
percent had mGFR greater than 30 and 5 percent had mGFR less than 15 mL/min per 1.73
m2. The eGFR based on cystatin C did not provide substantial improvement.
The ASN and NKF task force recommended the immediate adoption of the 2021 CKD-EPI
creatinine equation which estimates kidney function without a race variable. The task
force also recommended increased use of cystatin C combined with serum creatinine to
confirm GFR [9]. (See 'Confirmation of eGFR (when needed)' below.)
One consequence of the 2021 CKD-EPI creatinine equation, when applied to the
population, is a higher estimated prevalence of chronic kidney disease (CKD) among Black
individuals (by 2 percent) and a lower estimated prevalence of CKD among other
individuals (by 1.5 percent) ( figure 2). The magnitude of the change is lower at lower
levels of GFR. As an example, the estimated prevalence of stage 4 CKD (eGFR 15 to 29
mL/min/1.73 m2) only increased by 0.1 percent in Black individuals and decreased by only
0.38 percent in other individuals.
Another consequence is a minimization of the racial differences in risk of end-stage kidney

disease (ESKD, also called kidney failure) at specific levels of creatinine-based eGFR. When
eGFR was calculated using equations that included a race term, Black individuals had a
substantially higher risk of ESKD at any given baseline eGFR [25]. Conversely, when the
2021 CKD-EPI creatinine equation was used to estimate eGFR among individuals with CKD
(ie, eGFR <60 mL/min/1.73 m2), there was no significant difference in ESKD risk by race (
figure 4) [26]. However, when the 2021 CKD-EPI using both creatinine and cystatin C
was used, which is known to be more accurate than the creatinine-based equation, the
racial differences persisted.
Other equations have emerged using standardized serum creatinine assays, such as the
revised Lund-Malmö equation, which was developed in predominantly White populations,
and the European Kidney Function Consortium (EKFC) equation, which, although also
developed in predominantly White populations, uses a race-specific Q value [27-31]. In
one study, the European Kidney Function Consortium creatinine equation was slightly
more accurate than the 2021 CKD-EPI creatinine equation in both White and Black
populations [32]. However, we use equations that do not take race into account.
There are also outstanding questions about calculating creatinine-based eGFR in Eastern
Asian populations [33]. In Japan, for example, a modified CKD-EPI equation is used that
applies a correction factor of 0.813, thereby decreasing the eGFR for a given creatinine
value in this population. Such calibration factors are not generalizable across countries,
which may also reflect population differences in non-GFR determinants or differences in
methods to measure GFR or assay creatinine. Cystatin C-based eGFR appears to be more
accurate than creatinine-based eGFR in some, but not all, Eastern Asian countries and
does not require a calibration factor [33-35]. We do not use these correction factors for
people from the Eastern Asian countries who are currently living in the United States. We
would more readily consider confirmatory tests if the clinical situation requires a more
accurate value.
Limitations of creatinine-based eGFR — There are several key limitations of using

creatinine to estimate GFR (eGFR). These include variations in creatinine production,
variations in creatinine secretion, extrarenal creatinine excretion, and issues associated
with creatinine measurement.
A rise in serum creatinine from a previously stable baseline almost always represents a
reduction in GFR ( figure 5). However, certain drugs can interfere with either creatinine
secretion or the assay used to measure the serum creatinine, and dietary changes or
dietary supplements can alter creatinine production. In these settings, there will be a
change in eGFR, but no change in measured GFR, no change in cystatin C-based eGFR
(eGFRcys), and no concurrent elevation in the (blood urea nitrogen) BUN. (See "Drugs that
elevate the serum creatinine concentration".)
● Variation in creatinine production – The production of creatinine differs among

and within people over time. As examples, individuals with significant variations in
dietary intake (vegetarian diet, creatine supplements) or reduction in muscle mass
(amputation, malnutrition, muscle wasting) produce different amounts of creatinine

than the general population. There is a great deal of variation in the effect of all of
these among individuals. The accuracy of estimation equations appears to be
affected to a greater extent among lower extremity amputees, given the much
greater reduction in muscle mass, compared with upper extremity amputations.
There are certain settings in which there may be an acute increase in creatinine load.
One example is a recent meal of cooked meat. In addition, it has been suggested
that the serum creatinine rises more rapidly with rhabdomyolysis (up to 2.5 mg/dL or
220 micromol/L per day) than with other causes of acute kidney injury [36]. Release
of preformed creatinine from injured muscle and/or release of creatine phosphate
that is then converted into creatinine in the extracellular fluid have been proposed as
explanations for this finding. However, neither of these mechanisms appears to
account for most of the increase in the serum creatinine concentration [37]. An
alternative explanation is that rhabdomyolysis often affects healthier individuals with
higher muscle mass, while other forms of acute kidney injury frequently affect
patients who are chronically ill and have lower muscle mass.
● Variation in creatinine secretion – The accuracy of GFR estimation with both the
creatinine clearance and creatinine-based estimation equations is limited by the fact
that as the GFR falls, the rise in the serum creatinine is partially opposed by
enhanced proximal tubular creatinine secretion [38-42]. In early kidney disease when
the GFR is still near normal, an initial decline in GFR may lead to only a slight increase
(0.1 to 0.2 mg/dL [9 to 18 micromol/L]) in the serum creatinine. The net effect is that
patients with a true GFR as low as 60 to 80 mL/min (as measured by the clearance of
a true filtration marker such as inulin or radioisotopic iothalamate or
diethylenetriaminepentaacetic acid [DTPA] [38,43,44]) may still have a serum
creatinine that is ≤1 mg/dL (88 micromol/L) [45]. Thus, a relatively stable serum
creatinine in the normal or near-normal range does not necessarily imply that the
disease is stable.
However, once the serum creatinine exceeds 1.5 to 2 mg/dL (132 to 176 micromol/L),
the secretory process is effectively saturated. After this, a stable value usually
represents a stable GFR [45].
Apart from the increase in creatinine secretion with a decline in true GFR, creatinine
secretion can vary over time and can also be affected by certain disorders and
medications [38,46,47]:
• Tubular creatinine secretion is significantly increased in patients with the

nephrotic syndrome. In one study, in which GFR was determined by inulin
clearance, decreased serum albumin levels were associated with a marked
increase in tubular creatinine secretion (36 mL/min per 1.73 m2 for nephrotic
patients with serum albumin levels less than 2.6 g/dL versus 11 mL/min per 1.73
m2 for normal controls) [46]. Patients with sickle cell disease may also have an
increase in creatinine secretion. Thus, patients with nephrotic syndrome and
sickle cell disease may have a GFR that is substantially lower than what can be
estimated from the serum creatinine.
• The presence of certain drugs may increase the level of the serum creatinine by
as much as 0.4 to 0.5 mg/dL (35 to 44 micromol/L) by decreasing creatinine
secretion. These drugs are discussed separately. (See "Drugs that elevate the
serum creatinine concentration".)
● Extrarenal creatinine excretion – Extrarenal creatinine elimination is increased in

advanced kidney failure (eg, eGFR <15 mL/min per 1.73 m2). In this setting, there are
intestinal bacterial overgrowth and increased bacterial creatininase activity [48]. As a
result, the serum creatinine concentration is lower than would be expected from the
GFR.
● Requirement for stable serum creatinine – Endogenous filtration markers (eg,

creatinine, cystatin C) can only be used to estimate GFR in individuals with stable
serum creatinine [49]. Early in the course of acute kidney injury, for example, the GFR
is markedly reduced, but there has not yet been time for the filtration marker to
accumulate and, therefore, for the filtration marker to reflect the degree of kidney
disease severity. An equation has been developed that estimates the true GFR given
the rate of change in creatinine [50].
● Measurement issues – Serum creatinine is most often measured by the alkaline

