Effect of Remote Ischemic Preconditioning on AKI among patients undergoing cardiac surgery

Zarbock A, Schmidt C, Van Aken H, Wempe C, Martens S, Zahn PK, Wolf B, Goebel U, Schwer CI, Rosenberger P, Haeberle H, Görlich D, Kellum JA, Meersch M; RenalRIPC Investigators.

PMID: 26024502

We'd like to thank JAMA for supporting NephJC by making this study open access for the week leading up to the discussion. Follow this link to access the paper without a paywall.

Also thanks to Hector Madariaga for preparing the summary. The discussion was on August 11th at 9pm Eastern and the 12th at 8pm GMT (Noon Pacific time).

Pre-Chat summary

Background

AKI is a well-known complication after cardiac surgery; it has been reported that up to 30% of the patients developed AKI. 

Remote ischemic preconditioning (RIPC) refers to the protection conferred to ischemic tissue by preceding small periods of ischemia. It was originally described by Murry et al. in canine myocardium. He found that use of RIPC preserved high-energy phosphates and reduced tissue necrosis. It has primarily been studied in cardiovascular surgery, but it was also described as a technique to reduce contrast-induced nephropathy (P = NS) and in another study (P<0.003). RIPC also showed up in NephMadness 2014.

RIPC may attenuate AKI by stimulating the release of molecules signaling Toll-like receptors in the proximal tubule epithelia. This induces natural defenses such as bioenergetic down-regulation and temporary cell-cycle arrest that protect the kidneys from inflammatory and ischemic insults. This study was designed to answer ambiguities from previous studies.

Methods

Design: Multi-center, double-blind, randomized trial.
 

Setting: Universities of Münster, Tübingen, Freiburg, and Bochum; all located in Germany. From August 2013 to June 2014

Inclusion criteria.  A Cleveland Clinic Foundation score of 6 or higher was used to define patients at risk for AKI

Exclusion criteria:

  • Acute myocardial infraction up to 7 days before surgery.
  • Age <18 years.
  • Off-pump heart surgery.
  • Preexisting AKI.
  • Kidney transplantation.
  • CKD (eGRF < 30mL/min)
  • Pregnancy
  • Peripheral vascular disease.
  • Hepatorenal syndrome.
  • Drug therapy with sulfonamide or nicorandil

Randomization and Blinding. People were randomized on a 1:1 basis to RIPC or a sham RIPC procedure. Patients were randomized on the day of surgery.

Intervention: Provided by investigator not involved in further care of the patients.

After anesthesia induction, they performed RIPC consisting of 3 cycles of 5-minute inflation of a BP cuff to 200 mmHg (or at least to a BP 50 mmHg higher than the systolic arterial pressure) to one upper arm, followed by 5-min reperfusion with the cuff-deflated. Sham RIPC was 3 cycles of upper limb pseudo-ischemia (low pressure, 5-min BP cuff inflation to 20 mmHg followed by 5-min cuff deflation).

Results

Of 790 patients screened, 240 patients were enrolled and randomized. One hundred twenty to the intervention group and 120 to the control group.

Primary end-point: AKI within 72 hours after the procedure. There were fewer patients in the RIPC arm that developed AKI (37.5%) in comparison to the sham RIPC arm (52.5%)

RIPC and biomarkers in AKI: This is the first study that included AKI biomarkers to assess RIPC. There was no difference of (TIMP-2) x (IGFBP7)- better known as Nephrocheck® (See NephJC discussion)- and NGAL between the two groups, although the control group had higher (TIMP-2) x (IGFBP7) at 4 hours after the RIPC and 12 hours after the cardiopulmonary bypass and higher NGAL at 4 hours after cardiopulmonary bypass compared with the RIPC group.

Also, RIPC induced (TIMP-2) x (IGFBP7) release immediately after the RIPC before cardiopulmonary bypass compared with the control group. NGAL remained unchanged.

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”

How does RIPC prevent AKI?

The authors stated that RIPC releases mediators that induce G1 cell-cycle arrest-(which has been implicated in AKI) as indicated by increased (TIMP-2) x (IGFBP7). Cell-cycle arrest is a purported epithelial cell defense mechanism. Another protein, known as HMGB-1 (High mobility group box 1), binds to Toll-like receptors, is released after RIPC and induces cell-cycle arrest in tubular cells.

Discussion

This intervention reduced the incidence of AKI after cardiac surgery. It also reduced renal replacement therapy and decreased ICU length of stay. RICP is inexpensive, safe and leverages the ubiquitous blood pressure cuff for a therapeutic role after a century of diagnostic work. Short-term benefits have been proven in this trial, however morbidity and mortality was not reduced in this trial. Perhaps, a larger trial could demonstrate this. Is a reduction in ICU length of stay, biochemical AKI and the need for dialysis enough, or do you need improved mortality?