eGFR is taken as an estimated measurement of the graft function in renal transplant patients.
- What are the formulae used and how accurate they are in transplant and non-transplant populations compared to inulin clearance?
- How accurate is serum creatinine as a measure of kidney function?
- How were they validated?
- What is the difference between these formulae and the Cockcroft-Gault formula?
- What are the advantages and disadvantages of these formulae?
What are the formulae used and how accurate they are in transplant and non-transplant populations compared to inulin clearance?
1-Cockroft Gault equation: Using Age, Weight, Gender, Serum creatinine
2- Modification of Diet in Renal Disease (MDRD) equation
3- CKD-EPI equation using serum creatinine
4- CKD-EPI equation using serum creatinine and Cystatin C
5- CKD-EPI 2021: Using Gender, Age, Creatinine (without race)
6- Nankivell Equation
In the majority of studies, this equations(MDRD, Cockcroft-Gault and Nankivell) persistently testified progressive decrease in GFR overestimation and/or increase in GFR underestimation as graft function ameliorated . CKD-EPI equation showed better performance at higher GFRs compared with better performance of MDRD Study equation at lower GFRs .
How accurate is serum creatinine as a measure of kidney function?
Multiple factors contribute to reduce the accuracy of SCr as an indicator of the GFR, including sex, age, race, muscle mass and dietary protein intake. Serum Creatinine measurement by the most common method (Jaffé) is subject to interferences by chromogens such as bilirubin, glucose and uric acid, and the enzymatic method is prone to interference by bilirubin and some antibiotics. Particularly, in renal transplantation there are other determinants that may interfere with Cr metabolism such as corticosteroids, which have a direct catabolic effect and cause a changed muscle mass ratio to total body weight. Catabolic illnesses such as infection and acute rejection, and prolonged dialysis, can also be partly responsible.Cr tubular secretion can be blocked by some drugs such as trimethoprim, commonly used in kidney transplantation. Also, chronic rejection and acute tubular necrosis, can contribute, because tubular secretion of creatinine is reduced .
How were they validated?
Methods to measure GFR using exogenous markers, such as inulin clearance, the gold standard, and others such as radiolabeled isotopes (51Cr EDTA, 99mTc DTPA or 125I Iothalamate) and non-radioactive contrast agents (Iothalamate or Iohexol), are laborious as well as expensive, being rarely used in clinical practice. Endogenous markers, such as serum creatinine (SCr) or cystatin C (CyC), are used to estimate kidney function. Any endogenous kidney function marker has limitations, and understandably.
What is the difference between these formulae and the Cockcroft-Gault formula?
Cockroft-Gault formula utilizes body weight in calculating GFR which is not utilized in other equations
What are the advantages and disadvantages of these formulae?
1- Cockroft Gault formula:
overestimates GFR in obese or patients with edema (due to body weight being a crucial element in calculation) and underestimates GFR in elderly.
2-MDRD equation
is not applicable in young children and elderly individuals, pregnancy and races other than African-Americans and Caucasians. It underestimates GFR in patients with GFR more than 60 ml/min/1.73m2. It is useful for non-hospitalized population. Performa better at lower GFRs.
3-CKD-EPI
overestimates GFR if the GFR is above 60ml/min. It is preferred in elderly and obese individuals. Performs better at higher GFRs.
4-CKD-EPI Cystatin
is not reliable in pregnancy, rapid change in GFR, steroid use, thyroid dysfunction, old age
5-CKD-EPI 2021 equation
does not use race as a factor. So, it underestimates GFR in African-Americans
References:
1. Shemesh O, Golbetz H, Kriss JP, Myers BD. Limitations of creatinine as a filtration marker in glomerulopathic patients. Kidney Int. 1985;28:830–838. [PubMed] [Google Scholar]
2. Horber FF, Scheidegger J, Frey FJ. Overestimation of renal function in glucocorticosteroid treated patients. Eur J Clin Pharmacol. 1985;28:537–541. [PubMed] [Google Scholar]
3. El Haggan W, Hurault de Ligny B, Partiu A, Sabatier JP, Lobbedez T, Levaltier B, Ryckelynck JP. The evolution of weight and body composition in renal transplant recipients: Two-year longitudinal study. Transplant Proc. 2006;38:3517–3519. [PubMed] [Google Scholar]
4 Nankivell BJ, Gruenewald SM, Allen RD, Chapman JR. Predicting glomerular filtration rate after kidney transplantation. Transplantation. 1995;59:1683–1689. [PubMed] [Google Scholar]
5. Berglund F, Killander J, Pompeius R. Effect of trimethoprim-sulfamethoxazole on the renal excretion of creatinine in man. J Urol. 1975;114:802–808. [PubMed] [Google Scholar]
6. Raju DL, Grover VK, Shoker A. Limitations of glomerular filtration rate equations in the renal transplant patient. Clin Transplant. 2005;19:259–268. [PubMed] [Google Scholar]
7. White CA, Akbari A, Doucette S, Fergusson D, Knoll GA. Estimating glomerular filtration rate in kidney transplantation: is the new chronic kidney disease epidemiology collaboration equation any better? Clin Chem. 2010;56:474–477. [PubMed] [Google Scholar]
8. Masson I, Flamant M, Maillard N, Rule AD, Vrtovsnik F, Peraldi MN, Thibaudin L, Cavalier E, Vidal-Petiot E, Bonneau C, et al. MDRD versus CKD-EPI equation to estimate glomerular filtration rate in kidney transplant recipients. Transplantation. 2013;95:1211–1217. [PubMed] [Google Scholar]
.
What are the formulae used and how accurate they are in transplant and non-transplant populations compared to inulin clearance?
Formulas were constructed in attempts to overcome the limitation of serum cr ie weight, age, gender, and/or race
The KDIGO position statement includes the proposal that Cr-based eGFR equations should be used to
evaluate renal function in the everyday management of renal transplant recipients].
1. The Cockcroft-Gault
2. The MDRD equation, published in 1999 and simplified in 2000 and reexpressed in 2005,
3. The Nankivell equation: is the only one that was derived from kidney transplant recipients. however, some of these transplant patients were in an early post-transplant phase or with acute dysfunction, which has implications in the prediction of GFR.
4. chronic kidney disease epidemiology collaboration (CKD-EPI) was developed to overcome the systematic underestimation of GFR and lack of precision of the MDRD formulas inpatients with relatively well-preserved kidney function, but only 4% of the CKD-EPI derivation cohort consisted of organ transplant recipients CKD-EPI shows improved estimation ability compared with MDRD equation, but still with suboptimal precision
· estimate true GFR by > 30% in 1 of 5 patients but CKD-EPI equation showed better performance at higher GFRs compared with better performance of MDRD Study equation at lower GFRs,
How accurate is serum creatinine as a measure of kidney function?
serum creatinine (SCr) o the result of the breakdown of creatine phosphate in the muscle freely filtered with tubular secretion about 10% also increases with declining GFR depending on muscle state, diet, sex, age.
In transplant patients, corticosteroids have a catabolic effect on the muscle with impaired muscle to body ratio. infection and acute rejection, and prolonged dialysis also affect the muscle
Tubular secretion also blocked by trimethoprim used in transplantation rejection causing tubular injury
So at the end of the day GFR may decrease to half before the creatinine increases
Some circumstances the changes in the serum creatinine lags and are unable to detect the progressive usually subclinical changes as in CNI toxicity so the GFR is barely correlated with serum creatinie in transplant patients 26,28].
How were they validated?
What is the difference between these formulae and the Cockcroft-Gault formula?
What are the advantages and disadvantages of these formulae?
Glomerular filtration rate is the gold standard for the evaluation of kidney function. In transplant recipients, it is correlated with long term graft survival and cardiovascular mortality
Estimation maybe with
exogenous markers: (rarely used in clinical practice)
a. inulin clearance (gold standard)
b. radiolabeled isotopes: (51Cr EDTA, 99mTc DTPA or 125I Iothalamate)
c. non-radioactive contrast agents: (Iothalamate or Iohexol),
endogenous markers: are used to estimate kidney function
a.
b. Creatinine clearance: utilize serum creatinine with its drawbacks and the creatinine excreted all over the day: but it also overestimates GFR due to the cr secretion of overestimates GFR also in transplant populations[28,34,35], besides the additional errors in urine collection.
c. cystatin C (CyC) :
Serum CyC: CyC is a 122-amino acid, 13-kDa protein that is a member of a family of competitive inhibitors of lysosomal cysteine proteinases.
With certain characteristics that allow it to be an acceptable marker for kidney function
a. constant production rate,
b. free filtered, complete reabsorption and catabolism by the proximal tubules with not absorbed nor secreted.
c. correlate better with GFR than Cr alone, especially at higher levels of GFR,
d. less influenced by demographic factors ie age, race, gender, or muscle mass compared with SCr[38,39].
Cons
a. But influenced by uncontrolled thyroid disease, rapid cell turnover, and those under steroid therapy[42], like kidney transplant recipients.
b. CyC is quite costly
c. unavailable in many transplant center
Measurement of GFR is important to evaluate the graft function in patients who received kidney transplantation The most accurate method is inulin clearance which is difficult in practice.
Commonly used formulas include:
1) Cockroft Gault equation: Using Age, Weight, Gender, Serum creatinine
2) Modification of Diet in Renal Disease (MDRD) equation
3) CKD-EPI equation using serum creatinine
4) CKD-EPI equation using serum creatinine and Cystatin C
Creatinine is the product of creatine metabolism in muscle and is produced with a fixed daily rate, related to muscle mass. It is not metabolized or reabsorbed but duo to tubular secretion there is more creatinine in urine.
limitations with serum creatinine include:
Variation due to dietary changes (amount of meat in meal),
Variation due to change in muscle mass (malnutrition, amputation, muscle wasting),
Variation due to tubular secretion (nephrotic syndrome, sickle cell disease, drugs like trimethoprim and cimetidine decrease tubular secretion).
What is the difference between these formulae and the Cockroft-Gault formula?
Cockroft-Gault formula utilizes body weight in calculating GFR which is not utilized in other equations
E) What are the advantages and disadvantages of these formulae?
Most important advantage of these formulae is quick estimation of GFR, which is important while taking decisions bedside.
Cockroft Gault formula: overestimates GFR in obese or patients with edema (due to body weight being a crucial element in calculation)
Formulas used in the prediction of GFR
Formulas derived using variables that influence GFR can provide varying degrees of accuracy in estimating GFR.
The widely used
Modification of Diet in Renal Disease Study Group (MDRD) employs four variables, including serum creatinine, age, ethnicity, and albumin levels.
A further complex version of MDRD includes blood urea nitrogen and serum albumin in its formula. However, since MDRD formula does not adjust for body size, results of eGFR are given in units of ml^-1 min^-1 1.73m^-2, 1.73m^2 due to body surface area in an adult with a mass of 63kg and height of 1.7m.
Other formulas used for GFR calculations and their employed variables to estimate GFR include Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formulas. The CKD-EPI formulas are in categories based on patients that are a black female, black male, non-black female, and non-black male.
The Mayo Quadratic formula was developed to better estimate GFR in patients that have preserved renal function.
Estimation of GFR in children uses the Schwartz formula, which employs serum creatinine (mg/dL) and child’s height (cm).
In current clinical practice, the use of creatinine derived the KDIGO clinical practice guidelines recommend CKD-EPI formula for the estimation of GFR
For assessment of accuracy of GFR BY
the modification of diet in renal disease (MDRD),
Cockcroft-Gault (CG), and
chronic kidney disease epidemiology (CKD-EPI) formulas in potential kidney donors compared with 24-h urine creatinine clearance,
In one study 207 potential live kidney donors is assessed .
The accuracy of the MDRD formula was 48.8% and the CG formula was 41.5% whereas the accuracy of the CKD-EPI formula was 78.2%.
The accuracy of the eGFR using the MDRD formula was significantly higher in males than females (57.9% vs. 33.3% P = 0.001), while there was no statistically significant difference in the eGFR between them in case of the use of the CG and the CKD-EPI formulas.
BMI and obesity had no effect on the accuracy of eGFR by the use of the different formulas.
The performance of GFR estimation formulas was sub optimal and these either underestimated and/or over-estimated the GFR in healthy subjects.
CKD-EPI is closer to 24 -h urinary creatinine clearance in the calculation of eGFR.
However, none of the eGFR formulas can be used in renal transplant donors because of their low accuracy, and 24-h urine creatinine clearance should be used for evaluation of the GFR in this population. 1
Inulin is the ideal substance for assessing GFR because it is
– Non toxic
– Not metabolized
– Freely filtered
– Not reabsorbed by renal tubule
– Not excreted by renal tubule
But its use is not practical .
Serum creatinine cannot be used to assess GFR because the relation between s creatitne and GFR is not linear . means there may be aloes of 50% of renal function but still the s creatinine is within normal rang e .
Estimated Glomerular Filtration Rate From Serum Creatinine
GFR can be estimated from serum creatinine (eGFRcr) by equationsthat use age, gender, race, and body size as surrogates for creatinine generation. Despite ongoing refinements in recent years, GFR estimates remain imprecise; none of the equations is expected to work as well in patients with extreme levels for creatinine generation, such as amputees, large or small individuals, patients with muscle-wasting conditions, or people with atypical pattern of meat consumption
Also, equations developed in one racial or ethnic group are unlikely to be accurate in multiethnic populations. As discussed later, further improvements will probably require additional filtration
markers.2
Serum creatinine cannot be used to assess GFR because the relation between s creatitne and GFR is not linear . means there may be aloes of 50% of renal function but still the s creatinine is within normal rang e.
Reffrences
Danovitch GM. Handbook of Kidney Transplantation. Sixth Edition, Wolters Kluwer, eISBN 9781496388841, 2017.
Shahbaz H, Gupta M. Creatinine Clearance. [Updated 2021 Jul 26]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK544228/
) What are the formulae used and how accurate they are in transplant and non-transplant populations compared to inulin clearance?
Glomerular filtration rate (GFR) measurement is an important step in evaluation of renal function.
Estimated GFR (eGFR) equations are commonly used for calculating GFR as the standard methods of measuring GFR are time consuming, costly, and technically demanding.
Commonly used formulas include:
1) Cockroft Gault equation: Using Age, Weight, Gender, Serum creatinine
2) Modification of Diet in Renal Disease (MDRD) equation
3) CKD-EPI equation using serum creatinine
4) CKD-EPI equation using serum creatinine and Cystatin C
5) CKD-EPI 2021: Using Gender, Age, Creatinine (without race)
6) Nankivell Equation
7) Full Age Spectrum (FAS)
In kidney transplant recipients, MDRD, Cockroft Gault and Nankivell equations were evaluated and found to underestimate the GFR, and the degree of underestimation increased with improvement in graft kidney function. (4) CKD-EPI equation also did not significantly improve accuracy over the MDRD equation in transplant recipients.
B) How accurate is serum creatinine as a measure of kidney function?
