Serum creatinine concentration is maintained by the balance between its generation and excretion by the kidneys. Levels are affected by factors that influence the generation, glomerular filtration, and tubular secretion of serum creatinine. There is considerable variation in the excretion of creatinine based on individual patient factors and the time and method of testing. Since creatinine is generated in a steady manner and can be measured very simply from blood samples, it has become a useful test to estimate glomerular filtration rate (GFR), which is a measurement of kidney function.
The reference range of serum creatinine is:
60 to 110 micromol/L (0.7 to 1.2 mg/dL) for men
45 to 90 micromol/L (0.5 to 1.0 mg/dL) for women.
Estimated GFR (eGFR) equations, based on serum creatinine, are generally used to stage chronic kidney disease (CKD). However, the value of eGFR equations in the acute clinical setting has not been validated. Several web-based calculators are available to estimate GFR from serum creatinine values.
Creatinine is an amino acid breakdown product of creatine and phosphocreatine and is found almost exclusively (90%) in skeletal muscle. It is generated at a fairly constant rate and freely filtered through the glomerulus. In addition, 5% to 10% of creatinine is secreted by the proximal tubules.
Typically, serum creatinine rises from 0.5 to 1 mg/day to 1 to 2 mg/day in acute kidney injury (AKI), but it can exceed 5 mg/day in patients with severe rhabdomyolysis, due to massive breakdown of skeletal muscle. In patients with acute and rapidly progressive glomerulonephritis, 90% of renal function can be lost within weeks to months owing to glomerular destruction and this manifests as a 'galloping' rise in serum creatinine.
Serum creatinine is commonly measured by alkaline picrate (Jaffe reaction), enzymatic, and high-performance liquid chromatography (HPLC) methods. These methods are standardised to the isotope dilution mass spectrometry (IDMS) method. Point-of-care testing (POCT) is now commonly available in healthcare settings.
IDMS is the diagnostic standard. It is highly specific and offers the most accurate results for serum creatinine, but is available only in selected laboratories.
The Jaffe method is subject to interference by a large number of substances and may overestimate serum creatinine by up to 25%, depending on the severity of renal dysfunction.
Enzymatic methods are subject to less interference than the Jaffe method, but in a study of Japanese children, age, sex, and body length appeared to affect reference serum creatinine levels determined by enzymatic methods.
In the compensated Jaffe method, 26.5 micromol/L (0.3 mg/dL) is subtracted from the Jaffe method to match the enzymatic method results.
HPLC methods have better specificity than the Jaffe and enzymatic methods and are less prone to interference. However, measurement errors can occur owing to calibration differences between measurement procedures and to random measurement errors.
Combining HPLC with IDMS provides highly accurate results, but is not available in most centres.
POCT-based serum creatinine measurement appears to be sufficiently accurate for clinical use. POCT of creatinine can be used for screening patients at risk for contrast-induced AKI prior to contrast-enhanced diagnostic imaging.
One innovative method of creatinine measurement, especially for screening CKD, is to measure creatinine on a dry blood spot sample. This method has a sensitivity of 96% and specificity of 55%.
Interfering chromogens can falsely increase serum creatinine values with the Jaffe method by 20% or more in conditions such as diabetic ketoacidosis. The non-creatinine chromogens do not significantly affect urine creatinine levels, and have a smaller effect on the total reaction in advanced renal dysfunction than in normal renal function.
Another issue is monitoring renal function in patients treated with drugs that interfere with secretion of serum creatinine (e.g., the novel antiretroviral medications). In this situation, the Jaffe method results in a higher Model for End-Stage Liver Disease (MELD) score than the enzymatic method. This can lead to a systematic preference in organ allocation in patients requiring liver transplantation.
Attempts have been made to standardise the measurement of creatinine. However, studies show disappointing inter-assay variation of serum creatinine results. Use of certified reference materials may be useful for validating routine clinical methods and ensuring accuracy, reliability, and comparability of results from different clinical laboratories. Clinical reference materials are prepared with mixtures of creatinine from healthy people and from people with CKD, assigned by liquid chromatography-IDMS, validated by using standard reference material from the National Institute of Standards and Technology, and confirmed by an international intercomparison.
