1 di 27 Prevention of AKI: experimental promises and clinical realities Michael Joannidis, Innsbruck, Austria Chairs:Norbert Lameire, Ghent, Belgium Gert Mayer, Innsbruck, Austria Prof. Michael Joannidis Medical Intensive Care and Emergency Unit Department of Internal Medicine Medical University Innsbruck Innsbruck, Austria slide 1 clinical realities here might consider in my conflicts that slide 2
2 di 27 the idea is very futile to prevent AKI in the clinical situation. slide 4 Honestly, the only time I saw a pill working as a therapy for acute AKI slide 5
3 di 27 was when a pill was treating in Star trek AKI but you know things are easy slide 4/2 when living in the future, we are living in the present and now we have to think about what we should do. slide 6
4 di 27 The problem is there have been a lot of interventions, single interventions focusing on special pathophysiological processes like trying to optimise renal perfusion, just think of selective renovasal dilatation or modulating renal metabolism of pathophysiology, think of reducing oxygen consumption, reducing reproduction of oxygen radicals, trying to do anti-obstructive measures for tubular obstructions, anti-inflammation or stimulation of renal repair. slide 6/1 However, each single intervention or target even if it was defective in animals and attending was a fellow there told me everything works in rats, nothing works in humans. So the problem is that every single target has largely been unsuccessful slide 7
5 di 27 in the human situation and why is that? As nephrologists, we have mostly a very nephrocentric view, we know that AKI is influencing many other organs and is deteriorating the function. slide 7/1 However, in reality when we look at our patients who have AKI, usually it is the other way round also the kidney has many enemies. There are many changes in organ functions with influences in addition to AKI, influenced renal function and given additional risk factor and an additional deterioration of renal function. For example, you have pneumonia, we have cytokine release and the cytokines increase in the circulating blood circulation, which further deteriorates the kidney. While ventilator patients get additional cytokines, additional deterioration of renal function. slide 7/2
6 di 27 If they have heart failure the same here, they have an additional problem with renal perfusion to AKI and you have created a syndrome, cardiorenal syndrome for that. slide 7/3 There is hepatorenal syndrome slide 7/4
7 di 27 and I m sure very soon, we will hear that microbiota changes will influence also renal function. So what I mean is that the single intervention for any process in AKI might be futile if you re not considering the other deteriorations in the system. slide 8 So maybe a pleiotropic approach would be necessary for preventing AKI. What I m going to do now for the next few minutes is very speculative but I want to let you go home with some ideas on what can be helpful in the future and what studies are going on. Because we ve heard already from our colleague from the UK that there are usual measures which should be taken like optimising blood flow or taking away any nephrotoxins. slide 9
8 di 27 So I want to just address shortly four promising substances: Levosimendan, alkaline phosphatase, statins and dexmedetomidine which have some promising aspects. slide 10 Let s start with Levosimendan, which actually we think of as an inodilator which decreases preand after-load of the heart. It s a calcium sensitizer but it has also anti-inflammatory properties, anti-apoptotic properties, modulates NO release and also preserves mitochondrial function by modulating the ATP-dependent potassium channels. slide 11
9 di 27 It has been shown in small randomised trials where 2:1 randomisation is compared to dobutamine but in patients with acute decompensated heart failure Levosimendan is improving renal function over 96 hours by improving commercial clearance which was not the case when you use dobutamine having the same effect on cardiac output but not on renal function. slide 12 There is an effect which is independent of improving cardiac function by Levosimendan, which has been shown just recently in anesthetised pigs where it is a hemoreperfusion experiment and you reperfuse the kidney with a perfusion medium, which includes Levosimendan, you can see here this is this hemoreperfusion damage, tunnel staining, apoptotic cells, a lot of them which you can abolish significantly slide 12/1
10 di 27 by giving Levosimendan. slide 13 So it might be interesting and there has been just a recent randomised controlled trial, small as many trials in the ICU where they gave Levosimendan versus placebo in patients who underwent cardiac surgery and they looked at cardiac output, at cardiac index, they could improve this significantly. This was associated with improved renal blood flow as compared to placebo and it also improved GFR in these patients. So it had an influence, which was also associated with cardiac index or renal blood flow and a GFR. But we would say that this is only due to the improved cardiac output. slide 14
11 di 27 Now that s not the case, they compared this data to previous data they had on the same patient category where they gave dobutamine, they had the same change in cardiac index but they did not observe the changes in renal blood flow and the changes in GFR that they could show with Levosimendan. slide 1 Overall, in a meta-analysis in patients going under cardiac surgery, it has recently been shown that those patients who have decreased ejection fraction, those patients when they are treated with Levosimendan have a reduced requirement of renal replacement therapy, which is not the case if the patients slide 15/1
