Slide 1

Dear Colleagues, clinical performance targets are very important and every one of us knows this very well for advancing the quality of clinical care in dialysis units.

Slide 2

To start my reasoning on clinical indicators I have chosen a paper which appeared last year in Biomedical Centre.

Slide 3

In this paper the authors considered 5 clinical indicators: albumin less than 4 g/dL, calcium-phosphate product less than 55, haemoglobin greater than 11, Kt/V greater than 1.2 and the type and the management  of vascular access.

Slide 4

Let’s look at the results. You see there was a clear  effect of clinical indicators on  mortality and the difference between patients that achieved almost all targets and those who did not achieve any target was huge. The effect size was 30%, mortality was 30% less in patients who achieved all targets.

Slide 5

Now, what is striking in this graph is that mortality remains very high even in patients who have achieved all these clinical targets. Mortality is 8% a year that is a mortality which is 16 times higher than in age matched ad sex matched individuals in the general population.

Slide 6

Now, these are the indicators and to me there is one indicator lurking the background. Because in this  study no clinical indicator reflecting  fluids volume and cardiovascular status was used, and you will see  why I’m emphasising this. We as nephrologists are obsessed with dry weight, we are obsessed with testing for dry weight and we use symptoms but apart from symptoms we use tests, vena cava diameter, bioimpedance and sometimes, we measure plasma blood volume by using radio-isotopic methods  or other markers like inulin to measure inulin space.

Slide 7

But it’s fair to say that all these techniques are either not sufficiently reliable or unpractical. In fact, none of these methods are actually incorporated in the clinical decision  process in the vast majority of dialysis centres around the world.

Slide 8

This is not new because this has been known since the 50s that extracellular volume measurements have limited discriminatory power for capturing volume overload, this is a paper by Warner published in 1952 in Circulation.

Slide 9

Warner measured extracellular volume by using total sodium space which is a very reliable technique  based on radioisotopic sodium. The control populations were all normal adults and let’s see the normal values in all normal persons. The values are quite variable between 9 and 16 L/m². Please note that these data are normalised by surface area. So, the difference in body building between subjects does not explain the variability. This variability is very huge and this explains why extracellular volume has low ability to discriminate between expanded and non-expanded individuals. These are individuals with clinically evident mild oedema, these are individuals with clear-cut oedema. These are patients with severe oedema, so the discriminatory power is low also in patients with severe oedema. You should study patients with extremely severe oedema in order to get complete discrimination.

Slide 10

So, the modest discriminatory value of extracellular volume estimates is an old story not a new story. The problem is that volume cannot be separated from cardiac function, it’s a Janus problem.

Slide 11

Why is this so?

Slide 12

The extracellular volume, the sodium space is about 16 L and about a third of this volume is in the vascular space. The vascular space is an adjustable compartment because it may change because of compliance or resistance. Under normal conditions this vascular space is filled with 5.6 L.

Slide 13

This is the blood volume and the blood volume is instrumental for maintaining a filling pressure of 8-10 mm/Hg which is the pressure that drives cardiac output.

Slide 14

Now, the kidney is fundamental for maintaining constant the left ventricular (LV) pressure because it adjusts the balance minute by minute.

Slide 15

In dialysis patients this is done by the artificial kidney externally and intermittently and this explains the  jig-saw profile of extracellular volume. But forget the jig-saw  profile the fact remains that like in other conditions left ventricular filling pressure in end stage renal patients reflects the loading condition of the left ventricle. It is something that we should not forget.

Slide 16

Now, how can we measure the left ventricular pressure? What we need is a Swan-Ganz catheter, we have to push the catheter into a branch of the pulmonary artery and inflate the balloon. When the balloon is inflated the pressure beyond the balloon drops and equilibrates the pressure at capillary valvular level, the wedge pressure. Wedge pressure is identical to atrial pressure, which is in turn the driving pressure of the left diastolic filling pressure.
Now, left ventricular (LV) filling pressure depends on 2 components, a volume component and a functional component, that is left ventricular function. So LV filling pressure  reflects the loading condition of the left ventricle at a given blood volume.

Slide 17

Now, this is a very reliable measurement but it is invasive and it is applied only in the acute setting not in the chronic setting, i.e. where we need it.

Slide 18

Now, we as nephrologists use increasingly echocardiography. Echocardiography gives us information on left ventricular mass but apart from this it gives us information on left atrial volume. Left atrial volume is a good surrogate of left ventricular pressure and echocardiography gives us information also on cardiac function, left ventricular ejection fraction.

left atrial volume is very good for prognosis because if you stratify patients according to left atrial volume, those in the third thirtile, those with the highest left atrial volume are those who are more likely to die but measuring the atrial volume is good also for the follow up of patients because an increasing left atrial volume of just 5 ml underlies a  76%increase in the risk of death.

Slide 19

The same is true for ejection fraction. Cardiovascular event free survival is worse in patients in the first thirtile that is those with the lowest ejection fraction. Ejection fraction is good also for the follow up of patients because an increase in the ejection fraction of just 5% per year underlies a risk increase of 56%.

Slide 20

These are quite interesting data but the reality is that echocardiography is not applied because it’s costly, it needs a cardiologist or a trained technician and it’s very infrequently performed. Everyone is convinced that it’s important but no one uses it enough.