Efforts are also under way to establish measurement traceability. Note that calculation of the MELD score, which is used to prioritise patients for liver transplantation, may be significantly influenced by recalibration of creatinine assays.
The most accurate method for calculating GFR is by measuring the clearance of exogenous filtration markers, such as iothalamate, iohexol, or inulin. However, this is expensive and requires exposure to radiation and compliance with strict regulatory guidelines. In practice, therefore, creatinine clearance is used to estimate GFR. Creatinine is freely filtered, has minimal tubular secretion and absorption, is simple and inexpensive to measure from random blood samples, and has relatively good accuracy. A rise in serum creatinine is used as a marker of reduced GFR. It varies inversely with GFR, but the relationship is not linear.
The use of serum creatinine as an indirect filtration marker is limited by the following factors:
bias and non-specificity affecting creatinine measurement
alterations in circulating serum creatinine produced by non-renal disease states
differences in GFR range and creatinine production in healthy people compared with people with CKD.
As a result of these confounding factors, there is a risk of overestimating the GFR, and the magnitude of the overestimation is not predictable.
Equations for estimating GFR
Equations for estimating GFR from serum creatinine levels are mainly used for staging CKD and should not be used to interpret acute increases in serum creatinine. Correction factors for black people have generally been derived from studies in African-American people.
Available equations include:
Four-variable Modification of Diet in Renal Disease (MDRD) formula
Isotope dilution mass spectrometry (IDMS)-traceable 4-variable MDRD equation (MDRD-IDMS)
Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation
Mayo Clinic equation
Lund-1 equation without body weight measure.
A comparison of GFR estimation equations reveals that the MDRD study equation performs well in populations with a low range of GFR, and often outperforms the Cockcroft-Gault equation. Both equations have lower precision in high-GFR populations, and the MDRD equation underestimated the GFR in some studies. In addition, the Cockcroft-Gault, simplified MDRD, and CKD-EPI equations showed high variability in a study of critically ill patients, and are not recommended in the intensive care unit (ICU) setting.
An equation to estimate GFR across the full age spectrum (FAS) has been developed. Previously, separate equations have been used for children, younger adults, middle-aged adults, and older adults. The FAS equation is based on normalised serum creatinine (SCr/Q), where Q is the median SCr from healthy populations to account for age and sex. FAS eGFR is presented as:
eGFR = 107.3/SCr/Q for people aged ≥2 years and <40 years
eGFR = (107.3/SCr/Q) x 0.988 (age-40) for people aged >40 years.
eGFR overestimates GFR in low GFR states (due to increased tubular secretion of creatinine).
It is inaccurate in high GFR states (due to the lack of actual eGFR values above 60 mL/minute/1.73 m²).
Studies suggest that the Cockroft-Gault and MDRD formulas correctly assigned only 64% and 62% of patients, respectively, to their actual CKD classification GFR group. Based on US National Health and Nutrition Examination Surveys (NHANES 1988-1994; 1999-2004) and US population census data (2000), this suggests that around 10 million people (38%) may have been misclassified in the US.
Serum creatinine and eGFR may not be equivalent in all clinical situations. In contrast media-induced nephropathy, an increase in serum creatinine, but not eGFR, was predictive for long-term mortality, with a threshold of 44.2 micromol/L (0.5 mg/dL) or more indicating worse prognosis.
The controversy regarding the optimal method to estimate GFR for disease detection and monitoring is unresolved. Comparisons of GFR estimation, using the CKD-EPI equation and other creatinine-based equations in different populations found that these equations are not applicable to all populations and need to be individually validated prior to their routine use.
eGFR is based on the assumption of a steady state creatinine concentration. However, AKI is a non-steady state and eGFR in this situation is unreliable. KeGFR is an estimate of immediate biomarker clearance based on two serum creatinine measurements at different timepoints. It reflects dynamic changes in renal function and can be determined from routine tests carried out in acutely ill patients.
