Download - Cystatin C A Clinician‘s Perspective
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Cystatin C
A Clinician‘s Perspective
A. Bökenkamp, MD PhD
Pediatric Nephrology, Vrije Universiteit Medical Center, Amsterdam (NL)
Cystatin C
A Clinician‘s Perspective
A. Bökenkamp, MD PhD
Pediatric Nephrology, Vrije Universiteit Medical Center, Amsterdam (NL)
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Publications on Cystatin C since 1985
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„Cystatin C = potential renal function parameter“ Development of automated test kits
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Variability of 24-hour Creatinine-Clearance
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S-Crea Schwartz cCrea Crea excretion Urine flow
Coefficient of Variation (%) 10 consecutive measurements
in 16 children (10m, 6f),
mean age 12 years
Bökenkamp et al, unpublished
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Clinical Indications for the Assessment of Kidney Function
GFR in "Steady State"
Changes in GFR Kidney functionon dialysis
Korrelation mit
Inulin clearance
Kidney Transplantation
ARFDialysis
Reference range
Correlation withgold-standard
GFR
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Serum Creatinine - Children -
Age [years]
Creatinine [µmol/L]
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Serum Cystatin C - Children -
Age [years]
Cystatin C [mg/L]
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Bökenkamp et al, Ped Nephrol 1998
Reference range> 1st year of life
0.7 - 1.38 mg/L (PETIA)
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Reference Values for Cystatin C - PETIA vs. PENIA -
Children Range
PETIA (DAKO) 0.70 - 1.38 mg/L[n = 187, Pediatr. Nephrol. 12 (1998): 125-9]
PENIA (Behring) 0.51 - 0.95 mg/L[n = 96, Clin.Chem 45 (1999): 1856-8]
Adults Range
PETIA (DAKO) 0.70 - 1.21 mg/L [n = 121, Scand.J.Clin.Lab.Invest. 57 (1997): 463-70]
PENIA (Behring) 0.50 - 0.98 mg/L [n = 139, Clin.Chem. 47 (2001): 2031-3]
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Polymorphisms in the Cystatin C Promotor
0,66
0,68
0,7
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• Combined presence of impairing polymorphisms
-82 G/C, -78 T/G, -5 G/A, + 4 A/C, +148 G/A
• N = 639 healthy men age 50 years
• Frequency of haplotypes- wild-type 75%- mutant except pos. -5: 20%- mutant in all positions: 5%
Serum Cys C (mg/l)
P < 0.01
Eriksson et al, Arterioscler Throm Vasc Biol 2004
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Cystatin C in Spina bifida
Cystatin C (AUC 0.952 ± 0.051)
Schwartz-GFR (AUC 0.764 ± 0.125)
P < 0.05
N = 27 children
Abnormal GFR in 3/27
DTPA-clearance Cut-off 90 ml/min/1.73m2
Filler et al, J.Urol. 2003
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CyC based formula for GFR estimation
74.835• GFR estim. = ——————
CysC 1/0.75
Formula calculated by regression analysis
between serum Cysatin C
and inulin clearance in 209 patients with
different underlying renal disease.
Dade Behring, 2004
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Performance of GFR-Prediction Formulae in Adults
• 146 125J-Iothalamate-clearances in 123 adults (median age 50 y)
• Median GFR 81 ml/min/1.73m2 [12 - 157]
• Linear regression: GFR ~ 80/CysC - 4.3
Mean diff. -2,4 [-26.1 to 21.3 ml/min/1.73m2] Mean diff. 15.9 [-14.4 to 46.1 ml/min/1.73m2]
Hoek et al, NDT 2003
Cystatin C Cockcroft & Gault
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Performance of GFR-Prediction Formulae in Children
Filler et al, Pediatr.Nephrol. 2003
logGFR ~ 1.962 + 1.123 * log (1/CysC) GFR ~ height * k / creatinine[k = 38, in pubertal boys k = 48]
Cystatin C Counahan-Schwartz
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Imprecision of Different Formulae for the Prediction of GFR- MDRD-Study, n = 558 -
Levey et al, Ann. Intern. Med. 1999
Intraindividual variability of inulin clearance ~ 10%
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Scatter between Surrogate GFR Markers and CIothalamate
Perkins et al, JASN 2005
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Prediction of GFR from Serum Markers A Fata Morgana?
