Review

Received 10.4.06 | Revisions Received 10.30.06 | Accepted 12.27.06

Renal Function Tests:

A Clinical Laboratory Perspective
Henry O. Ogedegbe, PhD, BB(ASCP)SC, CLS(NCA)
(Department of Clinical Laboratory Sciences, University of Medicine and Dentistry of New Jersey, Newark, NJ)
DOI: 10.1309/RWG5DY7RG1CYBUR7

Abstract
Worldwide, chronic kidney disease has become
a public health problem with increasing
prevalence and high cost for treatment and
prevention. It is projected that by 2030 there
will be about 2 million patients needing dialysis
and transplantation. Kidneys perform vital
functions in the homeostatic processes of the
human body including the filtration of blood,
maintenance of acid base, water and
electrolyte balance, regulation of hormone
levels, and removal of waste products and
unwanted substances from plasma. Various
hormones that have metabolic and
physiological functions such as erythropoietin,
the prostaglandins, and so forth, are produced
by the kidneys. Several diseases, such as
acute nephrotic syndrome, acute
glomerulonephritis, and others, can singly or in
combination precipitate renal diseases. Various
clinical laboratory tests are useful in the
investigation and evaluation of kidney function.
Different treatment options available for the
management and prevention of renal disease
complications include dialysis and
transplantation.

Background the evaluation of kidney function is limited and imprecise; there-

Chronic kidney disease (CKD) has become a major public
health problem worldwide, and in the United States renal dis-
ease is a common occurrence with poor health outcome and
increase in health expenditure. Kidney failure and cardiovascular
disease (CVD) are complications associated with CKD.1,2 Ac-
cording to the National Kidney Foundation, 11% of the United
States adult population has CKD or are at increased risk of de-
veloping the disorder.1-5 It is projected that the number of pa-
tients treated with dialysis or transplantation will increase from
340,000 in 1999 to 651,000 in 2010.5 By 2030, the number of
patients needing dialysis or transplantation will jump to 2 mil-
lion.4 Death arising from CVD is 10 to 20 times higher in pa-
tients on dialysis than in the general population, and it has been
suggested that CKD is a risk factor for CVD.6
The number of patients requiring dialysis and transplanta-
tion in the United Kingdom is on the rise, and the number is
not expected to reach a steady state for another 25 years.7 The
clinical practice guidelines on CKD was published in February
2002 by the Kidney Disease Outcome Quality Initiative
(K/DOQI) of the National Kidney Foundation.5 The goals of
the work group were to define and classify CKD; evaluate labo-
ratory measurements for the diagnosis of kidney disease; associate
level of kidney function with CKD complications; and stratify
risk for loss of kidney function and development of CVD.5
The kidneys are involved in vital functions associated with
homeostatic processes of the human body, such as filtration of
blood, regulation of acid, water and electrolyte balance, regula-
tion of hormone levels in the blood, and removal of waste prod-
ucts and unwanted substances from plasma. Kidney function
tests are used for the assessment of kidney diseases, acid-base dis-
orders, and water balance. Use of physical examination alone in
fore, laboratory measurement of various substances in plasma and
urine is required for the accurate assessment of kidney function.
Determinations of importance include glomerular filtration rate
(GFR), urine protein levels, disturbances in electrolytes, and
serum concentrations of creatinine, urea, and uric acid.8 Evalua-
tion of patients with CKD should determine diagnosis, comorbid
conditions, severity of disease, complications related to kidney
function, risk of loss of kidney function, and risk of CVD.9
Renal Anatomy
Kidneys are bean-shaped paired organs located in the poste-
rior part of the abdomen on both sides of the spinal column
(Figure 1). The glomerulus is housed in the cortex underneath
the capsule of fibrous tissue enclosing each kidney. The medulla
houses the collecting duct while the pelvis, into which newly
formed urine passes, is a cavity located at the upper end of the
ureter. The ureter connects the kidney to the urinary bladder
(Figure 2). The urinary bladder is a reservoir where urine is
stored until voided from the body via the urethra. Each kidney
has about 1 million nephrons which are tubelike structures. The
nephrons terminate in an enlarged area called Bowman’s capsule.
Other parts of the nephron include the glomerulus, proximal
convoluted tubule (PCT), the loop of Henle, the distal convo-
luted tubule (DCT), and the collecting tubule (Figure 3).10 The
collecting duct into which the DCT empties carries formed
urine from the renal cortex towards the papilla. At the end of
the renal papilla are several collecting ducts which merge into
the papillary duct, and the papillary duct subsequently empties
into the calyx.

