
Renal functions include maintaining an
acid–base balance; regulating
fluid balance
Fluid balance is an aspect of the homeostasis of organisms in which the amount of water in the organism needs to be controlled, via osmoregulation and behavior, such that the concentrations of electrolytes (salts in solution) in the various body ...
; regulating
sodium
Sodium is a chemical element; it has Symbol (chemistry), symbol Na (from Neo-Latin ) and atomic number 11. It is a soft, silvery-white, highly reactive metal. Sodium is an alkali metal, being in group 1 element, group 1 of the peri ...
,
potassium
Potassium is a chemical element; it has Symbol (chemistry), symbol K (from Neo-Latin ) and atomic number19. It is a silvery white metal that is soft enough to easily cut with a knife. Potassium metal reacts rapidly with atmospheric oxygen to ...
, and other
electrolyte
An electrolyte is a substance that conducts electricity through the movement of ions, but not through the movement of electrons. This includes most soluble Salt (chemistry), salts, acids, and Base (chemistry), bases, dissolved in a polar solven ...
s;
clearing toxin
A toxin is a naturally occurring poison produced by metabolic activities of living cells or organisms. They occur especially as proteins, often conjugated. The term was first used by organic chemist Ludwig Brieger (1849–1919), derived ...
s; absorption of
glucose
Glucose is a sugar with the Chemical formula#Molecular formula, molecular formula , which is often abbreviated as Glc. It is overall the most abundant monosaccharide, a subcategory of carbohydrates. It is mainly made by plants and most algae d ...
,
amino acid
Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although over 500 amino acids exist in nature, by far the most important are the 22 α-amino acids incorporated into proteins. Only these 22 a ...
s, and other small molecules; regulation of
blood pressure
Blood pressure (BP) is the pressure of Circulatory system, circulating blood against the walls of blood vessels. Most of this pressure results from the heart pumping blood through the circulatory system. When used without qualification, the term ...
; production of various
hormone
A hormone (from the Ancient Greek, Greek participle , "setting in motion") is a class of cell signaling, signaling molecules in multicellular organisms that are sent to distant organs or tissues by complex biological processes to regulate physio ...
s, such as
erythropoietin
Erythropoietin (; EPO), also known as erythropoetin, haematopoietin, or haemopoietin, is a glycoprotein cytokine secreted mainly by the kidneys in response to cellular hypoxia; it stimulates red blood cell production ( erythropoiesis) in th ...
; and activation of
vitamin D
Vitamin D is a group of structurally related, fat-soluble compounds responsible for increasing intestinal absorption of calcium, magnesium, and phosphate, along with numerous other biological functions. In humans, the most important compo ...
.
The
kidney
In humans, the kidneys are two reddish-brown bean-shaped blood-filtering organ (anatomy), organs that are a multilobar, multipapillary form of mammalian kidneys, usually without signs of external lobulation. They are located on the left and rig ...
has many functions, which a well-functioning kidney realizes by filtering blood in a process known as
glomerular filtration. A major measure of
kidney function
Assessment of kidney function occurs in different ways, using the presence of symptoms and medical sign, signs, as well as measurements using urine tests, blood tests, and medical imaging.
Renal physiology, Functions of a healthy kidney include ...
is the glomerular filtration rate (GFR).
The glomerular filtration rate is the flow rate of filtered fluid through the kidney. The creatinine clearance rate (C
Cr or CrCl) is the volume of
blood plasma
Blood plasma is a light Amber (color), amber-colored liquid component of blood in which blood cells are absent, but which contains Blood protein, proteins and other constituents of whole blood in Suspension (chemistry), suspension. It makes up ...
that is cleared of
creatinine
Creatinine (; ) is a breakdown product of creatine phosphate from muscle and protein metabolism. It is released at a constant rate by the body (depending on muscle mass).
Biological relevance
Serum creatinine (a blood measurement) is an impor ...
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
Cimetidine, sold under the brand name Tagamet among others, is a histamine H2 receptor antagonist that inhibits stomach acid production. It is mainly used in the treatment of heartburn and peptic ulcers.
With the development of proton pump ...
. Both GFR and C
Cr 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 eC
Cr) The results of these tests are used to assess the excretory function of the kidneys.
