Slide 1

Thank you. I would like to concentrate on 3 aspects. The new biomarkers of acute kidney injury, as Norbert Lameire told you it’s very important to find very early during the course of acute renal failure the beginning of injury and then we’ll talk about renal replacement therapy in acute renal failure with a big question whether continuous methods are better than intermittent methods. Finally, I will end with 2 important studies published about the incidence and prognosis of acute renal failure and I strongly recommend you to read the editorial written by Norbert Lameire in JASN about these 2 studies.

Slide 2

So why to identify new early biomarkers of acute kidney injury? Actually, there is an urgent need for these biomarkers because we know that delay in treatment may explain the poor efficacy of specific therapeutic intervention in human acute kidney injury and it’s well known that in experimental models many, many drugs have shown to be effective but when they are used in humans usually there is no effect, probably because the model is not identical to the human disease but also because the intervention is too late. Also we have new available biomarkers but these are limited due to the lack of sensitivity and specificity, the lack of sufficient validation and the lack of standardised assays.

Slide 3

In 2005 the group of Mishra published in the Lancet probably an important paper about these biomarkers about the neutrophil gelatinase-associated lipocalin as a biomarker of acute renal injury after cardiac surgery. Just to demonstrate this is the level of urine NGAL expressed as micrograms/L, 2 hours after surgery in children who underwent cardiac surgery. As you can see here, those who developed acute renal failure later, there are 20 have an increased level of NGAL in urine as compared to those who will not develop acute renal failure later, so there are 51.

Slide 4

So this test is very discriminant between the 2 conditions and this is the time force of evolution of urine NGAL as expressed as micrograms/L in the urine of children who developed later acute renal failure and this is in the green bar is represented 24-48 and even 72 hours after surgery the increase in serum creatinine which could detect at this time at the renal failure according to the RIFLE criteria and so you can see that NGAL in urine is increased at 2 and 4 hours, very early, so after cardiac surgery.

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Slide 5

Here is the same time course but urine NGAL is expressed as nanograms/g of creatinine. So in the control group, which will not develop acute renal failure, there is no increase in NGAL in urine thus this marker could be used as an early marker of kidney injury like troponin is used by cardiologists for the early cardiac ischemia.
When they use the urine NGAL, 50 microgram/L as test, 2 hours after cardiopulmonary bypass, the ROC curve was really nice and as you can see, the specificity was 1

Slide 6

So, the summary and conclusion of this important study that by multivariate analysis the amount of NGAL in urine at 2 hours after cardiopulmonary bypass was the most powerful independent predictor of acute kidney injury. For concentration in urine of NGAL at 2 hours the area under the receiver-operating characteristic curve was 0.99, sensitivity was 1, specificity 0.98 and concentrations in urine and serum of NGAL represent sensitive and specific and highly predictive early biomarkers for acute renal injury after cardiac surgery. So this biomarker has now to be tested in other medical conditions. An ELISA test has been made and probably we will see in the next months or year the use of this marker to test the acute kidney injury.

Slide 7

The other question I want to focus on is what is better, CVVHDF for continuous veno-venous hemodiafiltration or intermittent haemodialysis? As you know, there is a large debate about these 2 techniques, especially in intensivists and according to the areas around the world the use of the intermittent method is prominent while in other countries like Australia, the continuous methods are preferred. So to test and to answer this question we have to focus on in-hospital mortality, length of hospital stay, the hemodynamic instability of the patient and the length of recovery of renal function.

Slide 8

In one of the leading journals in nephrology, it has been published in 2005 that a comparison of continuous and intermittent renal replacement therapy for acute renal failure. It was a Swiss group that published this prospective randomised trial. 191 ICU patients with acute renal failure requiring renal replacement therapy were included in this study but due to the lack of enough hemodiafiltration devices, the randomisation could not be performed each time, so there were 62 patients which were not randomised for non-medical reasons that is logistic reasons and 129 patients could be randomised and the randomisation, it’s a bit complicated but has also to be modified according to the availability of the HDF ---. So 125 patients were correctly randomised and at the end 70 patients were in the group, CVVHDF and 55 patients in the group of intermittent haemodialysis. There was no difference between the 2 groups concerning the demographic data and the cause of acute renal failure. When the statistical analysis was performed to predict the in-hospital mortality, it was shown here that the technique used to treat these patients, CVVHDF or intermittent haemodialysis did not influence the percentage of mortality in the 2 groups. So there is no difference for this parameter.

Slide 9

When the 2 techniques were compared, the in-hospital mortality was not different according to gender, pre-existing chronic renal failure, age, number of organs failing, liver failure. There was a difference according to the SAPS score and the severity of the patient at admission and also for the need for catecholamines indicating hemodynamic instability in these patients.

Slide 10

What about the dose of dialysis or the mean urea level during the in-hospital stay? As you can see here, the average daily duration of renal replacement therapy was, of course, longer for the continuous technique, more than 20 hours as compared to 3 hours for the intermittent method. The urea clearance during the session was low with the continuous method but high with the intermittent method and as a rule, the average daily urea clearance was similar in the 2 groups. So there was no obvious difference in the dose of dialysis in these 2 groups of patients.

Slide 11

So the summary and conclusions of this probably one of the single prospective randomised study comparing the 2 techniques in the literature, so the summary is that mortality rate in the hospital and in the ICU were independent of the technique of renal replacement therapy applied. The hospital length of stay in the survivors was comparable in patients on CVVHDF and in those on intermittent haemodialysis. The duration of renal replacement therapy required was the same in both groups. So the present investigation provides no evidence for a survival benefit of continuous versus intermittent renal replacement therapy in ICU patients with ARF.

