Cystatin C A Clinician‘s Perspective

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

0

20

40

60

80

100

120

140

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

0

10

20

30

40

50

60

70

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Bökenkamp et al, unpublished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]

••

•••••

••••

••••

•••

•

••

•

•

•

•

••••••••••••••••••••••••

•

•

••

•

•

•••••••••••••••••

•

•••

•

•••

•

•••••••••••••••••

••••••

••••••••••••••••

•

•••••••

•

••••••••

•

•

••••••••••••••••••••••••••••••

•••••••••••••••••••

••••

•

•

••

••••

•

•

••••••••••••••

•

••••

•

••••••••••••••

••••••

••••••

••

•

•

•

••

•

••

••

•••

••

•

•

•

••

•••• •

0

20

40

60

80

100

0 2 4 6 8 10 12 14 16 18

Bökenkamp et al, Ped Nephrol 1998

Serum Cystatin C - Children -

Age [years]

Cystatin C [mg/L]

•••••••••••••

•••••••••••••••

••••

•

••

••

••••••••••••••••••••••

••

••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••

•••••••••••••••••••••••••••••••••••••••••••••••••

••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••

•

••••••

0

0,5

1

1,5

2

2,5

3

0 2 4 6 8 10 12 14 16 18

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

0,66

0,68

0,7

0,72

0,74

0,76

0,78

• 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

0

200

400

600

800

1000

0 2 4 6 8 10 12 14

0

1

2

3

4

5

0 2 4 6 8 10 12 14

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

•

••

•• • • • • • • • •

•

•• • • • • • • • • • •

0

100

200

300

400

500

600

700

800

900

0

1

2

3

4

5

6

7

8

9

-2 0 2 4 6 8 10 12

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

0

,2

,4

,6

,8

0 20 40 60 80

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 -

50

100

150

200

250

S c h wa rtz -GF R

,5

,6

,7

,8

,9

1,0

Cys

,4

,6

,8

1,0

1,2

1,4

1,6

1,8

2,0

ß 2 M

2,0

2,4

2,8

3,2

3,6

4,0

4,4

4,8

5,2

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:

0

0.5

1

1.5

2

2.5

3

3.5

1 2 3 4 5 6 7 8 9

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

0

0.5

1

1.5

2

2.5

3

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 -

0.01

0.1

1

10

100

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

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

80

100

120

140

160

180

0 1 2 3

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?