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Plasma creatinine and the estimation of glomerular filtration rate (GFR)
R Neil DaltonWellChild Laboratory
King’s College London/ Guy’s Hospital
ACB South West & Wessex Region Scientific MeetingSalisbury, 4th July 2006
Glomerular Filtration Rate
Why the sudden interest in estimating GFR from plasma creatinine?
Final realisation that a plasma creatinine normal range is meaningless
Conceptual difficulty relating plasma creatinine to GFRFormulae attempting to fix the problem - eGFR
eGFR routine in paediatric nephrology for nearly 30y
The Glomerulus
Glomerular Filtration Rate
fundamental to:diagnosis of kidney disease
early detectionstratification
monitoring the progression of kidney diseaseprognosisefficacy of treatmentfacilitate timing of therapeutic interventions
drug dosageelimination of drugs/drug metabolites by the kidney
Glomerular Filtration Rate
Glomerular filtration rate (GFR) is the clearance, by the kidney, of a marker in plasma, expressed as the volume of plasma completely cleared of the marker per unit time
UV ml/min
P .
Requires accurately timed urine collection!
Glomerular Filtration Rate
The ideal marker is endogenous, freely filtered by
the glomerulus, neither reabsorbed nor secreted by the kidney tubule, and eliminated only by the kidney
No ideal marker described!
Defined using exogenous markers,primarily inulin
Glomerular Filtration Rate
Hence, formal measurement of GFR rarely performed
Difficult!
Reliable?
Logistics of test performance
Radiochemical/biochemical tracer analysis
Failure to appreciate the clinical importance
Glomerular Filtration Rate
Clinical importance
Detection of kidney disease
Cardiovascular risk
Glomerular Filtration Rate
Compromise:24h creatinine clearance
Ucr * VPcr
All the hassle and responsibility on the patientAs a result unreliable
Problem of tubular secretion of creatinine
Glomerular Filtration Rate
Measurement of GFR in children with type 1 diabetes
Clearance Diabetics (n=11) Controls (n=12)ml/min/1.73m2 ml/min/1.73m2
Inulin 126 + 34 112 + 13Creatinine 172 + 45 (137%) 145 + 16 (129%)51Cr-EDTA 116 + 30 (92%) 104 + 13 (93%)
Diabetics, median age 13.9y (5.5-19.3)Controls, median age 21.0y (16.2-34.0)
Glomerular Filtration Rate
Further compromise:
24h creatinine clearance
Ucr * V
Pcr
Therefore,
creatinine clearance 1/Pcr
Only need to measure plasma creatinine!
Glomerular Filtration Rate
Basics
As GFR declines, the elimination of a metabolite that relies on clearance by the kidney, e.g. creatinine, is
maintained by increases in its plasma concentration
Glomerular Filtration Rate
As kidney function declines urine creatinine excretion remains the same
i.e. creatinine excretion is independent of kidney function
creatinine clearance = (Ucr x V)/Pcr ml/min
Implies: creatinine clearance x Pcr = Uc rx VCcr Pcr Ucr x Vml/min µmol/l µmol/min
Subject A 120 70 8.4
Subject B 60 140 8.4
Subject C 30 280 8.4
Serum creatinine v inulin clearanceShemesh O et al, Kidney International, 1985
predicted creatinine
Glomerular Filtration Rate
Plasma creatinine determined by:GFRsecretion by kidney tubulesproduction rate
children the worst case – increasing production rate with age and anabolic growth
spurtsValuable demonstration of estimating GFR from plasma
creatinine
Glomerular Filtration RatePlasma creatinine v Inutest GFR in children
Glomerular Filtration Rate
creatinine clearance 1/Pcr
Glomerular Filtration Rate1/Pcr v Inutest GFR in children
y = 0.0224x - 0.006
R2 = 0.6557
0.00
0.50
1.00
1.50
2.00
2.50
3.00
0 20 40 60 80 100 120 140 160
GFR (ml/min/1.73m2)
1/cr
eatin
ine
(l/µm
ol)
Glomerular Filtration Rate
creatinine clearance 1/Pcr
creatinine clearance = k/Pcr
Glomerular Filtration Rate
creatinine clearance 1/Pcr
creatinine clearance = k/Pcr
Schwartz et al, 1976
analysis of 1/Pcr, ht/PCr, & SA/Pcr v CrCl
best fit with height (length)
Glomerular Filtration Ratecreatinine clearance v 0.55*ht(cm)/Pcr(mg/dl)
