aki biomarker 2016 chaken maniyan

Novel AKI biomarker

CHAKEN MANIYAN MDNephrology fellow

Phramongkutklao hospital19 Aug 2016

Conceptual model for AKI

Adapted from KDIGOreg AKI Guideline 2012

Who is at riskDifferential diagnosis

Early diagnosisPrognosis

Limitation of Serum creatinine

Lisowska-Myjak B Blood Purif 201029357ndash365Endre ZH et al Clin Biochem Rev 2011 I 121-4

Sources of creatinine error in GFR estimation

Source of error ExampleFactors affecting creatininegeneration

bull Raceethnicity bull Extremes of muscle massbull Extremes of body sizebull Diet and nutritional status

- High protein diet- Creatine supplements

bull Muscle wasting diseasesbull Ingestion of cooked meat

KDIGO CKD 2012 Kidney International Supplements (2013) 3 5ndash14

Source of error ExampleFactors affecting tubular secretion of creatinine

Decrease by drug-induced inhibitionbull Trimethoprimbull Cimetidinebull Fenofibrate

Factors affecting extra-renal elimination of creatinine

bull Dialysisbull Decrease by inhibition of gut

creatininase by antibioticsbull Increased by large volume

losses of extracellular fluid



E me r g i n gB i oma r k e r s

Kidney biomarkers for AKI

Belcher JM et al Am J Kidney Dis 2011 57(6)930-940

Koyner JL et al nd critical illness Clin J Am Soc Nephrol 2013 8(6) 1034ndash42

Anatomical correlation of AKI biomarkers

Type of AKI biomarkersBiomarker Type Biomarker

Functional markerSerum creatininSerum cystatin CUrine albumin

Up-regulated proteins

Kidney injury molecule 1 (KIM-1)Neutrophil gelatinase-associated lipocalin (NGAL)Liver-type fatty acidndashbinding protein (L-FABP)Interleukin 18 (IL-18)β-trace protein (BTP)Asymmetric dimethylarginine (ADMA)

Low-molecular-weight proteins Serum and Urine cystatin C

Enzymes

N-acetyl-glucosaminidase(NAG)Glutathione-s-transferase (GST)Gamma-glutamyl transpeptidase(GGT)Alanine aminopeptidase (AAP)Lactate dehydrogenase (LDH)

Gene product (cell cycle arrest)TIMP2IGFBP7

Adapted from Betjes MGet al Clin Kidney J 2012 5 (2) 102-108

Cystatin C

133 kDabull Freely filtered by glomerulus reabsorbed completely by

PCT and not secretedglomerular filtration

bull Urinary excretion of the cystatin C correlates with severity of acute tubular damage

bull Serum cystatin C early marker of impaired GFR not significantly affected by age gender race or overall muscle mass

Nguyen MT et al Pediatr Nephrol 2008 23 2151ndash2157

Coca SG et al Kidney Int 2008 73 1008ndash1016

Serum cystatin C and creatinine on the three days prior on the day AKI

In 85 critically ill patients at high risk for developing AKI

Serum cystatin C increased already by 50 15plusmn06 days earlier compared to creatinine

Adapted from Herget-Rosenthal S Kidney Int 2004 66 1115ndash1122

0

50

100

150

200

250

300

R-Day-3 R-day-2 R-Day-1 R-Day-0

Cystatin CCreatinine

Urinary cystatin C as an early biomarker of AKI following adult

cardiothoracic surgery

Koyner JL et al Kidney Int 2008 74 1059ndash1069

Pre CPB Post CPB ICU 6 h ICU Day 1Uri

ne C

yCu

rine

cre

atin

ine

(mg

g) 50-

40-

30-

20-

10-

00-

Urinary CyC at the time of ICU arrival and the urinary CyC level 6 hours after ICU admission were most useful for predicting AKI

AKI with RRT

NO AKI

Serum CystacinC prognostic factor to death CV death ESRD

Michael G Shlipak N Engl J Med 2013369932-943

Sources of cystatin C error in GFR estimation

Source of error ExampleFactors affecting cystatin C generation bull Disorders of thyroid function

bull Administration of corticosteroidsbull Other hypothesized factors based

on epidemiologic associations (diabetes adiposity)

Factors affecting tubular reabosrptionof cystatin C

None identified

Factors affecting extra-renal elimination of cystatin C

Increased by severe decrease in GFR


No effect by gender age race or muscle mass unlike serum creatinine





Low-molecular-weight proteins Urine cystatin C

Enzymes




Kidney Injury Molecule-1 (KIM-1)

bull Type 1 transmembrane protein of renal tubular origin

bull KIM-1 is not detectable in a healthy kidney

bull KIM-1-positive proximal tubules (90) in various human

renal diseases)