Creatinine is breakdown product of creatine derived from dietary meat and skeletal muscle and hence depends on dietary protein intake as well as body muscle mass. Creatinine is freely filtered across the glomerulus. A small amount is secreted in the proximal tubule. So, if there is reduction in GFR with constant muscle mass and dietary pattern, there should be corresponding increase in serum creatinine. But, in reality, when there is reduction in GFR, the tubular secretion of creatinine increase and hence blunts the rise in serum creatinine
Limitations with serum creatinine include:
Variation due to dietary changes (amount of meat in meal),
Variation due to change in muscle mass (malnutrition, amputation, muscle wasting),
Variation due to tubular secretion (nephrotic syndrome, sickle cell disease, drugs like trimethoprim and cimetidine decrease tubular secretion). This variation is less once GFR goes below 60.
Variation due to technical errors (alkaline picrate method recognizes acetoacetate or bilirubin in blood as creatinine, giving rise to falsely high values of creatinine)
C) How were they validated?
validated against the gold standard inulin clearance depending upon 3 criterias: Bias, Precision, and accuracy.
D) What is the difference between these formulae and the Cockroft-Gault formula?
Cockroft-Gault formula utilizes body weight in calculating GFR which is not utilized in other equations
E) What are the advantages and disadvantages of these formulae?
Most important advantage of these formulae is quick estimation of GFR, which is important while taking decisions bedside.
Cockroft Gault formula: overestimates GFR in obese or patients with edema (due to body weight being a crucial element in calculation) and underestimates GFR in elderly.
MDRD equation is not applicable in young children and elderly individuals, pregnancy and races other than African-Americans and Caucasians. It underestimates GFR in patients with GFR more than 60 ml/min/1.73m2. It is useful for non-hospitalized population. Performa better at lower GFRs
CKD-EPI overestimates GFR if the GFR is above 60ml/min. It is preferred in elderly and obese individuals. Performs better at higher GFRs.
CKD-EPI Cystatin is not reliable in pregnancy, rapid change in GFR, steroid use, thyroid dysfunction, old age
CKD-EPI 2021 equation does not use race as a factor. So, it underestimates GFR in African-Americans
FAS is valid even in patients with GFR more than 60 ml/min/1.73m2
The major disadvantage with these formulae is that they are dependent on serum creatinine and hence all the limitations of creatinine apply to these formulae. Cystatin C based equations are also not accurate in transplant patients as the cystatin C levels get affected by steroid use.
References:
1) Salvador C, Hartmann A, Asberg A, et al. Estimating Glomerular Filtration Rate in Kidney Transplant Recipients: Comparing a Novel Equation With Commonly Used Equations in this Population. Transplant Direct 2017;3: e332.
2) Inker LA, Eneanya ND, Coresh J, et al. Chronic Kidney Disease Epidemiology Collaboration. New Creatinine- and Cystatin C-Based equations to estimate GFR without race. N Eng J Med 2021 Sep 23
3) Nankivell BJ, Gruenewald SM, Allen RD, et al. Predicting glomerular filtration rate after kidney transplantation. Transplantation 1995;59:1683-1689.
4)Santos j, Marins LS. Estimating glomerular filtration rate in kidney transplantation: still searching for the best marker. World J Nephrol 2015;4:345-353.
5) White CA, Akbari A, Doucette S, et al. Estimating glomerular filtration rate in kidney transplantation: Is the new chronic kidney disease epidemiology collaboration equation any better? Clin Chem 2010;56:474-477.
Estimation of glomerular filtration rate renal transplant patients is often assessed by application of creatinine-based equations.
Cockroft-Gault :estimation of creatinine clearance in a patient with stable serum creatinine , it takes into account that creatinine production decrease by age
and female has smaller muscle mass.
but not adjusted for body surface area and it was developed before the use of standardized creatinine assays so its use result in a 10 to 40 percent overestimate serum creatinine and it is less accurate in obese patients
Modification of Diet in Renal Disease (MDRD) :The equation has been validated extensively in Caucasian and African American populations between the ages of 18 and 70* with impaired kidney function (eGFR < 60 mL/min/1.73 m2 ) and has shown good performance for patients with all common causes of kidney disease.
The equation has not been validated in patients older than 70 and appear to be less accurate in obese patients
Chronic Kidney Disease Epidemiology Collaboration :CKD-EPI equation is more accurate for values > 60 mL/min/1.73 m2 than is the MDRD Study equation
SCr analysis is inexpensive and generally accessible. Creatinine is a breakdown product of creatinephosphate in muscle tissue, produced at a relatively constant rate, depending on the muscle mass, and filtered in the glomerulus but also actively secreted in the proximal tubule . Tubular secretion contributes normally to 10% of renal Cr removal, but increases when GFR decreases , causing SCr to remain in the normal range until GFR drops below 60-70 mL/min. Some Cr is also incorporated from the diet. Ingestion of meat contributes substantially to the urinary Cr excretion, both as a result of expansion of the total creatine pool and as a result of gastrointestinal absorption of Cr. Thus, multiple factors contribute to reduce the accuracy of SCr as an indicator of the GFR, including sex, age, race, muscle mass and dietary protein intake.
Creatinine-based estimating equations are not recommended for use with:
However GFR measurement using inulin clearance, the gold standard for its measurement and exogenous markers such as radiolabeled isotopes ,and non-radioactive contrast agents is laborious as well as expensive, being rarely used in clinical practice. Therefore, endogenous markers, such as serum creatinine or cystatin C, are used to estimate kidney function, and equations using these markers adjusted to other variables, mainly demographic, are an attempt to improve accuracy in estimation of GFR
UP TO Date
Kamaruzaman L, Mohd R, Zaki FM, Hod R, Aziz AA. Estimating glomerular filtration rate in adult kidney transplant recipients in the Asian population. Saudi J Kidney Dis Transpl 2019;30:587-96
What are the formulae used and how accurate they are in transplant and non-transplant populations compared to inulin clearance?
How were they validated?
What is the difference between these formulae and the Cockcroft-Gault formula?
What are the advantages and disadvantages of these formulae?
How accurate is serum creatinine as a measure of kidney function?
Urinary clearance of exogenous marker like inulin is considered the gold standard to measure GFR [1]. It’s expensive need continuous infusions with multiple urine collection, not routinely available, so it has remained a method for research purposes. alternative methods used for accurate measuring of GFR by using renogram with Cr51-EDTA renogram, Tc – DPTA .
Serum creatinine is an endogenous marker that freely filtered by glomerulus which is widely used to estimate GFR, it’s not considered as an accurate marker for renal function as its affected by many factors like age, race, muscle mass, drug effect, diet, also its secreted by tubules with variability especially with hypoalbuminemia with is associated with overestimation of the GFR due to hyperfiltration with tubular excretion the methods used for serum creatinine calibration are not standardized across laboratories, which can affect the quality of studies that include creatinine measurements from different laboratories. Komenda et al showed that standardization of creatinine measurements reduced the average measurement error from 23.9 to 8.7%. (2) , the most widely used methods for e GFR is the Modification of diet in renal disease MDRD with 4 – 6 variables including creatinine , age ethnicity black , gender Some studies it has shown that using MDRD equation for e GFR is more accurate than the Cockcroft-Gault formula that used for measuring creatinine clearance based on age wt and creatinine with body mass , the CG formula accuracy limited by the inaccurate urine collection and the body mass ,in fact both formulas are not reliable for GFR values above 60ml/min/1.73m2 and subjective to underestimation in lean patients , elderly and overestimation in obese patients with edema , pregnancy (1).
Serum cystatin C is a low molecular weight protein that functions as a cysteine protease inhibitor and is produced at a constant rate by all nucleated cells (2). In the kidney, it is freely filtered and catabolized in the proximal tubule without being secreted (2). Studies to date suggest that cystatin C is a better marker of GFR than serum creatinine (4) Factors that affect the level of cystatin C based on evidence from cohort study Prevention of Renal and Vascular End stage Disease (PREVEND) age, male gender, weight, height, cigarette smoking, and inflammation were independently associated with cystatin C levels after adjusting for creatinine clearance.
In one study shows that plasma cystatin C appears superior to creatinine and 24-h creatinine clearance for evaluation of GFR in the postoperative follow-up of adult kidney transplant recipient
CKD -EPI this formula preferred for eGFR in CKD patients with GFR 60ml/miv/1.73m2 and above
in kidney transplant work up still we are using the e GFR by MDRD equation with creatinine clearance in 24 hour urine collection and the isotope DPTA renogram , in regards to monitor renal graft function post transplant still e GFR by using serum creatinine its not accurate to assess graft function its rather marker of damage , need further research regarding new urinary biomarkers that help in better detection and monitoring of graft function
Ref 1: Jonathan Barratt, Kevin Harris, Peter Topham, oxford DESK Reference Nephrology
Ref2:Laterza OF, Price CP, Scott MG: Cystatin C: An improved estimator of glomerular filtration rate? Clin Chem 48: 699 – 707, 2002
Ref 3 Dharnidharka V, Kwon C, Stevens G: Serum cystatin C is superior to serum creatinine as a marker of kidney function: A meta-analysis. Am J Kidney Dis 40: 221–226, 2002
Ref 4: Pierre Fesler & Albert Mimran
Ref 5: Risch L, Blumberg A, Huber A. Rapid and accu rate assessment of glomerular filtration rate in patients with renal transplants using serum cystatin C. Nephrol Dial Transplant 1999;14-6
There is multiple fourmola for calculation of renal graft function .and substances to measure eGFR.
Each of them has its advantage in some patients and not best in accuracy in the others.
1.Inulin clearance inspite being one of the most accurate but not widely used in laboratories for technical issues
2.s.creat. as only parameter for monitor kidney function has a lot of fallacies as it will not be increased untill 50٪of kidney function affected.and depend on muscle mass of patient and affected by certain drugs such as cimetidine.
Small rise in s.creat from normal basal may be indicator for great loss in eGFR as increase of s.creat from 1mg/dl to 1.5mg/dl.
3.CKD.EPI formula used mainly in GFR more than 60ml/min
4.MDRD used frequently but better not to be used in extreme of ages and pregnant ladies.
5.COCKROFT GAULT formoula used widely to modify drug dosing but over estimate eGFR in obese and eodematous patient
6.shwartz equation used in pediatrics.
Refrences,,,
1. Biological variation database specifications. http://www.westgard.com/biodatabase1.htm (Accessed 15 November 2010).
2Perrone RD, Madias NE, Levey AS: Serum creatinine as an index of renal function: new insights into old concepts. Clin Chem 1992;38:1933–1953.
I POSTED MY CONTRIBUTION TODAY EARLY MORNING ,WITH 16 REFERENCES;UNFORTUNATELY,I DID NOT FIND AMONG OTHER CONTRIBUTION.
SORRY
Dear All
Thank you for your replies. Feel free to contribute to the discussion for those who did not. Also, let us not forget week 2.
Using creatinine to estimate GFR is limited by:
1-Changes in creatinine production related protein intake and muscle mass .Rhabdomyolysis commonly affects healthy men with increased muscle mass,(1).
2-Changes in creatinine secretion :with GFR falling, the increase in serum creatinine is partially delayed by proximal tubular secretion,(2)
3-Intestinal bacterial overgrowth with enhanced creatininase activity in advanced kidney failure,(3)
4-Measurement falacies: variation in creatinine assays has considerable effect on renal function testing,(4).Some substances could interfere with creatinine assay causing false increase like acetoacetate and bilirubin (5).Some drugs like Flucytosine and Cefoxitin have comparable effect.
eGFR Formulae:
-Cockroft-Gault: implemented by use of serum creatinine with stable creatinine level(6).Adjustment for body surface area is needed for more accuracy,(7).It overestimates creatinine clearance in 10-40% of cases without lab standard caliberation.
-MDRD :
It is accurate in CKD(8).Both MDRD &Cockroft-Gault formulae are less accurate in obese patients,(9).Abbreviated MDRD formula is commonly used in kidney allograft recipients,(10&11).
-CKD-EPI:
2009 CKD : its development used data from 10 studies and validated against data from 16 studies with iothalamate.It was found as accurate as MDRD formula with eGFR less than 60 ml /min. and more accurate with higher GFR values(12).
Overall accuracy ;also at GFR more than 60 ml/min is more in CKD-EPI formula than MDRD formula(13&14).
In 2021,new CKD-EPI formula was developed without race involvement .It was validated using data of 4050 candidate in twelve studies. Although 2021 CKD-EPI formula was less accurate than CKD-EPI2009,its application was generally acceptable. Measured GFR of black people was underestimated by 2021 CKD-EPI. However ,both 2009&2021 CKD-EPI formulae maintained acceptable accuracy. In addition ,higher prevalence CKD-EPI of CKD was found in black people using 2021(15).eGFRcr with differences muscle mass or protein intake needs confirmatory test of eGFR cyst(16).
REFERENCES:
1-Oh Ms, Does serum creatinine rise faster in rhabdomyolysis? Nephron 1993;63;255
2-Levey AS,Measurerment of renal function in chronic renal disease ,Kidney Int,1990;38;167
3-Dunn SR, Gabuzda, GM,Superdock KR,et al,Induction of creatininase activity in chronic renal failure ;timing of creatinine degradation and effect of antibiotics ;Am
J Kidney Dis;1997;29;72.
4-Stevens,LA,CoreshJ,Greene T,Levey,AS, Assessing kidney function ;me,ClinBasured and estimated glomerular filtration rate,N Eng J Med,2006;354;2473
5-Soldin ,SJ,Hendersonl,Hill JG,The effect of bilirubin and ketones on reaction rate methods for the measurement of creatinine,Clin Biochem,1978;11;82
6-Cockroft DW,Gault M;Prediction 0f creatinine clearance from serum creatinine;Nephron;1967;16;31
7-ShokerA,Hossain,MA,Koru-Sengul t;et al; Performance of creatinine clearance equations on the original Cockroft-Gault population ;Clin Nephrol;2006;66;89
8-Poggio ED ,Wang X,Greene T;et al; Performance of the modification ofdiet in renal disease and Cockroft-Gault equations in the estimation of GFR in health and chronic kidney disease ;J Am Soc Nephrol;2005;16;459
9-Foissart M,Rossert J;Jacquot C;et al;Predictive performanceof the modification of diet in renal disease and Gault-Cockroft equation for estimating renal function;Am J Soc Nephrol;2005;16;763
10-Mariat C;Alamartine E;Barthelemy JC ;et al ;Adressing renal graft function in clinical trials;can tests predicting glomerular filtration rate substitute for a reference method?;Kid Int;2004;65;289
11-Stoves J,Lindley EJ,Barnfield MC,et al ;MDRD equation estimates of glomerular filtration rate in potential living kidney donors and renal transplant recipients with impaired graft function
12-Levey AS,Stevens LA,Schmid CH,et al;A new equation to estimate glomerular filtration rate; Ann Intern Med;2009;150;604
13-Stevens LA,Schmid CH,Greene T,et al,Comparative performance of the CKD Epidemiology Collaboration (CKD-EPI)and the Modification of Diet in Renal Disease (MDRD);Study equations for estimating GFR levels above 60 ml/min/1.73 m2;Am J Kidney Dis ;2010;56;486
14-Kilbride HS; Stevens PE,Eaglestone G,et al ;Adequacy of the MDRD (Modification of Diet in Renal Disease );Study and CKD-EPI(CKD Epidemiology and Collaboration ) equations for estimation of GFR in the elderly,Am J Kidney Dis;2013;61;57
15-Frossisart M ,Rossert J,Jacquot C,et al :Predictive performance of the modification of diet in renal disease and Cockroft-Gault equations for estimating renal function ,J Am Soc Nephrol;2005;16;763
16-Herget-Rosenthal S,Marggraf G,Hussing J,et al;Early detection of acute renal failure by serum cystatin c;Kidney Int;2004;66(3):1115-112
,
1.The formulae used in calculating GFR in non-transplant patients include
Cockcroft Gault formula
MDRD [Modification of Diet in Renal Disease] Formula
CKD-EPI [Chronic Kidney Disease Epidemiology Collaboration] Formula
In transplant patients, during the early phase when creatinine values are rapidly changing, these formulae are not accurate in calculating GFR, as they need a steady state to be accurate.