KeGFR has been shown to improve prediction of dialysis and recovery after renal transplant.
Cystatin C is an alternate marker for estimating GFR. It is produced at a constant rate in all cells of the body and is excreted by glomerular filtration. Cystatin C may be useful where creatinine measurement is not appropriate: for example, in people who have liver cirrhosis, are very obese, are malnourished, or have a reduced muscle mass. However, it is not widely used in practice.
There is considerable debate regarding the magnitude of serum creatinine increase that constitutes AKI.
abrupt reduction in kidney function, defined as an absolute increase in serum creatinine of ≥26.5 micromol/L (≥0.3 mg/dL) within 48 hours
an increase in serum creatinine to 1.5-fold from baseline within the last 7 days
a reduction in urine output (documented oliguria of <0.5 mL/kg/hour for >6 hours).
Stage 1 AKI is defined as an increase in serum creatinine >26.5 micromol/L (>0.3 mg/dL) or 150% to 200% of baseline values.
Stage 2 AKI is defined as an increase of 200% to 300% (2- to 3-fold) of baseline values.
Stage 3 AKI is defined as >300% (3-fold) increase in serum creatinine from baseline.
Use of serum creatinine to detect and assess the severity of AKI is limited. Serum levels are influenced by many factors, so the absolute level does not reflect the severity of the underlying kidney damage. Rises in serum creatinine after marked injury take 12 to 24 hours to occur and do not detect early-stage damage. In addition, creatinine kinetic studies have shown that the time to reach a 50% increase in serum creatinine is directly related to baseline kidney function and ranges from 4 hours (normal kidney function) to 27 hours (in stage 4 chronic renal failure). An alternative definition of AKI that incorporates absolute changes in serum creatinine over a 24- to 48-hour period has been proposed. Adding to this complexity is the new concept of acute kidney disease (AKD), characterised by renal biopsy findings of diffuse, acute abnormalities. Not all people with AKD have AKI. In fact, only two-thirds of patients with AKD were diagnosed with the clinical presentation of AKI in one study.
The RIFLE (Risks, Injury, Failure, Loss of function and End-stage renal disease) classification of AKI aims to standardise the definition and stratification of AKI based on changes in serum creatinine and urine output. It has 3 severity classes of AKI (risks, injury, and failure) and 2 outcomes (loss of function and end-stage renal disease). A modified version of RIFLE, known as the AKIN criteria, was published in 2007.
Data on the incidence of AKI vary, depending on the cutoff serum creatinine values, the period of observation, and the population studied. In patients undergoing general surgery, and defining AKI as an increase in serum creatinine of at least 177 micromol/L (2 mg/dL) or requiring dialysis, the incidence of AKI was 1% over a 30-day period. The incidence was 64.4% in patients with septic shock using the RIFLE criteria; 3.1% in older Medicare patients using ICD-9-CM codes 584.x to define AKI; and 5% to 10% in patients undergoing cardiac surgery. AKI may be present in 1% of hospital admissions in the US, and in 5.7% of critically ill patients during their ICU stay.
Kidney damage for ≥3 months as defined by structural or functional abnormalities of the kidney, with or without decreased GFR, manifest by pathological abnormalities, markers of kidney damage (e.g., haematuria or proteinuria), or abnormalities in imaging tests
GFR <60 mL/minute/1.73 m² for ≥3 months, with or without kidney damage.
CKD is divided into 6 distinct stages based on GFR:
Stage 1: kidney damage with normal or increased GFR, ≥90 mL/minute/1.73m²
Stage 2: kidney damage with mild decrease in GFR, 60 to 89 mL/minute/1.73m²
Stage 3a: kidney damage with moderate decrease in GFR, 45 to 59 mL/minute/1.73m²
Stage 3b: kidney damage with moderate decrease in GFR, 30 to 44 mL/minute/1.73m²
Stage 4: kidney damage with severe decrease in GFR, 15 to 29 mL/minute/1.73m²
Stage 5: kidney failure (end-stage kidney disease), with GFR <15 mL/minute/1.73m².
