Effects of Different Doses of Remote Ischemic Preconditioning on Kidney Damage Among Patients Undergoing Cardiac Surgery: A Single-Center Mechanistic Randomized Controlled Trial
Authors: Meersch Melanie , Küllmar Mira , Pavenstädt Hermann , Rossaint Jan , Kellum John A. , Martens Sven , Klausmeyer Pia , Schmidt Elisa A. , Kerschke Laura , Zarbock Alexander 
Published: June 2020

Objectives:
We have previously shown that remote ischemic preconditioning reduces acute kidney injury (acute kidney injury) in high-risk patients undergoing cardiopulmonary bypass and that the protective effect is confined to patients who exhibit an increased urinary tissue inhibitor of metalloproteinases-2 and insulin-like growth factor–binding protein 7 in response to remote ischemic preconditioning. The purpose of this study was to determine the optimal intensity of remote ischemic preconditioning to induce required [tissue inhibitor of metalloproteinases-2]*[insulin-like growth factor–binding protein 7] changes and further explore mechanisms of remote ischemic preconditioning.

Design:
Observational and randomized controlled, double-blind clinical trial.

Setting:
University Hospital of Muenster, Germany.

Patients:
High-risk patients undergoing cardiac surgery as defined by the Cleveland Clinic Foundation Score.

Interventions:
In the interventional part, patients were randomized to receive either one of four different remote ischemic preconditioning doses (3 × 5 min, 3 × 7 min, 3 × 10 min remote ischemic preconditioning, or 3 × 5 min remote ischemic preconditioning + 2 × 10 min remote ischemic preconditioning in nonresponders) or sham-remote ischemic preconditioning (control).

Measurements and Main Results:
The primary endpoint of the interventional part was change in urinary [tissue inhibitor of metalloproteinases-2]*[insulin-like growth factor–binding protein 7] between pre- and postintervention. To examine secondary objectives including acute kidney injury incidence, we included an observational cohort. A total of 180 patients were included in the trial (n = 80 observational and n = 100 randomized controlled part [20 patients/group]). The mean age was 69.3 years (10.5 yr), 119 were men (66.1%). Absolute changes in [tissue inhibitor of metalloproteinases-2]*[insulin-like growth factor–binding protein 7] were significantly higher in all remote ischemic preconditioning groups when compared with controls (p < 0.01). Although we did not observe a dose-response relationship on absolute changes in [tissue inhibitor of metalloproteinases-2]*[insulin-like growth factor–binding protein 7] across the four different remote ischemic preconditioning groups, in the 15 patients failing to respond to the lowest dose, nine (60%) responded to a subsequent treatment at a higher intensity. Compared with controls, fewer patients receiving remote ischemic preconditioning developed acute kidney injury within 72 hours after surgery as defined by both Kidney Disease: Improving Global Outcomes criteria (30/80 [37.5%] vs 61/100 [61.0%]; p = 0.003).

Conclusions:
All doses of remote ischemic preconditioning significantly increased [tissue inhibitor of metalloproteinases-2]*[insulin-like growth factor–binding protein 7] and significantly decreased acute kidney injury compared with controls. High-dose remote ischemic preconditioning could stimulate [tissue inhibitor of metalloproteinases-2]*[insulin-like growth factor–binding protein 7] increases in patients refractory to low-dose remote ischemic preconditioning.