Cystatin C A Clinician

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Cystatin C A Clinicians Perspective
Cystatin C A Clinicians 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)
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Publications on Cystatin C since 1985
Cystatin C potential renal function parameter
Development of automated test kits
3
Variability of 24-hour Creatinine-Clearance
Coefficient of Variation ()
10 consecutive measurements in 16 children (10m,
6f),mean age 12 years
70
60
50
40
30
20
10
0
S-Crea
Schwartz
cCrea
Crea excretion
Urine flow
Bökenkamp et al, unpublished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
Dialysis
Kidney Transplantation ARF
Reference range
Correlation withgold-standard GFR
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Serum Creatinine - Children -
Creatinine µmol/L
Age years
Bökenkamp et al, Ped Nephrol 1998
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Serum Cystatin C - Children -
Cystatin C mg/L
Reference rangegt 1st year of life 0.7 - 1.38
mg/L (PETIA)
Age years
Bökenkamp et al, Ped Nephrol 1998
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Reference Values for Cystatin C - PETIA vs.
PENIA -

• Children Range
• PETIA (DAKO) 0.70 - 1.38 mg/Ln
  187, Pediatr. Nephrol. 12 (1998) 125-9
• PENIA (Behring) 0.51 - 0.95 mg/Ln
  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
Serum Cys C (mg/l)

• 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

P lt 0.01
Eriksson et al, Arterioscler Throm Vasc Biol 2004
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Cystatin C in Spina bifida
N 27 children Abnormal GFR in
3/27 DTPA-clearance Cut-off 90 ml/min/1.73m2
Cystatin C (AUC 0.952 0.051) Schwartz-GFR
(AUC 0.764 0.125) P lt 0.05
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

Cystatin C
Cockcroft Gault
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
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Performance of GFR-Prediction Formulae in Children
Cystatin C
Counahan-Schwartz
logGFR 1.962 ?1.123 log (1/CysC)?
GFR height k / creatininek 38, in
pubertal boys k 48
Filler et al, Pediatr.Nephrol. 2003
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Imprecision of Different Formulae for the
Prediction of GFR- MDRD-Study, n 558 -
Intraindividual variability of inulin clearance
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Levey et al, Ann. Intern. Med. 1999
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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
Dialysis
Kidney Transplantation ARF
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
mgl/l
µmol/l
left
right
right
left
control nefrectomy
Days after left nefrectomy
Days after left nefrectomy
Bökenkamp, Renal Failure 2001
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Cystatin C and Creatinine after Kidney
Transplantation

Creatinine µmol/l
Cystatin C mgl/l
RTx
mean SD
Time after transplantation days
Bökenkamp, Clin.Nephrol. 1999
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Cystatin C in Transplanted vs Non-transplanted
Patients
Non-transplanted
Transplanted
1 / Cystatine C (l/mg)
Cin (ml/min 1.73 m2)
Bökenkamp et al, Clin.Chem.1999
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Influence of Corticosteroids on Cystatin C
Concentration
0.5 g Metpred CyA Aza lt 10 mg Pred CyA
Aza CyA Aza CyA
3 x Methylpred. bolus 0.5 g A - 17 dags prior
(2 - 67) B before Methylprednisolone C 3
days D 8 days (6 - 11)
Risch et al, Clin.Chem.2001
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Steroid Therapy of Nephrotic Syndrome- Effect on
GFR Markers -
Serum-Albumin
Cystatin C
mg/l
Legend recurr Recurrence cont Prednisone
60 mg/m2 d alt Prednisone 45 mg/m2
48h remiss Remisson
g/dl
recurr. cont. alt. remiss.
recurr. cont. alt. remiss.
ml/min1.73m2
Schwartz-GFR
ß2-Microglobulin
mg/l
recurr. cont. alt. remiss.
recurr. cont. alt. remiss.
Bökenkamp et al, Clin. Chem. 2002
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Prediction of ARF by Cystatin C- Study Design -
Definition of ARF by creatinine-based
RIFLE-criteria
R delta creat gt 50 I delta creat gt
100 F delta creat gt 200
I day-2
I day 0
F day-2
F day 0
R day-2
R day 0
Herget-Rosenthal et al, KI 2004
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Prediction of ARF- RIFLE-Criterium R -
Serum cystatin C Serum creatinine
Creat ANV

CysC ANV



R- 3 R 2 R 1 R
0 R1
Herget-Rosenthal et al, KI 2004
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Prediction of ARF by Cystatin C
Definition of ARF by creatinine-based
RIFLE-criteria
Herget-Rosenthal et al, KI 2004
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Prediction of RRT by LMW-Proteinuria-
Measurement 4 days prior to start RRT -

• IC patients
• Rapid rise in creatinine
• 3 ARF criteria
• FENa gt1- Casts- Art. hypotension-
  Sepsis/SIRS- Rhabdomyolysis- Nephrotox. med

Cut-off
Herget-Rosenthal et al, Clin Chem 2004
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Incidence of Heart Failure in the Elderly- Based
on GFR-markers 8 years before -
Unadjusted incidence 5th quintiles CysC gt
1.26 mg/l Creat gt 85 µmol/l f gt 111µmol/l
m MDRD lt 58.6 ml/min
Sarrnak et al, Ann.Intern. Med. 2005
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Risk for Heart Failure in the Elderly- Based on
GFR-markers 8 years before -
Hazard ratios adjusted for age, sex, ethnic
background and traditional cardiovascular risk
factors.
Sarnak et al, Ann.Intern. Med. 2005
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All-cause Mortality in Elderly- Based on
GFR-markers 8 years before -
Annual mortality rate classified by serum
creatinine and cystatin C quintiles
Shlipak et al, NEJM 2005
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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
Rel. rise from upper reference value
ROC-analysis
Cystatin C
Creatinine-blind range
AUC Cys 0.954CG 0.873Creat 0.812 P
lt 0.05
Creatinine
N 52 adults 51Cr-EDTA clearance Cut-off 80
ml/min/1.73m2
Mussap et al, Kidney Int. 2002
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Longitudinal Follow-up Diabetes Mellitus Type 2
Cystatin C
Cockroft-Gault
Within-individual residual SD Ciothalamate 12.1
100/Cys 9.0 100/Creat 13.8 CG 14.2 MDRD 16.6
Creatinine
MDRD
Perkins et al, JASN 2005
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Longitudinal Change in GFR in Diabetes mellitus
Type 2
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
• gt cystatin C creatinine
• Acute renal failure
• gt cystatin C (serum urine) /- creatinine
• Follow-up chronic renal disease
• gt cystatin C (serum urine) /- creatinine
• Quality of dialysis / indication for dialysis
• gt urea creatinine
• Kidney function in utero gt cystatin C
  ß2-microglobulin (fetal serum / urine)
• Altered metabolism with- thyroid dysfunction-
  high-dose corticosteroids?

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Questions?