picrate method. Certain substances may interfere with the assay, thereby
artifactually increasing the serum creatinine concentration. This colorimetric assay
can recognize other compounds as creatinine chromogens, particularly acetoacetate
in diabetic ketoacidosis, or bilirubin [51-55]. In the setting of diabetic ketoacidosis,
https://www.uptodate.com/contents/assessment-of-kidney-functio…result&selectedTitle=1%7E150&usage_type=default&display_rank=1 Página 10 de 44
the serum creatinine can rise by 0.5 to >2 mg/dL (44 to 176 micromol/L), a change
that is rapidly reversed with insulin therapy [54,56]. Cefoxitin and flucytosine are
drugs that can produce a similar effect. (See "Drugs that elevate the serum
creatinine concentration".)
Differences in method and equipment used to determine the creatinine values can
lead to variation in reported serum creatinine values [52,57]. This variation has been
substantially reduced by the national program established by the National Kidney
Disease Education Program to standardize creatinine assays so that they are all
traceable to reference materials. Most manufacturers now use such calibrators, and
therefore most clinical laboratories in the United States have assays traceable to
these reference materials [58].
The variation in serum creatinine measurement methods leads to variation in

creatinine-based GFR estimation [59]. This difference can result in substantial
variations in GFR estimation when the serum creatinine concentration is relatively
normal.
eGFR from cystatin C — Cystatin C is increasingly being used in in clinical practice. If

cystatin C is used to estimate GFR (eGFR), we recommend the 2021 CKD-EPI creatinine-
cystatin C equation (which employs both markers) or the 2012 CKD-EPI cystatin C
equation. Of these, the equation that uses both creatinine and cystatin C is more accurate.
Equations that estimate GFR based upon cystatin C can be found [60-68].
Cystatin C is a low-molecular-weight protein that is a member of the cystatin superfamily

of cysteine protease inhibitors. Cystatin C is filtered at the glomerulus and not
reabsorbed. However, it is metabolized in the tubules, which prevents use of cystatin C to
directly measure clearance.
There are several non-GFR determinants of serum cystatin C; higher cystatin C levels are,
for example, associated with male sex, greater height and weight, higher lean body mass,
higher fat mass, diabetes, higher levels of inflammatory markers (eg, C-reactive protein),
hyper- and hypothyroidism, and glucocorticoid use [34,49,69-76]. In addition, cystatin C
levels increase with age [69] and vary by race ( figure 6) [77] although, for both, the
effect is less than observed for creatinine. Thus, like creatinine, non-GFR determinants of
cystatin C also need to be considered in interpreting estimates of GFR that include cystatin
C. The most accurate GFR estimates come from equations that contain both markers.
The 2012 CKD-EPI cystatin C and creatinine-cystatin C equation was developed using data
pooled from 10 studies and validated against data derived from 16 additional studies in
which the gold standard was direct measurement of GFR using external filtration markers
(eg, iothalamate). The study population included people with and without kidney disease
who had a wide range of GFRs. In the validation dataset, the 2012 CKD-EPI creatinine-
cystatin C equation was more accurate than either the CKD-EPI creatinine or cystatin C
equation.
Like the 2021 CKD-EPI creatinine equation, the 2021 CKD-EPI creatinine-cystatin C
equation was developed without a term for race. The equation was generated using the
same dataset used for development of the 2012 CKD-EPI creatinine-cystatin C equation
and was validated in a new dataset composed of 4050 participants in 12 studies [16]. As
noted above, the 2021 CKD-EPI creatinine equation is modestly less accurate than the
2012 CKD-EPI creatinine equation (underestimating GFR in Black individuals and
overestimating eGFR in other individuals) ( figure 7). However, such differences among
race groups are attenuated with the 2021 CKD-EPI creatinine-cystatin C equation.
Confirmation of eGFR (when needed) — As noted above, confirmation of creatinine-

based estimated GFR (eGFR) is appropriate in the following settings ( algorithm 1):
● Individuals with prominent non-GFR determinants of serum creatinine:
• High muscle mass

• Creatine supplements
• Low muscle mass (eg, children, chronic heart failure, amputations,
neuromuscular disease)
• High animal protein diet
• Vegetarian diet
• Liver disease
• Extreme frailty
● For confirmation of the diagnosis of CKD when the creatinine-based eGFR is 45 to 60

mL/min per 1.73 m2 and there are no other features of CKD (such as albuminuria or
radiologic abnormalities).
● Kidney donor evaluation – In the United States, performance of a clearance

measurement (24-hour urine for creatinine clearance or urinary or plasma clearance
of exogenous filtration markers) is required for GFR evaluation. Given errors in these
measurements, it is helpful to interpret clearance measurements in light of the eGFR
results [78,79]. An online tool for performing this evaluation is available. Very high
posttest probabilities for creatinine-based eGFR (eGFRcr) or creatinine- and cystatin
C-based eGFR (eGFRcrcys) provide reassurance that measured GFR is above the
threshold, while very low posttest probabilities provide reassurance that measured
GFR is below the threshold. (See 'Measurement of GFR (selected settings)' below and
"Calculation of the creatinine clearance".)
With the exception of evaluating a potential kidney donor that requires clearance
measurement in the United States, we first use the 2021 CKD-EPI creatinine-cystatin C
equation to confirm eGFR in these settings.
If the eGFRcr and eGFRcrcys are in close agreement, one can be more certain of the level
of eGFR, and, in most cases, there is no need to progress to clearance methods. However,
if the two estimates differ, or if there are concerns that both creatinine and cystatin C may
be unreliable markers of GFR, then we proceed to alternative methods.
These include measurement of GFR (using plasma or urinary clearance of an exogenous

marker) or calculation of the creatinine clearance from a 24-hour urine collection, as is
done to evaluate potential kidney donors. However, these methods are more cumbersome
and can be reserved for when there remain additional questions about the accuracy of
GFR estimation based upon serum markers. (See "Calculation of the creatinine clearance".)
As with the 2021 CKD-EPI creatinine equation, there can be important individual-level
differences between eGFR (using the 2021 CKD-EPI creatinine-cystatin C equation) and
measured GFR [22,24].
Methods of estimation we do not use — As noted above, we use the 2021 CKD-EPI
creatinine equation to estimate GFR. If confirmation is needed, we use the 2021 CKD-
EPI creatinine-cystatin C equation, calculate the creatinine clearance on a 24-hour urine
collection, or measure GFR using an exogenous filtration marker. (See 'Confirmation of
eGFR (when needed)' above.)
We do not recommend the use of the following methods to estimate GFR:
● The Modification of Diet in Renal Disease (MDRD) equation – The first modern-era
GFR estimating equation was derived from data on adult patients with
predominantly nondiabetic CKD who were enrolled in the MDRD study and who had
GFR measured at baseline using urinary clearance of iothalamate (calculator 2) [80].
● The Cockcroft-Gault equation – The Cockcroft-Gault equation estimates creatinine

clearance from the serum creatinine in a patient with a stable serum creatinine [81].
This formula takes into account assumptions that creatinine production decreases
with advancing age and is greater in individuals with greater weight. However, this
equation was developed at a point in history when obesity was far less common. In
the current era, higher weight may mean greater fat mass and not greater muscle
mass. For females, the formula requires multiplication by 0.85 to account for smaller
muscle mass compared with males (calculator 3), but this is based on a hypothetic
assumption [82,83].
The equation is not adjusted for body surface area. Thus, to compare with normal
values, the result should be adjusted for body surface area. Normalization for body
surface increases the accuracy of this equation, particularly among those with
decreased kidney function [84].
The Cockcroft-Gault equation was developed prior to the use of standardized

