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Plasma creatinine and the estimation of glomerular filtration rate (GFR)

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### Plasma creatinine and the estimation of glomerular filtration rate (GFR)

R Neil Dalton

WellChild Laboratory

King’s College London/ Guy’s Hospital

ACB South West & Wessex Region Scientific Meeting

Salisbury, 4th July 2006

Glomerular Filtration Rate filtration rate (GFR)

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 GFR

Formulae attempting to fix the problem - eGFR

eGFR routine in paediatric nephrology for nearly 30y

The Glomerulus filtration rate (GFR)

Glomerular Filtration Rate filtration rate (GFR)

fundamental to:

diagnosis of kidney disease

early detection

stratification

monitoring the progression of kidney disease

prognosis

efficacy of treatment

facilitate timing of therapeutic interventions

drug dosage

elimination of drugs/drug metabolites by the kidney

Glomerular Filtration Rate filtration rate (GFR)

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 filtration rate (GFR)

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 filtration rate (GFR)

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 filtration rate (GFR)

Clinical importance

Detection of kidney disease

Cardiovascular risk

Glomerular Filtration Rate filtration rate (GFR)

Compromise:

24h creatinine clearance

Ucr * V

Pcr

All the hassle and responsibility on the patient

As a result unreliable

Problem of tubular secretion of creatinine

Glomerular Filtration Rate filtration rate (GFR)

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 + 13

Creatinine 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 filtration rate (GFR)

Further compromise:

24h creatinine clearance

Ucr * V

Pcr

Therefore,

creatinine clearance µ 1/Pcr

Only need to measure plasma creatinine!

Glomerular Filtration Rate filtration rate (GFR)

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 filtration rate (GFR)

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 V

Ccr Pcr Ucr x V

ml/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 clearance filtration rate (GFR)Shemesh O et al, Kidney International, 1985

predicted creatinine

Glomerular Filtration Rate filtration rate (GFR)

Plasma creatinine determined by:

GFR

secretion by kidney tubules

production rate

children the worst case

– increasing production rate with age and anabolic growth spurts

Valuable demonstration of estimating GFR from plasma creatinine

Glomerular Filtration Rate filtration rate (GFR)Plasma creatinine v Inutest GFR in children

Glomerular Filtration Rate filtration rate (GFR)

creatinine clearance µ 1/Pcr

Glomerular Filtration Rate filtration rate (GFR)1/Pcr v Inutest GFR in children

Glomerular Filtration Rate filtration rate (GFR)

creatinine clearance µ 1/Pcr

creatinine clearance = k/Pcr

Glomerular Filtration Rate filtration rate (GFR)

creatinine clearance µ 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 Rate filtration rate (GFR)creatinine clearance v 0.55*ht(cm)/Pcr(mg/dl) in children (Schwartz et al, 1976)

Glomerular Filtration Rate filtration rate (GFR)

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 filtration rate (GFR)

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 filtration rate (GFR)

k

Morris et al, 1982

40.0 (Pcr µmol/l)

51Cr-EDTA plasma clearance ml/min/1.73m2

Method: automated kinetic Jaffe

Glomerular Filtration Rate filtration rate (GFR)35*ht/Pcr (MSMS) v Inutest plasma clearance ml/min/1.73m2 in children

Glomerular Filtration Rate filtration rate (GFR)Difference plot35*ht/Pcr (MSMS) – Inutest plasma clearance v Inutest plasma clearance ml/min/1.73m2 in children

Glomerular Filtration Rate filtration rate (GFR)Lessons 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 filtration rate (GFR)

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 Rate filtration rate (GFR)Serum creatinine (MSMS) v formal GFR

Serum creatinine v inulin clearance filtration rate (GFR)Shemesh O et al, Kidney International, 1985

predicted creatinine

Glomerular Filtration Rate filtration rate (GFR)

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 filtration rate (GFR)Gowans & Fraser 1988, Ann. Clin. Biochem. 25:259-263

Glomerular Filtration Rate filtration rate (GFR)

Glomerular Filtration Rate filtration rate (GFR)

Glomerular Filtration Rate filtration rate (GFR)

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 filtration rate (GFR)

