Renal function
Encyclopedia
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 important in assessing the excretory function of the kidneys. For example, grading of chronic renal insufficiency and dosage of drugs that are excreted primarily via urine are based on GFR (or creatinine clearance).
It is commonly believed to be the amount of liquid filtered out of the blood that gets processed by the kidneys. In physiological terms, these quantities (volumetric blood flow and mass removal) are related only loosely.
concentrations of the waste substances of creatinine
and urea
(U), as well as electrolyte
s (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.
Another prognostic marker for kidney disease is an elevated level of protein in the urine. The most sensitive marker of proteinuria is elevated urine albumin. Persistence presence of more than 30 mg albumin per gram creatinine in the urine is diagnostic of chronic kidney disease (Microalbuminuria
is a level of 30–299 mg/g; a concentration of albumin
in the urine
that is not detected by usual urine dipstick
methods).
(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).
Glomerular filtration rate (GFR) can be calculated by measuring any chemical that has a steady level in the blood, and is freely filtered but 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 the 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).
into the plasma. Since inulin is neither reabsorbed nor secreted by the kidney after glomerular filtration, its rate of excretion is directly proportional to the rate of filtration of water and solutes across the glomerular filter. Compared to the MDRD formula, 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.
Where:
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:
Where:
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:
Where:
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:
Where:
This value is almost always taken to be equal to zero because, in a healthy nephron
, there should be no proteins in the Bowman's Capsule.
is a break-down 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 10-20%. 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. One of the equations, the Cockcroft and Gault equation (see below) does not correct for race, and it is known that African Americans, for example, both men and women, have a higher amount of muscle mass than Caucasians; hence, African Americans will have a higher serum creatinine level at any level of creatinine 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 may actually have a moderately severe degree of renal insufficiency, whereas a young muscular male, in particular if African American, 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 may have a moderately severe degree of renal insufficiency.
Creatinine clearance (CCr) is calculated from the creatinine concentration in the collected urine sample (UCr), urine flow rate
(V), 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×V) 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 (1.6-1.9), extremely obese or slim patients should have their CCr corrected for their actual BSA.
The creatinine clearance is not widely done any more, due to the difficulty in assuring a complete urine collection. When doing such a determination, 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."
measurements and a patient's weight to predict the creatinine clearance.
The formula, as originally published, is:
When serum creatinine is measured in µmol/L:
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 (120 is twice as great as 60). 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.
The most commonly used formula is the "4-variable MDRD," which estimates GFR using four variables: serum creatinine, age, race, 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 mg/dL:
For creatinine in µmol/L:
A more elaborate version of the MDRD equation also includes serum albumin
and blood urea nitrogen
(BUN) levels:
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).
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%.
The CKD-EPI equation, expressed as a single 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.
A clearer version may be as follows:
For creatinine (IDMS calibrated) in mg/dL:
African American Female
If serum creatinine (Scr) <= 0.7
If serum creatinine (Scr) > 0.7
African American Male
If serum creatinine (Scr) <= 0.9
If serum creatinine (Scr) > 0.9
White or other race Female
If serum creatinine (Scr) <= 0.7
If serum creatinine (Scr) > 0.7
White or other race Male
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.
The equation is:
If Serum Creatinine < 0.8 mg/dL, use 0.8 mg/dL for Serum Creatinine
(mg/dL), the child's height(cm) and a constant to estimate the glomerular filtration rate:
The method of selection of the K-constant value 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 measured in addition to serum creatinine.
, 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 creatinine and cystatin.
, is similar in men and women, and is in the range of 100-130 ml/min/1.73m2. In children, GFR measured by inulin clearance remains close to about 110 ml/min/1.73m2 down to about 2 years of age in both sexes, and then it progressively decreases. After age 40, GFR decreases progressively with age, by about 0.4 - 1.2 mL/min per year.
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.
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
):
Note: others add a "T" to patients who have had a transplant regardless of stage.
Not all clinicians agree with the above classificaiton, suggesting that it may overlabel 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.
Nephrology
Nephrology is a branch of internal medicine and pediatrics dealing with the study of the function and diseases of the kidney.-Scope of the specialty:...
