Transcript Creatinine and the eGFR

AACB-AIMS Annual Scientific meeting Hobart 2006
Creatinine and the eGFR
Graham Jones
Department of Chemical Pathology
St Vincent’s Hospital, Sydney
Summary
• Creatinine measurement
– Past
– Present
– Future
Creatinine measurement
• 1886: Jaffe devised Alkaline Picrate assay for
creatinine
• Not specific for creatinine
• Measurand: “chemical reactivity with picrate in
alkaline environment”
• Also responds to: protein, albumin, ketones,
bilirubin, cephalosporins, ...
Jaffe assays
• Following Jaffe there has been over 100 years of
modifications to the Jaffe reaction to improve
specificity
• Read-frame adjustment
• Rate-blanking
• Reagent concentration optimisation
• Detergent addition (at 41 degrees)
• NOT ALL JAFFE assays are the same
Jaffe
Reactions
• Effect of
different
reaction
conditions
Jaffe Reactions
• Absorbance-time
curves for
various analytes
in Jaffe reaction
Jaffe Creatinine Assays
Enzymatic assays
• Brought into routine use
• Only method on Vitros analysers
• Not widely used on other platforms in Australia
– Investigate unexpected high creatinine
– Specific patients
• In common use in some countries
• Some interferences (trinder reaction)
Interferences
Case 4
Jaffe v Enzymatic Creatinine
0.4
0.3
Jaffe Creatinine
(mmol/L)
0.2
0.1
0
0
0.1
0.2
0.3
Enzymatic Creatinine (mmol/L)
0.4
[Creatinine] (mmol/L)
Creatinine
Interferences
Measurement
0.2
0.18
0.16
0.14
0.12
0.1
0.08
0.06
0.04
0.02
0
Jaffe
Enzymatic
4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19
Day of admission
Hydralazine
Methyldopa
Other assays
• Fullers earth
• HPLC
• IDMS
• Manufacturers have chosen various methods as
accuracy base for their assays.
GFR
• Glomerular Filtration Rate
• Single most important parameter of renal
function
• Key factor in definition of CKD
• “CKD” - Chronic Kidney Disease
Measuring GFR
• Exogenous substances
– Inulin, Cr-EDTA, Iothalamate
– Time consuming, expensive, radioactivity
• Endogenous substances
– Creatinine (cystatin-C)
– Over 40 GFR estimation equations based on serum
creatinine
Cockcroft and Gault
• Developed in 1976 from 249 people (96% male)
– Subsequently validated in at least 58 studies
• A measure of creatinine clearance
• Estimate urine creatinine based on age, weight
and sex of patient.
• False elevation of serum creatinine assays (in
1976) gave lower results, serendipitously
approximating the GFR
• Newer (better) creatinine assays give falsely
elevated GFR estimates (approx 15%)
MDRD
• 1990s: Modification of Diet in Renal Disease
study.
• Can progression of renal disease be slowed by
dietary modification?
• Multiple ancillary studies to validate tools
• Devised and published the MDRD formulae for
GFR estimation
• Used Beckman-Coulter CX3 assay at Cleveland
Clinic Laboratory
MDRD - Levy 1999
> +/- 30% scatter using results from one instrument
MDRD - Opportunity
• MDRD formula adopted by the NKDEP
• National Kidney Disease Education Program
• Aim to highlight moderate to severe renal
disease more simply than can be done from
serum creatinine alone.
• Renal disease is bad for patients and health
systems
• Earlier detection (pre-symptomatic) allows
better chance for intervention
Clin Biochem Reviews 2003
Guidelines Review
The National Kidney Foundation Guideline on
Estimation of the Glomerular Filtration Rate: a
critical appraisal.
Regarding: Am J Kidney Dis 2002; 39(S1): S76-S110
Reviewed by Graham RD Jones and Ee-Mun Lim.
“However, for the reasons stated above, we do not believe
that the MDRD equation is yet ready for routine use.”
Australia: RCPA,AACB,KHA
“Lab pack”
What about creatinine?
