Kreatinine Verklaard !?

1
Kreatinine Verklaard !?

• eGFR introductie anno 2006
• Take-home-messages

CM Cobbaert 14 september 2006
2
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!

3

• Introductie

I. Lab issues choices have to be made!
4
GFR

estimation



Perc
e
nt

of

es
tim
ate
s

within

30


of

th
e

m
eas
ur
e
d
G
FR

in

th
e

M

DRD

Study

va
lid
a
tion

sa
m

pl
e

(n



558
).
10
0
GFR estimate
8
0
Creat clearance estimate
6
0
4
0
2
0
0
Coc
kroft-
2
4-H
o
ur
Cockro
ft
-
24
-H
ou
r

Re
c
i
p
r
oca
l
Rec
i
p
r
oca
l
M
D
RD

6
M
DRD

4

G
au
l
t
C
r
e
at
i
n
i
n
e
G
au
l
t
C
C
reat
i
n
i
n
e
SC
r
SC
r

C
Pa
rameter
Pa
rameter
C
l
eara
n
ce
C
l
earance

C
Redr
a
wn from K/
D
OQI Cli
n
ical pra
c
tic
e
gui
d
eli
n
es for chronic kidne
y
disease. Am
J

Kidne
y

Di
s
20
0
2
3
9
S
1-S
2
66.
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)


u
se 186 for CONVENTIONAL calibration


u
se 175 for calibration TRACEABLE TO IDMS
6
4P-MDRD equation limitations
Applicable in adult (18-70 years) whites and

African-Americans with chronic GFR lt90
mL/min/1.73
m
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
14
0
- 5
-8

mL/min



-12

error
0
12
0
5
-17

mL/min



-27

error
10
0
11
8
0
27
6
0
4
0
2
0
Large effects gt 60
0
0
20
40
60
80
1
0
0
12
0
2
eGFR without bias in serum
c
r
e
a
tinine, mL/min/1.73 m
M
y
ers et al. Cli
n

Che
m

2006525-18
9
Impact of imprecision on GFR
160
95

Confidence

Interva
l

for

eGFR
140
at

creatinine



88.4 ?mol/L (1 mg/dL)

53-70

mL/min/1.73
m
at SD 5.3 ?mol/L
120
2

46-85

mL/min/1.73
m
at SD 11.5 ?mol/L
2

100
80
60
40
20
0
88.4 µmol/L
0.
0
1
.
0
2.
0
3
.
0
4.0
Creatinine, mg/dL
M
y
ers et al. Cli
n

Che
m

2006525-18
10
What creatinine method
performance

is

needed?
Total

error

in

creatinine

measurement

is

not

to
increase

the

variability

in

eGF
R
more

than
10

in

the

critical

creatinine

range

1.0-1.5
mg/dL (88-133
µ
mol/L)
Comparable performance is needed in the 0.6-
?
1.0

mg/dL

(
53-88
µ
mol/L) range for pediatric
patients and to extend eGF
R
to higher values
Method non-specificity also needs to be
?
addressed
11
Total Error budget for creatinine
measurement in the range 88-133 µmol/L
M
y
ers et al. Cli
n

Che
m

2006525-18
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
if

African-American Caucasian
?
est




If

value

is
60,

report

rounded

to

a

whole



number

(e.g.

53

mL/min/1.73

m
)
2
If

value

is

gt

60,

report

as

gt60

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-Gaul
t
estimation or creatinine clearance is
?
commonly used by pharmacists (mfr. claims)
Criteria based only on seru
m
creatinine concentration
?
Pediatrics recommend a measured GFR or
creatinine
?
clearance for critical and potentially toxic drug
effects
15
Effect of ? equations on eGFR
eGFR
Serum creatinine is measured with an
IDMS-traceable enzymatic method (Roche) N 375
Serum creatinine (?mol/L)
16
eGFR regression Cockroft-Gault versus 4
parameter IDMS_MDRD
Creatinine clearance estimate
Amphia database N 375 eGFR estimates are
derived from enzymatic serum creatinine (Roche)
GFR estimate
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 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
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
Desirable imprecision
Introductie CNS
CNS Combi Nieuwe Stijl (commuteerbaar
EQA-materiaal waardetoekenning met
referentiemethode)
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
Manufacturer directive 98/79/ECon IVD-MD
JCTLMTraceability chain
Monitoring sCr std. efforts

• 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 lt SKML

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














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

Thanks!