Biomarkers of AKI

My top five, their strengths and weaknesses

M. Joannidis
Professor of Internal Medicine
Division of Intensive Care and Emergency Medicine
Department of Internal Medicine
Medical University Innsbruck, Austria

Potential use of biomarkers in acute kidney injury: report and

summary of recommendations from the 10th Acute Dialysis
Quality Initiative consensus conference

Murray PT et al , Kidney Int. 2014 Mar;85(3):513-21

Cystatin C

Serum
Cys C
MW : 13 kDa (protein)
produced by nucleated cells
constant production rate
free glomerular filtration
complete reabsorption via megalin
receptor and degradation in proximal
tubule
small volume for distribution (high
sensitivity for changes in GFR)

PT Tubular damage ->

HL Reduced reabsorption
CD
Increased urinary CysC

Detection of decreased glomerular filtration rate in

intensive care units: serum cystatin C versus serum
creatinine

Delanaye P, BMC Nephrology 2014, 15:9

Comparison of serum creatinine and serum cystatin C

as biomarkers to detect sepsis- induced acute kidney
injury and to predict mortality in CD-1 mice

Leelahavanichkul A, Am J Physiol Renal Physiol (August 20, 2014)

Serum cystatin C levels

during intermittent haemodialysis
Pediatric patient

Adult ESRD patients

(high flux membrane)

Marsenic O, Pediatric Nephrology
2013, Volume 28, Issue 4, pp 647-653

Huang S-H S et al, Clin J Am

Soc Nephrol 6: 319325, 2011

Serum Cystatin C - limitations

plasma release may influenced by
corticosteroids, thyroid dysfunction,
neoplasm
urinary cys S unreliably predicts AKI
role for estimating residual function
during RRT (recovery) to be determined

NGAL
(Neutrophil gelatinase-associated lipocalin)
MW : 25 kDa protein
Released by activated
neutrophils
Filtered in the glomerulum
Expression in kidney after
Ischemia
Appears in urine (secreted
by TAL and CD)

Plasma NGAL
Predictive of non-septic AKI

Sens 73.4 (62.3-82.2)

Spec 86.6 (72.0-94.3)
AUC-ROC 0.775 (0.679-0.869)
Cut off > 150 ng/ml (?)

Predictive of outcome in patients

requiring RRT
Predictive of requirement of RRT

Haase M et al, Am J Kidney Dis. 2009 Dec;54(6):1012-24

The Outcome of Neutrophil Gelatinase-Associated

Lipocalin-Positive Subclinical Acute Kidney Injury: A
Multicenter Pooled Analysis of Prospective Studies
2,322 patients (cardiac surgery, critically ill) from 10 prospective observational
studies of NGAL

patients at risk for AKI

Haase M et al, J Am Coll Cardiol 2011

NGAL
Limitations
Questionable reliability of current NGAL
assays to detect various NGAL variants
in urine and to predict AKI
Marker of systemic inflammation
Limited use in sepsis

Haase M et al, Am J Kidney Dis. 2009 Dec;54(6):1012-24

Kidney Injury Molecule-1 (KIM-1)

Charlton J R et al. Nephrol. Dial. Transplant. 2014;29:1301-1311

Kidney injury molecule 1 (KIM-1)

Han WK, Kidney Int. 2002

Performance of Kidney Injury Molecule-1

as Biomarker of AKI after Cardiac Surgery

Parikh CP et al, Clin J Am Soc Nephrol 8: 10791088, 2013

KIM - 1
Specific for tubular damage indicating injury or repair
response to injury
FDA approved for as AKI marker for preclinical drug
development
Limitations
Modest prediction of AKI

Liver Fatty Acid-Binding Protein (L-FABP)

Charlton J R et al. Nephrol. Dial. Transplant. 2014;29:1301-1311

Performance of Urinary Liver-Type Fatty Acid

Binding Protein in Acute Kidney Injury:
A Meta-analysis

Susantitaphong P et al., Am J Kidney Dis. 61(3):430-439, 2013

Evaluation of new acute kidney injury biomarkers in

a mixed intensive care unit
New AKI within 1 week

14-d Mortality

Doi K et al., Crit Care Med 2011; 39:2464 2469

Performance of L-FBP as Biomarker of

AKI after Cardiac Surgery

Parikh C R et al. CJASN 2013;8:1079-1088

L-FABP Summary
Index marker of renal hypoxia and susceptibility to
additional insult
Predictive for AKI in cardiac surgery and critically ill
including sepsis up to one week before
Approved as diagnostic test for AKI in Japan
Limitations:
Prediction period undefined
Low prediction of RRT requirements
Prediction of AKI moderate (low AUCs)

TIMP-2 and IGFBP7

Tissue Inhibitor of
Metalloproteinases 2
Insulin-like Growth Factor
Binding Protein 7

TIMP-2 and IGFBP7 Performance

Kashani et al. Critical Care 2013, 17:R25

TIMP-2 and IGFBP7 Were Discovered And Validated For Risk

Assessment In Four Independent Clinical Studies
Bihorac A et al, Am J Respir Crit Care Med. Published online February 21, 2014

67 sites

# Clinical
Sites

Topaz
FDA
Validation

1811 pts

23 clinical sites
408 patients
AUC = 0.82
Opal
AUC
0.79

38

Sapphire Study
35 clinical sites
728 patients
AUC = 0.80

Discovery AUC=0.8
500

1000

# Patients

1500

Clinical application of cell cycle arrest biomarkers

in human acute kidney injury
ROC curves and operating characteristics for the
Sapphire (solid) and Opal (dash) cohorts for AKI 3 or 3

Relative risk of AKI Stage 2 or 3 within 12h in the Opal (light

gray), Sapphire (medium gray), and combined Opal and
Sapphire (dark gray) cohort

2.0 Cutoff
Defines highest risk

0.3 Cutoff
Defines high risk

[TIMP-2][IGFBP7] =(ng/mL)2/1000

E. Hoste et al, NDT 2014

Quantification of urinary TIMP-2 and IGFBP-7: an

adequate diagnostic test to predict acute kidney
injury after cardiac surgery?
42 patients admitted to ICU after CS
involving cardiopulmonary bypass
AKI
no AKI

Wetz A et Critical Care (2015) 19:3

Limitations
Discrimination between transient (prerenal) and persistent AKI not shown
Risk prediction period for AKI very short
(i.e.12 h)
Prediction of RRT only moderate
/test

My favorite Biomarkers
Serum Cys C

GFR

Plasma NGAL

inflammation

Urinary KIM-1

tubular damage/repair

Urinary L-FAB

susceptibility to AKI

Urinary TIMP-2 and IGFBP7

tubular stress
early diagnosis of AKI

(Nephrocheck)