Staging of
chronic kidney disease
Chronic kidney disease (CKD) is a type of long-term kidney disease, defined by the sustained presence of abnormal kidney function and/or abnormal kidney structure. To meet criteria for CKD, the abnormalities must be present for at least three mo ...
is based on categories of GFR as well as
albuminuria and cause of
kidney disease
Kidney disease, or renal disease, technically referred to as nephropathy, is damage to or disease of a kidney. Nephritis is an Inflammation, inflammatory kidney disease and has several types according to the location of the inflammation. Infla ...
.
Estimated GFR (eGFR) is recommended by clinical practice guidelines and regulatory agencies for routine evaluation of GFR whereas measured GFR (mGFR) is recommended as a confirmatory test when more accurate assessment is required.
Definition
Glomerular filtration rate (GFR) is the volume of fluid filtered from the
renal
In humans, the kidneys are two reddish-brown bean-shaped blood-filtering organs that are a multilobar, multipapillary form of mammalian kidneys, usually without signs of external lobulation. They are located on the left and right in the retrop ...
(kidney)
glomerular
''Glomerulus'' (; : glomeruli) is a common term used in anatomy to describe globular structures of entwined vessels, fibers, or neurons. ''Glomerulus'' is the diminutive of the Latin ''glomus'', meaning "ball of yarn".
''Glomerulus'' may refer to ...
capillaries into the
Bowman's capsule
Bowman's capsule (or the Bowman capsule, capsula glomeruli, or glomerular capsule) is a cup-like sac at the beginning of the Renal tubule, tubular component of a nephron in the mammalian kidney that performs the first step in the filtration of b ...
per unit time. Central to the physiologic maintenance of GFR is the differential basal tone of the afferent (input) and efferent (output) arterioles (see diagram). In other words, the filtration rate is dependent on the difference between the higher blood pressure created by vasoconstriction of the afferent arteriole versus the lower blood pressure created by lesser vasoconstriction of the efferent arteriole.
GFR is equal to the
renal 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
In renal physiology, the filtration fraction is the ratio of the glomerular filtration rate (GFR) over the renal plasma flow (RPF).
Filtration Fraction, FF = GFR/RPF, or FF = \frac.
The filtration fraction, therefore, represents the proportion o ...
.
:
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
Creatinine
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
Creatinine (; ) is a breakdown product of creatine phosphate from muscle and protein metabolism. It is released at a constant rate by the body (depending on muscle mass).
Biological relevance
Serum creatinine (a blood measurement) is an impor ...
is a breakdown product of
creatine phosphate
Phosphocreatine, also known as creatine phosphate (CP) or PCr (Pcr), is a phosphorylated form of creatine that serves as a rapidly mobilizable reserve of high-energy phosphates in skeletal muscle, myocardium and the brain to recycle adenosine trip ...
, 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 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.
Inulin
The GFR can be determined by injecting
inulin
Inulins are a group of naturally occurring polysaccharides produced by many types of plants, industrially most often extracted from chicory. The inulins belong to a class of dietary fibers known as fructans. Inulin is used by some plants as a ...
or the inulin-analog
sinistrin into the blood stream. 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. Incomplete urine collection is an important source of error in inulin clearance measurement.
Using inulin to measure
kidney function
Assessment of kidney function occurs in different ways, using the presence of symptoms and medical sign, signs, as well as measurements using urine tests, blood tests, and medical imaging.
Renal physiology, Functions of a healthy kidney include ...
is the
"gold standard" for comparison with other means of estimating
glomerular filtration rate
Renal functions include maintaining an acid–base balance; regulating fluid balance; regulating sodium, potassium, and other electrolytes; clearance (medicine), clearing toxins; absorption of glucose, amino acids, and other small molecules; reg ...
.
In 2018, the French
pharmacovigilance
Pharmacovigilance (PV, or PhV), also known as drug safety, is the pharmaceutical science relating to the "collection, detection, assessment, monitoring, and prevention" of adverse effects with pharmaceutical products.
