Creatinine

Author
Gary L Horowitz, MD Associate Professor of Pathology, Harvard Medical School; Director of Clinical
Chemistry Laboratory, Department of Pathology, Division of Laboratory Medicine, Beth Israel
Deaconess Medical Center

Reference Range
The reference ranges for serum creatinine and urine creatinine are listed below.

Serum creatinine
Adult males: 0.51.2 mg/dL*
Adult females: 0.4 1.1 mg/dL*
Children (up to 12 years of age): 0.00.7 mg/dL
* The reference interval varies with gender, race, and ethnicity. As a result, one should look at the
calculated eGFR (estimated glomerular filtration rate), reported from the measured serum creatinine,
to assess renal function. The GFR can also be calculated from the creatinine clearance (see below).
Table 1. Glomerular Filtration Rate[1]
Mean GFR

Age (Years)

(mL/min/1.73 m2)

20-29

116

30-39

107

40-49

99

50-59

93

60-69

85

70+

75

Urine creatinine [2]

Adult males: 20-25 mg/kg/day (roughly 1575 mg/day for a 70-kg male)
Adult females: 15-20 mg/kg/day (roughly 1050 mg/day for a 60-kg female)
Note that urine creatinine concentrations (mg/dL) vary with water intake (hydration status) and
therefore are not very meaningful by themselves.

Interpretation
Low serum creatinine values are rare and almost always reflect low muscle mass. In theory, they may
also reflect increased glomerular filtration rates (GFRs).
Serum creatinine increases with decreases in GFR (acute kidney injury or chronic kidney disease). [3, 4]

For mathematical reasons,[2] the increase in serum creatinine is relatively minor at the earliest stages
of disease. That is, a patient whose baseline creatinine is 0.6 would have to lose more than 50% of
his GFR before the creatinine would increase to 1.3 and first be noted to be "abnormal" by most
reference intervals. This is because of inter-individual differences in muscle mass, related to gender,
age, and ethnicity (among other things).
As a result, for adult patients (age 18 and over), most clinical labs now report an estimated GFR
(eGFR) along with every measured serum creatinine. [1, 5] The eGFR takes into account some of these
variables, and it can alert physicians to significant reductions in GFR even when the serum creatinine
appears to be normal or only minimally elevated. For example, a white woman with a serum creatinine
of 1.0 (a value within the traditional reference interval) has an eGFR of 59 mL/min/1.73 m 2, a value
consistent with chronic kidney disease.[1]
Note, though, that the calculation is not valid in various situations (eg, pediatric patients, very elderly
patients, pregnant individuals, extremes of body habitus, malnutrition, paraplegia, patients with
skeletal muscle disease, those with rapidly changing kidney function).
In some of these cases, more accurate information on the GFR can be obtained from a 24-hour
creatinine clearance, which requires an accurate 24-hour urine collection and measurement of urine
and serum creatinine.
All 24-hour urine collections should be assessed for accuracy/completeness by calculating the 24hour total creatinine excretion. Typical values for men and women are listed in the Reference Range
section.
Urine creatinine values can also be used to correct for hydration status for analytes excreted
throughout the day in relatively consistent amounts (no diurnal variation), obviating the need for 24hour collections. In particular, urine protein/creatinine ratios and urine albumin/creatinine ratios have
proved exceedingly helpful in the evaluation of proteinuria.

Collection and Panels

Serum creatinine

Specimen: Blood
Container: Red-top tube, serum separator tube, green-top tube
Collection method: Routine venipuncture

Urine creatinine

Specimen: Urine
Container: Plastic leakproof container (no preservative). Urine GUARD collection container is
preferred for a timed urine sample.
Collection method: For timed urine collections, empty the bladder, discard the voided sample,
and note the start time. Collect all urine voided for the specified time period. At the end of the
collection period, note the time and add the last voided sample to the container by emptying the
bladder. Bring the refrigerated container to the laboratory.

