professor of critical care medicine, medicine, · professor of critical care medicine, medicine,...

Professor of Critical Care Medicine, Medicine,

Bioengineering and Clinical & Translational Science

Vice Chair for Research

Director, Center for Critical Care Nephrology

AKI biomarker FAQs

John A. Kellum, MD, MCCM

DisclosuresConsulting:• Adrenomed• AM Pharma• Astellas• Astute Medical• Atox Bio• Baxter• Bioporto• Cheetah Medical• Cytosorbents• Davita• Eliaz Pharma• Elsevier• Grifols• Hepa Wash

•Grant support:• Astellas• Astute Medical• Atox Bio• Baxter• Bioporto• RenalSense• TES Pharma

• Intellectual Property:• Astute Medical• Cytosorbents• PhotoPhage

• Mallinckrodt• Medibeacon• MedScape• Mitobridge• Novartis• NxStage• Oncogna• PhotoPhage• Potrero• Singulex • Sphingotech• Spectral Diagnostics• Sulfateq• TES Pharma

Updated Jan 2019

Damage

GFR

Death

Revised Conceptual Model for AKI

Complications

Normal Risk* Stage 1 Stage 2 Stage 3

Serum Creatinine,

Cystatin C

and Urine output

NGAL

KIM-1

IL-18

*Combines susceptibility and exposure

Nat Rev Nephrol 2011

Function Damage

B

Function Damage

A

Stress

Function Damage

C

Kellum, J. A Current Opinion in Critical Care, 2016: 22(6), 513–519.

Kidney Stress?

•Response to “non-lethal” cell injury or noxious stimuli

•May include a protective response pattern or down-regulation of non-vital cell functions

Gomez et al. SHOCK, Vol. 41, No. 1, pp. 3Y11, 2014

Gomez et al. SHOCK, Vol. 41, No. 1, pp. 3Y11, 2014

Cecal ligation and puncture induced a decline in whole tissue ATP levels at 8 hours

Sham CLP0

20

40

60

80

100

AT

P (

pm

ol/u

g p

rote

in)

Sham

CLP

Urine [TIMP-2]●[IGFBP7]

Urine [TIMP-2]●[IGFBP7]

Cell Cycle Arrest In Response To Cell Stress

Oxygen-Nutrient Deprivation

C N O C N O

PROX IGFBP7 DIST TIMP2

FO

LD

IN

CR

EA

SE

6HR REPERFUSION

24HR REPERFUSION

6

4

2

0

8

6

4

2

0

IL-6

2.5

2.0

1.5

1.0

0.5

0

LDH

3

2

1

0

4

6

5

C N O C N O

PROXIMAL DISTAL

FO

LD

IN

CR

EA

SE

Emlet et al., AJP-Renal 2016

17

Acute kidney injury biomarkers

Zarbock et al. JAMA 2015

KDIGO: Kidney Disease Improving Global Outcomes; Kidney International Supplements. 2012;2,1. doi: 0.1038/kisup.2012

.

Why Risk Assessment Is Needed and What To Do For a Positive Test

KDIGO Management Options

[TIMP-2]x[IGFBP7] Increases in Patients Who Develop AKI Around the Time of Vancomycin Administration

Ostermann et al., Critical Care Medicine, Published Online November 20, 2017

•Avoid nephrotoxins(NSAIDs, ACEi/ARBs)

•Avoid hyperglycemia

•Optimize volume status and hemodynamics

SVV

CI

MAP

Goal achieved

Check every 3h up to 12h after randomization

≤ 11

> 3l/min/m2

> 65 mmHg

No

Yes

Volume: crystallois 500-1000 ml

dobutamine or epinephrine

norepinephrine

> 12

< 3l/min/m2

< 65 mmHg

Meersch et al. ICM 2017

Meersch et al. ICM 2017

Nature Reviews Nephrology 2017

Using biomarker enrichment the authors were able to achieve an effect with a number needed to treat of only 6. Without biomarkers it would have been >33.

Repeated NEPHROCHECK® Tests In The Sapphire Study Show Benefit Of A 12 Hour Prediction Window For High NPV

++

+

Curve Test result (relative to 0.3 cutoff)0h 12h 24h

0%

5%

10%

15%

20%

25%

30%

35%

40%

0 24 48 72 96 120 144 168

Stag

e 2

-3 A

KI (

% o

f p

atie

nts

)

Hours from enrollment

Curves show percent of patients who developed stage 2-3 AKI

3% risk (corresponds to % false negatives for 12 hour prediction)

A negative test result is good (~97% NPV) for about 12 hours

AKI can develop more than 12 hours after a positive test result These AKIs counted as

false positives in our trials since the AKI developed outside the 12h window

Any positive test result in the first 24 hours indicates substantial risk (30-40%) for stage 2-3 AKI in the next week

Three negative test results in the first 24h indicates substantially lower risk (~11%) over the next week, indicating the majority of exposures/stress occur in the first 24h

Conclusions

Unpublished data—manuscript in preparation

Repeated NEPHROCHECK® Tests Show That Magnitude And Duration Of Kidney Stress Matter

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

0 24 48 72 96 120 144 168

Stag

e 2

-3 A

KI (

% o

f p

atie

nts

)

Hours from first occurrence of [TIMP-2]∙[IGFBP7] > 0.3

Curves show % of patients who developed stage 2-3 AKI

0 of 3 test results > 2.0

1 of 3 test results > 2.0

2 of 3 test results > 2.0

3 of 3 test results > 2.0

All patients included had at least 1 test result > 0.3

Unpublished data—manuscript in preparation

Higher test elevations (e.g., >2.0) indicate higher AKI risk

Longer duration of high stress (more test results >2.0) indicates higher AKI risk

Three test results > 2.0 have 100% PPV for stage 2-3 AKI

Suggests that treating patients to lessen magnitude and duration of kidney stress could improve outcomes

Conclusions

What do we do with biomarkers?

Kellum et al. AJRCCM Sept 2016

Kellum et al. AJRCCM Sept 2016

Urine CCL14 Concentrations are Highly Elevated in Patients with Persistent Stage 3 AKI

Under review

Conclusions• AKI Biomarkers can differentiate risk profiles with high sensitivity and

specificity.

• However... Function, Damage and Stress AND Time course represent different aspects of the syndrome we call AKI.

• The renal stress response occurs with even “non-lethal” cell injury or noxious stimuli and may include a protective response pattern or down-regulation of non-vital cell functions

• Markers of cell-cycle arrest appear to be measures of kidney stress rather than damage per se

• Persistent stress becomes “diagnostic” for AKI and identifies risk for worse outcomes.

• Clinical utility for biomarkers unfolds with clinical experience…

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