Renal function, in nephrology, is an indication of the state of the kidney and its role in renal physiology. Glomerular filtration rate (GFR) describes the flow rate of filtered fluid through the kidney. Creatinine clearance rate (CCr or CrCl) is the volume of blood plasma that is cleared of creatinine per unit time and is a useful measure for approximating the GFR. Creatinine clearance exceeds GFR due to creatinine secretion, which can be blocked by cimetidine. In alternative fashion, overestimation by older serum creatinine methods resulted in an underestimation of creatinine clearance, which provided a less biased estimate of GFR. Both GFR and CCr may be accurately calculated by comparative measurements of substances in the blood and urine, or estimated by formulas using just a blood test result (eGFR and eCCr).
The results of these tests are used to assess the excretory function of the kidneys. Staging of chronic kidney disease is based on categories of GFR as well as albuminuria and cause of kidney disease.
Dosage of drugs that are excreted primarily via urine may need to be modified based on either GFR or creatinine clearance.
- 1 Indirect markers
- 2 Glomerular filtration rate
- 3 Creatinine-based approximations of GFR
- 4 Estimated values
- 4.1 Estimated creatinine clearance rate (eCCr) using Cockcroft-Gault formula
- 4.2 Estimated GFR (eGFR) using Modification of Diet in Renal Disease (MDRD) formula
- 4.3 Estimated GFR (eGFR) using the CKD-EPI formula
- 4.4 Estimated GFR (eGFR) using the Mayo Quadratic formula
- 4.5 Estimated GFR for children using Schwartz formula
- 4.6 Importance of calibration of the serum creatinine level and the IDMS standardization effort
- 4.7 Cystatin C
- 5 Normal ranges
- 6 See also
- 7 References
- 8 External links
Most doctors use the plasma concentrations of the waste substances of creatinine and urea (U), as well as electrolytes (E), to determine renal function. These measures are adequate to determine whether a patient is suffering from kidney disease.
However, blood urea nitrogen (BUN) and creatinine will not be raised above the normal range until 60% of total kidney function is lost. Hence, the more accurate Glomerular filtration rate or its approximation of the creatinine clearance is measured whenever renal disease is suspected or careful dosing of nephrotoxic drugs is required.
Elevated protein levels in urine mark some kidney disease. The most sensitive marker of proteinuria is elevated urine albumin. Persistent presence of more than 30 mg albumin per gram creatinine in the urine is diagnostic of chronic kidney disease (microalbuminuria is a level of 30 mg/L to 299 mg/L urine or 30–299 mg/24 h; a concentration of albumin in the urine that is not detected by usual urine dipstick methods).
Glomerular filtration rate
Glomerular filtration rate (GFR) is the volume of fluid filtered from the renal (kidney) glomerular capillaries into the Bowman's capsule per unit time. Central to the physiologic maintenance of GFR is the differential basal tone of the afferent and efferent arterioles (see diagram). In other words, the filtration rate is dependent on the difference between the higher blood pressure created by vasoconstriction of the input or afferent arteriole versus the lower blood pressure created lesser vasoconstriction of the output or efferent arteriole.
Glomerular filtration rate (GFR) is equal to the Clearance Rate when any solute is freely filtered and is neither reabsorbed nor secreted by the kidneys. The rate therefore measured is the quantity of the substance in the urine that originated from a calculable volume of blood. Relating this principle to the below equation - for the substance used, the product of urine concentration and urine flow equals the mass of substance excreted during the time that urine has been collected. This mass equals the mass filtered at the glomerulus as nothing is added or removed in the nephron. Dividing this mass by the plasma concentration gives the volume of plasma which the mass must have originally come from, and thus the volume of plasma fluid that has entered Bowman's capsule within the aforementioned period of time. The GFR is typically recorded in units of volume per time, e.g., milliliters per minute mL/min. Compare to filtration fraction.
There are several different techniques used to calculate or estimate the glomerular filtration rate (GFR or eGFR). The above formula only applies for GFR calculation when it is equal to the Clearance Rate.
Measurement using inulin
The GFR can be determined by injecting inulin or the inulin-analog sinistrin into the plasma. Since both inulin and sinistrin are neither reabsorbed nor secreted by the kidney after glomerular filtration, their rate of excretion is directly proportional to the rate of filtration of water and solutes across the glomerular filter. Compared to the MDRD formula[clarification needed], the inulin clearance slightly overestimates the glomerular function. In early stage renal disease, the inulin clearance may remain normal due to hyperfiltration in the remaining nephrons. Incomplete urine collection is an important source of error in inulin clearance measurement.