, is an indication of the state of the kidney
Kidney
The kidneys, organs with several functions, serve essential regulatory roles in most animals, including vertebrates and some invertebrates. They are essential in the urinary system and also serve homeostatic functions such as the regulation of electrolytes, maintenance of acid–base balance, and...
and its role in renal physiology
Renal physiology
Renal physiology is the study of the physiology of the kidney. This encompasses all functions of the kidney, including reabsorption of glucose, amino acids, and other small molecules; regulation of sodium, potassium, and other electrolytes; regulation of fluid balance and blood pressure;...
. 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
Blood plasma
Blood plasma is the straw-colored liquid component of blood in which the blood cells in whole blood are normally suspended. It makes up about 55% of the total blood volume. It is the intravascular fluid part of extracellular fluid...
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 important in assessing the excretory function of the kidneys. For example, grading of chronic renal insufficiency and dosage of drugs that are excreted primarily via urine are based on GFR (or creatinine clearance).
It is commonly believed to be the amount of liquid filtered out of the blood that gets processed by the kidneys. In physiological terms, these quantities (volumetric blood flow and mass removal) are related only loosely.
Indirect markers
Most doctors use the plasmaBlood plasma
Blood plasma is the straw-colored liquid component of blood in which the blood cells in whole blood are normally suspended. It makes up about 55% of the total blood volume. It is the intravascular fluid part of extracellular fluid...
concentrations of the waste substances of creatinine
Creatinine
Creatinine is a break-down product of creatine phosphate in muscle, and is usually produced at a fairly constant rate by the body...
and urea
Urea
Urea or carbamide is an organic compound with the chemical formula CO2. The molecule has two —NH2 groups joined by a carbonyl functional group....
(U), as well as electrolyte
Electrolyte
In chemistry, an electrolyte is any substance containing free ions that make the substance electrically conductive. The most typical electrolyte is an ionic solution, but molten electrolytes and solid electrolytes are also possible....
s (E), to determine renal function. These measures are adequate to determine whether a patient is suffering from kidney disease.
However, blood urea nitrogen (BUN
Blood urea nitrogen
The blood urea nitrogen test is a measure of the amount of nitrogen in the blood in the form of urea, and a measurement of renal function. Urea is a by- product from metabolism of proteins by the liver and is removed from the blood by the kidneys.-Physiology:The liver produces urea in the urea...
) and creatinine
Creatinine
Creatinine is a break-down product of creatine phosphate in muscle, and is usually produced at a fairly constant rate by the body...
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.
Another prognostic marker for kidney disease is an elevated level of protein in the urine. The most sensitive marker of proteinuria is elevated urine albumin. Persistence presence of more than 30 mg albumin per gram creatinine in the urine is diagnostic of chronic kidney disease (Microalbuminuria
Microalbuminuria
Microalbuminuria occurs when the kidney leaks small amounts of albumin into the urine, in other words, when there is an abnormally high permeability for albumin in the renal glomerulus.-Diagnosis:...
is a level of 30–299 mg/g; a concentration of albumin
Albumin
Albumin refers generally to any protein that is water soluble, which is moderately soluble in concentrated salt solutions, and experiences heat denaturation. They are commonly found in blood plasma, and are unique to other blood proteins in that they are not glycosylated...
in the urine
Urine
Urine is a typically sterile liquid by-product of the body that is secreted by the kidneys through a process called urination and excreted through the urethra. Cellular metabolism generates numerous by-products, many rich in nitrogen, that require elimination from the bloodstream...
that is not detected by usual urine dipstick
Dipstick
A dipstick is one of several measurement devices.Some dipsticks are dipped into a liquid to perform a chemical test or to provide a measure of quantity of the liquid....
methods).
Glomerular filtration rate
Glomerular filtration rate (GFR) is the volume of fluid filtered from the renalKidney
The kidneys, organs with several functions, serve essential regulatory roles in most animals, including vertebrates and some invertebrates. They are essential in the urinary system and also serve homeostatic functions such as the regulation of electrolytes, maintenance of acid–base balance, and...
(kidney) glomerular capillaries into the Bowman's capsule
Bowman's capsule
The Bowman's capsule is a cup-like sac at the beginning of the tubular component of a nephron in the mammalian kidney that performs the first step in the filtration of blood to form urine. A glomerulus is enclosed in the sac...
per unit time. Central to the physiologic maintenance of GFR is the differential basal tone of the afferent and efferent arterioles (see diagram).