Ichimura T et al Am J Physiol Renal Physiol 2004 286F552ndashF563Waanders F et al Journal of Pathology 2010 7ndash16

Comparison of urinary KIM-1 concentration in various forms of renal

diseases

Adapted from Kidney International Vol 62 (2002) pp 237ndash244

Urinary KIM-1 levels were higher in patients with ischemic ATN (292plusmn061 N=7) compared to levels in patients with other forms of AKI (063plusmn017 Plt

001) or CKD (072plusmn037 P lt001)

0

1

2

3

4

ischemic ATN CIN other ARF CRF normal

N=7

N=7N=9

N=8N=9

KIM

-1 le

vel

ngm

L

Preoperative cardiac surgeryKIM-1 predicted development of stage 1 and 3 AKI (subclinical proximal tubular injury) N=123

Koyner JLet al Clin J Am Soc Nephrol 2010 Dec 5(12) 2154ndash2165

van Timmeren et al Am J Physiol Renal Physiol 2006 291(2) F456ndash464

KIM-1 and tubulointerstitial damage

Kim-1 expression was limited to areas with inflammation and fibrosis (α-smooth muscle

actin)

0 1 2 3 4 5KIM-1 expression ( area)

R=0950plt0001

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Urinary KIM-1 markers of kidney injury can predict adverse clinical outcomes in patients with AKI

Second quartile of KIM-1 groups 14-fold (95 CI 06 to 30)

Third quartile of KIM-1 groups 14-fold (95 CI 06 to 30)

Forth quartile of KIM-1 groups 32-fold (95 CI 14 to 74)

Liangos O et al J Am Soc Nephrol 2007 18 904ndash912

0 5 10 15 20 25 30Urinary KIM-1 (ngmg creatinine)

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Dialysis requirement or hospital death (P =0034)

KIM-1 prognostic factor to ESRD






Enzymes




Neutrophil Gelatinase-Associated Lipocalin (NGAL)

bull NGAL is expressed by neutrophilsbull Major renal source of urinary NGAL is from the

TAL and collecting ducts

bull NGAL gene is strongly induced after kidney injury by ischemia sepsis or nephrotoxins

Lisowska-Myjak B Blood Purif 201029357ndash365


bull During AKI both urine and plasma NGAL are elevated

bull Urine NGAL production from TAL and CCD 3 hrs after injury

bull Plasma NGAL increased hepatic production after injury

Yamamoto T et al J Am Soc Nephrol 2007 Nov 18(11)2894-902

Koyner JL et al J Am Soc Nephrol 2012 May 23(5)905-14

TRIBE AKI

bull Large prospective multicenter international cohort of adult patients undergoing cardiac surgery (N = 1219)

bull What biomarkers measured at time of first clinical diagnosis of AKI after cardiac surgery can potentially predict AKI severity

bull plasma NGAL performing the best (category-free net reclassification improvement of 069 P lt 00001)

bull Plasma NGAL on day of AKI diagnosis improve risk stratification and identify patients at higher risk for progression of AKI and worse patient outcomes


NGAL expression in ischmia-reperfusion mice

Neal Paragas et al Nat Med 2011 Feb 17(2) 216ndash222

Volume depletion failed to activate NGAL expression


J Mishara et al Lancet 2005 365 1231ndash38


Major studies reporting use of NGAL as an early biomarker in AKI

Soni SS et al Blood Purif 200928165ndash174



Early diagnosis of cardiac surgery-associated AKI a meta-analysis

Zhou F Eur J Cardiothorac Surg 201649746ndash55

NGAL as a Biomarker in AKI

Dent CL et al Crit Care 2007 11R127 Bachorzewska H et al Nephrol Dial Transplant 2007 22 295ndash296

Wagener G et al Anesthesiology 2006105 485ndash491 Xin C et al Ren Fail 2008 30 904ndash913

NGAL and Progression of CKD

Bolignano D Clin J Am Soc Nephrol 20094337-344

Factors Influencing NGAL Measurement

Wagener G et al Am J Kidney Dis 2008 52 425ndash433Mitsnefes M et al Pediatr Nephrol 200722101ndash8






Enzymes




Liver-Type Fatty Acid-Binding Protein (L-FABP)

Tan HL et al Blood Purif 201641144-150

Urinary LFABP in AKI A Meta-analysis

PSusantitaphong Am J Kidney Dis 2013 Mar 61(3) 430ndash439






Enzymes




Interleukin-18 (IL-18)







Enzymes




Urinary Enzymes of Renal Origin



bull Cytoplasmic enzymes Isoenzymes of glutathione S transferase (GST)

bull GST- α proximal tubulebull GST-π distal tubule

bull Lysosomes of proximal tubular cells N-acetyl- β-D-glucosaminidase (NAG)

bull Brush border enzyme Alkaline phosphatase γ-glutamyl transpeptidase and alanine aminopeptidase

bull Proximal renal tubular epithelial antigen (HRTE-1)