Measurement with radioactive tracers
GFR can be accurately measured using radioactive substances, in particular Chromium-51 and Technetium-99m. These come close to the ideal properties of Inulin (undergoing only glomerular filtration) but can be measured more practically with only a few urine or blood samples. Measurement of renal or plasma clearance of 51Cr-EDTA is widely used in Europe but not available in the United States, where 99mTc-DTPA may be used instead. Renal and plasma clearance 51Cr-EDTA has been shown to be accurate in comparison with the gold standard, Inulin. Use of 51Cr‑EDTA is considered a reference standard measure in UK guidance.
More precisely, GFR is the fluid flow rate between the glomerular capillaries and the Bowman's capsule:
- is the GFR.
- is called the filtration constant and is defined as the product of the hydraulic conductivity and the surface area of the glomerular capillaries.
- is the hydrostatic pressure within the glomerular capillaries.
- is the hydrostatic pressure within the Bowman's capsule.
- is the colloid osmotic pressure within the glomerular capillaries.
- and is the colloid osmotic pressure within the Bowman's capsule.
Because this constant is a measurement of hydraulic conductivity multiplied by the capillary surface area, it is almost impossible to measure physically. However, it can be determined experimentally. Methods of determining the GFR are listed in the above and below sections and it is clear from our equation that can be found by dividing the experimental GFR by the net filtration pressure:
The hydrostatic pressure within the glomerular capillaries is determined by the pressure difference between the fluid entering immediately from the afferent arteriole and leaving through the efferent arteriole. The pressure difference is approximated by the product of the total resistance of the respective arteriole and the flux of blood through it:
- is the afferent arteriole pressure.
- is the efferent arteriole pressure.
- is the afferent arteriole resistance.
- is the efferent arteriole resistance.
- is the afferent arteriole flux.
- And, is the efferent arteriole flux.
The pressure in the Bowman's capsule and proximal tubule can be determined by the difference between the pressure in the Bowman's capsule and the descending tubule:
- is the pressure in the descending tubule.
- And, is the resistance of the descending tubule.
Blood plasma has a good many proteins in it and they exert an inward directed force called the colloid osmotic pressure on the water in hypotonic solutions across a membrane, i.e., in the Bowman's capsule. Because plasma proteins are virtually incapable of escaping the glomerular capillaries, this oncotic pressure is defined, simply, by the ideal gas law:
- R is the universal gas constant
- T is the temperature.
- And, c is concentration in mol/L of plasma proteins (remember the solutes can freely diffuse through the glomerular capsule).
Creatinine-based approximations of GFR
In clinical practice, however, creatinine clearance or estimates of creatinine clearance based on the serum creatinine level are used to measure GFR. Creatinine is produced naturally by the body (creatinine is a breakdown product of creatine phosphate, which is found in muscle). It is freely filtered by the glomerulus, but also actively secreted by the peritubular capillaries in very small amounts such that creatinine clearance overestimates actual GFR by 10% to 20%. This margin of error is acceptable, considering the ease with which creatinine clearance is measured. Unlike precise GFR measurements involving constant infusions of inulin, creatinine is already at a steady-state concentration in the blood, and so measuring creatinine clearance is much less cumbersome. However, creatinine estimates of GFR have their limitations. All of the estimating equations depend on a prediction of the 24-hour creatinine excretion rate, which is a function of muscle mass which is quite variable. One of the equations, the Cockcroft and Gault equation (see below) does not correct for race. With a higher muscle mass, serum creatinine will be higher for any given rate of clearance.
A common mistake made when just looking at serum creatinine is the failure to account for muscle mass. Hence, an older woman with a serum creatinine of 1.4 mg/dL may actually have a moderately severe degree of renal insufficiency, whereas a young muscular male can have a normal level of renal function at this serum creatinine level. Creatinine-based equations should be used with caution in cachectic patients and patients with cirrhosis. They often have very low muscle mass and a much lower creatinine excretion rate than predicted by the equations below, such that a cirrhotic patient with a serum creatinine of 0.9 mg/dL may have a moderately severe degree of renal insufficiency.
Creatinine Clearance CCr
One method of determining GFR from creatinine is to collect urine (usually for 24 h) to determine the amount of creatinine that was removed from the blood over a given time interval. If one removes 1440 mg in 24 h, this is equivalent to removing 1 mg/min. If the blood concentration is 0.01 mg/mL (1 mg/dL), then one can say that 100 mL/min of blood is being "cleared" of creatinine, since, to get 1 mg of creatinine, 100 mL of blood containing 0.01 mg/mL would need to have been cleared.