Glomerular filtration rate (GFR) can be calculated by measuring any chemical that has a steady level in the blood, and is freely filtered but 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 the 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
Minute
A minute is a unit of measurement of time or of angle. The minute is a unit of time equal to 1/60th of an hour or 60 seconds. In the UTC time scale, a minute on rare occasions has 59 or 61 seconds; see leap second. The minute is not an SI unit; however, it is accepted for use with SI units...
. Compare to filtration fraction
Filtration fraction
In renal physiology, the filtration fraction is the ratio of the glomerular filtration rate to the renal plasma flow .Filtration Fraction , FF = GFR/RPF...
.
There are several different techniques used to calculate or estimate the glomerular filtration rate (GFR or eGFR).
Measurement using inulin
The GFR can be determined by injecting inulinInulin
Inulins are a group of naturally occurring polysaccharides produced by many types of plants. They belong to a class of fibers known as fructans. Inulin is used by some plants as a means of storing energy and is typically found in roots or rhizomes...
into the plasma. Since inulin is neither reabsorbed nor secreted by the kidney after glomerular filtration, its rate of excretion is directly proportional to the rate of filtration of water and solutes across the glomerular filter. Compared to the MDRD formula, 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.
Pressure Definition
More precisely, GFR is the fluid flow rate between the glomerular capillaries and the Bowman's capsule:Where:
is the GFR.
is called the filtration constant and is defined as the product of the hydraulic conductivityHydraulic conductivityHydraulic conductivity, symbolically represented as K, is a property of vascular plants, soil or rock, that describes the ease with which water can move through pore spaces or fractures. It depends on the intrinsic permeability of the material and on the degree of saturation...
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 pressureOncotic pressureOncotic pressure, or colloid osmotic pressure, is a form of osmotic pressure exerted by proteins in blood plasma that usually tends to pull water into the circulatory system.Throughout the body, dissolved compounds have an osmotic pressure...
within the glomerular capillaries.- and
is the colloid osmotic pressure within the Bowman's capsule.
Hydraulic conductivity
Hydraulic conductivity, symbolically represented as K, is a property of vascular plants, soil or rock, that describes the ease with which water can move through pore spaces or fractures. It depends on the intrinsic permeability of the material and on the degree of saturation...
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:
Afferent
Afferent is an anatomical term with the following meanings:*Conveying towards a center, for example the afferent arterioles conveying blood towards the Bowman's capsule in the Kidney. Opposite to Efferent.*Something that so conducts, see Afferent nerve fiber...
arteriole and leaving through the efferent
Efferent
Efferent is an anatomical term with the following meanings:*Conveying away from a center, for example the efferent arterioles conveying blood away from the Bowman's capsule in the kidney. Opposite to afferent....
arteriole. The pressure difference is approximated by the product of the total resistance of the respective arteriole and the flux of blood through it:
Where:
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.
Where:
is the pressure in the descending tubule.- And,
is the resistance of the descending tubule.
Oncotic pressure
Oncotic pressure, or colloid osmotic pressure, is a form of osmotic pressure exerted by proteins in blood plasma that usually tends to pull water into the circulatory system.Throughout the body, dissolved compounds have an 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:
Where:
- 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).
Nephron
The renal tubule is the portion of the nephron containing the tubular fluid filtered through the glomerulus. After passing through the renal tubule, the filtrate continues to the collecting duct system, which is not part of the nephron....
, there should be no proteins in the Bowman's 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 (creatinineCreatinine
Creatinine is a break-down product of creatine phosphate in muscle, and is usually produced at a fairly constant rate by the body...
is a break-down 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 10-20%. 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. One of the equations, the Cockcroft and Gault equation (see below) does not correct for race, and it is known that African Americans, for example, both men and women, have a higher amount of muscle mass than Caucasians; hence, African Americans will have a higher serum creatinine level at any level of creatinine 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 may actually have a moderately severe degree of renal insufficiency, whereas a young muscular male, in particular if African American, 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 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-hours) to determine the amount of creatinine that was removed from the blood over a given time interval. If one removes, say, 1440 mg in 24 hours, 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
Urine flow rate
Urine flow rate is a measure of the quantity of urine produced in a specified period of time. Common periods of time used include "minute" and "24 hours"....
