Kreatinine Verklaard !?Kreatinine Verklaard !?

eGFR introductie eGFR introductie anno 2006 anno 2006

Take-home-messages Take-home-messages

CM Cobbaert14 september 2006

Chronische nierinsufficientieChronische nierinsufficientie

• Toenemende incidentie/prevalentie CNIToenemende incidentie/prevalentie CNI• Onderdiagnostiek en onderbehandelingOnderdiagnostiek en onderbehandeling

–sCr = ongevoelige marker voor detectie CNIsCr = 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 Betrouwbare eGFR mitsmits adequate assay/standaardisatie SCr adequate assay/standaardisatie SCr

------------------------------------------------------------------------------------------------------------------------------------•Rol klinisch chemische labs, diagnostica industrie en SKML!Rol klinisch chemische labs, diagnostica industrie en SKML!

IntroductieIntroductie

100

GFR estimationPercent of estim ates within 30% of the m easuredGFR in the M DRD Study validation sam ple (n = 558).

80

60

40

20

0Reciproca l

SCr

Cockroft-Gault

24-HourCreatinineClearance

Rec iproca lSCr [C]

Cockroft-G ault [C]

24-Hou rCreat inineClearance

[C]

M DRD 6Parameter

MDRD 4Parameter

Redr awn from: K/ DOQI Cli nical pra ctice guideli nes for chronic kidne y disease. Am J Kidne y Dis 2002;39:S1-S266.

Creat clearance estimate

GFR estimate

NKDEP recommends the MDRD fourparameter estimation equation for

adults age 18 and older

GFR (mL/min/1.73 m2) =

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

4P-MDRD equation limitations

• Applicable in adult (18-70 years) whites andAfrican-Americans with chronic GFR <90mL/min/1.73m2

Acceptable performance for diabetics

• Agreement with measured GFR is poorer for: Hospital inpatients Acute renal failure Normal renal function

• Validation is underway for additional ethnicgroups, patient groups, and individuals withnormal renal function

Creatinine measurement limitations affecting the 4 P-MDRD

• Conventional calibration has not beenstandardized among methods

Original MDRD equation was based on Beckman CX3routine method results from Cleveland Clinic

• Jaffe method non-specificity influences onindividual patient creatinine results

• Measurement bias and imprecision have a largerimpact on result variability as creatinine valuesget lower (GFR gets higher)

Impact of creatinine bias on GFRBias, 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

0 20 40 60 80 100 120

eGFR without bias in serum creatinine, mL/min/1.73 m2

Myers et al. Clin Che m 2006;52:5-18

Large effects > 60

Impact of imprecision on GFR

160

140

120

100

80

60

40

20

0

95% Confidence Interva l for eGFRat creatinine = 88.4 mol/L (1 mg/dL) 53-70 mL/min/1.73m2 at SD = 5.3 mol/L46-85 mL/min/1.73m2 at SD = 11.5 mol/L

0.0 1.0 2.0 3.0 4.0Creatinine, mg/dL

Myers et al. Clin Che m 2006;52:5-18

88.4 µmol/L

What creatinine methodperformance is needed?

Total error in creatinine measurement is not toincrease the variability in eGF R more than10% in the critical creatinine range 1.0-1.5mg/dL (88-133 μmol/L)

Comparable performance is needed in the 0.6-1.0 mg/dL (53-88 μmol/L) range for pediatricpatients and to extend eGF R to higher values

Method non-specificity also needs to beaddressed

Total Error budget for creatininemeasurement in the range 88-133 µmol/L

Myers et al. Clin Che m 2006;52:5-18

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 issimilar to that of the routine method used in the MDRDstudy.

• Use the IDMS-traceable 4P-MDRD equation formethods calibrated to IDMS

• Use creatinine reported to two decimals (mg/dL),or nearest whole number (µmol/L), in the MDRDcalculation

Reporting 4 P - MDRD

• Report GFR selectively (metabolic stable pts) (Consider if appropriate for inpatients)

• Report two values?

