ACUTE KIDNEY INJURY AND CRITICAL ILLNESS: CAUSE OR CON­SEQUENCE?

Ravindra L. Mehta, San Diego, USA

Chair: Ravindra L. Mehta, San Diego, USA

Eric Rondeau, Paris, France

Prof R.L. Mehta Department of Medicine, Division of Nephrology University of California San Diego Medical Center San Diego, CA, USA

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Slide 1

Thank you Professor Rondeau. I’d like to thank the ERA-EDTA organising committee for giving me the opportunity to be here.

Slide 2

 

I have a task to take you through some emerging concepts in acute renal failure or as the proposed term is acute kidney injury and I will take you through these 4 questions; Is acute kidney injury a consequence of critical illness? Does it lead to organ dysfunction? What are the pathways and mechanisms? How can we learn from what we have the knowledge of currently?

Slide 3

So, let’s ask the first question. Is it a consequence of critical illness?

Slide 4

Over the last several years what’s quite clear is that renal failure is common in an ICU population and these have been, I’ve just summarised for you some of these basic studies and I’ll walk you through these.

Slide 5

This multicentre study looking at the incidence of acute kidney injury across several ICUs in 16 countries clearly showed the difference between patients who had acute renal failure versus no acute renal failure in terms of mortality.

Slide 6

This study published from one single group in Pittsburgh showed that if in an ICU population the incidence of acute renal failure was 16%, those patients who did not require any haemodialysis had a low mortality, acute renal failure, no haemodialysis but look at what happens when you have acute renal failure requiring dialysis.

Slide 7

 

A case control study from Austria shows the same association. Renal replacement therapy, it can show differences between hospital mortality and the effect of renal replacement therapy added on.

Slide 8

In our own cohort which is the PICARD cohort in 5 centres in the United States we showed the incidence of acute renal failure in those patients who were dialysed versus non-dialysed, you can see the effect on hospital and ICU mortality with these patients.

Slide 9

Most recently this is the Best Kidney Study which was an observational study entered across multiple countries. You can see that out of almost 30.000 ICU patients 5.7% had acute renal failure and the most common factor was septic shock.

Slide 10

A study from China showing you the same thought process that you had a significant number of patients in the ICU and the mortality’s significantly higher, in contrast almost 10-fold higher here but what’s more important is a significant number of these patients also had pre-existing chronic kidney disease.

Slide 11

So, the first set is quite clear. The literature proves and suggests that it’s common in ICU patients. What about a specific relationship to other dysfunctions?  We know that in all of these conditions acute kidney injury has been reported and is fairly common.

Slide 12

For instance, this is a study from trauma patients again demonstrating that those patients who have acute kidney injury have a much higher mortality.

Slide 13

If you look at those patients with burns you have a significant component of those, the percentage of patients who have with and without acute renal failure have differences.

Slide 14

When you look at those patients in a septic population, this is a study from Doctor Hoste in Ghent, you can see quite clearly that those patients who have sepsis associated acute renal failure have a worse clinical outcome than those patients who don’t.

Slide 15

Same thing from another study of Yegenaga showing you the incidence of acute renal failure in the setting of sepsis.

Slide 16

We found the same thing in the PICARD cohort stratified for Apache 3 Score at consult start. Those patients who had sepsis and septic shock have the worse mortality in contrast to anybody else.

Slide 17

If you take even more specific conditions, this is bone marrow transplant, 21% acute renal failure, much higher mortality.

Slide 18

And if you take even in a coronary care unit, these patients who come in for cardiology settings, you can see that the development of acute kidney injury or pre-existing renal dysfunction has a strong influence on their cumulative survival over time.

Slide 19

Same thing with acute myocardial infarction showing you the effect on renal function.

Slide 20

So, it’s quite clear that not only do you have it common, it is associated with chronical conditions and the third aspect is that the underlying severity of illness affects it.

Slide 21

So, it’s very well documented that in an ICU critically ill population, if you have more than 1 organ dysfunction and you have different organ configurations, this affects mortality.

Slide 22

We found the same thing in our PICARD cohort looking at the effects and severity of illness and you can see 1-2 organ systems, 3 organs, 4.

Slide 23

You can see in all the centres overall there was a linear trend to an increase in mortality and this was no different whether the patient required dialysis or didn’t or the type of dialysis utilised in this population.

Slide 24

When you put this all into a logistic regression model predicting outcomes from acute kidney injury, what’s quite clear is the types of organ dysfunction are associated with this.

Slide 25

This was from our prior study and when this is repeated in the PICARD cohort, these parameters still maintain, so haematological liver failure, respiratory failure are clearly the organs of interest. So, there’s no debate, all of us are very clear in recognising that there is an association. So, you could go home and take the stand that well, acute renal failure happens, it is a part and parcel of critical illness and therefore, our approach should be only to think of it as such.