The Kinetic estimated GFR [keGFR] is used to calculate GFR in cases where there is rapidly changing creatinine values.
2.Creatinine is relatively accurate as a measure of renal function. The ideal molecule to be used to measure GFR should not be bound to protein; should be freely filtered by the glomerulus; should not be secreted by the tubules; and should be inert. Creatinine is secreted by the tublues and this can cause an overestination of GFR. Also creatinine values can remain normal even when there is marked loss of renal function. Inulin is a better molecule to be used to calculate GFR, but is extremely expensive to use.
3.These formulae used to calculate GFR have been validated using radionuclides
4.The difference between Cockcroft Gault and the other formulae is that Cockcroft Gault was got using people with normal kidney function as the population; whereas the other formulae used those with chronic kidney disease as their population
5.The advantages and disadvantages of the formulae include
Discuss the best approach in monitoring graft function
The main aim in post kidney transplantation is monitoring graft function to stave off graft loss and maximize the graft survival.
Serum creatinine
-Serum creatinine has been the indicator of the level of graft function and clue for graft loss. A change in creatinine level has been associated with intrinsic process such as acute rejection, renal artery stenosis, de novo Kidney disease, chronic graft injury and recurrence of original disease.
-24 hour urine collections for creative clearance can be used for monitoring graft function.
eGFR
-White et al – reduced accuracy due to both overestimates and underestimates mGFR.
-Kuala et al- Cockcroft Gault equation and MDRD are the. Closest to measure graft function.
-KDIGO – did not recommend as a monitriong tool ass it will not improve the ability of serum creatinine to estimate kidney function.
Proteinuria
Amer et al – proteinuria >150mg was found associated with reduced graft survival
Increasing levels of proteinuria at 1 year was associated with risk of graft loss at 5 years
Graft Pathology
-Mengel et al – presence of below banff level inflammation at first 26 week correlated with decreased renal function.
-Cosio et al- fibrosis, inflammation and glomerulopathy on surveillance biopsy at 1 year post transplantation predicted decrease in graft function and graft failure.
-Rush et al- with current IS regime ,protocol biopsy might not improve the outcome significantly
-Wayamunno et al- found that untrstructural changes seen as early as 1 month post transplantation suggested for early protocol biopsy.
-In general – protocol biopsy in the unsensitized stable transplant recipient is debatable and unwise to subject to sampling error, bleeding risk and cost of procedures.
-It may be useful in patient who are highly sensitised because they are more likely to have C4d on biopsies and development of DSA.
Time 0 biopsy
-Usually on those had marginal kidneys
-Anglicheau et al- Time 0 biopsy with assessment of baseline donor characteristic predicts graft survival
-Munivenkatappa et al- transcriptomes from T0 Biopsy predicted DGF
Monitor Immunologic status
-Immuknow Cylex assay- measures concentrates of ATP from stimulated CD4 cells. Not concise in predicting risk of rejection
-ELLISPOT assay- measures frequency of peripheral blood lymphocytes producing IFN-G in response to stimulator cells from kidney donor – but ot easily available
-Gill et al found that routinely testing for HLA antibodies not useful
urinary microRNA panel
-Usman Khalid et al showed a microRNA signature in urine that provides a non-invasive measure of DGF risk in kidney transplant recipients.
GFR , most commonly use to assess kidney function , grading and follow deterioration ..Assessment of GFR done either by direct measurement or Estimation. In most common mode of assessment serum creatinine is used with inherited problem of assessment at laboratory equipment error and its affected by age ,sex race and muscle mass ., still its affordable guide to dysfunction with serial measurement .especially early when steady state is not achieved i.e. in acute renal failure , Which need 3- 4 days to reach steady state.
Measurement GFR is either:
Measure of Clearance OF endogenous substance, like creatinine, urea or cystatin C .
Advantage:
More accurate, used to confirm GFR by estimation.
Disadvantage: affected by muscle mass, diet, race sex, some drugs. (Creatinine and urea), collection error.
Cystatin affected by corticosteroid, thyroid hormones, sex and DM and inflammation.
Measure of exogenous substance, like inulin, iohexol, DTPA OR EDTA(1).
Estimated GFR done by many equation common:
Cockcroft –Gault:
MDRD.
CKD-EPI .
CKD-EPI combined creatinine and cystacin.
CKD-EPI is more accurate than MDRD EQUATION AND BOTH BETTER THAN Cockcroft and Gualt.
CKD-EPI, Validated in dataset of 12studies.(2).American society of nephrology and national kidney foundation recommend usage 2021 revised CKD-EPI be used to estimate GFR.(3)
Cockroft Gault equation AND MDRD.:
Overestimate creatinine e clearance by 10-40%. ,less accurate in obese(4) . and in people with normal or near normal GFR(5).
Both overestimate GFR in Japan and other Asian population..
The three equation are limited by creatinine usage which affected by diet, muscle mass, diabetic ,pregnant and require stable kidney function.
In transplant patient creatinine based equation is advised to be used .MDRD perform better than CKD-EPI creatinine ,in transplant reverse in CKD patient, The CKD-EPIcreatinine+cys C formula was superior to the CKD-EPIcreatinine (6) .
Reference:
1-Rahn KH ,Heidenreich ,Brackner .How to assess GFR function and damage in human.J,Hypertension ,1999,.17(3):309.
2-.Inkerla et al,New creatinine and cystacin C based equation to estimate GFR .Neng.J med.2021.
3-Delgadoc c.Baweja M.Crew DC et al.A approach of GFR estiamtation, recommendation of NKF ,ASN task force.
ANJ.KID.Dis.2021.
4- Froissart M.Rossart et al,Predicive performance of MDRD and Cocraft Gault equation for estimation of renal function .Jan,society .Neprology,2005,16(3),783..5-Poggio ED etal ,Performance of MDRD and Cockraft GouLequation in estimation of GFR in health and CKD .Jam.Soc NC pharma.2005:16(2):459
6- Salvador C Hartmann AÅsberg A et al Estimating Glomerular Filtration Rate in Kidney Transplant Recipients: Comparing a Novel Equation With Commonly Used Equations in this Population. Transplantation Direct, 08 Nov 2017, 3(12):e332.
-Gfr is a gold standard measurement of kidney function
Can’t use in AKI
Also not reflect tubular function
Inulin clearance still the best one &cysteine c
Other equations not accurate (mdrd-cockcroft)
-Serum creatinine still good tool to evacuate kidney function but we can say that it’s rising is too late so their is more earlier markers available as n.Gal but not applicable as creatinine -we also should measure proteinuria
-cockcroft advantaged over serum creation measurement as it use age-sex-body weight
-disadvantages not use race and not accurate as inulin or cysteine but more applicable
Dear colleagues,
Allow me to summarize these wonderful contributions as a future simple and concise review for all of us (I feel it will be difficult for any of us to read all these valuable contributions as they exceeded 105 contributions. Additionally, we will have another 3-4 case scenarios weekly till the end of the module).
eGFR is taken as an estimated measurement of the graft function in renal transplant patients.
The glomerular filtration rate (GFR) measurement is considered the gold standard appraisal of the excretory kidney function (1). However, other kidney functions (e.g., tubular handling of electrolytes, acid-base control and endocrine functions) are not reflected by the measurement of GFR.
Historically, the GFR measurement relied on measuring the clearance of a substance from the blood to estimate the excretory functions of the kidney (2). The next challenge was to identify the ideal clearance marker which fulfils the following criteria (2):
– Safe to be used, easily measured and with stable plasma levels.
– Non-protein bound (to ensure uniform distribution through the extra-cellular fluid).
– It is not metabolized, reabsorbed, nor excreted by the kidney.
– It has no extra-renal metabolism.
– It is freely filtered through glomeruli.
Unfortunately, by applying these criteria, none of the available markers will fulfil all these points. Creatinine, for example, is widely used because it is an endogenous material and is easily measured in urine and serum everywhere. However, about 25% is derived from dietary meat intake (creatine mostly; creatinine if the meat is stewed). It is partially secreted by the proximal convoluted tubules (PCT) by about 10-20% with normal GFR. Additionally, there is some extra-renal metabolism through degradation in the GIT (1, 2).
Another agent used to measure GFR is Inulin (a fructose polysaccharide), which meets most of the criteria mentioned above. However, being not widely available in all laboratories in addition to technical difficulties (as it needs continuous infusion) has limited its use (1, 2).
The above challenges necessitate the search for an easy and reliable estimate of the GFR (eGFR) rather than the actual measurement, which requires more time and resources that make it unsuitable for daily practice except in some selected clinical scenarios.
· Clinicians used to utilize the Cockcroft– Gault formula that used the serum creatinine (Cr) levels to estimate the eGFR. In addition, it tried to correct the confounding factors of age, gender, and body weight as in the following formula (2):
In Male = ([140 − age] × weight [kg])/ (72 × S. Cr [mg/dL])
In Females: same as the formula for males above × 0.85
· Another widely used formula is the MDRD produced as a result of the Modification of Diet in Renal Disease study. The formula was created as follow:
eGFR = 186.3 x ((serum creatinine) exp [ – 1.154]) x (Age exp [ – 0.203]) x (0.742 if female) x (1.21 if African American)
Again, this formula was not applicable in extremes of age (too young or too old patients), pregnant ladies or ethnic groups other than Caucasian and African American.
· The CKD- EPI (Chronic Kidney Disease Epidemiology Collaboration) creatinine equation was developed to improve the accuracy of eGFR and be more reliable in patients with GFR higher than 60 ml/min (1).
· CKD-EPI Cystatin C. (some consider it of the same accuracy as a creatinine-based equation) (3).
· CKD-EPI Creatinine and Cystatin C. (more accurate than creatinine or Cystatin C alone) (3). It can be used as a confirmatory tool in specific populations (eating disorder, neuromuscular disorder, and limb amputation).
· Schwartz equation: estimating eGFR based on the serum Cr and height of the patient, used for young patients below 18 years old.
Despite all the scientific efforts to create a reliable eGFR equation to reflect the actual kidney function, yet all these equations share some critical weakness that can be summarized as follow (1, 2):
– They rely on the measurement of the serum Cr, which is not a reliable marker in cases of acute kidney injury (AKI) or any other condition associated with a rapidly changing serum Cr (e.g. serum Cr may take one day or more to be significantly elevated after the onset of a catastrophic kidney injury).
– The tubular secretion will keep the serum creatinine in the normal range until GFR drops below 60-70 mL/min.
– Other common obstacles are met in situations where there is a very high Cr generation (e.g. high muscle mass in Athletes and some African Americans) or very low generation of serum Cr (e.g. in cachectic cases and patients with amputated limbs), again using eGFR equations in these situations can give misleading results.
– There are some notes regarding the reliability of eGFR equations using cystatin C alone. First, substantial variation in the cystatin C assay has been observed, even when using the same instrument and the same reagent type by the same laboratory (4).
– Although Cystatin C was expected initially to be stable in the serum with no effect of age, gender, muscle mass or ethnicity, several studies have documented variability in serum Cystatin C levels with age, gender, fat mass, diabetes, markers of inflammation, hypo- and hyperthyroidism (5).
The measurement of GFR for the potential kidney donor is commonly done using renal isotope DTPA with split kidney function to determine which kidney will be donated as only an isotope scan can accurately measure the function of each kidney separately.
References:
1) Jonathan Barratt, Peter Topham, Sue Carr, eds. Oxford Desk Reference Nephrology. Second edition. United Kingdom: Oxford University Press, ISBN 978-0-19-877718- 2. 2021.
2) Steddon S, Ashman N, Chesser A, et al. Oxford Handbook of Nephrology and Hypertension. Second edition, Oxford University Press, ISBN 978–0–19–965161–0, 2014.
3) Salvador C., Hartmann A., Asberg A., Bergan S., et al. Estimating Glomerular Filtration Rate in Kidney Transplant Recipients: Comparing a Novel Equation With Commonly Used Equations in this Population. Transplant Direct. 2017; 3: e332.
4) Inker LA, Eckfeldt J, Levey AS, et al. Expressing the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) cystatin C equations for estimating GFR with standardized serum cystatin C values. Am J Kidney Dis. 2011; 58(4): 682.
5) Lesley A Inker, Ronald D Perrone. Assessment of kidney function. (UpToDate 2021). (Accessed on 4 November 2021).
• Glomerular filtration rate (GFR) is an indicator of graft and patient survival after kidney transplantation.
• Insulin clearance is a gold standard method for GFR measurement but it is difficult technique to use in daily clinical practice.
• Therefore there is always ongoing studies to reach to the optimal equation that suitable for different population with various range of GFR by using endogenous marker by simple way with accurate result as inulin clearance.
• There are many formulae used for estimation of GFR such as Cockcroft–Gault, MDRD, CKD-EPI and Cystatin C-based equations.
• Creatinine is discovered in 1847 and assigned as marker of filtration in 1926. It is easy, cheap and widely available marker for kidney function,
but unfortunately it an inaccurate marker because it is affected by many factors such as age, gender, ethnicity, muscle mass, diet and medications which interfere with its tubular secretion like cimetidine, trimethoprim.
• Validation of Cockcroft–Gault equation was done in 1976 from 249 patients, most of them were white males, but it overestimates GFR and does not take the ethnicity into the consideration. Also, it is not accurate in elderly and obese patients.
• MDRD equation was developed in 1999 and validated after study of 1628 CKD patients. It is more accurate in African Americans and Caucasian from 18 to 70 years especially in patients with renal impairment (eGFR 60 ml/min/1.73m². It takes age, gender and race into the consideration of the equation.
It is the most common equation used in kidney transplantation.
It is not recommended to use it when eGFR is more than 60 ml/min/1.73m². Also, it is not preferred equation in obese, malnourished or patients with limb amputation. It is more accurate when level creatinine is stable for long period, so it is less accurate in acute kidney injury.
• CKD-EPI equation validation came from 10 studies with 8254 patients. It is more accurate in GFR > 60 ml/min/1.73m². It takes age, gender and race into the consideration of the equation.
It is the most common equation used in kidney transplantation.
• Cystatin c is low-molecular weight protein (122-amino acid) which has role in immunity. It was discovered in 1979 and assigned as filtration marker in 1985. It has a constant rate of production and filtered freely in renal tubules.
It has a better correlation with measured GFR than creatinine because cystatin c is not influenced by diet or muscle mass and it has a weaker association with age, gender and ethnicity than creatinine.
