Creatinine and the eGFR

1. AACB-AIMS Annual Scientific meeting Hobart 2006 Creatinine and the eGFR Graham Jones Department of Chemical Pathology St Vincent’s Hospital, Sydney

2. Summary • Creatinine measurement • Past • Present • Future

3. 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, ...

5. 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

6. Jaffe Reactions • Effect of different reaction conditions

7. Jaffe Reactions • Absorbance-time curves for various analytes in Jaffe reaction

8. Jaffe Creatinine Assays

9. 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)

10. Case 4Jaffe v Enzymatic Creatinine Interferences Jaffe Creatinine (mmol/L) Enzymatic Creatinine (mmol/L)

11. Creatinine Measurement Interferences Jaffe Enzymatic [Creatinine] (mmol/L) Day of admission Methyldopa Hydralazine

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

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

15. 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

16. 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%)

17. 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

18. MDRD - Levy 1999 > +/- 30% scatter using results from one instrument

19. 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

21. 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.”

22. Australia: RCPA,AACB,KHA

23. “Lab pack”

24. What about creatinine?

25. 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”

26. 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!

27. 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!

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

30. NIST LN25 – May 2005 www.nkdep.nih.gov

31. Commutability Testing

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

34. WG-GFRA - October 2006 • IFCC website • Specific creatinine assays • Reference Lab network • Global introduction of revised equation • Terminology • Reporting >60 mL/min/1.73m2

35. www.ifcc.org

36. 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

37. 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)

38. 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

39. 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

40. MDRD DATA: Christchurch “186” formula MDRD eGFR, mL/min/m2 99Tc GFR, mL/min/1.73m2

41. Method Comparison

42. Creatinine Assays - Precision CV RCPA-QAP 2006 data calculated from within and between precision.

43. 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!