in children (Schwartz et al, 1976)
Glomerular Filtration Rate
k
Schwartz et al,1976
0.55 (Pcr mg/dl)
48.6 (Pcr µmol/l)
creatinine clearance ml/min/1.73m2
Method: end-point Jaffe
Glomerular Filtration Rate
k
Counahan et al, 1976
0.43 (Pcr mg/dl)
38.0 (Pcr µmol/l)51Cr-EDTA plasma clearance ml/min/1.73m2
Method: ion exchange absorption, end-point Jaffe
Glomerular Filtration Rate
k
Morris et al, 1982
40.0 (Pcr µmol/l)51Cr-EDTA plasma clearance ml/min/1.73m2
Method: automated kinetic Jaffe
Glomerular Filtration Rate35*ht/Pcr (MSMS) v Inutest plasma clearance ml/min/1.73m2
in children
Glomerular Filtration RateDifference plot
35*ht/Pcr (MSMS) – Inutest plasma clearance v Inutest plasma clearance ml/min/1.73m2 in children
Glomerular Filtration RateLessons learned from paediatrics
Can apply a simple formula to estimate a GFR from plasma creatinine, even in children, where creatinine production rate is increasing
Accuracy totally dependent on method for measuring plasma creatinine
Need to understand the measure of GFR any formula derived from
Does the formula correct for BSA, i.e. ml/min or ml/min/1.73m2?
Despite good correlation for a population it is important to appreciate that there are wide limits of agreement
Glomerular Filtration Rate
Application of a formula to estimate GFR from plasma creatinine in adults
We know plasma creatinine is a poor marker of glomerular filtration rate
Glomerular Filtration RateSerum creatinine (MSMS) v formal GFR
Serum creatinine v inulin clearanceShemesh O et al, Kidney International, 1985
predicted creatinine
Glomerular Filtration Rate
The early decline in GFR results in a relatively small increase in plasma creatinine
A population normal range is inappropriate
Biological Variation of Serum Creatinine
Gowans & Fraser 1988, Ann. Clin. Biochem. 25:259-263
Glomerular Filtration Rate
GFR PCr GFR PCrml/min/1.73m2 µmol/l ml/min/1.73m2µmol/l
120 70 30 280115 73 25 336110 76 20 420105 80 15 560100 84 10 84095 88 5 168090 9385 9980 10575 11270 12065 12960 140
Glomerular Filtration Rate
GFR PCr GFR PCrml/min/1.73m2 µmol/l ml/min/1.73m2µmol/l
120 50 30 200115 52 25 240110 55 20 300105 57 15 400100 60 10 60095 63 5 120090 6785 7180 7575 8070 8665 9260 100
Glomerular Filtration Rate
Application of a formula to estimate GFR from plasma creatinine in adults
Assumes individual production rates are predictable from demographics
Some reasonable measure of GFR essential for rationalisation of services for kidney disease
Glomerular Filtration Rate
16 March 1999 Volume 130 Number 6
Annals of Internal Medicine
A More Accurate Method To Estimate Glomerular Filtration Rate from Serum Creatinine: A New Prediction Equation
Andrew S. Levey, MD; Juan P. Bosch, MD; Julia Breyer Lewis, MD; Tom Greene, PhD; Nancy Rogers, MS; and David Roth, MD, for the Modification of Diet in Renal Disease Study Group*
Glomerular Filtration RateNational Kidney Foundation (NKF)
Kidney Disease Outcomes Quality Initiative (K/DOQI)
Glomerular Filtration RateNKF-K/DOQI guidelines
GUIDELINE 4. ESTIMATION OF GFR
Estimates of GFR are the best overall indices of the level of kidney function.
The level of GFR should be estimated from prediction equations that take into account the serum creatinine concentration and some or all of the following variables: age, gender, race, and body size.
The following equations provide useful estimates of GFR:
In adults, the MDRD Study and Cockcroft-Gault equations.
In children, the Schwartz and Counahan-Barratt equations.
Glomerular Filtration RateNKF-K/DOQI guidelines
The serum creatinine concentration alone should not be used to assess the level of kidney function.
Clinical laboratories should report an estimate of GFR using a prediction equation, in addition to reporting the serum creatinine measurement.
Autoanalyzer manufacturers and clinical laboratories should calibrate serum creatinine assays using an international standard.