The etymological roots ...
agency withdrew
inulin
Inulins are a group of naturally occurring polysaccharides produced by many types of plants, industrially most often extracted from chicory. The inulins belong to a class of dietary fibers known as fructans. Inulin is used by some plants as a ...
and
sinistrin-based products from the market after some patients experienced hypersensitivity reactions including a fatal outcome.
Consequently, the
contrast agent
A contrast agent (or contrast medium) is a substance used to increase the contrast of structures or fluids within the body in medical imaging. Contrast agents absorb or alter external electromagnetism or ultrasound, which is different from radiop ...
s
Iohexol
Iohexol, sold under the trade name Iodaque among others, is a contrast agent used for X-ray imaging. This includes when visualizing arteries, veins, ventricles of the brain, the urinary system, and joints, as well as during computed tomograph ...
and
Iothalamate have become more popular alternatives to determine GFR and are considered to show sufficient accuracy to determine GFR.
Radioactive tracers
GFR can be accurately measured using radioactive substances, in particular
chromium-51 and
technetium-99m
Technetium-99m (99mTc) is a metastable nuclear isomer of technetium-99 (itself an isotope of technetium), symbolized as 99mTc, that is used in tens of millions of medical diagnostic procedures annually, making it the most commonly used Radiophar ...
. 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
Ethylenediaminetetraacetic acid (EDTA), also called EDTA acid, is an aminopolycarboxylic acid with the formula . This white, slightly water-soluble solid is widely used to bind to iron (Fe2+/Fe3+) and calcium ions (Ca2+), forming water-solubl ...
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.
]
Cystatin C
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, adjusted cystatin C and creatinine. In 2022, the National Kidney Foundation (NKF) and American Society of Nephrology (ASN)'s Joint Task Force on Reassessing the Inclusion of Race in Diagnosing Kidney Diseases recommended national efforts to facilitate increased, routine, and timely use of cystatin C. They noted that cystatin C would be useful particularly to confirm estimated GFR in adults who are at risk for or have chronic kidney disease. They suggested that combining filtration markers (creatinine and cystatin C) is more accurate and would support better clinical decisions than either marker alone.
Calculation
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 conductivity
In science and engineering, hydraulic conductivity (, in SI units of meters per second), is a property of porous materials, soils and Rock (geology), rocks, that describes the ease with which a fluid (usually water) can move through the porosity, ...
and the surface area of the glomerular capillaries.
* is the hydrostatic pressure
Hydrostatics is the branch of fluid mechanics that studies fluids at hydrostatic equilibrium and "the pressure in a fluid or exerted by a fluid on an immersed body". The word "hydrostatics" is sometimes used to refer specifically to water and o ...
within the glomerular capillaries.
* is the hydrostatic pressure within the Bowman's capsule.
* is the colloid osmotic pressure
Oncotic pressure, or colloid osmotic-pressure, is a type of osmotic pressure induced by the plasma proteins, notably albumin, in a blood vessel's plasma (or any other body fluid such as blood and lymph) that causes a pull on fluid back into ...
within the glomerular capillaries.
* and is the colloid osmotic pressure within the Bowman's capsule.
Because this constant is a measurement of hydraulic conductivity
In science and engineering, hydraulic conductivity (, in SI units of meters per second), is a property of porous materials, soils and Rock (geology), rocks, that describes the ease with which a fluid (usually water) can move through the porosity, ...
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
The afferent arterioles are a group of blood vessels that supply the nephrons in many excretory systems. They play an important role in the regulation of blood pressure as a part of the tubuloglomerular feedback mechanism.
The afferent arteriole ...
and leaving through the efferent arteriole
The efferent arterioles are blood vessels that are part of the urinary tract of organisms. Efferent (from Latin ex + ferre) means "outgoing", in this case meaning carrying blood out away from the glomerulus. The efferent arterioles form a conver ...
. 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 ]hydrostatic pressure
Hydrostatics is the branch of fluid mechanics that studies fluids at hydrostatic equilibrium and "the pressure in a fluid or exerted by a fluid on an immersed body". The word "hydrostatics" is sometimes used to refer specifically to water and o ...
within the glomerular capillaries.
* 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:[
:
Where:
* 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 osmotic pressure
Osmotic pressure is the minimum pressure which needs to be applied to a Solution (chemistry), solution to prevent the inward flow of its pure solvent across a semipermeable membrane.
