Renal function
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2008-06-30T00:37:42Z
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'''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''' ('''C<sub>Cr</sub>''') is the volume of [[blood plasma]] that is cleared of creatinine per unit time and is a useful measure for approximating the GFR. Both GFR and C<sub>Cr</sub> 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<sub>Cr</sub>''').
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 primarily excreted 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. Physiologically, these quantities (volumetric blood flow and mass removal) are only related loosely. [[Renal clearance|Clearance]] is a ratio of the mass generation and concentration at a [[steady state]].
==Indirect markers==
Most doctors use the [[blood plasma|plasma]] concentrations of the waste substances of [[creatinine]] and [[urea]], as well as [[electrolyte]]s to determine renal function. These measures are adequate to determine whether a patient is suffering from [[Chronic kidney disease|kidney disease]].
Unfortunately, '''blood urea nitrogen''' ([[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''' are measured whenever renal disease is suspected or careful dosing of nephrotoxic drugs is required.
Another prognostic marker for kidney disease is [[Microalbuminuria]]; the measurement of small amounts of [[albumin]] in the [[urine]] that cannot be detected by urine [[dipstick]] methods.
== Glomerular filtration rate==
'''Glomerular filtration rate''' ('''GFR''') is the volume of fluid filtered from the [[kidney|renal]] (kidney) [[Glomerulus (kidney)|glomerular]] capillaries into the [[Bowman's capsule]] per unit time.<ref>{{GeorgiaPhysiology|7/7ch04/7ch04p11}} - "Glomerular Filtration Rate"</ref>
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. The GFR is typically recorded in units of ''volume per time'', e.g. milliliters per minute [[millilitre|ml]]/[[minute|min]]. Compare to [[filtration fraction]].
:<math>GFR = \frac { \mbox{Urine Concentration} \times \mbox{Urine Flow} }{ \mbox{Plasma Concentration} }</math>
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 [[inulin]] (not insulin) 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.
==Creatinine clearance approximation of GFR==
In clinical practice, however, '''creatinine clearance''' is used to measure GFR. Creatinine is produced naturally by the body ([[creatinine]] is a metabolite of [[creatine]], which is found in muscle). It is freely filtered by the glomerulus, but also actively secreted by the renal tubules 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.
===Calculation of Ccr===
Creatinine clearance (C<sub>Cr</sub>) can be calculated if values for creatinine's urine concentration (U<sub>Cr</sub>), urine flow rate (V), and creatinine's plasma concentration (P<sub>Cr</sub>) are known. Since the product of urine concentration and urine flow rate yields creatinine's excretion rate, creatinine clearance is also said to be its excretion rate (U<sub>Cr</sub>×V) divided by its plasma concentration. This is commonly represented mathematically as
:<math>C_{Cr} = \frac { U_{Cr} \times V }{ P_{Cr} }</math>
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.
:<math>C_{Cr} = \frac {1.25 mg/ml \times \frac{60ml}{60min}}{0.01 mg/ml} = \frac { {1.25 mg/ml} \times {1 ml/min}}{0.01 mg/ml} = \frac {1.25 mg/min}{0.01 mg/ml} = {125 ml/min}</math>
Commonly a 24 hour urine collection is undertaken, 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:
:<math>C_{Cr} = \frac { U_{Cr} \ \times \ \mbox{24-hour volume} }{P_{Cr} \ \times \ 24 \times 60 mins}</math>
To allow comparison of results between people of different sizes, the C<sub>Cr</sub> is often corrected for the [[body surface area]] (BSA) and expressed compared to the average sized man as ml/min/1.73 m<sup>2</sup>. While most adults have a BSA that approaches 1.7 (1.6-1.9), extremely obese or slim patients should have their C<sub>Cr</sub> corrected for their ''actual'' BSA.
:<math>C_{Cr-corrected} = \frac{{C_{Cr}} \ \times \ {1.73}} {BSA}</math>
:BSA can be calculated on the basis of weight and height.
==Estimated values==
A number of formulae have been devised to estimate GFR or C<sub>cr</sub> values on the basis of serum creatinine levels.