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Figure 1_The urinary system.
Figure 3_The nephron.
The renal capsule, PCT, and DCT are housed in the renal
cortex while the medulla houses the loop of Henle and the pap-
illary duct.11 The glomerulus is essentially a tuft of capillaries
formed by the afferent arteriole which is drained by the efferent
arteriole and surrounded by the Bowman’s capsule. The PCT
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Figure 2_A cross section of the kidney.
facilitates the reabsorption of 60% to 80% of the glomerular
filtrate, most of the glucose, K+, HCO3-, PO43-, SO42-, 90% of
H+, and 70% of the Na+ and Cl- secreted by the kidneys. The
PCT runs through the cortex and enters the medulla, forms the
descending and ascending limbs of the loop of Henle, which
reenters the cortex and then forms the DCT. Several DCTs
merge to form the collecting duct.11
Renal Physiology
As stated previously, the main physiological function of the
kidney is the maintenance of fluid and electrolytes homeostasis
in the body, formation of urine, regulation of acid-base balance,
excretion of waste products of protein metabolism, hormonal
function, and protein conservation. The ability of the kidneys to
perform these varied functions is predicated on the fact that
about 25% of the blood pumped by the heart circulates through
the kidney (between 1,000 and 5,000 mL of blood circulating
through the kidneys every minute).12,13 Glomerular filtration,
tubular reabsorption, and tubular secretion are the 3 basic
processes through which the kidneys perform their physiological
functions. A large volume of plasma is filtered by the kidney,
most of which is reabsorbed, and in the process a concentrated
solution containing waste products is produced and eventually
excreted (Table 1).
A semipermeable membrane in the glomerulus allows the
passage of water and electrolytes while excluding large
molecules.12 The end result of this process is the formation of
a filtrate, known as the ultrafiltrate, whose composition is sim-
ilar to that of plasma. About 170 to 200 L of the ultrafiltrate
passes through the glomeruli in a 24-hour period. This volume
of ultrafiltrate is subsequently reduced to a range of 0.4 to 2 L
through the reabsorption of solute and water at various sites
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Table 1_Tubular Reabsorption and Secretion be categorized into hypo-osmolar disorders and hyperosmolar
disorders. Presence of excess water relative to solute results in
Tubule Reabsorption Secretion hyponatremia, and, when the problem is deficiency of water
relative to solute, the result is hypernatremia.14
Proximal Tubule Glucose Para-amino-hippurate The regulation and conservation of water and electrolyte
Fructose Creatinine
Galactose Neurotransmitters by the kidneys is made possible through the action of AVP. The
Lactate Bile pigments synthesis of AVP takes place in specialized neural cells of the
Succinate Drugs hypothalamus. After synthesis, AVP is transported to the poste-
Amino acids Ammonia rior pituitary gland for storage within the neurosecretory gran-
Uric acid H+
Na+
ules from whence it is secreted into the blood circulation when
K+ stimulated.14 The maintenance of water balance is dependent on
Ca2+ several factors such as water intake, the thirst sensation, and the
Mg2+ excretion of water by the kidneys.15 The PCT is the site at
HCO3– which 70% of the water content of the tubular fluid is
HPO4–
Cl– reabsorbed. About 5% is reabsorbed in the loop of Henle, 10%
H2O in the DCT, and the reminder in the collecting duct. In
Urea response to increased osmolality, AVP is secreted into the circula-
tion, where it binds to the AVP receptors on the cells of the
Loop of Henle Na+
K+
basolateral membrane of the collecting duct. This results in a
Cl– mediated activation of adenylate cyclase and formation of cyclic
H2O adenosine monophosphate (cAMP). Upon formation, the
cAMP activates protein kinase A, which leads to the fusion of
Distal Tubule Cl– K+ vesicles containing the aquaporin-2 water channel proteins. As a
H2O H+
HCO3– result, the membrane becomes permeable to water molecules,
and water is reabsorbed into the collecting duct. In the absence
Collecting duct H2O of AVP, the water channels become impermeable to water.14,15
Urea More than a week’s supply of AVP is assured through storage of
a large amount in the pituitary gland. This allows for maximum
antidiuresis in situations of sustained dehydration.14
Electrolytes take part in many metabolic and homeostatic
along the length of the tubules. The transportation of solute and processes in the body. These processes include biochemical and
water across the cells lining the renal tubules is made possible enzymatic reactions, neurotransmission, conduction of nerve sig-
through active and passive transport processes that require recep- nals, adequate functioning of hormones, muscle contraction,
tors and mediator molecules. When adenosine triphosphate bone composition, fluid and acid-base balance, and cardiovascular
(ATP), such as Na+-K+-ATPase, is hydrolyzed, the energy functions.13 When patients are known to have electrolyte abnor-
released is made available for active transport processes. There malities, their electrolyte concentration, as well as signs and symp-
are ion channels made up of different protein molecules13 in the toms of specific electrolyte disorders, should be monitored. The
epithelial cells of renal tubules through which some molecules severity of a disorder, and the rate at which it develops and per-
can diffuse. sists, can be related to the severity of the symptoms presented by
The complete reabsorption of glucose and uric acid is a pas- the patient.16 The amount of HCO3- reabsorbed can be related to
sive process that takes place mainly in the PCT. This passive the GFR and the secretory rate of H+, while the reabsorption of
process depends on the presence of Na+.13 Dilute urine is pro- PO43- is affected by the parathyroid hormone, whose release is
duced subsequent to the reabsorption of more Na+ and Cl- with- controlled by the concentration of Ca2+ in plasma.13
out water being reabsorbed in the loops of Henle. The The reabsorption of glucose and amino acids in the PCT is
reabsorption of more water in the DCT is under the regulation controlled through specific active transport processes. Reaborp-
of Arginine vasopressin (AVP), which was earlier known as an- tion of 20% to 25% of filtered Na+ takes place in the ascending
tidiuretic hormone. Now that its biochemical characterization loop of Henle without water also being reabsorbed. This results
and structure is known, it is appropriate to refer to it with its in the production of dilute urine with an osmolality ranging
proper name. Regulation of the acid-base balance takes place in from 100 to 150 mOsm/kg. Secretion and reabsorption of Na+,
the DCT through the secretion of H+ and reabsorption of Na+ K+, and H+ takes place in the DCT. Aldosterone production is
and HCO3-. stimulated by high K+ concentration and the renin-angiotensin
system. When perfusion is inadequate, and the concentration of
Na+ is low, renin is stimulated. In order to maintain physiologi-
cal pH, the quantity of H+ secreted is decreased.13
Renal Homeostasis
Commonly-encountered problems in the practice of medi-
cine are disorders of fluid imbalance, which are due to the mech-
anisms controlling the intake and output of water and solutes. Endocrine Function
The largest constituent of the body, which constitutes approxi- The kidneys perform various endocrine functions which
mately 55% to 65% of body weight, is water. Water is distrib- are important in metabolic processes in the body, The kidneys
uted between the intracellular fluid (ICF) and the extracellular synthesize several substances such as erythropoietin,
fluid (ECF), of which 55% to 65% resides in the ICF and 35% prostaglandins, renin, and 1,25-dihydroxy vitamin D. Erythro-
to 45% resides in the ECF.14 Disturbance of water balance may poietin functions by stimulating the erythroid progenitor cells