Slide 26

Well, I’d like you to think a little beyond that and think a little differently and ask the question, does the development of acute kidney injury lead to organ dysfunction itself? And I’m going to try and show you in a series of slides why I think that maybe important.

 

Slide 27

First of all, let’s look at the sequence of involvement and there have been a couple of studies over the last few years.

Slide 28

This is the French Critical Care study looking at acute kidney injury. Now, notice that this was a study of patients who had severe renal dysfunction as characterised by meeting the definition of greater than 3.5 mg of creatinine and they classified those patients into different categories. Those patients who had the episode of acute renal failure at the time of admission, or those patients who developed the acute renal failure at a subsequent time point and what’s important to realise is that here is the original organ system failure at the time acute renal injury is diagnosed or the first episode of acute renal failure and what you see here is here’s the percentage of infection in those categories but those patients who develop acute kidney injury initially, the percentage of infection actually goes up. So, you can see that there is an effect of the acute kidney injury developing further infection as a complication from it.

Slide 29

 

Another aspect of this is that isolated renal injury contributes to an adverse outcome. Then in the last 5 years there have been subsequent studies which have shown this.

Slide 30

First of all, take a cohort of patients who undergo percutaneous cardiac catherisation. If you have a change in the creatinine from 10% going up to almost 50%, notice the increase in mortality associated with this.

Slide 31

Here is the survival in these patients. Those patients who develop renal dysfunction have a worse outcome whether or not they are stratified for diabetes or other comorbidities this trend persists.

Slide 32

In a more important study looking at the incidence of acute kidney injury stratified by baseline serum creatinine, diabetic status, here is your baseline serum creatinine, here is the risk overall and you can see that those patients who have acute kidney injury have a much higher adverse outcome than those and 22% of the patients who died in the index hospitalisation only compared to 1.4% without acute renal failure, a significant increase in mortality even after one contrast induced nephropathy after cardiac catherisation.

Slide 33

If you look at a segment of patients who undergo cardiac surgery, this is Doctor Paganini’s group looking at here’s the baseline GFR, so whether you have normal renal function or chronic kidney disease a 10% drop, a 30% drop, a 50% drop look at the overall mortality rate seen in these populations itself.

Slide 34

The third set of information which has just appeared in the last year or earlier this year is looking at the severity of renal dysfunction influencing outcome and this is based upon the RIFLE criteria, again the classification which Doctor Ronco showed you earlier looking at risk injury failure, loss of end stage kidney disease.

Slide 35

And you notice that this is a group in Pittsburgh looking at 5000 consecutive patients in an ICU, you can see that as you progress from risk injury to failure, the requirement for renal replacement therapy goes up but more importantly mortality goes from 5.5% for no acute kidney injury to as much as 26.3% on those patients who have failure.

Slide 36

If you look at a study from a single hospital in Melbourne, Australia, you can see that this association of mortality is significantly higher from risk all the way to failure as evidenced by this curve. So, as you get further severe in your renal dysfunction, you have increased mortality.

Slide 37

Finally, I think this is the most compelling evidence in terms of new onset organ dysfunction.

Slide 38

This study was published over 10 years ago looking at a cohort of patients who got contrast induced nephropathy and what they found was that there was an odds ratio of 6.5 in those patients who developed acute kidney injury but what was most interesting was that as they tracked these patients going from pre-existing to new onset, new onset sepsis, respiratory failure, mental status changes and bleeding were a clear feature of those patients who developed acute kidney injury.

Slide 39

When you looked at a more recent study published looking at cardiac surgery patients a 20% increase in plasma creatinine associated to other organ dysfunction in 80% of the patients. If you go through an organ dysfunction score, you find that there is a clear association of mortality, 2.7 versus 17.7%, anybody who has more than 3 organs down.

Slide 40

We found the same thing in the PICARD cohort. Here is the overall organ system failure relationship to mortality.

Slide 41

And when we looked at the PICARD cohort, we asked the question here is at the time of consultation, you find that out of the 554 patients here, you can see this is the mean number of organs which are down and here is the frequency of the different organ systems which are in failure mode at that point in time.

Slide 42

This categorises those in terms of septic shock, SIRS and no sepsis.

Slide 43

And you can see that across the centres there was wide variation in those patients in this characteristic. Well, we asked the question, if you took patients at the start, at consultation and you classified them that they remained never having sepsis versus those who had sepsis at the start of acute kidney injury or developed it subsequently, you find that there’s a significant number of patients who actually develop sepsis after acute kidney injury has occurred overall and you can see the characterisation here, there is some differentiation whether or not they had chronic kidney disease before or MDRD GFR, there doesn’t seem to be, there is a small relationship in terms of whether they’re oliguric or not.