However, it is affected by steroid and thyroid disorders. In addition to that, it is expensive and not available widely.
Addition of creatinine to cystatin c reinforces and strengths the GFR measurement.
☆ Reference
• Mutawa, Khuloud & Halawa, Ahmed & Camilleri, Brian. (2020). Identifying Kidney Dysfunction after Renal Transplantation; The Role of Biomarkers and Different eGFR Formulae. Transplantation science. 2. 121-127.
• Levey, A. and Inker, L. (2017), Assessment of Glomerular Filtration Rate in Health and Disease: A State of the Art Review. Clin. Pharmacol. Ther., 102: 405-419.
• Santos, Josefina & Martins, Lasalete. (2015). Estimating glomerular filtration rate in kidney transplantation: Still searching for the best marker. World journal of nephrology. 4. 345-53. 10.5527/wjn.v4.i3.345
eGFR is taken as an estimated measurement of the graft function in renal transplant patients.
What are the formulae used and how accurate they are in transplant and non-transplant populations compared to inulin clearance?
The gold standard method to measure GFR is by using an exogenous substance and measure its clearance, this includes Inulin clearance (time consuming, technically challenging, and not practically used), using renal isotopic scans(like 99mTC-DTPA, 51Cr-EDTA (expensive, technically difficult), using formulae which depend on commonly used endogenous markers like Creatinine, cystatin-C.
Commonly used formulas include:
1) The Cockcroft-Gault formula
e-GFR (male) = ([140-age] × weight in kg)/ (serum creatinine(mg/dl) × 72) CrCl (female) = CrCl (male) × 0.85.
e-GFR= (140 − age (years) × weight (kg) × constant/serum creatinine(μmol/L).
The published constants are 1.23 for males of any age, and 1.05 for females of any age.
2) Modification of Diet in Renal Disease (MDRD) equation
GFR (mL/min/1.73 m2) = 175 × (Scr)-1.154 × (Age)-0.203 × (0.742 if female) × (1.212 if African American)
3) CKD-EPI equation using serum creatinine
GFR = 141 * min(Scr/κ,1)α * max(Scr/κ, 1)-1.209 * 0.993Age * 1.018 [if female] * 1.159 [if black]
4) CKD-EPI equation using serum Cystatin C.
eGFR =133 xmin(Scys/0.8, 1)-0.499 xmax (Scys/0.8, 1)-1.328 x0.996Age x0.932 [if female]
5) CKD-EPI 2021: Using Gender, Age, Creatinine (without race).
eGFR =142*min(standardized Scr/K, 1)α *max(standardized Scr/K, 1)-1.200 *0.9938Age *
1.012 [if female]
6) Nankivell Equation.
e-GFR= 6.7/serum creatinine + 0.25 × weight – 0.5 × urea – 0.01 × height2 + 35(25 for woman).
7) Full Age Spectrum (FAS)
eGFR (mL/min/1.73m2) = 141 x (Cr/79.2)-1.209 x (0.993)Age.
In kidney transplant recipients, MDRD, Cockroft Gault and Nankivell equations were evaluated and found to underestimate the GFR, and the degree of underestimation increased with improvement in graft kidney function.
CKD-EPI equation also did not significantly improve accuracy over the MDRD equation in transplant recipients.
How accurate is serum creatinine as a measure of kidney function?
Creatinine is a commonly used as measure of kidney function.
The normal creatinine clearance test value is 110-150ml/min in male and in female it is 100-130ml/min.
The creatinine clearance test is used to monitor the progression of renal disease.
The diagnosis of renal failure is usually suspected when serum creatinine is greater than the upper limit of the “normal” interval.
In CKD and uremia, an eventual reduction occurs in the excretion of creatinine by both the glomeruli and the tubules. Creatinine values may alter as its generation may not be simply a product of muscle mass but influenced by muscle function, muscle composition, activity, diet and health status[6]. The increased tubular secretion of creatinine in some patients with kidney dysfunction could give false negative value. The elevated values are also seen in muscular dystrophy paralysis, anemia, leukemia and hyperthyroidism. The decreased values are noticed with glomerulonephritis, congestive heart failure, acute tubular necrosis, shock, polycystic kidney disease, and dehydration[5].
Creatinine is a useful indicator of renal health because it is excreted in the urine as an unchanged and easily measured by-product of muscle metabolism. In a healthy kidney, little or no creatinine is reabsorbed, whereas in kidney disease, the creatinine concentration in the blood may increase.
How were they validated?
The equations are validated against the gold standard inulin clearance depending upon 3 criterias: Bias, Precision, and accuracy.
· Bias:
Absolute bias = mean difference between estimated GFR and measured GFR using gold standard (true GFR)
Relative bias = absolute bias/ true GFR x 100
· Precision = standard deviation of difference between eGFR and true GFR (expresses variability of eGFR around the true GFR)
· Accuracy of the GFR estimates = distribution of difference between eGFR and true GFR
What is the difference between these formulae and the Cockcroft-Gault formula?
Cockroft-Gault formula utilizes body weight in calculating GFR which is not utilized in other equations
What are the advantages and disadvantages of these formulae?Advantage—àquick estimation of GFR.
Disadvantage–àdepends on serum creatinine and cystatin c with all of their limitations.
Cockroft Gault formula: because it uses body weight in calculating GFR so it overestimates GFR in obese or patients with edema and underestimates GFR in elderly.
MDRD equation:
1- Is not applicable in young children and elderly individuals, pregnancy and races other than African-Americans and Caucasians.
2- underestimates GFR in patients with GFR more than 60 ml/min/1.73m2.
3- It is useful for non-hospitalized population.
CKD-EPI overestimates GFR if the GFR is above 60ml/min.
CKD-EPI Cystatin is not reliable in pregnancy, rapid change in GFR, steroid use, thyroid dysfunction, old age
CKD-EPI 2021 equation does not use race as a factor. So, it underestimates GFR in African-Americans
FAS is valid even in patients with GFR more than 60 ml/min/1.73m2
E- Serum creatinine usually reaches a steady state after nephrectomy within 2-4 days
1-MDRD and CKD-EPI there are formula used to estimate the GFR
2-They found that the ckd-epi over estimate the GFR when compared with the measured GFR and the MDRD formula is most accurate
3-serum creatinine used as factor in those formulas to estimate the GFR but it’s a good marker for kidney function
4-validated by the comparison to the measure GFR
5-The advantage of those formulas were cheapest than measured method for GFR
but can give over or underestimation of GFR
The evaluation of graft function is mandatory in the management of renal transplant recipients. Glomerular filtration rate (GFR), is generally considered the best index of graft function and also a predictor of graft and patient survival. However, GFR measurement using inulin clearance is expensive and rarely used in clinical practice. Therefore, endogenous markers, such as serum creatinine or cystatin C, are used to estimate kidney function, and equations using these markers adjusted to other variables, mainly demographic, are an attempt to improve accuracy in the estimation of GFR (eGFR). Because Cr secretion is not predictable, the GFR can decrease to nearly half the normal value before the SCr increases, with remarkable consequences in kidney transplant outcome, where subclinical progressive damage, such as calcineurin toxicity and rejection will not be early identified.
Creatinine clearance (CCr) as measured from 24-h urine collection is often used in clinical practice to calculate GFR, but it overestimates GFR due to the secretion of Cr by the renal tubules and the inherent limitations of SCr as a kidney marker.
Performance of Creatinine-Based GFR Estimation Equations in Kidney Transplantation
The eGFR equations were an alternative to estimate GFR in the clinical context, as they allow us to overpass some of the limitations of the SCr.
In several studies in kidney transplantation, the efficiency of MDRD, Cockcroft-Gault and Nankivell equations has been consistently reviewed, with significant heterogeneity between studies, with low precision inducing limited accuracies, and this can be attributed to varied patient characteristics, differences in measure GFR methods and Cr assay calibration and, potentially, some inherent differences in this specific population of transplant recipients.
The CKD-EPI equation introduces a correction term to overcome the systematic underestimation of GFR of the MDRD formulas in patients with relatively well-preserved kidney function. In a cohort of 207 stable Kidney transplant recipients CKD-EPI shows improved estimation ability compared with MDRD equation, but still with suboptimal precision that limits the value of the CKD-EPI for monitoring changes in kidney function over time. Other studies compare the performances of the MDRD and CKD-EPI equations in a large transplant patient’s cohort and the authors concluded that the latter equation does not offer a better GFR estimation in this population.
More recently, Shaffi et al, conducted a systematic evaluation of the development methods of all published Cr-based eGFR equations, and assess their performance in a large population (n = 3622) of solid-organ transplant recipients, including 53% kidney transplant recipients and concluded that the CKD-EPI and IDMS-traceable 4-variable MDRD Study equations were more accurate than the alternative equations, including those developed in populations including only transplant recipients, and as accurate as observed in non-transplanted populations. The CKD-EPI creatinine and the MDRD Study equations perform better than the alternative creatinine-based estimating equations in solid-organ transplant recipients. They can be used for clinical management. Nevertheless, we can’t forget that these equations still misestimate true GFR by > 30% in 1 of 5 patients.
References:
1. Santos J, Martins LS. Estimating glomerular filtration rate in kidney transplantation: Still searching for the best marker. World J Nephrol. 2015 Jul 6;4(3):345-53. doi: 10.5527/wjn.v4.i3.345. PMID: 26167457; PMCID: PMC4491924.
2. White CA, Akbari A, Doucette S, Fergusson D, Knoll GA. Estimating glomerular filtration rate in kidney transplantation: is the new chronic kidney disease epidemiology collaboration equation any better? . Clin Chem. 2010;56:474–477.
3. Masson I, Flamant M, Maillard N, Rule AD, Vrtovsnik F, Peraldi MN, Thibaudin L, Cavalier E, Vidal-Petiot E, Bonneau C, et al. MDRD versus CKD-EPI equation to estimate glomerular filtration rate in kidney transplant recipients. Transplantation. 2013;95:1211–1217.
4. Shaffi K, Uhlig K, Perrone RD, Ruthazer R, Rule A, Lieske JC, Navis G, Poggio ED, Inker LA, Levey AS. Performance of creatinine-based GFR estimating equations in solid-organ transplant recipients. Am J Kidney Dis. 2014;63:1007–1018.
To evaluate graft function, measurement of GFR is necessary in kidney transplantation. The most accurate and gold-standard method is inulin clearance which is difficult in practice. Other GFR measuring methods like EDTA and DTPA are expensive. So estimated GFR by endogen markers such as creatinine and cystatin-c are practically used instead of measured GFR. In order to estimate GFR, Cockcraft- Gault, MDRD and CKD-EPI formulas were invented.
Creatinine is the product of creatine metabolism in muscle and is produced with a fixed daily rate, related to muscle mass. It is not metabolized or reabsorbed but duo to tubular secretion there is more creatinine in urine. In GFRs more than 60ml/min, GFR changes are accompanied with little serum creatinine changes. In conditions such as nephrotic syndrome or sickle cell creatinine secretion is increased. Drugs such as trimethoprim and H2-blockers can increase serum creatinine by decreasing tubular secretion. Methods of creatinine measurement are important. In Jaffei method, serum creatinine will be reported higher if hyperbilirubinemia or ketoacidosis is present. There are problems regarding Cockcraft- Gault method, such as higher weight not being a good indicator for higher muscle mass but might be duo to obesity. This formula is also not adjusted for BSA. There weren’t any enzymatic or standard method for measuring creatinine when this formula was introduced; hence, clearance of creatinine with this formula will be overestimated (about 10-40 %). MDRD formula is less accurate for obese people and in cases with near-normal GFR. To achieve this, it’s better to use CKD-EPI formula for estimating GFR when it is more than 60 ml/min. CKD-EPI formula gives a better GFR estimation compared to MDRD formula when the transplant patients have particularly higher GFR, BMI and are older. In diabetic patients, Asians, pregnant women and people with unusual body conditions like an amputation, these formulas are less accurate. Formulas that use both creatinine and cystatin-C are mostly prioritized, but since using steroid increases the amount of cystatin-C, the usage of cystatin-C formulas are limited in transplant patients
Cockroft & Gault equation:
predict creatinine clearance using age, weight, height and plasm creatinine with correction factors
limitations:
derived from hospitalized men, not adjusted for body surface area, all had CKD, require body weight (may be fat rather than muscle mass) and height
overestimate creatinine clearance
MDRD:
4 variable equation included age, gender, plasma creatinine and race (Black or White)
with no need for body weight or height
performs better at lower levels of GFR
limitations: not validated in children <18 years, >70 years, healthy individuals , pregnancy and extremes of body weight. It also underestimate renal function in those with normal GFR
CKD-EPI equation:
Use plasma creatinine, gender, race and age on natural scale
match accuracy of MDRD at GFR <60 ml/min/1.73m2 and greater accuracy in higher GFR
used in general population
Inulin clearance
the gold standard for GFR measurement but not used in practice due to unavailability
measuring GFR is more accurate but less used due to increased cost
the difference between estimation of GFR in general population and transplant patients is understudied.
several limitations of using creatinine:
it is affected by diet (vegetarian, creatine supplements), muscle mass (wasting, amputation)
in early renal disease: severity of GFR decline may be not apparent due to increase in creatinine secretion by proximal tubules
equations determine changes in GFR over time and aren’t accurate when GFR falls rapidly as in acute kidney injury
they are limited by the same limitations of creatinine
less accurate in diabetic patients, pregnancy, unusual muscle mass, morbid obesity
Dosing of drugs with narrow therapeutic window (especially in patients with extremes of muscle mass, unusual diet or extremes of weight) better to be based on measured creatinine clearance or using GFR estimated with cystatin based equation
Dear All
It was a good start, but feel free to add more contributions especially those who did not contribute much and did not contribute at all.
A) What are the formulae used and how accurate they are in transplant and non-transplant populations compared to inulin clearance?
Glomerular filtration rate (GFR) measurement is an important step in evaluation of renal function. Estimated GFR (eGFR) equations are commonly used for calculating GFR as the standard methods of measuring GFR are time consuming, costly, and technically demanding.
Commonly used formulas include: (1)
1) Cockroft Gault equation: Using Age, Weight, Gender, Serum creatinine
2) Modification of Diet in Renal Disease (MDRD) equation
3) CKD-EPI equation using serum creatinine
4) CKD-EPI equation using serum creatinine and Cystatin C
5) CKD-EPI 2021: Using Gender, Age, Creatinine (without race) (2)
6) Nankivell Equation (3)
7) Full Age Spectrum (FAS)
In kidney transplant recipients, MDRD, Cockroft Gault and Nankivell equations were evaluated and found to underestimate the GFR, and the degree of underestimation increased with improvement in graft kidney function. (4) CKD-EPI equation also did not significantly improve accuracy over the MDRD equation in transplant recipients. (5)
B) How accurate is serum creatinine as a measure of kidney function?