• Wide confidence intervals for GFR-prediction formulae using different
markers.
• May in part reflect variability of the „Golden Standard“ itself.
• In clinical practice, calculation of a surrogate GFR is still useful.
• Cystatin C-derived formulae perform at least equally to creatinine-based
formulae.
• Cystatin C-based GFR-estimations are independent of anthropomorphometric
data and can be done directly in the lab.
• In situations with alterations in creatinine production, Cystatin C is mandatory
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Clinical Indications for the Assessment of Kidney Function
GFR in "Steady State"
Changes in GFR
Kidney functionon dialysis
Korrelation mit
Inulin clearance
Kidney Transplantation
ARFDialysis
Reference range
Correlation withgold-standard
GFR
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Is Cystatin C Eliminated by Dialysis?
• No significant elimination by conventional hemodialysis(Kabanda et al: Kidney Int. 46 (1994): 1689 - 96)
• No significant elimination by peritoneal dialysis(Kabanda et al: Kidney Int. 48 (1995): 1946 - 52)
Cystatin C ß2-Microglobuline
Molecular weight 13.3 kDa 11.8 kDa
Reference range 0.7 - 1.4 mg/l 0.4 - 2.3 mg/l
Concentration pre-HD 7 - 11 mg/l 40 - 60 mg/l
x 10 x 30 - 100
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Sequential Bilateral Nephrectomy in a Rat Model
Cystatin C Creatinine[µmol/l] [mgl/l]
rightleft
left
Days after left nefrectomy
right
Days after left nefrectomy
control
nefrectomy
Bökenkamp, Renal Failure 2001
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Cystatin C and Creatinine after Kidney
Transplantation
Time after transplantation [days]
mean ± SD
Creatinine [µmol/l]
Cystatin C [mgl/l]RTx
Bökenkamp, Clin.Nephrol. 1999
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Cystatin C in Transplanted vs Non-transplanted Patients
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1 / C
ysta
tine
C (
l/m
g)
Cin (ml/min • 1.73 m2)
Transplanted
Non-transplanted
Bökenkamp et al, Clin.Chem.1999
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Influence of Corticosteroids on Cystatin C Concentration
0.5 g Metpred + CyA + Aza
< 10 mg Pred + CyA + Aza
CyA + Aza
CyA
Risch et al, Clin.Chem.2001
3 x Methylpred. bolus 0.5 g:
A - 17 dags prior (2 - 67)
B before Methylprednisolone
C + 3 days
D + 8 days (6 - 11)
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Steroid Therapy of Nephrotic Syndrome
- Effect on GFR Markers -
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S c h wa rtz -GF R
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A lb u min
Serum-Albumin
Schwartz-GFR
Cystatin C
ß2-Microglobulin
recurr. cont. alt. remiss.
recurr. cont. alt. remiss.
recurr. cont. alt. remiss.
recurr. cont. alt. remiss.
