Transcript Kreatinine Verklaard

Kreatinine Verklaard !?
eGFR introductie
anno 2006
Take-home-messages
CM Cobbaert
14 september 2006
Chronische nierinsufficientie
• Toenemende incidentie/prevalentie CNI
• Onderdiagnostiek en onderbehandeling
–sCr = ongevoelige marker voor detectie CNI
-----------------------------------------------------------------• Richtlijnen: rapporteer eGFR naast SCr!
• Keuze eGFR formule anno 2006: kritisch!
• Betrouwbare eGFR mits adequate assay/standaardisatie SCr
-----------------------------------------------------------------•Rol klinisch chemische labs, diagnostica industrie en SKML!
Introductie
GFR estimation
100
Percent of estimates within30% of the measured
GFR in the MDRD Studyvalidation sample (n = 558).
GFR estimate
80
Creat clearance estimate
60
40
20
0
Reciprocal
SCr
CockroftGault
24-Hour
Creatinine
Clearance
Reciprocal
SCr [C]
CockroftGault [C]
24-Hour
Creatinine
Clearance
[C]
MDRD 6
Parameter
MDRD 4
Parameter
Redrawn from: K/DOQI Clinical practice guidelines for chronic kidney disease. Am J Kidney Dis 2002;39:S1-S266.
NKDEP recommends the MDRD four
parameter 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 and
African-Americans with chronic GFR <90
mL/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 ethnic
groups, patient groups, and individuals with
normal renal function
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)
Impact of creatinine bias on GFR
Bias, mol/L
140
120
100
-5
-8 mL/min = -12% error
0
-17 mL/min = -27% error
5
11
80
27
60
40
20
Large effects > 60
0
0
20
40
60
80
100
120
eGFR without bias in serum creatinine, mL/min/1.73 m2
Myers et al. Clin Chem 2006;52:5-18
Impact of imprecision on GFR
160
95% Confidence Interval for eGFR
at creatinine = 88.4 mol/L (1 mg/dL)
53-70 mL/min/1.73m2 at SD = 5.3 mol/L
46-85 mL/min/1.73m2 at SD = 11.5 mol/L
140
120
100
80
60
40
20
0
88.4 µmol/L
0.0
1.0
2.0
Creatinine, mg/dL
Myers et al. Clin Chem 2006;52:5-18
3.0
4.0
What creatinine method
performance is needed?
Total error in creatinine measurement is not to
increase the variability in eGFR more than
10% in the critical creatinine range 1.0-1.5
mg/dL (88-133 μmol/L)


Comparable performance is needed in the 0.61.0 mg/dL (53-88 μmol/L) range for pediatric
patients and to extend eGFR to higher values
Method non-specificity also needs to be
addressed
Total Error budget for creatinine
measurement in the range 88-133 µmol/L
Myers et al. Clin Chem 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 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
Reporting 4 P - MDRD
• Report GFR selectively (metabolic stable pts)
(Consider if appropriate for inpatients)
• Report two values?
 GFRest if African-American
Caucasian
• If value is ≤ 60, report rounded to a whole
number (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, and
MDRD equation accuracy
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-Gault estimation or creatinine clearance is
commonly used by pharmacists (mfr. claims)
Criteria based only on serum creatinine concentration
Pediatrics: recommend a measured GFR or creatinine
clearance for critical and potentially toxic drug effects
Effect of ≠ equations on eGFR
250,0
200,0
150,0
Cockroft-G
Equation
e
G
F
R
MDRD (ext)
MDRD (simple)
MDRD (IDMS)
100,0
Serum creatinine is measured with an
IDMS-traceable enzymatic method (Roche);
N = 375
50,0
0,0
0
50
100
150
200
250
300
350
400
450
500
550
600
650
700
750
Krea (um ol/l)
Serum creatinine (mol/L)
800
850
900
950
1000
eGFR regression:
Cockroft-Gault versus 4 parameter IDMS_MDRD
250
200
Amphia
database; N =
375
Cockroft-G
150
eGFR
estimates are
derived from
enzymatic
serum
creatinine
(Roche)
100
50
y = 1,2343x + 1,1437
0
0
20
40
60
MDRD (IDMS)
80
100
120
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 1020% lower after standardization
• IVD manufacturers expect two years to
implement recalibration of existing methods
Calibration Traceability
- Routine Serum Creatinine Methods
1˚ Calibrator
NIST SRM 914a
1˚ RMP
GC-IDMS & LC-IDMS
2˚ Reference Materials
NIST SRM 967
MFR Selected Method
Product Calibrators
Routine Method
Clinical Sample
Result
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
Survey 2006.1
EQA-material is commutable
since January 2005
Creatinine, sample: C
Kreatinine: verloop tussenlab precisies in Nederland
in de periode 2003-2006
4,5
4,0
3,5
Precisie
3,0
Jaffe
Enzymatisch
Vitros
2,5
2,0
1,5
Desirable imprecision
1,0
0,5
0,0
2003
Introductie CNS
2003,5
2004
2004,5
2005
2005,5
2006
2006,5
Jaar en ronde
CNS: Combi Nieuwe Stijl (commuteerbaar EQA-materiaal; waardetoekenning met referentiemethode)
Effect of IVD/98/79 EC implementation and
introduction of commutable EQA-materials on
% MAB
mean absolute bias (MAB)
in the Netherlands
%7
% MAB
6
5
Desirable bias
4
2003-2004
2005-2006
3
2
1
0
Dry chemistry
Enzymatic creatinine
Total Jaffe
Manufacturer
& directive 98/79/EC
on IVD-MD & JCTLM
Traceability chain
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
CLUE =
commutability
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 IDMStraceable MDRD equation. Transition!
• Communicate the clinical issues associated
with IDMS-traceable creatinine results.
SKML - Chemistry Section
Dr. C.W. (Cas)
Weykamp
Dr. H. (Henk)
Dr. P.F.H. (Paul)
Baadenhuijsen Franck
Dr. ir. A.W.H.M.
(Aldy) Kuypers
Dr. M.H.M. (Marc) Dr. Ch.M. (Christa)
Thelen
Boersma-Cobbaert
Streekziekenhuis
Kon. Beatrix
UMC St Radboud
Ziekenhuis Leyenburg
Sint Annaziekenhuis
Amphia Ziekenhuis
NIJMEGEN
DEN HAAG
Maasziekenhuis
Pantein
GELDROP
BREDA
WINTERSWIJK
BOXMEER
Adviseurs:
Herman Steigstra & Wim De Jongh
Kreatinine Verklaard !?
ALL THINGS ARE
READY IF OUR MINDS
BE SO
William Shakespeare Henry V