Creatinine clearance (CCr) is calculated from the creatinine concentration in the collected urine sample (UCr), urine flow rate (Vdt), and the plasma concentration (PCr). Since the product of urine concentration and urine flow rate yields creatinine excretion rate, which is the rate of removal from the blood, creatinine clearance is calculated as removal rate per min (UCr×Vdt) divided by the plasma creatinine concentration. This is commonly represented mathematically as
Example: A person has a plasma creatinine concentration of 0.01 mg/ml and in 1 hour produces 60ml of urine with a creatinine concentration of 1.25 mg/mL.
The common procedure involves undertaking a 24-hour urine collection, from empty-bladder one morning to the contents of the bladder the following morning, with a comparative blood test then taken. The urinary flow rate is still calculated per minute, hence:
To allow comparison of results between people of different sizes, the CCr is often corrected for the body surface area (BSA) and expressed compared to the average sized man as mL/min/1.73 m2. While most adults have a BSA that approaches 1.7 m2 (1.6 m2 to 1.9 m2), extremely obese or slim patients should have their CCr corrected for their actual BSA.
- BSA can be calculated on the basis of weight and height.
Twenty-four-hour urine collection to assess creatinine clearance is no longer widely performed, due to difficulty in assuring complete specimen collection. To assess the adequacy of a complete collection, one always calculates the amount of creatinine excreted over a 24-hour period. This amount varies with muscle mass, and is higher in young people vs. old, in blacks vs. whites, and in men vs. women. An unexpectedly low or high 24-hour creatinine excretion rate voids the test. Nevertheless, in cases where estimates of creatinine clearance from serum creatinine are unreliable, creatinine clearance remains a useful test. These cases include "estimation of GFR in individuals with variation in dietary intake (vegetarian diet, creatine supplements) or muscle mass (amputation, malnutrition, muscle wasting), since these factors are not specifically taken into account in prediction equations."
A number of formulae have been devised to estimate GFR or Ccr values on the basis of serum creatinine levels. Where not otherwise stated serum creatinine is assumed to be stated in mg/dL, not µmol/L—divide by 88.4 to convert from µmol/Lto mg/dL.
Estimated creatinine clearance rate (eCCr) using Cockcroft-Gault formula
A commonly used surrogate marker for estimate of creatinine clearance is the Cockcroft-Gault (CG) formula, which in turn estimates GFR in ml/min: It is named after the scientists who first published the formula, and it employs serum creatinine measurements and a patient's weight to predict the creatinine clearance. The formula, as originally published, is:
- This formula expects weight to be measured in kilograms and creatinine to be measured in mg/dL, as is standard in the USA. The resulting value is multiplied by a constant of 0.85 if the patient is female. This formula is useful because the calculations are simple and can often be performed without the aid of a calculator.
When serum creatinine is measured in µmol/L:
- Where Constant is 1.23 for men and 1.04 for women.
One interesting feature of the Cockcroft and Gault equation is that it shows how dependent the estimation of CCr is based on age. The age term is (140 - age). This means that a 20-year-old person (140-20 = 120) will have twice the creatinine clearance as an 80-year-old (140-80 = 60) for the same level of serum creatinine. The C-G equation assumes that a woman will have a 15% lower creatinine clearance than a man at the same level of serum creatinine.
Estimated GFR (eGFR) using Modification of Diet in Renal Disease (MDRD) formula
The most recently advocated formula for calculating the GFR is the one that was developed by the Modification of Diet in Renal Disease Study Group. Most laboratories in Australia, and The United Kingdom now calculate and report the MDRD estimated GFR along with creatinine measurements and this forms the basis of chronic kidney disease. The adoption of the automatic reporting of MDRD-eGFR has been widely criticised.
The most commonly used formula is the "4-variable MDRD," which estimates GFR using four variables: serum creatinine, age, ethnicity, and gender. The original MDRD used six variables with the additional variables being the blood urea nitrogen and albumin levels. The equations have been validated in patients with chronic kidney disease; however both versions underestimate the GFR in healthy patients with GFRs over 60 mL/min. The equations have not been validated in acute renal failure.
For creatinine in µmol/L:
For creatinine in mg/dL:
- Creatinine levels in µmol/L can be converted to mg/dL by dividing them by 88.4. The 32788 number above is equal to 186×88.41.154.