creatinine assays and has not been revised for use with creatinine values traceable
to standardized reference materials. Thus, using the Cockcroft-Gault equation with
creatinine values measured by most laboratories in the United States today will
result in a 10 to 40 percent overestimate of creatinine clearance.
● Serum creatinine – Creatinine is freely filtered across the glomerulus and is neither
reabsorbed nor metabolized by the kidney. However, approximately 10 to 40 percent
of urinary creatinine is derived from tubular secretion by the organic cation secretory
pathways in the proximal tubule. Thus, if GFR, creatinine secretion by the renal
tubules, creatine intake (ie, diet), and the creatinine pool size (ie, muscle mass) all
remain constant, then the serum creatinine concentration should remain constant.
The serum creatinine concentration varies inversely with the GFR. If, for example, the
GFR falls by 50 percent, creatinine excretion will initially be reduced. Assuming that
tubular creatinine secretion, diet, and muscle mass do not change, this reduction in
GFR will lead to creatinine retention and a rise in the serum creatinine until it has
doubled ( figure 5); at this point, the filtered load will again be equal to excretion.
The shape of the curve relating the GFR to serum creatinine has an important clinical
implication ( figure 5): in patients with normal or slightly reduced GFR, a small rise
in serum creatinine usually reflects a marked fall in GFR, whereas a marked rise in
serum creatinine in patients with advanced disease reflects a small absolute
reduction in GFR.
However, this curve depicts a hypothetical relationship; in reality, a reduction in GFR

results in increased tubular creatinine secretion that blunts the rise in serum
creatinine. Thus, a 50 percent reduction in GFR does not produce a doubling of
serum creatinine but rather a smaller rise than would have occurred if the decrease
in GFR had occurred without an increase in secretion.
● Blood urea nitrogen (BUN) – Although the BUN, like serum creatinine, also varies
inversely with the GFR, it is generally less useful than the serum creatinine because
the BUN can change independently of the GFR [38,85]. The rate of urea production is
not constant, increasing with a high-protein diet and with enhanced tissue
breakdown due to hemorrhage, trauma, or glucocorticoid therapy; conversely, a low-
protein diet or liver disease can lower the BUN without change in GFR [86,87].
Approximately 40 to 50 percent of the filtered urea is passively reabsorbed, mostly in

the proximal tubule. Thus, when volume depletion is associated with enhanced
proximal sodium and water reabsorption, there is a parallel increase in urea
reabsorption. As a result, the BUN will rise out of proportion to any change in GFR
and therefore to any change in the serum creatinine. This elevation in the BUN-to-
creatinine ratio is one of the suggestive clinical signs of decreased kidney perfusion
(prerenal disease) as the cause for kidney failure. (See "Etiology and diagnosis of
prerenal disease and acute tubular necrosis in acute kidney injury in adults".)
The measurement of the clearance of urea is useful in one setting. Among patients
with severe kidney disease, the urea clearance significantly underestimates the GFR.
Since the creatinine clearance significantly overestimates this function, one method
to estimate the GFR in patients with advanced kidney disease is to average both the
creatinine and urea clearances [88,89]. (See "Calculation of the creatinine clearance".)
Measurement of GFR (selected settings) — Measurement of glomerular filtration rate

(GFR) is complex, time consuming, and cumbersome to do in clinical practice. As such, GFR
is usually estimated from serum markers. (See 'Measurement of GFR with plasma
clearance' below.)
However, in some clinical situations, it is important to have more precise knowledge of the
GFR than can be provided by estimates. (See 'Confirmation of eGFR (when needed)'
above.)
Measurement of GFR with urinary clearance — Although glomerular filtration rate

(GFR) cannot be measured directly, the best method for determining GFR is measurement
of the urinary clearance of an ideal filtration marker. Using a filtration marker (x), the
equation to calculate the clearance of x (Cx) is:
Equation 1: Cx = (Ux x V) ÷ Px
Where Px is the serum concentration of the marker, Ux is the urinary concentration of x,

and V is the urine flow rate.
An ideal filtration marker is defined as a solute that is freely filtered at the glomerulus,
nontoxic, neither secreted nor reabsorbed by the renal tubules, and not changed during
its excretion by the kidney. If these criteria are met, the filtered load is equal to the rate of
urinary excretion:
Equation 2: GFR x Px = (Ux x V)
Where GFR x Px is the filtered load, and Ux x V is the urinary excretion rate. By substitution
into Equation 1:
Equation 3: GFR = Cx
Various filtration markers are available:
● Inulin – The gold standard of exogenous filtration markers is inulin. Inulin is a

physiologically inert fructose polymer that is freely filtered at the glomerulus and is
neither secreted, reabsorbed, synthesized, nor metabolized by the kidney [90]. Thus,
the amount of inulin filtered at the glomerulus is equal to the amount excreted in the
urine, which can be measured. Inulin, however, is in short supply (and is no longer
available in the United States), expensive, and difficult to assay. In addition, the
classic protocol for measuring inulin clearance requires a continuous intravenous
infusion to achieve a steady state plasma concentration, multiple blood samples, and
bladder catheterization for accurate collection of a timed urine specimen.
● Alternative exogenous filtration markers – Because measurement of inulin

clearance is impractical, radioactive or nonradioactive iothalamate, iohexol, DTPA,
and ethylenediaminetetraacetic acid (EDTA) have been used to measure GFR [38,90-
92]. The marker is administered by intravenous bolus or bolus subcutaneous
injection. Subcutaneous injection allows for a slower release of the marker into the
circulation and more constant plasma levels. Multiple (two to four) 20- to 30-minute
urine collections are then obtained, and clearance is computed for each urine
collection period to obtain an average value. Administration of water before and
during the protocol is necessary to stimulate urine flow. Sources of error include
differences in properties of the exogenous filtration marker used to replace inulin,
errors in determining the concentration of the marker [6,93], or random errors due
to the complex procedure. A meta-analysis of studies comparing one marker to
another or to inulin concluded that renal clearances of 51Cr-EDTA or iothalamate and
plasma clearances of 51Cr-EDTA or iohexol are the most accurate methods [94].
Measurement of GFR with plasma clearance — Plasma clearance is an alternative to

urinary clearance for measurement of glomerular filtration rate (GFR). It is performed by
timed plasma measurements after administering a bolus intravenous injection of an
exogenous filtration marker; the clearance equation is:
Equation 4: Cx = Ax ÷ Px
Where Ax is the amount of the marker administered, and Px is the plasma concentration
computed from the entire area under the disappearance curve.
As noted above, plasma clearances of 51Cr-EDTA or iohexol are the most accurate methods
[94]. Measurement of GFR using plasma clearance takes longer than measurement using
urinary clearance (ie, 5 to 10 hours may be required to establish the disappearance curve,
depending on the severity of kidney function impairment). In addition, GFR may be
overestimated when measured by plasma clearance if a shorter protocol is used and
among patients with edema (because of a larger volume of distribution of the filtration
marker).
GLOMERULAR FILTRATION RATE FOR DRUG DOSING
Drug dosing guidelines have historically been developed using the Cockcroft-Gault
equation to estimate kidney function. This practice had been consistent with the original
recommendation of the US Food and Drug Administration (FDA) to pharmaceutical
industries to use an estimating equation, rather than serum creatinine alone, in
pharmacokinetic studies to determine drug dosing in kidney disease. Most
pharmacokinetic studies for drug dosing in kidney disease were performed using the
Cockcroft-Gault equation since this equation was suggested by the FDA prior to
publication of the Modification of Diet in Renal Disease (MDRD) study equation [95].
Standardization of creatinine assays created a problem with drug dosing because many
pharmacokinetic studies were performed using nonstandardized serum creatinine values,
and therefore the results of these studies cannot necessarily be translated reliably into
current clinical practice [96]. Use of the Cockroft-Gault equation could lead to inaccuracies
in drug dosing in patients with kidney disease. After creatinine values were standardized,
pharmacokinetic studies have been done using a variety of methods.
The Kidney Disease Improving Global Outcomes 2011 clinical update on drug dosing in
patients with acute and chronic kidney diseases recommended using the most accurate
method for glomerular filtration rate (GFR) evaluation for each patient (rather than
limiting the evaluation to the Cockcroft-Gault formula) and specifically including estimated
GFR (eGFR) as it is reported by clinical laboratories or measured GFR if creatinine-based
estimates are not accurate for individual patients [97].
If eGFR is used for drug dosing in very large or small patients, the reported eGFR (which is
normalized to body surface area) should be multiplied by the estimated body surface area
and then divided by 1.73 to obtain an eGFR in units of mL/min (ie, not normalized to body
surface area).
As noted above, for patients at the extremes of muscle mass, with unusual diets, or with
conditions associated with changes in creatinine secretion, all estimation equations that
use the serum creatinine are limited. In such cases, dosing decisions should be made
based upon GFR estimated with cystatin- or creatinine-cystatin-based equations, with
measured creatinine clearance, or with measured GFR using exogenous filtration markers,
particularly if prescribing drugs with a narrow therapeutic window. (See 'Measurement of
GFR (selected settings)' above.)
SOCIETY GUIDELINE LINKS
Links to society and government-sponsored guidelines from selected countries and

