cystatin c a clinician‘s perspective
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Cystatin C A Clinician‘s Perspective. Cystatin C A Clinician‘s Perspective. A. Bökenkamp, MD PhD Pediatric Nephrology, Vrije Universiteit Medical Center, Amsterdam (NL). A. Bökenkamp, MD PhD Pediatric Nephrology, Vrije Universiteit Medical Center, Amsterdam (NL). - PowerPoint PPT PresentationTRANSCRIPT
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)
Publications on Cystatin C since 1985
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1985 1987 1989 1991 1993 1995 1997 1999 2001 2003
„Cystatin C = potential renal function parameter“ Development of automated test kits
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Bökenkamp et al, unpublished
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
Serum Creatinine - Children -
Age [years]
Creatinine [µmol/L]
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Bökenkamp et al, Ped Nephrol 1998
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)
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]
Polymorphisms in the Cystatin C Promotor
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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
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
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
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
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
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%
Scatter between Surrogate GFR Markers and CIothalamate
Perkins et al, JASN 2005
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
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
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
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
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)
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
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
]
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%
Prediction of ARF- RIFLE-Criterium „R“
-
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
*
**
*
Prediction of ARF by Cystatin C
Herget-Rosenthal et al, KI 2004
Definition of ARF by creatinine-based RIFLE-criteria
Prediction of RRT by LMW-Proteinuria
- Measurement ± 4 days prior to start RRT -
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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
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
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.
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
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!
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
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%
Longitudinal Change in GFR in Diabetes mellitus Type 2
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Follow-up (years)
ml/
min
/1.7
3m2
GFR100/Cys100/CreaCGMDRD
Perkins et al, JASN 2005
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.
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?
Questions?