Download Evaluation of Kidney Function

Evaluation of Kidney
Function
Thomas C. Dowling
e|CHAPTER
KEY CONCEPTS
1
The stage of chronic kidney disease (CKD) should be
determined for all individuals based on the level of kidney
function, independent of etiology, in accordance with
the Kidney Disease: Improving Global Outcomes (KDIGO)
classification system.
2
Persistent proteinuria indicates the presence of chronic
kidney disease and is associated with mortality and risk of
end-stage renal disease (ESRD).
3
Quantitation of urine protein excretion, such as the
measurement of a spot urine albumin-to-creatinine ratio, is
critical for determining the severity of CKD and monitoring
the rate of disease progression.
4
The glomerular filtration rate (GFR) is the single best
indicator of kidney function.
5
Measurement of the GFR is most accurate when performed
following the exogenous administration of inulin,
iothalamate, or radioisotopes such as technetium-99m
diethylenetriamine pentaacetic acid (99mTc-DTPA).
6
Equations to estimate creatinine clearance or GFR are
commonly used in ambulatory and inpatient settings, and
incorporate patient laboratory and demographic variables
such as serum creatinine concentration (Scr), cystatin C, age,
sex, weight, and ethnicity.
7
Longitudinal assessment of GFR and proteinuria is important
for monitoring the efficacy of therapeutic interventions,
such as angiotensin-converting enzyme inhibitors and
angiotensin receptor blockers, which are used to slow or halt
the progression of kidney disease.
8
Assessments of kidney structure and function, such as
radiography, computed tomography, magnetic resonance
imaging, sonography, and biopsy, are predominantly used
for determining the diagnosis of a given condition.
Chronic kidney disease (CKD) is an increasingly alarming worldwide health concern, with nearly 2 million people in the United
States estimated to require hemodialysis or kidney transplantation by 2030.1 In response to this widespread problem, standardized approaches are now used for the identification of individuals
with CKD and their subsequent stratification into risk categories
for end-stage renal disease (ESRD) (see Chap. 29).1,2 These efforts
have heightened the awareness of the need for early identification of
patients with CKD and the importance of monitoring the progression of kidney disease.
Assessment of kidney function using both qualitative and quantitative methods is an important part of the evaluation of patients
18
and an essential characterization of individuals who participate in
clinical research investigations. Estimation of creatinine clearance
(CLcr) has been considered the clinical standard for assessment of
renal function for more than 40 years, and is the primary index of
kidney function stratification used in drug pharmacokinetic studies.3
New equations to estimate glomerular filtration rate (GFR) are now
used in many clinical settings to identify patients with CKD, and in
large epidemiology studies to evaluate risks of mortality and progression to ESRD.4,5 Other tests, such as urinalysis, radiographic
procedures, and biopsy, are also valuable tools in the assessment
of kidney disease, and these qualitative assessments are useful for
determining the pathology and etiology of kidney disease. Urinalysis, for example, may give clues to the primary location, such as
glomerular or tubular, of the renal disease. Follow-up studies, such
as imaging procedures or kidney biopsy, may then further differentiate the specific cause, thereby guiding the selection of the optimal
therapeutic intervention.
1 Quantitative indices of GFR or CLcr are considered the
most useful diagnostic tools for the identification of the presence
of CKD. These measures can also be used to quantify changes in
function that may occur as a result of disease progression, therapeutic intervention, or a toxic insult.6 The measurement or estimation of CLcr, however, remains the most commonly used index for
individualizing medication dosage regimens in patients with acute
and chronic kidney disease. Furthermore, CLcr has been the predominant index used to stratify patients in pharmacokinetic studies
which serve as the basis for the design of renal dosing algorithms
in FDA-approved package inserts and tertiary drug information
sources.7 The composite term renal function includes the processes
of filtration, secretion, and reabsorption, as well as endocrine and
metabolic functions. Alterations of all five renal functions, whether
declining or improving, are associated primarily with GFR. This
chapter critically evaluates the various methods that can be used for
the quantitative assessment of kidney function in individuals with
normal renal function, as well as in those with chronic kidney disease and acute kidney injury (AKI) (eTable 18-1). Where appropriate, discussion regarding the qualitative assessment of the renal
function is also presented, including the role of imaging procedures
and invasive tests such as kidney biopsy.
EXCRETORy FUNCTION
The kidney is largely responsible for the maintenance of body
homeostasis via its role in regulating urinary excretion of water,
electrolytes, endogenous substances such as urea, medications,
and environmental toxins. It accomplishes this through the combined processes of glomerular filtration, tubular secretion, and
reabsorption.
Copyright © 2014 McGraw-Hill Education. All rights reserved.
271
272
Secretion
eTable 18-1 Markers of Renal Function
SECTION
p-Aminohippurate (PAH)
131
l-Orthoiodohippurate (131l-OIH)
99m
Tc-mercaptoacetyltriglycine (99mTc-MAG3)
Glomerular
filtration rate
Inulin, sinistrin
Iothalamate
Iohexol
99m
Tc-diethylenetriaminepentaacetic acid (99mTc-DTPA)
125
I- Iothalamate
Creatinine
Cystatin C
Tubular
function
p-Aminohippurate (PAH)
N1-Methylnicotinamide (NMN)
Tetraethylammonium (TEA)
β2-Microglobulin
Retinol-binding protein (RBP)
Protein HC (α1-microglobulin)
N-Acetylglucosaminidase (NAG)
Alanine aminopeptidase (AAP)
Adenosine binding protein (ABP)
Renal plasma/
blood flow
2
Organ-Specific Function Tests and Drug-Induced Diseases
Glomerular Filtration
Glomerular filtration is a passive process by which water and smallmolecular-weight (<5 to 10 kDa) ions and molecules diffuse across
the glomerular–capillary membrane into the Bowman capsule and
then enter the proximal tubule (eFig. 18-1). Most proteins are too
large (>60 kDa) to be substantially filtered, and their filtration is
impeded by the electronegative charge on the epithelial surface of
the glomerulus. Thus, compounds presented to the glomerulus in the
protein-bound state are usually not significantly filtered and remain
in the peritubular circulation.
A
Secretion is an active process that predominantly takes place in
the proximal tubule and facilitates the elimination of compounds
from the renal circulation into the tubular lumen. Several highly
efficient anionic and cationic transport systems for a wide range of
endogenous and exogenous substances have been identified and the
renal clearance of these actively secreted entities can greatly exceed
GFR and in some cases approximate renal blood flow. Probenecid,
p-aminohippurate (PAH), and cidofovir are examples of anionic
substances, whereas creatinine, cimetidine, and procainamide are
well-characterized cations.8 The anionic and cationic transport systems are not mutually exclusive, as probenecid has been observed
to compete with the tubular secretion of cimetidine.9 Other transport
pathways, such as P-glycoprotein and multidrug resistance protein,
are also present in several tissues, including the kidney, liver, jejunum, colon, and brain. These efflux proteins are now recognized as
important contributors to the renal elimination of many drugs.10 For
example, P-glycoprotein, which is located on the apical membrane
of the proximal tubule, plays an important role in the renal elimination of a wide range of drugs, such as cimetidine, digoxin, and
procainamide. Blockade of P-glycoprotein could result in decreased
renal elimination of such compounds, leading to an increased drug
exposure. Verapamil and cyclosporine are the two most widely studied agents that reduce the activity of this tubular transport mechanism.11 The net process of tubular secretion for drugs is therefore
likely a result of multiple secretory pathways acting simultaneously.
Reabsorption
Reabsorption of water and solutes occurs throughout the nephron,
whereas the reabsorption of most medications occurs predominantly
Kidney
Renal
pelvis
C
Distal
convoluted
tubule
Ureter
Proximal
convoluted
tubule
Bladder
Macula
densa
Bowman’s
capsule
Urethra
Cortical
collecting
duct
Glomerulus
B
Cortex
Straight
proximal
tubule
Papilla
Calyx
Renal
pelvis
Afferent
and efferent
arterioles
Thick
ascending
limb of
Henle’s loop
Descending
thin limb
of Henle’s loop
Ureter
Medulla
(renal pyramids)
Medullary
collecting
duct
Papillary duct
Ascending
thin limb
of Henle’s loop
eFigure 18-1 Structures of the (A) urinary system, (B) kidney, and (C ) nephron, the functional unit of the kidney.
Copyright © 2014 McGraw-Hill Education. All rights reserved.
273
along the distal tubule and collecting duct. Urine flow rate and
physicochemical characteristics of the molecule influence these
processes: highly ionized compounds are not reabsorbed unless pH
changes within the urine increase the fraction unionized, so that
reabsorption may be facilitated.
Glomerular Filtration Capacity
GFR is dependent on numerous factors, one of which is protein load.
Bosch13 suggested that an appropriate comprehensive evaluation of
renal function should include the measurement of “filtration capacity” of the kidney. This is similar in context to a cardiac stress test.
The patient may have no hypoxic symptoms, for example, angina
while resting, but it may become quite evident when the patient
begins to exercise. Subjects with normal renal function administered
an oral or IV protein load prior to measurement of GFR have been
noted to increase their GFR by as much as 50%. As renal function
declines, the kidneys usually compensate by increasing the singlenephron GFR. The renal reserve, the maximal degree by which GFR
can be increased, will be reduced in those individuals whose kidneys
are already functioning at higher-than-normal levels because of preexisting renal injury. Thus renal reserve may be a complementary,
insightful index of renal function for many individuals with as yet
unidentified CKD.
Quantification of renal function is not only an important component of a diagnostic evaluation, but it also serves as an important parameter for monitoring therapy directed at the etiology of
the diminished function itself, thereby allowing for objective measurement of the success of treatment. Measurement of renal function also serves as a useful indicator of the ability of the kidneys
to eliminate drugs from the body. Furthermore, alterations of drug
distribution and metabolism have been associated with the degree of
renal function. A discussion of pharmacokinetic changes in patients
with renal disease is extensively reviewed in Chapter 33. Although
several indices have been used for the quantification of GFR in
the research setting, estimation of CLcr and GFR are the primary
approaches used in the clinical arena.
ENDOCRINE FUNCTION
The kidney synthesizes and secretes many hormones involved in
maintaining fluid and electrolyte homeostasis. Secretion of renin
by the cells of the juxtaglomerular apparatus and production and
metabolism of prostaglandins and kinins are among the kidney’s
endocrine functions.14 In addition in response to decreased oxygen
METABOLIC FUNCTION
The kidneys perform a wide variety of metabolic functions, including the activation of vitamin D, gluconeogenesis, and metabolism
of endogenous compounds such as insulin, steroids, and xenobiotics. It is common for patients with diabetes and stages 4 to 5
CKD to have reduced requirements for exogenous insulin,17 and
require supplemental therapy with activated vitamin D3 (calcitriol)
or other vitamin D analogs (paricalcitol, doxercalciferol) to avert
the bone loss and pain associated with CKD-associated metabolic
bone disease.18 Cytochrome P450 (CYP), N-acetyltransferase, glutathione transferase, renal peptidases, and other enzymes responsible for the degradation and activation of selected endogenous
and exogenous substances have been identified in the kidney. The
CYP enzymes in the kidneys are as active as those in the liver,
when corrected for organ mass. In vitro and in vivo studies have
shown that CYP-mediated metabolism is impaired in the presence
of renal failure or uremia. In clinical studies using CYP3A probes
in ESRD patients receiving hemodialysis, hepatic CYP3A activity was reported to be reduced by 28% from values observed in
age-matched controls; partial correction was noted following the
hemodialysis procedure.19,20 Impaired nonrenal clearance in the
presence of renal failure has been documented for a number of
drugs with a fraction eliminated renally unchanged of less than
30%, including those that undergo extensive CYP metabolism by
CYP1A2, CYP2D6, CYP3A4, and CYP2C9, such as duloxetine,
rosuvastatin, and telithromycin.21
Qualitative and
Semiquantitative Indices
of Kidney Function
Patients who develop CKD remain relatively asymptomatic until
they reach stage 4 to 5 and systemic manifestations and/or secondary complications become evident (eTable 18-2). As renal function
declines, patients may develop de novo or experience an exacerbation of hypertension, edema, electrolyte abnormalities, anemia, or
other complications (see Chap. 29). The National Kidney Foundation (NKF) currently recommends that all patients with CKD, and
those at increased risk for CKD, undergo at least yearly a comprehensive laboratory assessment comprised of (a) serum creatinine
concentration to estimate GFR; (b) albumin-to-creatinine ratio in
a spot urine specimen; (c) examination of urine sediment for red
blood cell and white blood cell counts; (d) renal ultrasonography;
(e) serum electrolytes, including sodium, potassium, chloride, and
bicarbonate; (f) urine pH; and (g) urine specific gravity.22 The role
of each of these indices in the identification and monitoring of CKD
is discussed in detail below.
Copyright © 2014 McGraw-Hill Education. All rights reserved.