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in the bone marrow to increase the number of red blood cells in Table 2_Summary of Renal Diseases
the blood stream.10 Erythropoietin is a polypeptide synthesized
by cells close to the PCT, and its production is regulated by the Laboratory Finding
level of oxygen in the blood. In the presence of tissue hypoxia,
an increased quantity of erythropoietin is produced. Patients Renal Diseases Urine Blood
who have chronic renal failure and are prone to developing ane- Acute kidney disease Low GFR High BUN
mia may benefit from treatment with recombinant erythropoi- Acidosis High serum creatinine
etin which is readily available. High K+
Renin, a component of the renin-angiotensin system is pro-
Chronic kidney disease Low GFR High BUN
duced in the presence of a decrease in fluid volume or blood Acidosis High serum creatinine
pressure. Renin catalyzes the synthesis of angiotensin through High K+
enzymatic cleavage of angiotensinogen to produce angiotensin.
Angiotensin is converted by angiotensin-converting enzyme to Acute High protein High BUN
a powerful vasoconstrictor called angiotensin II, which increases glomerulonephritis Proteinuria High creatinine
Hematuria
blood pressure and stimulates the adrenal cortex to release Low GFR
aldosterone. The function of aldosterone is to promote Na+
reabsorption and water conservation. Chronic Proteinuria High BUN
One of the 3 hormones required for phosphate and calcium glomerulonephritis Hematuria High serum creatinine
Low urine SG High K+
balance, as well as bone calcification, is 1,25-dihydroxy vitamin Waxy or broad casts
D. The enzyme required for its production is housed in the Dysmorphic RBCs
mitochondria of the renal cortex. Chronic renal insufficiency of
the hormone may lead to osteomalacia. The prostaglandins are Nephrotic syndrome High protein Low serum albumin
formed in any tissue and synthesized from arachidonic acid. It Proteinuria Hypoalbuminemia
Lipiduria Hyperlipidemias
has diverse actions such as increasing renal blood flow, Na+ and
water excretion, and release of renin.10 Autoimmune nephritis Hematuria Autoantibodies against basement
(Goodpasture’s membrane components
syndrome) Proteinuria High Bun
Pathological Processes in the Kidney High serum creatinine
Many diseases have been described which singly or in combi- Tubular necrosis High BUN
nation predispose an individual to developing renal diseases such High serum creatinine
as acute nephritic syndrome, acute glomerulonephritis, autoim- High uric acid
mune nephrititis, nephropathies secondary to systemic diseases,
Uremic syndrome Low GFR High BUN
and other miscellaneous diseases (Table 2). The causes, signs and High creatinine
symptoms of some of the renal diseases are shown in Table 3. High PO43-
Low Ca2+
High K+
Renal Diseases
ESRD Proteinuria High BUN
Acute glomerulonephritis. Acute glomerulonephritis causes Low GFR High serum creatinine
an increase in the concentration of blood urea nitrogen (BUN)
BUN = blood urea nitrogen, GFR = glomerular filtration rate, SG = Specific gravity
and serum creatinine while decreasing the GFR. Other labora-
tory findings in patients with the disorder include proteinuria,
hematuria, and anemia, and the disease may promote edema
and hypertension.12
Chronic glomerulonephritis. Chronic glomerulonephritis is complications. Alteration of salt and water metabolism leads to
a collection of several glomerular diseases leading to loss of hypertension and renal failure.
nephron mass. Many of the diseases associated with chronic Diabetes insipidus. The kidney’s inability to reabsorb ade-
glomerulonephritis may be asymptomatic but present with mild quate amounts of water leads to diabetes insipidus, a rare form of
hematuria, proteinuria, and slight reduction in renal function. diabetes.13 The disease has been diagnosed in patients who are
Hypertension is usually a complication of the disease in its late genetically predisposed and/or have defective AVP receptors, de-
stages and progression to end stage renal disease (ESRD) may fective aquaporin water channels in the collecting duct, or inade-
become apparent. quate production of AVP by the pituitary gland. Presence of the
Nephrotic syndrome. Patients with nephrotic syndrome disease leads to the kidney’s inability to concentrate urine, even
present with proteinuria, massive edema, hypoalbuminemia, when normal or elevated levels of AVP are present. Polyuria,
hyperlipidemias, and lipiduria. The increased proteinuria and polydipsia, and hypernatremia have been observed in patients.15
excretion of fat bodies seen in patients with this condition may A mutation of the gene that codes for the V2 receptor is seen in
be due to the increase in permeability of the glomerular mem- the X-linked form of congenital nephrogenic diabetes insipidus,
brane. The loss of protein in patients causes a decrease in while a mutation of the gene coding for the aquaporin-2 receptor is
intravascular oncotic pressure leading to a massive edema. associated with the autosomal recessive and autosomal dominant
Autoimmune nephritis. Presence of autoantibodies directed forms of the disease.15
against components of the basement membrane is a characteris- Acute kidney disease. Acute kidney disease has prerenal,
tic of autoimmune nephritis, an example of which is Goodpas- postrenal, and renal components. Prerenal failure is usually due
ture’s syndrome.13 Renal disease is commonly seen in patients to a decrease in the perfusion of the kidneys while obstruction
with type 1 or type 2 diabetes mellitus due to microvascular distal to the nephron causes postrenal disease. The disorder,