Measurement of creatinine clearance using timed (for example, 24-hour) urine collections does not improve the estimate of GFR over that provided by prediction equations.
Glomerular Filtration RateNKF-K/DOQI guidelines
A 24-hour urine sample provides useful information for:
Estimation of GFR in individuals with exceptional dietary intake (vegetarian diet, creatine supplements) or muscle mass (amputation, malnutrition, muscle wasting);
Assessment of diet and nutritional status;
Need to start dialysis.
Glomerular Filtration RateNational Service Framework (NSF) for Renal Services
Step three: Testing kidney function
Local health organisations can work with pathology services and networks to develop protocols for measuring kidney function by serum creatinine concentration together with a formula-based estimation of glomerular filtration rate (estimated GFR), calculated and reported automatically by all clinical biochemistry laboratories.
Glomerular Filtration RateNational Service Framework (NSF) for Renal Services
•QUALITY REQUIREMENT ONE: People at increased risk of developing or having undiagnosed chronic kidney disease, especially people with diabetes or hypertension, are identified, assessed and their condition managed to preserve their kidney function.
Markers of good practice
•All people at increased risk of CKD are identified, and given appropriate advice, treatment and support (which is sensitive to the differing needs of culturally diverse groups) to preserve their kidney function.
•People identified as having an increased risk of CKD have their kidney function assessed and appropriately monitored, using estimated GFR.•Implementation of the NICE clinical guideline on the management of Type 1 diabetes.
•Implementation of the NICE clinical guidelines on the management of Type 2 diabetes: renal disease; blood glucose; blood pressure and blood lipids.
•Implementation of the NICE clinical guideline on the management of hypertension in adults in primary care.
•For children and young people with potential urinary tract infection, accurate diagnosis and prompt antibiotic treatment, and investigation sufficient to identify structural renal defects and to prevent renal scarring.
•For children and young people with bladder dysfunction, planned investigation and follow-up, with access to urology services with paediatric expertise.
Glomerular Filtration RateLessons learned from paediatrics
Can apply a formula to estimate a GFR from plasma creatinine even in children where creatinine production rate is increasing
Accuracy totally dependent on method for measuring plasma creatinine
Need to understand the measure of GFR any formula derived from
Does the formula correct for BSA, i.e. ml/min or ml/min/1.73m2?
Despite good correlation for a population it is important to appreciate that there are wide limits of agreement
Glomerular Filtration Rate
Use of plasma creatinine for the estimation of GFR
Need to understand the factors on which a plasma creatinine depends
Need to appreciate the importance of the creatinine measurement
Need to understand the limitations of any formula derived eGFR
Glomerular Filtration Rate
Factors affecting plasma creatinine
GFR, tubular secretion, production rate
Calculation of eGFR assumes that the rate of production is related to a series of demographics,
e.g. height, weight, sex, ethnic origin, age
Statistically may be true for a population but not necessarily for the individual
Limitations of plasma creatinine determination and eGFR
Age Wt Pcr GFR C&G GFR inulin
y kg µmol/l ml/min/1.73m2
Subject1 40 80 68 144 116Subject2 40 80 120 82 118