18
Evaluation of Kidney Function
The “intact nephron hypothesis” described by Bricker,12 more than
40 years ago, proposes that “kidney function” of patients with renal
disease is the net result of a reduced number of appropriately functioning nephrons. As the number of nephrons is reduced from the initial complement of 2 million, those that are unaffected compensate;
that is, they hyperfunction. The cornerstone of this hypothesis is that
glomerulotubular balance is maintained, such that those nephrons
capable of functioning will continue to perform in an appropriate
fashion. Extensive studies have indeed shown that single-nephron
GFR increases in the unaffected nephrons; thus, the whole-kidney
GFR, which represents the sum of the single-nephron GFRs of the
remaining functional nephrons, may remain close to normal until
there is extensive injury. Based on this, one would presume that a
measure of one component of nephron function could be used as an
estimate of all renal functions. This, indeed, has been and remains
our clinical approach. We estimate GFR and assume secretion and
reabsorption remain proportionally intact.
e|CHAPTER Intact Nephron Hypothesis
tension in the blood, which is sensed by the kidney, erythropoietin
is produced and secreted by peritubular fibroblasts. Because these
functions are related to renal mass, decreased endocrine activity is
associated with the loss of viable kidney cells. In patients with stages
3 to 5 CKD and those with moderate-to-severe acute kidney injuries,
secretion of erythropoietin is impaired leading to reduced red blood
cell formation; normocytic anemia and symptoms of reduced oxygen delivery to tissues such as fatigue, dyspnea, and angina (see
Chap. 29). Indeed, anemia-induced renal hypoxia results indirectly
in erythropoietin gene activation, tubular necrosis, and apoptosis,
thereby contributing to further renal cell injury.15 This cyclic relationship between kidney disease, suppression of erythropoietin
secretion, and cardiovascular disease is also referred to as the cardio-renal anemia syndrome.16
274
eTable 18-2 Presentation of Chronic Kidney Disease (CKD)
SECTION
Early CKD
(Stages 1–2)
Late CKD
(Stages 3–4)
General
The patient may not
appear in distress
Patient may have edema
Symptoms
Not likely present
The patient may have
fatigue, malaise, pruritus,
nausea
Signs
Not likely present
May present with fluid
retention, anemia,
dyspnea, reduced urine
output
Laboratory tests
Microalbuminuria
Mildly elevated serum
creatine and blood
urea nitrogen
Persistent proteinuria
Reduced glomerular
filtration rate or
creatine clearance rate
Abnormal urinalysis
2
Organ-Specific Function Tests and Drug-Induced Diseases
Other diagnostic
tests
Renal ultrasound shows
reduced kidney mass
Laboratory Procedures to Detect
the Presence of Kidney Disease
Urinalysis is an important tool for detecting and differentiating various aspects of kidney disease, which often goes unnoticed as the
result of its asymptomatic presentation. Urinalysis can be used to
detect and monitor the progression of diseases such as diabetes mellitus, glomerulonephritis, and chronic urinary tract infections.23 A
typical urinalysis provides information about physical and chemical
composition, most of which can be completed quickly and inexpensively by visual observation (volume and color) and dipstick testing.
Chemical Analysis of Urine
pH The normal urine pH typically ranges from 4.5 to 7.8, and an
elevation above this may suggest the presence of urea-splitting bacteria. In patients with renal tubular acidosis, urine pH is usually >5.5
because of impaired hydrogen ion secretion in the distal tubule or
collecting duct.
Glucose Glucose is usually not present in the urine because the
kidney normally completely reabsorbs all the glucose filtered at the
glomerulus. When a patient’s blood glucose concentration exceeds
the maximum threshold for glucose reabsorption (~180 mg/dL
[~10.0 mmol/L]), glucosuria will be present. Routine assessment of
glucosuria to monitor diabetics has been replaced by newer methods
of direct blood glucose measurements. Urine glucose testing is now
predominantly used as a screening tool for the detection of diabetes.
Ketones Acetoacetate and acetone are not normally found in
the urine; they are however excreted in patients with diabetic
ketoacidosis. They are also present under conditions of fasting
or starvation. Typically, values of acetone excretion are reported
as small (<20 mg/dL [<3.4 mmol/L]), moderate (30 to 40 mg/dL
[5.2 to 6.9 mmol/L]), and large (>80 mg/dL [>13.8 mmol/L]).
Nitrite Nitrite is not usually present in urine. The presence of
nitrite is most commonly the result of conversion from urinary
nitrate by bacteria in the urine. The presence of nitrite thus suggests
that the patient has a urinary tract infection, commonly caused by
gram-negative rods such as Escherichia coli. Although false-positive
results are very rare, false-negative results are more common and
may be caused by lack of dietary nitrate, reduced urine nitrate concentration as a consequence of diuresis, or infections caused by bacteria such as enterococci and Acinetobacter, which do not reduce
nitrate, and pseudomonads, which convert nitrate to nitrogen gas.
Leukocyte Esterase Leukocyte esterase is released from lysed
granulocytes in the urine; its presence is suggestive of urinary tract
infection. False-positive tests can result from delayed processing of
the urine sample, contamination of the sample with vaginal secretions (such as blood or heavy mucus discharge), or by Trichomonas
infection (such as trichomoniasis). False-negative tests can be produced by the presence of high levels of protein or ascorbic acid.
Heme The heme test indicates the presence of hemoglobin or myoglobin in the urine. A positive test without the presence of red blood
cells suggests either red cell hemolysis or rhabdomyolysis.
Protein or Albumin 2 Evaluation of urinary protein or albumin
is now a standard tool to characterize the severity of CKD and to
monitor the rate of disease progression or regression.22 Persistent
proteinuria or albuminuria, that is, present on at least three occasions over a period of 3 to 6 months, is now considered a principal
marker of kidney damage.22 Under normal conditions, plasma proteins remain in the glomerular capillaries and thus do not cross the
glomerular basement membrane or enter the urinary space. Some
of these proteins, such as albumin and globulins are not filtered by
the glomerulus as a result of charge and size selectivity (>40 kDa).
Smaller proteins (<20 kDa) pass across the glomerular basement
membrane but are usually readily reabsorbed in the proximal tubule.
Most healthy individuals excrete between 30 and 150 mg/day of
total protein consisting of approximately 30 mg/day of albumin.
The other proteins that may be found in the urine are secreted by
the tubules (Tamm-Horsfall, immunoglobulin A, and urokinase)
or comprised of smaller proteins such as β2-microglobulin, apoproteins, enzymes, or peptide hormones. Increased renal excretion
of these low-molecular-weight proteins is considered a sensitive
marker of tubulointerstitial disease.
Historically, the sulfosalicylic acid test was used as a crude
measure of proteinuria. This test is performed by adding sulfosalicylic acid to urine and then visually comparing this admixture with
a tube of untreated urine; the degree of turbidity is then qualitatively
graded (0 to 4 plus) as the index of the presence of proteinuria. Dipstick tests are now the most common means to determine in a semiquantitative fashion a patient’s urinary protein or albumin excretion.
False-positive results can occur in the presence of alkaline urine
(pH more than 7.5), when the dipstick is immersed too long, in those
with highly concentrated urine, in the presence of drugs such as penicillin, sulfonamides, or tolbutamide, as well as blood, pus, semen,
or vaginal secretions. False-negative results occur with dilute urine
(specific gravity <1.015) and when proteinuria is caused by nonalbumin or low-molecular-weight proteins such as heavy or light
chains or Bence Jones proteins. The results of these dipstick tests are
graded as negative (<10 mg/dL [<100 mg/L]), trace (10 to 20 mg/
dL [100 to 200 mg/L]), 1+ (30 mg/dL [300 mg/L]), 2+ (100 mg/dL
[1000 mg/L]), 3+ (300 mg/dL [3000 mg/L]), or 4+ (>1,000 mg/dL
[>10,000 mg/L]). Portable desktop analyzers such as the Chemstrip
101 Urine Analyzer (Roche Diagnostics) and Clinitek 50 Urine
Chemistry Analyzer (Bayer Corporation) can also be used as an
alternative to visual urinalysis test-strip evaluation, and provides
rapid results for urinary albumin-to-creatinine ratio.24
3 Dipstick test strips that are specific for low levels of albuminuria (30 to 300 mg/day) should be employed when one is screening individuals at risk for CKD. Microalbuminuria test strips, such
as the Microalbumin 2-1 Combo Strip (Teco Diagnostics), is a
semiquantitative test for both albumin and creatinine in a spot urine
sample. When dipped into a urine sample, colors range from pale
green to aqua blue (for albumin) and shades of purple-brown (for
creatinine), depending on the amounts present in the sample.25 The
presence of hemoglobin (≥5 mg/dL [≥50 mg/L] or visibly bloody
urine) or bilirubin (≥15 mg/dL [≥257 μmol/L] or visibly dark brown
color urine) can interfere with test results from these strips, but no
Copyright © 2014 McGraw-Hill Education. All rights reserved.
275
In the past, measurement of urinary protein excretion
rate was accomplished using a 24-hour urine collection
in patients who were at risk for CKD. However, many now
advocate the use of an untimed “spot” urine sample with
either an albumin-specific dipstick or measurement of the
albumin-to-creatinine ratio.
Specific Gravity Specific gravity is a measure of urine weight relative to water (1.00) that is performed using a refractometer. Thus,
specific gravity is dependent on water intake and urine-concentrating ability. Normal values range from 1.003 to 1.030. Osmolality,
which is a measure of the number of solute particles in the urine,
is a more accurate measure of the kidney’s ability to make a concentrated urine. Generally the two values correlate; however, when
large quantities of heavier molecules, such as glucose, are in the
urine, the specific gravity may be elevated relative to the osmolality.
These tests are used in the assessment of urine-concentrating ability
and are most informative when interpreted along with the hydration
status of the patient and plasma osmolality.26
Microscopic Analysis of Urine
Microscopic examination is a critical aspect of urinalysis. Formed
elements that may be detected in the urine include erythrocytes and
leukocytes, casts, and crystals. An important consideration in the
assessment of hematuria is whether the cells are of renal origin.
More than two cells per high-power field is abnormal, and the presence of dysmorphic cells suggest renal parenchymal origin either
because they were damaged as they passed through the glomerulus
or due to exposure to the varying osmotic environments of the tubular lumen. White blood cells may be present in the urine in association with infection or inflammatory conditions, such as interstitial
nephritis. More than one cell per high-power field is usually considered abnormal. Contamination of the sample should also be considered when there are many cells and may be a result of the presence
of menses or of inadequate sample collection. Casts are cylindrical
forms composed of protein, with or without cells that take the shape
of the collecting tubules, where they are formed. Casts without cells
are labeled hyaline casts and consist of the Tamm-Horsfall mucoprotein, secreted by the renal tubules. They are nonspecific and may
appear in concentrated urine. In the presence of red or white blood
cells, casts may be formed that include the cells, indicating that the
cells were of renal origin. Solubility of the Tamm-Horsfall protein
Serum or Blood Urea Nitrogen
Amino acids metabolized to ammonia are subsequently converted
in the liver to urea, the production of which is dependent on protein
availability (diet) and hepatic function. Urea undergoes glomerular
filtration followed by reabsorption of up to 50% of the filtered load
in the proximal tubule. The nitrogen component of urea in serum
(SUN) or blood (BUN) is considered normal if it is in the range
of 5 to 20 mg/dL (1.8 to 5.1 mmol/L).28 The reabsorption rate of
urea is predominantly dependent on the reabsorption of water. The
excretion of urea may, therefore, be decreased under conditions
that necessitate water conservation such as dehydration although
the GFR may be normal or only slightly reduced. This condition is
evident when a patient exhibits prerenal azotemia, or an increase of
the blood urea nitrogen to a greater extent than the serum creatinine
concentration. The normal blood urea nitrogen-to-creatinine ratio is
10 to 15:1 using conventional units (or 0.04 to 0.06 mmol/L:μmol/L
using SI units), and an elevated ratio is suggestive of a decreased
effective circulating volume, which stimulates increased water, and
hence, urea reabsorption. Creatinine is not reabsorbed to any significant extent by the kidneys. Despite these limitations, the blood urea
nitrogen is usually used in combination with the serum creatinine
concentration as a simple screening test for the detection of renal
dysfunction.
Serum and Urine Creatinine
Creatinine remains the most important endogenous biomarker used
for the detection of kidney disease. The concentration of creatinine
in serum is a function of creatinine production and renal excretion.
Creatinine is a product of creatine metabolism from muscle; therefore, its production is directly dependent on muscle mass. At steady
state, the “normal” serum creatinine concentration range is generally reported as 0.5 to 1.5 mg/dL (44 to 133 μmol/L) for males and
females.28 Creatinine is eliminated primarily by glomerular filtration, and as GFR declines, the serum creatinine concentration rises
(eFig. 18-2).
The third National Health and Nutrition Examination Survey
(NHANES III) revealed a mean serum creatinine concentration in white women and men of 0.96 mg/dL (85 μmol/L) and
1.16 mg/dL (103 μmol/L), respectively.29 Values were lower among
Mexican Americans, and higher among African Americans. For
all groups, the serum creatinine concentration increased with age.
The report also estimated that among U.S. community-dwelling
adults, 10.9 million have a serum creatinine concentration greater
than 1.5 mg/dL (133 μmol/L); 3.0 million have a serum creatinine
concentration greater than 1.7 mg/dL (150 μmol/L); and 0.8 million have a serum creatinine concentration greater than 2.0 mg/dL
(177 μmol/L). Although the serum creatinine concentration alone
is not an optimal measure of kidney function, it is often used as a
marker for referral to a nephrologist. There is presently no accepted
single standard for an “abnormal” serum creatinine concentration,
as it is dependent on gender, race, age, and lean body mass.
Several methods have been used for the determination of the
serum creatinine concentration. The kinetic Jaffe reaction remains
the cornerstone of routine quantification of creatinine in most
Copyright © 2014 McGraw-Hill Education. All rights reserved.
18
Evaluation of Kidney Function
Clinical Controversy. . .
is increased as urine pH rises; therefore, sample collection for casts
should occur with the first morning void when the urine is most
acidic. Otherwise, casts may dissolve and elude detection.
A variety of crystals may be visualized in the urinary sediment
in healthy individuals as well as those with kidney diseases. The most
common crystals are those composed of uric acid, calcium oxalate,
calcium phosphate, calcium magnesium ammonium pyrophosphate,
and cystine. Many of these have a unique crystalline form, which
permits them to be identified with microscopy.27 Images of common
types of urinary casts and crystals can be found at multiple websites
such as http://www.ndt-educational.org/fogazzislidepart3.htm.
e|CHAPTER interferences have been observed with ascorbic acid. In patients with
a positive protein or albumin dipstick test, a 24-hour urine collection
with measurement of albumin excretion can be used to quantitate
precisely the degree of albuminuria. However, this method requires
a high degree of patient compliance and is being replaced by a similarly accurate but less cumbersome technique: calculation of the
ratio of protein or albumin (in mgs) to creatinine (in g [or mmol]) in
an untimed (spot) urine specimen. The normal ratio is <30 mg albumin or <200 mg protein per gram of creatinine (<3.4 mg albumin or
<22.6 mg protein per mmol of creatinine), with values between 30
and 300 mg of albumin per gram of creatinine (3.4 to 34.0 mg of
albumin per mmol of creatinine) considered to be in the microalbuminuria range.22 Positive test results should be repeated, particularly
in patients without an underlying cause for CKD, such as diabetes
or hypertension. Monitoring of the degree of glomerular injury in
CKD patients should use the albumin-to-creatinine ratio, whereas
for patients with clinical proteinuria, that is, excretion of >500 mg
per day or an albumin-to-creatinine ratio >500 mg/g (>56.6 mg/
mmol), the protein-to-creatinine ratio can be used.