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Table 3_Kidney Diseases: Causes, Signs and Symptoms Table 4_Stages of Chronic Kidney Disease

Disease Causes Signs and Symptoms Stage Description GFR (mL/min/

of Renal Diseases 1.73 m2)

Nephrotic Carcinoma Proteinuria 1 Kidney damage with normal or increased GFR ≥90
syndrome Diabetic glomerulosclerosis Hypoalbuminemia 2 Kidney damage with mild and decreased GFR 60-89
Polyarteritis nodosa Edema 3 Moderate and decreased GFR 30-59
Renal vein thrombosis Hypercholesterolemia 4 Severe decreased GFR 15-29
Constrictive pericarditis 5 Kidney failure <15 or dialysis
Malaria
Syphilis GFR = Glomerular filtration rate
Serum sickness
Bee sting
Gold salt
Transplant rejection
Severe preeclampsia
60 mL per minute per 1.73 m2 for 3 months or more, regardless
of the cause, and classified the stages of the disease based on
Acute Kidney Hypovolemia Arrhythmias GFR18 (Table 4). Due to its late onset in life and slow progress,
disease Rhabdomyolysis Ascites most patients with CKD usually die of CVD before renal failure
Cardiac failure Cognitive impairment sets in.
Acute tubular necrosis Coma
Shock leading to decreased Palpitation Uremic syndrome. Uremic syndrome is a leading cause of
blood flow Shortness of breath kidney failure. The syndrome is characterized by high concentra-
Hemolytic uremic syndrome Edema tions of BUN, creatinine, and other nitrogenous waste products
Glomerulonephritis in the blood. The ability of the kidney to maintain adequate
Vasculitis
Obstruction of lower urinary tract
excretory, regulatory, and endocrine functions is compromised.13
Symptoms presented by patients include a decrease in appetite,
Chronic kidney Systemic lupus erythematosus Hypertension nausea, progressive weakness and muscle wasting, abnormal
disease Polyarteritis nodosa Uremia mental function, metabolic acidosis, shallow respirations, coma,
Malignant hypertension Hyperkalemia and stupor leading to death. Failure to treat the disorder with
Renal vein thrombosis Anemia
Tuberculosis Hyperphosphatemia hemodialysis or kidney transplantation can lead to end stage
Chronic pyelonephritis Metabolic acidosis renal disease (ESRD).
Diabetic nephropathy Irritability End stage renal disease. The frequency of ESRD is on the
Hypertension Poor muscle tone rise worldwide, and the United States has the greatest incidence
Urinary tract obstruction Itching
Insomnia
and frequency.18,19 It is estimated that over 300 new patients per
million of the population have started dialysis treatment every
Glomerulonephritis Infections Hematuria year for the past few years.20 The disease appears to be familial in
Immune diseases Proteinuria nature and certain individuals may have a genetic predisposition
Hypertension Hypertension to developing it. It is believed that the familial risk of developing
Diabetic kidney disease Edema
the disease may be due to susceptibility to renal damage or an
ESRD Glomerulonephritis Decreased urine output aggregate collection of ESRD risks.18,21
Tubular diseases Nausea
Diabetes mellitus Vomiting
Hypertension Diarrhea Laboratory Investigation of Renal Function
Polycystic kidneys Loss of appetite
Interstitial disease Hypertension Various diseases affecting kidney function may be diag-
Systemic lupus Hypotension nosed through the measurements of components in blood and
erythematosus Uremia urine. Evaluation of the functioning capacity of the kidneys
Confusion may be ascertained through laboratory tests which can assist
Seizures
Coma the physician in making an accurate diagnosis. Some of the
investigative tools include the determination of the circulatory
levels of nonprotein nitrogenous substances, filtration capacity
of the nephrons, excretion of endogenous and exogenous
which is attributable to nephrotoxicity, is diagnosed frequently compound by the kidney, and the kidney’s ability to maintain
in hospitalized patients. The GFR may decline over a period of electrolyte and water balance.
a few days or weeks and lead to a decrease in the excretion of
nitrogenous waste products and failure to maintain fluid and
electrolyte balance.17 Patients with this condition usually have Glomerular Filtration Rate
high levels of BUN and serum creatinine. When the serum crea- Management of patients with renal dysfunction requires
tinine level rises by at least 0.5 mg/dL per day, and the urine knowledge of GFR. This knowledge is valuable in the general
output is less than 400 mL per day, then the possibility of a evaluation of kidney function to determine the correct dosage
complete shutdown of renal function may exist. of drugs cleared by the kidneys, detect early impairment of
Chronic kidney disease. Chronic kidney disease is character- renal function, prevent more deterioration, and manage trans-
ized by a slow but progressive loss of renal function. The main plant patients.22 The GFR is influenced by several factors, such
causes of CKD are diabetes, renal vascular disease, and glomeru- as the plasma flow in the glomeruli, the surface area of the
lonephritis. The National Kidney Foundation and the National glomerular capillaries, the oncotic pressure induced by proteins in
Kidney Disease Education Program defined CKD as GFR below the glomerular capillaries, and the hydrostatic gradient between