Legend
„recurr“ = Recurrence
„cont“ = Prednisone 60 mg/m2 • d
„alt“ = Prednisone 45 mg/m2 • 48h
„remiss“ = Remisson
mg/l
mg/l
g/dl
ml/min•1.73m2
Bökenkamp et al, Clin. Chem. 2002
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Prediction of ARF by Cystatin C
- Study Design -
Herget-Rosenthal et al, KI 2004
Definition of ARF by creatinine-based RIFLE-criteria:
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Days
Se
rum
cre
ati
nin
e [
mg
/dL
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F day-2
I day-2 I day 0
F day 0
R day-2 R day 0
„R“ = delta creat > 50%
„I“ = delta creat > 100%
„F“ = delta creat > 200%
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Prediction of ARF- RIFLE-Criterium „R“
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Herget-Rosenthal et al, KI 2004
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Days to ARF
S-c
ysC
[m
g/l
]/S
-cre
a [
mg
/dl] Serum cystatin C
Serum creatinine Creat: ANV
CysC: ANV
R- 3 R– 2 R– 1 R 0 R+1
*
**
*
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Prediction of ARF by Cystatin C
Herget-Rosenthal et al, KI 2004
Definition of ARF by creatinine-based RIFLE-criteria
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Prediction of RRT by LMW-Proteinuria
- Measurement ± 4 days prior to start RRT -
0.01
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1000
Cystatin C Alpha1 NAG Liano-score
RRT- RRT-RRT+RRT+RRT+RRT+ RRT- RRT-
mg
/g c
reat
inin
e
Herget-Rosenthal et al, Clin Chem 2004
= Cut-off
IC patients
Rapid rise in creatinine
≥ 3 ARF criteria:
- FENa >1%- Casts- Art. hypotension- Sepsis/SIRS- Rhabdomyolysis- Nephrotox. med
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Incidence of Heart Failure in the Elderly- Based on GFR-markers ± 8 years before -
Sarrnak et al, Ann.Intern. Med. 2005
Unadjusted incidence
5th quintiles:
CysC > 1.26 mg/l
Creat > 85 µmol/l f
> 111µmol/l m
MDRD < 58.6 ml/min
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Risk for Heart Failure in the Elderly
- Based on GFR-markers ± 8 years before -
Sarnak et al, Ann.Intern. Med. 2005
Hazard ratios adjusted for age, sex, ethnic background and traditional cardiovascular risk factors.
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All-cause Mortality in Elderly- Based on GFR-markers ± 8 years before
-
Shlipak et al, NEJM 2005
Annual mortality rate classified by serum creatinine and cystatin C quintiles
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But ....
• No adjustment for Gold-standard GFR made in studies
identifying cystatin C as risk factor for heart-disease
• Does increase in cystatin C merely reflect mild renal
insufficiency or a separate pathological mechanism?
• Direct toxicity of cystatin C?
• Low cystatin C levels in documented atherosclerosis/
aortic aneurysm!
• No signs of disease in the cystatin C knock-out mouse!
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Cystatin C in Diabetes mellitus Type 2
Mussap et al, Kidney Int. 2002
Cystatin C
Creatinine
Rel. rise from upper reference value ROC-analysis
AUC
Cys 0.954CG 0.873Creat 0.812
P < 0.05
N = 52 adults; 51Cr-EDTA clearance; Cut-off 80 ml/min/1.73m2
Creatinine-blind range
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Longitudinal Follow-up Diabetes Mellitus Type 2
Cystatin C
Creatinine
Cockroft-Gault
MDRD
Perkins et al, JASN 2005
Within-individual residual SD:
Ciothalamate 12.1%
100/Cys 9.0%
100/Creat 13.8%
CG 14.2%
MDRD 16.6%
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Longitudinal Change in GFR in Diabetes mellitus Type 2
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0 1 2 3
Follow-up (years)
ml/
min
/1.7
3m2
GFR100/Cys100/CreaCGMDRD
Perkins et al, JASN 2005
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Cystatin C as a Marker of GFR
• Facilitates assessment of renal function due to constant reference values.
• Allows for estimation of GFR independent of body composition.
• Allows for earlier detection of incipient acute renal failure.
• Detects mild deterioration of GFR during follow-up.
• Predicts heart failure / mortality (from CRF?) in the elderly.
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When to Order Which Renal Function Test?
• First consultation:
=> cystatin C + creatinine
• Acute renal failure:
=> cystatin C (serum & urine) +/- creatinine
• Follow-up chronic renal disease:
=> cystatin C (serum & urine) +/- creatinine
• Quality of dialysis / indication for dialysis:
=> urea + creatinine
• Kidney function in utero: => cystatin C + ß2-microglobulin (fetal serum /
urine)
• Altered metabolism with:
- thyroid dysfunction
- high-dose corticosteroids?
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Questions?