regions around the world are provided separately. (See "Society guideline links: Fluid and
electrolyte disorders in adults" and "Society guideline links: Chronic kidney disease in
adults".)
SUMMARY AND RECOMMENDATIONS
● Glomerular filtration rate (GFR) – The GFR is equal to the sum of the filtration rates
in all of the functioning nephrons. The normal value for GFR depends upon age, sex,
and body size, and is approximately 140 to 173 liters per day/1.73 m2 (100 to 120
mL/min/1.73 m2), with considerable variation even among healthy individuals. A fall
in GFR typically indicates a chronic or acute kidney injury. In addition, the level of GFR
has prognostic implications in patients with chronic kidney disease (CKD). (See
'Glomerular filtration rate' above.)
● Assessment of GFR in clinical practice – In most clinical settings, blood levels of

endogenous filtration markers are used to estimate GFR (eGFR). Creatinine, which is
widely available and frequently measured, is the most commonly used endogenous
marker ( algorithm 1). Cystatin C is another endogenous filtration marker. It is less
commonly available compared with creatinine and is recommended as a
confirmatory test. (See 'Assessment of GFR' above.)
● Estimating GFR (primary approach) – For estimating GFR in most clinical situations,
we and others recommend using the 2021 chronic kidney disease epidemiology
(CKD-EPI) creatinine equation (calculator 1) rather than other creatinine-based
estimating equations ( algorithm 1), such as the 2009 CKD-EPI equation, the
Modification of Diet in Renal Disease (MDRD) study equation, or the Cockcroft-Gault
equation. Importantly, the 2021 CKD-EPI equation does not include a term for race.
Compared with the 2009 CKD-EPI creatinine equation, the 2021 equation is slightly
less accurate; it underestimates measured GFR in Black individuals and
overestimates measured GFR in other individuals; however, the overall accuracy is
reasonable for both groups ( figure 2). There are several key limitations of using
creatinine to estimate GFR. These include variations in creatinine production,
variations in creatinine secretion, extrarenal creatinine excretion, and issues

associated with creatinine measurement. (See 'eGFR from creatinine (primary
approach)' above and 'Limitations of creatinine-based eGFR' above.)
● Confirmation of eGFR (when needed) – Confirmation of creatinine-based eGFR is

appropriate in the following individuals: those with prominent non-GFR
determinants of serum creatinine (eg, high or low muscle mass, a high protein diet,
creatine supplements, vegetarian diet, liver disease, extreme frailty); when
confirmation of a CKD diagnosis is required in someone with a creatinine-based
eGFR is 45 to 60 mL/min per 1.73 m2 and no other features of CKD (such as
albuminuria or radiologic abnormalities); and in potential kidney donors. To confirm
eGFR in most patients, we measure cystatin C and use the 2021 CKD-EPI
creatinine-cystatin C equation. If the creatinine-based eGFR and the creatinine-
cystatin C-based eGFR differ, or if there are concerns that both creatinine and
cystatin C may be unreliable markers of GFR, then we proceed to alternative
methods (measurement of GFR or calculation of creatinine clearance from a 24-hour
urine). (See 'Confirmation of eGFR (when needed)' above.)
● Measurement of GFR in selected settings – Measurement of GFR is complex, time

consuming, and cumbersome to do in clinical practice. However, when necessary,
GFR can be measured using urinary clearance of an ideal filtration marker (eg, inulin,
iothalamate, iohexol) or using plasma clearance (of 51Cr-EDTA or iohexol). (See
'Measurement of GFR (selected settings)' above.)
● GFR assessment for drug dosing – Drug dosing guidelines have historically been
developed using the Cockcroft-Gault equation to estimate kidney function. However,
for various reasons, use of the Cockroft-Gault equation could lead to inaccuracies in
drug dosing in patients with kidney disease. We recommended using eGFR (or
measured GFR if there are concerns about eGFR accuracy). If eGFR is used for drug
dosing in very large or small patients, the reported eGFR (which is normalized to
body surface area) should be multiplied by the estimated body surface area and then
divided by 1.73 to obtain an eGFR in units of mL/min. (See 'Glomerular filtration rate
for drug dosing' above.)
Use of UpToDate is subject to the Terms of Use.
REFERENCES
1. Denic A, Mathew J, Lerman LO, et al. Single-Nephron Glomerular Filtration Rate in

Healthy Adults. N Engl J Med 2017; 376:2349.
2. Stevens LA, Coresh J, Greene T, Levey AS. Assessing kidney function--measured and
estimated glomerular filtration rate. N Engl J Med 2006; 354:2473.
3. Jafar TH, Islam M, Jessani S, et al. Level and determinants of kidney function in a
South Asian population in Pakistan. Am J Kidney Dis 2011; 58:764.
4. Poggio ED, Rule AD, Tanchanco R, et al. Demographic and clinical characteristics
associated with glomerular filtration rates in living kidney donors. Kidney Int 2009;
75:1079.
5. Eriksen BO, Mathisen UD, Melsom T, et al. The role of cystatin C in improving GFR
estimation in the general population. Am J Kidney Dis 2012; 59:32.
6. Levey AS, Coresh J, Tighiouart H, et al. Measured and estimated glomerular filtration
rate: current status and future directions. Nat Rev Nephrol 2020; 16:51.
7. Inker LA, Titan S. Measurement and Estimation of GFR for Use in Clinical Practice:
Core Curriculum 2021. Am J Kidney Dis 2021; 78:736.
8. Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO 2012
Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney
Disease. Kidney Int Suppl 2013; 3:1.
9. Delgado C, Baweja M, Crews DC, et al. A Unifying Approach for GFR Estimation:
Recommendations of the NKF-ASN Task Force on Reassessing the Inclusion of Race in
Diagnosing Kidney Disease. Am J Kidney Dis 2022; 79:268.
10. Jones CA, McQuillan GM, Kusek JW, et al. Serum creatinine levels in the US population:
third National Health and Nutrition Examination Survey. Am J Kidney Dis 1998; 32:992.
11. Walser M. Creatinine excretion as a measure of protein nutrition in adults of varying

age. JPEN J Parenter Enteral Nutr 1987; 11:73S.
12. Heymsfield SB, Arteaga C, McManus C, et al. Measurement of muscle mass in
humans: validity of the 24-hour urinary creatinine method. Am J Clin Nutr 1983;
37:478.
13. Levey AS, Stevens LA, Schmid CH, et al. A new equation to estimate glomerular
filtration rate. Ann Intern Med 2009; 150:604.
14. Lewis J, Agodoa L, Cheek D, et al. Comparison of cross-sectional renal function
measurements in African Americans with hypertensive nephrosclerosis and of