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the glomerular capillaries and the Bowman’s capsule.14 The nor-
mal values of GFR are approximately 130 mL per minute per
1.73 m2 in young men and 120 mL per 1.73 m2 in young
women. Inulin is the ideal filtration marker, and it is considered
the gold standard. Other exogenous markers of importance in-
clude iothalamate, 51Cr-EDTA, diethylene triamine pentaacetic
acid, and iohexol.4,23
Serum and urine creatinine are essential in the evaluation of
renal function, and the results from these measurements can be
used to directly estimate the GFR.24 The use of serum creatinine
to estimate true renal function has inaccuracies and limitations
which have been recognized. The production of serum creati-
nine may be influenced by age, weight, sex, and race, and this
must be taken into consideration when serum creatinine is eval-
uated.25,26 Determination of clearance with the use of exogenous
markers is expensive, complex, and not easily amenable to rou-
tine clinical practice. Endogenous markers, such as creatinine,
can be derived from a timed collection of urine, such as a 24-
hour urine collection, along with blood sampling during the
urine collection period. Creatinine clearance reflects true GFR
but it is increasingly inaccurate at low filtration rates. Creatinine
clearance results are lower in women, the elderly, patients with
decreased muscle mass, and individuals with small stature. The
test is cumbersome, and its determination is no longer recom-
mended for routine use.12
The creatinine clearance equation is as follows:
C mL/min = U mg/dL × V mL/24 hours 1.73
P mg/dL × 1,440 minutes/24 hours A measurements in the estimation of GFR, as well as of factors
C = creatinine clearance in mL/min
U = urine concentration of creatinine
V = total volume of urine collected per unit time,
typically 24 hours
P = plasma concentration of creatinine
1.73 = body surface area of an average person
A = the body surface area of the individual in mm2
The serum level of an endogenous marker can be related to
the reciprocal of the level of GFR and used to estimate the GFR
without the need for urine collection.4 It is important to note
that endogenous markers can also be affected by other factors,
such as tubular secretion or reabsorption, as well as the produc-
tion and extrarenal removal of the markers.4 Other endogenous
markers of importance include, urea, β2-microglobulin, β-Trace
protein (BTP), retinol-binding protein, β1-microglobulin, and
cystatin C.
The GFR should be estimated with equations that use
serum creatinine concentrations and other variables such as age,
gender, race, and body size. A direct measure of GFR can be
obtained by the infusion of exogenous markers, such as inulin or
51Cr-EDTA, but, as previously stated, the methods are both
time consuming and expensive. As a result, the National Kidney
Foundation recommends the use of prediction equations to esti-
mate GFR from serum creatinine values and other variables in
the diagnosis and stratification of CKD.27 Two equations that
are useful for this purpose in adults are the Modification of Diet
in Renal Disease (MDRD) study and Crockcroft-Gault equa-
tions. The Schwartz and Counahan-Barratt equations may be
employed in children. Measurement of creatinine clearance does
not improve the estimate of GFR over that provided by the pre-
diction equations. The usefulness of a 24-hour urine sample
might be found in the estimation of GFR in individuals who are
vegetarians, or are on creatine supplements, or have exceptional
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body mass. It may also be used to assess diet and nutrition status
or the need to start dialysis.9
Modification of Diet in Renal Disease Study
Equation (MDRD)
Evaluation of the MDRD study and the Crokcroft-Gault
equations in various populations, such as blacks, whites, and
Asians with nondiabetic kidney disease, patients with diabetes
and kidney disease, patients without kidney disease, kidney
transplant patients, and potential kidney donors, have been per-
formed. The MDRD study equation was developed in 1999
with data from 1,628 patients who were predominantly non-
diabetics with kidney disease, and was subsequently validated in
another study in which 1,775 subjects in the African-American
Study of Kidney Disease participated.4,28,29 Unlike the Crock-
croft-Gault equation, the estimation of the GFR with the
MDRD study equation is adjusted for body-surface area and is
recommended by the National Kidney Foundation K/DOQI
guidelines for estimating GFR in patients at risk of renal dis-
ease. For any estimated GFR values that are <60 mL/min per
1.73 m2, clinical laboratories were recently asked by the
National Kidney Disease Education Program (NKDEP) to pro-
vide an MDRD study estimate of the patient’s GFR next to the
serum creatinine value.26 An understanding by laboratorians
worldwide of the importance of having reliable serum creatinine
affecting the measurement of creatinine, is part of a global pub-
lic health initiative designed to maximize the diagnosis and
treatment of patients with CKD. To this end, a Creatinine
Standardization Program aimed at decreasing variation in
creatinine assay calibration between laboratories and ensuring
accurate estimates of GFR was launched by the NKDEP Labo-
ratory Working Group in collaboration with the International
Federation of Clinical Chemistry and the European Communi-
ties Confederation of Clinical Chemistry. The aim of the pro-
gram is to assist healthcare providers in identifying and treating
CKD in patients, thus preventing or delaying kidney failure
and improving patient outcome.29
The MDRD study equation is as follows:
GFR (mL/minute/(1.73 m2)) =
186 × (serum creatinine [mg/dL]–1.154) × (age in years)-0.203
× (0.742 if female) × (1.210 if African American).4
If converting to SI units (GFR in micromoles per liter) is
desired, replace 186 with 32,788.
In a study conducted by Rule and colleagues30 designed to
determine whether estimated GFR with the MDRD study equa-
tion was accurate in healthy patients compared with patients
with CKD, they reviewed the records of kidney transplant pa-
tients between 1996 and 2002 at the Mayo Clinic. The study
included 599 potential donors whose iothalamate clearance tests
to measure GFR were obtained routinely before a clinic visit.
After excluding those without serum creatinine determination
and those younger than 17 years old, the healthy subjects con-
sisted of 580 potential donors. The records of 501 consecutive
patients in whom an iothalamate clearance test had been
obtained for any reason between October 1999 and March 2000
were reviewed.30 The result from the study showed that even
though the abbreviated MDRD study equation was relatively
accurate in patients with CKD, the GFR was significantly un-
derestimated in healthy persons, probably due to the fact that