Panels
Serum creatinine is typically part of the following panels:

Basic metabolic panel

Comprehensive metabolic panel
Creatinine clearance test
Urine creatinine is typically part of the following panels:
Microalbumin test
Urine protein test
Creatinine clearance test

Background
Description

Creatinine has several interesting properties that make it critically important in assessing renal
function. In blood, it is a marker of glomerular filtration rate; in urine, it can obviate the need for 24hour collections for many analytes or be used as a quality assurance tool to assess the accuracy of a
24-hour collection.
Creatinine is formed at a relatively constant rate in muscle. Chemically, it is the anhydride
(dehydration product) of creatine, and, once formed, it cannot be converted back into creatine. Thus,
the amount of creatinine formed on a daily basis is related to muscle mass, which varies with age,
gender, and ethnicity.
Creatinine is freely filtered through the glomerulus, and it is not appreciably re-absorbed or secreted
by the renal tubules.* As a result, the serum concentration of creatinine represents a balance between
its production (related to muscle mass) and GFR (glomerular filtration rate). For any given patient, the
serum creatinine is constant, so long as muscle mass doesnt change and GFR remains constant. In
other words, the clearance of creatinine, unlike that of most analytes, is an excellent surrogate for
GFR.[4]
Creatinine clearance formula.

Put differently, if the GFR decreases, with production (and daily excretion) remaining constant, the
serum concentration must increase. Indeed, it increases until the concentration is such that, when
multiplied by the GFR, the product matches the daily excretion. Thus, if one loses half of ones renal
function, the creatinine doubles; a creatinine increase from 1.0 to 2.0 represents the same decrement
in renal function as a creatinine increase from 2.0 to 4.0 or 4.0 to 8.0, as reflected in the following
graph:

The graph shows the relationship of the glomerular filtration rate (GFR) to
steady-state serum creatinine and blood urea nitrogen (BUN) levels. As shown in this figure, in early renal disease,
substantial decline in GFR may lead to only a slight elevation in serum creatinine. Elevation in serum creatinine is
apparent only when the GFR falls to about 70 mL/min.

*(In advanced renal failure, secretion, though minor in absolute amount, may represent a significant
fraction of total excretion.)

Indications/applications
Since different individuals have different muscle masses, using a single reference interval is
misleading. A serum creatinine of 1.0 in a 50-year-old white woman represents a significantly reduced
GFR; the same value in a 25-year-old black male represents a normal GFR.
Determining GFR accurately requires onerous methods (intravenous infusions, esoteric laboratory
measurements [inulin], and/or radioactive compounds [ 125 I-iothalamate]). But a "semi-practical" way of
determining the GFR has been the creatinine clearance, which requires a 24-hour urine collection,
measurement of urine and serum creatinine, and use of the formula above.
In the absence of an indwelling catheter, the urine collection involves discarding the first morning urine
and then collecting all urine for about the next 24 hours, up to and including the first morning urine the
following day. All 24-hour urine collections should be assessed for accuracy/completeness by
calculating the 24-hour total creatinine excretion. Typical values for men and women are listed in the
Reference Range section. If the patient includes 2 morning urines (overcollects) or misses one or
more urine specimens (undercollects), clearly one will overestimate or underestimate the GFR. This
happens all too frequently.
In addition to reduced GFR, the other major form of CKD is proteinuria, defined as more than 30 mg
albumin per gram of creatinine in a random urine sample (24-hour collections are no longer needed or

even suggested).[1] The reason one cannot simply use the urine albumin (or urine protein)
concentration (mg/dL) to assess the degree of proteinuria is that different individuals excrete different
amounts of water depending on their fluid intake.
Historically, one addressed this limitation by collecting a 24-hour urine sample, allowing one to assess
the 24-hour albumin (or protein) excretion. However, in any given spot urine sample, since the amount
of water diluting the albumin (or protein) is the same as the amount of water diluting the creatinine, the
ratio provides an accurate assessment of the degree of albuminuria (or proteinuria). Then, by applying
the patients expected 24-hour creatinine excretion (related to muscle mass, as noted earlier), one
can estimate the 24-hour albumin (or protein) excretion. [6]

