Transcript The NEW Chronic Kidney Disease Testing Guidelines: Effects

ANALYTICAL AND CLINICAL EFFECTS OF
CREATININE STANDARDISATION
• Prof. J. Delanghe,
MD, PhD
• Dept. Clinical
Chemistry
• Ghent University
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Creatinine according to Jaffe….
• Analysis following
deproteinisation
• pseudochromogens 
time window
• Lloyds’s reagent
• optimalisation
• extremely cheap
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Jaffe reaction
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VARIATION BETWEEN METHODGROUPS
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Variability in Jaffé’s method (I)
(Hanser et
al, Ann Biol Clin 2001;59:737-42)
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Technical evolution
• 1954 Skeggs: dialysis membrane
• 1970 centrifugal analyzer→ no longer
dialysis step!→ protein error
introduced
• 1980 random acess analyzer
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The protein error got into the
determination!
• 1970 - 2000: Jaffé rules the creatinine
market in Europe and VS
• Protein error leads to underestimation
of GFR! (CrCl << GFR)
• some enzymatical determinations
recalculated to Jaffé-equivalence!
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What happened with creatinine?
• Protein error got into the
determination!
• Only ref. values were adapted!!!!
• Physiology books, derived formulas,
• pharmacokinetics??????
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Pseudochromogens
• Enzymatic methods theoretically
eliminate effect of pseudochromogens
• Not widely used (cost price)
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Creatinine clearance
• urine collection often difficult in
practice
• Intra individual CV 10 %
• practical formulas:
• e.g. Cockroft & Gault Nephron
1976;16:31-41
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COCKROFT & GAULT
Cl = (140 -L) (year) x W(kg)
S (mg/dl) x 72
for women  result x 0.85
MDRD (classical)
GFR (mL/min/1.73 m2) = 186 x (Scr)-1.154 x (Age)-0.203 x (0.742 if female) x
(1.210 if African American)
SCHWARTZ
practical in children and infants
GFR (ml/min/1.73 m2) = 0.55 x L (cm)/P (mg/dl)
(Pediatrics 1976; 58:259)
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7.12.2003 CE GUIDELINES
• CE Guideline 98/79/EG on in-vitro diagnostics
• PROBLEMS:
• Calibration using standard of “higher order”
• link with literature?
• What with derived calculations?
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Creatinine Clearance
(enzymatic)
200
180
160
140
120
100
80
60
Jaffé
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Jaffé compensated
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0
0
50
100
150
200
Creatinine Clearance (Jaffé and Jaffé compensated)18
REALITY AND THEORY IN
DISAGREEMENT!
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serum creatinine
Jaffé compensated
Jaffé
Creatinine in children
3,5
3
2,5
2
1,5
1
0,5
0
0
0,5
1
1,5
2
2,5
3
3,5
serum creatinine enzymatisch21
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CREATININE IN CHILDREN
creatinine Jaffé compensated
1,2
y = -0,9926x3 + 2,2024x2 - 0,3023x
1
R2 = 0,9932
0,8
0,6
0,4
0,2
0
-0,2 0
0,5
1
1,5
cre atinine Jaffé nie t ge compe ns e e rd
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Clinical impact of a change in CrCl,
reference range
• Fields of potential risk
• drugs eliminated by renal excretion
aminoglycosides/glycopeptides/carboplatine
• Important for borderline Clcr for antibiotics
• management for some antineoplastic agents
• for clinical trials
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LOOKING INTO THE FUTURE
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Cystatin C vs. creatinine
• Advantages:
• 1/[Cys C] ~ GFR
• independent from muscle mass, diet
• urinary determination not needed
• valuable in the “blind range” zone of
creatinine
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NIST SRM 967
• Commutable reference material
• Submitted bij JCTML
• IDMS
• 0.8 mg/dl
• 4 mg/dl
• Revised MDRD
• Release postponed!!
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• PREPARATION OF SRM 967 CREATININE IN HUMAN SERUM
• Prepared at Solomon Park Research Institute, Kirkland, Washington
• Human serum with the following characteristics:
• Master Pool comprised of units drawn from postmenopausal female
donors
• to yield pool with creatinine of 0.8 mg/dL or lower.