276
10
eTable 18-3 Factors That May Alter Creatinine Clearance
Determinations
SECTION
2
Serum creatinine concentration (mg/dL)
9
8
7
6
5
4
3
2
1
0
0
20
40
60
80
100
120
Analytical
Physiologic
Acetoacetate
Ascorbic acid
Cephalosporins (cephalothin, cefazolin,
cephalexin, cefoxitin, cefaclor, cephradine)
Clavulanic acid
Dobutamine
Dopamine
5-Flucytosine
Fructose
Glucose
Protein
Pyruvate
Uric acid
Age, weight, gender
Diet
Diurnal variation
Cimetidine
Trimethoprim
Probenecid
Exercise
Creatinine clearance (mL/min)
Organ-Specific Function Tests and Drug-Induced Diseases
eFigure 18-2 Relationship between serum creatinine and
creatinine clearance.
clinical laboratories. This colorimetric method is based on the reaction of creatinine with alkaline picrate. This nonspecific method
also reacts with noncreatinine chromogens in the serum, including bilirubin and proteins such as albumin, and hemoglobin, which
may result in a falsely increased serum creatinine concentration.23
The noncreatinine chromogens are not present in the urine in sufficient quantities to interfere with the urinary creatinine measurement, because the concentration of creatinine in urine is several-fold
greater than the serum concentration.
This “normal” interference results in an increase in the serum
creatinine concentration of approximately 10% and thereby the
measured CLcr would underestimate the true GFR by 10%. In subjects with normal renal function, this tends to counterbalance the
effect of the contribution of tubular secretion of creatinine, which
increases urine creatinine by nearly 10%. Thus, a measured CLcr
has been proposed to serve as a good measure of GFR in subjects
with normal renal function. However, this false increase in serum
creatinine concentration becomes less noticeable as the true creatinine concentration rises, due to the increasing contribution of tubular secretion to the renal clearance of creatinine.30 This becomes of
major importance when kidney function is reduced to less than 50%
of normal.
Diabetic ketoacidosis may produce increased concentrations
of acetoacetate, which serves as a chromophore in the Jaffe reaction, thereby increasing the serum creatinine concentration. Other
substances that also react with this procedure in the serum include
glucose, protein, pyruvate, fructose, uric acid, and ascorbic acid
(eTable 18-3). In addition, some antibiotics are associated with a false
increase in the serum creatinine concentration, including cephalothin, cefazolin, cephalexin, cefoxitin, cefaclor, cephradine, and clavulonic acid,31,32 whereas other agents, such as the fluoroquinolones
(ciprofloxacin, fleroxacin, lomefloxacin, ofloxacin, levofloxacin,
sparfloxacin, and temafloxacin), do not produce a false elevation
in serum creatinine concentration.33 The degree of interference is
dependent on the serum concentration of the antibiotic, so blood
samples for creatinine should be obtained when the antibiotic concentration is lowest (at the end of a dosing interval). These interferences are not observed when the serum creatinine concentration is
measured using an enzymatic technique employing creatinine iminohydrolase, creatininase, creatinase, or sarcosine oxidase.
Endogenous and drug interferences continue to plague creatinine measurements for both the Jaffe and enzymatic methods.
Recent modifications to the Jaffe method have been employed to
address some nonspecific aspects of the assay.34 For example, the
“compensated Jaffe” method is used on the Roche Diagnostics, and
Siemens analyzers. Here, a fixed concentration is subtracted from
all results in order to adjust for nonspecific protein influence. The
“uncompensated Jaffe” method used by Abbott, Beckman, and
Siemens has been reported to be less susceptible to interferences by
bilirubin when compared to other Jaffe methods.35
A new approach to standardize serum creatinine concentration assays between manufacturers and institutions has been implemented in most hospital clinical laboratories.35 The method involves
calibration of creatinine values based on standardized reagents that
are traceable to an isotope dilution-mass spectrometry (IDMS)
method. This approach has significantly improved interlaboratory
variability in serum creatinine concentration values, and has resulted
in a downward shift of the “normal range” for serum creatinine concentration values by 0.1 to 0.2 mg/dL (9 to18 μmol/L) when compared to noncalibrated ranges. For example, the normal reference
range reported by the UNC Hospitals laboratory for healthy males
was reduced from 0.8 to 1.4 mg/dL (71 to 124 μmol/L; pre-IDMS)
to 0.7 to 1.3 mg/dL (62 to 115 μmol/L; post-IDMS).36 Other recent
modifications include reporting serum creatinine concentration values in mg/dL to two decimal places (e.g., 0.93 mg/dL), and values in
μmol/L to the nearest whole number (e.g., 82 μmol/L). This practice
is aimed at reducing rounding errors that in the past contributed to
bias between creatinine-based GFR or CLcr estimates, but it does not
improve GFR estimation in those without CKD.
Despite alterations in creatinine assay methods, many drugs
still interfere with these assays resulting in false elevations or reductions in serum creatinine concentration values. The antifungal agent
5-flucytosine cross-reacts with creatinine when measured using the
Ektachem enzymatic system, but does not interact with the Jaffe
method.37 Daly et al.38 reported a false-negative effect of dobutamine and dopamine on the serum creatinine concentration value
when measured using the Ektachem system. The interference is concentration dependent and results in a 10% to 100% decrease of the
serum creatinine concentration. The authors hypothesized that both
drugs compete with the chromogenic dye for oxidation by hydrogen peroxide in a concentration-dependent manner. The problem is
most evident when blood samples are contaminated with residual
IV solution containing the interfering drug. Thus, standardization of
procedures within the clinic setting and awareness of the creatinine
assay method used at the institution are critical to properly interpret
each patient’s serum creatinine concentration value.
Other compounds are known to truly alter the serum creatinine concentration by inhibition of the active tubular secretion of
creatinine. Among these are cimetidine and trimethoprim, which
compete for creatinine secretion at the cationic transport system in a
dose-dependent fashion. Cimetidine, given as a single 400-mg dose
can result in a reduction of the CLcr-to-inulin clearance ratio from
Copyright © 2014 McGraw-Hill Education. All rights reserved.
277
Cystatin C is a 132-amino-acid (13.3-kDa) cysteine protease inhibitor produced by all nucleated cells of the body that is considered a
biomarker of renal function. It is freely filtered at the glomerulus
and undergoes both reabsorption and catabolism in the proximal
tubule. The renal handling of this biomarker is distinctly different from creatinine and exogenous GFR markers such as inulin,
Alternative Methodologies
to Identify Kidney Injury
Biomarkers measured in urine, such as kidney injury molecule-1
(KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), and
cystatin C have shown promise in detecting AKI63 (see Chap. 28).
Because it is normally reabsorbed and metabolized in the renal
proximal tubule, it is hypothesized that tubular damage would lead
to increased urinary excretion of cystatin C. Koyner et al.64 showed
that postop cardiac surgery patients with early elevated urinary cystatin C-to-creatinine ratios had the highest prevalence of developing AKI. Here, plasma creatinine concentrations did not peak until
48 hours after intensive care unit (ICU) admission, suggesting that
Copyright © 2014 McGraw-Hill Education. All rights reserved.
18
Evaluation of Kidney Function
Serum and Urine Cystatin C
iohexol, and iothalamate. Originally introduced in Europe, it was
recommended as a biomarker of kidney function because of findings
that serum concentrations significantly correlated with GFR as well
as serum creatinine concentration. It was hypothesized that since
cystatin C production was not affected by muscle mass, it would
provide a more reliable estimate of renal function than serum creatinine concentration. However, it has now been shown that serum
cystatin C concentrations can be altered by many factors other than
kidney function, such as age, nutritional status, gender, weight,
height, cigarette smoking, serum C-reactive protein levels, steroid
therapy, and rheumatoid arthritis.47,48 Recent studies have reported
conflicting results about the sensitivity of cystatin C compared to
creatinine in predicting various forms of AKI.49–52 Cystatin C has
been show to perform better than serum creatinine concentration for
predicting contrast-induced kidney injury, resulting in a new definition of contrast-induced acute kidney injury (CIAKI), consisting
of a >10% increase in cystatin C within 24 hours after exposure to
contrast media.49,50 Serum cystatin C also detected AKI up to 2 days
earlier than creatinine in critically ill patients,51 and cystatin C concentration was a better predictor of AKI in pediatric cardiac surgery
patients.52 However, three prior studies did not show a clear advantage for serum cystatin C level in predicting AKI in cardiopulmonary bypass and cardiothoracic surgery.53–55 In a recent multicenter
study of 1,150 adults followed after cardiac surgery, cystatin C was
noted to be a less sensitive biomarker than creatinine for detecting
AKI in the postoperative period.55 These differential findings suggest that the role of cystatin C in assisting with the diagnosis of AKI
is yet to be fully determined.
The recent development of automated immunoassay techniques for cystatin C is based on a latex enhanced immunoturbidimetric assay. Here, cystatin C in the sample binds to anti-cystatin C
antibody, which is coated on latex particles, resulting in agglutination. The degree of the turbidity caused by agglutination is measured
optically (at 540 nm) and is proportional to the amount of cystatin
C in the sample. The range of values is 0.13 mg/L to 8.0 mg/L
(10 to 599 nmol/L), with normal values of 0.55 to 1.18 mg/L (41 to
88 nmol/L) for women and 0.60 to 1.11 mg/L (45 to 83 nmol/L) for
men based on data from the NHANES study.56
The utility of cystatin C as a quantitative measure of GFR is
gaining acceptance in the clinical and research settings. In a 4-year
longitudinal study in 30 Pima Indians without CKD, the reciprocal
cystatin C index (100/cystatin C) was shown to be a better predictor of declining GFR than estimated GFR, or CLcr.57 However in
patients being treated for malignant disease, Page et al.58 reported
increased cystatin C concentrations that were independent of CLcr.
Cystatin C concentrations were also noted to be independent of
GFR and weakly associated with measured CLcr, in pediatric and
adult renal transplant recipients, possibly because of the formation
of cystatin–immunoglobulin complexes or reduced tubular catabolism.59,60 Two additional studies have shown a strong association
between serum cystatin C and cardiovascular disease in elderly and
non-CKD patients, suggesting that it may provide useful prognostic
information in some populations.61,62
e|CHAPTER 1.30 to 1.03, without a change in inulin clearance. Ranitidine, an
H2-receptor antagonist similar to cimetidine, however, does not have
a similar effect on creatinine secretion following single doses of 300
to 1,200 mg.39
The serum creatinine concentration is dependent on the “input”
function, or formation rate, and “output” function, or elimination
rate. Its formation rate depends on the zero-order production from
creatine metabolism, as well as input from other sources, such
as dietary intake. Over 95% of creatine stores are found in skeletal muscle, with creatine metabolism being directly proportional
to muscle mass. Thus, individuals with more muscle mass have a
higher serum creatinine concentration at any given degree of kidney function than those with less muscle mass. Strenuous exercise
is associated with an increase of approximately 10% in the serum
creatinine concentration. In contrast, cachectic patients, as the result
of minimal muscle mass, will have very low serum creatinine concentrations, as do those with spinal cord injuries.40 Elderly patients
and those with poor nutrition may also have low serum creatinine
concentrations (<1.0 mg/dL [88 μmol/L]) secondary to decreased
muscle mass.
Creatine or methyl guanidine acetic acid are found in many
commonly ingested foods sources such as fish and red meat. During
the cooking of meat, some creatine is converted to creatinine, which
is rapidly absorbed following ingestion. Serum creatinine concentrations may rise as much as 50% within 2 hours of a meat meal
and remain elevated for as long as 8 to 24 hours.41 Ingestion of creatine as an ergogenic dietary supplement is currently popular, as a
means to increase skeletal muscle stores of phosphocreatine leading
to adenosine triphosphate (ATP) resynthesis of adenosine diphosphate (ADP). There are conflicting reports as to the effect of creatine
ingestion on the serum creatinine concentration. Poortsmans et al.42
evaluated a short-term regimen of 20 g creatine per day for 5 days
in healthy subjects, and reported no significant change in the serum
creatinine concentration, creatinine excretion rate, or CLcr. Robinson et al.43 and Jagim et al.,44 reported a 25% to 40% increase in the
serum creatinine concentration after ingestion of 20 g creatine per
day for either 5 days or 8 weeks. The renal excretion rate of creatinine was not measured. Spillane et al.45 reported that creatine ethyl
ester intake at a dose of 20 g/day for 6 days had a nearly threefold
greater increase in serum creatinine concentrations than creatine
monohydrate, indicating that different forms of creatine likely have
differing effects on serum creatinine concentration values.
The issue of whether, or not, creatine ingestion adversely
affects kidney function was studied by Edmonds et al.46 They noted
that creatine supplementation led to an increase in renal disease
progression in a rat model for renal cystic disease, suggesting that
creatine supplementation may be a risk factor in patients with preexisting renal disease. Thus it is important to question ambulatory
patients regarding their dietary intake for the 24 hours preceding the
measurement of serum creatinine concentration or CLcr.
Diurnal variation in serum creatinine concentration may also
affect the accuracy of the CLcr determination. Although the fluctuation is minimal, the observed peak plasma creatinine concentration
generally occurs at approximately 7:00 PM, whereas the nadir is
in the morning. The impact of diurnal variation is minimized by
using serum creatinine concentration measurements that are drawn
at similar times during longitudinal evaluations, or using 24-hour
urine collections for CLcr measurements.
278
SECTION
2
urinary biomarkers such as cystatin C may be beneficial in early
diagnosis of AKI. Use of cystatin C as a quantitative measure of
GFR requires further evaluation, and may yield useful information
for comprehensive evaluations of health and cardiovascular status,
including detection of acute and chronic changes in kidney function.
