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This slide is very confusing and you can see the incidence of acute kidney injury in sepsis patients varies a lot between 11-89% in this slide. It has all to do with definitions. First of all, you have different severity of sepsis, severity of illness of sepsis. You have sepsis that is infection or severe infection better said. Then you have severe sepsis that is infection with associated organ failure or septic shock. So, there’s an increasing degree of illness of sepsis and that makes a difference. The incidence of acute kidney injury in sepsis, the least severe form, is probably somewhere between 11-16%. The incidence of acute kidney injury in severe sepsis patients is somewhere between 37% and 40%.

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There’s another issue, there’s a whole range of definitions for acute kidney injury. We are all very well aware of that. There are more than 35 definitions for acute kidney injury. That’s also one of the explanations for this huge variation in incidence numbers. We’re very fortunate that for a few years we have had a consensus definition for acute kidney injury and probably in the future we will not have this wide variation anymore in incidence numbers. We have RIFLE criteria that have been modified recently in the AKI staging criteria.

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Septic patients with acute kidney injury do worse compared to sepsis patients without acute kidney injury; that has been demonstrated in several trials. Mortality is almost double or is double in patients with acute kidney injury compared to patients without acute kidney injury. When you define acute kidney injury according to the RIFLE criteria, you see a stepwise increase according to the severity of acute kidney injury. A stepwise increase in mortality that is.

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Of course, you can argue, well these patients are probably more severely ill, they have other diseases but all studies that are corrected for other variables that could explain higher mortality, all studies found that in multivariable analysis acute kidney injury had an independent effect on mortality.

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Second scenario; acute kidney injury patients with sepsis or without sepsis

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First interesting data are from a large study, the BEST kidney study, 53 centres, a worldwide study on ICU patients and the first thing they found was that septic shock was the most important contributing factor to the development of acute kidney injury. So, sepsis is an important contributor to the development of acute kidney injury.

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It is not surprising to see that patients with sepsis do worse compared to AKI patients without sepsis and that was already demonstrated in a multicentre study in the early 90s in France. You see here septic patients have a worse survival compared to non-septic patients. When there’s more severe sepsis, the mortality is higher.

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This was confirmed in later studies like the large SOFA study and recent in Australia and New Zealand large database on AKI patients.

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Again, patients with sepsis do worse compared to patients without sepsis. AKI patients with sepsis have a worse survival even when corrected for other covariates that could explain mortality.

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This brings me to the pathophysiology.

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This is almost an insult to show this slide in this audience of nephrologists but it only serves to explain that in sepsis patients ATN, acute tubular necrosis is probably the most important cause of acute renal failure either on the basis of ischemic lesions or toxic injury.

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This has been the traditional way of thinking about acute renal failure in sepsis conditions. There’s a whole set of variables that are increased in sepsis and this leads to decreases of renal blood flow and this in turn will lead to tubular necrosis, especially in the region of the outer medullary region that is already at risk for hypoxia because of the particular vasculature of the kidney.

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But there’s some disturbing data already dating back to the 90s that in sepsis patients renal blood flow in fact is not reduced. Barry Brenner has already demonstrated that rats with sepsis did not have a reduced renal blood flow. This was confirmed in later animal studies in septic sheep that demonstrated that sheep with sepsis do not have decreased renal blood flow and they even looked into detail and it’s not on this slide but there’s no decreased medullary blood flow or cortical blood flow in septic sheep. So the old concept of the reduced renal blood flow leading to acute tubular necrosis is not confirmed in animal studies.

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What is causing acute kidney injury? Probably the magic word is inflammation. Patients with acute kidney injury have a profound inflammatory response in the kidneys and you see here profound increase of the whole set of inflammatory mediators; TNF-α and IL-1 β, IL-6 etc. this leads to a whole set of untoward effects; vasoconstriction, neutrophil aggregation etc., all effects not at macrocirculation, renal blood flow but it affects the microcirculation so there’s probably a problem with ischemia but not at a macrocirculatory level not on renal blood flow but at the microcirculatory level.