healthy persons did not participate in the study from which the
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equation was derived. The study also showed that at similar
serum creatinine levels, age, and gender, GFR was on average
20% higher in healthy persons than in those with CKD. They
concluded that a new quadratic GFR equation might be more
accurate than the MDRD study equation when estimating GFR
in the absence of knowledge of the kidney disease status of a
patient.30
Crockcroft-Gault Equation
The Crockcroft-Gault equation was developed in 1973 and
used data from 249 men who had creatinine clearances ranging
from 30 to 130 mL/minute.4 The Crockcroft-Gault equation
overestimates the GFR due to the secretion of creatinine in the
tubules and the fact that there is no adjustment of the values for
body-surface area as compared with creatinine clearance.
The Crockcroft-Gault equation is as follows:
GFR mL/minute = [(140 – age in years) × (wt, kg)]/ 72 × P
(mg/L) × 0.85 (if subject is female).
If converting to SI units (GFR in micromoles per liter) is
desired, replace 72 in the denominator with 0.84.
Rigalleau and colleagues compared the Cockcroft-Gault
formula and MDRD study equation estimates of GFR with
51CR-EDTA determinations in 160 diabetic patients presenting
with a wide range of GFRs. The subjects consisted of 91 males
and 69 females of which 50 had type 1 diabetes mellitus and
110 had type 2 diabetes mellitus.27 The results showed that the
sensitivity and accuracy of the Cockcroft-Gault formula is re-
duced due to overestimation at low GFR levels and the influence
of weight. They found that, in clinical practice, the MDRD
study equation underestimates GFR at high levels and is more
difficult to calculate. However, the MDRD study equation was
found to have better accuracy in diagnosis and stratification of
patients with CKD and in those with diabetes mellitus.27 The
estimation of GFR in diabetic patients who have normal serum
creatinine levels is problematic because both the MDRD study
formula and the Crockcroft-Gault creatinine estimate were de-
veloped in non-diabetic patients.26
Schwartz and Counahan-Barratt Formula
The Schwartz and Counahan-Barratt formulas are used to
estimate GFR in children. These formulas use estimates of the
proportionality between the GFR and height/serum creatinine
values. The difference in the constants used in the 2 formulas is
due to the fact that different assays are used to measure creati-
nine. The “true” value of creatinine and GFR by 51Cr-EDTA
plasma clearance was used to develop the Counahan-Barrat for-
mula. Creatinine measured by a modified Jaffe reaction and in-
ulin clearance was used to develop the original Schwartz
formula. The creatinine measurement may overestimate the true
creatinine concentration.31
Cystatin C
Cystatin C is a nonglycosylated low-molecular-weight ser-
ine protease inhibitor produced at a constant rate by all nucle-
ated cells. It is found in body fluids and serum and freely
filtered by the glomerulus but not secreted.32 It is reabsorbed by
the tubules and completely metabolized there. Since the 1980s,
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cystatin C has been under investigation as a marker of renal
function.33 Cystatin C participates in immune defense through
the inhibition of human polymononuclear cell chemotaxis.34
The serum concentration of cystatin C is inversely correlated
with GFR due to the fact that it is freely filtered in the kidney.
The renal clearance of cystatin C cannot be measured because
its catabolization in the PCT is almost complete; however, its
concentration in plasma is a reflection of the GFR. Since it is
not affected by infection, inflammation, neoplastic diseases,
muscle mass, sex, age, diets, or drugs, it is a better and more
reliable endogenous renal function marker than creatinine.32,35
Cystatin C is a better predictor of congestive heart failure in
elderly patients; however, it has yet to be subjected to adequate
evaluation as an index of GFR.6,19
In a study designed to assess cystatin C in serum as a GFR
marker in decompensated cirrhosis in which 36 male patients
with liver cirrhosis and 56 noncirrhotic men were enrolled, Or-
lando and colleagues showed that unlike creatinine, cystatin C is
not affected by decompensated cirrhosis and is as reliable a GFR
marker in such patients as it is in healthy individuals. They added
that plasma creatinine concentration and the Cockcroft-Gault
method are not useful as GFR markers in cirrhotic patients and
that the diagnostic accuracy of plasma cystatin C and creatinine
clearance in decompensated cirrhosis patients are similar, but the
advantage of cystatin C over creatinine clearance is the avoidance
of the inconvenience and inaccuracy of urine collection.32
In a study aimed at investigating the ability of cystatin C to
predict GFR in patients after orthotopic liver transplantation,
Schuck and colleagues evaluated the serum level of cystatin C in
58 liver transplant patients who underwent their procedures be-
tween 1955 and 1999. The subjects consisted of 31 men and 27
women ranging from 10 to 61 years of age. The result of the
study showed a satisfactory correlation between cystatin C and
inulin clearance but cystatin C was not better than serum creati-
nine.36 In another study designed to examine the diagnostic use-
fulness of cystatin C as a sensitive and specific clinical marker of
GFR in renal disease patients suffering from prolonged rheuma-
toid arthritis (RA), Mangge and colleagues analyzed, in addition
to plasma creatinine, estimated GFR, creatinine clearance, and
plasma cystatin C. Fifty-six patients affected with RA for more
than 5 years were enrolled in the study. Elevated levels of cys-
tatin C were observed in 60% of the RA patients, while 3 of 56
patients had elevated plasma creatinine levels even though 57%
of the patients had decreased creatinine clearance levels. There
was a better correlation between cystatin C and creatinine clear-
ance than with plasma creatinine. Mangge and colleagues con-
cluded that cystatin C is a less tedious test compared with
creatinine clearance and, thus, may be more suitable for screen-
ing purposes.37 Automated immunoassays employing latex or
polystyrene particles coated with cystatic C specific antibodies
are available for quantifying cystatin C.23
Beta Trace Protein
Beta trace protein has a molecular weight of 23,000 to
29,000 with 68 amino acids. It is isolated mainly from cere-
brospinal fluid, and its concentration is increased in patients
with renal diseases.23 Beta trace protein (BTP) is a member
of the lipocalin protein family. It is increased in patients with
renal disease and might be a better indicator of decreased
GFR than serum creatinine. It is not considered better than
cystatin C.38
May 2007 䊏 Volume 38 Number 5 䊏 LABMEDICINE 301
 Review