GFRest if African-AmericanCaucasian

• If value is ≤ 60, report rounded to a wholenumber (e.g. 53 mL/min/1.73 m2)

• If value is > 60, report as “>60 mL/min/1.73 m2”Limited by calibration variability, imprecision, andMDRD equation accuracy

Clinical issues to communicate

• Creatinine reference interval change

Creatinine clearance change if urine and serumcalibrations are affected differently

• IDMS-calibrated creatinine results will affectdecision algorithms used to adjust drug doses

Cockcroft-Gaul t estimation or creatinine clearance iscommonly used by pharmacists (mfr. claims)

Criteria based only on seru m creatinine concentration

Pediatrics: recommend a measured GFR or creatinineclearance for critical and potentially toxic drug effects

0,0

50,0

100,0

150,0

200,0

250,0

0 50 100 150 200 250 300 350 400 450 500 550 600 650 700 750 800 850 900 950 1000

Krea (umol/l)

Equ

atio

n

Cockroft-G

MDRD (ext)

MDRD (simple)

MDRD (IDMS)

Effect of ≠ equations on eGFR

Serum creatinine is measured with an IDMS-traceable enzymatic method (Roche); N = 375

Serum creatinine (mol/L)

eGFR

eGFR regression:

Cockroft-Gault versus 4 parameter IDMS_MDRD

y = 1,2343x + 1,1437

0

50

100

150

200

250

0 20 40 60 80 100 120

MDRD (IDMS)

Co

ckro

ft-G

Amphia database; N = 375

eGFR estimates are derived from enzymatic serum creatinine (Roche)

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 ofestimated GFR

• Creatinine results for most methods will be 10-20% lower after standardization

• IVD manufacturers expect two years toimplement recalibration of existing methods

Calibration Traceability Calibration Traceability - Routine Serum Creatinine Methods- Routine Serum Creatinine Methods

11˚ RMP˚ RMP

MFR Selected MethodMFR Selected Method

Routine MethodRoutine Method

Clinical Sample Result

11˚ Calibrator˚ Calibrator

22˚ Reference Materials˚ Reference Materials

Product CalibratorsProduct Calibrators

NIST SRM 914a

GC-IDMS & LC-IDMS

NIST SRM 967

III. SKML issues

• Accommodate grading of results fromparticipants during the transition fromconventional to IDMS-traceable calibration

A bimodal distribution of results may occur

• Communicate with IVD manufacturers regardingtiming of calibration standardization

• Introduce programs that use commutable serummaterials and evaluate eGFR performance

Survey 2006.1 Creatinine, sample: C

EQA-material is commutable

since January 2005

Kreatinine: verloop tussenlab precisies in Nederland in de periode 2003-2006

0,0

0,5

1,0

1,5

2,0

2,5

3,0

3,5

4,0

4,5

2003 2003,5 2004 2004,5 2005 2005,5 2006 2006,5

Jaar en ronde

Pre

cisi

e Jaffe

Enzymatisch

Vitros

Introductie CNS

CNS: Combi Nieuwe Stijl (commuteerbaar EQA-materiaal; waardetoekenning met referentiemethode)

Desirable imprecision

% MAB

0

1

2

3

4

5

6

7

Dry chemistry Enzymatic creatinine Total Jaffe

%

2003-2004

2005-2006

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

% MAB

Desirable bias

EQA provider / SKML EQA provider / SKML chemistry section:chemistry section:

post-market vigilance of post-market vigilance of analytical performanceanalytical performance

tools:tools: trueness controlstrueness controls

Clinical chemistClinical chemist in case of excessive bias: in case of excessive bias:

temporary (re)calibrationtemporary (re)calibration tools:tools: secondary reference secondary reference

materials < SKMLmaterials < SKML

ManufacturerManufacturer& directive 98/79/EC& directive 98/79/ECon IVD-MD & JCTLMon IVD-MD & JCTLM

Traceability Traceability chainchain

CLUE =

commutability

Summary

• Report eGFR with creatinine results using thecorrect 4P-MDRD equation. Limitations!

• Coordinate use of a creatinine method withIDMS-traceable calibration with use of the IDMS-traceable MDRD equation. Transition!

• Communicate the clinical issues associated with IDMS-traceable creatinine results.

SKML - Chemistry SectionSKML - 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

ALL THINGS ARE READY IF OUR MINDS BE SO

William Shakespeare Henry V

Kreatinine Verklaard !?Kreatinine Verklaard !?