(V), 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×V) 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
Body surface area
In physiology and medicine, the body surface area is the measured or calculated surface of a human body. For many clinical purposes BSA is a better indicator of metabolic mass than body weight because it is less affected by abnormal adipose mass...
(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 (1.6-1.9), 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.
The creatinine clearance is not widely done any more, due to the difficulty in assuring a complete urine collection. When doing such a determination, 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."
Estimated values
A number of formulae have been devised to estimate GFR or Ccr values on the basis of serum creatinine levels.Estimated creatinine clearance rate (eCCr) using Cockcroft-Gault formula
A commonly used surrogate marker for estimate of creatinine clearance is the Cockcroft-Gault formula, which in turn estimates GFR in mL/min: It is named after the scientists who first published the formula, and it employs serum creatinineCreatinine
Creatinine is a break-down product of creatine phosphate in muscle, and is usually produced at a fairly constant rate by the body...
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 kilogramKilogramThe kilogram or kilogramme , also known as the kilo, is the base unit of mass in the International System of Units and is defined as being equal to the mass of the International Prototype Kilogram , which is almost exactly equal to the mass of one liter of water...
s 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 calculatorCalculatorAn electronic calculator is a small, portable, usually inexpensive electronic device used to perform the basic operations of arithmetic. Modern calculators are more portable than most computers, though most PDAs are comparable in size to handheld calculators.The first solid-state electronic...
.
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 (120 is twice as great as 60). 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#Staging. 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, race, and gender. The original MDRD used six variables with the additional variables being the blood urea nitrogen
Blood urea nitrogen
The blood urea nitrogen test is a measure of the amount of nitrogen in the blood in the form of urea, and a measurement of renal function. Urea is a by- product from metabolism of proteins by the liver and is removed from the blood by the kidneys.-Physiology:The liver produces urea in the urea...
and albumin
Albumin
Albumin refers generally to any protein that is water soluble, which is moderately soluble in concentrated salt solutions, and experiences heat denaturation. They are commonly found in blood plasma, and are unique to other blood proteins in that they are not glycosylated...
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 mg/dL:
For creatinine in µmol/L:
- 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.
A more elaborate version of the MDRD equation also includes serum albumin
Serum albumin
Serum albumin, often referred to simply as albumin is a protein that in humans is encoded by the ALB gene.Serum albumin is the most abundant plasma protein in mammals. Albumin is essential for maintaining the osmotic pressure needed for proper distribution of body fluids between intravascular...
and blood urea nitrogen
Blood urea nitrogen
The blood urea nitrogen test is a measure of the amount of nitrogen in the blood in the form of urea, and a measurement of renal function. Urea is a by- product from metabolism of proteins by the liver and is removed from the blood by the kidneys.-Physiology:The liver produces urea in the urea...
(BUN) levels:
- 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%.
The CKD-EPI equation, expressed as a single 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.
A clearer version may be as follows:
For creatinine (IDMS calibrated) in mg/dL:
African American Female
If serum creatinine (Scr) <= 0.7
If serum creatinine (Scr) > 0.7
African American Male
If serum creatinine (Scr) <= 0.9
If serum creatinine (Scr) > 0.9
White or other race Female
If serum creatinine (Scr) <= 0.7
If serum creatinine (Scr) > 0.7
White or other race Male
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.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
In children, the Schwartz formula is used. This employs the serum creatinineCreatinine
Creatinine is a break-down product of creatine phosphate in muscle, and is usually produced at a fairly constant rate by the body...
(mg/dL), the child's height(cm) and a constant to estimate the glomerular filtration rate:
- Where k is a constant that depends on muscle mass, which itself varies with a child's age:
- In first year of life, for pre-term babies K=0.33 and for full-term infants K=0.45
- For infants and children of age 1 to 12 years, K=0.55.
The method of selection of the K-constant value 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 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). At the present time in late 2009 not all labs in the U.S. have 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.Cystatin C
Problems with creatinine (varying muscle mass, recent meat ingestion, etc.) have led to evaluation of alternative agents for estimation of GFR. One of these is cystatin CCystatin C
Cystatin C or cystatin 3 , a protein encoded by the CST3 gene, is mainly used as a biomarker of kidney function. Recently, it has been studied for its role in predicting new-onset or deteriorating cardiovascular disease...