• Collected and handled following NCCLS C37-A
• All units tested and found negative for viral markers
• Pooled and split into 2 sub-pools:
• Low level, High level, second sub-pool spiked with crystalline
creatinine
• to bring the concentration to 4.0 mg/dL.
• LC/MS METHOD FOR SERUM CREATININE
• [P. Stokes, G. O’Connor, J Chromatog B 794, 125-136 (2003)]
• Spike serum with creatinine-d3, Precipitate proteins with cold
ethanol, Centrifuge, Decant supernatant and dry under nitrogen
• Reconstitute in water and filter, Dilute with 10 mM NH4 acetate
• LC/MS
• Phenomenex LUNA C-18; Gradient: 10 mM NH4 acetate for 7 min,
• Then acetonitrile:10 mM NH4 acetate (80:20) and hold for 13 min
• Electrospray ionization – positive mode monitoring (M+H)+ at 31
114/117
NIST SRM 967
• 2006-2009:Adaptation by IVD
industry
• 2010: problem solved?
• In the mean time MDRD is pushing!!!!
• Risks for confusion !
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Some Statistics (United States)
• End-stage renal disease (ESRD)
• Prevalence (2003): 452,957 U.S. residents were under
treatment
• Resulting from these primary diseases:
• Diabetes: 165,113
Hypertension: 109,642
Glomerulonephritis: 74,444
Cystic kidney: 20,409
All other: 83,349
• Number of kidney transplants performed
• 2003: 16,043
2000: 14,557
1995: 12,021
1990: 10,012
1988: 7,501
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• MDRD: THE SOLUTION??
• Limitations (age, CrCl value,
ethnicity,..)
• Confusion still ungoing
• “Some unwanted side effects”
• Drug dosage schemes!
• Pediatrics?
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• Conventional Calibration MDRD Equation
• This equation should be used only with those creatinine
methods that have not been recalibrated to be traceable
to IDMS. If you have any question about the traceability
of the calibration for the method, NKDEP recommends
that you contact the reagent and/or calibrator
manufacturer for assistance.
• The equation requires 4 variables:
• Serum, or plasma, creatinine (Scr)
• Age in years (18 years or older)
• Sex
• Race (African American or not)
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When Scr is in mg/dL (conventional units):
GFR (mL/min/1.73 m2) = 186 x (Scr)-1.154 x
(Age)-0.203 x (0.742 if female) x (1.210 if 35
African American)
CONFUSION……
• Conventional Calibration MDRD Equation
• should be used only with those creatinine methods that
have not been recalibrated to be traceable to IDMS. For
more information, visit NKDEP's Laboratory Professionals
section.
• GFR (mL/min/1.73 m2) = 186 x (Scr)-1.154 x (Age)0.203 x (0.742 if female) x (1.210 if African American)
(conventional units)
• IDMS-Traceable MDRD Equation
• should be used only with those creatinine methods that
have been recalibrated to be traceable to IDMS. For more
information, visit NKDEP's Laboratory Professionals section.
• GFR (mL/min/1.73 m2) = 175 x (Scr)-1.154 x (Age)-0.203 x
(0.742 if female) x (1.210 if African American) (conventional
units)
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• IDMS-Traceable MDRD Equation
• This equation should be used only with those
creatinine methods that have been calibrated to be
traceable to IDMS. If you have any question about the
traceability of the calibration for the creatinine
method, NKDEP recommends that you contact the
reagent and/or calibrator manufacturer for assistance.
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The equation requires 4 variables:
Serum, or plasma, creatinine (Scr)
Age in years (18 years or older)
Sex
Race (African American or not)
When Scr is in mg/dL (conventional units):
GFR (mL/min/1.73 m2) = 175 x (Scr)-1.154 x (Age)0.203 x (0.742 if female) x (1.210 if African
American)
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Conclusions (I)
• Compensated Jaffé method results in a
more correct approximation of GFR
• Cockroft & Gault, MDRD : only valid for
enzymatic or “compensated” methods
• Schwartz formula not usable for
compensated (or enzymatic) method!!!
• Adaptation of reference values is
insufficient !!!!!
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CONCLUSIONS (II)
• Careful when using nomograms for drug
dosage!
• Creatinine standardisation: situation is still
confuse! Vigilance necessary
• MDRD has limitations (CrCl value, age,
standardisation) which should be respected
• Task for industry, laboratories, clinicians,
pharmacists
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