- Where the creatinine and blood urea nitrogen concentrations are both in mg/dL. The albumin concentration is in g/dL.
These MDRD equations are to be used only if the laboratory has NOT calibrated its serum creatinine measurements to isotope dilution mass spectrometry (IDMS). When IDMS-calibrated serum creatinine is used (which is about 6% lower), the above equations should be multiplied by 175/186 or by 0.94086.
Since these formulae do not adjust for body mass, they (relative to the Cockcroft-Gault formula) underestimate eGFR for heavy people and overestimate it for underweight people. (see Cockcroft-Gault formula above).
Estimated GFR (eGFR) using the CKD-EPI formula
The CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) formula was published in May 2009. It was developed in an effort to create a formula more accurate than the MDRD formula, especially when actual GFR is greater than 60 mL/min per 1.73 m2.
Researchers pooled data from multiple studies to develop and validate this new equation. They used 10 studies that included 8254 participants, randomly using 2/3 of the data sets for development and the other 1/3 for internal validation. Sixteen additional studies, which included 3896 participants, were used for external validation.
The CKD-EPI equation performed better than the MDRD (Modification of Diet in Renal Disease Study) equation, especially at higher GFR, with less bias and greater accuracy. When looking at NHANES (National Health and Nutrition Examination Survey) data, the median estimated GFR was 94.5 mL/min per 1.73 m2 vs. 85.0 mL/min per 1.73 m2, and the prevalence of chronic kidney disease was 11.5% versus 13.1%. Despite its overall superiority to the MDRD equation, the CKD-EPI equations performed poorly in certain populations, including black women, the elderly and the obese, and was less popular among clinicians than the MDRD estimate.
The CKD-EPI equation is:
where SCr is serum creatinine (mg/dL), k is 0.7 for females and 0.9 for males, a is -0.329 for females and -0.411 for males, min indicates the minimum of SCr/k or 1, and max indicates the maximum of SCr/k or 1.
As separate equations for different populations: For creatinine (IDMS calibrated) in mg/dL:
If serum creatinine (Scr) <= 0.7
If serum creatinine (Scr) > 0.7
If serum creatinine (Scr) <= 0.9
If serum creatinine (Scr) > 0.9
Female, not black
If serum creatinine (Scr) <= 0.7
If serum creatinine (Scr) > 0.7
Male, not black
If serum creatinine (Scr) <= 0.9
If serum creatinine (Scr) > 0.9
This formula was developed by Levey et al.
The formula CKD-EPI may provide improved cardiovascular risk prediction over the MDRD Study formula in a middle-age population.
Estimated GFR (eGFR) using the Mayo Quadratic formula
Another estimation tool to calculate GFR is the Mayo Quadratic formula. This formula was developed by Rule et al., in an attempt to better estimate GFR in patients with preserved kidney function. It is well recognized that the MDRD formula tends to underestimate GFR in patients with preserved kidney function. Studies in 2008 found that the Mayo Clinic Quadratic Equation compared moderately well with radionuclide GFR, but had inferior bias and accuracy than the MDRD equation in a clinical setting.
The equation is:
If Serum Creatinine < 0.8 mg/dL, use 0.8 mg/dL for Serum Creatinine.
Estimated GFR for children using Schwartz formula
- Where k is a constant that depends on muscle mass, which itself varies with a child's age:
The method of selection of the constant k has been questioned as being dependent upon the gold-standard of renal function used (i.e., creatinine clearance, inulin clearance, etc.) and also may be dependent upon the urinary flow rate at the time of measurement.
In 2009 the formula was updated to use standardized serum creatinine (recommend k=0.413) and additional formulas that allow improved precision were derived if serum cystatin is measured in addition to serum creatinine.
Importance of calibration of the serum creatinine level and the IDMS standardization effort
One problem with any creatinine-based equation for GFR is that the methods used to assay creatinine in the blood differ widely in their susceptibility to non-specific chromogens, which cause the creatinine value to be overestimated. In particular, the MDRD equation was derived using serum creatinine measurements that had this problem. The NKDEP program in the United States has attempted to solve this problem by trying to get all laboratories to calibrate their measures of creatinine to a "gold standard", which in this case is isotope dilution mass spectrometry (IDMS). In late 2009 not all labs in the U.S. had changed over to the new system. There are two forms of the MDRD equation that are available, depending on whether or not creatinine was measured by an IDMS-calibrated assay. The CKD-EPI equation is designed to be used with IDMS-calibrated serum creatinine values only.