12 di 27 do not have ejection fractions below 30%. slide 16 But as I said, Levosimendan may have other effects also and what we could show nicely in patients with both acute heart failure and in patients with septic associated heart failure is that when you take the PMNs of the patient, so the neutrophils of these patients, after 1 hour or 2 hours of treatment and stimulate them or just measure their oxygen radical release, you can see that they are attenuated in the response. So it seems that the activation of the neutrophils is reduced by Levosimendan and we could also show this in vitro. slide 17
13 di 27 This might be the reason why in another randomised trial in sepsis associated acute cardiac insufficiency, so acute myocardial depression by sepsis, Levosimendan, again, this was a small trial with 30 patients as compared to dobutamine, was a substance which could increase creatinine clearance after 24 hours, slide 17/1 which was not the case for dobutamine but it also improved urinary output. So this might be quite interesting. I thinks there s more trials, slide 17/2
14 di 27 further investigations slide 18 are definitely warranted. How about alkaline phosphatase? Alkaline phosphatase, the mechanism, which is supposed to work for alkaline phosphatase, is that it dephosphorylates ATP down to adenosine and it prevents ATP, which is released from damaged cells by activating inflammatory responses in endothelial and epithelial cells. There is adenosine itself which activates anti-inflammatory mechanisms and is tissue protective. slide 18/1
15 di 27 Also, the other idea is that alkaline phosphatase might find LPS and reduce lipoprotein-binding protein, which has been shown in data I will show. slide 19 Small clinical trials have been done with alkaline phosphatase. This is from bovine origin and this was a 2:1 randomised trial in patients with sepsis. They didn t look at AKI first but then they realised in this study, these were again just roughly 35, 36 patients but they realised in those patients who developed AKI that their creatinine increase was less in these patients who had sepsis slide 19/1
16 di 27 and they could also see that the release of urinary damage markers was reduced in patients with sepsis who received alkaline phosphatase and that this reduction of urinary biomarkers was associated with reduced NO metabolites in the urine. So the idea was maybe this has a protective effect on the kidney in sepsis and therefore, slide 20 they did a follow-up study with Peter Pickkers and they included now only patients who had already some degree of AKI and sepsis. What they could show, this is again a small trial, 35 patients but what they could show was that creatinine increase was significantly lower in sepsis patients who had already a low degree of AKI as those patients who did receive placebo. This was not alone significant but they could show reduced renal replacement therapy requirements and reduced duration of renal replacement therapy and when they took this as a combined endpoint, they just got significance. Of course, this is just hypothesis generating and there is a large phase II trial now initiated on alkaline phosphatase and this now will be recombinant human alkaline phosphatase in sepsis-associated AKI and see if this is preventive. slide 21
17 di 27 I think we can skip this or maybe just as a short notion in this trial I showed you, it was also interesting that CRP was consistently lower as I said before the endotoxin might be bound by this and they had reduced lipoprotein binding protein levels and they had reduced IL-6 levels in these patients with alkaline phosphatase. slide 22 Now statins we know a lot about statins and there have been trials in statins in ischemic AKI, which were negative, and we know that statins have additional anti-inflammatory properties and abilities to improve endothelial function and have possibly anti-apoptotic effects. slide 23
18 di 27 These have been shown also in in vitro experiments both using MDCK cells or HK2 cells where they incubated these with radio contrast medium. In that case, it was Iodixanol and what they could show is that when you add to Iodixanol the atorvastatin, then you could reduce significantly the apoptotic effects of tunnel staining and interestingly it was quite similar to the effect of N-acetyl cysteine. slide 24 There have been meta-analysis prior to this, showing that giving statins might be effective in the prevention of conscious nephropathy but there have been recently three very big studies on that topic and I think this is very exceptional. There has been a single centre trial with 400 patients, reduced renal function, elective coronary angiography. They gave atorvastatin at the doses of 80 mg for 24 hours before contrast exposure and they could significantly reduce contrast induced AKI from 70-44.5%. A huge trial with 3.000 patients in a multi-centre randomised progressed CKD and diabetes; the patients had elective coronary angiography or peripheral angiography. They gave rosuvastatin 10 mg, two days before and 3 days after. Again they could get a significant reduction of c-contrast induced AKI. slide 25