N-acetyl- β -D -glucosaminidase(NAG)


Urinary NAG Activity Are Associated with Adverse Outcomes in AKI


0 50 100 150 200 250 300Urinary NAG (ngmg creatinine)

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N-acetyl- β -D -glucosaminidase (NAG)







Enzymes




Urinary Tissue Inhibitor of Metalloproteinase-2 Insulin-Like Growth Factor-Binding Protein 7

A Sharfuddin et al Nat Rev Nephrol 20117189-200

TIMP-2 and IGFBP-7


SAPPHIRE study methodology

Kianoush Kashani et al Crit Care 2013 17(1) R25

SAPPHIRE STUDY

sect [TIMP-2][IGFBP7] identified ndash risk

sect Improved risk stratification for AKI well ahead of Cr UOP

sect These markers performed well in patients with

sect sepsis (with area under receiver operating characteristics curve [AUC] of 082)

sect postsurgery (AUC 085)


03

gt20

SAPPHIRE STUDY


(TIMP-2)sdot (IGFBP7) Levels Are Associated with Long-Term Outcomes in Patients with AKI

Jay L Koyner J Am Soc Nephrol 26 2015

Biomarkers of AKI and cardiac surgery

Biomarkers of AKI and outcomes in critically ill

Biomarkers of AKI and outcomes in cardiorenal syndrome

Biomarkers of AKI and outcomes in kidney transplantation

Future of biomarker-assisted approaches for AKI management

Patrick T Murray et al Kidney Int 2014 March 85(3) 513ndash521

Proposed new AKI criteria

Functional criteria Damage criteria


Modified conceptual model of AKI


Thank you for your attention

Conceptual model for AKI

Adapted from KDIGOreg AKI Guideline 2012

Who is at riskDifferential diagnosis

Early diagnosisPrognosis



























Enzymes




Cystatin C











0

50

100

150

200

250

300







ne C

yCu

rine

cre

atin

ine

(mg

g) 50-

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30-

20-

10-

00-


AKI with RRT

NO AKI








None identified










Enzymes








renal diseases)



diseases




0

1

2

3

4


N=7

N=7N=9

N=8N=9

KIM

-1 le

vel

ngm

L






actin)


R=0950plt0001

100-

75-

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acro

phag

es(n

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Mac

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of d

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Enzymes















TRIBE AKI






























Enzymes













Enzymes











Enzymes


















08-

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Enzymes






TIMP-2 and IGFBP-7




SAPPHIRE STUDY







03

gt20

SAPPHIRE STUDY










































Enzymes




Cystatin C











0

50

100

150

200

250

300







ne C

yCu

rine

cre

atin

ine

(mg

g) 50-

40-

30-

20-

10-

00-


AKI with RRT

NO AKI








None identified










Enzymes








renal diseases)



diseases




0

1

2

3

4


N=7

N=7N=9

N=8N=9

KIM

-1 le

vel

ngm

L






actin)


R=0950plt0001

100-

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50-

25-

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acro

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es(n

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Alp

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Enzymes















TRIBE AKI






























Enzymes













Enzymes











Enzymes


















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Enzymes






TIMP-2 and IGFBP-7




SAPPHIRE STUDY







03

gt20

SAPPHIRE STUDY
















Cystatin C











0

50

100

150

200

250

300







ne C

yCu

rine

cre

atin

ine

(mg

g) 50-

40-

30-

20-

10-

00-


AKI with RRT

NO AKI








None identified










Enzymes








renal diseases)



diseases




0

1

2

3

4


N=7

N=7N=9

N=8N=9

KIM

-1 le

vel

ngm

L






actin)


R=0950plt0001

100-

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Enzymes















TRIBE AKI






























Enzymes













Enzymes











Enzymes


















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Enzymes






TIMP-2 and IGFBP-7




SAPPHIRE STUDY







03

gt20

SAPPHIRE STUDY




















0

50

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200

250

300







ne C

yCu

rine

cre

atin

ine

(mg

g) 50-

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30-

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10-

00-


AKI with RRT

NO AKI








None identified










Enzymes








renal diseases)



diseases




0

1

2

3

4


N=7

N=7N=9

N=8N=9

KIM

-1 le

vel

ngm

L






actin)


R=0950plt0001

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Enzymes















TRIBE AKI






























Enzymes













Enzymes











Enzymes


















08-

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Enzymes






TIMP-2 and IGFBP-7




SAPPHIRE STUDY







03

gt20

SAPPHIRE STUDY




















ne C

yCu

rine

cre

atin

ine

(mg

g) 50-

40-

30-

20-

10-

00-


AKI with RRT

NO AKI








None identified










Enzymes








renal diseases)



diseases




0

1

2

3

4


N=7

N=7N=9

N=8N=9

KIM

-1 le

vel

ngm

L






actin)