primary formulas to estimate glomerular filtration rate. Am J Kidney Dis 2001; 38:744.
15. Delgado C, Baweja M, Burrows NR, et al. Reassessing the Inclusion of Race in
Diagnosing Kidney Diseases: An Interim Report From the NKF-ASN Task Force. Am J
Kidney Dis 2021; 78:103.
16. Diao JA, Inker LA, Levey AS, et al. In Search of a Better Equation - Performance and
Equity in Estimates of Kidney Function. N Engl J Med 2021; 384:396.
17. Eneanya ND, Yang W, Reese PP. Reconsidering the Consequences of Using Race to
Estimate Kidney Function. JAMA 2019; 322:113.
18. Powe NR. Black Kidney Function Matters: Use or Misuse of Race? JAMA 2020; 324:737.
19. Hsu CY, Yang W, Go AS, et al. Analysis of Estimated and Measured Glomerular
Filtration Rates and the CKD-EPI Equation Race Coefficient in the Chronic Renal
Insufficiency Cohort Study. JAMA Netw Open 2021; 4:e2117080.
20. van Deventer HE, George JA, Paiker JE, et al. Estimating glomerular filtration rate in
black South Africans by use of the modification of diet in renal disease and Cockcroft-
Gault equations. Clin Chem 2008; 54:1197.
21. Fabian J, George JA, Etheredge HR, et al. Methods and reporting of kidney function: a
systematic review of studies from sub-Saharan Africa. Clin Kidney J 2019; 12:778.
22. Inker LA, Eneanya ND, Coresh J, et al. New Creatinine- and Cystatin C-Based Equations
to Estimate GFR without Race. N Engl J Med 2021; 385:1737.
23. Hsu CY, Yang W, Parikh RV, et al. Race, Genetic Ancestry, and Estimating Kidney
Function in CKD. N Engl J Med 2021; 385:1750.
24. Shafi T, Zhu X, Lirette ST, et al. Quantifying Individual-Level Inaccuracy in Glomerular
Filtration Rate Estimation : A Cross-Sectional Study. Ann Intern Med 2022; 175:1073.
25. Choi AI, Rodriguez RA, Bacchetti P, et al. White/black racial differences in risk of end-
stage renal disease and death. Am J Med 2009; 122:672.
26. Gutiérrez OM, Sang Y, Grams ME, et al. Association of Estimated GFR Calculated Using
Race-Free Equations With Kidney Failure and Mortality by Black vs Non-Black Race.
JAMA 2022; 327:2306.
27. Levey AS, Tighiouart H, Simon AL, Inker LA. In Reply to 'How Valid Are GFR Estimation
Results From the CKD-EPI Databases?'. Am J Kidney Dis 2018; 71:447.
28. Levey AS, Tighiouart H, Simon AL, Inker LA. In Reply to 'Newer GFR Estimating
Equations Require Validation in Different Populations'. Am J Kidney Dis 2017; 70:586.
29. Levey AS, Tighiouart H, Simon AL, Inker LA. Comparing Newer GFR Estimating
Equations Using Creatinine and Cystatin C to the CKD-EPI Equations in Adults. Am J
Kidney Dis 2017; 70:587.
30. Pottel H, Björk J, Courbebaisse M, et al. Development and Validation of a Modified Full
Age Spectrum Creatinine-Based Equation to Estimate Glomerular Filtration Rate : A
Cross-sectional Analysis of Pooled Data. Ann Intern Med 2021; 174:183.
31. Levey AS, Tighiouart H, Inker LA. Improving Glomerular Filtration Rate Estimation-
Across the Age and Diversity Spectrum. Ann Intern Med 2021; 174:265.
32. Pottel H, Björk J, Rule AD, et al. Cystatin C-Based Equation to Estimate GFR without the
Inclusion of Race and Sex. N Engl J Med 2023; 388:333.
33. Teo BW, Zhang L, Guh JY, et al. Glomerular Filtration Rates in Asians. Adv Chronic
Kidney Dis 2018; 25:41.
34. Wang Y, Levey AS, Inker LA, et al. Performance and Determinants of Serum Creatinine
and Cystatin C-Based GFR Estimating Equations in South Asians. Kidney Int Rep 2021;
6:962.
35. Jafar TH, Schmid CH, Levey AS. Serum creatinine as marker of kidney function in
South Asians: a study of reduced GFR in adults in Pakistan. J Am Soc Nephrol 2005;
16:1413.
36. Grossman RA, Hamilton RW, Morse BM, et al. Nontraumatic rhabdomyolysis and
acute renal failure. N Engl J Med 1974; 291:807.
37. Oh MS. Does serum creatinine rise faster in rhabdomyolysis? Nephron 1993; 63:255.
38. Levey AS. Measurement of renal function in chronic renal disease. Kidney Int 1990;
38:167.
39. DOOLAN PD, ALPEN EL, THEIL GB. A clinical appraisal of the plasma concentration
and endogenous clearance of creatinine. Am J Med 1962; 32:65.
40. Kim KE, Onesti G, Ramirez O, et al. Creatinine clearance in renal disease. A
reappraisal. Br Med J 1969; 4:11.
41. van Acker BA, Koomen GC, Koopman MG, et al. Creatinine clearance during
cimetidine administration for measurement of glomerular filtration rate. Lancet 1992;
340:1326.
42. Petri M, Bockenstedt L, Colman J, et al. Serial assessment of glomerular filtration rate
in lupus nephropathy. Kidney Int 1988; 34:832.

43. Perrone RD, Steinman TI, Beck GJ, et al. Utility of radioisotopic filtration markers in
chronic renal insufficiency: simultaneous comparison of 125I-iothalamate, 169Yb-
DTPA, 99mTc-DTPA, and inulin. The Modification of Diet in Renal Disease Study. Am J
Kidney Dis 1990; 16:224.
44. Bostom AG, Kronenberg F, Ritz E. Predictive performance of renal function equations
for patients with chronic kidney disease and normal serum creatinine levels. J Am Soc
Nephrol 2002; 13:2140.
45. Shemesh O, Golbetz H, Kriss JP, Myers BD. Limitations of creatinine as a filtration
marker in glomerulopathic patients. Kidney Int 1985; 28:830.
46. Branten AJ, Vervoort G, Wetzels JF. Serum creatinine is a poor marker of GFR in
nephrotic syndrome. Nephrol Dial Transplant 2005; 20:707.
47. Myers BD, Chagnac A, Golbetz H, et al. Extent of glomerular injury in active and
resolving lupus nephritis: a theoretical analysis. Am J Physiol 1991; 260:F717.
48. Dunn SR, Gabuzda GM, Superdock KR, et al. Induction of creatininase activity in
chronic renal failure: timing of creatinine degradation and effect of antibiotics. Am J
Kidney Dis 1997; 29:72.
49. Rule AD, Bergstralh EJ, Slezak JM, et al. Glomerular filtration rate estimated by cystatin
C among different clinical presentations. Kidney Int 2006; 69:399.
50. Chen S. Retooling the creatinine clearance equation to estimate kinetic GFR when the
plasma creatinine is changing acutely. J Am Soc Nephrol 2013; 24:877.
51. Soldin SJ, Henderson L, Hill JG. The effect of bilirubin and ketones on reaction rate
methods for the measurement of creatinine. Clin Biochem 1978; 11:82.
52. Miller WG, Myers GL, Ashwood ER, et al. Creatinine measurement: state of the art in
accuracy and interlaboratory harmonization. Arch Pathol Lab Med 2005; 129:297.
53. Molitch ME, Rodman E, Hirsch CA, Dubinsky E. Spurious serum creatinine elevations
in ketoacidosis. Ann Intern Med 1980; 93:280.
54. Greenberg N, Roberts WL, Bachmann LM, et al. Specificity characteristics of 7