It is also defined as the measure of the tendency of a soluti ...
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
The molar gas constant (also known as the gas constant, universal gas constant, or ideal gas constant) is denoted by the symbol or . It is the molar equivalent to the Boltzmann constant, expressed in units of energy per temperature, temperature ...
* T is the temperature.
* And, c is concentration in mol/L of plasma ''proteins'' (remember the solutes can freely diffuse through the glomerular capsule).
This value is almost always taken to be equal to zero because in a healthy nephron
The nephron is the minute or microscopic structural and functional unit of the kidney. It is composed of a renal corpuscle and a renal tubule. The renal corpuscle consists of a tuft of capillaries called a glomerulus and a cup-shaped structu ...
, there should be no proteins in the Bowman's capsule.[
]
Clearance and filtration fraction
Filtration fraction
The filtration fraction is the amount of plasma that is actually filtered through the kidney. This can be defined using the equation:
* FF is the filtration fraction
In renal physiology, the filtration fraction is the ratio of the glomerular filtration rate (GFR) over the renal plasma flow (RPF).
Filtration Fraction, FF = GFR/RPF, or FF = \frac.
The filtration fraction, therefore, represents the proportion o ...
* GFR is the glomerular filtration rate
* RPF is the renal plasma flow
Normal human FF is 20%.
Renal clearance
* is the clearance of X (normally in units of mL/min).
* is the urine concentration of X.
* is the plasma concentration of X.
* is the urine flow rate.
Estimation
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
Creatinine (; ) is a breakdown product of creatine phosphate from muscle and protein metabolism. It is released at a constant rate by the body (depending on muscle mass).
Biological relevance
Serum creatinine (a blood measurement) is an impor ...
is a breakdown product of creatine phosphate
Phosphocreatine, also known as creatine phosphate (CP) or PCr (Pcr), is a phosphorylated form of creatine that serves as a rapidly mobilizable reserve of high-energy phosphates in skeletal muscle, myocardium and the brain to recycle adenosine trip ...
, 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 which is quite variable. The Cockcroft-Gault and CKD-EPI 2021 equations (see below) do 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 chronic kidney disease
Chronic kidney disease (CKD) is a type of long-term kidney disease, defined by the sustained presence of abnormal kidney function and/or abnormal kidney structure. To meet criteria for CKD, the abnormalities must be present for at least three mo ...
, 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
Cirrhosis, also known as liver cirrhosis or hepatic cirrhosis, chronic liver failure or chronic hepatic failure and end-stage liver disease, is a chronic condition of the liver in which the normal functioning tissue, or parenchyma, is replaced ...
. 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 chronic kidney disease.
Estimated GFR (eGFR) is now recommended by clinical practice guidelines and regulatory agencies for routine evaluation of GFR whereas measured GFR (mGFR) is recommended as a confirmatory test when more accurate assessment is required.
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 (V''dt''), 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''dt'') 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 60 mL 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
In physiology and medicine, the body surface area (BSA) is the measured or calculated surface area 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 ad ...
(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/old, and in men/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.
Cockcroft–Gault formula
A commonly used surrogate marker for the estimation of creatinine clearance is the Cockcroft–Gault (CG) formula, which in turn estimates GFR in ml/min: It is named after the scientists, the asthmologist (b. 1946) and the nephrologist (1925–2003), who first published the formula in 1976, and it employs serum creatinine
Creatinine (; ) is a breakdown product of creatine phosphate from muscle and protein metabolism. It is released at a constant rate by the body (depending on muscle mass).
Biological relevance
Serum creatinine (a blood measurement) is an impor ...
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 kilogram
The kilogram (also spelled kilogramme) is the base unit of mass in the International System of Units (SI), equal to one thousand grams. It has the unit symbol kg. The word "kilogram" is formed from the combination of the metric prefix kilo- (m ...
s and creatinine to be measured in mg/dL, as is standard in the US. 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
An electronic calculator is typically a portable electronic device used to perform calculations, ranging from basic arithmetic to complex mathematics.
The first solid-state electronic calculator was created in the early 1960s. Pocket-si ...
.