Effect of 50% loss of renal functionSubject1 40 80 136 73 58Subject2 40 80 240 41 59
Normal range for creatinine 55-120µmol/l
Glomerular Filtration Rate
Plasma creatinine measurement is critical
Accuracy very poor
Assays vary in standardisation, linearity, and relative interferences between and within supplier
Glomerular Filtration Rate
Measurement of plasma creatinine
Comparison of various routine methods with isotope-dilution electrospray mass spectrometry-mass
spectrometry
Fully validated method using a NIST traceable standard and EC certified reference materials
Between assay CV 2%
Zero bias
-30
-20
-10
0
10
20
40 90 140 190 240
Serum creatinine (ID-MS, umol/L)
Dif
fere
nce
be
twe
en
me
tho
ds
(O
rth
o e
nzy
mat
ic -
ID-M
S, u
mo
l/L)
Plasma creatinine - isotope-dilution MSMSmethod comparison
Zero bias
-30
-20
-10
0
10
20
40 90 140 190 240
Serum creatinine (ID-MS, umol/L)
Dif
fere
nce
be
twe
en
me
tho
ds
(R
och
e e
nzy
mat
ic -
ID-M
S,
um
ol/L
)
Plasma creatinine - isotope-dilution MSMSmethod comparison
Zero bias
-30
-20
-10
0
10
20
40 90 140 190 240
Serum creatinine (ID-MS, umol/L)
Dif
fere
nce
be
twe
en
me
tho
ds
(J
affe
- ID
-MS
, um
ol/L
)
Plasma creatinine - isotope-dilution MSMSmethod comparison
Glomerular Filtration Rate
Difference plotPlasma creatinine (µmol/l) Jaffe v MSMS
-200
-150
-100
-50
0
50
0.0 200.0 400.0 600.0 800.0 1000.0 1200.0 1400.0 1600.0
creatinine (µmol/l) MSMS
crea
tin
ine
(µm
ol/l
) Ja
ffe
- M
SM
S
Glomerular Filtration Rate
Difference plotPlasma creatinine (µmol/l) compensated Jaffe v MSMS
-200.0
-150.0
-100.0
-50.0
0.0
50.0
100.0
0.0 200.0 400.0 600.0 800.0 1000.0 1200.0 1400.0 1600.0
creatinine (µmol/l) MSMS
crea
tin
ine
(µm
ol/l
) co
mp
ensa
ted
Jaf
fe -
M
SM
S
Glomerular Filtration Rate
Difference plotPlasma creatinine (µmol/l) enzymatic v MSMS
-300.0
-250.0
-200.0
-150.0
-100.0
-50.0
0.0
50.0
100.0
0.0 200.0 400.0 600.0 800.0 1000.0 1200.0 1400.0 1600.0
creatinine (µmol/l) MSMS
cre
ati
nin
e (
µm
ol/l)
en
zym
ati
c -
MS
MS
Glomerular Filtration Rate
Difference plotPlasma creatinine (µmol/l) Cleveland Jaffe v MSMS
-80.0
-60.0
-40.0
-20.0
0.0
20.0
40.0
60.0
80.0
100.0
0.0 200.0 400.0 600.0 800.0 1000.0 1200.0 1400.0 1600.0
creatinine (µmol/l) MSMS
crea
tin
ine
(µm
ol/l
) C
leve
lan
d J
affe
- M
SM
S
Measurement of GFR
-15
-10
-5
0
5
10
15
20
25
30
35
40
45
50
55
0 100 200 300 400 500 600 700 800 900Mass Spec Creatinine (umol/L)
All methods
OCD (J&J) slides [1JJ]
Abbott reagents [11AB]
Bayer reagents [11TE]
Beckman reagents [11BK]
Olympus reagents [11OL]
Roche Integra reagents [11RO]
Roche Modular reagents [11BO]
In-house reagents [14OO]
Olympus reagents [14OL]
Synermed reagents [14SR]
ILab reagents [6IL]
Glomerular Filtration Rate
Plasma creatinine methods synonymous with lack of uniformity
Alignment with the MDRD formula laboratory would improve uniformity, but is wrong
Plasma creatinine: the importance of being consistently wrong
Finally, alignment with isotope dilution MS
Glomerular Filtration Rate
Analytical variation in plasma creatinine will have a significant impact on estimated GFR (eGFR), e.g. Lamb et al. Susceptibility of glomerular filtration rate estimations to variations in creatinine methodology: a study in older patients.
Ann Clin Biochem 2005
Glomerular Filtration Rate
Alignment of plasma creatinine standardisation and methodology, preferably to a true reference standard,
could significantly improve the situation
However, interferences represent a major problem on a patient by patient basis, e.g. the impact of under-
recognised renal failure in liver disease
Use eGFR in this patient group?