Urea
The first endogenous marker measured in serum to assess
renal function was urea. Urea is a major by-product of protein
metabolism and more than 90% of it is cleared by the kidneys.23
It is not secreted by the tubules but freely filtered at the
glomerulus with about 40% to 70% of it being reabsorbed at
the tubules. Consequently, urea clearance may be used as a
measure of GFR. However, in situations in which there is de-
creased renal perfusion, its concentration will underestimate
GFR since some of the filtered urea will return to the blood cir-
culation. Another consideration is the variation in its concentra-
tion from diet, hepatic function, and other disease states.23
Urinalysis
Urinalysis involves detailed examination of kidney function
through physical, chemical, and microscopic analysis of easily-
obtained urine samples (Table 5). It is a cheap, productive test,
and the readings can be obtained visually or through automated
readings.39 Urinalysis should be employed as part of the initial
investigation of patients. In addition to its usefulness as a screen-
ing tool for assessing renal function, it may also be used as a
quick indicator of glucose status, and hepatic-biliary function.
Since urine is concentrated by overnight retention, morning
specimens are preferred.
Appearance of urine. The color of the urine sample corre-
lates with its concentration, and, hence, the darker the sample the
more concentrated it is. Abnormal urine colors may be attributed
to foods, medications, metabolic products, and infections. The
odor produced by urine is usually due to the presence of volatile
substances, and a normal urine odor is described as urinoid. The
odor may be strong when the urine is concentrated, which may
not imply infection.40 Urine turbidity is usually due to the pres-
ence of dissolved substances. The specific gravity of urine meas-
ures the concentrating ability of the kidneys as well as the state
of hydration or dehydration in an individual. The normal range
of urine specific gravity is 1.002 to 1.030.10
Chemical analysis. The concentration of protons in urine is
expressed as pH41 and normal urine has a pH range of 4.5 to
7.5. The pH obtained from a urine sample may be influenced
by the type of food ingested and is essentially similar to the pH
of serum, except when tubular acidosis is present.40 When urea-
splitting organisms are present in the urine, the pH is usually
alkaline which may suggest infection and a diagnosis of urinary
tract infection.
Various chemicals present in urine can easily be analyzed
using plastic reagent strips coated with reagents capable of de-
tecting and quantifying different substances. Some of the sub-
stances include glucose, ketones, protein, nitrites, bilirubin, and
hemoglobin (Table 5). According to the National Kidney Foun-
dation guidelines, patients with a protein excretion rate greater
than 1 g/d should have aggressive therapy designed to lower
their blood pressure.1,42 Small amounts of protein are excreted in
urine by normal individuals.43 Albuminuria may be associated
with heightened adverse cardiovascular and renal events when
the following clinical situations are present: diabetes mellitus,
hypertension, central obesity, advanced age, African American,
Hispanics, Native American, Pacific Islander, and a family his-
tory of cardiovascular or renal disease.44