19 di 27 Now we have seen this with many substances before but there have been these studies which I think make the evidence a little bit stronger. These are patients with acute coronary syndrome decreased renal function when they got the contrast, it s more than 500 patients, rosuvastatin was the statin which was investigated and they gave 40 mg pre-treatment followed by 20mg. Again there is significant reduction for contrast induced AKI but what makes the data stronger is when they looked at other events, adverse events at 30 days, so for example, dialysis, persistent CI-AKI, myocardial infarctions, stroke when you take the overall adverse events, they could get this significant benefit when reducing the overall adverse effects. So, I think this evidence is getting stronger and getting more interesting for this substance in terms of prevention. slide 26 Although, it doesn t work in every form of AKI and that s what I mentioned when I was beginning my talk. This analysis by Murugan nearly in 2000 patients with community-acquired pneumonia showed that in those patients who had statins and continued statin use they didn t have a difference in AKI incidence or AKI outcome. So as I said before, the interventions sometimes only work very specifically only in a specific situation slide 27
20 di 27 Now, dexmedetomidine, you could think why should this work in AKI. It just came over the data because we re updating our recommendations for the European Society of Intensive Care Medicine on prevention of AKI. Then we did an extensive literature research and we are using this actually as a sedative and as an analgesic, which is not depriving the respiratory drive so much. It has additional effects, it decreases sympathetic activity and there s some data on neuroprotection but there are also some indications that via the Fα2 adrenalin receptors, which the proximal distal tubules or peritubular vasculature might have additional beneficial effects. slide 28 There is in the literature data, which started already in 2004 when they used Dexmedetomidine in rats in endotoxin-induced shock. This is the control and the addition of Dex without endotoxin. When you give endotoxin, you have the release of TNF and IL-6. You can modulate this release by adding the Dexmedetomidine. What is interesting is that the mortality was improved, this is the mortality without Dex and this is the modality including Dex in these animals. Interestingly, also distant organ damage, so damage from the lung, so the water content of the lung and cellular infiltration was reduced by using this substance. slide 29
21 di 27 Does it work also for the kidney? It has been investigated just recently in a reperfusion ischemia model in mice. It preserved histology, I won t show you the data. It reduced tunnel staining, it reduced apoptosis but what is interesting is they were further looking at mechanisms and this is the immunohistology of TLR-4 expression. You can see that the TLR-4 expression was reduced but the accent here is the Western Blot when Dex was added to hemoreperfusion, then TLR-4 expression significantly reduced and this was associated with reduced serum levels of high mobility group protein. One, which also plays a role in the sepsis. slide 30 As I said, histology was preserved and renal function was also preserved by this substance showing here the reduced urine creatinine, creatinine and urea and improved survival by Dex. slide 31
22 di 27 The mechanism, which was this I think is what we have heard already several times before today is that while the AT2 receptors but this is specific of this substance, you get a down regulation of TLR-4 by reduced HMGB1 and that by reduced TLR-4, you have a reduced inflammatory process. slide 32 Does this convert to studies in humans? There s one small paediatric study in 60 patients, say very small children between 6 72 months who underwent cardiac angiography and they got contrast and contrast-associated AKI was measured according to prifle. slide 32/1
23 di 27 What they could show is that they measured 60 patients, 30 in each group, they could show that the patients who were treated with Dexmedetomidine reduced NGAL release as compared to control. They had reduced livers. slide 32/2 And although creatinine was not so different in the two groups, the pre-defined contrast-induced AKI was significantly reduced in this specific patient population. slide 33
24 di 27 There has been another study where they looked at cardiac surgery but this is not a prospective, this is a retrospective study where they just looked at over 1000 patients, 500 of them received Dexmedetomidine for sedation, the others did not. slide 33/1 When they compared those two groups and they corrected for all major confounders by a propensity score so we all know how good this often does or does not work. Mortality however was significantly reduced but and this was interesting, we would have expected slide 33/2
25 di 27 that they would have reduced slide 33/3 renal replacement therapy, this was not the case in these patients. So as I said, this is a completely different set of patients. So maybe it doesn t work but however it has to be investigated further. slide 34
26 di 27 So prevention of AKI is where the promise lies. I think summing up this very preliminary data I think modulation of the inflammatory reaction appears to be the key concept independent on what the origin is of AKI. However, even if we target this process, we will not be effective when we do not regard the other influences in that specific situation. Therefore, the success of any intervention will always be how we beneficially interact with other pathophysiology processes, which are going on. slide 35 Thank you for your attention. slide 36
27 di 27 Chairman: Thank you very much Michael. Are there questions on this interesting promising but still needing further trials? Are there questions on that? No, you have convinced everybody. Thank you very much. Thank you very much also to you who have remained until the last minute. I admire and also my Co-Chair admires your courage and we want to thank you for your presence. Thank you very much. See you next year in London.