Intensive Care Society - State of the Art Meeting 2015

1. The injured kidney
‘Can you treat it?’
Peter Pickkers
Intensive Care Medicine
Radboud University Medical Centre Nijmegen
State of Art 2015, London

2. The answer is easy
• “No”

3. The answer is easy
• “No”
• The only treatment liscenced to treat AKI is…
dialysis

4. • 2308 patients
• At risk for contrast-induced AKI
• Acetylcysteine 1200 mg or placebo

5. Why is it so difficult
to treat/prevent AKI?

6. Ischemicinsult
Hemodynamic alterations
Toxins
Bacteremia
Age
Pre-existing disease
Hemodynamic insult
Pharmacotherapy
Other interventions
(fluids , antibiotics,
vasopressors, RRT)
Inflammation Modifiers
Primary Modifiers Secondary Modifiers
Inflammatory response
AKI Outcome
Sepsis,
Ischemia/
reperfusion,
Toxins
ConsequencesTriggers
( DAMP/PAMPs/PRRs)
Response
( Resident + recruited innate
and adaptive immunecells)
AKIAKI AKI
time
Genome- Encoded
Response Program
(Mitochondrial injury, apoptosis,
cytokine/chemokine secretion)

8. Severity – RIFLE criteria

12. Target injurious
inflammation
Promote reparative
inflammation
Kidney Insult
Risk of disrupting
repair process
Cell Death Repair and Regeneration
Acute
Inflammatory
Response

13. New recent data:
Intensive Care Over Nations
• ICON
• 10069 patients included
• 30% sepsis, 70% non-sepsis
• In sepsis patients: 67% AKI
• In non-sepsis patients: 57% AKI

14. Kinetics of AKI
0 20 40 60 80 100
Percentage (%)
No AKI
Risk
Injury
Failure
AKI in first 48h at ICU020406080100
Sepsis
Percentage(%)
Kinetics of AKI
Follow-up until day 7

15. Prevention = cause no further harm

16. What is currently done?
• Evaluate the patient when kreat increases >40 µmol/L:
• Exclude pre-renal causes
(volume depletion, cirrhosis, cardiac failure, NSAID, ACE-i)
• Avoid hypotension
• Avoid excessive fluid resuscitation
• Maintain fluid balance
• Treat hyperkalemia
• Adjust doses of other drugs

17. Renal response during sepsis
ACE-i, ARB’sNSAID’s

18. What is currently done?
• Evaluate the patient when kreat increases >40 µmol/L:
• Exclude pre-renal causes
(volume depletion, cirrhosis, cardiac failure, NSAID, ACE-i)
• Avoid hypotension
• Avoid excessive fluid resuscitation
• Maintain fluid balance
• Treat hyperkalemia
• Adjust doses of other drugs

19. • Target MAP 65-70
vs 80-85 mmHg

20. What is currently done?
• Evaluate the patient when kreat increases >40 µmol/L:
• Exclude pre-renal causes
(volume depletion, cirrhosis, cardiac failure, NSAID, ACE-i)
• Avoid hypotension
• Avoid excessive fluid resuscitation
• Maintain fluid balance
• Treat hyperkalemia
• Adjust doses of other drugs
“… these are the simple things….”

21. Future treatments

22. AKI - AP depletion in damaged renal cortex
AP levels are depleted in
Acute Kidney Injury*
Ischemia (in min)
*Khundmiri et al. Am. J. Physiol. 273 (Renal Physiol. 42): F849–F856, 1997

23. Alkaline Phosphatase (AP)
• Dephosphorylating enzyme1
• Detoxifying properties
• Localized in kidney
• Improved renal function with AP treatment in patients with sepsis-associated AKI2,3
• Two phase-IIa clinical trials
1
Coleman et al. Biophys Biomol Struct (1992)

24. AP-treatment improves kidney function in patients with AKI, and prevents AKI occurrence
First Phase-II Study
Sepsis patients (n=36)Sepsis patients (n=36)
AKI at baseline (n=16)AKI at baseline (n=16) No AKI at baseline (n=20)No AKI at baseline (n=20)
Reduced RRT RequirementReduced RRT Requirement
Placebo biAP
0
20
40
60
80
100
%needforRRT
(4/5)
(4/11)
AKI occurrence after start of studyAKI occurrence after start of study
Placebo biAP
0
20
40
60
80
100
%AKI
(4/6)
(4/14)
Heemskerk et al. Crit Care Med (2009)

25. Second Phase-II Study in AKI with bovine AP
Bolus 67.5 U/kg, maintenance 132.5 U/kg/24 hrs during 48 hrs

26. recAP is a recombinant chimeric
human alkaline phosphatase

27. Human recAP AKI Development Plan
27
2012201220122012 2013201320132013 2014201420142014 2015201520152015
recAP DevelopmentrecAP Development
Animal testing
and tox study
Animal testing
and tox study
recAP ManufacturerecAP Manufacture
FDA &
EMA
FDA &
EMA
Phase IPhase I
Phase IIPhase II
Pre-clinical
PK/PD/dose
finding
Pre-clinical
PK/PD/dose
finding

28. Conclusions
• Diminished kidney function is frequent and influences outcome
• Different mechanisms of action are relevant,
during different windows of oppertunity to interfer
• Staging of AKI is difficult
• Determination of renal function is challenging
• Do the simple things right
• It’s a challenge

29. • Alkaline Phosphatase appears to limit AKI in sepsis patients
• A new phase 2 trial with human recAP is currently being conducted
Conclusions
Thanks for your kind attention!