commercial creatinine measurement procedures by enzymatic and Jaffe method
principles. Clin Chem 2012; 58:391.
55. McGill MR, Vijayan A, Trulock EP, et al. Falsely Elevated Plasma Creatinine Due to an
Immunoglobulin M Paraprotein. Am J Kidney Dis 2016; 68:789.
56. Kemperman FA, Weber JA, Gorgels J, et al. The influence of ketoacids on plasma
creatinine assays in diabetic ketoacidosis. J Intern Med 2000; 248:511.
57. Coresh J, Astor BC, McQuillan G, et al. Calibration and random variation of the serum
creatinine assay as critical elements of using equations to estimate glomerular
filtration rate. Am J Kidney Dis 2002; 39:920.
58. Killeen AA, Ashwood ER, Ventura CB, Styer P. Recent trends in performance and
current state of creatinine assays. Arch Pathol Lab Med 2013; 137:496.
59. Karger AB, Eckfeldt JH, Rynders GP, et al. Long-Term Longitudinal Stability of Kidney
Filtration Marker Measurements: Implications for Epidemiological Studies and Clinical
Care. Clin Chem 2021; 67:425.
60. Newman DJ, Thakkar H, Edwards RG, et al. Serum cystatin C measured by automated
immunoassay: a more sensitive marker of changes in GFR than serum creatinine.
Kidney Int 1995; 47:312.
61. Coll E, Botey A, Alvarez L, et al. Serum cystatin C as a new marker for noninvasive
estimation of glomerular filtration rate and as a marker for early renal impairment.
Am J Kidney Dis 2000; 36:29.
62. Fliser D, Ritz E. Serum cystatin C concentration as a marker of renal dysfunction in the
elderly. Am J Kidney Dis 2001; 37:79.
63. Mussap M, Dalla Vestra M, Fioretto P, et al. Cystatin C is a more sensitive marker than
creatinine for the estimation of GFR in type 2 diabetic patients. Kidney Int 2002;
61:1453.
64. Ahlström A, Tallgren M, Peltonen S, Pettilä V. Evolution and predictive power of serum
cystatin C in acute renal failure. Clin Nephrol 2004; 62:344.
65. Hoek FJ, Kemperman FA, Krediet RT. A comparison between cystatin C, plasma
creatinine and the Cockcroft and Gault formula for the estimation of glomerular
filtration rate. Nephrol Dial Transplant 2003; 18:2024.
66. Dharnidharka VR, Kwon C, Stevens G. Serum cystatin C is superior to serum creatinine
as a marker of kidney function: a meta-analysis. Am J Kidney Dis 2002; 40:221.
67. Pöge U, Gerhardt T, Stoffel-Wagner B, et al. Cystatin C-based calculation of

glomerular filtration rate in kidney transplant recipients. Kidney Int 2006; 70:204.
68. Stevens LA, Coresh J, Schmid CH, et al. Estimating GFR using serum cystatin C alone
and in combination with serum creatinine: a pooled analysis of 3,418 individuals with
CKD. Am J Kidney Dis 2008; 51:395.

69. Knight EL, Verhave JC, Spiegelman D, et al. Factors influencing serum cystatin C levels
other than renal function and the impact on renal function measurement. Kidney Int
2004; 65:1416.
70. Groesbeck D, Köttgen A, Parekh R, et al. Age, gender, and race effects on cystatin C
levels in US adolescents. Clin J Am Soc Nephrol 2008; 3:1777.
71. Macdonald J, Marcora S, Jibani M, et al. GFR estimation using cystatin C is not
independent of body composition. Am J Kidney Dis 2006; 48:712.
72. Manetti L, Pardini E, Genovesi M, et al. Thyroid function differently affects serum
cystatin C and creatinine concentrations. J Endocrinol Invest 2005; 28:346.
73. Stevens LA, Schmid CH, Greene T, et al. Factors other than glomerular filtration rate
affect serum cystatin C levels. Kidney Int 2009; 75:652.
74. Liu X, Foster MC, Tighiouart H, et al. Non-GFR Determinants of Low-Molecular-Weight

Serum Protein Filtration Markers in CKD. Am J Kidney Dis 2016; 68:892.
75. Oddoze C, Morange S, Portugal H, et al. Cystatin C is not more sensitive than
creatinine for detecting early renal impairment in patients with diabetes. Am J Kidney
Dis 2001; 38:310.
76. Perkins BA, Nelson RG, Ostrander BE, et al. Detection of renal function decline in
patients with diabetes and normal or elevated GFR by serial measurements of serum
cystatin C concentration: results of a 4-year follow-up study. J Am Soc Nephrol 2005;
16:1404.
77. Köttgen A, Selvin E, Stevens LA, et al. Serum cystatin C in the United States: the Third
National Health and Nutrition Examination Survey (NHANES III). Am J Kidney Dis 2008;
51:385.
78. Huang N, Foster MC, Lentine KL, et al. Estimated GFR for Living Kidney Donor
Evaluation. Am J Transplant 2016; 16:171.
79. Gaillard F, Flamant M, Lemoine S, et al. Estimated or Measured GFR in Living Kidney
Donors Work-up? Am J Transplant 2016.
80. Levey AS, Bosch JP, Lewis JB, et al. A more accurate method to estimate glomerular
filtration rate from serum creatinine: a new prediction equation. Modification of Diet
in Renal Disease Study Group. Ann Intern Med 1999; 130:461.
81. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine.
Nephron 1976; 16:31.

82. Sokoll LJ, Russell RM, Sadowski JA, Morrow FD. Establishment of creatinine clearance
reference values for older women. Clin Chem 1994; 40:2276.
83. Canaday BR, Poe TE, Sawyer WT, Paladino JA. Fractional adjustment of predicted
creatinine clearance in females. Am J Hosp Pharm 1984; 41:1842.
84. Shoker A, Hossain MA, Koru-Sengul T, et al. Performance of creatinine clearance
equations on the original Cockcroft-Gault population. Clin Nephrol 2006; 66:89.
85. Dossetor JB. Creatininemia versus uremia. The relative significance of blood urea
nitrogen and serum creatinine concentrations in azotemia. Ann Intern Med 1966;
65:1287.
86. Papadakis MA, Arieff AI. Unpredictability of clinical evaluation of renal function in
cirrhosis. Prospective study. Am J Med 1987; 82:945.
87. Sherman DS, Fish DN, Teitelbaum I. Assessing renal function in cirrhotic patients:
problems and pitfalls. Am J Kidney Dis 2003; 41:269.
88. Lubowitz H, Slatopolsky E, Shankel S, et al. Glomerular filtration rate. Determination
in patients with chronic renal disease. JAMA 1967; 199:252.
89. Dombros N, Dratwa M, Feriani M, et al. European best practice guidelines for
peritoneal dialysis. 2 The initiation of dialysis. Nephrol Dial Transplant 2005; 20 Suppl
9:ix3.
90. Rahn KH, Heidenreich S, Brückner D. How to assess glomerular function and damage
in humans. J Hypertens 1999; 17:309.
91. Brändström E, Grzegorczyk A, Jacobsson L, et al. GFR measurement with iohexol and
51Cr-EDTA. A comparison of the two favoured GFR markers in Europe. Nephrol Dial
Transplant 1998; 13:1176.
92. Stevens LA, Levey AS. Measured GFR as a confirmatory test for estimated GFR. J Am
Soc Nephrol 2009; 20:2305.
93. Seegmiller JC, Eckfeldt JH, Lieske JC. Challenges in Measuring Glomerular Filtration
Rate: A Clinical Laboratory Perspective. Adv Chronic Kidney Dis 2018; 25:84.
94. Soveri I, Berg UB, Björk J, et al. Measuring GFR: a systematic review. Am J Kidney Dis
2014; 64:411.
95. Food and Drug Administration. Guidance for industry: Pharmacokinetics in patients w
ith impaired renal function — Study design, data analysis, and impact on dosing and l
abeling. US Department of Health and Human Services, Rockville, MD 1998. http://ww