When serum creatinine is measured in μmol/L:
:
:Where ''Constant'' is for men and 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.
Modification of Diet in Renal Disease (MDRD) formula
Another formula for calculating the GFR is the one developed by the ''Modification of Diet in Renal Disease Study Group''. Most laboratories in Australia, and the United Kingdom now calculate and report the estimated GFR along with creatinine measurements and this forms the basis of diagnosis of chronic kidney disease
Chronic kidney disease (CKD) is a type of long-term kidney disease, defined by the sustained presence of abnormal kidney function and/or abnormal kidney structure. To meet criteria for CKD, the abnormalities must be present for at least three mo ...
. 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
Albumin is a family of globular proteins, the most common of which are the serum albumins. All of the proteins of the albumin family are water- soluble, moderately soluble in concentrated salt solutions, and experience heat denaturation. Alb ...
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.
A more elaborate version of the MDRD equation also includes serum albumin
Serum albumin, often referred to simply as blood albumin, is an albumin (a type of globular protein) found in vertebrate blood. Human serum albumin is encoded by the ''ALB'' gene. Other mammalian forms, such as bovine serum albumin, are chem ...
and blood urea nitrogen (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 size, results are given in units of mL/min per 1.73 m2, 1.73 m2 being the estimated body surface area of an adult with a mass of 63 kg and a height of 1.7 m.
CKD-EPI formula
The CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) formula was first 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. This is the formula currently recommended by NICE in the UK.
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 2009 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:
;Male, not black
: 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
::
;Black male
: If serum creatinine (Scr) ≤ 0.9
::
: If serum creatinine (Scr) > 0.9
::
;Black female
: If serum creatinine (Scr) ≤ 0.7
::
: If serum creatinine (Scr) > 0.7
::
This formula was developed by Levey et al.
The 2009 CKD-EPI formula was suggested to improve cardiovascular risk prediction over the MDRD Study formula in a middle-age population.
The 2021 CKD-EPI formula does not include a race coefficient (see discussion below).
The 2021 CKD-EPI equation is:
:
where SCr is serum creatinine (mg/dL), k is 0.7 for females and 0.9 for males, a is −0.241 for females and −0.302 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:
;Male
: If serum creatinine (Scr) ≤ 0.9
::
: If serum creatinine (Scr) > 0.9
::
;Female
: If serum creatinine (Scr) ≤ 0.7
::
: If serum creatinine (Scr) > 0.7
::
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.
]
Schwartz formula
In children, the Schwartz formula is used. This employs the serum creatinine
Creatinine (; ) is a breakdown product of creatine phosphate from muscle and protein metabolism. It is released at a constant rate by the body (depending on muscle mass).
Biological relevance
Serum creatinine (a blood measurement) is an impor ...
(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 constant ''k'' has been questioned as being dependent upon the gold-standard of renal function used (i.e. inulin clearance, creatinine 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 C'' is measured in addition to serum creatinine.
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.
Normal ranges
The normal range of GFR, adjusted for body surface area
In physiology and medicine, the body surface area (BSA) is the measured or calculated surface area 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 ad ...
, is 100–130 average 125 mL/min/1.73m2 in men and 90–120 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 0.4–1.2 mL/min per year.
Decreased GFR
A decreased renal function can be caused by many types of kidney disease
Kidney disease, or renal disease, technically referred to as nephropathy, is damage to or disease of a kidney. Nephritis is an Inflammation, inflammatory kidney disease and has several types according to the location of the inflammation. Infla ...
. Upon presentation of decreased renal function, it is recommended to perform a history
History is the systematic study of the past, focusing primarily on the Human history, human past. As an academic discipline, it analyses and interprets evidence to construct narratives about what happened and explain why it happened. Some t ...
and physical examination
In a physical examination, medical examination, clinical examination, or medical checkup, a medical practitioner examines a patient for any possible medical signs or symptoms of a Disease, medical condition. It generally consists of a series of ...
, as well as performing a renal ultrasound and a urinalysis
Urinalysis, a portmanteau of the words ''urine'' and ''analysis'', is a Test panel, panel of medical tests that includes physical (macroscopic) examination of the urine, chemical evaluation using urine test strips, and #Microscopic examination, m ...