===Estimated creatinine clearance rate (eCcr) using Cockcroft-Gault formula===
A commonly used surrogate marker for actual [[creatinine clearance]] is the Cockcroft-Gault formula, which may be used to calculate an Estimated Creatinine Clearance, which in turn estimates GFR:<ref>[http://www.cato.at/webservice/servlet/location?goto=SERVICE_CALC&lang=EN&URL=%22calc/cato_GFR_CG.htm%22 GFR Calculator at cato.at - Cockcroft-Gault] - GFR calculation (Cockcroft-Gault formula)</ref> It is named after the scientists who first published the formula, and it employs [[creatinine]] measurements and a patient's weight to predict the Creatinine clearance.<ref name="pmid1244564">{{cite journal |author=Cockcroft DW, Gault MH |title=Prediction of creatinine clearance from serum creatinine |journal=Nephron |volume=16 |issue=1 |pages=31–41 |year=1976 |pmid=1244564 |doi=}}</ref><ref name="Gault MH et al">Gault MH et al: Predicting Glomerular Function from Adjusted Serum Creatinine. Nephron 1992;62:249-256</ref>
The formula, as originally published, is:
:<math>eC_{Cr} = \frac { \mbox{(140 - Age)} \ \times \ \mbox{Mass (in kilograms)} \ \times \ [{0.85\ if\ Female}]} {\mbox{72} \ \times \ \mbox{Serum Creatinine (in mg/dl)}}</math>
:This formula expects weight to be measured in [[kilogram]]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 relatively simple and can often be performed without the aid of a [[calculator]].
For creatinine in µmol/L:
:<math>eC_{Cr} = \frac { \mbox{(140 - Age)} \ \times \ \mbox{Mass (in kilograms)} \ \times \ {Constant} } {\mbox{Serum Creatinine (in } \mu \mbox{mol/l)}}</math>
:Where ''Constant'' is ''1.23'' for men and ''1.04'' for women.
===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''.<ref name="pmid10075613">{{cite journal |author=Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D |title=A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group |journal=Ann. Intern. Med. |volume=130 |issue=6 |pages=461–70 |year=1999 |pmid=10075613 |doi= |url=http://www.annals.org/cgi/reprint/130/6/461.pdf |format=PDF}}</ref> Most laboratories in Australia,<ref name="pmid17937643">{{cite journal |author=Mathew TH, Johnson DW, Jones GR |title=Chronic kidney disease and automatic reporting of estimated glomerular filtration rate: revised recommendations |journal=Med. J. Aust. |volume=187 |issue=8 |pages=459–63 |year=2007 |pmid=17937643 |doi=}}</ref> 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#Stages_of_Chronic_Kidney_Disease|Chronic kidney disease#Staging]].<ref>{{cite web |author=Joint Specialty Committee on Renal Disease |title=Chronic kidney disease in adults: UK guidelines for identification, management and referral |date=June 2005 |url=http://www.renal.org/CKDguide/full/UKCKDfull.pdf |format=PDF}}</ref> The adoption of the automatic reporting of MDRD-eGFR has been widely criticised.<ref name="pmid16398632">{{cite journal |author=Davey RX |title=Chronic kidney disease and automatic reporting of estimated glomerular filtration rate |journal=Med. J. Aust. |volume=184 |issue=1 |pages=42–3; author reply 43 |year=2006 |pmid=16398632 |doi=}}</ref><ref name="pmid17041249">{{cite journal |author=Twomey PJ, Reynolds TM |title=The MDRD formula and validation |journal=QJM |volume=99 |issue=11 |pages=804–5 |year=2006 |pmid=17041249 |doi=10.1093/qjmed/hcl108 |url=http://qjmed.oxfordjournals.org/cgi/content/full/99/11/804}}</ref><ref name="pmid18219370">{{cite journal |author=Kallner A, Ayling PA, Khatami Z |title=Does eGFR improve the diagnostic capability of S-Creatinine concentration results? A retrospective population based study |journal=Int J Med Sci |volume=5 |issue=1 |pages=9–17 |year=2008 |pmid=18219370 |doi= |url=http://www.medsci.org/v5p9.htm}}</ref>
