Remote ischemic pre conditioning in prevention of AKI

1. Effect Of Remote Ischemic
Preconditioning On AKI Among
Patients Going For Cardiac Surgery
DR NAYYAR SALEEM
ASSISTANT CONSULTANT NEPHROLOGY

2. Outcome
variable
AKI definition Level Odds ratio P-value AUC (95% CI)
Mortality AKIN Per 1 stage 5.3 (4.3-6.6) <0.001 0.82 (0.77-0.87)

3. NO SPECIFIC THERAPY IS AVAILABLE

5. Remote Ischemic Pre-Conditioning
Lancet. 2007;370(9587):575-579.
Does this protect acute kidney injury?

6. Yang et al, Meta Analysis
Am J Kidney Dis. 2014 Oct;64(4):574-83. doi: 10.1053/j.ajkd.2014.04.029. Epub
2014 Jun 20
CONCLUSION. Current evidence is not robust enough to make a
recommendation. Adequately powered trials are needed to
provide more evidence in the future

7. Pathophysiology
 RIPC may attenuate renal injury by releasing various damage associated
molecular patterns that are then filtered by the kidney and signal through
Toll-like receptors in the proximal tubule epithelia
 This signaling may then induce natural defenses such as bioenergetic
down-regulation and temporary cell cycle arrest.
 These defenses, once engaged, can then protect the kidney during
subsequent inflammatory or ischemic stress

8. JAMA. 2015 Jun 2;313(21):2133-41. doi: 10.1001/jama.2015.4189
A Multicentre, Randomized, controlled clinical trial conducted at universities of
Munster, Tubingen, Freiburg, or Bochum (all in Germany) between
August 2013 and June 2014

9. Inclusion Criteria
 Age >18 years
 Patients scheduled for surgey on cardiopulmonary bypass
 High risk for AKI (Cleveland foundation score of 6 or more)
 Written informed consent

10. Cleveland Clinic foundation Score
Thakar CV et al, J Am Soc Nephrol. 16: 162-168, 2005

11. Exclusion Criteria
 Age < 18 years
 Myocardial infarction up to 7 days before surgery
 Off-pump heart surgery
 Preeexisting AKI
 Kidney transplantation
 Hepatorenal syndrome
 eGFR < 30 ml/min
 peripheral vascular disease affecting the upper limbs
 Drug therapy with sulphonamide or nicorandil
 Pregnancy

12. Primary and Secondary End points
 Primary
 Occurrence of AKI within 72 hours (AKI KDIGO definition)
 Secondary
 Severe AKI (stage 2-3) within 72 hrs
 30 day all-cause mortality
 Need for renal replacement therapy
 Length of hospital and ICU stay
HYPOTHESIS
RIPC mitigates AKI in high risk patients
undergoing cardiac surgery

13. • MEASUREMENT OF DAMP AND BIOMARKERS IN THE
BLOOD AND URINE
HYPOTHESIS
RIPC mitigates AKI in high risk patients
undergoing cardiac surgery

14. Randomization and blinding
 Patients were randomized on 1:1 basis
 Randomization codes were computer generated
 Intervention was provided by the investigator not involved in the care of
the patient.
 Anesthetist, staff providing care of the patient, cardiac surgeon and ICU
physician were unaware of treatment assignment.

15. Sample size
 The expected AKI rate in previous studies was 50% in control
group
 With the expected Absolute risk reduction of 18% sample size
was calculated which was
117 patients per group (with power of 80)

16. Patient Disposition
790 patients underdoing cardiac surgery screened
550 Excluded:
532 has cleaveland clinic <6
3 declined to participate
15 no reasons reccorded
240 subjects randomized
120 randomized to
receive ischemic PC
120 randomized to
sham procedure
120 completed and included
In the trial
120 completed and included
In the trial
JAMA. 2015 Jun 2;313(21):2133-41. doi: 10.1001/jama.2015.4189.