Slide 21

This is let’s say officially endorsed by current guidelines, these are the DOQI guidelines. They say you should do echocardiography once every 3 years.

Slide 22

Now, is there any surrogate for echocardiography? The heart is a biochemical factory, it synthesises ANP and BNP. Let’s look at the relationship between ANP and left ventricle. A nice relationship – 0.5, the two variables have a 25% common variance.

What about the ejection fraction of BNP? Again a  good relationship, an inverse relationship that is the lower the ejection fraction, the higher the BNP. Again, a high  common variance about 16%. Notwithstanding this reasonably good relationships ANP and BNP are not used in clinical practice in dialysis patients because these peptides are considered  unsuitable because they are retained in end stage renal disease.

Slide 23

But let’s have a close view about the ability of ANP or BNP of reflecting LV mass. These are the values in healthy subject these are the values in patients with left ventricular hypertrophy either eccentric or concentric where ANP and BNP are  4 times higher. In patients with normal ventricular mass ANP and BNP  values are higher than normal but definitely much less than in patients with left ventricular dysfunction or left ventricular hypertrophy.

Slide 24

So, there is discriminatory power there. I think that it is fair to comment that alteration in left ventricular mass and funcion rather than pure accumulation are the major determinants of ANP and BNP in end stage renal disease.

Slide 25

Now, let’s see the prognostic power of these substances. ANP has a strong prognostic power because patients with high ANP are more likely to  die. The same is true with BNP, those with the highest BNP have the worst outcome. So, we have a strong parallelism, two markers that predict shorter survival. So, we should pose the question of the mutual relationship between these two markers.

Slide 26

It’s important to emphasise that although ANP and BNP are made by separate heart chambers, ANP is synthesised at an increasing rate by the ventricle  when the loading condition of the left ventricle is high. So, the left ventricle produces more peptides in patients with overload and this explains why these two peptides are strongly correlated, very strongly, 0.8 that is a 64% common variance. Now, we have a legitimate question at this time, do these peptides overlap in predicting left ventricular function?

Slide 27

In order to answer this question we should introduce the concept of diagnostic testing that is we need to know the proportion of patients with high ANP or BNP who are correctly diagnosed as having left ventricular dysfunction and this is the positive predictive  value and also we need to know the negative predictive value that is the proportion of patients with  normal or low BNP or ANP where  the disease,  left ventricular dysfunction,  is correctly excluded. We need information about the ROC curve analysis. In ROC curve analysis you plot the relationship between the true positive rates and the false negative rate. When the true positive rates and the false negative rate grow in parallel, in a strict proportionality,  it means that there is no discriminatory power. When the area under the curve is increasingly higher, it means that there is an increasing discriminating power.

Slide 28

Now, let’s see the positive predictive value. The positive predictive value was very low both for ANP and BNP but the predictive value of BNP was somewhat higher. The negative predictive value which is an important clinical indicator was very high with both peptides, 97% and 95%.

Slide 29

Now, let’s see the roc curve. The roc curve, BNP was 76% that is fairly good and ANP 78% --somewhat higher but fairly good again.

Slide 30

That is do we gain in discriminatory power, if we use the two markers at the same time? The answer is no. You see there is no gain in prediction power, when the markers are used simultaneously.

Slide 31

So, it’s sufficient using just one marker ANP and BNP because BNP is a slightly better marker.

Slide 32

Now, the question is, may we use BNP to guide the treatment of our patients? At this stage I must say that there is no trial testing the usefulness of BNP for monitoring the patient but there is a study in patients with heart failure by dr. Mark Richards and other New Zealand investigators. They studied patients with heart failure, New York Heart Association class II-IV. They divided patients in 2 groups. The first group was managed clinically and the second group, the active arm of the study,  was managed according to BNP. The treatment was very well standardised and investigators in this arm used the Heart Framingham score that is a very reliable score. In the other arm the treatment was guided on the basis of BNP. The median follow up was 9 months and let’s see the main results.

Slide 33

This was the survival in the group that was managed according to the clinical score. This was the survival in those where the treatment was monitored by BNP. There is a quite high difference between the 2 groups. I would like to emphasise that just with 69 patients a highly significant difference in mortality emerged.

Slide 34

Should we start using BNP to guide the treatment of our dialysis patients? No, because we have no specific trial and we know that our patients are special patients. So, we cannot extrapolate data obtained in other populations to treat our patients.

Slide 35

But a trial can be done, instruments are available where you just need a drop of blood in a strip and you get the measurement.

Slide 36

Now, I think that we should remain focused on the fact that mortality in our patients, even in patients who are optimally treated remains very high.

Slide 37

Therefore, I believe that at this stage it is fully justified doing a clinical trial to test whether BNP maybe useful to guide treatment in our patients.

Slide 38

Let me summarise. Volume control and optimal treatment of cardiomiopathy is of great importance in our patients. The methods for estimating extracellular volume in these patients are either not sufficiently reliable or unpractical. BNP in particular reflects left ventricular dysfunction and left ventricular mass and predicts adverse outcomes. Doing a clinical trial to see whether these markers maybe useful to improve the clinical management of our patients appears fully justified. Thank you for your attention.