, 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 creatinine and cystatin.
Normal ranges
The normal range of GFR, adjusted for body surface areaBody surface area
In physiology and medicine, the body surface area is the measured or calculated surface of a human body. For many clinical purposes BSA is a better indicator of metabolic mass than body weight because it is less affected by abnormal adipose mass...
, is similar in men and women, and is in the range of 100-130 ml/min/1.73m2. In children, GFR measured by inulin clearance remains close to about 110 ml/min/1.73m2 down to about 2 years of age in both sexes, and then it progressively decreases. After age 40, GFR decreases progressively with age, by about 0.4 - 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.
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
Proteinuria
Proteinuria means the presence of anexcess of serum proteins in the urine. The protein in the urine often causes the urine to become foamy, although foamy urine may also be caused by bilirubin in the urine , retrograde ejaculation, pneumaturia due to a fistula, or drugs such as pyridium.- Causes...
):
- 0) Normal kidney function – GFR above 90mL/min/1.73m2 and no proteinuriaProteinuriaProteinuria means the presence of anexcess of serum proteins in the urine. The protein in the urine often causes the urine to become foamy, although foamy urine may also be caused by bilirubin in the urine , retrograde ejaculation, pneumaturia due to a fistula, or drugs such as pyridium.- Causes...
- 1) CKD1 – GFR above 90mL/min/1.73m2 with evidence of kidney damage
- 2) CKD2 (Mild) – GFR of 60 to 89 mL/min/1.73m2 with evidence of kidney damage
- 3) CKD3 (Moderate) – GFR of 30 to 59 mL/min/1.73m2
- 4) CKD4 (Severe) – GFR of 15 to 29 mL/min/1.73m2
- 5) CKD5 Kidney failure - GFR less than 15 mL/min/1.73m2 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 classificaiton, suggesting that it may overlabel 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.
See also
- ClearanceClearance (medicine)In medicine, the clearance is a measurement of the renal excretion ability. Although clearance may also involve other organs than the kidney, it is almost synonymous with renal clearance or renal plasma clearance. Each substance has a specific clearance that depends on its filtration characteristics...
- DialysisDialysisIn medicine, dialysis is a process for removing waste and excess water from the blood, and is primarily used to provide an artificial replacement for lost kidney function in people with renal failure...
- Filtration fractionFiltration fractionIn renal physiology, the filtration fraction is the ratio of the glomerular filtration rate to the renal plasma flow .Filtration Fraction , FF = GFR/RPF...
- Kt/VKt/VIn medicine, Kt/V is a number used to quantify hemodialysis and peritoneal dialysis treatment adequacy.*K - dialyzer clearance of urea*t - dialysis time*V - volume of distribution of urea, approximately equal to patient's total body water...
- PharmacokineticsPharmacokineticsPharmacokinetics, sometimes abbreviated as PK, is a branch of pharmacology dedicated to the determination of the fate of substances administered externally to a living organism...
- Renal clearance ratio
- Renal failureRenal failureRenal failure or kidney failure describes a medical condition in which the kidneys fail to adequately filter toxins and waste products from the blood...
- Standardized Kt/VStandardized Kt/VStandardized Kt/V, also std Kt/V, is a way of measuring dialysis adequacy. It was developed by Frank Gotch and is used in the USA to measure dialysis. Despite the name, it is quite different from Kt/V...
- Tubuloglomerular feedback
- Urea reduction ratio
Cockcroft-Gault calculators
- Online GFR Calculator (Cockcroft-Gault Formula)
- Online calculator for Cockcroft-Gault and MDRD formulae.
MDRD calculators
- Online calculator for Cockcroft-Gault and MDRD formulae.
Cockcroft - Gault / MDRD Combination Calculators
- Online GFR Calculator utilizing the Cockcroft-Gault formula, the MDRD formula, and a combination of both formulas.
Calculator also computes the expected GFR for age and the percentage of the patient's current GFR as compared to normal.
Other formulas calculators
Reference links
- National Kidney Disease Education Program website. Includes professional references and GFR calculators