w.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/
ucm072127.pdf (Accessed on September 03, 2014).
96. Stevens LA, Levey AS. Use of the MDRD study equation to estimate kidney function for
drug dosing. Clin Pharmacol Ther 2009; 86:465.
97. Matzke GR, Aronoff GR, Atkinson AJ Jr, et al. Drug dosing consideration in patients
with acute and chronic kidney disease-a clinical update from Kidney Disease:
Improving Global Outcomes (KDIGO). Kidney Int 2011; 80:1122.
Topic 2359 Version 57.0
GRAPHICS
Major functions of nephron segments
Nephron segment Major functions
Glomerulus Forms an ultrafiltrate of plasma
Proximal tubule Reabsorbs isosmotically 60 to 65 percent of the filtered NaCl and H2O
Reabsorbs 90 percent of the filtered HCO3-
Major site of ammonia production in the nephron
Reabsorbs almost all of filtered glucose and amino acids
Reabsorbs K+, phosphate, calcium, magnesium, urea, and uric acid
Secretes organic anions (such as urate) and cations (such as creatine);

this pathway is also used for excretion of protein-bound drugs and
toxins
Loop of Henle Reabsorbs 25 to 35 percent of filtered NaCl
Countercurrent multiplier as NaCl reabsorbed in excess of water
Major site of active regulation of magnesium excretion
Distal tubule Reabsorbs about 5 percent of filtered NaCl but almost no water
Major site, with connecting segment, of active regulation of calcium

excretion
Connecting segment Principal cells reabsorb Na+ and Cl- and secrete K+ under the influence
and cortical collecting of aldosterone
tubule
Intercalated cells secrete H+, reabsorb K+, and, in metabolic alkalosis,
secrete HCO3-
Reabsorb water in the presence of antidiuretic hormone
Medullary collecting Site of final modification of the urine

tubule
Reabsorb NaCl, the concentration of which can be reduced to less than 1
meq/L
Reabsorb water and urea relative to the amount of antidiuretic hormone

present, allowing a concentrated or dilute urine to be excreted
Secrete H+ and NH3; urine pH can be reduced to as low as 4.5 to 5.0
Can contribute to potassium balance by reabsorption or secretion of K+
Contribution of the different nephron segments to solute and water homeostasis.
Graphic 57561 Version 2.0
Solute reabsorption by the kidney
Percent net
Substance Filtered Excreted
reabsorption
Water 180 liters 0.5 to 3 liters 98 to 99
Na+ 26,000 meq 100 to 250 meq >99
Cl– 21,000 meq 100 to 250 99
HC03– 4800 meq 0 ~100
K+ 800 meq 40 to 120 meq 80 to 95
Urea 54 grams 27 to 32 grams 40 to 50
Summary of the net daily reabsorptive work performed by the kidney. These values are for a
normal adult male on a typical Western diet. The glomerular filtration rate and therefore the
filtered load of solutes and water is approximately 25% lower in females.
Assessment of glomerular filtration rate for clinical practice
GFR: glomerular filtration rate; eGFR: estimated glomerular filtration rate; CKD-EPI: Chronic Kidney
Disease Epidemiology Collaboration.
Performance of the CKD-EPI and MDRD Study equations in estimating

measured GFR
Reproduced with permission from: Levey AS, Stevens LA, Schmid CH, et al. A new equation to estimate glomerular filtration
rate. Ann Intern Med 2009; 150:604. Copyright © 2009 American College of Physicians.
Difference between mGFR and eGFR-creatinine comparing the 2009 versus

2021 CKD-EPI creatinine equations
The equations are referred to by year of development. The vertical bars indicate 95% confidence
intervals. The dotted black line represents the difference in the GFR equation performance
between race groups.
(A) Bias as shown as median difference between mGFR and eGFR. Units are mL/min per 1.73 m 2 . A
positive number indicates underestimate of mGFR, and a negative number indicates overestimate
of mGFR. Solid gray line is the line of identity. Dashed gray lines are drawn at the median difference
of 5 and –5 mL/min per 1.73 m 2 , which is defined as small bias.
(B) Accuracy as shown as percentage of eGFR values that differ from the corresponding mGFR by
less than 30% (P30). A P30 of 90% is considered optimal; a P30 between 80 to 90% is considered
acceptable.
(C) Agreement between mGFR and eGFR categories using guideline-recommended CKD GFR (G)
stages (<30, 30 to 44, 45 to 59, 60 to 89, and ≥90 mL/min per 1.73m 2 ). More than 70% agreement
is considered optimal, and between 60 to 70% is considered acceptable [1-3] .
CKD-EPI: Chronic Kidney Disease Epidemiology Collaboration; GFR: glomerular filtration rate;
mGFR: measured glomerular filtration rate; eGFR: estimated glomerular filtration rate; cr:
creatinine.
References:
1. Kidney Disease: Improving Global Outcomes (KDIGO). KDIGO 2012 Clinical Practice Guideline for the Evaluation and
Management of Chronic Kidney Disease. Kidney Int Suppl 2013.
2. Levey AS, Stevens LA, Schmid CH, et al. A new equation to estimate glomerular filtration rate. Ann Intern Med 2009;
150:604.
3. Inker LA, Schmid CH, Tighiouart H, et al. Estimating glomerular filtration rate from serum creatinine and cystatin C.
N Engl J Med 2012; 367:20.
Differences between measured and estimated creatinine-based eGFR at

different eGFR thresholds
The eGFRCR is calculated from the CKD-EPI race-free creatinine equation, and the selected values
(15, 30, 45, 60, and 90 mL/min/1.73 m 2 ) correspond to the guideline-recommended thresholds for
CKD staging. Each vertical bar corresponds to the probability that mGFR exceeds the eGFRCR plus
or minus a certain range on an absolute scale. A difference greater than ±5 mL/min/1.73 m 2
implies that at a given eGFR, the mGFR is outside of a 10 mL/min/1.73 m 2 range of the eGFR value;
±10 corresponds to a range of 20 mL/min/1.73 m 2 and ±15 to a range of 30 mL/min/1.73 m 2 .
eGFRCR: glomerular filtration rate estimated from serum creatinine; mGFR: measured glomerular
filtration rate; CKD: chronic kidney disease; CKD-EPI: Chronic Kidney Disease Epidemiology
Collaboration.
From Annals of Internal Medicine, Shafi T, Zhu X, Lirette ST, et al. Quantifying individual-level inaccuracy in glomerular
filtration rate estimation: A cross-sectional study. Ann Intern Med 2022; 175(8):1073-82. Copyright © 2022 American
College of Physicians. All Rights Reserved. Reprinted with the permission of American College of Physicians, Inc.
Racial differences in the risk of kidney failure according to eGFR calculated

with or without a race term
Vertical dotted lines show the difference in log hazard ratios between Black and non-Black
participants for a given eGFR, which are smaller for 2021 eGFRcr(AS) than for the other equations.
The hazard ratio is adjusted for age and sex and calculated versus the reference point (80
mL/min/1.73 m 2 in the non-Black population).
eGFR: estimated glomerular filtration rate; eGFRcr: creatinine-based eGFR; AS: adjusted for age and
sex; ASR: adjusted for age, sex, and race.
Reproduced with permission from: Gutiérrez OM, Sang Y, Grams ME, et al. Association of estimated GFR calculated using
race-free equations with kidney failure and mortality by Black vs non-Black race. JAMA 2022; 327(23): 2306-2316. Copyright
© 2022 American Medical Association. All rights reserved.
Serum creatinine and GFR
Idealized steady-state relationship between the serum creatinine concentration (SCr) and the GFR.
A fall in GFR decreases creatinine filtration and produces a proportionate rise in the serum
creatinine concentration.
Variations in cystatin C based upon sex, race, and ethnicity
Serum cystatin C percentiles (5th, 50th, and 95th) by age and (A) sex and (B) race/ethnicity graphed
by using an inverse transformation. (-1/cystatin C) is analyzed and the corresponding values for
serum cystatin C are shown on the y-axis. The horizontal line at a serum cystatin C value of 1.12
mg/L indicates the cutoff value for increased serum cystatin C level.
From: Köttgen A, Selvin E, Stevens LA, et al. Serum cystatin C in the United States: the Third National Health and Nutrition
Examination Survey (NHANES III). Am J Kidney Dis 2008; 51:385. Illustrations used with the permission of Elsevier Inc. All
rights reserved.
Difference between mGFR and eGFR-creatinine-cystatin C comparing the