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As nephrologists, we tend to feel that the kidney is the most important organ in the body and well, there’s some data that supports this feeling of ours. There’s the concept of so-called organ crosstalk, a bit the same like the lungs can exert damage to the kidneys, the other way around is also true. The kidneys can exert also damage to other organs. It has been demonstrated in models of isolated acute kidney injury that inflammatory mediators lead to upregulation of certain genes in the lungs and this leads to opening of sodium channels, aquaporins etc. and rats that are exposed to an isolated acute kidney injury will develop ARDS, as has been demonstrated in several models.

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What else can be a cause of acute kidney injury in septic patients?
Abdominal compartment syndrome. This is of course, a very grotesque way of abdominal compartment syndrome but you also have less grotesque ways of abdominal compartment syndrome. It’s already been known since 1930 that an increase of venous pressure will decrease renal blood flow, decrease urine output.

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This has been confirmed in several studies, when you increase intra-abdominal pressure from 10-25mmHg you will see that renal blood flow is altered and the resistance index is increasing.

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When you classify patients according to increase of intra-abdominal pressure 12mmHg or higher, you can see that patients with increased intra-abdominal pressure or intra-abdominal hypertension will develop acute kidney injury and they will have a greater incidence of acute kidney injury compared to patients without intra-abdominal hypertension.

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Summary of the pathophysiology: inflammation is the magic word. Ischemia also but not ischemia because of reductions of renal blood flow but ischemia because of alterations at the microcirculatory level. In some patients intra-abdominal hypertension will play a role. Of course there can be toxic influences like for example after administration of aminoglycocytes and there maybe, there is a certain amount of patients that will have drug-induced interstitial nephritis but data on that are scarce.

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This brings me to therapy.

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This is kind of a summary of any textbook of nephrology, editions 1952 till now. Medical therapy of acute kidney injury prevents hypovolemia and we had a talk on that before. Prevention of hypotension and stop all nephrotoxic agents.

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Prevention of hypovolemia. It’s easier said than done and that’s elegantly illustrated by Doctor Krenn. How do you assess hypovolemia? It’s not that easy and we just had 20 minutes of lecturing on it and I assume you will have the same experience, on the bad side there’s always discussion is a patient hypovolemic or not?

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Most of the times it ends up that we fill up the patients either with colloids or with crystalloids.

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But fluid replacement may cause harm, as illustrated in this cartoon in a recent number of CHEST.

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This has been demonstrated in several studies. In sepsis, positive fluid balance is an independent predictor of mortality and this has been demonstrated in a large multicentre SOAP study. 10% increased risk fro mortality per litre of positive fluid balance in sepsis patients.

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In ARDS when you expose patients to a conservative fluid management strategy or to a liberal fluid management strategy, patients exposed to a conservative fluid management strategy have more ventilated free days but does it come with a price for the kidney? Intuitively you would say yes, if you keep the kidney dry, probably there will be more acute kidney injury.

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Surprise, it doesn’t come with a price,  look here, conservative patients exposed to the conservative fluid management strategy have less, it’s not statistically significant but there’s a clear trend, have less need for renal replacement therapy.

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Ok we have talked about fluid balance and mortality in sepsis patients and fluid balance in ARDS patients but it is not logic that fluids are able to prevent development of acute kidney injury in sepsis patients. We all have this same feeling but in several observational studies this could not be confirmed. Patients who did not have acute kidney injury at onset of sepsis developed acute kidney injury despite a more positive fluid balance during the first day of treatment.

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This brings us to the second part of the textbook of nephrology on medical therapy of acute kidney injury; prevention of hypotension and you probably have the same experience when you enter the unit and you prescribe nor-epinephrine to a patient who is hypotensive. The surgeon will come in and say, ‘don’t do that it’s a vasoconstrictor and the renal blood flow will decrease because of this vasoconstrictor’. In fact, this is probably not the case.

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Again, animal experiments I have already demonstrated some of the data from the Belomo group. Septic sheep and this is renal blood flow after administration of nor-epinephrine, renal blood flow goes up, it doesn’t go down, it goes up. This is in humans. Septic humans before and after nor-epinephrine, serum creatinine goes down, so norepinephrine is not that bad in certain conditions and this is kind of a nice statement by Paul Marek who is provocative in many ways and he says well, let’s forget the concept of renal dose dopamine, let’s talk about renal dose norepinephrine.

