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AKI Biomarker 2016 Chaken
AKI Biomarker 2016 Chaken
Limitation of Serum
creatinine
Not specific for AKI
Typically diagnosis is 24-72 hours following AKI
Rising creatinine only when lost 50% of their
functional capacity
Surrogate marker of GFR, not tubular function
Not allow differentiation between hemodynamically
mediated changes, such as pre-renal azotemia from
intrinsic renal failure or obstructive uropathy
Sources of creatinine
error in GFR estimation
Source of error
Factors affecting
creatinine generation
Example
Race/ethnicity
Extremes of muscle
mass
Extremes of body size
Diet and nutritional
status
- High protein diet
- Creatine
supplements
Muscle wasting
diseases
KDIGO CKD 2012. Kidney International Supplements
Ingestion of cooked
Sources of creatinine
error in GFR estimation
Source of error
Factors affecting
tubular secretion of
creatinine
Example
Decrease by drug-induced
inhibition
Trimethoprim
Cimetidine
Fenofibrate
Factors affecting extra- Dialysis
renal elimination of
Decrease by inhibition of
creatinine
gut creatininase by
antibiotics
Increased by large
volume losses of
KDIGO CKD 2012. Kidney
International
Supplements
extracellular
fluid
(2013) 3, 514
E me r g i n g
B i oma r k e
rs
Biomarker
Functional marker
Serum creatinin
Serum cystatin C
Urine albumin
Up-regulated proteins
Low-molecular-weight
proteins
Enzymes
TIMP2
IGFBP7
Adapted from Betjes MG,,et al. Clin Kidney J. 2012; 5 (2): 102-10
Cystatin C
MW: 13.3 kDa
Freely filtered by glomerulus, reabsorbed
completely by PCT, and not secreted
Early marker of impaired glomerular filtration
rather than of tubular lesion
Urinary excretion of the cystatin C : correlates
with severity of acute tubular damage
Serum cystatin C : early marker of impaired
GFR, not significantly affected by age, gender,
race, or overall muscle mass
Coca SG, et al. Kidney Int 2008; 73: 10081016.
Nguyen MT, et al. Pediatr Nephrol 2008; 23:
Cystati
nC
150
100
50
0
R-Day-3
R-day-2
R-Day-1
R-Day-0
**
**
4.0-
3.0-
2.01.0-
NO AKI
0.0Pre CPB
Post CPB
ICU
6 h ICU
Day 1
Example
None identified
Increased by severe
decrease in GFR
Biomarker
Functional marker
Serum creatinin
Serum cystatin C
Urine albumin
Up-regulated proteins
Low-molecular-weight
proteins
Urine cystatin C
N-acetyl-glucosaminidase (NAG)
Glutathione-s-transferase (GST)
Gamma-glutamyl transpeptidase (GGT)
Alanine aminopeptidase (AAP)
Lactate dehydrogenase (LDH)
Enzymes
TIMP2
IGFBP7
Adapted from Betjes MG,,et al. Clin Kidney J. 2012; 5 (2): 102-10
KIM-1
*
4
mg/dL
ng/mL
2
1
sham
I10
I20
I30
I45
Ischemia/Reperfusion
sham
I10
I20
I30
I45
Ischemia/Reperfusion
N=9
N=9
N=8
Macrophages
(number/interstitial flield)
Alpha-SMA expression
Macrophage expression
R=0.950
p<0.001
00
1
2
3
4
KIM-1 expression (% area)
5
10
15
20
25
Urinary KIM-1 (ng/mg creatinine)
30
Biomarker
Functional marker
Serum creatinin
Serum cystatin C
Urine albumin
Up-regulated proteins
Low-molecular-weight
proteins
Urine cystatin C
N-acetyl-glucosaminidase (NAG)
Glutathione-s-transferase (GST)
Gamma-glutamyl transpeptidase (GGT)
Alanine aminopeptidase (AAP)
Lactate dehydrogenase (LDH)
Enzymes
TIMP2
IGFBP7
Adapted from Betjes MG,,et al. Clin Kidney J. 2012; 5 (2): 102-10
TRIBE AKI
Large prospective, multicenter international
cohort of adult patients undergoing cardiac
surgery (N = 1219)
What biomarkers measured at time of first
clinical diagnosis of AKI after cardiac surgery can
potentially predict AKI severity
NGAL expression in
ischmia-reperfusion mice
NGAL as a Biomarker in
AKI
Factors Influencing
NGAL Measurement
Urinary NGAL levels were
signicantly elevated in all patients
(with or without AKI)
initiates inflammation and activation of
neutrophils leading to increased NGAL
levels.