Problems with creatinine (varying muscle mass, recent meat ingestion (much less dependent on the diet than urea), etc.) have led to evaluation of alternative agents for estimation of GFR. One of these is cystatin C, a ubiquitous protein secreted by most cells in the body (it is an inhibitor of cysteine protease).
Cystatin C is freely filtered at the glomerulus. After filtration, Cystatin C is reabsorbed and catabolized by the tubular epithelial cells, with only small amounts excreted in the urine. Cystatin C levels are therefore measured not in the urine, but in the bloodstream.
Equations have been developed linking estimated GFR to serum cystatin C levels. Most recently, some proposed equations have combined (sex, age and race) adjusted cystatin C and creatinine. The most accurate is (sex, age and race) adjusted cystatin C, followed by (sex, age and race) adjusted creatinine and then cystatine C alone in slightly different with adjusted creatinine.
The normal range of GFR, adjusted for body surface area, is 100 mL/min/1.73m2 to 130 mL/min/1.73m2 in men and 90 mL/min/1.73m2 to 120 ml/min/1.73m2 in women younger than the age of 40. In children, GFR measured by inulin clearance is 110 mL/min/1.73 m2 until 2 years of age in both sexes, and then it progressively decreases. After age 40, GFR decreases progressively with age, by about 0.4 mL/min to 1.2 mL/min per year.
Chronic kidney disease stages
Risk factors for kidney disease include diabetes, high blood pressure, family history, older age, ethnic group and smoking. For most patients, a GFR over 60 mL/min/1.73m2 is adequate. But significant decline of the GFR from a previous test result can be an early indicator of kidney disease requiring medical intervention. The sooner kidney dysfunction is diagnosed and treated the greater odds of preserving remaining nephrons, and preventing the need for dialysis.
|CKD stage||GFR level (mL/min/1.73 m2)|
|Stage 1||≥ 90|
|Stage 2||60 – 89|
|Stage 3||30 – 59|
|Stage 4||15 – 29|
|Stage 5||< 15|
The severity of chronic kidney disease (CKD) is described by six stages; the most severe three are defined by the MDRD-eGFR value, and first three also depend on whether there is other evidence of kidney disease (e.g., proteinuria):
- 0) Normal kidney function – GFR above 90 mL/min/1.73 m2 and no proteinuria
- 1) CKD1 – GFR above 90 mL/min/1.73 m2 with evidence of kidney damage
- 2) CKD2 (mild) – GFR of 60 to 89 mL/min/1.73 m2 with evidence of kidney damage
- 3) CKD3 (moderate) – GFR of 30 to 59 mL/min/1.73 m2
- 4) CKD4 (severe) – GFR of 15 to 29 mL/min/1.73 m2
- 5) CKD5 kidney failure - GFR less than 15 mL/min/1.73 m2 Some people add CKD5D for those stage 5 patients requiring dialysis; many patients in CKD5 are not yet on dialysis.
Note: others add a "T" to patients who have had a transplant regardless of stage.
Not all clinicians agree with the above classification, suggesting that it may mislabel patients with mildly reduced kidney function, especially the elderly, as having a disease. A conference was held in 2009 regarding these controversies by Kidney Disease: Improving Global Outcomes (KDIGO) on CKD: Definition, Classification and Prognosis, gathering data on CKD prognosis to refine the definition and staging of CKD.
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- Renal clearance ratio
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- Bauer C, Melamed ML, Hostetter TH (2008). "Staging of Chronic Kidney Disease: Time for a Course Correction". American Society of Nephrology. 19 (5): 844–46. doi:10.1681/ASN.2008010110.
- Eckardt KU, Berns JS, Rocco MV, Kasiske BL (June 2009). "Definition and Classification of CKD: The Debate Should Be About Patient Prognosis—A Position Statement From KDOQI and KDIGO" (PDF). American Journal of Kidney Diseases. 53 (6): 915–920. doi:10.1053/j.ajkd.2009.04.001. PMID 19406541.
- "KDIGO Controversies Conference: Definition, Classification and Prognosis in CKD, London, October 2009". Kidney Disease: Improving Global Outcomes (KDIGO). 2009.
- Online GFR Calculator
- Schwartz formula for estimating pediatric renal function
- Creatinine clearance calculator (Cockcroft-Gault Equation)- by MDCalc
- MDRD GFR Equation
- National Kidney Disease Education Program website. Includes professional references and GFR calculators
- eGFR at Lab Tests Online