Slide 1

Mr Chairman, Ladies and Gentlemen, I thought I’d start this showing you a very simple scheme of maintenance of volume status. This is a PD patient, this green block. Such a patient has a fluid intake, the patient has intake of sodium and Doctor Van Biesen showed you that fluid intake and sodium intake are very much coupled because of thirst. What you do to get rid of the excess fluid is of course, by urine production and residual renal function which, of course, decreases during follow up and there’s peritoneal ultrafiltration and peritoneal sodium removal and also that decreases in some patients.

Slide 2

Well, I’ll start showing you some evidence that hypervolemia is indeed a problem in some PD patients. So, I’ll show you some data on hypertension, what happens after transfer from PD, left ventricular hypertrophy and measurements of extracellular volume.

This slide from a study in Italy in more than 500 patients showed that hypertension is indeed an important problem. It was present in 88% of those patients. The vast majority had to be treated with antihypertensives and 53 patients even needed 3 antihypertensives.

Slide 3

This is from an observation by Professor Lameire. In patients who were switched from CAPD to haemodialysis what you see is that there was a decrease in their body weight suggesting that they have been overhydrated. A small decrease in mean arterial pressure but the percentage of patients on antihypertensive also decreased markedly.

Slide 4

Left ventricular hypertrophy estimated by the criteria of Koren or those of the Framingham study showed that in this analysis CAPD patients have more LVH than haemodialysis patients.

Slide 5

To go on with functional measurements this is from a study done in Leeds by Doctor Jones where he divided his PD population based on the median value of serum albumin. Then he compared these two groups. It appeared that the ones with a low albumin had a somewhat higher body weight, similar CRPs but the extracellular volume was higher in the ones with a low albumin and in the ones and that was the case when it was expressed as a percentage of lean body mass and also when it was expressed as a percentage of total body water.

Slide 6

You see that this is displayed graphically over here. These are the ones with a low albumin, these are the ones with a high albumin. This is extracellular volume when expressed as percentage of actual body weight. Here it is expressed as percentage of lean body mass. Here as percentage of total body water and you see that clearly this one is higher than that one.

Slide 7

So indeed suggesting an increase in extracellular volume and when you do extracellular volume measurements as has been done by Doctor Konings from the Netherlands this is extracellular volume related to body surface area, you see that PD patients had a higher extracellular volume than patients after transplantation.

Slide 8

So indeed, all these studies point to the presence of hypervolemia but it should be appreciated I think that all these studies were in CAPD patients using conventional dialysis solutions. So there’s no icodextrin in it and there’s no APD in it. Another important thing is that no attention was paid to residual renal function and it’s significant and I’ll come back to that later. But first of all before doing that I think the question is, is hypervolemia related to survival?

Slide 9

Does it indeed influence survival of patients? I’ll show you some results of the NECOSAD study where it was clear that there is an association of systolic blood pressure with survival and also in a more recent analysis that found an association of high levels of natriuretic hormones with survival.

Slide 10

This is from the NECOSAD I the analysis done by Kitty Jager. These are the relative risks. This is the 95% confidence interval and you see that indeed systolic blood pressure increased the relative risk of death significantly with 42%. Also the appearance of creatinine had some protective effects here.

Slide 11

So indeed systolic blood pressure is important and increases the chances of dieing. This is the analysis in a subgroup of the NECOSAD population on natriuretic peptides. So, the 68 patients, 90% had diabetes, a residual GFR of 3.8. This is the N- ANP level, it is of an extremely wide range. This is the BNP level also with a very wide range. These are median values.

Slide 12

They looked at the Kaplan-Meier curves then you see that the ones above the median value had a smaller survival compared to the ones below and the same was found for BNP, the ones below 7.5 did better than the other ones.

Slide 13

Of course, the best way to analyse that is to do a Cox regression and that’s shown over here adjusted both ANP and BNP were significant after adjustment for age comorbidity and residual GFR only BNP was significantly related to the chances of dieing.

Slide 14

This is a summary of 3 studies showing associations between fluid removal and the relative risk of death. First of all the CANUSA study, more than 600 patients and in that study it was evident that peritoneal ultrafiltration had no effects but urine volume had an effect.
This study from Turkey showed that both had an effect, both urine volume and peritoneal ultrafiltration but the analysis was done on average values and not time-dependently as it should have been done. In the NECOSAD cohort just as in the CANUSA urine volume was important and peritoneal ultrafiltration was not.

Slide 15

I’ll show you some pictures of these studies. First of all the reanalysis of the CANUSA study as done by Doctor Joanne Bargman, the orange figures are the significant relative risks. For instance, when you go to the bottom here, urine volume reduced the relative risk of death significantly. While for instance, peritoneal creatinine clearance, which is very much dependent on peritoneal ultrafiltration, had no significant effects. Also transport status was not significantly related.
So indeed residual renal function and urine volume in this situation is important.