Biomarker
Functional marker
Serum creatinin
Serum cystatin C
Urine albumin
Up-regulated proteins
Low-molecular-weight
proteins
Urine cystatin C
N-acetyl-glucosaminidase (NAG)
Glutathione-s-transferase (GST)
Gamma-glutamyl transpeptidase (GGT)
Alanine aminopeptidase (AAP)
Lactate dehydrogenase (LDH)
Enzymes
TIMP2
IGFBP7
Adapted from Betjes MG,,et al. Clin Kidney J. 2012; 5 (2): 102-10
Biomarker
Functional marker
Serum creatinin
Serum cystatin C
Urine albumin
Up-regulated proteins
Low-molecular-weight
proteins
Urine cystatin C
N-acetyl-glucosaminidase (NAG)
Glutathione-s-transferase (GST)
Gamma-glutamyl transpeptidase (GGT)
Alanine aminopeptidase (AAP)
Lactate dehydrogenase (LDH)
Enzymes
TIMP2
IGFBP7
Adapted from Betjes MG,,et al. Clin Kidney J. 2012; 5 (2): 102-10
Interleukin-18 (IL-18)
22-kD pro-inflammatory cytokine formed in proximal
tubular cells.
Urinary IL-18 is elevated following renal injury
Caspase-1 activation, resulting in IL-18 maturation.
Mature IL-18 mediates inflammatory response through
upregulating NF-kB pathway including TNF-, iNOS,
chemokines attracting microphage and neutrophils
IL-18 worsens tubular necrosis in ischemic-reperfusion
and nephrotoxin animal models
AKI patients with high urine IL-18 concentration could
potentially benefit from anti-IL-18 therapy
Biomarker
Functional marker
Serum creatinin
Serum cystatin C
Urine albumin
Up-regulated proteins
Low-molecular-weight
proteins
Urine cystatin C
N-acetyl-glucosaminidase (NAG)
Glutathione-s-transferase (GST)
Gamma-glutamyl transpeptidase (GGT)
Alanine aminopeptidase (AAP)
Lactate dehydrogenase (LDH)
Enzymes
TIMP2
IGFBP7
Adapted from Betjes MG,,et al. Clin Kidney J. 2012; 5 (2): 102-10
N-acetyl- -D
-glucosaminidase (NAG)
Lysosomal enzyme of proximal
tubular epithelial cells
Specic urinary marker for the
tubular cells
Relatively high molecular weight
(>130 kDa)
Increase in urinary NAG activity
Damage to tubular cells
Increased lysosomal activity
without cellular damage
Liangos O, et al. J Am Soc Nephrol 2007; 18:
Sensitivity
Indexed to urinary
creatinine
concentration, (GT),
alkaline
phosphatase,and
NAG were higher in
the AKI group on
admission (P<0.05).
0.8
0.6
0.4
0.2
Urinary NAG
increased in
tandem with
APACHE II and
Multiple Organ
Failure scores.
Urinary NAG
markers of
kidney injury can
predict adverse
clinical outcomes
in patients with
50
100
150
200
250
300
Urinary NAG (ng/mg creatinine)
N-acetyl- -D
-glucosaminidase (NAG)
More sensitive diagnostic marker
than tubular proteinuria
Enzymes of renal tubules for the
detection and monitoring of kidney
lesions in patients with AKI in the
earliest phase of the disease
Limitation
Very low thresholds for release of
tubular enzymes
Technical difficulty in the
Biomarker
Functional marker
Serum creatinin
Serum cystatin C
Urine albumin
Up-regulated proteins
Low-molecular-weight
proteins
Urine cystatin C
N-acetyl-glucosaminidase (NAG)
Glutathione-s-transferase (GST)
Gamma-glutamyl transpeptidase (GGT)
Alanine aminopeptidase (AAP)
Lactate dehydrogenase (LDH)
Enzymes
TIMP2
IGFBP7
Adapted from Betjes MG,,et al. Clin Kidney J. 2012; 5 (2): 102-10
SAPPHIRE study :
methodology
728 ICU pts: 35 clinical sites in North America
and Europe
critical illness and without evidence of AKI at
enrollment
1oendpoint
SAPPHIRE STUDY
[TIMP-2][IGFBP7]
identified risk
Improved risk
stratification for
AKI well ahead of
Cr, UOP
These markers
performed well in
patients with
sepsis (with area
under receiver
operating
characteristics
curve [AUC] of
0.82)
postsurgery (AUC
Kianoush Kashani et al Crit Care. 2013; 17(1): R2
0.85)
SAPPHIRE STUDY
Risk for major
adverse kidney
events (MAKE)
- Death
- Dialysis
- Persistent renal
dysfunction within
30 days (MAKE30)
elevated sharply for
[TIMP-2][IGFBP7]
above 0.3 and
doubled when values
At 9th month
TIMP2 IGFBP7
levels > 0.3
associated with
death or RRT only
in subjects who
developed AKI
Future of biomarker-assisted
approaches for AKI management
Conrm proposed expansion of diagnostic AKI criteria
Determine mechanistic pathways
Dene prognostic value of combined use of functional
and damage markers in sequential measurements
Combination of damage and functional markers can
improve recognition of AKI in the setting of CKD
Large population-based studies
Establish standard techniques for collection, handling
and presentation of biomarker data that permits
appropriate interpretation across settings.
Damage criteria
Modied conceptual
model of AKI