1. Kreatinine Verklaard !? eGFR introductie anno 2006 Take-home-messages CM Cobbaert 14 september 2006

2. Chronische nierinsufficientie Toenemende incidentie/prevalentie CNI Toenemende incidentie/prevalentie CNI Onderdiagnostiek en onderbehandeling Onderdiagnostiek en onderbehandeling –sCr = ongevoelige marker voor detectie CNI ------------------------------------------------------------------ Richtlijnen: rapporteer eGFR naast SCr! Richtlijnen: rapporteer eGFR naast SCr! Keuze eGFR formule anno 2006: kritisch! Keuze eGFR formule anno 2006: kritisch! Betrouwbare eGFR mits adequate assay/standaardisatie SCr Betrouwbare eGFR mits adequate assay/standaardisatie SCr------------------------------------------------------------------ Rol klinisch chemische labs, diagnostica industrie en SKML!Rol klinisch chemische labs, diagnostica industrie en SKML!

3. Introductie

4. 100 GFR estimation Percent of estim ates within 30% of the m easured GFR in the M DRD Study validation sam ple (n = 558). 80 60 40 20 0 Reciprocal SCr Cockroft- Gault 24-Hour Creatinine Clearance Reciprocal SCr [C] Cockroft- G ault [C] 24-Hour Creatinine Clearance [C] M DRD 6 Parameter MDRD 4 Parameter Redrawn from: K/DOQI Clinical practice guidelines for chronic kidney disease. AmJ Kidney Dis2002;39:S1-S266. Creat clearance estimate GFR estimate

5. NKDEP recommends the MDRD four parameter estimation equation for adults age 18 and older GFR (mL/min/1.73 m 2 ) = 186 * x creat serum / 88.4 (µmol/L) -1.154 x Age -0.203 x 0.742 (If Female) x 1.210 (If African-American) * use 186 for CONVENTIONAL calibration; * use 175 for calibration TRACEABLE TO IDMS

6. 4P-MDRD equation limitations Applicable in adult (18-70 years) whites and African-Americans with chronic GFR <90 mL/min/1.73m 2 Acceptable performance for diabetics Agreement with measured GFR is poorer for: Hospital inpatients Acute renal failure Normal renal function Validation is underway for additional ethnic groups, patient groups, and individuals with normal renal function

7. Creatinine measurement limitations affecting the 4 P-MDRD Conventional calibration has not been standardized among methods Original MDRD equation was based on Beckman CX3 routine method results from Cleveland Clinic Jaffe method non-specificity influences on individual patient creatinine results Measurement bias and imprecision have a larger impact on result variability as creatinine values get lower (GFR gets higher)

8. Impact of creatinine bias on GFR Bias,  mol/L 140 120 100 80 60 -8 mL/min = -12% error -17 mL/min = -27% error - 5 0 5 11 27 40 20 0 020406080100120 eGFR without bias in serumcreatinine, mL/min/1.73 m 2 Myers et al. Clin Chem 2006;52:5-18 Large effects > 60

9. Impact of imprecision on GFR 160 140 120 100 80 60 40 20 0 95% Confidence Interval for eGFR at creatinine = 88.4  mol/L (1 mg/dL) 53-70 mL/min/1.73m 2 at SD = 5.3  mol/L 46-85 mL/min/1.73m 2 at SD = 11.5  mol/L 0.01.02.03.04.0 Creatinine, mg/dL Myers et al. Clin Chem 2006;52:5-18 88.4 µmol/L

10. What creatinine method performance is needed? Total error in creatinine measurement is not to increase the variability in eGFRmore than 10% in the critical creatinine range 1.0-1.5 mg/dL (88-133μmol/L) Comparable performance is needed in the 0.6- 1.0 mg/dL (53-88μmol/L) range for pediatric patients and to extend eGFRto higher values Method non-specificity also needs to be addressed

11. Total Error budget for creatinine measurement in the range 88-133 µmol/L Myers et al. Clin Chem 2006;52:5-18

12. Implement 4 P-MDRD now!! Use the conventional calibration 4P-MDRD eq. for methods not calibrated to IDMS Many routine methods have a calibration bias that is similar to that of the routine method used in the MDRD study. Use the IDMS-traceable 4P-MDRD equation for methods calibrated to IDMS Use creatinine reported to two decimals (mg/dL), or nearest whole number (µmol/L), in the MDRD calculation