2012 versus 2021 CKD-EPI creatinine-cystatin C equations
The equations are referred to by year of development. The vertical bars indicate 95% confidence
intervals. The dotted black line represents the difference in the GFR equation performance
between race groups.
(A) Bias as shown as median difference between mGFR and eGFR. Units are mL/min per 1.73 m 2 . A
positive number indicates underestimate of mGFR, and a negative number indicates overestimate
of mGFR. Solid gray line is the line of identity. Dashed gray lines are drawn at the median difference
of 5 and –5 mL/min per 1.73 m 2 , which is defined as small bias.
(B) Accuracy as shown as percentage of eGFR values that differ from the corresponding mGFR by
less than 30% (P30). A P30 of 90% is considered optimal; a P30 between 80 to 90% is considered
acceptable.
(C) Agreement between mGFR and eGFR categories using guideline-recommended CKD GFR (G)
stages (<30, 30 to 44, 45 to 59, 60 to 89, and ≥90 mL/min per 1.73m 2 ). More than 70% agreement
is considered optimal, and between 60 to 70% is considered acceptable [1-3] .
CKD-EPI: Chronic Kidney Disease Epidemiology Collaboration; GFR: glomerular filtration rate;
mGFR: measured glomerular filtration rate; eGFR: estimated glomerular filtration rate; cr-cys:
creatinine-cystatin C.
References:
1. Kidney Disease: Improving Global Outcomes (KDIGO). KDIGO 2012 Clinical Practice Guideline for the Evaluation and
Management of Chronic Kidney Disease. Kidney Int Suppl 2013.
2. Levey AS, Stevens LA, Schmid CH, et al. A new equation to estimate glomerular filtration rate. Ann Intern Med 2009;
150:604.
3. Inker LA, Schmid CH, Tighiouart H, et al. Estimating glomerular filtration rate from serum creatinine and cystatin C.
N Engl J Med 2012; 367:20.
Contributor Disclosures
Lesley A Inker, MD, MS Grant/Research/Clinical Trial Support: Chinook Therapeutics [Ig, Alport
syndrome]; Omeros [IgA nephropathy]; Reata [Alport syndrome]. Consultant/Advisory Boards:
DiaMetrix [CKD endpoints]; Goldfinch [CKD endpoints]; Tricida [CKD endpoints]. All of the relevant
financial relationships listed have been mitigated. Ronald D Perrone, MD Grant/Research/Clinical
Trial Support: Kadmon [Polycystic kidney disease]; PalladioBio [Polycystic kidney disease]; Reata
[Polycystic kidney disease]; Regulus [Polycystic kidney disease]; Sanofi [Polycystic kidney disease].
Consultant/Advisory Boards: Janus [Polycystic kidney disease]; Navitor [Polycystic kidney disease];
Otsuka [Polycystic kidney disease]; Palladiobio [Polycystic kidney disease]; Reata [Polycystic kidney
disease]; Sanofi-Genzyme [Polycystic kidney disease]. All of the relevant financial relationships listed
have been mitigated. Richard H Sterns, MD No relevant financial relationship(s) with ineligible
companies to disclose. John P Forman, MD, MSc No relevant financial relationship(s) with ineligible
companies to disclose.
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found,
these are addressed by vetting through a multi-level review process, and through requirements for
references to be provided to support the content. Appropriately referenced content is required of all
authors and must conform to UpToDate standards of evidence.
Conflict of interest policy

Assessment of Kidney Function - UpToDate

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Assessment of Kidney Function - UpToDate

Uploaded by

Copyright:

Available Formats

Assessment of kidney function - UpToDate 07/04/2024 19:05

Official reprint from UpToDate®

Literature review current through: Mar 2024.

The kidney performs many functions, including elimination of nitrogenous wastes;

● (See "Urinalysis in the diagnosis of kidney disease".)

OVERVIEW OF KIDNEY FUNCTION

● It participates in the maintenance of the constant extracellular environment that is

● It secretes hormones that participate in the regulation of systemic and renal

GLOMERULAR FILTRATION RATE

Significance of a declining GFR — In patients with kidney disease, a fall in glomerular

These concepts have important consequences:

because they have a normal GFR.

Cystatin C is another endogenous filtration marker. It is less commonly available

and clinical scenarios [7].

As an example, in an analysis of 3223 participants from four prospective cohorts in the

Another consequence is a minimization of the racial differences in risk of end-stage kidney

Limitations of creatinine-based eGFR — There are several key limitations of using

● Variation in creatinine production – The production of creatinine differs among

(amputation, malnutrition, muscle wasting) produce different amounts of creatinine

• Tubular creatinine secretion is significantly increased in patients with the

● Extrarenal creatinine excretion – Extrarenal creatinine elimination is increased in

● Requirement for stable serum creatinine – Endogenous filtration markers (eg,

● Measurement issues – Serum creatinine is most often measured by the alkaline

The variation in serum creatinine measurement methods leads to variation in

eGFR from cystatin C — Cystatin C is increasingly being used in in clinical practice. If

Cystatin C is a low-molecular-weight protein that is a member of the cystatin superfamily

Confirmation of eGFR (when needed) — As noted above, confirmation of creatinine-

● Individuals with prominent non-GFR determinants of serum creatinine:

• High muscle mass

● For confirmation of the diagnosis of CKD when the creatinine-based eGFR is 45 to 60

● Kidney donor evaluation – In the United States, performance of a clearance

These include measurement of GFR (using plasma or urinary clearance of an exogenous

We do not recommend the use of the following methods to estimate GFR:

● The Cockcroft-Gault equation – The Cockcroft-Gault equation estimates creatinine

The Cockcroft-Gault equation was developed prior to the use of standardized

However, this curve depicts a hypothetical relationship; in reality, a reduction in GFR

Approximately 40 to 50 percent of the filtered urea is passively reabsorbed, mostly in

Measurement of GFR (selected settings) — Measurement of glomerular filtration rate

Measurement of GFR with urinary clearance — Although glomerular filtration rate

Where Px is the serum concentration of the marker, Ux is the urinary concentration of x,

Equation 2: GFR x Px = (Ux x V)

Various filtration markers are available:

● Inulin – The gold standard of exogenous filtration markers is inulin. Inulin is a

● Alternative exogenous filtration markers – Because measurement of inulin

Measurement of GFR with plasma clearance — Plasma clearance is an alternative to

GLOMERULAR FILTRATION RATE FOR DRUG DOSING

SOCIETY GUIDELINE LINKS

Links to society and government-sponsored guidelines from selected countries and

SUMMARY AND RECOMMENDATIONS

● Assessment of GFR in clinical practice – In most clinical settings, blood levels of

variations in creatinine secretion, extrarenal creatinine excretion, and issues

● Confirmation of eGFR (when needed) – Confirmation of creatinine-based eGFR is

● Measurement of GFR in selected settings – Measurement of GFR is complex, time

Use of UpToDate is subject to the Terms of Use.

1. Denic A, Mathew J, Lerman LO, et al. Single-Nephron Glomerular Filtration Rate in

11. Walser M. Creatinine excretion as a measure of protein nutrition in adults of varying

14. Lewis J, Agodoa L, Cheek D, et al. Comparison of cross-sectional renal function

measurements in African Americans with hypertensive nephrosclerosis and of

Equations Require Validation in Different Populations'. Am J Kidney Dis 2017; 70:586.

in lupus nephropathy. Kidney Int 1988; 34:832.

54. Greenberg N, Roberts WL, Bachmann LM, et al. Specificity characteristics of 7

67. Pöge U, Gerhardt T, Stoffel-Wagner B, et al. Cystatin C-based calculation of