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

Increased urinary CysC

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 HL CD

Tubular damage -> Reduced reabsorption

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

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

Pediatric patient Adult ESRD patients

(high flux membrane)

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

Haase M et al, J Am Coll Cardiol 2011

2,322 patients (cardiac surgery, critically ill) from 10 prospective observational studies of NGAL

patients at risk for AKI

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

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

Kidney Injury Molecule-1 (KIM-1)

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

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

Liver Fatty Acid-Binding Protein (L-FABP)

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

Performance of Urinary Liver-Type Fatty AcidBinding Protein in Acute Kidney Injury:

A Meta-analysis

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

Evaluation of new acute kidney injury biomarkers in a mixed intensive care unit

New AKI within 1 week 14-d Mortality

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

Performance of L-FBP as Biomarker of AKI after Cardiac Surgery

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

# Clinical Sites

# Patients

Discovery AUC=0.8

Sapphire Study 35 clinical sites 728 patients AUC = 0.80

Opal AUC 0.79

500 1500 1000

67 sites

3

1811 pts

38

Topaz FDA

Validation 23 clinical sites

408 patients AUC = 0.82

Bihorac A et al, Am J Respir Crit Care Med. Published online February 21, 2014

Clinical application of cell cycle arrest biomarkers in human acute kidney injury

E. Hoste et al, NDT 2014

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

0.3 Cutoff Defines high risk

2.0 Cutoff Defines highest risk

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

Quantification of urinary TIMP-2 and IGFBP-7: an adequate diagnostic test to predict acute kidney

injury after cardiac surgery?

Wetz A et Critical Care (2015) 19:3

42 patients admitted to ICU after CS involving cardiopulmonary bypass

AKI

no AKI

Limitations

Discrimination between transient (pre-renal) 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

Plasma NGAL

Urinary KIM-1

Urinary L-FAB

Urinary TIMP-2 and IGFBP7

(Nephrocheck)

GFR

tubular stress early diagnosis of AKI

inflammation

tubular damage/repair

susceptibility to AKI

Biomarkers of AKIMy top five, their strengths and weaknesses Potential use of biomarkers in acute kidney injury: report and summary of recommendations from the 10th Acute Dialysis Quality Initiative consensus conferenceCystatin C Detection of decreased glomerular filtration rate in intensive care units: serum cystatin C versus serum creatinineComparison of serum creatinine and serum cystatin C as biomarkers to detect sepsis- induced acute kidney injury and to predict mortality in CD-1 miceSerum cystatin C levels during intermittent haemodialysisSerum Cystatin C - limitationsNGAL (Neutrophil gelatinase-associated lipocalin)The Outcome of Neutrophil Gelatinase-Associated Lipocalin-Positive Subclinical Acute Kidney Injury: A Multicenter Pooled Analysis of Prospective Studies NGALLimitationsKidney Injury Molecule-1 (KIM-1)Kidney injury molecule 1 (KIM-1)Performance of Kidney Injury Molecule-1 as Biomarker of AKI after Cardiac SurgeryKIM - 1Liver Fatty Acid-Binding Protein (L-FABP)Performance of Urinary Liver-Type Fatty AcidBinding Protein in Acute Kidney Injury: A Meta-analysisEvaluation of new acute kidney injury biomarkers in a mixed intensive care unitPerformance of L-FBP as Biomarker of AKI after Cardiac SurgeryL-FABP SummarySlide Number 20TIMP-2 and IGFBP7 PerformanceTIMP-2 and IGFBP7 Were Discovered And Validated For Risk Assessment In Four Independent Clinical StudiesClinical application of cell cycle arrest biomarkers in human acute kidney injury Quantification of urinary TIMP-2 and IGFBP-7: anadequate diagnostic test to predict acute kidneyinjury after cardiac surgery?LimitationsMy favorite Biomarkers