17. Procedures
 Volatile Anesthesia (No propofol)
 MAP was kept 60-70mm of Hg
 Non-pulsatile cardiopulmonary bypass
 Hematocrit values of 25-30%
 Blood glucose level less than 200mg/dl
 Use of arterial line for monitoring

18. Procedures (cont)
 After induction of anesthesia and before skin incision, RIPC
consisting of 3 cycles of 5-minute inflation of a BP cuff to
200mmHg (or at least to a pressure 50mmHg higher than the
systolic arterial pressure) to one upper arm, followed by 5-
minute reperfusion with the cuff deflated
 Wile in sham control group, RIPC intervention was induced by
3 cycles of upper limb pseudo ischemia (5-minute blood
pressure cuff inflation to a pressure of 20 mm Hg and 5-
minute cuff deflation)

19. Blood and urine samples
 Blood samples were drawn before surgery,4 hours after
cardiac surgery and on every morning for at least 3 days after
cardiac surgery
 Urine samples for biomarkers were collected before RIPC or
sham procedure, after inducing each one and at 4, 12, and 24
hours after surgery

20. 5 min
inflation of
BP cuff to
200mm
then
deflate for
5 min
5 min
inflation of
BP cuff to
20mm then
deflate for
5 min

21. Results

22. Demographics
Baseline characterstics Control (n=120) RIPC (n=120)
Age, mean (SD), y 70.6 (9.9) 70.1 (9.1)
Male sex, No. (%) 75 (62.5) 76 (63.3)
Cleveland Clinic Foundation
score, median (IQR), points
6 (6-6) 6 (6-6)
Preoperative creatinine, mean
(SD), mg/dL)
1.2 (0.4) 1.1 (0.4)
eGFR, mean (SD), mL/min/1.73
m2
56.4 (15.8) 56.7 (13.4)
Co-morbidities
Hypertension
Congestive heart failure
Diabetes
COPD
Chronic kidney disease
Previous heart surgery
LVEF <35%
116 (96.7)
101 (84.2)
44 (36.7)
40 (33.3)
39 (32.5)
14 (11.7)
13 (10.8)
116 (96.7)
101 (84.2)
46 (38.3)
36 (30.0)
35 (29.2)
13 (10.8)
23 (19.2)

23. Operative Characteristics
control RIPC

24. Outcomes

25. Analysis of biomarkers
ALARM BIOMARKER DAMAGE BIOMARKER

26. Discussion
 First study to measure biomarkers in RIPC studies
 Differences in outcomes across RIPC trials might also have been due to
differences in study protocols, confounding comorbidities, anesthetic
regimens and surgical technique
 RIPC induces the release of various molecules that appear to mediate the
protective effect of this intervention
 These mediators might be inducing G1 cell-cycle arrest in the kidney, as
indicated by increased urinary (TIMP-2)× (IGFBP7) after RIPC.

27. Pathophysiology

28. Study Limitations
 Although a multicenter study but was adequately powered only to analyze
prospectively the rate of AKI thus phase 2 study
 The secondary end points for which study was not adequately powered
showed reduced kidney damage
 Although ICU physician were blinded to study group allocation but
initiation of RRT was at their discretion. Timing of initiation of RRT remains
a controversial issue.
 There were important associations with intermediary end points but
authors could not prove the mechanism.

29. Study limitations (cont)
 Study did not detect reduction in mortality between two
groups: As expected this secondary end point is uncommon
and study was too small.
 According to 30 day mortality result , it will need 4000
patients (183 deaths) to detect difference in mortality with
80% power.

30. Conclusion
 Among high-risk patients undergoing cardiac surgery, remote
ischemic preconditioning compared with control significantly
reduced the rate of acute kidney injury and use of renal
replacement therapy
 The observed reduction in the rate of acute kidney injury and
the need for renal replacement warrant further investigations.

31. Thank you