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 filtration rate (GFR)National Kidney Foundation (NKF)Kidney Disease Outcomes Quality Initiative (K/DOQI)

Glomerular Filtration Rate filtration rate (GFR)NKF-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 Rate filtration rate (GFR)NKF-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 Rate filtration rate (GFR)NKF-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 Rate filtration rate (GFR)National 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 Rate filtration rate (GFR)National 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 Rate filtration rate (GFR)Lessons 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 filtration rate (GFR)

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 filtration rate (GFR)

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 filtration rate (GFR)

Age Wt Pcr GFR C&G GFR inulin

y kg µmol/l ml/min/1.73m2

Subject1 40 80 68 144 116

Subject2 40 80 120 82 118

Effect of 50% loss of renal function

Subject1 40 80 136 73 58

Subject2 40 80 240 41 59

Normal range for creatinine 55-120µmol/l

Glomerular Filtration Rate filtration rate (GFR)

Plasma creatinine measurement is critical

Accuracy very poor

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

Glomerular Filtration Rate filtration rate (GFR)

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%

Plasma creatinine - isotope-dilution MSMS filtration rate (GFR)method comparison

Plasma creatinine - isotope-dilution MSMS filtration rate (GFR)method comparison

Plasma creatinine - isotope-dilution MSMS filtration rate (GFR)method comparison

Glomerular Filtration Rate filtration rate (GFR)

Glomerular Filtration Rate filtration rate (GFR)

Glomerular Filtration Rate filtration rate (GFR)

Glomerular Filtration Rate filtration rate (GFR)

Measurement of GFR filtration rate (GFR)

Glomerular Filtration Rate filtration rate (GFR)

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 filtration rate (GFR)

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 filtration rate (GFR)

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 filtration rate (GFR)

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 filtration rate (GFR)

Levey et al, 1999

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

True GFR measure

radioactive iothalamate clearance

Glomerular Filtration Rate filtration rate (GFR)

Equation 1: Serum creatinine

GFR (ml/min/1.73m2) =0.69 *[100/Pcr]

Equation 2: Cockcroft–Gault formula

GFR (ml/min) =0.84 *[(140-age) * wt]/(Pcr *72) note for females 85

Equation 3: Creatinine clearance

GFR (ml/min) =0.81 *[Ccr]

Equation 4: Average of creatinine and urea clearance

GFR (ml/min/1.73m2) =1.11 *[(Ccr + Curea)/2]

Equation 5: Creatinine clearance, urea clearance, and demographic variables

GFR (ml/min/1.73m2) =1.04 * [Ccr]0.751 *[Curea]0.226* [1.109 if patient is black]

Glomerular Filtration Rate filtration rate (GFR)

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 filtration rate (GFR)

No bias

Equation 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 filtration rate (GFR)

Glomerular Filtration Rate filtration rate (GFR)

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 GFR

Good enough?

Glomerular Filtration Rate filtration rate (GFR)

Glomerular Filtration Rate filtration rate (GFR)

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 filtration rate (GFR)

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 filtration rate (GFR)Gowans & Fraser 1988, Ann. Clin. Biochem. 25:259-263

Glomerular Filtration Rate filtration rate (GFR)

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 filtration rate (GFR)

Limits of agreement also a problem

for 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 filtration rate (GFR)

Actions

Improve creatinine standardisation and methodology

Quote 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 marker

Cystatin C any better?

Measurement of GFR filtration rate (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 filtration rate (GFR)

Beware: Deacon’s Challenge No:54

Complexity of eGFR calculation

MDRD eGFR 41ml/min/1.73m2

Creatinine clearance 29ml/min

Comments:

inaccuracy of timed urine collection

failure to correct Ccr for BSA

Ccr should always be corrected for BSA

creatinine is secreted by tubules so Ccr is always higher than GFR

the 2 values are actually within the limits of agreement of the 2 methods – that is the problem!

Acknowledgements filtration rate (GFR)

Charles Turner

Edmund Lamb and colleagues

Finlay McKenzie

Frederick van Lente

Carlo Donadio

The WellChild Trust

Guy’s & St Thomas’ Charity

Guy’s & St Thomas’ NHS Foundation Trust

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