Glomerular Filtration Rate
eGFR
The formulae
Glomerular Filtration Rate
16 March 1999 Volume 130 Number 6
Annals of Internal Medicine
A More Accurate Method To Estimate Glomerular Filtration Rate from Serum Creatinine: A New Prediction Equation
Andrew S. Levey, MD; Juan P. Bosch, MD; Julia Breyer Lewis, MD; Tom Greene, PhD; Nancy Rogers, MS; and David Roth, MD, for the Modification of Diet in Renal Disease Study Group*
Glomerular Filtration Rate
Levey et al, 1999
Comparison of a range, 7 in total, of eGFR formulae
True GFR measure
radioactive iothalamate clearance
Glomerular Filtration Rate
Equation 1: Serum creatinineGFR (ml/min/1.73m2) = 0.69 * [100/Pcr]Equation 2: Cockcroft–Gault formulaGFR (ml/min) = 0.84 * [(140-age) * wt]/(Pcr *72) note for females 85 Equation 3: Creatinine clearanceGFR (ml/min) = 0.81 * [Ccr]Equation 4: Average of creatinine and urea clearanceGFR (ml/min/1.73m2) = 1.11 * [(Ccr + Curea)/2]Equation 5: Creatinine clearance, urea clearance, and demographic
variablesGFR (ml/min/1.73m2) = 1.04 * [Ccr]0.751 * [Curea] 0.226 * [1.109 if
patient is black]
Glomerular Filtration Rate
Equation 6: Demographic, serum, and urine variables
GFR (ml/min/1.73m2) = 198 * [Pcr]-0.858 * [Age]-0.167 * [0.822 if patient is female] * [1.178 if patient is black] * [SUN]-0.293 * [UUN]0.249
Equation 7: Demographic and serum variables only
GFR (ml/min/1.73m2) = 170 * [Pcr]-0.999 * [Age]-0.176 * [0.762 if patient is female] * [1.180 if patient is black] * [SUN]-0.170 * [Alb]0.318
Reduced/practical MDRD formula:
GFR (ml/min/1.73m2) = 186 (175) * [Pcr/88.4]-1.154 * [Age]-0.203 * [0.742 if patient is female] * [1.121 if patient is black]
Glomerular Filtration Rate
No biasEquation 6 the most precise, R2=91.2%
Equation 7, R2=90.3%
Reduced formula only appeared in abstract form, performance equivalent to equation 7
Glomerular Filtration Rate
Glomerular Filtration Rate
90th centile %age absolute errors
19.1 ml/min/1.73m2 (47.5%) for Cockcroft & Gault formula
12.9 ml/min/1.73m2 (28.4%) for equation 7
A more accurate method to estimate GFRGood enough?
Glomerular Filtration Rate
Glomerular Filtration Rate
Limits of agreement a problem
NB the study done in one laboratory with a particular creatinine method
In practice, without equivalence of creatinine methods eGFR not going to be clinically useful
MDRD with ECOS (evolving connectionist systems)?
Glomerular Filtration Rate
Limits of agreement a problem
Even with equivalence of creatinine methods eGFR will not significantly improve early detection
eGFR of 80ml/min/1.73m2 could be anywhere from 56 to 104ml/min/1.73m2 – 90% of the time!
Only reporting values <60 ml/min/1.73m2 while prudent does not improve early detection
Biological Variation of Serum Creatinine
Gowans & Fraser 1988, Ann. Clin. Biochem. 25:259-263
Glomerular Filtration Rate
The key to early detection of renal disease using plasma creatinine is to provide an assay with
excellent between assay precision and monitor change
True primary care medicine
Urinary albumin/creatinine ratio?
Glomerular Filtration Rate
Limits of agreement also a problemfor classification of disease stage
eGFR useful for monitoring progression of kidney disease once baseline established using formal GFR
but so is plasma creatinine
Beware therapeutics affecting creatinine production, e.g. fibrates, and/or tubular secretion, e.g. cimetidine
Glomerular Filtration Rate
Actions
Improve creatinine standardisation and methodologyQuote limits with every eGFR report
Develop a formula relevant to the UK demographic using a valid renal clearance technique (i.e. collect some urine!)
Early detection of kidney disease requires a better plasma markerCystatin C any better?
Measurement of GFR
Early detection of kidney disease and appropriate staging remains a challenge
eGFR is a significant start, provided all associated professionals understand what it means
Kidney disease is a major public health problem and a significant determinant of cardiovascular risk that necessitates early detection and treatment
Measurement of GFR
Beware: Deacon’s Challenge No:54Complexity of eGFR calculationMDRD eGFR 41ml/min/1.73m2
Creatinine clearance 29ml/minComments: inaccuracy of timed urine collectionfailure to correct Ccr for BSACcr should always be corrected for BSAcreatinine is secreted by tubules so Ccr is always higher than GFRthe 2 values are actually within the limits of agreement of the 2
methods – that is the problem!
Acknowledgements
Charles TurnerEdmund Lamb and colleagues
Finlay McKenzieFrederick van Lente
Carlo Donadio
The WellChild TrustGuy’s & St Thomas’ Charity
Guy’s & St Thomas’ NHS Foundation Trust