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Enzymes















TRIBE AKI






























Enzymes













Enzymes











Enzymes


















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Enzymes






TIMP-2 and IGFBP-7




SAPPHIRE STUDY







03

gt20

SAPPHIRE STUDY























None identified










Enzymes








renal diseases)



diseases




0

1

2

3

4


N=7

N=7N=9

N=8N=9

KIM

-1 le

vel

ngm

L






actin)


R=0950plt0001

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Enzymes















TRIBE AKI






























Enzymes













Enzymes











Enzymes


















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Enzymes






TIMP-2 and IGFBP-7




SAPPHIRE STUDY







03

gt20

SAPPHIRE STUDY





















Enzymes








renal diseases)



diseases




0

1

2

3

4


N=7

N=7N=9

N=8N=9

KIM

-1 le

vel

ngm

L






actin)


R=0950plt0001

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Enzymes















TRIBE AKI






























Enzymes













Enzymes











Enzymes


















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Enzymes






TIMP-2 and IGFBP-7




SAPPHIRE STUDY







03

gt20

SAPPHIRE STUDY




















renal diseases)



diseases




0

1

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4


N=7

N=7N=9

N=8N=9

KIM

-1 le

vel

ngm

L






actin)


R=0950plt0001

100-

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Enzymes















TRIBE AKI






























Enzymes













Enzymes











Enzymes


















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Enzymes






TIMP-2 and IGFBP-7




SAPPHIRE STUDY







03

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SAPPHIRE STUDY

















diseases




0

1

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N=7

N=7N=9

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KIM

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vel

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L






actin)


R=0950plt0001

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Enzymes















TRIBE AKI






























Enzymes













Enzymes











Enzymes


















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Enzymes






TIMP-2 and IGFBP-7




SAPPHIRE STUDY







03

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SAPPHIRE STUDY





















actin)


R=0950plt0001

100-

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acro

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es(n

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Enzymes















TRIBE AKI






























Enzymes













Enzymes











Enzymes


















08-

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Enzymes






TIMP-2 and IGFBP-7




SAPPHIRE STUDY







03

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SAPPHIRE STUDY






















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Enzymes















TRIBE AKI






























Enzymes













Enzymes











Enzymes


















08-

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Enzymes






TIMP-2 and IGFBP-7




SAPPHIRE STUDY







03

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SAPPHIRE STUDY






















Enzymes















TRIBE AKI






























Enzymes













Enzymes











Enzymes


















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Enzymes






TIMP-2 and IGFBP-7




SAPPHIRE STUDY







03

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SAPPHIRE STUDY



























TRIBE AKI






























Enzymes













Enzymes











Enzymes


















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ent

or h

ospi

tal d

eath








Enzymes






TIMP-2 and IGFBP-7




SAPPHIRE STUDY







03

gt20

SAPPHIRE STUDY











































Enzymes













Enzymes











Enzymes


















08-

07-

06-

05-

04-

03-Pred

icte

d pr

babi

lity

of d

ialy

sis

requ

irem

ent

or h

ospi

tal d

eath








Enzymes






TIMP-2 and IGFBP-7




SAPPHIRE STUDY







03

gt20

SAPPHIRE STUDY

























Enzymes











Enzymes


















08-

07-

06-

05-

04-

03-Pred

icte

d pr

babi

lity

of d

ialy

sis

requ

irem

ent

or h

ospi

tal d

eath








Enzymes






TIMP-2 and IGFBP-7




SAPPHIRE STUDY







03

gt20

SAPPHIRE STUDY























Enzymes


















08-

07-

06-

05-

04-

03-Pred

icte

d pr

babi

lity

of d

ialy

sis

requ

irem

ent

or h

ospi

tal d

eath








Enzymes






TIMP-2 and IGFBP-7




SAPPHIRE STUDY







03

gt20

SAPPHIRE STUDY






























08-

07-

06-

05-

04-

03-Pred

icte

d pr

babi

lity

of d

ialy

sis

requ

irem

ent

or h

ospi

tal d

eath








Enzymes






TIMP-2 and IGFBP-7




SAPPHIRE STUDY







03

gt20

SAPPHIRE STUDY























Enzymes






TIMP-2 and IGFBP-7




SAPPHIRE STUDY







03

gt20

SAPPHIRE STUDY


















TIMP-2 and IGFBP-7




SAPPHIRE STUDY







03

gt20

SAPPHIRE STUDY


















SAPPHIRE STUDY







03

gt20

SAPPHIRE STUDY
















03

gt20

SAPPHIRE STUDY
















aki biomarker 2016 chaken maniyan

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