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Loop diuretics. Loop diuretics have been around for many, many years, 40 years or more and surprisingly, there’s not that much data on prevention or therapy of acute kidney injury and loop diuretics. The data are summarised in this recent meta-analysis and there are others also and you can see the summary, it crosses the line, there’s no good data that supports the use of loop diuretics in the medical therapy of acute kidney injury.

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Renal dose dopamine. I’ve already alluded to it. Well, there’s good data on renal dose dopamine. Renal dose dopamine does not prevent development of acute kidney injury or a whole set of other outcome parameters. So forget the concept of renal dose dopamine.

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This is data from Doctor Schetz who was on the podium before. Intensive insulin therapy in acute kidney injury. You maybe well aware that intensive insulin therapy has been demonstrated in two separate studies from the Leuven group Belgium that intensive insulin therapy is able in general ICU patients to decrease mortality. It was demonstrated first in surgical ICU patients and later in a subanalysis of medical ICU patients again, intensive insulin therapy was able to decrease mortality. Doctor Schetz re-analysed these data with emphasis on occurrence of acute kidney injury and he found that in both groups, especially in surgical ICU patients, intensive insulin therapy resulted in a decreased incidence of acute kidney injury. As ever, it’s never as simple as it seems to be and there’s some conflicting data on this too.

This is another trial on intensive insulin therapy and there are many flaws in this trial but well let’s look at the hard data. It’s a trial of intensive insulin therapy in sepsis patients the topic of today and surprisingly, they couldn’t demonstrate in this multicentre German study a beneficial effect on two outcome parameters for acute kidney injury. Occurrence rate of acute renal failure or need for renal replacement therapy. No difference and no trend that demonstrated the benefits for intensive insulin therapy. So we need more data on that.

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This comes back to the inflammation part on the pathophysiology. It has been demonstrated by Bruce Monatoris’ lab that animals that have sepsis have impaired microcirculation in the kidney and that this is illustrated in this cartoon in this figure. Here you see that white blood cells adhere to the endothelium, there’s rolling and adherence and after administration of activated protein C, Xigris, the wonder drug of 7 years ago for sepsis, there’s normalisation of microvasculature. Rolling and adherence of white blood cells is decreased and micro phosphorous circulation is normalised again. This for medical treatment of acute kidney injury in sepsis patients.

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Now renal replacement therapy. This has been elegantly summarised in a recent review paper by Pannu in JAMA. You see here a whole set of different modalities of renal replacement therapy and it’s very hard to read for you but you can see that the summary statistics of all modalities all cross the line. There’s no hard data that support one modality over the other in treatment of acute kidney injury but it has to be said there’s no real good well-powered study yet, so we’re waiting for that.

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What we did know was that a higher dose of continuous renal replacement therapy leads to improved survival and it was demonstrated in the hallmark study by Claudio Ronco and he demonstrated that a dose of 35 ml/kg/hour of CVVH is superior compared to a dose of 20 ml/kg/hour. This was confirmed in a Swiss study by – and he also confirmed that a higher dose of CRT leads to better survival. But there are two other studies that could not confirm this. There’s a small study by Katherine Bowman, it’s only a small study but there’s a recent study by --- that again could not confirm that high dose of continuous renal replacement therapy leads to improved survival. I summarise these data in a meta-analysis and you see there’s still a trend for better survival in patients that are treated with a higher dose but the diamond crosses the line so are lined up.

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This is almost the last slide. This is kind of going down in evidence-based medicine hierarchy. You see the therapies that are on the least beaten track. High volume of hemofiltration in sepsis patients there are some observational data that demonstrated that high volume filtration leads to improved survival. High permeability hemofiltration, surrogate endpoints, improved sepsis patients and absorption there is some data that demonstrate that absorption might be of benefit in sepsis patients but definite trials have to be awaited for that.

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This brings to the conclusion. Sepsis is the most important aetiology of AKI in ICU patients. 50% of AKI is caused by sepsis and 50% of sepsis patients will develop AKI. Sepsis and AKI are independent factors for mortality. The pathogenesis of AKI is multifactorial and it’s inflammation and microcirculation that play a central role in this. The therapy of AKI at least in medical therapy was still stuck with the same text book dating back to the 50s.

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Thank you very much.