. The most relevant items in the history are medications
Medication (also called medicament, medicine, pharmaceutical drug, medicinal product, medicinal drug or simply drug) is a drug used to medical diagnosis, diagnose, cure, treat, or preventive medicine, prevent disease. Drug therapy (pharmaco ...
, edema
Edema (American English), also spelled oedema (British English), and also known as fluid retention, swelling, dropsy and hydropsy, is the build-up of fluid in the body's tissue (biology), tissue. Most commonly, the legs or arms are affected. S ...
, nocturia
Nocturia is defined by the International Continence Society (ICS) as "the complaint that the individual has to wake at night one or more times for voiding (''i.e., to urinate'')". The term is derived from Latin ''nox'' – "night", and Greek '' ...
, gross hematuria
Hematuria or haematuria is defined as the presence of blood or red blood cells in the urine. "Gross hematuria" occurs when urine appears red, brown, or tea-colored due to the presence of blood. Hematuria may also be subtle and only detectable with ...
, family history
Genealogy () is the study of families, family history, and the tracing of their lineages. Genealogists use oral interviews, historical records, genetic analysis, and other records to obtain information about a family and to demonstrate kins ...
of kidney disease, diabetes
Diabetes mellitus, commonly known as diabetes, is a group of common endocrine diseases characterized by sustained high blood sugar levels. Diabetes is due to either the pancreas not producing enough of the hormone insulin, or the cells of th ...
and polyuria
Polyuria () is excessive or an abnormally large production or Frequent urination, passage of urine (greater than 2.5 L or 3 L over 24 hours in adults). Increased production and passage of urine may also be termed as diuresis. Polyuria often appe ...
. The most important items in a physical examination are signs of vasculitis
Vasculitis is a group of disorders that destroy blood vessels by inflammation. Both artery, arteries and veins are affected. Lymphangitis (inflammation of lymphatic vessels) is sometimes considered a type of vasculitis. Vasculitis is primarily c ...
, lupus erythematosus
is a collection of autoimmune diseases in which the human immune system becomes hyperactive and attacks healthy tissues. Symptoms of these diseases can affect many different body systems, including joints, skin, kidneys, blood cells, heart, ...
, diabetes
Diabetes mellitus, commonly known as diabetes, is a group of common endocrine diseases characterized by sustained high blood sugar levels. Diabetes is due to either the pancreas not producing enough of the hormone insulin, or the cells of th ...
, endocarditis
Endocarditis is an inflammation of the inner layer of the heart, the endocardium. It usually involves the heart valves. Other structures that may be involved include the interventricular septum, the chordae tendineae, the mural endocardium, o ...
and hypertension
Hypertension, also known as high blood pressure, is a Chronic condition, long-term Disease, medical condition in which the blood pressure in the artery, arteries is persistently elevated. High blood pressure usually does not cause symptoms i ...
.
A urinalysis is helpful even when not showing any pathology, as this finding suggests an extrarenal etiology. Proteinuria
Proteinuria is the presence of excess proteins in the urine. In healthy persons, urine contains very little protein, less than 150 mg/day; an excess is suggestive of illness. Excess protein in the urine often causes the urine to become fo ...
and/or urinary sediment usually indicates the presence of glomerular disease
''Glomerulus'' (; : glomeruli) is a common term used in anatomy to describe globular structures of entwined vessels, fibers, or neurons. ''Glomerulus'' is the diminutive of the Latin ''glomus'', meaning "ball of yarn".
''Glomerulus'' may refer to ...
. Hematuria
Hematuria or haematuria is defined as the presence of blood or red blood cells in the urine. "Gross hematuria" occurs when urine appears red, brown, or tea-colored due to the presence of blood. Hematuria may also be subtle and only detectable with ...
may be caused by glomerular disease or by a disease along the urinary tract
The human urinary system, also known as the urinary tract or renal system, consists of the kidneys, ureters, bladder, and the urethra. The purpose of the urinary system is to eliminate waste from the body, regulate blood volume and blood pressu ...
.