β-Trace protein (BTP) has recently been proposed as a new
alternate endogenous marker of GFR.65,66 Similar to cystatin C, it is
a low-molecular-weight glycoprotein (168 amino acids) that is filtered through the glomerular basement membrane and reabsorbed in
the renal proximal tubule. Elevated concentrations of BTP in serum
have been reported in patients with chronic kidney disease,67 kidney
transplant recipients,68 and children.69 Equations to estimate GFR
that incorporate BTP concentrations in adults and pediatric populations are currently being evaluated.70
Organ-Specific Function Tests and Drug-Induced Diseases
MEASUREMENT OF
KIDNEY FUNCTION
The gold standard quantitative index of kidney function is a measured GFR. A variety of methods may be used to measure and
estimate kidney function in the acute care and ambulatory settings.
Measurement of GFR is important for early recognition and monitoring of patients with chronic kidney disease and as a guide for
drug dose adjustment.
It is important to recognize conditions that may alter renal function independent of underlying renal pathology. For example, protein
intake, such as oral protein loading or an infusion of amino acid solution, may increase GFR.13 As a result, inter- and intrasubject variability must be considered when it is used as a longitudinal marker
of renal function. Dietary protein intake has been demonstrated to
correlate with GFR in healthy subjects. Brändle et al.71 evaluated
renal function in four groups of healthy volunteers, each ingesting
a diet controlled for protein over a 4-month period. The GFR was
nonlinearly related to the urine nitrogen excretion, with an observed
maximum of 181.7 mL/min (3.03 mL/s) at a urinary nitrogen excretion rate of 20 g/day (1.43 mol/d), or 125 g/day protein intake. Subjects who are vegetarian have a lower GFR because of their reduced
dietary protein intake relative to individuals who consume a similar
caloric but normal-protein-content diet. When challenged with a protein load, the vegetarian subjects are able to increase their GFR to the
“normal” range.13 Findings from the Nurses’ Health Study72 indicate
that longitudinal changes in GFR are independent of the source of
protein (nondairy animal, dairy, or vegetable) in women with normal renal function. However, women with mild renal insufficiency
(GFR 71 ± 7 mL/min [1.18 ± 0.12 mL/s]) who consumed the highest
amount of protein (93 g/day) had a threefold greater risk of a ≥5 mL/
min (≥0.08 mL/s) decline in GFR compared to the lowest protein
group (60 g/day); rates of decline were highest in those consuming
nondairy animal protein. The increased GFR following a protein load
is the result of renal vasodilation accompanied by an increased renal
plasma flow. The exact mechanism of the renal response to protein is
unknown, but may be related to extrarenal factors such as glucagon,
prostaglandins, and angiotensin II, or intrarenal mechanisms, such
as alterations in tubular transport and tubuloglomerular feedback.73,74
Despite the evidence of a “renal reserve,” standardized evaluation
techniques have not been developed. Therefore, assessment of a measured GFR must consider the dietary protein status of the patient at
the time of the study.
Measurement of Glomerular
Filtration Rate
4 A measured GFR remains the single best index of kidney func-
tion. As renal mass declines in the presence of age-related loss of
nephrons or disease states such as hypertension or diabetes, there
is a progressive decline in GFR. The rate of decline in GFR can be
used to predict the time to onset of stage 5 CKD, as well as the risk
of complications of CKD. Accurate measurement of GFR in clinical
practice is a critical variable for the individualization of the dosage
regimens of renally excreted medications so that one can maximize
their therapeutic efficacy and avoid potential toxicity.
The GFR is expressed as the volume of plasma filtered across
the glomerulus per unit time, based on total renal blood flow and
capillary hemodynamics. The normal values for GFR are 127 ±
20 mL/min/1.73 m2 (1.22 ± 0.19 mL/s/m2) and 118 ± 20 mL/min/
1.73 m2 (1.14 ± 0.19 mL/s/m2) in healthy men and women, respectively. These measured values closely approximate what one would
predict if the normal renal blood flow were approximately 1.0 L/
min/1.73 m2 (0.01 mL/s/m2), plasma volume was 60% of blood volume, and filtration fraction across the glomerulus was 20%: then
the normal GFR would be expected to be approximately 120 mL/
min/1.73 m2 (1.16 mL/s/m2).
Optimal measurement of GFR involves determining the renal
clearance of a substance that is freely filtered without additional
clearance because of tubular secretion or reduction as the result of
reabsorption. Additionally, the substance should not be susceptible
to metabolism within renal tissues and should not alter renal function. Given these conditions, the measured GFR is equivalent to the
renal clearance of the solute marker:
GFR = renal CL = (Ae)/AUC0–t
where renal CL is renal clearance of the marker, Ae is the amount
of marker excreted in the urine in a specified period of time, t, and
AUC0-t is the area under the plasma-concentration-versus-time curve
of the marker.
Under steady-state conditions, for example during a continuous infusion of the marker, the expression simplifies to
GFR = renal CL = (Ae)/[Css) × t]
where Css is the steady-state plasma concentration of the marker
achieved during continuous infusion. The continuous infusion
method can also be employed without urine collection, where
plasma clearance is calculated as CL = infusion rate/Css. This
method is dependent on the attainment of steady-state plasma concentrations and accurate measurement of infusate concentrations.
Plasma clearance can also be determined following a single-dose
IV injection with the collection of multiple blood samples to estimate area under the curve (AUC0-∞). Here, clearance is calculated as
CL = dose/AUC. These plasma clearance methods commonly yield
clearance values 10% to 15% higher than GFR measured by urine
collection methods.75,76
5 Several markers have been used for the measurement of
GFR and include both exogenous and endogenous compounds.
Those administered as exogenous agents, such as inulin, sinistrin, iothalamate, iohexol, and radioisotopes, require specialized
administration techniques and detection methods for the quantification of concentrations in serum and urine, but generally provide
an accurate measure of GFR. Methods that employ endogenous
compounds, such as creatinine or cystatin C, require less technical expertise, but produce results with greater variability. The
GFR marker of choice depends on the purpose and cost of the test,
ranging from $2,000 per vial for radioactive for 125I-iothalamate
(Glofil-125, QOL Medical)to $6 per vial for nonradiolabeled
iothalamate (Conray-60, Mallincrodt) or iohexol (Omnipaque-300,
GE Medical) (eTable 18-4).
Inulin and Sinistrin Clearance
Inulin is a large fructose polysaccharide (5,200 Da), obtained from
the Jerusalem artichoke, dahlia, and chicory plants. It is not bound
Copyright © 2014 McGraw-Hill Education. All rights reserved.
279
eTable 18-4 Sensitivity and Clinical Utility of Renal
Function Tests
Accuracy
Clinical Utility
Cost
Inulin clearance
++++
+
$$$$
+++
+
$$$
+++
++
$$$
Creatinine clearance
++
+++
$$
Serum creatinine
+
++++
$
Radiolabeled Markers
Iothalamate Clearance
Creatinine
Iothalamate is an iodine-containing radiocontrast agent that is available in both radiolabeled (125I) and nonradiolabeled forms. This agent
is handled in a manner similar to that of inulin; it is freely filtered at
the glomerulus and does not undergo substantial tubular secretion
or reabsorption. The nonradiolabeled form is most widely used to
measure GFR in ambulatory and research settings, and can safely
be administered by IV bolus, continuous infusion, or subcutaneous
injection.76 Plasma and urine iothalamate concentrations can be measured using high-performance liquid chromatography.79,80 Plasma
iothalamate clearance methods that do not require urine collections
have been shown to be highly correlated with iothalamate renal
clearance, making them particularly well-suited for longitudinal
evaluations of renal function.76,81 These plasma clearance methods
require two-compartment modeling approaches because accuracy is
dependent on duration of sampling. For example, Agarwal et al.81
demonstrated that short sampling intervals can overestimate GFR,
particularly in patients with severely reduced GFR. In individuals
with GFR >30 mL/min/1.73 m2 (>0.29 mL/s/m2), a 2-hour sampling
strategy yielded GFR values that were 54% higher compared with
10-hour sampling, whereas the 5-hour sampling was 17% higher.
In individuals with GFR <30 mL/min/1.73 m2 (<0.29 mL/s/m2), the
5-hour GFR was 36% higher and 2-hour GFR was 126% higher than
the 10-hour measurement. The authors proposed a 5 to 7 hour sampling time period with eight plasma samples to be the most appropriate and feasible approach for most GFR evaluations.
Iohexol
Iohexol, a nonionic, low osmolar, iodinated contrast agent, has also
been used for the determination of GFR. It is eliminated almost
entirely by glomerular filtration, and plasma and renal clearance values are similar to observations with other marker agents: Strong correlations of 0.90 or greater and significant relationships such with
Measured Creatinine Clearance Although the measured
(24-hour) CLcr has been used as an approximation of GFR for
decades, it has limited clinical utility for a multiplicity of reasons.
Short-duration witnessed measured CLcr correlates well with iothalamate clearance performed using the single-injection technique. In a
multicenter study89 of 136 patients with type 1 diabetic nephropathy,
the correlations of simultaneous measured CLcr, and 24-hour CLcr
(compared to CLiothalamate) were 0.81 and 0.49, respectively, indicating increased variability with the 24-hour clearance determination.
In a selected group of 110 patients, measurement of a 4-hour CLcr
during water diuresis provided the best estimate of the GFR as determined by the CLiothalamate. Furthermore, the ratio of CLcr to CLiothalamate
did not appear to increase as the GFR decreased. These data suggest
that a short collection period with a water diuresis may be the best
CLcr method for estimation of GFR.
A limitation of using creatinine as a filtration marker is that it
undergoes tubular secretion. Tubular secretion augments the filtered
creatinine by approximately 10% in subjects with normal kidney
function. If the nonspecific Jaffe reaction is used, which overestimates the serum creatinine concentration by approximately 10%
because of the noncreatinine chromogens, then the measurement of
CLcr is a very good measure of GFR in patients with normal kidney function. Tubular secretion, however, increases to as much as
100% in patients with renal insufficiency.30 The result is that measured CLcr markedly overestimates GFR. For example, Bauer et al.30
reported that the CLcr-to-CLinulin ratio in subjects with mild impairment was 1.20; for those with moderate impairment, it was 1.87; and
in those with severe impairment, it was 2.32. Thus, a measured CLcr
is a poor indicator of GFR in patients with moderate to severe renal
insufficiency, that is, stages 3 to 5 CKD.
Because cimetidine blocks the tubular secretion of creatinine
the potential role of several oral cimetidine regimens to improve the
Copyright © 2014 McGraw-Hill Education. All rights reserved.
18
Evaluation of Kidney Function
to plasma proteins, is freely filtered at the glomerulus, is not
secreted or reabsorbed, and is not metabolized by the kidney. The
volume of distribution of inulin approximates extracellular volume,
or 20% of ideal body weight. Because it is eliminated by glomerular filtration, its elimination half-life is dependent on renal function
and is approximately 1.3 hours in subjects with normal renal function. Measurement of plasma and urine inulin concentrations can be
performed using high-performance liquid chromatography.77 Sinistrin, another polyfructosan, has similar characteristics to inulin; it
is filtered at the glomerulus and not secreted or reabsorbed to any
significant extent. It is a naturally occurring substance derived from
the root of the North African vegetable red squill, Urginea maritime, which has a much higher degree of water solubility than inulin.
Assay methods for sinistrin have been described using enzymatic
procedures, as well as high-performance liquid chromatography
with electrochemical detection.78 Alternatives have been sought for
inulin as a marker for GFR because of the problems of availability,
high cost, sample preparation, and assay variability.
The GFR has also been quantified using radiolabeled markers, such as 125I-iothalamate (614 Da, radioactive half-life of 60
days), 99mTc-diethylenetriamine pentaacetic acid (99mTc-DPTA;
393 Da, radioactive half-life of 6.03 hours), and 51Cr-ethylenediaminetetraacetic acid (51Cr-EDTA; 292 Da, radioactive half-life of
27 days).86 These relatively small molecules are minimally bound to
plasma proteins and do not undergo tubular secretion or reabsorption to any significant degree. 125I-iothalamate and 99mTc-DPTA are
used in the United States, whereas 51Cr-EDTA is used extensively
in Europe. The use of radiolabeled markers allows one to determine
the individual contribution of each kidney to total renal function.87
Various protocols exist for the administration of these markers and
subsequent measurement of GFR using either plasma or renal clearance calculation methods. The nonrenal clearance of these agents
appears to be low (3 to 8 mL/min [0.05 to 0.13 mL/s]), suggesting
that plasma clearance is an acceptable technique except in patients
with severe renal insufficiency (GFR <30 mL/min [<0.50 mL/s]).
Indeed, highly significant correlations between renal clearance
among radiolabeled markers has been demonstrated.88 Although
total radioactive exposure to patients is usually minimal, use of one
of these agents does require compliance with radiation safety committees and appropriate biohazard waste disposal.
+, least acceptable; ++, adequate; +++, better; ++++, best.
e|CHAPTER Radiolabeled markers
Nonisotopic contrast agents
iothalamate have been reported.82–84 These data support iohexol as a
suitable alternative marker for the measurement of GFR. A reported
advantage of this agent is that a limited number of plasma samples
(as few as two collected at 120 and 300 min after injection) can
be used to quantify iohexol plasma clearance.85 For patients with a
reduced GFR more time must be allotted—more than 24 hours if the
estimated GFR is less than 20 mL/min (0.33 mL/s).
280
Organ-Specific Function Tests and Drug-Induced Diseases
Estimation of GFR
6 Because of the invasive nature and technical difficulties of
directly measuring GFR in clinical settings, many equations for estimating GFR have been proposed over the past 10 years (eTable 18-5).
