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

1
Plasma creatinine and the estimation of
glomerular filtration rate (GFR)

• R Neil Dalton
• WellChild Laboratory
• Kings College London/ Guys Hospital
• ACB South West Wessex Region Scientific Meeting
• Salisbury, 4th July 2006

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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 GFR
• Formulae attempting to fix the problem - eGFR
• eGFR routine in paediatric nephrology for nearly
  30y

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The Glomerulus
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Glomerular Filtration Rate

• 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

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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!

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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

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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

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Glomerular Filtration Rate

• Clinical importance
• Detection of kidney disease
• Cardiovascular risk

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Glomerular Filtration Rate

• 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

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Glomerular Filtration Rate

• Measurement of GFR in children with type 1
  diabetes
• Clearance Diabetics (n11) Controls (n12)
• 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)

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Glomerular Filtration Rate

• Further compromise
• 24h creatinine clearance
• Ucr V
• Pcr
• Therefore,
• creatinine clearance µ 1/Pcr
• Only need to measure plasma creatinine!

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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

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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 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

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Serum creatinine v inulin clearanceShemesh O et
al, Kidney International, 1985
predicted creatinine
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Glomerular Filtration Rate

• 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

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Glomerular Filtration RatePlasma creatinine v
Inutest GFR in children
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Glomerular Filtration Rate

• creatinine clearance µ 1/Pcr

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Glomerular Filtration Rate1/Pcr v Inutest GFR in
children
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Glomerular Filtration Rate

• creatinine clearance µ 1/Pcr
• creatinine clearance k/Pcr

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Glomerular Filtration Rate

• 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)

21
Glomerular Filtration Ratecreatinine clearance v
0.55ht(cm)/Pcr(mg/dl) in children (Schwartz et
al, 1976)
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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

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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

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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

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Glomerular Filtration Rate35ht/Pcr (MSMS) v
Inutest plasma clearance ml/min/1.73m2 in children
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Glomerular Filtration RateDifference
plot35ht/Pcr (MSMS) Inutest plasma clearance
v Inutest plasma clearance ml/min/1.73m2 in
children
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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

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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

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Glomerular Filtration RateSerum creatinine
(MSMS) v formal GFR
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Serum creatinine v inulin clearanceShemesh O et
al, Kidney International, 1985
predicted creatinine
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Glomerular Filtration Rate

• The early decline in GFR results in a relatively
  small increase in plasma creatinine
• A population normal range is inappropriate

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Biological Variation of Serum CreatinineGowans
Fraser 1988, Ann. Clin. Biochem. 25259-263
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Glomerular Filtration Rate
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Glomerular Filtration Rate
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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

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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
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Glomerular Filtration RateNational Kidney
Foundation (NKF)Kidney Disease Outcomes Quality
Initiative (K/DOQI)
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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.

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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.

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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.
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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.

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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.
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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

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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

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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

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Limitations of plasma creatinine determination
and eGFR

• Age Wt Pcr GFR CG 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

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Glomerular Filtration Rate

• Plasma creatinine measurement is critical
• Accuracy very poor
• Assays vary in standardisation, linearity, and
  relative interferences between and within supplier

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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

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Plasma creatinine - isotope-dilution MSMSmethod
comparison
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Plasma creatinine - isotope-dilution MSMSmethod
comparison
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Plasma creatinine - isotope-dilution MSMSmethod
comparison
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Glomerular Filtration Rate
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Glomerular Filtration Rate
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Glomerular Filtration Rate
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Glomerular Filtration Rate
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Measurement of GFR
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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

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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

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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?

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Glomerular Filtration Rate

• eGFR
• The formulae

61
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
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Glomerular Filtration Rate

• Levey et al, 1999
• Comparison of a range, 7 in total, of eGFR
  formulae
• True GFR measure
• radioactive iothalamate clearance

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Glomerular Filtration Rate

• Equation 1 Serum creatinine
• GFR (ml/min/1.73m2) 0.69 100/Pcr
• Equation 2 CockcroftGault 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 Ccr0.751 Curea
  0.226 1.109 if patient is black

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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
  UUN0.249
• 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
  Alb0.318
• 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

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Glomerular Filtration Rate

• No bias
• Equation 6 the most precise, R291.2
• Equation 7, R290.3
• Reduced formula only appeared in abstract form,
  performance equivalent to equation 7

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Glomerular Filtration Rate
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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 GFR
• Good enough?

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Glomerular Filtration Rate
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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)?

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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 lt60 ml/min/1.73m2 while
  prudent does not improve early detection

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Biological Variation of Serum CreatinineGowans
Fraser 1988, Ann. Clin. Biochem. 25259-263
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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?

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Glomerular Filtration Rate

• 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

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Glomerular Filtration Rate

• 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?

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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

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Measurement of GFR

• Beware Deacons Challenge No54
• 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!

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Acknowledgements

• Charles Turner
• Edmund Lamb and colleagues
• Finlay McKenzie
• Frederick van Lente
• Carlo Donadio
• The WellChild Trust
• Guys St Thomas Charity
• Guys St Thomas NHS Foundation Trust