A joint Congress by ERA-EDTA and ISN

REMOTE ISCHEMIC PRECONDITIONING

Derek M. Hausenloy, London, UK

Chair: Joseph Bonventre, Boston, USA

Masaomi Nangaku, Tokyo, Japan

Dr. D.M. Hausenloy The Hatter Cardiovascular Institute University College London London, United Kingdom

Slide 1

Good afternoon Chairman, Ladies and Gentlemen. I’d like to first thank the organisers for giving me the opportunity to come and talk at this World Congress of Nephrology. I’m actually cardiovascular scientist so please bear with me. I’ll be mainly talking about the heart but where applicable talk about the kidney. So I’ve been asked to talk about remote ischemic preconditioning which is an endogenous cardioprotective phenomenon which can be applied to other organs including the kidney.

Slide 2

So as we all know, acute renal ischemia-reperfusion injury either occurring as a consequence of arterial occlusion, shock or organ transplantation is a common cause of renal cell death, renal failure and renal graft dysfunction.
Therefore, we need news strategies to reduce renal ischemia-reperfusion injury and improve clinical outcomes. As we have heard, ischemic preconditioning and more recently described postconditioning require an intervention which is applied directly to the organ you want to protect such as the kidney. However, if we want to bring this into the clinical setting, we need an intervention which can be applied to an organ or tissue away from the heart.

Slide 3

So what is remote ischemic preconditioning? So I’m just showing this in reference to heart ischemia-reperfusion but one could imagine this as kidney ischemia-reperfusion. If we subject a heart to a sustained episode of ischemia-reperfusion, clearly we’re going to get a sustained myocardial infarction. If however, we subject an organ or tissue away from the heart such as the intestine, the liver or a limb, or the kidney, if we subject any of these organs to an episode of brief ischemia-reperfusion prior to the myocardial infarction, one is able to reduce infarct size significantly. This phenomenon is called remote ischemic conditioning.

Slide 4

This is the original study which first described it. It used canine hearts and they subjected canine hearts to a left anterior descending coronary artery occlusion for 60 minutes and 4.5 hours of reperfusion. This is the sustained infarction here. If however, one applied several short episodes of ischemia to the circumflex artery territory prior to the LDA infarct, one was able to reduce infarct size significantly. So this is an example of intramyocardial preconditioning or in other words protecting one coronary artery against another. This was the first example of remote ischemic preconditioning.

Slide 5

Our laboratory back in 1988 showed that one was able to subject the kidney to an episode of brief ischemia-reperfusion such that it didn’t cause damage to the kidney and if you did this prior to a myocardial infarction, one could reduce infarct size significantly.
So if one applied a brief episode, in this case, ten minutes of renal ischemia in a rabbit heart model prior to the myocardial infarction one could reduce infarct size significantly. So this is showing that one can subject an organ to a brief ischemic episode and protect another organ.

Slide 6

Now this concept has been taken beyond the heart and the kidney in such that one can apply ischemia, brief ischemia to any of these organs or tissues and protect the hearts. If one misses the heart out of the equation, one is able to protect say the brief ischemia to the limb, can protect the liver and I’ve just highlighted here in green, experimental studies have shown that brief ischemia to the liver, lower limb, or the small intestine is able to protect the kidney which is subjected to a sustained episode of ischemia-reperfusion. So this phenomenon is able to apply to organs other than the kidney and the heart and the important thing is that if one applies the preconditioning stimulus to the upper limb or the lower limb, one is able to get system wide organ protection.

Slide 7

So what are the potential mechanisms underlying remote ischemic preconditioning? These are currently unknown but one is believed that there is this endogenous cardioprotective signalling pathway as we heard before in ischemic preconditioning. The question is how does the cardioprotective stimulus get from the remote organ or tissue, from the limb, from the kidney to the heart?
The mechanism for this is unclear but several orticoids have been suggested, such as adenosine, bradykinin, perhaps a humoral factor such as a peptide, a small peptide which is carried from the distal organ or tissue to the heart or the kidney but it’s not clear. The current hypothesis proposes a neural pathway or humoral pathway that links the remote organ or tissue to the heart or the kidney that you want to protect but the actual mechanism underlying this is unknown.
So how does one take this into the clinical setting? We’ve shown that if we subject the kidney to brief ischemia, we can protect the heart but clearly in the clinical setting one wants to be able to apply ischemia-reperfusion to a tissue which is readily accessible.

Slide 8

Professor’s MacAllister group from London in 2002 showed that if one puts a blood pressure cuff on the upper limb and subjects the forearm to brief episodes of ischemia and reperfusion one is able to protect against endothelial dysfunction in the opposite limb. So if one applies several episodes of ischemia and reperfusion to this arm, one is able to reduce the endothelial dysfunction in the contralateral arm. So this is the first showing of remote ischemic preconditioning in human volunteers but more importantly it provides a non-invasive intervention which can be taken into the clinical setting. So for this it was 3, 5, minute episodes of ischemia with 5 minutes reperfusion in between and one was able to protect the opposite arm.