Considerations
A landmark paper in 2006 showed that one could calculate a reasonably good estimate of the GFR by
using the serum creatinine, age, gender, and ethnicity of the patient. [7] The equation was called the
MDRD equation, because it was based on a study called the Modification of Diet in Renal Disease. A
recommendation was made (and has largely been adopted) that laboratories report an estimated GFR
(eGFR) with every measured serum creatinine. Although it has a few limitations, the eGFR works
quite well, especially in detecting reduced GFR at early stages, and it has been promoted as a
valuable tool in screening for CKD.[1, 5]
Among its limitations, the eGFR calculation is not valid in various situations (eg, pediatric patients,
very elderly patients, pregnant individuals, extremes of body habitus, malnutrition, paraplegia, patients
with skeletal muscle disease, those with rapidly changing kidney function).
Although the MDRD equation is used by most clinical laboratories for reporting eGFR in adults,
several other equations for calculating GFR can be used, some of which should be mentioned here
(eg, CKD EPI, Bedside Schwartz, and Cockcroft-Gault).
The MDRD equation was designed to detect reduced GFR, and it does not work well for values above
60 mL/min/1.73 m2, which is why labs typically report such values simply as ">60." Using the same
variables as the MDRD equation, the CKD EPI formula purports to be more accurate with higher
(normal) GFRs.[8]
Recall that the NKDEP recommendation is that estimated GFRs be reported automatically for adults.
When an estimated GFR is needed for pediatric patients, the MDRD equation should not be used.
Instead, the Bedside Schwartz equation, which is based on the serum creatinine and patients height,
should be used.[1]
Last, although still widely used, the Cockcroft-Gault equation has been superseded, deservedly, by
the newer equations already mentioned, except in one notable area: drug dosing. Since most drugs
received FDA approval prior to the existence of the MDRD equation, their renal dosing guidelines are
typically based on the Cockcroft-Gault equation. Although controversial, the truth is that differences in
GFR generated by the 2 equations are usually insignificant. [9] When present, differences can often be
ascribed to the fact that the assumptions underlying the Cockcroft-Gault equation have not been met,
as follows:

Current creatinine methods are calibrated differently

Failure to use the patients "lean body mass"

References
1. Health Professionals: Chronic Kidney Disease (CKD) Overview. Available
athttp://nkdep.nih.gov/professionals/index.htm.
2. Medscape: Azotemia. Available at http://emedicine.medscape.com/article/238545-overview.
3. Medscape: Acute Renal Failure. Available at http://nkdep.nih.gov/professionals/index.htm.
4. Medscape: Chronic Kidney Disease. Available
at http://emedicine.medscape.com/article/238798-overview.

5. Chronic Kidney Disease in Primary Care. Available

at http://www.medscape.com/viewarticle/725635.
6. Ginsberg JM, Chang BS, Matarese RA, Garella S. Use of single voided urine samples to
estimate quantitative proteinuria. N Engl J Med. Dec 22 1983;309(25):1543-6. [Medline].
7. Levey AS, Coresh J, Greene T, Stevens LA, Zhang YL, Hendriksen S. Using standardized
serum creatinine values in the modification of diet in renal disease study equation for
estimating glomerular filtration rate. Ann Intern Med. Aug 15 2006;145(4):247-54. [Medline].
8. Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF 3rd, Feldman HI. A new equation to
estimate glomerular filtration rate. Ann Intern Med. May 5 2009;150(9):604-12. [Medline].
9. Drug Dosing Consideration in Patients With Acute and Chronic Kidney Disease. Available
athttp://www.medscape.com/viewarticle/753988.

http://emedicine.medscape.com/article/2054342