Creatinine is breakdown product of creatine derived from dietary meat and skeletal muscle and hence depends on dietary protein intake as well as body muscle mass. Creatinine is freely filtered across the glomerulus. A small amount is secreted in the proximal tubule. So, if there is reduction in GFR with constant muscle mass and dietary pattern, there should be corresponding increase in serum creatinine. But, in reality, when there is reduction in GFR, the tubular secretion of creatinine increase and hence blunts the rise in serum creatinine
Limitations with serum creatinine include:
Variation due to dietary changes (amount of meat in meal),
Variation due to change in muscle mass (malnutrition, amputation, muscle wasting),
Variation due to tubular secretion (nephrotic syndrome, sickle cell disease, drugs like trimethoprim and cimetidine decrease tubular secretion). This variation is less once GFR goes below 60.
Variation due to technical errors (alkaline picrate method recognizes acetoacetate or bilirubin in blood as creatinine, giving rise to falsely high values of creatinine)
C) How were they validated?
The equations are validated against the gold standard inulin clearance depending upon 3 criterias: Bias, Precision, and accuracy.
Bias:
Absolute bias = mean difference between estimated GFR and measured GFR using gold standard (true GFR)
Relative bias = absolute bias/ true GFR x 100
Precision = standard deviation of difference between eGFR and true GFR (expresses variability of eGFR around the true GFR)
Accuracy of the GFR estimates = distribution of difference between eGFR and true GFR
D) What is the difference between these formulae and the Cockroft-Gault formula?
Cockroft-Gault formula utilizes body weight in calculating GFR which is not utilized in other equations
E) What are the advantages and disadvantages of these formulae?
Most important advantage of these formulae is quick estimation of GFR, which is important while taking decisions bedside.
Cockroft Gault formula: overestimates GFR in obese or patients with edema (due to body weight being a crucial element in calculation) and underestimates GFR in elderly.
MDRD equation is not applicable in young children and elderly individuals, pregnancy and races other than African-Americans and Caucasians. It underestimates GFR in patients with GFR more than 60 ml/min/1.73m2. It is useful for non-hospitalized population. Performa better at lower GFRs
CKD-EPI overestimates GFR if the GFR is above 60ml/min. It is preferred in elderly and obese individuals. Performs better at higher GFRs.
CKD-EPI Cystatin is not reliable in pregnancy, rapid change in GFR, steroid use, thyroid dysfunction, old age
CKD-EPI 2021 equation does not use race as a factor. So, it underestimates GFR in African-Americans
FAS is valid even in patients with GFR more than 60 ml/min/1.73m2
The major disadvantage with these formulae is that they are dependent on serum creatinine and hence all the limitations of creatinine apply to these formulae. Cystatin C based equations are also not accurate in transplant patients as the cystatin C levels get affected by steroid use.
References:
1) Salvador C, Hartmann A, Asberg A, et al. Estimating Glomerular Filtration Rate in Kidney Transplant Recipients: Comparing a Novel Equation With Commonly Used Equations in this Population. Transplant Direct 2017;3: e332.
2) Inker LA, Eneanya ND, Coresh J, et al. Chronic Kidney Disease Epidemiology Collaboration. New Creatinine- and Cystatin C-Based equations to estimate GFR without race. N Eng J Med 2021 Sep 23
3) Nankivell BJ, Gruenewald SM, Allen RD, et al. Predicting glomerular filtration rate after kidney transplantation. Transplantation 1995;59:1683-1689.
4)Santos j, Marins LS. Estimating glomerular filtration rate in kidney transplantation: still searching for the best marker. World J Nephrol 2015;4:345-353.
5) White CA, Akbari A, Doucette S, et al. Estimating glomerular filtration rate in kidney transplantation: Is the new chronic kidney disease epidemiology collaboration equation any better? Clin Chem 2010;56:474-477.
Excellent
Cockcroft-Gault formula, Creatinine clearance, MDRD, CKD-EPI , Cystatin C based or both creatinine and cystatin C. currently there is a work on a new formula without including the race factor. in general although there are not 100% accurate but there are the only tools we have it at the moment. For example in elderly you can easily diagnosed them as CKD and yet there not. They can underestimate and as well overestimate renal function simply because these are equations but they are very quick to give idea about renal function. In transplant setting the same applies but in general there is a tendency towards MDRD. inulin is the best way to do because it some thing you measure and not estimates like the equations. The main problem is that it is practicalities, cumbersome to do it as you need both urine and blood samples, time consuming, plus the availability in low resource setting. it is very good to use for research purposes. Now days people are trying to use biomarkers as alternative to creatinine in assessing renal function because creatinine usually appears late 48h after the kidney injury and the biomarkers can be detected early in the course of kidney injury, e.g. NGAL. They are can also give prognostic information but the challenge is that there no ideal biomarker and most them still in infancy and not widely used in clinical setting.
How accurate is serum creatinine as a measure of kidney function?
It is not accurate. Serum creatinine is a 113 KD protein produced from the muscle protein creatine. Creatinine production is not constant, it is affected by muscle mass, race, age, gender. Creatinine is freely filtered across the glomerulus, but it s secreted across the tubule but not re absorbed. In transplant patients trimethoprim can compete for the tubular secretion of creatinine when given in doses more than 160mg. Hence it does not give an accurate estimation of glomerular filtration rate. But it is widely used in various equation for the ease of availability.
What are the formula used and how accurate are they in transplant and non transplant patient?
The various formulas used are indirect methods used for estimation of GFR. Direct methods used for GFR estimation are using radiological isotopes using DTPA, iohexol, iothalamate and the traditional inulin clearance. They give the most accurate estimate of the GFR, but a cumbersome and expensive. Indirect or endogenous methods use creatinine and cystacin C (another protein produced by all nucleated cells, affected partly by steroid use, thyroid disorders, GI metabolism). They are the
Cockgroft Gault formula: using age, body weight, race and creatinine. Over estimates GFR for obese, edematous. Creatinine increases only after a significant portion of GFR comes down, hence it is not accurate in predicting early decrease in GFR.
MDRD equation: Modification of diet in Renal Diseases. uses age, creatinine, race. Again it is not accurate in predicting GFR in extremes of age, obese. It does not predict GFR in those with age more than 60 years. it is not to be used in pediatric transplantation
CKD EPI equation: The Epidemiological colloborative study. This equation is used for those more than 60 years and has a better GFR prediction at higher stages of normal GFR. There are CKD EPI equations based on serum creatinine and those based on serum cystatin C. The most accurate is the CKD EPI using cystatin C.
But the CKD EPI equation had only 4% of all the patients as transplant patients and MDRD study did not have information about transplant patients at all.
The study published in Transplantation in 1995 was the probably the only study which included all the transplant patients used urea, creatinine, height, weight and sex for the GFR calculation. Again in transplant settings creatinine may get affected due to altered tubular secretion in ATN or rejections episodes, making it not a reliable marker.
GFR FORMULAE ;ESTIMATED AND MEASURED
Formulae that are commonly used in estimating GFR are Cockcroft-Gault, MDRD, CKD-EPI and the Nankivell formula which is an equation derived from kidney transplant recipients.
In terms of accuracy, studies showed that CG, MDRD, and Nankivell equation fared only 73%, 76%, and 68%, respectively.
Overall ,estimation of GFR in solid organ Tx is poorly validated and numerous sources of bias exist.
The reasons why GFR estimation formulas fail both in short- and long-term studies compared with measured formulas are addressed and are mainly due to:
MEASURED VS ESTIMATED GFR FORMULAE:
Measured glomerular filtration rate (mGFR) with an exogenous filtration marker is the most accurate, either with inulin, 51CrEDTA-clearance, 99mTc DTPA, iohexol or iothalamate. However, these methods are complex and more expensive to use in daily clinical routine.
Therefore many centers prefer to use the estimating methods, (eGFR) being an easy measure of GFR . However, it should be clear that these methods are based on correlations or linear regression models between P-creatinine, P-cystatin C or both and variable patient variables and mGFR, in rather heterogeneous populations. Despite high correlation quotients between eGFR and mGFR seen in many of these studies, it is questionable whether such correlations reflect a clinically useful agreement between eGFR and mGFR in different patient populations, which most often they do not. In this context, it is important to look at predictive performance of different equations, that is, absolute bias, relative bias and accuracy, as suggested in the KDOQI guidelines.
Serum Creatinine as a measure of Kidney function :
Serum creatinine is an unreliable marker of renal function in transplanted patients due to many factors:
there are multiple simple formulae used for eGFR as Cockroft-Gault formula, MDRD, CKD-EPI …. etc. each one has its own advantages and disadvantages. each one has a reasonable range of accuracy. we can easily refer to any of them for more details. however, the most accurate tests for eGFR includes creatinine clearance and isotope scan. creat.clearance has some practical difficulties regarding 24 hour urine calculation. isotope scan is expensive and not widely available.
GFR FORMULAE ;ESTIMATED AND MEASURED
Formulae that are commonly used in estimating GFR are Cockcroft-Gault, MDRD, CKD-EPI and the Nankivell formula which is an equation derived from kidney transplant recipients.
In terms of accuracy, studies showed that CG, MDRD, and Nankivell equation fared only 73%, 76%, and 68%, respectively.
Overall ,estimation of GFR in solid organ Tx is poorly validated and numerous sources of bias exist.
The reasons why GFR estimation formulas fail both in short- and long-term studies compared with measured formulas are addressed and are mainly due to:
MEASURED VS ESTIMATED GFR FORMULAE:
Measured glomerular filtration rate (mGFR) with an exogenous filtration marker is the most accurate, either with inulin, 51CrEDTA-clearance, 99mTc DTPA, iohexol or iothalamate. However, these methods are complex and more expensive to use in daily clinical routine.
Therefore many centers prefer to use the estimating methods, (eGFR) being an easy measure of GFR . However, it should be clear that these methods are based on correlations or linear regression models between P-creatinine, P-cystatin C or both and variable patient variables and mGFR, in rather heterogeneous populations. Despite high correlation quotients between eGFR and mGFR seen in many of these studies, it is questionable whether such correlations reflect a clinically useful agreement between eGFR and mGFR in different patient populations, which most often they do not. In this context, it is important to look at predictive performance of different equations, that is, absolute bias, relative bias and accuracy, as suggested in the KDOQI guidelines.
Serum Creatinine as a measure of Kidney function :
Serum creatinine is an unreliable marker of renal function in transplanted patients due to many factors:
Assessment of graft function is vital in the follow up of the renal transplant patients.
KDIGO recommended the use of serum creatinine-based GFR equations for the estimation of the renal graft function .
Exogenous markers as inulin clearance (the gold standard) is considered non practical being expensive and not available easily.
Needless to say that Serum creatinine is the most common to use in assessment of kidney functions as it’s available and cheap .Creatinine itself is an unreliable index for graft function as it varies according to age, sex, nutrition status, race, muscle bulk, moreover GFR can decline before the serum creatinine rise.
Creatinine-based equations include: the Modification of Diet in Renal Disease (MDRD), and Chronic Kidney Disease Epidemiology Collaboration (CKD- EPI) formula Cockcroft-Gault (CG) :
– Cockcroft Gault
Male :(140-age) x weight / 72x Sr.Cr
Female : GFR x0.85
The Cockcroft-Gault is simple but overestimates the GFR because creatinine is both filtered and secreted.
– MDRD (It is considered to be more accurate than Cockroft Gault)
Male GFR (mL/min/1.73 m²) = 175 × (Scr)-1.154 × (Age)-0.203 × (0.742 if female)
– CKD-EPI
GFR :141 × min(Scr/κ, 1)α × max(Scr/κ, 1)-1.209 × 0.993Age × 1.018 [if female] /1.159 if black.
CKD-EPI equation is recommended by the National Kidney Foundation (NKF).
Although Nankivell equation was used RTx patients but it’s said to be inaccurate as it was used only in the early phases on transplant. GFR (mL/minute) : 6.7/serum creatinine + 0.25 × weight – 0.5 × urea – 0.01 × height2 + 35(25 for woman).
Serum creatinine is the most widely used method to estimate renal function but it isn’t accurate way thats why it depends on variable factors like age,sex,race, muscle bulk and protein diet.
Many formulas now used like Cockcroft– Gault formula,MDRD and CKD EPI formula which considered the most accurate method to estimate renal function compared to the others
Glomerular filtration rate (GFR) in general is considered the best index for assessing renal function in transplant and non-transplant patients .the GFR measurement relied on measuring the clearance of a substance from the blood to estimate the excretory functions of the kidney.
The commonly used equations are:
1. MDRD: derived from patients with CKD, it under estimate GFR.1
2. CKD-EPI creatinine: derived from patients with GFR> 60.1
3. CKD-EPI cystatin c.1( some consider it of the same accuracy as creatinine based equation).
4. CKD-EPI creatinine+ cystatin c.1( more accurate than creatinine or cystatin c alone).
5. Cockcroft-Gault formula: creatinine was. require age, gender and weight.
regardless all these equations , they are not 100% accurate.
they have some disadvantages.
many factors contribute to reducing the accuracy of Serum Cr as an indicator of the GFR, including sex, age, race, muscle mass and dietary protein intake.
The gold standard for measuring GFR is clearance of inulin because it is freely filtered and not protein bound, and is not reabsorbed, secreted or metabolized by the kidney.
The gold standard method to assess GFR is through am measured GFR (mGFR) with the clearance of an exogenous ideal marker such as Inulin, Iothalamate or Iohexol but this is not feasible clinical practice as the technique is invasive and expensive for routine use. Thus alternative methods to assess GFR are used including several Cr based equations (Schaeffner, E .,2017).
1- Formulae to estimate GFR :
a- Cockcroft–Gault (CG) formula ;
Dependents on several variable as age, gender, weight, SCr
Limitations :over estimate Cr Cl in overweight patients ( either due to obesity or volume overload)
b- Modification of Diet in Renal Disease (MDRD) Study
Limitations :
· More accurate in patients with GFR < 60 mL/min/1.73 m
· Not validated in certain situations
old age , children and pregnant women
nonsteady states of kidney function as AKI
affected by race :more accurate in white and African American than other races.
Overestimate the GFR in critically ill , hospitalized patients.
c- CKD-EPI
Dependents on several variables including: age, gender, race, S Cr
Types:
CKD-EPI(creat): depends on SCr-alone
CKD-EPI(cys) ; depends on cystatin C (cys) alone
CKD-EPI(creat-cys) includes both SCr and cystatin C (The most accurate one) .
d- Full age spectrum (FAS)
Advantages : It is valid even in patients with e GFR > 60 mL/min.
Limitations of e GFR formulas
All are Less accurate in nonsteady state.
As all include S cr as a variable so their accuracy is affected by the presence of factors other than GFR that alter SCr levels
2- s Cr is not a very accurate marker for kidney function assessment as it is affected by several factors including:
a- Dietary intake of protein , malnutrition
b- Muscle mass and limb amputation
c- Volume status
d- Decrease in case of LCF due to decrease hepatic synthesis.
e- Small part is secreted by renal tubules (leads to overestimation of GFR).
GFR assessment in renal transplantation
As most of the previous equations were originally derived from non transplant population , so their performance in transplant population Is a matter of debate . Shaffi et al,2014 examined the performance of the CKD-EPI and MDRD Study equations in transplant recipients and concluded that were more accurate than the other alternative equations in transplant populations and were as accurate as observed in non transplanted populations (Masson I et al ).
For Cys C-based equations , these equations were not preffered in transplant patients as Cys C is increased secondary to corticosteroid therapy (Keddis, Mira T., et al).