Slide 9

So this was taken into the clinical setting in 2006 by Professor Reddington’s group in Toronto where 37 children requiring corrective cardiac surgery were randomised to receive either remote ischemic preconditioning and in this case the cuff was placed on the lower limb and inflated to 50 mmHg above systolic blood pressure for 5 minutes for 4 times. Then Troponin-I inotrope requirement and airway resistance were all measured. Those children who had been randomised to receive remote ischemic preconditioning, these are the triangles here released less troponin-I, this is an indicator of myocardial injury during surgery. They also required they had less airway pressures, these are the hatch columns here and in addition their inotrope requirements were less.

Slide 10

So this was the first clinical application of RIPC in the clinical setting. We then went on to show RIPC being protective in adult patients undergoing elective cardiac surgery. As you may all be aware, CK-MB/Trop release during CABG surgery has been linked to worse clinical outcomes. So we randomised 57 adult CABG patients to RIPC or control and again this was cuff inflation on the arm. We measured troponin-T release over 72 hours and in this purple line this is the remote preconditioned group we can see that we could reduce the amount of troponin release during cardiac surgery by 43% but clearly further studies are required to determine the clinical impact of this.

Slide 11

A further study by a group in Cambridge looked at abdominal aortic aneurysm repair and 30% of such operations are accompanied by high troponin-T. They randomised 82 patients who underwent AAA repair to receive RIPC, in this case our RIPC was induced by a 10 minute clamp of the right and then the common left iliac artery. They found that RIPC could reduce myocardial injury but more importantly they found that a single limb ischemia was able to preserve the kidney function post AAA surgery.
So this graph here shows troponin-I release in patients who had received RIPC versus control but importantly this is the serum creatinine post surgery for AAA repair and one can see that the rise in creatinine that followed surgery in the control patients was reduced suggesting potentially that this intervention not only is protecting the heart but can also protect the kidney.

Slide 12

We have analysed a cohort of patients of 80 patients undergoing elective CABG surgery who received RIPC and controlled. We looked specifically at renal outcomes using AKI criteria. We found that RIPC reduced the development of AKI. So if we look at the outcome of controls in RIPC here 39 patients received RIPC prior to cardiac surgery, 41 patients didn’t and if we look at the number of patients experiencing AKI criteria 1-3, we find that significantly reduced numbers of patients who received RIPC went on to develop acute kidney injury.
So a blood pressure cuff prior to cardiac surgery has the potential to protect the heart and the kidney.

Slide 13

RIPC has been looked at in elective PCI, in patients undergoing coronary angioplasty. 200 patients who were planned to have elective percutaneous coronary intervention were randomised to RIPC and control and RIPC again was found to reduce Trop-I from 0.16-0.06 median. This is the periprocedural injury associated with standard percutaneous coronary intervention.

Slide 14

However, these interventions I’ve described have to be instituted prior to the myocardial ischemia or prior to the renal ischemia but the question is do these interventions work if applied after the ischemia?

Slide 15

In other words, I’m referring to remote ischemic postconditioning. Can a stimulus or a protective stimulus to an organ be applied after the onset of the organ of interest ischemia? This is remote ischemia postconditioning and this was described in 2005 in an in vivo rat model where a heart was subjected to ischemia-reperfusion but just 5 minutes before reperfusion the kidney was subjected to 5 minutes of ischemia and reperfused prior to cardiac reperfusion. This is the myocardial infarct
Size. So in control hearts it’s 50% however in those animals that had received a brief episode of kidney ischemia just prior to myocardial reperfusion infarct size was reduced significantly. Interestingly if one did not reperfuse the kidney prior to the myocardial reperfusion, one did not see protection at all suggesting a washout of a particular humoral factor or protective factor from the kidney to the heart.

Slide 16

Remote ischemic postconditioning has recently been applied to the clinical setting of ST-elevation myocardial infarction patients. A Danish group led by Hans Botker et al in a recent ACC presentation randomised 246 STEMI patients to receive remote ischemic postconditioning in the ambulance on the leg for 4-5 minutes, on the leg whilst in the ambulance by the paramedics. They then underwent primary PCI as normal and they had the myocardial salvage index determined and this was found to be improved at 30 days and infarct size was reduced at 30 days.

Slide 17

So in conclusion remote ischemic preconditioning is a non-invasive, virtually cost free strategy for reducing myocardial and renal injury in a range of different clinical settings.

Slide 18

I’d like to thank Professor Yellon and my colleagues in the lab and I’d like to thank you for your attention.