A series of related GFR estimating equations (eGFR) have been
developed for the primary purpose of identifying and classifying
CKD in many patient populations.92–99 The initial equation was
derived from multiple regression analysis of data obtained from the
1,628 patients enrolled in the Modification of Diet in Renal Disease
Study (MDRD) where GFR was measured using the renal clearance of 125I-iothalamate methodology. The first regression model
yielded a six-variable Modification of Diet in Renal Disease Study
(MDRD6) equation.92 This equation (r2 = 0.902) provided a more
precise estimate of the measured GFR in the MDRD population than
measured CLcr (r2 = 0.866) or CLcr estimated by the Cockcroft-Gault
eTable 18-5 Equations for the Estimation of GFR in Adults with Stable Renal Function
Levey et al.92 (MDRD6)
GFR = 170 × (Scr)–0.999 × [age]–0.176 × [0.762 if patient is female] × [1.180 if patient is black] × [BUN]–0.170 × [Alb]0.318
Levey et al.93 (MDRD4)
GFR = 186 × (Scr)–1.154 × (age)–0.203 × (0.742 if patient is female) × (1.210 if patient is black)
Levey et al. (MDRD4-IDMS)
GFR = 175 × (Scr)–1.154 × (age)–0.203 × (0.742 if patient is female) × (1.210 if patient is black)
Levey et al.
GFR = 141 × min(Scr/k, 1)α × max(Scr/k, 1)−1.209 × 0.993age × 1.018 [if female] × 1.159 [if black]
94
100
(CKD-EPI)
5.249
−
2.114
− 0.00686 × Age − 0.205 (if female)]
Rule et al.102 (MCQ)
GFR = exp[1.911 +
Larsson et al.109
GFR = 77.24 × (CysC in mg/L)–1.2623
Macdonald et al.108
Log10eGFR = 2.222 + − 0.802 ×
CKD-EPI
Equation 8112
eGFR = 127.7 × (CysC in mg/L)−1.17 × (age in years)−0.13 × 0.91 (if female) × 1.06 (if black)
*eGFR = 127.7 × (−0.105 + 1.13 × standardized SCysC)−1.17 × age−0.13 × (0.91 if female) × (1.06 if black)
CKD-EPI
Equation 9112
eGFR (mL/min/1.73 m2) = 76.7 × (CysC in mg/L)−1.19
*eGFR (mL/min/1.73 m2) = 76.7 × (−0.105 + 1.13 × CysC in mg/L)−1.19
CKD-EPI
eGFR (mL/min/1.73 m2) = 177.6 × (Scr in mg/dL)−0.65 × (CysC in mg/L)−0.57 × (age in years)−0.20 × 0.82 [if female] × 1.11 [if black]
*eGFR (mL/min/1.73 m2) = 177.6 × (Scr in mg/dL)−0.65 × (−0.105 + 1.13 × CysC in mg/L)−0.57 × (age in years)−0.20 × 0.82 [if female] ×
1.11 [if black]
Equation 10
112
Scr*

Scr2
CysC in

SECTION
2
equation (r2 = 0.842). A newer four-variable version of the original
MDRD equation (MDRD4), based on plasma creatinine, age, sex,
and race, was shown to provide a similar estimate of GFR results
compared to the six-variable equation predecessor93 and has been
subsequently updated according to nationally recognized serum creatinine concentration (IDMS) assay results.94 The MDRD4–IDMS
equation is recommended by the NKF and the National Kidney
Disease Education Program (NKDEP) for calculating the estimated
GFR (eGFR) in patients with a history of CKD risk factors and a
GFR <60 mL/min/1.73 m2 (<0.58 mL/s/m2). The performance of the
MDRD4 equations has been assessed in a variety of patient populations with GFR < 60 mL/min/1.73 m2 (<0.58 mL/s/m2), including
those with diabetic nephropathy and renal transplant patients. However, the MDRD4 equations have been shown to be significantly
biased in healthy subjects, diabetic patients with normal GFR (88 to
182 mL/min/1.73 m2 [0.85 to 1.75 mL/s/m2]), and healthy potential
kidney donors.95 In patients with GFR values >60 mL/min/1.73 m2
(>0.58 mL/s/m2), the values provided by the MDRD4 equation
have been shown to be highly variable and less accurate than other
traditional estimation methods, perhaps in part due to the fact that
the original study population consisted of only patients with low
GFR values (<60 mL/min/1.73 m2 [<0.58 mL/s/m2]). The study also
included few Asians, elderly patients, and those with diabetes, or
ill, hospitalized patients.96,97 A recent study conducted by the FDA
compared the eGFR estimated by the MDRD4 equation to the CLcr
estimated by the Cockcroft-Gault equation in 973 subjects enrolled
in pharmacokinetic studies conducted for new chemical entities submitted to the FDA from 1998 to 2010.98 The MDRD4 equation eGFR
consistently overestimated the CLcr calculated by the CockcroftGault method. The FDA investigators concluded that “For patients
with advanced age, low weight, and modestly elevated serum creatinine concentration values, further work is needed before the MDRD
equations can replace the Cockcroft-Gault equation for dose adjustment in approved product information labeling.”
accuracy and precision of measured CLcr as an indicator of GFR has
been evaluated. The CLcr-to-CLDPTA ratio declined from 1.33 with
placebo to 1.07 when 400 mg of cimetidine was administered four
times a day for 2 days prior to and during the clearance determination.90 Similar results were observed when a single 800-mg dose of
cimetidine was given 1 hour prior to the simultaneous determination
of CLcr and CLiothalamate; the ratio of CLcr to CLiothalamate was reduced
from a mean of 1.53 to 1.12.91 Thus a single oral dose of 800 mg of
cimetidine should provide adequate blockade of creatinine secretion
to improve the accuracy of a CLcr measurement as an estimate GFR
in patients with stages 3 to 5 CKD.
To minimize the impact of diurnal variations in serum creatinine concentration on CLcr, the test is usually performed over a
24-hour period with the plasma creatinine obtained in the morning,
as long as the patient has stable kidney function. Collection of urine
remains a limiting factor in the 24-hour CLcr because of incomplete
collections, and interconversion between creatinine and creatine that
can occur if the urine is not maintained at a pH <6.
mg
+ (0.009876 × LM)
L
Alb, serum albumin concentration (g/dL); BUN, blood/serum urea nitrogen concentration (mg/dL); CLcr, creatinine clearance in mL/min; IBW, ideal body weight (kg); Scr, serum
or plasma creatinine (mg/dL).
k is 0.7 for females and 0.9 for males, α is −0.329 for females and −0.411 for males, min indicates the minimum of Scr/k or1, and max indicates the maximum of Scr/k or 1.
(*If SCr < 0.8 mg/dL, use 0.8 for SCr). For SI conversion purposes serum/plasma creatinine is converted from µmol/L to mg/dL by multiplying by 0.0113; BUN is converted
from mmol/L to mg/dL by multiplying by 2.80; Alb is converted from g/L to g/dL by multiplying by 0.1.
Conversion from eGFR conventional units of mL/min/1.73 m2 to eGFR SI units of mL/s/m2 requires multiplication by 0.00963; conversion from creatinine clearance or eGFR
conventional units of mL/min to SI units of mL/s requires multiplication by 0.0167; Cystatin C in nmol/L can be converted to mg/L by multiplication using 0.01335 as the
conversion factor.
The starred equations were developed for use with standardized CysC assays.112
Copyright © 2014 McGraw-Hill Education. All rights reserved.
281
Clinical Controversy. . .
Chronic Kidney Disease–EPI Equation
The CKD-EPI study equation was recently compared to the MDRD
equation using pooled data from patients enrolled in research or
clinical outcomes studies, where GFR was measured by any exogenous tracer.100 The findings of the study indicated that the bias of
CKD-EPI equation was 61% to 75% lower than the MDRD equation for patients with eGFR of 60 to 119 mL/min/1.73 m2 (0.58 to
1.15 mL/s/m2). Based on these findings, the CKD-EPI equation
is most appropriate for estimating GFR in individuals with eGFR
values >60 mL/min/1.73 m2 (>0.58 mL/s/m2). Currently the Australasian Creatinine Consensus Working Group is one of the first
to recommend that clinical laboratories switch from the MDRD4
to CKD-EPI for routine automated reporting.103 If one’s clinical
lab does not automatically calculate eGFR using the CKD-EPI, it
becomes a bit of a challenge since the equation requires a more
complex algorithm than the MDRD equation.
Most labs now use IDMS–calibrated creatinine assays and
with the recommendation that a revised “CKD-EPI–IDMS” equation be used based on the estimated 5% lower creatinine values
that result from the using the IDMS–calibrated assay are near fully
implemented.4,104
Limitations of the pooled analysis approach used to develop
the MDRD and CKD-EPI equations include the use of different
GFR markers between studies (iothalamate, 51CR-EDTA, 99mTcDTPA), different methods of administration of the GFR markers
(subcutaneous and IV), and different clearance calculations (renal
clearance vs. plasma disappearance). These limitations may partly
explain the reduced accuracy observed with the MDRD4 equation
at GFR values >60 mL/min/1.73 m2 (>0.58 mL/s/m2). Additionally, a recent inspection of the MDRD GFR study data showed
that large intrasubject variability in GFR measures was a likely
contributor to the inaccuracy of the gold standard method ([125I]
Mayo Clinic Quadratic Equation
The MCQ equation was developed by Rule et al.102 to estimate GFR
from a population of CKD (n = 320) and healthy individuals (n =
580), using 1/Scr, 1/Scr,2 age, and sex as the covariates. Using the
NHANES database, Snyder et al.99 reported that MCQ GFR values
resulted in 28% fewer patients being categorized as CKD stage 3 or
4 when compared to MDRD4.
Combined Serum Creatinine
and Cystatin C Equations
Addition of serum cystatin as a covariate in equations to estimate
GFR has been employed as a means to improve creatinine-based
estimations that historically were limited to lean body mass (LM),
age, sex, race, and serum creatinine concentration (Scr).108–113
Serum Cystatin C Equations
A significant limitation of serum cystatin C as a renal biomarker
is the influence of body mass on serum concentrations. Studies by
MacDonald et al.108 and Vupputuri et al.111 reported that fat-free mass
is a significant covariate in GFR determination using cystatin C.
Using GFR measured as plasma inulin clearance, lean body mass
accounted for at least 16.3% of the variance in GFR values obtained
using cystatin C (p < 0.001). When using a cystatin C-based estimate
of GFR, which incorporates the CysC, age, race, and sex, a higher
prevalence of CKD was reported in obese patients when compared
to the MDRD4 equation.111 In a recent retrospective analysis of over
1,000 elderly individuals (mean age 85 y) enrolled in the Cardiovascular Health Study, GFR was estimated using the CKD-EPI and
CKD-EPI-CysC equations.113 In this population, all-cause mortality
rates were significantly different between equations. The CKD-EPI
equation yielded a U-shaped association, whereas the CysC equation
yielded a linear relationship at eGFR values <60 mL/min/1.73 m2
(<1.0 mL/s/m2), suggesting that CysC does not accurately predict
mortality risk in patients with low serum creatinine concentration,
reduced muscle mass and malnutrition. This further highlights the
important relationship between muscle mass and serum CysC concentrations, and cautions against the use of CysC-based equations in
the elderly.
Copyright © 2014 McGraw-Hill Education. All rights reserved.
18
Evaluation of Kidney Function
A single GFR equation may not be best suited for all populations, and choice of equation has been shown to impact CKD
prevalence estimates.99 This has led to a revitalized interest in the
development of new equations to estimate GFR. The newest equations to be proposed for the estimation of GFR have been derived
from wider CKD populations than the MDRD study, and include the
Chronic Kidney Disease Epidemiology Study (CKD-EPI)100 and the
Mayo Clinic Quadratic Equation102 or MCQ. The CKD-EPI equation was developed from pooled study data involving 5,500 patients
(including the original MDRD population), with mean GFR values of 68 ± 40 mL/min/1.73 m2 (0.65 ± 0.39 mL/s/m2) (range 2 to
190 mL/min/1.73 m2 [0.02 to 1.83 mL/s/m2]). It has been reported
that the CKD-EPI equation is less biased (2.5 vs. 5.5 mL/min/
1.73 m2 [0.024 vs. 0.053 mL/s/m2]) but similarly imprecise compared to MDRD4.101
e|CHAPTER Some practitioners are advocating the use of the
four-variable Modification of Diet in Renal Disease
Study equation (MDRD4) in patients without chronic
kidney disease (CKD), although it appears to have a
weaker correlation with glomerular filtration rate (GFR)
than the Cockcroft-Gault equation. Recent evidence
suggests that the MDRD4 equation should be reserved
for patients with a GFR <60 mL/min/1.73 m2 (<1.0 mL/s/
m2). The use of newer equations, such as the CKD-EPI,
has improved accuracy in patients with GFR >60 mL/
min/1.73 m2 (<1.0 mL/s/m2); however, further studies
incorporating additional biomarkers such as cystatin
C are underway.
iothalamate urinary clearance) that was used to create the MDRD
equation.105
Numerous studies have consistently reported that the MDRD4
eGFR equation overestimates CLcr estimated by the Cockcroft-Gault
equation in more than 40,000 patients. For example, Wargo et al.106
evaluated 409 patients with CKD admitted to a tertiary care clinic.
The CKD-EPI equation significantly overestimated the CockcroftGault equation (39.9 mL/min vs. 34.8 mL/min [0.67 mL/s vs.
0.58 mL/s], respectively; p < 0.001), with 95% of cases ranging
from –5.1 mL/min to +15.3 mL/min (–0.09 mL/s to +0.26 mL/s).
In the largest retrospective study comparing the Cockcroft-Gault
and MDRDIND conducted to date, Melloni et al.107 reported that
use of MDRDIND eGFR resulted in a failure to make manufacturerrecommended dose reductions for enoxaparin and the glycoprotein
IIb/IIIa inhibitor (GPI) eptifibatide in up to 50% of their cohort of
more than 49,000 patients. The excessive MDRDIND-derived doses
were also correlated with major bleeding episodes (odds ratio 1.57
[95% CI 1.35–1.84]). Thus, the MDRDIND equation should not be
used in lieu of Cockcroft-Gault for renal dose adjustments for these
drugs. Thus, it is important to understand that eGFR equations such
as MDRD4 and CKD-EPI were developed for the purpose of identifying and stratifying CKD based on large multicenter epidemiologic
studies. Extension of their use for individualized drug dosing has
not been fully evaluated and automatic substitution of MDRD4 or
CKD-EPI in place of estimated or measured CLcr for drug dose
calculations should be avoided (eFig. 18-3).