The most relevant assessments in a renal ultrasound are renal sizes, echogenicity and any signs of hydronephrosis
Hydronephrosis is the hydrostatic dilation of the renal pelvis and Renal calyx, calyces as a result of obstruction to urine flow downstream. Alternatively, hydroureter describes the dilation of the ureter, and hydronephroureter describes the dila ...
. Renal enlargement usually indicates diabetic nephropathy, focal segmental glomerular sclerosis or myeloma
Multiple myeloma (MM), also known as plasma cell myeloma and simply myeloma, is a cancer of plasma cells, a type of white blood cell that normally produces antibodies. Often, no symptoms are noticed initially. As it progresses, bone pain, a ...
. Renal atrophy suggests longstanding chronic renal disease.
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/1.73 m2 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 is the presence of excess proteins in the urine. In healthy persons, urine contains very little protein, less than 150 mg/day; an excess is suggestive of illness. Excess protein in the urine often causes the urine to become fo ...
):
: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.
Removal of race from eGFR Calculations
In 2017, Beth Israel Deaconess Medical Center dropped the Black race coefficient in their estimated glomerular filtration rate (eGFR) report, resulting in a steady increase in the percentage of Black patients listed before starting dialysis. Hoenig et al said on the topic "Race is a social construct that cannot be measured, can be used imprecisely and may contribute to disparities in kidney transplant access for Black patients."
In 2020, Vyas et al published an article in ''The New England Journal of Medicine
''The New England Journal of Medicine'' (''NEJM'') is a weekly medical journal published by the Massachusetts Medical Society. Founded in 1812, the journal is among the most prestigious peer-reviewed medical journals. Its 2023 impact factor w ...
'' criticizing the use of race in eGFR calculations which resulted in higher reported eGFR values for black-identifying patients. They noted that "The algorithm developers justified these outcomes with evidence of higher average serum creatinine concentrations among black people than among white people. Explanations that have been given for this finding include the notion that black people release more creatinine into their blood at baseline, in part because they are reportedly more muscular. Analyses have cast doubt on this claim, but the "race-corrected" eGFR remains the standard." They concluded saying "As long as uncertainty persists about the cause of racial differences in serum creatinine levels, we should favor practices that may alleviate health inequities over those that may exacerbate them."
In February 2022, the National Kidney Foundation (NKF) and American Society of Nephrology (ASN)'s Joint Task Force on Reassessing the Inclusion of Race in Diagnosing Kidney Diseases recommended use of the 2021 CKD-EPI equation which discontinues using a race modifier.
In July 2022 the OPTN Board eliminated race-based calculations for transplant candidate listing across all transplant hospitals in the US.
See also
* Clearance
* Dialysis
* Filtration fraction
In renal physiology, the filtration fraction is the ratio of the glomerular filtration rate (GFR) over the renal plasma flow (RPF).
Filtration Fraction, FF = GFR/RPF, or FF = \frac.
The filtration fraction, therefore, represents the proportion o ...
* Kt/V
* Pharmacokinetics
Pharmacokinetics (from Ancient Greek ''pharmakon'' "drug" and ''kinetikos'' "moving, putting in motion"; see chemical kinetics), sometimes abbreviated as PK, is a branch of pharmacology dedicated to describing how the body affects a specific su ...
* Renal clearance ratio
The renal clearance ratio or fractional excretion is a relative measure of the speed at which a constituent of urine passes through the kidneys. It is defined by following equation:
: clearance\ ratio\ of\ X = \frac
* X is the analyte substance
* ...
* Renal failure
Kidney failure, also known as renal failure or end-stage renal disease (ESRD), is a medical condition in which the kidneys can no longer adequately filter waste products from the blood, functioning at less than 15% of normal levels. Kidney fa ...
* Standardized Kt/V
* Tubuloglomerular feedback
In the renal physiology, physiology of the kidney, tubuloglomerular feedback (TGF) is a feedback system inside the kidneys. Within each nephron, information from the nephron#Renal tubule, renal tubules (a downstream area of the tubular fluid) is si ...
* Urea reduction ratio
References
External links
Reference links
National Kidney Disease Education Program website.
Includes professional references and GFR calculators
* eGFR a
Lab Tests Online
{{DEFAULTSORT:Renal Function
Diagnostic nephrology
Renal physiology
Blood tests