The presence of CKD is an important prognostic factor for patients admitted to hospital, due to the associated increased risk of in-hospital AKI.
The secretion of creatinine is not constant, and varies between and within individuals with CKD.
It is unclear whether estimation of GFR adds useful information to the serum creatinine measurement when determining CKD severity, or for guiding treatment. An increasing portion of serum creatinine is excreted by tubular secretion rather than by glomerular filtration in advanced CKD, contributing to gross overestimation of GFR. Extra-renal secretion of serum creatinine is also increased, so the uptake of creatine generated by bacterial breakdown of creatinine in the gut, normally a negligible source of creatine, becomes significant.
Serum creatinine can overestimate GFR in advanced renal dysfunction.
Testing for salivary urea and creatinine, both of which are elevated in CKD, is low cost and non-invasive. The tests may be of value in resource-poor settings, where they could be used for screening, diagnosing, monitoring treatment outcomes, and ascertaining prognosis of CKD. However, further validation is warranted.
According to the US National Health and Nutrition Examination Surveys (NHANES 1988-1994; 1999-2004), 26.3 million Americans have CKD, and the numbers are rising, partly due to the increasing prevalence of diabetes and hypertension. One population-based study in Sweden reported a substantial decline in renal function after 80 years of age. More than 25% of the oldest participants demonstrated eGFR <30 mL/minute/1.73 m². Cockroft-Gault and eGFR-cystatin C yielded the highest prevalence of decline, and MDRD the lowest.
Studies indicate that elevated serum creatinine during hospitalisation is an independent risk factor for poor outcome.
Mild increases in in-hospital serum creatinine have been associated with short-term mortality, progression to CKD, and accelerated progression to end-stage renal disease. They present a higher long-term mortality risk, especially in those with partial renal recovery. They may also have prognostic significance for estimating the risk of death in many disease states: for example, an increase of only urea levels and a combination of increased urea and creatinine levels, but not isolated elevated creatinine, were independent risk factors of death from acute coronary syndromes.
While findings from observational studies suggest that minimal and/or transient elevations in serum creatinine predict poor prognosis, one meta-analysis of placebo-controlled trials found no appreciable effect on CKD, or mortality, months after mild to moderate (often temporary) elevations in serum creatinine. The meta-analysis findings are consistent with US Food and Drug Administration guidance that new therapies should demonstrably benefit long-term kidney function or reduce mortality.
Patients with chronically elevated serum creatinine (i.e., impaired baseline renal function) have a higher risk for AKI during hospital stays and are more often dialysis-dependent at hospital discharge than those without. Chronically elevated serum creatinine has been linked to progression of CKD, increased mortality, and post-operative complications following cardiac surgery. Elevated serum creatinine after endovascular aneurysm repair has been reported to be a significant and strong predictor of post-operative mortality and complications.
Assistant Professor of Medicine
Division of Cardiology, Respiratory Medicine, and Nephrology
Hirosaki University Graduate School of Medicine
MS declares that she has no competing interests.
Associate Professor of Medicine
Division of Hospital Medicine
University of Florida
BD declares that he has no competing interests.
Professor of Medicine
Division of Nephrology, Hypertension and Transplantation
University of Florida
AAE declares that he has no competing interests.
Dr Michiko Shimada, Dr Bhagwan Dass, and Dr A. Ahsan Ejaz would like to gratefully acknowledge Dr Puneet Sood, a previous contributor to this topic. PS declares that he has no competing interests.
Royal Derby Hospital
JL has been reimbursed by Abbott for attending several conferences. JL has also received a fee from Shire for attending an advisory board meeting.
Professor of Medicine
Division of Nephrology, Hypertension and Transplantation
University of Florida
ZT declares that he has no competing interests.
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