Slide 44

But what’s most important is that whether you develop sepsis before or you have sepsis after, the mortality characteristic is the same. So, it doesn’t matter, the moment you have sepsis you have changed the characteristic of an acute kidney injury developing into further mortality.

Slide 45

When you ask the overall question, so here’s the in-hospital mortality, there’s post ARF, 44% and never septic 21%, dialysed 70%, 51% any poor outcome that is dialysis dependency or non-survival, you can see a significant difference and in the mean length of stay.

Slide 46

So the development of sepsis post acute kidney injury is a major factor contributing to adverse outcome and this shows you the cumulative percent of patients who are developing sepsis from acute renal failure start and this is the cumulative percent who have dialysed patients who develop sepsis. Notice that you start seeing a plateau almost 50% in the early days.

Slide 47

So within the first few days of acute kidney injury you have an increasing amount of patients getting acute sepsis and here’s there's from start to sepsis start, you can see never oliguric or oliguric there doesn’t seem to be a differentiation.

Slide 48

So whether or not you’re making it urine doesn’t seem to matter, you do have a high incidence of sepsis developing here and whether or not you ultimately get dialysed or not this is not necessarily related to the dialysis intervention itself, it is a feature of acute kidney injury by itself. I mean look at this in terms of the cumulative percentage of dialysis requirement.

Slide 49

Those who are never septic have a lesser dialysis requirement than those who ultimately become septic.

Slide 50

So what I’ve tried to show you is that there’s increasing evidence coming out that acute kidney injury itself is contributing to renal dysfunction and if that is the case, then we need to be asking ourselves why is it that acute kidney injury would be contributing and what are the pathways and mechanisms that could be incriminated in this?

Slide 51

These are overall the areas that we have some knowledge of and this is an incomplete list but I’ll show you some of the pieces of evidence which are falling into place here.

Slide 52

When we looked at the PICARD cohort and these with the Himmelfarb’s data cell looking at 2 centres out of those and you see the plasma cytokine levels in those patients with acute kidney injury, here is IL-6 and IL-8, IL-10 you can see here are patients who are acute renal failure, healthy subjects and end-stage renal disease controls and it’s quite obvious, look at the height of these bars in comparison to healthys or end stage renal disease and if you look at IL-6 in some of the quartiles, here is the odds ratio of death and also surprisingly the odds ratio of IL-10.

Slide 53

We ask a different question if you look at the monocyte performance in these patients here this shows you again that theIMC production or responsiveness to stimuli is significantly different in those patients with acute kidney injury and with end stage renal disease. You can see here in comparison with healthy subjects with those with critically ill, IL-6 or acute renal failure patients in general.

Slide 54

Now, whether or not this is based upon a genetic predisposition is just starting to be explored. This is data from Bertrand Jaber’s group looking at the differentiation of patients in the allelic differentiation of their production of IL stimulant growth factor and IL-10, so those who produce high TNF and low IL-10 tend to have the worst prognosis with acute kidney injury in this setting.

Slide 55

A second sequence of events which tends to happen once you have acute kidney injury is the setting off of oxidative stress, insulin resistance and metabolic pathways.

Slide 56

When we look at the PICARD data set here is carbonyls and thiols. Low thiols and high carbonyls are features of oxidative stress and what you find is quite clearly there’s a significant differentiation in those patients as you go through the sequence of acute kidney injury.

Slide 57

More importantly, insulin resistance is a feature of acute kidney injury. As you track these patients and differentiate survivors from non- survivors, insulin resistance is a feature of non-survival, it is also associated with the level of glucose and you can find that as has been shown in other critically ill patients that the hyperglycaemia contributes to this. What you see here is here is the quartile of insulin level.

Slide 58

 

Again a reflection of insulin resistance and again, showing you the differentiation based upon the insulin binding protein levels that there’s a clear association.

Slide 59

Now, there is some experimental preclinical data which is now changing our thought process into what might be happening and this is Doctor Rabb who is a nephrologist in Johns Hopkins did this initial study where he looked at a rat model of ischemia reperfusion to the kidney.

Slide 60

And looked at what happens to the lung 24 hours later and what you find is a few hours after or 48-96 hours after only ischemia/reperfusion to the kidney, you find increased permeability in the lung. So there seems to be a kidney-lung combination or organ cross talk happening.

Slide 61

This is further exemplified by serum taken from patients who were in the ARDS network study with the low volume versus high volume ventilation, that serum put into rabbit kidney model showed increased apoptosis in those rabbits treated with the high volume ARDS network patients demonstrating that apoptosis can be transferred by a serum factor in this setting.

Slide 62

This is Doctor Kelly’s data which Doctor Ronco eluded to and showed you again showing ischemia renal ischemia/reperfusion affecting cardiac apoptosis and changes in circulating and tissue cytokines in this animal model.