The most commonly used formula is the "4-variable MDRD" which estimates GFR using four variables: serum creatinine, age, race, and gender.<ref name="pmid11904577">{{cite journal |author= |title=K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification |journal=Am. J. Kidney Dis. |volume=39 |issue=2 Suppl 1 |pages=S1–266 |year=2002 |pmid=11904577 |doi=|url=http://www.kidney.org/professionals/kdoqi/guidelines_ckd/p5_lab_g4.htm}}</ref> The original MDRD used six variables with the additional variables being the [[blood urea nitrogen]] and [[albumin]] levels.<ref name="pmid10075613">{{cite journal |author=Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D |title=A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group |journal=Ann. Intern. Med. |volume=130 |issue=6 |pages=461–70 |year=1999 |pmid=10075613 |doi=|url=http://www.annals.org/cgi/content/full/130/6/461}}</ref> 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.<ref name="pmid15611490">{{cite journal |author=Rule AD, Larson TS, Bergstralh EJ, Slezak JM, Jacobsen SJ, Cosio FG |title=Using serum creatinine to estimate glomerular filtration rate: accuracy in good health and in chronic kidney disease |journal=Ann. Intern. Med. |volume=141 |issue=12 |pages=929–37 |year=2004 |pmid=15611490 |doi=|url=http://www.annals.org/cgi/content/full/141/12/929}}</ref><ref name="pmid16908915">{{cite journal |author=Levey AS, Coresh J, Greene T, ''et al'' |title=Using standardized serum creatinine values in the modification of diet in renal disease study equation for estimating glomerular filtration rate |journal=Ann. Intern. Med. |volume=145 |issue=4 |pages=247–54 |year=2006 |pmid=16908915 |doi=}}</ref> The equations have not been validated in acute renal failure.
For creatinine in mg/dL:
:<math>\mbox{eGFR} = \mbox{186}\ \times \ \mbox{Serum Creatinine}^{-1.154} \ \times \ \mbox{Age}^{-0.203} \ \times \ {[1.21\ if\ Black]} \ \times \ {[0.742\ if\ Female]}</math>
For creatinine in µmol/L:
:<math>\mbox{eGFR} = \mbox{32788}\ \times \ \mbox{Serum Creatinine}^{-1.154} \ \times \ \mbox{Age}^{-0.203} \ \times \ {[1.21\ if\ Black]} \ \times \ {[0.742\ if\ Female]}</math>
:Creatinine levels in µmol/L can be converted to mg/dL by dividing them by 88.4. The 32788 number above is equal to 186×88.4<sup>1.154</sup>.
A more elaborate version of the MDRD equation also includes [[serum albumin]] and [[blood urea nitrogen]] (BUN) levels:
:<math>\mbox{eGFR} = \mbox{170}\ \times \ \mbox{Serum Creatinine}^{-0.999} \ \times \ \mbox{Age}^{-0.176} \ \times \ {[0.762\ if\ Female]} \ \times \ {[1.180\ if\ Black]} \ \times \ \mbox{BUN}^{-0.170} \ \times \ \mbox{Albumin}^{+0.318}</math>
:Where the creatinine and blood urea nitrogen concentrations are both in mg/dL. The albumin concentration is in g/dL.