282
Yes
Does patient have
stable kidney
function?
SECTION
Does patient have condition
associated with altered
creatinine generation, e.g.,
malnourishment, low or high
muscle mass, amputee?
2
Organ-Specific Function Tests and Drug-Induced Diseases
No
Yes
No
If using narrow therapeutic
window drugs, but TDM is
unavailable, obtain a measured CLcr
Calculate renal dose regimen
Calculate CLcr by C-G (mL/min)
*If BMI >40 kg/m2, use lean
body weight
Calculate eGFR
(mL/min/1.73 m2)
Calculate renal dosing
regimen based on C-G CLcr
Use eGFR for CKD staging
according to KDIGO, etc.
eFigure 18-3 Algorithm for estimating kidney function using eGFR and/or eCLcr approaches. Creatinine clearance is converted from
mL/min to mL/s by multiplying by 0.0167. (BMI, body mass index; C-G, Cockcroft-Gault; CLcr, creatinine clearance; eGFR, estmated
glomerular filtration rate.)
Use of CysC-based equations to estimate GFR may also be
problematic in patients with autoimmune disorders. It has been
reported that cystatin C levels are associated with disease activity in patients with rheumatoid arthritis, which may be due to the
presence of C-reactive protein or analytical interference from
drugs such as glucocorticoids and infliximab. A single dose of infliximab (3 mg/kg) resulted in a 14% (p < 0.05) increase in CysC,
whereas no change was observed in serum creatinine concentration or GFR values.114
In 167 patients with rheumatoid arthritis and 91 controls,
CysC levels were significantly higher in RA than controls (15%;
p < 0.001]. Furthermore, CysC levels correlated positively with
erythrocyte sedimentation rate (p < 0.001), and C-reactive protein
(p = 0.01), indicating that CysC levels are associated with severity of
disease.115 Thus, CysC-based equations should be used with caution
in the obese, elderly and those with inflammatory conditions such as
rheumatoid arthritis.
Additional research on the utility of these newer eGFR equations in diverse ethnic groups has resulted in modifications or
“correction factors,” such as those for Japanese116 and Chinese117
populations.
A variety of online resources provide GFR calculators such
as the NKDEP website,118 which provides aGFR calculator based
on the MDRD4–IDMS equation. The NKDEP also recommends
that laboratories report eGFR values greater than or equal to 60 as
“ >60 mL/min/1.73 m2 (>1.0 mL/s/m2), not as an exact number,” due
to inaccuracies of the MDRD4 equation at higher levels of GFR. It
should be noted that one must verify that a given equation is appropriate for the institutional creatinine reporting method.
Clinical Controversy. . .
Drug-dose individualization is often required in patients
with chronic kidney disease (CKD). Approved drug labeling
typically includes dose-adjustment information based on
the patient’s estimated creatinine clearance (CLcr) using the
Cockcroft-Gault method. Automated estimated glomerular
filtration rate (eGFR) reporting by many hospital laboratories
has now raised the question if the four-variable Modification
of Diet in Renal Disease Study equation (MDRD4)/ CKD-EPI
or any other GFR estimation equations should be used as a
guide for drug-dose adjustments.
Estimation of Creatinine Clearance
7 Many equations describing the mathematical relationships
between various patient factors and measured CLcr, the most widely
recognized surrogate for GFR in clinical settings. Most equations
incorporate factors such as age, gender, weight, and serum creatinine concentration, without the need for urine collection. The most
widely used of these estimators is the Cockcroft-Gault equation,119
which identified age and body mass as factors, which significantly
contribute to the estimate of CLcr. This relationship was based on
Copyright © 2014 McGraw-Hill Education. All rights reserved.
283
And BMI is calculated as:
BMI (kg/m2) = weight (kg) / height (m)2
Regardless of the approach used to estimate renal function in
obese patients, it is imperative that drug therapy outcomes be monitored closely in this population.
Clinical Controversy. . .
The use of ideal or lean body weight for estimating
creatinine clearance (CLcr) in obese patients is controversial.
Some clinicians recommend using a weight adjustment in
patients that are greater than 30% above ideal body weight
(IBW), such as using an adjusted body weight. However,
recent studies by the FDA indicate that use of IBW should
be avoided. Further research evaluating weight-based
adjustments and drug pharmacokinetic outcomes is needed.
Luke et al.121 evaluated the ability of the Cockcroft-Gault
method and four other methods to determine eCLcr, with inulin
clearance being considered the standard measure of GFR. The
simultaneously determined inulin and measured creatinine clearances correlated best, r2 = 0.85, and the measured CLcr overestimated CLinulin by approximately 15% due to tubular secretion of
creatinine. Of the five estimated creatinine clearances, the ones
calculated by the Cockcroft-Gault and Mawer et al. methods122
correlated the best with GFR. Other methods, such as Jelliffe123
and Hull et al.,124 consistently underestimated the measured CLcr
(eTable 18-6).
Patients undergoing screening for participation in the African
American Study of Kidney Disease (AASK) were evaluated for
kidney function based on eCLcr, simultaneous 125I-iothalamate and
measured 24-hour CLcr.125 The simultaneous measured CLcr provided the best estimate of GFR. The Cockcroft-Gault method was
the preferred method for eGFR, based on performance and ease of
use. This method was noted to underestimate the GFR by 9%, perhaps because of the increased excretion rate of creatinine by black
patients.126
Equations for the Estimation of Creatinine
Clearance in Adults with Stable Renal
Function
Cockroft and
Gault119
Men: CLcr = (140 − age)ABW/(Scr × 72)
Women: CLcr × 0.85
Jelliffe123
Men: CLcr = (100/Scr) − 12
Women: CLcr = (80/Scr) − 7
Jelliffe123
Men: CLcr = 98 − [0.8 (age − 20)]/Scr
Women: CLcr × 0.9
Mawer et al.122
Men: IBW [29.3 − (0.203 × age)] [1 − (0.03 × Scr)]/(14.4 × Scr)
Women: IBW [25.3 − (0.175 × age)] [1 − (0.03 × Scr)]/(14.4 × Scr)
Hull et al.124
Men: CLcr = [(145 − age)/Scr] − 3
Women: Clcr × 0.85
CLcr, creatinine clearance in mL/min; IBW, ideal body weight (kg); Scr, serum or
plasma creatinine (mg/dL).
For SI conversion purposes serum/plasma creatinine is converted from µmol/L
to mg/dL by multiplying by 0.0113. Conversion from creatinine clearance
conventional units of mL/min to SI units of mL/s requires multiplication
by 0.0167.
Administration of cimetidine has also resulted in improved
performance of the Cockcroft-Gault equation as means to calculate
eGFR. Ixkes et al.127 gave patients three 800-mg doses of cimetidine
in 24 hours, and measured creatinine plasma levels from 3 to 7 hours
following the final dose. During this 4-hour period, the CLiothalamate
was determined as the measure of GFR. The Cockcroft-Gault calculations were performed with the plasma creatinine measurement
3 hours after the last dose of cimetidine. The ratio of the CockcroftGault eCLcr-to-CLiothalamate decreased from 1.28 ± 0.21 to 0.98 ± 0.11
in the presence of cimetidine. This cimetidine dosing schedule also
improved the accuracy of Cockcroft-Gault eCLcr relative to GFR in
renal transplant patients with GFR values ranging from 20 to 80 mL/
min/1.73 m2 (0.19 to 0.77 mL/s/m2).128,129
Liver Disease
The estimation of CLcr or GFR is particularly problematic in
patients with preexisting liver disease and renal impairment.
Lower-than-expected serum creatinine concentration values may
result from reduced muscle mass, protein-poor diet, diminished
hepatic synthesis of creatine (a precursor of creatinine), and fluid
overload can lead to significant overestimation of CLcr. Orlando
et al.130 evaluated 10 healthy subjects, 10 patients with mild liver
disease, and 10 with severe liver disease, and observed a measured
CLcr-to-CLinulin ratio of 1.05, 1.03, and 1.04 for each group, respectively. When the CLcr of patients with severe liver disease was
estimated using the Cockcroft-Gault equation, the resultant ratio
(eCLcr-to-CLinulin) was 1.23. Lam et al.131 likewise noted an overestimation by Cockcroft-Gault of the measured CLcr in patients with
severe disease, by 40% to 100%.
Studies of renal function in patients with severe hepatic disease
confirm the earlier observations of Hull et al.124 and Caregaro et al.132
who reported that measured CLcr overestimated GFR by up to
50% in hepatic patients with a GFR of 56 ± 19 mL/min/1.73 m2
(0.54 ± 0.18 mL/s/m2) because of increased tubular secretion of creatinine. The effect of cimetidine administration on measured CLcr
was evaluated in a small study by Sansoe et al.133 In 12 patients
with compensated cirrhosis, serum creatinine concentration values
increased from 0.68 ± 0.11 to 0.94 ± 0.14 mg/dL (69 ± 10 μmol/L
to 83 ± 12 μmol/L) during coadministration of cimetidine (1,000
mg given as 400 mg × 1 then 200 mg every 3 hours) during a 9-hour
clearance period. The measured CLcr declined from 138 ± 20 prior
to cimetidine administration to 89 ± 13 mL/min (2.30 ± 0.33 to 1.49
± 0.22 mL/s), with no change in measured GFR.
Copyright © 2014 McGraw-Hill Education. All rights reserved.
18
Evaluation of Kidney Function
LBW (kg, males) (9270 × weight) / (6680 + 216 × BMI)
LBW (kg, females) (9270 × weight) / (8780 + 244 × BMI)
eTable 18-6
e|CHAPTER observations from 249 male patients with stable kidney function
in whom the creatinine production rates were estimated. Estimated
creatinine clearance (eCLcr), using the Cockcroft-Gault equation, is
one of the methods endorsed by the FDA for stratifying patients in
drug development pharmacokinetic studies, and has been reported
most often in FDA-approved package inserts for new drug entities
since the 1990s.7,96
One of the key considerations with the use of this equation is
whether or not a modified weight index should replace actual body
weight. Several modified weight indices have been proposed and
this remains a controversial issue. For obese individuals, defined as
those with a body mass index (BMI) greater than or equal to 30 kg/
m2 but less than 40 kg/m,2 it is generally recommended that total
or actual body weight be used. This is based on a recent analysis
by the FDA indicating that the Cockcroft-Gault equation had <10%
bias in nearly 600 normal weight, overweight, and obese individuals enrolled in drug pharmacokinetic studies.120 In morbidly obese
individuals (BMI ≥ 40 kg/m,2 obesity class III) an alternate measure of body weight such as lean body weight was shown to significantly reduce bias in the Cockcroft-Gault equation, where lean body
weight (LBW) is calculated as:
284
SECTION
2
Organ-Specific Function Tests and Drug-Induced Diseases
In cirrhotic patients being evaluated for liver transplant (GFR
58 ± 5.1 mL/min/1.73 m2 [0.56 ± 0.049 mL/s/m2]) the eGFR by the
MDRD4 and MDRD6, and the eCLcr by Cockcroft-Gault significantly overestimated measured GFR by 30% to 50%, and all three
were considered unacceptable methods for renal function assessment in liver transplant patients.134,135
Recently, Gerhart et al.136 evaluated the performance of the
CKD-EPI and MDRD4–IDMS equations in patients with liver
disease following transplantation (group 1, n = 59) and those with
cirrhosis (group 2; n = 44). When compared to measured GFR,
both equations yielded positively biased estimates of GFR (4 to
9 mL/min/1.73 m2 [ 0.04 to 0.09 mL/s/m2]) in transplanted patients.
However, in patients with hepatic cirrhosis, both equations were
more significantly positively biased (40 to 42 mL/min/1.73 m2 [0.39
to 0.40 mL/s/m2]), with low precision (21 to 26 mL/min/1.73 m2
[0.20 to 0.25 mL/s/m2]) and low accuracy with only 7% of patients
having eGFR values within 30% of the measured GFR.
Thus, renal function assessment in patients with hepatic disease should be performed by measuring glomerular filtration, and
estimation equations for GFR or CLcr should be avoided.
Other Special Populations
Davis and Chandler137 confirmed the accuracy of the CockcroftGault eCLcr method in trauma patients with stable kidney function,
and Thakur et al.40 demonstrated its acceptable performance in 42
paraplegic patients. Renal transplant recipients are frequently monitored for renal function, as numerous complications may occur during the life of the allograft. Ruiz-Esteban et al.138 evaluated the bias
and precision of the MDRD4 and CKD-EPI relative to CockcroftGault in 153 postrenal transplant patients. Here, the mean bias for
MDRD4 was –10.6 ± 12.7 compared to –9.8 ± 11.3 mL/min/1.73
m2 (–0.10 ± 0.12 compared to –0.09 ± 0.11 mL/s/m2) for CKDEPI (p = 0.006), with the CKD-EPI having a higher percentage of
patients within 30% of the Cockcroft-Gault value than the MDRD
equation (86.9% vs. 81.7%), p <.001). Huang et al.139 reported the
inability of several CLcr equations to predict renal function in hospitalized patients with advanced human immunodeficiency virus
(HIV) disease. All of the prediction methods overestimated the
measured 24-hour CLcr. The reasons for the poor predictability of
these methods are unclear, although 24-hour collection methods
result in increased variability, often because of inadequate collection of urine.
Renal function assessment during pregnancy is usually performed using a 24-hour CLcr determination, and estimation equations have been shown to perform poorly particularly in the
preeclampsia population. For example, Alper et al.140 recently
evaluated the Cockcroft-Gault, MDRD4 and CKD-EPI equations in
543 women, aged 16 to 49 years, with preeclampsia after the 20th
week of gestation. When compared to 24-hour measured CLcr (mean
133 ± 43 mL/min [2.22 ± 0.72 mL/s]), the Cockcroft-Gault equation
was positively biased (36 ± 2 mL/min [0.60 ± 0.03 mL/s]) whereas
both the MDRD4 and CKD-EPI were negatively biased (–20 ±
1.5 mL/min [–0.33 ± 0.025 mL/s]).Thus, kidney function estimating
equations should not be used during pregnancy.