So a better approach to assess GFR in transplant patients is through using combination of different bio markers of graft function as SCr, CyC, and albuminuria (Santos et al 2015 ).
Ref
Schaeffner, E. (2017). Determining the glomerular filtration rate—an overview. Journal of Renal Nutrition, 27(6), 375-380.
Masson I, Flamant M, Maillard N, Rule AD, Vrtovsnik F, Peraldi MN, Thibaudin L, Cavalier E, Vidal-Petiot E, Bonneau C, Moranne O, Alamartine E, Mariat C, Delanaye P. MDRD versus CKD-EPI equation to estimate glomerular filtration rate in kidney transplant recipients. Transplantation 2013; 95: 1211-1217 [PMID: 23511243 DOI: 10.1097/tp.0b013e318288caa6]
Keddis, Mira T., et al. “Creatinine–Based and Cystatin C–Based GFR Estimating Equations and Their Non-GFR Determinants in Kidney Transplant Recipients.” Clinical Journal of the American Society of Nephrology 11.9 (2016): 1640-1649.
What is the current recommended method for estimating GFR?
– The Cockcroft-Gault formula
– The MDRD Study equation
The MDRD Study equation, which has four variables, was developed in 1999 using data from 1628 CKD patients with GFRs ranging from 5 to 90 milliliters per minute per 1.
Creatinine clearance is more accurate than creatinine clearance estimated using the Cockcroft-Gault algorithm or determined from test urine samples given over 24 hours.
– The CKD-EPI equation (Chronic Kidney Disease Epidemiology Collaboration) The CKD-EPI equation, which uses serum creatinine, age, gender, and race to compute GFR, was developed in 2009.
The CKD-EPI equation is equally accurate as the MDRD Study equation in the subgroup with estimated GFR less than 60 mL/min/1. 73 m2, and substantially more accurate in the subgroup with estimated GFR greater than 60 mL/min/1. 73 m2.
– Injecting inulin and monitoring its clearance by the kidneys is the gold standard for assessing GFR. GFR is commonly calculated using the biochemical marker creatinine, which can be detected in both serum and urine.
Creatinine clearance is the amount of creatinine removed from blood plasma per unit of time. Both CrCl and GFR can be determined by comparing creatinine levels in blood and urine.
– S-Cys C is also used in several equations, either alone or in combination with S-Cr.
– The eGFR formulas based on S-Cr are only valid in steady-state circumstances.-
– Serum creatinine is an incorrect indicator of renal function in transplanted patients due to a multitude of factors, including the catabolic state present in chronic disease, starvation, weight shift caused by muscle atrophy, and fluid overload.
References:
– https://www.kidney.org/sites/default/files/12-10-4004_FAQ-ABE.pdf
– Shahbaz, H. and Gupta, M., 2019. Creatinine clearance . available at : https://www.ncbi.nlm.nih.gov/books/NBK544228/ (Accessed 3/11/2021)
– Naicker, J., 2012. Glomerular filtration rate (GFR) and estimation of the GFR (eGFR) in adults. CME: Your SA Journal of CPD, 30(7), pp.235-237.Available at : file:///C:/Users/clinic3/Downloads/80192-Article%20Text-189418-1-10-20120817.pdf (Accessed 3/11/2021)
– Hornum, M. and Feldt-Rasmussen, B., 2017. Glomerular filtration rate estimation in renal and non-renal solid organ transplantation. Nephron, 136(4), pp.298-301.Available at : https://www.karger.com/Article/Fulltext/447673 (Accessed 3/11/2021)
Dear All
Why not to use Cystatin-C based formula routinely if there is some indication of being more accurate?
sir, reagents and clinical assays for cystatin c have had considerable differences over time,which has resulted in numerous cystatin c based eGFR equations with different coefficients to account for the variation in concentration measured.the lack of uniformity has made it difficult to reproduce data across various institutions.also caliberation changes by manufacturers is a concern over the past 10-20 years.siemens has come up with IFCC reference material and is now replacing non calibrated kits with IFCC calibrated cystatin c reagent kits which will bring about an uniformity in measurement of cystatin c across all labs.
There are some notes regarding the reliability of eGFR equations using cystatin C alone. First, substantial variation in the cystatin C assay has been observed, even when using the same instrument and the same reagent type by the same laboratory (1).
Although Cystatin C was expected initially to be stable in the serum with no effect of age, gender, muscle mass or ethnicity, several studies have documented variability in serum Cystatin C levels with age, gender, fat mass, diabetes, markers of inflammation, hypo- and hyperthyroidism (2).
References:
1) Inker LA, Eckfeldt J, Levey AS, et al. Expressing the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) cystatin C equations for estimating GFR with standardized serum cystatin C values. Am J Kidney Dis. 2011; 58(4): 682.
2) Lesley A Inker, Ronald D Perrone. Assessment of kidney function. (UpToDate 2021). (Accessed on 4 November 2021).
First it thought free of affect by muscle mass, nutition But prove its affected by DM, inflammation, thyroid hormone . Second there poor standraization of result in Different lab..
Sir
Cystatin C although more accurate, have considerable differences have been observed with age, gender, fat distribution, diabetes, inflammatory states, thyroid disorders, heart failure. Well standardized kits were not available till recently. There were wide variation in the reporting and the coefficients used in the equation. For validation, standardization is first needed which is fully yet to crystalize with cystatin C. Advantages are it is not affected by diet or muscle mass and it has been shown to predict AKI earlier and GFR better than creatinine
The biggest challenge is cost and standardization of assays. Due to higher cost and requirement of technical expertise, Cystatin C is not widely available.
With such limitations of Cr and Cystatin C, what is the possible approach? What about the guidelines? How you apply this knowledge to your local area of practice?
Serum creatinine being a cheaper test, can be used in routine and cystatin C can be used in conditions when there is a doubt in the diagnosis.
As per KDIGO guidelines for CKD, Cystatin C can be used in case of isolated decreased GFR in an otherwise healthy individual. Cystatin C based eGFR should be used in
a) patients with eGFR 45-59 ml/min/1.73 m2 in the absence of any other signs of CKD, for confirming the diagnosis of CKD
b) for organ donation
c) for dosage adjustment of drugs with renal excretion
Reference:
KDIGO 2012 Clinical Practice guideline for the evaluation and management of chronic kidney disease.
Because cystatin C levels fluctuate with changes in GFR, there has been interest in the cystatin C test as one method of evaluating kidney function.
●Although cystatin C is less variable and less affected by age, body mass& diet than creatinine in some individuals, it is not a perfect test and can be affected by a (( number of drugs)) and ((other medical conditions)))
I.e. Some studies have reported increased cystatin C levels associated with higher levels of (((CRP)) or (((BMI))),
Hyperthyroidism,
Steroid use,
m
Malignant diseases
HIV/AIDS
Rheumatic diseases
Certain metabolic conditions such as hyperhomocysteinemia (increased homocysteine).
●In addition, other studies suggest that cystatin C can be cleared by non- kidney pathways, such as in the gut, and that its levels tend to fluctuate among patients with kidney transplants.
What is the current recommended method for estimating GFR?
-The Cockcroft-Gault formula
The Cockcroft-Gault formula was developed in 1973 using data from 249 males with creatinine clearance (CCr) values ranging from 30 to 130 milliliters per square meter.
It is used to adjust the body’s surface area.
CCr=((140-age) x weight)/(72 SCr) x 0.85 if you’re a girl, where CCr is measured in milliliters per minute. SCr = serum creatinine in milligrams per deciliter, age (in years), weight (in kilograms), and SCr = serum creatinine in milligrams per deciliter
-The MDRD Study equation
The MDRD Study equation, which has four variables, was developed in 1999 using data from 1628 CKD patients with GFRs ranging from 5 to 90 milliliters per minute per 1.73 m2. It computes GFR after adjusting for body surface area.
Creatinine clearance is more accurate than creatinine clearance estimated using the Cockcroft-Gault algorithm or determined from test urine samples given over 24 hours.
– The CKD-EPI equation (Chronic Kidney Disease Epidemiology Collaboration)
The CKD-EPI equation, which uses serum creatinine, age, gender, and race to compute GFR, was developed in 2009. The CKD-EPI equation is equally accurate as the MDRD Study equation in the subgroup with estimated GFR less than 60 mL/min/1.73 m2, and substantially more accurate in the subgroup with estimated GFR greater than 60 mL/min/1.73 m2.
– Injecting inulin and monitoring its clearance by the kidneys is the gold standard for assessing GFR. Inulin treatment is a painful, time-consuming, and expensive procedure. GFR is commonly calculated using the biochemical marker creatinine, which can be detected in both serum and urine. Creatinine clearance is the amount of creatinine removed from blood plasma per unit of time (CrCl). It is a straightforward and low-cost method of measuring renal function. Both CrCl and GFR can be determined by comparing creatinine levels in blood and urine.
– S-Cys C is also used in several equations, either alone or in combination with S-Cr. It will be interesting to see if standardizing S-Cys C improves eGFR prediction equation accuracy. The eGFR formulas based on S-Cr are only valid in steady-state circumstances.
– Serum creatinine is an incorrect indicator of renal function in transplanted patients due to a multitude of factors, including the catabolic state present in chronic disease, starvation, weight shift caused by muscle atrophy, and fluid overload. Another important component is changes and swings in creatinine tubular secretion.
References:
– https://www.kidney.org/sites/default/files/12-10-4004_FAQ-ABE.pdf
– Shahbaz, H. and Gupta, M., 2019. Creatinine clearance . available at : https://www.ncbi.nlm.nih.gov/books/NBK544228/ (Accessed 3/11/2021)
– Naicker, J., 2012. Glomerular filtration rate (GFR) and estimation of the GFR (eGFR) in adults. CME: Your SA Journal of CPD, 30(7), pp.235-237.Available at : file:///C:/Users/clinic3/Downloads/80192-Article%20Text-189418-1-10-20120817.pdf (Accessed 3/11/2021)
– Hornum, M. and Feldt-Rasmussen, B., 2017. Glomerular filtration rate estimation in renal and non-renal solid organ transplantation. Nephron, 136(4), pp.298-301.Available at : https://www.karger.com/Article/Fulltext/447673 (Accessed 3/11/2021)
What is the current recommended method for estimating GFR?
– The Cockcroft-Gault formula
The Cockcroft-Gault formula was developed in 1973 using data from 249 males with creatinine clearance (CCr) values ranging from 30 to 130 milliliters per square meter.
It is used to adjust the body’s surface area.
CCr=((140-age) x weight)/(72 SCr) x 0.85 if you’re a girl, where CCr is measured in milliliters per minute. SCr = serum creatinine in milligrams per deciliter, age (in years), weight (in kilograms), and SCr = serum creatinine in milligrams per deciliter
– The MDRD Study equation
The MDRD Study equation, which has four variables, was developed in 1999 using data from 1628 CKD patients with GFRs ranging from 5 to 90 milliliters per minute per 1.73 m2. It computes GFR after adjusting for body surface area.
Creatinine clearance is more accurate than creatinine clearance estimated using the Cockcroft-Gault algorithm or determined from test urine samples given over 24 hours.
– The CKD-EPI equation (Chronic Kidney Disease Epidemiology Collaboration)
The CKD-EPI equation, which uses serum creatinine, age, gender, and race to compute GFR, was developed in 2009. The CKD-EPI equation is equally accurate as the MDRD Study equation in the subgroup with estimated GFR less than 60 mL/min/1.73 m2, and substantially more accurate in the subgroup with estimated GFR greater than 60 mL/min/1.73 m2.
– Injecting inulin and monitoring its clearance by the kidneys is the gold standard for assessing GFR. Inulin treatment is a painful, time-consuming, and expensive procedure. GFR is commonly calculated using the biochemical marker creatinine, which can be detected in both serum and urine. Creatinine clearance is the amount of creatinine removed from blood plasma per unit of time (CrCl). It is a straightforward and low-cost method of measuring renal function. Both CrCl and GFR can be determined by comparing creatinine levels in blood and urine.
– S-Cys C is also used in several equations, either alone or in combination with S-Cr. It will be interesting to see if standardizing S-Cys C improves eGFR prediction equation accuracy. The eGFR formulas based on S-Cr are only valid in steady-state circumstances.
– Serum creatinine is an incorrect indicator of renal function in transplanted patients due to a multitude of factors, including the catabolic state present in chronic disease, starvation, weight shift caused by muscle atrophy, and fluid overload. Another important component is changes and swings in creatinine tubular secretion.
References:
– https://www.kidney.org/sites/default/files/12-10-4004_FAQ-ABE.pdf
– Shahbaz, H. and Gupta, M., 2019. Creatinine clearance . available at : https://www.ncbi.nlm.nih.gov/books/NBK544228/ (Accessed 3/11/2021)
– Naicker, J., 2012. Glomerular filtration rate (GFR) and estimation of the GFR (eGFR) in adults. CME: Your SA Journal of CPD, 30(7), pp.235-237.Available at : file:///C:/Users/clinic3/Downloads/80192-Article%20Text-189418-1-10-20120817.pdf (Accessed 3/11/2021)
– Hornum, M. and Feldt-Rasmussen, B., 2017. Glomerular filtration rate estimation in renal and non-renal solid organ transplantation. Nephron, 136(4), pp.298-301.Available at : https://www.karger.com/Article/Fulltext/447673 (Accessed 3/11/2021)
For assessment of kidney function, we can utilize mGFR (measured GFR) or eGFR (estimated GFR) by applying different formula.
In some situations, we need more precise knowledge of the amount of GFR such as prior to kidney donation so in such situation measurement of GFR may be reasonable, although it is cumbersome.
For measuring GFR the ideal substance is that only freely filtrated at the glomeruli and is not metabolized, neither secreted nor reabsorbed by the tubules like exogenous filtration marker, inulin, that although meet almost all of these criteria but application of it in clinical setting is accompanied by some difficulties and limitations.
Alternative infiltration factors such as iothalamate, iohexol, DTPA are available. Although the application of them is with less cumbersome, they have own disadvantage that make use of them somehow unpractical.
For measuring GFR, we can use some endogenous filtration marker consist of serum Cr, cystatin C and urea (less accurate) that all of which have some limitation in application and interpretation.
Utilizing both measurement of Cr clearance and eGFR equations rely upon Cr as a marker of kidney function.
There is significant limitation for using serum Cr as a filtration marker for estimating GFR, including:
Increase in production of Cr either by consuming meat meal or increase muscle mass. Increase in serum Cr in other circumstances without any decline in kidney function like rhabdomyolysis make interpretation of serum Cr more difficult.
There is a fact that concordant with decline in kidney function, secretion of Cr increase in proximal tubule so in the early stages of kidney injury, despite significant decline in GFR, serum Cr doesn’t rise.
Nephrotic syndrome and sickle cell anemia also can increase Cr secretion
Taking some drugs such as trimethoprim can increase serum Cr level by competition in secretion as well.
Increased amount of extrarenal elimination of Cr in advanced kidney dysfunction and some technical issues in measurement of serum Cr by alkaline picrate method (for example artificially increase in serum Cr in diabetic ketoacidosis and hyperbilirubinemia) can make interpretation of serum Cr in different situations more complicated.