JCTLM
• 2004 Formation of JCTLM
• Joint Committee for Traceability in Laboratory
Medicine
• “Joint” of: BIPM, IFCC, ILAC
• The Role of the BIPM is “worldwide uniformity
of measurement”
Creatinine
• NKDEP Lab working group
• Sets total error criteria for serum creatinine
measurement at +/- 15%
• Decides to adopt Reference Method from
JCTLM
• Isotope Dilution Mass Spectrometry
WOW!
NKDEP Lab Group
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•
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•
Established need for standardisation
Agreed on accuracy base
Met with industry
Industry has agreed to revise assay calibration to
align with IDMS
• Will occur over next 6 - 18 months
WOW!
NKDEP Working Group
• Working with NIST (USA) to produce and
validate commutable reference material
• On-going review of assay performance
NIST LN25 – May 2005
www.nkdep.nih.gov
Commutability Testing
IFCC WG-GFRA
• Working Group - GFR Assessment
• 1st Meeting July 2005
• One of many IFCC WG
WG-GFRA - October 2006
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•
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IFCC website
Specific creatinine assays
Reference Lab network
Global introduction of revised equation
Terminology
Reporting >60 mL/min/1.73m2
www.ifcc.org
Specific Creatinine Assays
• Should more specific creatinine assays be
recommended
• Brief literature review
– No current data
• Aim to study magnitude and significance of
assay non-specificity
The revised eGFR formula
Original “4 variable” MDRD equation:
eGFR = 186 x (creat/88.4)-1.154 x age-0.203 x F x R
F = 0.742 if female; R = 1.2 if African American
Revised IDMS aligned MDRD equation:
eGFR = 175 x (creat/88.4)-1.154 x age-0.203 x F
Gives same answer if IDMS creatinine assays 0.95 x
original Cleveland Clinic Beckman CX3 method
(Ann Int Med 2006)
Serum Creatinine and Reporting Limits
Creatinine (umol/L)
140
120
100
M - 60 mL/min
80
M - 90 mL/min
60
F - 60 mL/min
40
F - 90 mL/min
20
0
20
40
60
80
100
Age (years)
Reporting to 90 mL/min – creatinine down to about 55 umol/L
Reporting to 60 mL/min – creatinine down to about 80 umol/L
“175” equation, IDMS aligned assays
RCPA-AACB-KHA
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Meeting planned December 2006
Current status of Australian assays
Introduction of “175” formula
Reporting up to 90 mL/min/1.73m2
Age-related decision points
Effects of race
Drug dosing decisions
Common reference intervals
MDRD DATA: Christchurch
“186” formula
n=601
y = 3.1023 + 1.0047x
250
200
150
100
50
0
0
50
100
150
200
99Tc GFR, mL/min/1.73m2
250
Method Comparison
2.000
Lab 1 Hitachi 917 Jaffe
1.800
1.600
Lab 3 Beckman CX4 Jaffe
1.400
1.200
Lab 3 Beckman CX4 Roche
Enzymatic
1.000
0.800
Lab 4 Dimension RXL
Jaffe
0.600
Lab 5 Dimension AR
Jaffe
0.400
0.200
0.000
0.000
Lab 6 Vitros 950 Dry Chem
Enzymatic
0.500
1.000
LC-MS-MS
1.500
2.000
Total method
precision
Creatinine
Assays
- Precision
CV
AbbottA
12%
Beckma
kinetic n
10%
Dade Be
n=55
8%
Olympus
kinetic n
6%
Ortho-C
Amidohy
4%
Roche D
Picrate-
2%
Roche D
(Integra)
0%
Roche D
(Hitachi)
n=115
0
100
200
300
400
RCPA-QAP 2006 data calculated from within and between precision.
Conclusion
• We are seeing an example of co-operation
– Clinicians
– Laboratories
– International Organisations (NKDEP, IFCC,
JCTLM)
– Local Organisations (AACB, RCPA, KHA)
• With the aim of improving patient care!