===Estimated GFR for Children using Schwartz formula===
In children, the Schwartz formula is used.<ref name="pmid951142">{{cite journal |author=Schwartz GJ, Haycock GB, Edelmann CM, Spitzer A |title=A simple estimate of glomerular filtration rate in children derived from body length and plasma creatinine |journal=Pediatrics |volume=58 |issue=2 |pages=259–63 |year=1976 |pmid=951142 |doi=}}</ref><ref name="pmid6726515">{{cite journal |author=Schwartz GJ, Feld LG, Langford DJ |title=A simple estimate of glomerular filtration rate in full-term infants during the first year of life |journal=J. Pediatr. |volume=104 |issue=6 |pages=849–54 |year=1984 |pmid=6726515 |doi=}}</ref> This employs the serum [[creatinine]], the child's height and a constant to estimate the glomerular filtration rate:
:<math>\mbox{eGFR} = \frac{ {k} \times {Height} }{Serum\ Creatinine}</math>
: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<ref name="pmid3761090">{{cite journal |author=Brion LP, Fleischman AR, McCarton C, Schwartz GJ |title=A simple estimate of glomerular filtration rate in low birth weight infants during the first year of life: noninvasive assessment of body composition and growth |journal=J. Pediatr. |volume=109 |issue=4 |pages=698–707 |year=1986 |pmid=3761090 |doi=}}</ref> and for full-term infants K=0.45<ref name="pmid6726515">{{cite journal |author=Schwartz GJ, Feld LG, Langford DJ |title=A simple estimate of glomerular filtration rate in full-term infants during the first year of life |journal=J. Pediatr. |volume=104 |issue=6 |pages=849–54 |year=1984 |pmid=6726515 |doi=}}</ref>
::For infants between ages of 1 and 12 years, K=0.55<ref name="pmid951142">{{cite journal |author=Schwartz GJ, Haycock GB, Edelmann CM, Spitzer A |title=A simple estimate of glomerular filtration rate in children derived from body length and plasma creatinine |journal=Pediatrics |volume=58 |issue=2 |pages=259–63 |year=1976 |pmid=951142 |doi=}}</ref>.<!-- K=0.55 adolescent girls, or K=0.70 in adolescent boys needs citing -->
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.<ref name="pmid10079885">{{cite journal |author=Haenggi MH, Pelet J, Guignard JP |title=[Estimation of glomerular filtration rate by the formula GFR = K x T/Pc] |language=French |journal=Arch Pediatr |volume=6 |issue=2 |pages=165–72 |year=1999 |pmid=10079885|doi=10.1016/S0929-693X(99)80204-8}}</ref>
===Calculation using Starling equation===
It is also theoretically possible to calculate GFR using the [[Starling equation]].<ref>{{GeorgiaPhysiology|7/7ch04/7ch04p12}} - "Forces Driving the Glomerular Filtration Rate":</ref>
:<math>J_v = K_f ( [P_c - P_i] - \sigma[\pi_c - \pi_i] )</math>
The equation is used both in a general sense for all capillary flow, and in a specific sense for the glomerulus:
{| class="wikitable"
| '''General usage''' || '''Glomerular usage''' || '''Meaning of variable''' || '''Relationship to GFR''' || '''Description'''
|-
| ''P''<sub>''c''</sub> || ''P''<sub>''gc''</sub> || Capillary [[hydrostatic pressure]] || Direct || Increased by dilation of [[afferent arteriole]] or constriction of [[efferent arteriole]]
|-
| ''P''<sub>''i''</sub> || ''P''<sub>''bs''</sub> || Interstitial hydrostatic pressure || Inverse ||
|-
| π<sub>''c''</sub> || π<sub>''gc''</sub> || Capillary [[oncotic pressure]] || Inverse || Decreased by [[nephrotic syndrome]]
|-
| π<sub>''i''</sub> || π<sub>''bs''</sub> || Interstitial oncotic pressure || Direct ||
|-
| ''K''<sub>''f''</sub> || ''K''<sub>''f''</sub> || Filtration coefficient || Direct || Increased by [[inflammation]]
|-
| σ || σ || Reflection coefficient || Inverse ||
|-
| ''J''<sub>''v''</sub> || GFR || net filtration || n/a ||
|}
Note that <math> ( [P_c - P_i] - \sigma[\pi_c - \pi_i] )</math> is the net driving force, and therefore the net filtration is proportional to the net driving force.
In practice, it is not possible to identify the needed values for this equation, but the equation is still useful for understanding the factors that affect GFR, and providing a theoretical underpinning for the above calculations.