In kidney transplant recipients, in addition to the reviewed points, there are some other determinants that interfere with serum Cr metabolism such as corticosteroids which have direct metabolic effect and can change muscle mass ratio to the body weight, furthermore catabolic state such as infection or rejection can also be responsible for these interferences, and block of secretion of Cr by trimethoprim can play a role as well.
As you know when the process of kidney dysfunction progresses, the amount of secretion of Cr and reabsorption of urea increase, so it is suggested to use the average of clearance of urea and Cr in patients with CKD.
eGFR can be calculated with different formulas like Cockcroft Gault equation, MDRD equation, and CKD-EPI equation, which of Them have some advantage and disadvantage and can be used in different setting.
CKD-EPI equation is more accurate than MDRD equation, and both are more accurate than Cockcroft Gault equation.
In Cockcroft Gault equation, age, weight, and gender are considered. The result of this equation should be adjusted for body surface area (BSA).
Using Cockcroft Gault equation may lead to 10-40% overestimation of Cr clearance.
MDRD equation and CKD-EPI are a logarithmic equation and consider race in addition to age and gender.
Cockcroft Gault and MDRD equations are less accurate in obese patients and in individuals with normal or near normal GFR.
There are various results about accuracy of MDRD equation among recipient of allograft kidney in different studies. In spite of some limitation of MDRD equation, most experts use an abbreviated formula in this setting.
CKD-EPI equation develops to provide more accurate estimate of GFR in patients with normal or near normal GFR. In individuals with GFR<60 ml/min CKD-EPI equation is as accurate as MDRD equation in estimation of GFR, and overall CKD-EPI equations’ precision is not more than MDRD equation.
Accuracy of CKD-EPI equation as compared with MDRD equation may differ according to GFR and patient’s characteristic, for example it is more accurate in transplant status, older patients, diabetics, and obese patients but less accurate in patients with lower GFR.
CKD-EPI and MDRD equations are normalized to BSA.
Based upon various studies, it can be concluded CKD-EPI equation is more accurate than alternative equations in estimating GFR in kidney transplant recipients.
Other equation such as Lund Malmo Revised (LMR) and Full Age Spectrum (FAS) equations have been emerged.
In a one recent study, the performance of CKD-EPI, MDRD, and FAS equations was significantly lower than the LMR regard to the mean difference in bias.
Here are some points:
There is no exact correlation between loss of nephron number and decreasing in GFR because of compensatory mechanisms in remaining nephrons.
Endogenous filtration markers can only be utilized to estimate GFR in stable kidney function situation.
In situations that we have limitation in using serum Cr as filtration marker such as in patients with unusual body mass (morbid obesity, amputees), pregnant women, we can use cystatin C-base equation or combined Cr- cystatin C equation for confirmation.
More over Cystatin C-base equation may be more accurate in special setting such as kidney transplantation, but the results of studies are controversial. In addition, steroid use may affect cystatin C level in kidney transplant recipients and may estimate GFR more than actual.
GFR is the best index of kidney function as well, the long-term graft survival and the risk of cardiovascular mortality, which is the primary cause of death in kidney transplant recipients. The complications related to renal function loss like hypertension, anemia, and MBD increase as the GFR decline. In addition, the decline in GFR is going with increased health care costs. So accurate determination of GFR is crucial.
1-measured GFR (m GFR)
mGFR done by using exogenous markers, such as inulin clearance, which is the gold standard but expensive.
other exogenous markers such as radiolabeled isotopes (51Cr EDTA, 99mTc DTPA, or 125I Iothalamate) and non-radioactive contrast agents (Iothalamate or Iohexol), are difficult, expensive, and rarely used in clinical practice.
2- estimated GFR (e GFR)
Endogenous markers, such as serum creatinine (SCr) or cystatin C (CyC), are used to estimate kidney function. These markers are adjusted to demographic variables in mathematic equations in an attempt to increase their accuracy.
The substance used to measure GFR needs to be freely filtered through the glomeruli and neither reabsorbed nor metabolized
SCr
It is the end product of muscle protein, and dietary meat, released to circulation at a constant rate, and freely filtered through the glomeruli but, secreted through the renal tubules.
Tubular secretion normally represents about 10% of renal Cr removal, this increases when GFR decreases, as a result, SCr remains within the normal range until GFR decreases below 60-70
· multiple factors contribute to reducing the accuracy of SCr as an indicator of the GFR, including sex, age, race, muscle mass, and dietary protein intake. Drugs like cimitedine, chr rejection, and tubular necrosis
The relation between scr and GFR is not linear as an initial rise in scr reflects marked change in GFR and marked rise in scr with advanced disease reflects only a small absolute reduction in GFR. so GFR can decrease to half the normal value before the SCR increases. That can lead to the failure of early detection of subclinical progressive damage, such as calcineurin toxicity and rejection. Many studies revealed that the SCR and GFR were hardly correlated.
Cysteine C
CyC is a protein that is an inhibitor of lysosomal cysteine proteinases. Its actions include extracellular proteolysis, immune modulation, and antimicrobial activities.
It has a constant production rate, free glomerular filtration, neither reabsorbed nor tubular secreted. S. CyC level correlates with GFR better than sCr, especially at higher levels of GFR. Also, it is less affected by certain demographic factors as compared with SCr.
Smoking, high serum C-reactive protein, weight, height, thyroid disease, steroid use as in transplant patients are independently affect the S CyC level. it is costly and unavailable in many centers
· Creatinine clearance(Ccr): UV/P ( U=Urine Cr / V = volume of urine in 24 hrs/ P plasma Cr)
The Ccr overestimates the GFR due to tubular secretion of Cr. In addition to errors in urine collection
Measurement of GFR by this method may become more reliable after administration of the cimetidine, which inhibits tubular secretion. Although it does not give additional information about the renal function than other methods.
Equations to measure GFR
Creatinine based formulae:
· Modification of Diet in Renal Disease (MDRD)
· Cockcroft-Gault
· chronic kidney disease epidemiology collaboration (CKD-EPI)
CKD-EPI equation showed better performance at higher GFRs compared with better performance of MDRD Study equation at lower GFRs
Cysteine C based formulae
There are two formulae (RULE and Le Bricon equations)
The majority of the CyC –based equation exhibited 30% and 50% accuracy improvements as compared to Cr-based MDRD equation.
CyC level affected by Steroid used in the transplant patients.
KDIGO still do not support the regular clinical use of CyC based formula, due to paucity of validated studied in these patients.
Many studies reveal that cyC and cyC-based equations predicted motality and graft outcome better than Cr-based eGFR
Reference:
Santos J, Martins LS. Estimating glomerular filtration rate in kidney transplantation: Still searching for the best marker. World J Nephrol [Internet]. 2015 Jul 6;4(3):345–53. Available from: https://pubmed.ncbi.nlm.nih.gov/26167457
Assessment of glomerular filtration rate (GFR) is essential in the follow-up of kidney transplanted patients. There are many equations used for the assessment of GFR, some of them depend on creatinine which is affected by muscle mass, GFR, trimethoprim, and ingestion of protein.
The formula for eGFR:
1. Modification of diet in renal disease (MDRD): it underestimates GFR in a population with higher GFR.
2. Chronic kidney disease –Epidemiology collaboration(CKD-EPI): it is more accurate at eGFR in the population of higher GFR than MDRD.
3. Cockcroft-Gault equation: it overestimates GFR in an obese and edematous patient.
Inulin is considered a gold stander filtration marker but it is expensive and time-consuming, so is commonly used in research.
When GFR reduce it take time for creatinine to increase; so serum creatinine may be normal with severe kidney damage
As elaporated by my colleagues, these equations are used to monitor kidney functions among transplant patients.
Although not highly accurate, they are convenient and avilable, not like isotopic tracers and other markers as inulin.
Cockcroft Gault formula is a measurement of creatinine clearance, not an estimations as MRDR,CKD-EPI equations.
Thanks, Mahmoud
I’m pleased that you have read your colleagues replies and responded.
Currently recommended method to estimate GFR?
– The Cockcroft-Gault formula
In 1973, the Cockcroft-Gault formula was created using data from 249 males with creatinine clearance (CCr) ranging from 30 to 130 milliliters per square meter
It is for body surface area adjustment
If you’re a girl, CCr=((140-age) x weight)/(72 SCr) x 0.85, where CCr is measured in milliliters per minute. age (in years), weight (in kilos), and SCr = serum creatinine in milligrams per deciliter
– the MDRD Study equation
The MDRD Study equation, which has four variables, was constructed in 1999 using data from 1628 individuals with CKD with GFRs ranging from 5 to 90 milliliters per minute per 1.73 m2. It calculates GFR has been adjusted for body surface area .
Creatinine clearance is more accurate than measured creatinine clearance from a test urine samples taken over 24 hours or calculated using the Cockcroft-Gault algorithm.
– the CKD-EPI equation (Chronic Kidney Disease Epidemiology Collaboration)
In 2009, the CKD-EPI equation was created to calculate GFR using serum creatinine, age, gender, and race. In the subgroup with estimated GFR less than 60 mL/min/1.73 m2, the CKD-EPI equation is equally accurate as the MDRD Study equation, and much more accurate in the subgroup with estimated GFR more than 60 mL/min/1.73 m2.
– The gold standard for determining GFR is to inject inulin and monitor its clearance by the kidneys. Inulin therapy is an invasive, time-consuming, and costly operation. Alternatively, the biochemical marker creatinine, which can be found in both serum and urine, is frequently used to calculate GFR. The volume of blood plasma cleared of creatinine per unit time is known as creatinine clearance (CrCl). It is a simple and inexpensive approach for determining renal function. The comparative levels of creatinine in blood and urine can be used to determine both CrCl and GFR.
– There are also certain equations that use S-Cys C, either alone or in combination with S-Cr. It will be interesting to observe if standardizing S-Cys C increases the accuracy of eGFR prediction equations. The S-Cr-based eGFR formulae are only valid in steady-state situations.
– Due to a variety of circumstances, including the catabolic condition found in chronic disease, malnutrition, weight shift generated by muscle wasting, and fluid overload, serum creatinine is an inaccurate index of renal function in transplanted patients. Changes and fluctuations in creatinine tubular secretion are another crucial factor.
References:
– https://www.kidney.org/sites/default/files/12-10-4004_FAQ-ABE.pdf
– Shahbaz, H. and Gupta, M., 2019. Creatinine clearance . available at : https://www.ncbi.nlm.nih.gov/books/NBK544228/ (Accessed 3/11/2021)
– Naicker, J., 2012. Glomerular filtration rate (GFR) and estimation of the GFR (eGFR) in adults. CME: Your SA Journal of CPD, 30(7), pp.235-237.Available at : file:///C:/Users/clinic3/Downloads/80192-Article%20Text-189418-1-10-20120817.pdf (Accessed 3/11/2021)
– Hornum, M. and Feldt-Rasmussen, B., 2017. Glomerular filtration rate estimation in renal and non-renal solid organ transplantation. Nephron, 136(4), pp.298-301.Available at : https://www.karger.com/Article/Fulltext/447673 (Accessed 3/11/2021)
The gold standard method to assess GFR is through am measured GFR (mGFR) with the clearance of an exogenous ideal marker such as Inulin, Iothalamate or Iohexol but this is not feasible clinical practice as the technique is invasive and expensive for routine use. Thus alternative methods to assess GFR are used including several Cr based equations (Schaeffner, E .,2017).
1- Formulae to estimate GFR :
a- Cockcroft–Gault (CG) formula ;
Dependents on several variable as age, gender, weight, SCr
Limitations :over estimate Cr Cl in overweight patients ( either due to obesity or volume overload)
b- Modification of Diet in Renal Disease (MDRD) Study
Limitations :
· More accurate in patients with GFR < 60 mL/min/1.73 m
· Not validated in certain situations
old age , children and pregnant women
nonsteady states of kidney function as AKI
affected by race :more accurate in white and African American than other races.
Overestimate the GFR in critically ill , hospitalized patients.
c- CKD-EPI
Dependents on several variables including: age, gender, race, S Cr
Types:
CKD-EPI(creat): depends on SCr-alone
CKD-EPI(cys) ; depends on cystatin C (cys) alone
CKD-EPI(creat-cys) includes both SCr and cystatin C (The most accurate one) .
d- Full age spectrum (FAS)
Advantages : It is valid even in patients with e GFR > 60 mL/min.
Limitations of e GFR formulas
All are Less accurate in nonsteady state.
As all include S cr as a variable so their accuracy is affected by the presence of factors other than GFR that alter SCr levels
2- s Cr is not a very accurate marker for kidney function assessment as it is affected by several factors including:
a- Dietary intake of protein , malnutrition
b- Muscle mass and limb amputation
c- Volume status
d- Decrease in case of LCF due to decrease hepatic synthesis.
e- Small part is secreted by renal tubules (leads to overestimation of GFR).
GFR assessment in renal transplantation
As most of the previous equations were originally derived from non transplant population , so their performance in transplant population Is a matter of debate . Shaffi et al,2014 examined the performance of the CKD-EPI and MDRD Study equations in transplant recipients and concluded that were more accurate than the other alternative equations in transplant populations and were as accurate as observed in non transplanted populations (Masson I et al ).
For Cys C-based equations , these equations were not preffered in transplant patients as Cys C is increased secondary to corticosteroid therapy (Keddis, Mira T., et al).
So a better approach to assess GFR in transplant patients is through using combination of different bio markers of graft function as SCr, CyC, and albuminuria (Santos et al 2015 ).
Ref
Schaeffner, E. (2017). Determining the glomerular filtration rate—an overview. Journal of Renal Nutrition, 27(6), 375-380.
Masson I, Flamant M, Maillard N, Rule AD, Vrtovsnik F, Peraldi MN, Thibaudin L, Cavalier E, Vidal-Petiot E, Bonneau C, Moranne O, Alamartine E, Mariat C, Delanaye P. MDRD versus CKD-EPI equation to estimate glomerular filtration rate in kidney transplant recipients. Transplantation 2013; 95: 1211-1217 [PMID: 23511243 DOI: 10.1097/tp.0b013e318288caa6]
Keddis, Mira T., et al. “Creatinine–Based and Cystatin C–Based GFR Estimating Equations and Their Non-GFR Determinants in Kidney Transplant Recipients.” Clinical Journal of the American Society of Nephrology 11.9 (2016): 1640-1649.
1)The re-expressed MDRD equation and the CKD-EPI equation,CG equation were developed to estimate GFR in non-transplant ckd patients whereas the Nankivell equation was created to estimate GFR in transplant patients.in a study done in Thailand among the various equations which are derived mainly from Caucasian and/or non-transplant status,the CKD-EPI had the least bias compared with other eGFR equations and reference GFR measured by 99mTc-DTPA plasma clearance.
Clin Nephrol2013 Mar;79(3):206-13. doi: 10.5414/CN107662
2)Serum creatinine is affected by large no of conditions affecting its non-GFR determinants like muscle mass which is dependant on age,gender,race,nutritional status,dietary protein ingestion.Hence there is wide range of GFR for a given serum creatinine level,for ex a sr creatinine 0f 1.5mg/dl may correspond to a GFR from approximately 20 to 90 ml/min/1.73m2.
