Plasma Creatine estimation of GFR

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


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 (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!


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


Hence, formal measurement of GFR rarely performed

Difficult!

Reliable?

Logistics of test performance

Radiochemical/biochemical tracer analysis

Failure to appreciate the clinical importance


Clinical importance

Detection of kidney disease

Cardiovascular risk


Compromise:24h creatinine clearance

Ucr * VPcr

All the hassle and responsibility on the patientAs a result unreliable

Problem of tubular secretion of creatinine


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)


Further compromise:

24h creatinine clearance

Ucr * V

Pcr

Therefore,

creatinine clearance 1/Pcr

Only need to measure plasma creatinine!


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


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


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 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

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0 20 40 60 80 100 120 140 160

GFR (ml/min/1.73m2)

1/cr

eatin

ine

(l/µm

ol)



creatinine clearance = k/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)


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


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


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


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


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


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


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


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


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.


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.


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


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


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


Plasma creatinine measurement is critical

Accuracy very poor

Assays vary in standardisation, linearity, and relative interferences between and within supplier


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

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10

20

40 90 140 190 240

Serum creatinine (ID-MS, umol/L)

Dif

fere

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be

twe

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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


Dif

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be

twe

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me

tho

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(R

och

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ID-M

S,

um

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)


Zero bias

-30

-20

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20

40 90 140 190 240


Dif

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be

twe

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(J

affe

- ID

-MS

, um

ol/L

)



Difference plotPlasma creatinine (µmol/l) Jaffe v MSMS

-200

-150

-100

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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

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(µm

ol/l

) Ja

ffe

- M

SM

S


Difference plotPlasma creatinine (µmol/l) compensated Jaffe v MSMS

-200.0

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crea

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(µm

ol/l

) co

mp

ensa

ted

Jaf

fe -

M

SM

S


Difference plotPlasma creatinine (µmol/l) enzymatic v MSMS

-300.0

-250.0

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-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


cre

ati

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µm

ol/l)

en

zym

ati

c -

MS

MS


Difference plotPlasma creatinine (µmol/l) Cleveland Jaffe v MSMS

-80.0

-60.0

-40.0

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0.0 200.0 400.0 600.0 800.0 1000.0 1200.0 1400.0 1600.0


crea

tin

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(µm

ol/l

) C

leve

lan

d J

affe

- M

SM

S

Measurement of GFR

-15

-10

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0

5

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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]


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


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


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?


eGFR

The formulae


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*


Levey et al, 1999

Comparison of a range, 7 in total, of eGFR formulae

True GFR measure

radioactive iothalamate clearance


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]


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]


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


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?


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)?


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


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?


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


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

Plasma Creatine estimation of GFR

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