13. Reporting 4 P - MDRD Report GFR selectively (metabolic stable pts) (Consider if appropriate for inpatients) Report two values? GFR est if African-American Caucasian If value is ≤ 60, report rounded to a whole number (e.g. 53 mL/min/1.73 m 2 ) If value is > 60, report as “>60 mL/min/1.73 m 2 ” Limited by calibration variability, imprecision, and MDRD equation accuracy

14. Clinical issues to communicate Creatinine reference interval change Creatinine clearance change if urine and serum calibrations are affected differently IDMS-calibrated creatinine results will affect decision algorithms used to adjust drug doses Cockcroft-Gaultestimation or creatinine clearance is commonly used by pharmacists (mfr. claims) Criteria based only on serumcreatinine concentration Pediatrics: recommend a measured GFR or creatinine clearance for critical and potentially toxic drug effects

15. Effect of ≠ equations on eGFR Serum creatinine is measured with an IDMS-traceable enzymatic method (Roche); N = 375 Serum creatinine (  mol/L) eGFReGFR

16. eGFR regression: Cockroft-Gault versus 4 parameter IDMS_MDRD Amphia database; N = 375 eGFR estimates are derived from enzymatic serum creatinine (Roche)

17. II. IVD manufacturer issues - Creatinine standardization programme Eliminate the bias between different methods Make calibration traceable to IDMS reference measurement procedure (gold standard) Improve the accuracy and consistency of estimated GFR Creatinine results for most methods will be 10- 20% lower after standardization IVD manufacturers expect two years to implement recalibration of existing methods

18. Calibration Traceability - Routine Serum Creatinine Methods 1˚ RMP MFR Selected Method Routine Method Clinical Sample Result 1˚ Calibrator 2˚ Reference Materials Product Calibrators NIST SRM 914a GC-IDMS & LC-IDMS NIST SRM 967

19. III. SKML issues Accommodate grading of results from participants during the transition from conventional to IDMS-traceable calibration A bimodal distribution of results may occur Communicate with IVD manufacturers regarding timing of calibration standardization Introduce programs that use commutable serum materials and evaluate eGFR performance

20. Survey 2006.1 Creatinine, sample: C EQA-material is commutable since January 2005

21. Introductie CNS CNS: Combi Nieuwe Stijl (commuteerbaar EQA-materiaal; waardetoekenning met referentiemethode) Desirable imprecision

22. Effect of IVD/98/79 EC implementation and introduction of commutable EQA-materials on mean absolute bias (MAB) in the Netherlands % MAB Desirable bias

23. EQA provider / SKML chemistry section:  post-market vigilance of analytical performance  tools: trueness controls Clinical chemist  in case of excessive bias: temporary (re)calibration  tools: secondary reference materials < SKML Manufacturer & directive 98/79/EC on IVD-MD & JCTLM Traceability chain CLUE = commutability

24. Summary Report eGFR with creatinine results using the correct 4P-MDRD equation. Limitations! Coordinate use of a creatinine method with IDMS-traceable calibration with use of the IDMS- traceable MDRD equation. Transition! Communicate the clinical issues associated with IDMS-traceable creatinine results.

25. SKML - Chemistry Section Dr. P.F.H. (Paul) Franck Ziekenhuis Leyenburg DEN HAAG Dr. H. (Henk) Baadenhuijsen UMC St Radboud NIJMEGEN Dr. C.W. (Cas) Weykamp Streekziekenhuis Kon. Beatrix WINTERSWIJK Dr. Ch.M. (Christa) Boersma-Cobbaert Amphia Ziekenhuis BREDA Dr. M.H.M. (Marc) Thelen Sint Annaziekenhuis GELDROP Dr. ir. A.W.H.M. (Aldy) Kuypers Maasziekenhuis Pantein BOXMEER Adviseurs: Herman Steigstra & Wim De Jongh

26. ALL THINGS ARE READY IF OUR MINDS BE SO William Shakespeare Henry V Kreatinine Verklaard !?