3)Serum creatinine is determined by IDMS reference enzymatic methods,using which eGFR is estimated using various equations like CKD-EPI,MDRD,CG and then validated against a reference standard like inulin clearance or 99mTc-DTPA which gives measured GFR using statistical analysis.
4)CG equation is
a not precise especially for GFR range above 60ml/min
b it estimates Clcr rather than GFR and thus overestimates GFR
c CG equation was derived by older asssay methods for serum creatinine,which cannot be calibrated to newer assay methods leading to bias
d it overestimates Clcr in edematous or obese patients
e all older adults will have lower levels of estimated GFR calculated by CG equation.CKD-EPI equation is the best predictor of GFR in indian population
5) advantages
measuring GFR by exogenous markers is cumbersome,labour intensive,costly while estimating GFR by equations is easy with readily available calculators
disadvantages
since egfr equations are based on creatinine which is affected by many conditions. also these equations have been validated in caucasian population and caucasian ckd patients and there is limited data on its performance in other ethnic population.
At a constant creatinine generation rate of 60mg/hr and complete cessation of CrCl,the time required to reach a steady state is 14hrs when baseline Scr is 2.0, and 7hrs when baseline Scr is 1mg/dl
J Am Soc Nephrol. 2009 Mar; 20(3): 672–679.
GFR is used for measuring the average filtration rate of the filtering unit of the kidneys (the nephron) normal GFR level is approximately 130ml/min/1.73m² for men and 120 ml/ min/ m² for women, many factors affecting GFR such as sex age (over the age of 40 there is decline in GFR by 0.75 ml/min/year) ,body surface area, diet ,physical activity,drugs and physical state(like pregnancy and diabetes) .
GFR measured by using exogenous or endogenous markers so it cannot be measured directly .
Regarding exogenous markers solute used should be less than 20000 dalton’s molecular weight ,not bound to plasma proteins and freely filtered by the glomeruli such as inulin,lothalamate,Tc_DTPA ,Cr_EDTA and loxol.
Endogenous markers are substances generated inside the body with low molecular weight such as urea creatinine and nystatin C
GFR equations :
Cockcroft _Gault (CG)
Based on creatinine and affected by tubular secretion, extrarenal elimination and rate of creatinine production
MDRD
Most commonly used for CKD classification, tends to be underestimate GFR and still less accurate in old age and children groups, pregnancy and ethnic group.
CKD_EPI
Used for normal or near normal GFR
Overestimate GFR .
As all agree the handicap of using creatinine as a marker for renal function is being influenced by multiple factors mainly body mass. May be adjusted in formulae consşdering age but still we have some considerations in special situations like being very cachectic etc.
İn patients considered for renal transplantation as donors still CDK-epi is considered but should be followed by a 24-hour collection for clearance though this işs another issue
Patients already transplanted have some considerations in addition to standards mentioned (like body mass etc) being on some medications like Bactrim for a period of time. Having acei and ARB medications.
İn the article published in 2013(The validation of estimated glomerular filtration rate (eGFR) equation for DOI: 10.5414/CN107662) CKD-EPI did not Show superiority over mdrd when confirmed in the aspect of being near to the true GFR measured by TDPA 64% vs 74%.İnulin in impractical because it is not commercially available. Nuclear measures are good but for special cases especially when we need differential GFR measurement before transplantation or in the case of atrophic kidneys to help the decision.Cocroft gault, MDRD and CDK-epi cr are the most used . in the era of mobile applications, we mostly use ckd -epi with creatinine version as cystatin c though may be available in some centers it is sent to distatnt labs and results in some centers are late to consider . in paper published in 2004 ( DOI: 10.1111/j.1523-1755.2004.00517.x) crp cigarette smoking and age were shown as independent factors increasing cystatin c levels.
The main difference between mdrd , CKD-EPI in regard to the Cockroft gault formula is the weight being part of the latter.
Most laboratories integrate mdrd in their system. Some have both. İt is important to know which formüle is that based on.
CKD-EPI was shown to be more accurate in the case of high GFR (10.3748/wjg.v17.i40.4532)
The determination of GFR level is important in the follow up of kidney transplanted patients and in the pre-operative evaluation of kidney donors.
Serum creatinine was used as a marker for GFR but it has many disadvantages: it’s concentration is changed with age, sex, weight, muscle mass, it’s excreted by the tubules and certain drugs which blocks it’s tubular secretion can lead to elevated serum creatinine without changing the actual GFR.
The GFR can be measured or can be estimated.
Measured GFR can be calculated through measuring the clearance of Exogenous substances ( Inulin , Iothalamate, Cr-EDTA, Iohexol, Tc-DTPA) or Endogenous substances (creatinine, cystatine, urea ) .
Inulin clearance is regarded as the gold standard test for measuring GFR, but it’s uses in clinical practice is limited due to the need for continuous infusion and it’s cost.
Creatinine clearance can be measured by measuring serum creatinine and 24 hour urine volume and creatinine. Cr clearance overestimates GFR because creatinine is excreted by the tubules.
There are many equations used for estimating GFR :
Kidney transplantation is the choice `of treatment in advance CKD or ESRD. Graf function evaluation is important in management of renal transplant. Measurement of renal a allograft function has been using GFR as the best index of overall of kidney function although it is still a topic of debate.
As we know eGFR can be measured using exogenous and endogenous markers. Laborious markers such as insulin clearance ( gold standard ), radiolabeled isotopes ( 51 Cr. EDTA , 99Tc DTPA or 125 I Iothalamate) and non radio radioactive ( Iothalamate or Iohexol) are being too experimental and rarely practical to use in daily practises.
Endogenous markers are still preferred as its cheap and easily measured in daily practise. Examples of endogenous markers are Serum Creatinine and Cystatin C
An interesting article by Jamal Saleh from king Saud University which measured the accuracy and precision of the CKD EPI and MDRD predictive equations compared with glomerular filtration rate and measured by insulin clearance in Saudi population. This study compared 31 participants (23 CKD and 8 transplanted patients). The study showed that CKD-EPI has shown to be more accurate than other predictive equations. The study also reported that CKD-EPI cystatin C and creatinine equation had maximum bias compared with CKD-EPI and MDRD.in transplanted patients, CKD EPI showed superiority by accuracy when compared with MDRD. It is closer to measured GFR by inulin. This finding has been supported by study by White et al.
Another study by Levey et al showed that CKD -EPI creatinine was more accurate and less bias compared to urinary clearance by ionathalamate.
Cater et al estimated GFR in UK adult populations reported that a higher eGFR by CKD EPI, mostly seen among 18-59 years old as compared to MDRD.
Lujan et al found that MDRD equation predicts lower GFR than CKD EPI creatinine in a comparison of 85 living kidney donors using non radiolabeled Iothalamate clearance.
Serum creatinine is the most commonly used marker for estimation of kidney function. As we know creatinine is a b real down of creatinephosphate in muscle tissue depending on muscle mass, and filtered in the glomerulus and it’s actively in the proximal tubule. Serum creatinine might incorporated from diet,altered by sex age , race dan muscle mass.
In renal transplantation, there are more determinants that may alter the creatinine metabolism. Steroid has direct direct catabolism effect and may cause muscle mass ratio to body weight. Medications such as trimethoprim, prophylaxis used in kidney transplantation may block the Creatinine tubular secretions.
The GFR is the best method to asses the overall kidney functions ,is a determinant of long term graft survival and is thought to be independent risk factor for the cardiovascular mortality (which is main cause of death in transplant patients
GFR is measured using exogenous and endogenous markers
Exogenous markers as inulin clearance ( the gold standard ) radiolabeled isotopes and non radioactive contrast agents , all are considered non practical as they are expensive and not available.
Endogenous markers including serum creatinine and Cystatic C are more practically used in estimation of glomerular filtration, being incorporated in mathematical formulas , to increase accuracy of estimation
Serum creatinine is the most common to use in assessment of kidney functions being available and cheap , however many limitations exist making it less useful in accurate estimation of GFR .
serum creatinine and CrCl are not sensitive measures of kidney damage, for many reasons:-
1)significant renal damage can take place before any decrease in the GFR occurs.
2) great reduction in the GFR may lead to only minimal elevation in serum creatinine . Because of compensatory hypertrophy and hyperfiltration of the remaining healthy nephrons.
Many factors can affect creatinine levels including Age ,sex, muscle mass, dietary protein intake as well as tubular secretion of creatinine which contributes to 10% to creatinine removal, which increases more when GFR declines ,leading to constant creatinine levels until GFR below 60 ml/min , which may lead to irreversible kidney damage before creatinine levels start to rise .
To overcome the limitations of serum creatinine as an indicator of kidney functions, several formulas were constructed , including:-
1) Cockcroft Gault
Male (140-age) x weight / 72x Sr.Cr
Female : GFR x0.85
2) MDRD
Male GFR (mL/min/1.73 m²) = 175 × (Scr)-1.154 × (Age)-0.203 × (0.742 if female) × (1.212 if African American) (conventional units)
It is considered to be more accurate than Cockroft Gault , as creatinine alone can’t detect early declines is GFR .
The 2 above formulas have limitations: the Cockcroft-Gault is simple to use but unfortunately overestimates the GFR by 10-15% because creatinine is both filtered and secreted.
The MDRD is a very complex equation can’t be calculated manually and has been found to underestimate GFR by 6.2% in patients with CKD and by 29% in healthy persons.
A 3rd formula, the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration)
equation, GFR = 141 × min(Scr/κ, 1)α × max(Scr/κ, 1)-1.209 × 0.993Age × 1.018 [if female] _ 1.159 [if black].
It is used to overcome the underestimated GFR obtained from MDRD formula in patients with relatively preserved kidney functions .
Only 4% of the derivation cohort was transplant patients.
The National Kidney Foundation (NKF) recommends using the CKD-EPI equation to estimate GFR
Nankivell equation GFR (mL/minute) = 6.7/serum creatinine + 0.25 × weight – 0.5 × urea – 0.01 × height2 + 35(25 for woman).
Is the only one that was obtained from transplant patients , but most of them were in early post transplant phase and with acute dysfunctions , making it not accurate in determination of GFR
Although accuracy of these equations in transplant patients was not studied enough , yet KDIGO stated that creatinine based equations should be used in daily management of the transplant patients to evaluate renal functions
Assessment of graft function is very important in the follow up of the renal trans-plant patients
Kidney Disease Improving Global Outcomes Initiative (KDOQI) guideline recommends the use of serum creatinine-based GFR equations to estimate kidney function in the routine clinical care of kidney transplant recipients.
At present, there is no standard equation to accurately measure the GFR in this population. The commonly used creatinine-based equations in both chronic kidney disease (CKD) and kidney transplant patients are Cockcroft-Gault (CG), Modification of Diet in Renal Disease (MDRD), and Chronic Kidney Disease Epidemiology Collaboration (CKD- EPI) formula. But
serum creatinine itself is unreliable index of graft function as it is depended on various patients’ factors such as age, sex, nutrition status, race, muscle bulk, and immobility and affected by certain medications such as trimethoprime also GFR can decline to approximately half the normal value before the serum creatinine rises above the reference range.
CG was derived from normal kidney function population taking into consideration the patient’s serum creatinine, age, and weight so CG tends to overestimate GFR in obese or edematous patients. Whereas the MDRD was derived from CKD population and adjusted to the body surface area. CKD-EPI formula was derived from the MDRD introduces a “correction” for patients with lower creatinine values. It is as accurate as MDRD in estimating GFR in patients with GFR <60 mL/min/1.73 m2 and better than MDRD at estimating higher GFR. On the other hand, the Nankivell equation was derived from an Australian-Caucasian kidney transplant recipients who treated with calcineurin inhibitors. Studies showed that CG, MDRD, and Nankivell equation fared only 73%, 76%, and 68%, respectively and all three equations demonstrates a progressive decrease in GFR overestimation and/or increase in GFR underestimation as the graft function improved.
These equations are also insensitive to the detection of mild-to-moderate reductions in GFR and the available equations also have poor sensitivity at detecting changes in GFR over time in renal transplant patients. But still Both CKD-EPI and MDRD had the best accuracy
In 2017 Cathtin L etal published a
new equation, estimated GFR (eGFR) = 991.15 × (1.120sex/([age0.097] × [cystatin C0.306] × [creatinine0.527]); where sex is denoted: 0, female; 1, male, demonstrating a better accuracy with a low bias as well as good precision compared with reference equations. Trimethoprim did not influence the performance of the new equation.
I agree with my colleagues, Several equations are based on creatinine which is affected by muscle mass and ingestion of protein or creatine. Plasma creatinine is also somewhat limited as a marker for GFR since it is subjected to a degree of tubular secretion.
The endogenous protein cystatin C has also been used as a marker for renal function with the advantage that it is less dependent on muscular mass.
The CKD-EPI creatinine and the MDRD Study equations perform better than the alternative creatinine-based estimating equations in solid-organ transplant recipients. They can be used for clinical management.
however, CKD-EPI has shown to be more reliable than MDRD or Ccroft-Gault equations
Also, there are new eGFR equations such as CKD-EPI-Cystatin C and CKD-EPI creatinine-Cystatin C equations which have shown improvement in accuracy of determining GFR but are still uncertain about its correlation to clinical significance and cost-effectiveness
The normal serum creatinine reference interval does not necessarily reflect a normal GFR for a patient. Because mild and moderate kidney injury is poorly inferred from serum creatinine alone. Limitations of using creatinine — There are several key limitations of using creatinine to estimate GFR. These include variations in creatinine production, variations in creatinine secretion, extrarenal creatinine excretion, and issues associated with creatinine measurement.
An estimated GFR (eGFR) calculated from serum creatinine using an isotope dilution mass spectrometry (IDMS) traceable equation is a simple and effective way in which laboratories can help health care providers detect CKD among those with risk factors; diabetes, hypertension, cardiovascular disease, or family history of kidney disease.
Assessment of kidney function through eGFR is essential once albuminuria is discovered and inpatient with a kidney transplant.
The Modification of Diet in Renal Disease (MDRD) Study equation and the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation are the most widely used IDMS traceable equations for estimating GFR in patients age 18 and over. For estimating GFR from serum creatinine in patients under age 18 (including infants, toddlers, children, and teens), the Bedside Schwartz equation should be used.
Direct comparison of the MDRD and CKD-EPI equations to other equations such as Cockcroft-Gault and to creatinine clearance measured from 24-hour urine collections, has demonstrated this superiority.
Note that creatinine clearance should be considered for assessing kidney function when the patient’s basal creatinine production is very abnormal. This may be the case with patients of extreme body size or muscle mass (e.g., obese, severely malnourished, amputees, paraplegics, or other muscle-wasting diseases), or with unusual dietary intake (e.g., vegetarian, creatine supplements).
Both measurements of the creatinine clearance and estimation equations rely upon creatinine as a marker of kidney function. Other markers of kidney function include the blood urea nitrogen (BUN), which is less useful than the serum creatinine, and serum cystatin C
Thank you All
I’m impressed with the excellent contributions. Well done
Please see my question about the time required for creating to reach a steady-state posted above.
The time required to reach a steady-state is 72 hours