Slide 63

And associated with a functional abnormality in terms of cardiac output in this model.

Slide 64

So one of the thought processes which comes up is that once you develop acute kidney injury, there are several mechanisms which are introduced and once that introduction occurs, this can be mediated by the uremic state itself, by the injured kidney itself or renal replacement therapies. So, it is up to us to start recognising that the development of acute kidney injury has a significant contribution by itself and the process factors we do, do develop further problems.

Slide 65

If you were to take this all into context, what would be the lessons learned and what would be the things that you would want to apply?

Slide 66

First of all, I’d like you to start thinking and for all of us to collectively think that acute kidney injury is not single organ injury. Acute kidney injury is a systemic disorder.

Slide 67

We must start thinking of it in that manner and that will change our thought process of how we will manage it. For example, the consequences of acute kidney injury are in all organs. They don’t stop just at the kidney level. It manifests itself in all organ dysfunction as exemplified here in this setting.

Slide 68

So it contributes to organ dysfunction, it has broad downstream effects, it initiates various pathways across systems and the clinical manifestations are not limited to the kidney and it contributes directly to morbidity and mortality. So it is in its own right an important feature for us to start working towards and thinking of.

Slide 69

The second thing I’d like you to think about is that time is of the essence. This is not a disorder where you can wait for months and weeks before you intervene, you have to intervene earlier now what’s the evidence for that?

Slide 70

Andrea Lassnigg’s group in Vienna looked at patients with postcardiac surgery, 48 hours post cardiac surgery a change in creatinine of as low as 0.2 mg/dL was associated with a significant decrease of survival in these patients.

Slide 71

More compelling is a patient, this is a placebo group of sepsis patients, in critically ill patients from the Levy studies and this was published in Critical Care Medicine last year. This is the effect of baseline creatinine, you can see that within 24 hours if you start with a baseline of less than 1.2 and you increase your baseline, your mortality significantly increases.

Slide 72

So no matter what baseline increase is worse but what’s most important is if you do a Kaplan and Meir survival, you find here’s a less than 0.2 change, 0.2-05 greater than 0.5 what you find is a significant number of people will die early on by related to that change and when you put this into a logistic regression model the presence or this change of renal dysfunction is one of the clearest criteria influencing mortality.

Slide 73

A third piece of evidence is from looking at an overall population and a hospital population seeing the change in serum creatinine and look at the odds ratio of it even at 0.3. This has resulted over the last year or so of the development of a new concept which we will hopefully have the opportunity to present to you at some point in the next year. It’s called the acute kidney injury network and what we are proposing is a new interim definition of acute kidney injury related to a 0.3 mg/dL change to be constituted as a diagnostic criteria for acute kidney injury.

Slide 74

So, the last part is if we know that time is of the essence, is there evidence that early intervention might work?

Slide 75

We know that preservation of organ function is very important in all these organs, heart, brain, lung. Stroke within 24 hours you have to intervene. In terms of myocardial infarction you have to intervene early.

Slide 76

Why not the kidney? We already know from the transplant population that cold ischemia matters. If you have a cold ischemia for more than 24 hours, the kidney doesn’t work very well but yet our general principal of looking at acute kidney injury is so variable and we have based that largely because of failure of large trials previously in terms of ANP or  IGF1.

Slide 77

But more recently this trial was published in 2004 looking at ANP again and the trial design this time was recognising patients early in the course.

Slide 78

And for the first time what you find is that the same outcomes measures as the prior ANP trials, there’s actually an improved survival and a reduction in dialysis requirements.

Slide 79

So, I think that it is up to us as a community to start recognising that if we are going to intervene and make a difference in this disease process, we have to have therapy targeted to windows of opportunity.

Slide 80

From an experimental model it is proposed that there are various phases of acute renal failure. What we need to know is with the ability to diagnose these diseases which area or which phase of the disease is the patient in and therefore, we can target this in a very specific manner.

Slide 81

This is absolutely necessary if we are going to be able to change the mortality across the years from this disease and this disorder.

Slide 82

And we must be able to change this graph instead of staying in this level here to coming down and that has to be a common problem for all of us to face not only as us as nephrologists but also as us as people dealing with the critical care community and in the hospital population itself.

Slide 83

So, I’d like to leave you with some final thoughts. I think acute kidney injury contributes to critical illness. I think that this is a multidisciplinary problem and research is needed to identify and characterise the pathways and the mechanisms and that one of the major areas which has been hampering this is standardising the terminology definitions and classification and the acute kidney injury, the AKI classification hopefully will go a long way towards that and finally I think all of us need to start thinking of it as a systemic disorder not just the kidney and that’ll change our collective thought process.

Slide 84

Thank you for your attention.

Chairman: Thank you very much Ravi for this excellent presentation.