Unstable Renal Function
Patients with unstable kidney function or AKI present a unique situation because serum creatinine concentration values are changing,
and steady state cannot be assumed, which is one of the assumptions
of all the above-mentioned eCLcr methods. It is now widely accepted
that a change in the serum creatinine concentration of more than
50% over a period of 7 days, or an increase in serum creatinine concentration by at least 0.3 mg/dL (≥27 μmol/L) over a 24- to 48-hour
period indicates the presence of AKI.141 Methods to measure GFR in
this population, such as 125I-iothalamate clearance, are cumbersome
and costly especially in the acute care setting. Although several
equations have been proposed the calculate eCLcr in AKI patients
or those with rapidly progressive renal disease,142–144 a rigorous
evaluation of the accuracy and precision of each of these proposed
methods is lacking and none of them is currently recommended for
clinical use. Use of semiquantitative approaches is preferred for the
purpose of estimating severity of disease using RIFLE and AKIN
criteria (see Chap. 28 for more details).
Use of abbreviated CLcr measurements (<24 h) may be valuable for detecting early evidence of AKI in critically ill patients.
Pickering et al.145 recently reported that 4-hour CLcr measurements
were significantly better at predicting AKI events than serum creatinine concentration alone in 484 patients. However, the lack of true
measured GFR in these patients prevented assessment of the accuracy and precision of the CLcr values. Hoste et al.146 used 1-hour CLcr
measurements to evaluate the Cockcroft-Gault and MDRD equations in critically ill patients within 1 week of ICU admission. Both
equations were poorly correlated with CLcr (R < 0.5), and were
similarly imprecise with Bland-Altman 95% confidence intervals
ranging from –77 to 64 mL/min (–1.29 to 1.07 mL/s) for CockcroftGault and –77 to 58 mL/min/1.73 m2 (–0.74 to 0.56 mL/s/m2) for
MDRD. Changes in serum creatinine concentration have also been
shown to be more sensitive than cystatin C in early AKI.
It is thus, ultimately, most important to recognize that renal function in patients with AKI is generally markedly lower than one would
estimate using steady-state methods, and dose adjustments should be
made if necessary to avoid drug toxicity (see Chaps. 28 and 33).
Kidney Function in Children
Kidney function in the neonate is difficult to assess because of difficulty in urine and blood collection, the frequent presence of a non–
steady-state serum creatinine concentration, and apparent disparity
between development of glomerular and tubular function. Preterm
infants demonstrate significantly reduced GFR prior to 34 weeks,
which rapidly increases and becomes similar to term infants within
the first week of life.147 Evaluation of GFR in preterm infants on day
3 of life, using an inulin infusion, failed to identify a relationship
between patient weight and GFR. Gestational age, which ranged
from 23.4 to 36.9 weeks (mean: 30.2 weeks), however, correlated
with both GFR and reciprocal of serum creatinine concentration
(Scr). The inulin clearance increased from 0.67 to 0.85 mL/min
(0.011 to 0.014 mL/s) in those with gestational age <28 weeks versus those of 32 to 37 weeks of age, while Scr decreased from 1.05
to 0.73 mg/dL (93 to 65 μmol/L), respectively. Creatinine was measured using a specific enzymatic method to avoid interference from
bilirubin or drugs.148 Creatinine clearance has also been evaluated
in infants younger than 1 week of age, and values of 17.8 mL/min/
1.73 m2 (0.171 mL/s/m2) on day 1 increased to 36.4 mL/min/1.73 m2
(0.351 mL/s/m2) by day 6.149 In light of these rapid changes in GFR,
estimation of GFR is not recommended for infants younger than
1 week of age. Kidney function expressed as GFR standardized
to body surface area increases with age and stabilizes at approximately 1 year. In older children, GFR is best assessed using standard
measurement techniques for GFR. Subcutaneous administration of
125
I-iothalamate has been effectively used to measure GFR in children ranging in age from 1 to 20 years.150 The original equation to
estimate GFR as described by Schwartz et al.151 is dependent on the
child’s age and length:
GFR = [length (cm) × k] / (Scr in mg/dL)
where k is defined by age group: infant (1 to 52 weeks) = 0.45;
child (1 to 13 years) = 0.55; adolescent male = 0.7; and adolescent female = 0.55. Serum creatinine in mmol/L can be converted
to mg/dL by multiplication using 0.0113 as the conversion factor.
A newer version of the Schwartz equation152 was developed from
a population of 349 children (age 1 to 19 y) with mild-to-moderate
Copyright © 2014 McGraw-Hill Education. All rights reserved.
285
CKD enrolled in the Chronic Kidney Disease in Children (CKiD)
study. This simple equation is commonly referred to as the Schwartz
“Bedside” formula:
GFR = 0.41 * [length (cm)/Scr in mg/dL]
× (30/BUN)0.079 × 1.076male × [ht(m)/1.4]0.179
This equation had the lowest root-mean square error (0.147),
highest R2 (0.863) and highest frequency of values within 30% of
iohexol-measured GFR (91.3%) when compared to seven other
GFR equations.
Kidney Function in the Elderly
Cross-sectional studies have historically shown that GFR declines
as a function of age.156,157 The largest prospective study conducted
in healthy elderly individuals is the Baltimore Longitudinal Study
on Aging (BLSA).157 In an initial analysis of 254 BLSA participants without kidney disease, it was reported that measured CLcr
decreases at the rate of approximately 0.75 mL/min/1.73 m2/y
(0.0072 mL/s/m2/y) beginning at the fourth decade of life. These
subjects were then evaluated prospectively for up to 23 years. Interestingly, approximately one-third of the subjects showed no change
in renal function from their baseline value, and a small number
showed an increased clearance. These changes may be a result of
normal physiologic changes or of subclinical insults to the kidneys
initiating the events leading to chronic progressive loss of renal
function. Fliser et al.158 studied renal functional reserve in healthy
young (23 to 32 years) and elderly (61 to 82 years) volunteers using
an amino acid infusion technique. Measured GFR increased by
16% in young and 17% in elderly subjects following the infusion.
Renal functional reserve thus appears to be maintained in healthy
elderly individuals.
Interpretation of the serum creatinine concentration alone is
difficult in the elderly patient primarily because of the decreased
muscle mass and resultant lower production rate of creatinine. Thus,
the serum creatinine concentration often remains within the normal
range despite a reduction in the number of functional nephrons. As
renal function declines, the kidneys excrete a larger fraction of creatinine. This perpetuates the “normal” serum creatinine concentration. Recent recommendations such as the adoption of standardized
creatinine assays by clinical laboratories and reporting of serum
creatinine concentration values to two decimal places will likely
Estimation of creatinine clearance in elderly with low serum
creatinine values is controversial. Some clinicians advocate
correction of serum creatinine to 1.0 mg/dL (88 μmol/L)
to account for reduced muscle mass. This practice should
be avoided, and the impact of this correction factor
on glomerular filtration rate (GFR) estimates using the
four-variable Modification of Diet in Renal Disease Study
equation (MDRD4) or other equations has yet to be
evaluated in this population.
The Cockcroft-Gault formula119 continues to provide a valid
estimate of the CLcr of elderly patients. Smythe et al.159 estimated
CLcr in 23 patients >60 years of age using seven different methods,
and compared the results to a measured 24-hour CLcr determination. Estimations were performed with the actual serum creatinine
concentration and also with the serum creatinine concentration
rounded up to 1.0 mg/dL (88 μmol/L) if the actual value was
<1.0 mg/dL (<88 μmol/L). Rounding the serum creatinine concentration to 1.0 mg/dL (88 μmol/L) resulted in a significantly lower
eCLcr (–28.8 mL/min [–0.481 mL/s]) compared to the unadjusted
serum creatinine concentration (+2.3 mL/min [+0.038 mL/s]).
In patients >60 years of age with serum creatinine concentration
<1.0 mg/dL (<88 μmol/L), rounding the serum creatinine concentration value up to 1.0 mg/dL (85 μmol/L) resulted in dose estimates
for gentamicin that were significantly lower (–90 ± 67 mg/day) than
doses calculated based on the actual serum creatinine concentration
value.160 Until further data are available, fixing or rounding serum
creatinine concentration to an arbitrary value in elderly patients is
not recommended.
An alternative to the estimation of GFR or a 24-hour measured
CLcr is a 4-hour measured clearance performed during water diuresis. This approach correlated with the inulin clearance as well as
with an observed inpatient 24-hour measured CLcr.87 However, one
must be aware of the potential risk of hyponatremia in the geriatric patient who is unable to tolerate an oral water load, as well as
the need for complete bladder emptying to ensure accurate results.
O’Connell et al.161 assessed the accuracy of 2- and 8-hour urine collections compared with 24-hour CLcr determinations in 45 hospitalized patients >65 years old with indwelling urethral catheters.
The 8-hour timed urine collection for CLcr showed minimal bias
(2.2 mL/min [0.037 mL/s]) as compared with the 24-hour value,
whereas the 2-hour determination was both positively biased
(11 mL/min [0.18 mL/s]) and less precise (25 mL/min [0.42 mL/s]).
Impact on Drug Dosing Recommendations
The automated reporting of eGFR in the clinical setting has led
some practitioners to consider substituting eGFR in place of eCLcr
for renal dose adjustments. Concerns with this approach, particularly in the elderly, include the uncertainty of applying eGFR values
to eCLcr-based dosage adjustment algorithms in package inserts,
which may result in dosing errors and toxicity especially for drugs
with narrow therapeutic indices.104,162–169 Roberts et al.162 reported
that the MDRD eGFR values overestimated gentamicin clearance
by 29% (p < 0.001), whereas the Cockcroft-Gault yielded only 10%
overestimation (p < 0.01), and MDRD overestimated renal function
as age increased. Retrospective studies in more than 1,200 patients
with renal disease have shown that overestimation of renal function using the MDRD4 with or without IDMS creatinine equation
results in up to 30% to 60% higher doses for digoxin, amantadine
Copyright © 2014 McGraw-Hill Education. All rights reserved.
18
Evaluation of Kidney Function
eGFR (mL/min/1.73 m2) = 39.8 × [ht(m)/Scr]0.456
× (1.8/cystatin C)0.418
Clinical Controversy. . .
e|CHAPTER Lee et al. recently reported that this new Bedside Schwartz
equation performed better than the original Schwartz equation for
patients with mild-moderate CKD, but was less accurate in patients
with mild CKD. Thus, the appropriate use of the Bedside Schwartz
equation and accuracy in subpopulations of CKD is yet to be fully
determined.
Equations derived from adult populations have also been evaluated in pediatric patients. Peirrat et al.154 compared the MDRD,
Schwartz, and Cockcroft-Gault equations in children 3 to 19 years of
age. In children <12 years, the Schwartz and MDRD equations were
significantly more biased than Cockcroft-Gault, and CockcroftGault provided the best prediction of GFR in children >12 years.
The results of these investigations suggest that further studies will
be needed to clarify the value of any of these predictive methods in
children. Most recently, an equation for GFR based on beta-trace
protein was shown to yield similar values of GFR compared to the
Schwartz equation in 387 pediatric patients (age 10.7 ± 7.1 y) who
underwent a 99mTC-DTPA GFR scan.70 The most recent GFR equation evaluated in pediatrics includes use of cystatin C, BUN, serum
creatinine concentration (in mg/dL) and demographic data derived
from over 600 pediatric patients enrolled the CKiD study155:
153
improve the accuracy of renal function estimation in the elderly
population.34
286
ASSESSMENT OF PROGRESSION
Organ-Specific Function Tests and Drug-Induced Diseases
7 Chronic kidney disease (see Chap. 29) will eventually lead to
ESRD, necessitating dialysis (see Chap. 30) or transplantation for
survival (see Chap. 70). The rate of progression can be slowed and
in some cases halted through dietary modification, strict blood pressure control, initiation of angiotensin-converting enzyme inhibitor
or angiotensin receptor blocker therapy to reduce urinary protein
excretion, and improved glucose control in patients with diabetes
mellitus (see Chap. 29). The efficacy of these interventions is optimally assessed with the sequential measurement of an accurate and
sensitive index of GFR such as iohexol, iothalamate, or radioisotope
clearance.171
Alternatively, use of newer methods to estimate GFR, such as
cystatin C and the CKD-EPI equation or traditional methods, such
as the linear decline in the reciprocal of the Scr as a function of time,
can be used to evaluate the rate of progression of renal disease and
to predict the time when dialysis will be needed.1,29
eFigure 18-4 depicts the change in estimated GFR or CLcr over
time in a typical patient with progressive CKD. Clinicians can
use the eGFR or CLcr plotted as a function of time as a prognostic
tool, to predict when dialysis may be needed (eCLcr <15 mL/min
[<0.25 mL/s]) or as a marker for evaluating the success of therapeutic interventions to alter the rate of decline in renal function.
Several factors, such as changes in dietary intake of creatinine and
decreased muscle mass, which are associated with a reduction in
45
Estimated GFR or CLcr concentration (mg/dL)
SECTION
2
and various antimicrobials compared to doses calculated using
eCLcr.104,164–169 A recent study by Stevens et al.170 reported that use
of a back-corrected value of eGFR, based on a calculated body surface area (BSA), yields dose calculations that are similar to those
calculated using a measured GFR. This back-correction approach
has not been validated and calculating BSA in clinical settings is
inconvenient and unlikely to occur. A more detailed discussion of
application of renal function estimates and renal dosing approaches
is provided in Chapter 33.