Slide 12

As Norbert Lameire, I did my homework and moreover, I went to get some secrets that is some future publications which will appear in the Lancet about the same subject, this is about the study called Hemodiaf, a prospective multicentre randomised clinical trial comparing CVVHDF to intermittent haemodialysis for the treatment of acute renal failure with multiple organ dysfunction syndrome. So that is a very severe form of acute renal failure. The study, the principle investigator was Christophe Vinsonneau in Paris. This study includes a larger group of patients as compared to the previous one I talked about and it was a multicentre study with a cohort randomisation.

Slide 13

So, 360 patients were randomised between 1999 and 2003. 184 were assigned to the intermittent haemodialysis group. Finally, 184 were analysed. 176 were assigned to the CVVHDF group and 31 were switched later or due to a technical complication in the intermittent haemodialysis group. Finally, 175 were analysed.

Slide 14

As a summary, no significant difference between the 2 groups concerning age, weight, sex, reason for admission, previous health status. The severity scores were also similar in the 2 groups. The need for catecholamine, as well as the requirement for mechanical ventilation. The delayed ARF was also observed in a similar proportion in the 2 groups, oliguria also and the creatininemia was similar in the 2 groups. There was a difference for the presence of sepsis as 69% was observed in the intermittent haemodialysis group as compared to 56 % in the continuous group and this difference was statistically significant.

Slide 15

There was no surprise concerning the treatment modalities concerning the duration of session, blood flow, dialysate flow, ultrafiltration flow and as you can see, the mean urea level during hospitalisation was similar in the 2 groups.

Slide 16

These are the most important results showing that by Kaplan-Meir estimation of survival rate according to treatment group there is no difference in the survival between the continuous or intermittent group. What is not indicated on this slide is that when analysed time by time during the study the authors observed an increase in the survival rate of the patient in the intermittent haemodialysis group. This increase was significant and could not be explained by any change in the protocol.

Slide 17

They mentioned that all the groups who participated, all the centres who participated in this study were trained to use either the intermittent haemodialysis or the continuous method.

Slide 18

What about the adverse events? The hypotension was observed in both groups, as well as bleeding events which is usually advocated against the continuous methods. Thrombocytopenia was similar, hypoglycaemia, hypophosphatemia was also observed. Hypothermia was more frequent in the CVVHDF group and there was no difference for arrhythmia or catheter infection.

Slide 19

In conclusion, the efficacy of continuous renal replacement therapy and intermittent haemodialysis did not appear different to treat ARF as part of multiorgan dysfunction syndrome. The efficacy and the tolerance are similar even in the hemodynamically unstable patients. The optimal use of IHD may benefit from implementation of strict guidelines to improve tolerance and metabolic control in the critically ill patient with ARF.

Slide 20

Finally, I’ll go to the third and last point of my review about incidence and prognosis of acute renal failure. How did they change with medical and technical improvements?

Slide 21

The literature is very disappointing about this subject and we always read that the mortality rate still remained very high and didn’t change over the last 50 years and this was also said in this paper in the American Journal of Medicine, it’s from Belgium I think and this paper said that using Medline search and bibliography from 1956 to 2004, 45 papers fulfilling the criteria was taking into account the number of patients, the percentage of survivals and so on and finally, 15897 patients could be analysed with a mortality rate greater than 30% in most studies and no change over time. The conclusion is that despite technical progress in the management of acute renal failure over the last 50 years, mortality rates seem to have remained unchanged at around 50%.

Slide 22

This is shown on this slide. This is the percentage, the mortality rate which you see is very high between 42-63% and this is the number of patients with acute renal failure who are reported each year during the time period from 1956-2003.

Slide 23

So is this true? And why is this? So, in 2006 two papers appeared in the Journal of the American Society of Nephrology maybe saying other --. In this first paper they used the US Medicare database, so a huge number of patients and discharged from hospital. From 1992-2001, the overall incidence rate of acute renal failure was 23.8 cases per 1.000 discharges with rates increasing by approximately 11% per year. So this is true.

Slide 24

So this is the incidence starting from 1992-2003. Overall, you can see that it’s more than doubling in about 12 years. Here it’s increasing in all categories of age, as shown here on this slide, less than 64 to more than 85. It’s increasing in men and women and also it’s increasing in all races.

Slide 25

The incidence is increasing starting also from 1992 as acute renal failure as a principal diagnosis or as a secondary diagnosis and it’s increasing for acute renal failure requiring dialysis or not requiring dialysis. You can see that those not requiring dialysis are increasing and maybe some toxic drugs are involved here or angiotensin converting enzyme inhibitors and so on.

Slide 26

Concerning the odds ratio for 90 days of death there is a decline in this. This is true for acute renal failure at the principal diagnosis or at a secondary diagnosis and this is also true for patients without acute renal failure. The odds ratio for death is also declining in patients requiring dialysis and in those not requiring dialysis.

Slide 27

Slide 28

There is a decline in in-hospital mortality for patients with acute renal failure from 40-20% and those requiring dialysis from 41-28%. There is at the same time an increase in the comorbidity index in patients with acute renal failure. The decreased odds ratio for death between 1993 and 1998 and between 1998 and 2002 showing a decline in mortality.

Slide 29

This is the same slide showed by Norbert Lameire before showing that there is a decline in the mortality of patients with acute renal failure requiring dialysis and in those with acute renal failure as a whole.

Slide 30

In conclusion, during the last 15-year period an increase in the incidence of acute renal failure and acute renal failure requiring dialysis and a decline in mortality was found. Despite declining mortality rate outcomes that are associated with acute renal failure remain unacceptably poor. I remind you that the survival was about 30% in the haemodialysis group. New strategies for the prevention and treatment of acute renal failure are desperately needed. Thank you for your attention.