Creatinine%20and%20the%20eGFR

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Creatinine and the eGFR
AACB-AIMS Annual Scientific meeting Hobart 2006

• Graham Jones
• Department of Chemical Pathology
• St Vincents Hospital, Sydney

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Summary

• Creatinine measurement
• Past
• Present
• Future

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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, ...

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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

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Jaffe Reactions

• Effect of different reaction conditions

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Jaffe Reactions

• Absorbance-time curves for various analytes in
  Jaffe reaction

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Jaffe Creatinine Assays
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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)

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Case 4Jaffe v Enzymatic Creatinine
Interferences
Jaffe Creatinine (mmol/L)
Enzymatic Creatinine (mmol/L)
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Creatinine Measurement
Interferences
Jaffe
Enzymatic
Creatinine (mmol/L)
Day of admission
Methyldopa
Hydralazine
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Other assays

• Fullers earth
• HPLC
• IDMS
• Manufacturers have chosen various methods as
  accuracy base for their assays.

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GFR

• Glomerular Filtration Rate
• Single most important parameter of renal function
• Key factor in definition of CKD
• CKD - Chronic Kidney Disease

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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

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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)

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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

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MDRD - Levy 1999
gt /- 30 scatter using results from one
instrument
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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

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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.

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Australia RCPA,AACB,KHA
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Lab pack
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What about creatinine?
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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

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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!
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NKDEP Lab Group

• 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!
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NKDEP Working Group

• Working with NIST (USA) to produce and validate
  commutable reference material
• On-going review of assay performance

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NIST LN25 May 2005
www.nkdep.nih.gov
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Commutability Testing
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IFCC WG-GFRA

• Working Group - GFR Assessment
• 1st Meeting July 2005
• One of many IFCC WG

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WG-GFRA - October 2006

• IFCC website
• Specific creatinine assays
• Reference Lab network
• Global introduction of revised equation
• Terminology
• Reporting gt60 mL/min/1.73m2

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www.ifcc.org
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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

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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)

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Serum Creatinine and Reporting Limits
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
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RCPA-AACB-KHA

• 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

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MDRD DATA Christchurch
186 formula
MDRD eGFR, mL/min/m2
99Tc GFR, mL/min/1.73m2
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Method Comparison
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Creatinine Assays - Precision
CV
RCPA-QAP 2006 data calculated from within and
between precision.
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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!