40
35
30
25
20
Therapeutic
intervention
15
10
5
0
0
1
2
3
4
5
6
7
8
9
10
Time (months)
eFigure 18-4 Illustration of rate of eGFR or CLcr decline over
time showing change in renal function in a hypothetical patient
with progressive renal impairment. The arrow indicates a change
in the rate of progression, which may be related to a therapeutic
intervention. CLcr, creatinine clearance; eGFR, estmated
glomerular filtration rate.
the production of creatinine, may alter the utility of the relationship. Microalbuminuria has been identified as an early marker of
renal disease in patients with diabetic nephropathy172 and numerous
other conditions, such as hypertension and obesity.173–175 Albuminuria is a more sensitive marker than total protein for monitoring
CKD progression, as well as a modifiable risk factor for renal disease progression and cardiovascular disease.61 Thus patients with
microalbuminuria (30 to 300 mg/day) on at least two occasions or
overt albuminuria (>300 mg/day) should begin to receive pharmacotherapy. For children, microalbuminuria is considered present if
albumin excretion exceeds 0.36 mg/kg/day, and overt albuminuria
has been defined as an excretion rate that exceeds 4 mg/kg/day.
The urinary albumin-to-creatinine ratio is also an accurate predictor of 24-hour proteinuria, a marker of renal disease. Guidelines
for monitoring indicate that a urine albumin to creatinine ratio of
>30 mg/g (>3.4 mg/mmol) places the patient at increased risk of
developing diabetic nephropathy, mortality, and ESRD and is an
indication for the initiation of pharmacotherapeutic intervention.4,23
Microalbuminuria has also been suggested as a risk factor for renal
dysfunction among patients with essential hypertension.175 Based
on the established link between albuminuria and adverse clinical
outcomes in more than 1.5 million individuals with varying levels of eGFR, the albumin-to-creatinine ratio is now included with
eGFR as part of an updated approach for staging CKD recommended by KDIGO.5
MEASUREMENT OF RENAL
PLASMA AND BLOOD FLOW
Measurement of renal plasma and blood flow is rarely if ever determined in the clinical setting; and it is only occasionally used in
research settings to evaluate hemodynamic changes related to disease or drug therapy. The kidneys receive approximately 20% of cardiac output and representative values of renal blood flow in men and
women of about 1,200 ± 250 and 1,000 ± 180 mL/min/1.73 m2 (11.6 ±
2.4 and 9.6 ± 1.7 mL/s/m2) have been reported, respectively.176 Renal
plasma flow (RPF) is estimated to be 60% of blood flow if it is
assumed that the average hematocrit is 40% and that it can be measured by the use of model compounds that are eliminated from the
plasma compartment on a single pass through the kidneys. Because
only 20% of the plasma is filtered at the glomerulus, the compound
must undergo active tubular secretion and minimal to no reabsorption to be completely eliminated. To accurately reflect RPF, the
extraction through the kidney must be nearly 100%. PAH is an
organic anion that has been used extensively for the quantification
of renal plasma flow. PAH is approximately 17% bound to plasma
proteins and is eliminated extensively by active tubular secretion.
Because PAH elimination is active, saturation of the transport processes should be anticipated, and concentrations of PAH in plasma
should not exceed 10 mg/L. Furthermore, PAH is also metabolized,
possibly within the kidney, to N-acetyl-PAH, and it is important for
the analytical method to differentiate the parent compound from the
metabolite.80,177 The extraction ratio (ER) for PAH is 70% to 90% at
plasma concentrations of 10 to 20 mg/L; hence, the term “effective”
renal plasma flow (ERPF) has been used when the clearance of PAH
is not corrected for the extraction ratio or if it is assumed to be 1.8
Normal values are about 650 ± 160 mL/min (10.9 ± 2.7 mL/s) for
men and 600 ± 150 mL/min (10.0 ± 2.5 mL/s) for women.176 Children will reach normalized adult values by 3 years of age, and ERPF
will begin to decline as a function of age after 30 years, reaching
about one-half of its peak value by 90 years of age. The method
for calculation of ERPF is based on the relationship between organ
clearance, ER, and flow:
ERPF = renal PAH CL = RPF × ER
Copyright © 2014 McGraw-Hill Education. All rights reserved.
287
Effective renal blood flow (ERBF) can be estimated from
ERPF by assuming the extraction ratio is 1 and correcting for the
red blood cell volume of the blood (hematocrit [HCT]):
ERBF = ERPF/(1 – HCT)
Although GFR is the best overall indicator of renal function, it may
not provide an accurate measure of tubular function, either secretory capacity or cellular function, suitable for use in the research
environment.180 Tubular secretory function can be assessed by measuring PAH transport as the prototype marker of the organic anion
secretory system. N1-methylnicotinamide (NMN) and tetraethylammonium are prototype compounds secreted by the cationic transport
system and may be used as markers of cationic secretory capacity.
Edwards et al.181 demonstrated delayed recovery of NMN clearance
among patients with psoriasis treated with low-dose cyclosporine,
as compared with the recovery of GFR and renal blood flow Dowling et al.177 explored the usefulness of famotidine as a marker for
dose-dependent cationic transport, but was unable to demonstrate
saturation at doses up to ten times clinically indicated values, likely
due to the contribution from other parallel secretory pathways such
as P-glycoprotein.182
Furthermore, Karyekar et al.183 demonstrated that itraconazole,
a P-glycoprotein inhibitor, significantly reduced the renal tubular secretion of cimetidine in healthy individuals, suggesting that
cimetidine may be used as an in vivo probe of renal P-glycoprotein
function. It should also be recognized that these transport systems
are not necessarily mutually exclusive. Indeed, probenecid, which
is secreted by the anionic pathway, inhibits the secretion of cationic
compounds. Quantitative measures of tubular transport capacity are
currently limited primarily to the research setting.
Other measures of tubular function are less specific and are
regarded primarily as indices of damage within the nephron. Lowmolecular weight proteins located in the proximal tubule, such as
β2-microglobulin, can be used as urinary biomarkers to detect early
tubular toxicity of drugs such as carboplatin, ifosfamide and etoposide.184 Other low-molecular-weight proteins used as markers of
tubular function include retinol-binding protein (21 kDa), protein
HC (also known as α1-microglobulin, 27 kDa), KIM-1, NGAL,
interleukin-18, and fatty-acid binding proteins (FABPs).63,185,186
These proteins are normally freely filtered at the glomerulus and
then completely reabsorbed by the proximal tubule. Increases in
their excretion are thus suggestive of tubular dysfunction but are not
diagnostic. In each case, the maximal reabsorptive capacity may be
exceeded, leading to net excretion of the protein.
Numerous urinary enzymes such as N-acetylglucosaminidase,
alanine aminopeptidase, alkaline phosphatase, γ-glutamyltransferase,
pyruvate kinase, glutathione transferase, lysozyme, and pancreatic
ribonuclease have been used as diagnostic markers for renal disease. Jung et al.187 compared the ability of five enzymes (N-acetylglucosaminidase, alanine aminopeptidase, alkaline phosphatase,
γ-glutamyltransferase, and lysozyme) to detect early rejection episodes in kidney transplant patients. Only N-acetylglucosaminidase
Radiologic Studies
8 The etiology of kidney disease can be evaluated using several
qualitative diagnostic techniques, including radiography, ultrasonography, magnetic resonance imaging, and biopsy. The standard
radiograph of the kidneys, ureters, and bladder (the KUB) provides
a gross estimate of kidney size and identifies the presence of calcifications.86 Although easy to perform, the value of the information
is minimal, and more detailed evaluations are often necessary. The
IV urogram (formerly known as IV pyelogram) involves the administration of a contrast agent to facilitate visualization of the urinary
collecting system. It is primarily used in the assessment of structural changes that may be associated with hematuria, pyuria, or flank
pain, resulting from recurrent urinary tract infections, obstruction,
or stone formation. For patients with low GFRs, retrograde administration of dye into the ureters may be performed to facilitate visualization of the collecting system. Contrast agents are also employed
during renal angiography for the assessment of renovascular disease. The captopril (angiotensin-converting enzyme inhibitor) test
is also a useful adjunct. Under conditions of unilateral renal artery
stenosis, the affected kidney produces large quantities of angiotensin II, which constricts the efferent arteriole to maintain GFR. The
administration of captopril results in reduced uptake of the contrast
agent because the efferent arteriole is dilated, thereby decreasing the
perfusion pressure of the affected kidney. For patients with bilateral
disease, a decrease in uptake is observed in both kidneys.188 Computed tomography is a cross-sectional anatomic imaging procedure.
The procedure is frequently performed with contrast to enhance
imaging. Spiral, or helical, computed tomography, a more recent
technique, provides for three-dimensional visualization of tissues.
Computed tomography is performed as a test for the evaluation of
obstructive uropathy, malignancy, and infections of the kidney.
Renal Ultrasonography
Ultrasonography uses sound waves to generate a two-dimensional
image. The echogenicity of the kidney is compared with that of an
adjacent organ—liver on the right and spleen on the left—with an
increased echogenicity indicating an abnormal finding. Ultrasonography can distinguish the renal pyramids, medulla, and cortex, and
abnormalities in structure, such as occurs with obstruction. Renal
ultrasonography is also used as a guide for site localization during
percutaneous kidney biopsy.
Magnetic Resonance Imaging
Magnetic resonance imaging is based on aligning hydrogen nuclei
in the body with the use of a powerful magnet and applying radiofrequency pulses. The signals emitted by the hydrogen nuclei during realignment on repeated pulses allows for generation of the
tissue image. Realignment times can also be altered with the use
of contrast agents (gadolinium, gadopentetate), leading to increased
signal intensity and improved imaging. Magnetic resonance imaging is useful for the assessment of obstruction, malignancy, and
Copyright © 2014 McGraw-Hill Education. All rights reserved.
18
Evaluation of Kidney Function
QUANTITATIVE ASSESSMENT
OF TUBULAR FUNCTION
QUALITATIVE DIAGNOSTIC
PROCEDURES
e|CHAPTER ERPF can also be measured using the radioisotopes132
I-orthoiodohippurate (131I-OIH) or 99mTc-mercaptoacetyltriglycine
(99mTc-MAG3).178 One important advantage of this method is its
ability to measure ERPF in total or for each kidney independently, as
well as its ability to produce renal images. Russell and Dubovsky,179
using a single-injection technique, compared clearance methods
with and without urine collection and showed similar results with
each method.
and alanine aminopeptidase were early predictors of rejection.
N-acetylglucosaminidase is an enzyme contained within the lysosome of the tubular cell and is released when the lysosome is damaged, whereas alanine aminopeptidase is an enzyme of the brush
border. Both markers were increased approximately 2 days earlier
than serum creatinine concentration in patients with transplant
rejection.
288
renovascular lesions. The relative advantages and limitations of
these procedures are discussed in more detail in recent reviews.86,189
Biopsy
SECTION
2
Organ-Specific Function Tests and Drug-Induced Diseases
Renal biopsy is used in several conditions to facilitate diagnosis when clinical, laboratory, and imaging findings prove inconclusive. Proteinuria and hematuria are both associated with renal
parenchymal disease. When less-invasive studies are unsuccessful
in differentiating the cause and the possible causes have different
therapeutic approaches, biopsy may be indicated. Functional status
of the kidney is not assessed with biopsy, and severity of disease
and progression is best measured using quantitative tests discussed
above. Contraindications to renal biopsy include a solitary kidney,
severe hypertension, bleeding disorder, severe anemia, cystic kidney, and hydronephrosis, among others. Complications resulting
from biopsy primarily include hematuria, which may last for several
days, and perirenal hematoma.23
CLINICAL BOTTOM LINE
Comprehensive approaches to evaluate renal function in CKD
patients include the Cockcroft-Gault equation for estimating CLcr
and drug dosing, the CKD-EPI equation for estimation of GFR
and staging of CKD, and measurement of urinary protein excretion or albumin-to-creatinine ratio as a marker of the integrity of
the glomerular basement membrane. Measurement of GFR using
exogenous administration of iothalamate, iohexol or radioisotope
techniques such as 99mTc-DPTA is increasingly being employed to
assess progression of disease or acceptability to be a kidney donor.
Other qualitative assessments of kidney function, such as radiography, computed tomography, magnetic resonance imaging, sonography, and biopsy, are most useful to investigate the underlying cause
of kidney disease.
ABBREVIATIONS
ADP
AKI
AASK
ATP
AUC
adenosine diphosphate
acute kidney injury
African American Study of Kidney Disease
adenosine triphosphate
area under the plasma concentration versus time
curve
BLSA
Baltimore Longitudinal Study on Aging
BMI
body mass index
BSA
body surface area
BTP
β-trace protein
BUN
blood urea nitrogen
CIAKI
contrast-induced acute kidney injury
CKD
chronic kidney disease
CKD-EPI
Chronic kidney disease epidemiology collaboration
CKiD
Chronic Kidney Disease in Children
CLclearance
CLcr
creatinine clearance
51
51
Cr-EDTA
Cr-ethylenediaminetetraacetic acid
Css
concentration of a substance in plasma under
steady-state conditions
CYP
cytochrome P450
eCLcr
estimated creatinine clearance
eGFR
estimated glomerular filtration rate
ER
extraction ratio
ERBF
effective renal blood flow
ERPF
effective renal plasma flow
ESRD
end-stage renal disease
FABP
fatty-acid binding protein
FDA
Food and Drug Administration
GFR
glomerular filtration rate
GPI
glycoprotein IIb/IIIa inhibitor
HCThematocrit
HIV
human immunodeficiency virus
ICU
intensive care unit
IDMS
isotope dilution-mass spectrometry
131
131
I-OIH
I-orthoiodohippurate
KDIGO
Kidney Disease: Improving Global Outcomes
KUB
kidneys, ureters, and bladder
MCQ
Mayo Clinic Quadratic Equation
MDRD
Modification of Diet in Renal Disease study
MDRD4
four-variable Modification of Diet in Renal Disease
Study equation
MDRD6
six-variable Modification of Diet in Renal Disease
Study equation
NHANES
National Health and Nutrition Examination Survey
NKDEP
National Kidney Disease Education Program
NKF
National Kidney Foundation
NMN
N1-methylnicotinamide
PAH
para-aminohippuric acid
RPF
renal plasma flow
Scr
serum creatinine concentration
SUN
serum urea nitrogen
99m
Tc-DTPA technetium-99m diethylenetriamine pentaacetic acid
99m
Tc-MAG3 99mTc-mercaptoacetyltriglycine
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