Professor of Critical Care Medicine, Medicine, · Professor of Critical Care Medicine, Medicine,...
27
Transcript of 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…
ccm.pitt.edu/center-critical-care-nephrologyFollow @CCCNPitt