==Normal ranges==
For most patients, a GFR over 60 ml/min is adequate. But, if the GFR has significantly declined from a previous test result, this 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 normal ranges of GFR, adjusted for body surface area, are:<ref>[http://www.merck.com/mmpe/sec17/ch226/ch226b.html#sec17-ch226-ch226b-54 Creatinine clearance at merck.com] - The normal ranges of GFR.</ref>
* Males: 70 ± 14 mL/min/m<sup>2</sup>
* Females: 60 ± 10 mL/min/m<sup>2</sup>
Normal [[reference ranges]] for creatinine clearance are:
{|class="wikitable"
!Gender
!Low
!High
|Units
|-
| male || 55 <ref name=hcc>[http://www.health-care-clinic.org/medical-tests/creatinine-clearance.htm health-care-clinic.org] - Creatinine Clearance</ref> || 146<ref name=hcc/> || ml/minute/1.73 m2
|-
| female || 52<ref name=hcc/> || 134<ref name=hcc/> || ml/minute/1.73m2
|}
Risk factors for kidney disease include diabetes, high blood pressure, family history, older age, ethnic group.
GFR can increase due to [[hypoproteinemia]] because of the reduction in plasma oncotic pressure. GFR can also increase due to constriction of the [[efferent arteriole]] but decreases due to constriction of the [[afferent arteriole]].
===Chronic Kidney Disease stages===
{{main|Chronic kidney disease}}
The [[chronic kidney disease#Stages of Chronic Kidney Disease|severity of chronic kidney disease]] (CKD) is described by 6 stages, the most severe three are defined by the MDRD-eGFR value, and first three also depend whether there is other evidence of kidney disease (e.g. protein in the urine):
:0) Normal kidney function – GFR above 90ml/min/1.73m2 and no evidence of Kidney damage (protein in the urine)
:1) CKD1 – GFR above 90ml/min/1.73m2 with evidence of Kidney damage
:2) CKD2 (Mild) – GFR above 60 to 89 ml/min/1.73m2 with evidence of Kidney damage
:3) CKD3 (Moderate) – GFR above 30 to 59 ml/min/1.73m2
:4) CKD4 (Severe) – GFR above 15 to 29 ml/min/1.73m2
:5) CKD5 Kidney failure (dialysis or kidney transplant needed) – GFR less than 15 ml/min/1.73m2
==See also==
*[[clearance (medicine)|Clearance]]
*[[Dialysis]]
*[[filtration fraction]]
*[[Kt/V]]
*[[Pharmacokinetics]]
*[[Renal clearance ratio]]
*[[Renal failure]]
*[[Standardized Kt/V]]
*[[Tubuloglomerular feedback]]
*[[Urea reduction ratio]]
==References==
{{reflist|2}}
==External links==
*[http://www.nkdep.nih.gov/professionals/index.htm National Kidney Disease Education Program website.] Includes professional references and GFR calculators
*[http://www.pace-med-apps.com/gfrcalc.htm Online GFR Calculator using MDRD, Gault, and Combo] Also shows GFR expected for age and current GFR percentage of expected.
*[http://www.cato.eu/gfr-cockcroft-gault.html Online GFR Calculator (Cockcroft-Gault Formula)]
*[http://www.anaemiaworld.com/portal/eipf/pb/m/aw/egfr_calculator Online GFR Calculator] - AnaemiaWorld.com
* [http://www.nephron.com/ Online calculator] for Cockroft-Gault and MDRD formulae.
* [http://www-users.med.cornell.edu/~spon/picu/calc/crclschw.htm Schwartz formula] - cornell.edu
* {{FPnotebook|REN70}}
{{Renal physiology}}
[[Category:Renal physiology]]
[[de:Glomeruläre Filtrationsrate]]
[[es:Índice de filtrado glomerular]]
[[fr:Débit de filtration glomérulaire]]
[[nl:Kreatinineklaring]]
[[nl:Glomerulaire filtratiesnelheid]]
[[ja:クレアチニンクリアランス]]
[[pl:GFR]]
[[pt:Depuração de creatinina]]
[[pt:Taxa de filtração glomerular]]
[[pt:Função renal]]
[[ru:Проба Реберга — Тареева]]
[[sv:Glomerulär filtrationshastighet]]