Table 5_Urinalysis

Analysis Normal Change Cause

Physical Changes

Color Pale yellow Darker color Oxidation or reduction of metabolites

Odor Aromatic Foul odor Bacterial growth, decomposition
Turbidity Clear High Bacterial growth, crystal formation, precipitation of amorphous materials
Specific gravity 1.002–1.030 Low Diabetes insipidus, tubular damage
High Diabetes mellitus, dehydration, congestive heart failure

Chemical Changes

pH 4.5–7.5 High Bacterial decomposition of urea

Low Glucose converted to acids
Glucose Negative High Diabetes mellitus
Low Glycolysis
Ketones Negative Low Volatilization of acetone, breakdown of acetoacetate by bacteria
Proteins Negative High Glomerular damage, strenuous exercise, exposure to cold, fever
Bilirubin Negative Low Exposure to light
Urobilinogen 0.2–1.0 mg/dL High Oxidation of urobilin, hemolytic anemia
Low Billiary obstruction
Nitrite Negative High Indicator of urinary tract infection, bacterial production
Blood Negative High Renal disease
Leukocyte esterase Negative High Urinary tract infection, inflammation

Microscopic Changes

Red blood cells 0–3 RBCs/HPF Lysed Standing in dilute urine

White blood cells 0–5 WBCs/HPF High Acute renal infection, cystitis, urethritis, urinary tract infection
Epithelial cells Few High Tubular injury, damaged epithelial basement cells
Casts Negative High Glomerular damage, nephritis
Crystals Negative High
Bacteria Negative High Bacterial proliferation

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Microscopic analysis. Centrifuged sediments of urine are
subjected to microscopic examination to evaluate the presence of
cells such as red blood cells, white blood cells, epithelial cells,
spermatozoa, and yeast cells. Other miscellaneous elements
found in urine during microscopic examination include casts
and crystals. Urine may be cultured, especially when urinary
tract infection is suspected. Normally, urine is sterile, therefore if
bacteria is detected it might indicate the presence of an infec-
tion.10 A clinically significant microscopic hematuria is defined
by the American Urology Association as 3 or more red cells per
high-power field on microscopic examination.45
Urinary, lysozyme, and N-acetylglucosaminidase. Lysozyme,
an enzyme found in neutrophils, monocytes, and macrophages is
produced by many organs of the body and is freely filtered by the
kidney and absorbed by the PCT. High levels of lysozyme in urine
might be seen in tubular damage. Increased synthesis of lysozyme
is associated with monocytic leukemia, and inflammatory bowel
disease. N-acetylglucosaminidase is an enzyme occasionally en-
countered in the urine of healthy persons; however, different iso-
forms of the enzyme are seen in a variety of renal diseases.13
Osmolality. The concentration of all the solute in a given
weight of water is known as osmolality. The concentrating abil-
ity of the kidney can be more reliably determined by measuring
the osmotic concentration rather than specific gravity of the
urine. Urine osmolality depends on the state of hydration, and
the result obtained from different individuals varies widely. In
individuals who have consumed excess fluids, the osmotic con-
centration of urine may decrease to as low as 50 mOsm/kg,
whereas in those individuals in which fluid intake has been se-
verely curtailed, concentration of as much as 1,200 mOsm/kg
may be observed. The result of osmolality commonly seen in
normal individuals ranges from 300 to 900 mOsm/kg.13 A sec-
ondary response to an increase in net water reabsorption is a
decrease in the flow of urine followed by an increase in urine
osmolality.13 Conditions attributable to abnormally high osmo-
lality include Addison’s disease, irregularities in AVP, and conges-
tive heart failure. Abnormally low osmolality may be due to
aldosteronism, diabetes insipidus, kidney damage, and
pyelonephritis. Thus, measurement of serum and urine osmolal-
ity and determination of serum-to-uringurine ratio is a useful
indicator of renal function. When the concentrating ability of
the kidney is intact, the ratio should be between 1:1 and 1:3.
Treatment
The treatment options for renal diseases include specific
therapy tailored to diagnosis, evaluation, and management of
comorbid conditions, slowing the loss of kidney function, pre-
vention, and treatment of CVD. Other options include the pre-
vention and treatment of complications of decreased kidney
function, preparation for kidney failure, and kidney
replacement therapy and replacement of kidney function by
dialysis and transplantation in the presence of signs and symp-
toms of uremia.9
Dialysis. Various potentially toxic substances can be
removed from the blood by utilizing differences in the diffusion
rates through a semipermeable membrane of various sized mole-
cules. This process of ridding the blood of toxic substances in an
individual with a failing kidney is called hemodialysis. Solutes
diffuse down a concentration gradient through a semipermeable
membrane into a dialysate. Water and substances with small mo-
lecular weights diffuse across the membrane while excluding cel-
lular elements which are retained in the vascular space.13
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Review
Peritoneal dialysis is designed to rid the body of toxic sub-
stances which the diseased kidney cannot perform by itself. In
this procedure, a special fluid is passed through a tube into the
peritoneum which lines the abdominal cavity. Nitrogenous waste
and other toxic elements are subsequently removed from the
blood through the tube. Of the 3 types of peritoneal dialysis
techniques available, continuous ambulatory peritoneal dialysis is
the most popular. It does not require a machine and is usually
performed at home. A procedure performed at night while the
patient is asleep uses the continuous cyclical peritoneal dialysis
requiring a machine. The third type is the intermittent
peritoneal dialysis, which also requires a machine, and it is usu-
ally done in the hospital.13
Kidney Transplantation. Kidney transplantation is a treat-
ment option which is available to patients with failing kidneys.
The transplant is performed to replace deceased kidneys with
healthy ones through surgical procedures. Family members usu-
ally donate the kidney to a relative, otherwise the kidney can
come from a deceased organ donor. One kidney is usually do-
nated, but if the organ donor is diseased, and the recipient is a
child, then the child might receive two kidneys. The responsibil-
ity for transplant organ distribution in the United States is the
United Network for Organ Sharing.
Conclusion
Kidney disease is becoming common in the United States
with a concomitant increase in the cost of managing and treat-
ing the complications associated with this condition. A knowl-
edge of the pathophysiology of the disease and the diagnostic
and prognostic options available to the clinician and patient are
important aspects of managing the disease. Various clinical lab-
oratory tests can be very helpful in the diagnosis of the different
associative syndromes of the disease, and, hence, the laboratory
performs an important function in the management of this dis-
order. Therapeutic options such as dialysis and transplantation
are available to patients with kidney disease.
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