Slide 1

Thank you Mr Chairman, Dear Ladies and Gentlemen.

Slide 2

There’s a question mark at the end of the topic, so I thought the question mark should best be approached by looking at European Best Practice Guidelines for haemodialysis issued in part 1 and now in part 2 in 2007 and look at what is haemodialysis adequacy. You will find the words haemodialysis dose and quantifications, small solutes and middle molecules. You see the terms dose and residual renal function, the activation of the body measured with biochemical reactions is a topic, reactions to membrane and in a way also fluid purity, haemodialysis associated infections and will be in some way influenced by many of these parameters. You may also --- vascular access when you talk about infection inflammation, clotting extracorporeals and several strategies. This is haemodialysis adequacy. If you then look at inflammatory markers, which may predict or which can be grouped to haemodialysis adequacy and you’re looking at the activated acute phase response, it becomes difficult. There are so many inflammatory markers so far and you will not succeed to group them into these various topics. You can look at beta 2 microglobulin or another inflammatory parameters and the best studied, of course, is C-reactive protein which is nothing else than IL-6. In some studies we have heard about BNP when you think about dose, haemodialysis dose. Increase may control volume and you may talk about BNP in this respect. You look at the biochemical reactions to membranes, complement activation, leukocyte products or other proteins, oxidative stress parameters. Of course, CRP can be attributed to nearly all of these haemodialysis adequacy subcomponents.

Slide 3

Other acute phase proteins react as CRP are highly correlated and for example, albumin is a negative acute phase protein as well as fetuin is a negative acute phase protein and they correlate highly with C-reactive protein and other molecules. I cannot cover all. I will only focus on some where you can find literature, for example, on C-reactive protein and reactions to membrane.

Slide 4

There are a number of papers out there saying that haemodialysis adequacy can influence inflammation via improving the purity of dialysis. So one topic is saying ultra pure dialysis fully lowers the cardiovascular morbidity in patients on maintenance haemodialysis by reducing continuous microinflammation. Effects of ultra pure dialysis fluid has impact on nutritional status and inflammatory parameters as well as ultra pure dialysate improves high urine – and erythropoietin response in chronic dialysis patients but there are small prospective studies out there.

Slide 5

If you look at one paper from the Schiffl group, for example, and this has been shown in NDT several years ago, 36 patients are grouped into 2 groups, one with conventional dialysate and the other with ultra pure dialysate. There you can see the difference in C-reactive protein measured in mg/dL which is significant. Well, we would like to see this in a larger number of patients. Selection bias should be ruled out by the sample size and other questions. So this is the type of studies that are out there and you must acknowledge the sample size of these trials.

Slide 6

Other questions have been answered, for example, nocturnal haemodialysis improves cytokine profile and enhances erythropoietin responsiveness. Surrogate end point markers are associated with the increase in dialysis dose but samples of patients are very small. C-reactive protein predicts vascular access thrombosis, other kinds of vascular access influence the baseline inflammatory status and again erythropoietin resistance is influenced by the response to erythropoietin chronic haemodialysis is influenced. That’s all you can find out there.

Slide 7

So there’s not much and Professor Zoccali outlined that there are prospective studies lacking using these biomarkers in respect to haemodialysis adequacy. For example, C-reactive protein or a precursor IL-6 has a relationship with erythropoietin requirements, the relationship is 0.3 IL-6 hypo response. These types of trials were designed, some closed and were not successful because they are expensive and a large number of patients are required.

Slide 8

What is C-reactive protein when we look further into it? And how can C-reactive protein increase or be influenced? We have number of stimulus from the endogenous pathway and you see that angiotensin II, LPS, oxidised LDH, cytokines, some comorbidity factors, they all can induce oxidative stress. Oxidative stress signals via transcription factors, activates genes and adhesion molecules, cytokines and chemokines are produced, the most important is IL-6 which stimulates the liver to produce C-reactive protein. But there are also other exogenous causes which can stimulate CRP, such as our Endotoxin in the dialysate, the vascular access inflammation, catheters are prominent at the membrane. So, many things influence CRP and there’s not a silver bullet that can decrease C-reactive protein, such as a statin or an angiotensin receptor antagonist.

Slide 9

Recently a group was sitting together and providing us, the clinician some feeling, what is C-reactive protein? So, the first thing is we have to acknowledge that in the general US population a normal value is 1.5. This is normal so what is normal for the dialysis patient? We felt that these are up to 5mg/L. This was recently published but it’s a consensus, it’s an opinion guidance, smouldering this CRP up to 50 chronically raised but stable, clearly CRP above 50 has major impact on many things and this maybe infection and smouldering maybe inflammation and the range of normal maybe what you see as microinflammation.

Slide 10

You can group a number of conditions to these stages and can influence it by haemodialysis procedures. The C-reactive protein to give you a feeling across Europe, if you look at the Swedish, the German and the Italian population and combine them you have 600 out there, so there is 50% of the patients who have a C-reactive protein above or below 8. This is the distribution across Europe.

Slide 11

In 2002 from CRPs coming out of testings around 1998-2000. The CRP has predictive power and you see the all cause mortality and cardiovascular mortality and we assume when we have impact with haemodialysis adequacy on CRP, it may have impact on mortality but this is an assumption, association and all the studies do not prove causality.

Slide 12

So, only prospective studies addressing this can prove our assumptions. You may look at the median. I will come back to these quartiles of C-reactive protein. This has been done also with all the countries together and a similar thing in 600 patients was seen, a little bit higher CRP across Europe than if you go to single countries.

Slide 13

Let’s look at albumin and go into a study before this study which was mentioned.

Slide 14

This was on atorvastatin 20 mg placebo with cardiovascular complication in 1255 type II diabetic patients and look what we have there?

Slide 15

If we can impact albumin, for example, in those who have albumin below 4, then it may have an impact on the risk. The risk is highest in the lowest thirtile with those below 3.6 and the risk is more than 50% higher in those above 4.

Slide 16

So, we have markers there that we can use in prospective trials. Phosphate maybe one and the risk to have a phosphate above 1.6 is increasing as has been shown by Block. This is confirmed in a prospective evaluation of end points and the risk above 2.26 phosphate is more than 80% higher. So, it’s powerful discrimination.

Slide 17

Let’s go back again to the markers and look at other inflammatory markers, for example NT-proBNP and BNP and reinforce this was what Doctor Zoccali has shown.

Slide 18

So, what should we do at the moment with haemodialysis adequacy and influencing these molecules? The group, the consensus felt that high impact is reduced in centre use of lines for dialysis access approach maximum use of fistula, remove clotted arterial grafts of intermediate impact according to the studies we have. Provision of ultra pure dialysis may be one solution, withdrawal --- if you have --- fluxes and increased dialysis dose at the same time or use biocompatible membranes. These are suggestions, there’s no proof out there only small studies guide us to recommend this but we should investigate this.

Slide 19

Let’s look at again at the median of CRP in one country and this is Germany in 280 patients. This assay has been used 5 years later in the 4D trial in respect to CRP and cardiovascular complications.

Slide 20

So I conclude, in patients with elevated CRP above 5, for example, biocompatibility of dialyser membranes and haemodialysis fluid quality should be checked. If chronic inflammation persists, optimisation of the dialysis protocol and dose should be aimed for. That’s not very solid what we can conclude but at least look for a patient with a CRP above 20 should be screened for silent infection and access, visual control is the best thing at the moment, periodontal disease should be looked for or any low grade infection such as diabetic ulcer. Inflammation infection has a strong limiting effect on the effectiveness of haemoterapy and Hb levels.

Slide 21

This concludes my presentation and I thank you for your attention.