Slide 16

This is from the study by Doctor Ates and coworkers from Turkey. You see that the group, this is total fluid removal, so peritoneal plus residual renal function that the ones with the lowest removal less than 1200 ml had the lowest survival.

Slide 17

This is from the NECOSAD study. You see that the residual GFR reduced the risk of death significantly, urine production also did. Residual Kt/V urea was not significant but there again was no effect of peritoneal creatinine clearance and also not of peritoneal Kt/V urea. So, markedly related to the ultrafiltered sodium.

Slide 18

So, conclusion at this point is I think that residual urine production is clearly more important than peritoneal fluid removal. So the consequence of this is that preservation of residual renal function is very important.

Slide 19

Already a long time ago 25 years ago that Doctor Rottemburg from France showed that preservation of residual renal function was better in CAPD patients compared to Hemo patients. It’s a small study both at a similar creatinine clearance in the beginning but at the end there was a marked difference between the haemodialysis patients and the PD patients.

Slide 20

Well, these first results have been confirmed in a large number of studies. These are 3 retrospective studies all showing the same thing. There has been an analysis in the USRDS registry, showing it the NECOSAD study is a prospective cohort study and this also showed this difference between haemodialysis and peritoneal dialysis.

Slide 21

I’ll show you the figures from the NECOSAD study, the lower line is haemodialysis and the upper line is peritoneal dialysis and this is an observation of the first year on peritoneal dialysis.

Slide 22

Well of course, you can do multivariate analyses in these studies to try to determine the most important factors associated with loss of residual renal function and in the USRDS analysis it appeared that the use of an ACE inhibitor protected and also the use of a calcium channel blocker. In the NECOSAD study diastolic blood pressure the higher, the worse survival. Proteinuria the higher, the worse survival and hypovolemia, more hypovolemia meant a lower survival. Of course, when you see this, it’s evident what you have to do. You have to give your patients an ACE inhibitor because that provides treatment for diastolic blood pressure and for proteinuria and you have to avoid hypovolemia.

Slide 23

That the use of an ACE inhibitor indeed protects somewhat against loss of residual renal function was shown in this randomised controlled trial from Hong Kong by Doctor Ph-T Li and coworkers. You see that the placebo group did worse in the first year on peritoneal dialysis than the group that was treated with ramipril. So indeed, giving patients an ACE inhibitor gives protection against loss of residual renal function.

Slide 24

So what should you do to preserve residual renal function in clinical practice? Well of course, avoid the use of nephrotoxic drugs as much as possible like aminoglycosides, X-ray contrast media and so on. Avoid hypovolemia, don’t make your patients too dry. So they should not be too wet but also not too dry. They should be just right. I think that clinical experience is very important here. Of course, treat hypertension, use an ACE inhibitor or and ARB. Doctor Van Biesen already pointed a bit to this increased urine production of salt excretion by using high dose loop diuretics.

Slide 25

So what do they do? Well, they increase urine production and sodium excretion but have no effect on GFR. There is also no evidence that they influence the natural course of the decline in GFR and I’ll show you some data on this.

Slide 26

You’ve seen part of these ones already in the presentation of Doctor Van Biesen but I’ve presented them in a slightly different way here. These were CAPD patients who were studied without diuretics and then one week later were taking a high dose that was only given for 2 days but was to enhance of course, the effect and you see that there is a significant difference in urine production, almost 3 times. But there was no effect on inulin clearance, there was no effect  on creatinine clearance, no effect on urea clearance but an important effect on the fractional excretion of sodium and also an important effect on the fractional excretion of potassium.

Slide 27

So when you give these high dosages of diuretics, it means that salt restriction and fluid restriction maybe a bit less severe than in another situation. This is from a randomised controlled trial by Doctor Metcalf from the United Kingdom where patients were randomised either to placebo or to furosemide and this is the urine volume after 12 months and you see that in the furosemide group it increased while it decreased in the placebo group.

Slide 28

They gave 250 mg daily and you see here that the number of patients of that study that was similar. This is the change in 24-hour urinary sodium excretion. So in the controls it went down in that year and then a bit up in the patients treated with furosemide and there was no effect on creatinine clearance. So indeed, it did not influence the natural cause of the decline of creatinine clearance.

Slide 29

So this is the situation when patients have lost their residual renal function. So then they are dependant on peritoneal ultrafiltration and peritoneal sodium removal.

Slide 30

I extended now the table I showed you previously. These are the results of studies done in patients that are a mixture of ones with residual renal function and without residual renal function but these are two studies done in auric PD patients. So they are totally dependant on the peritoneal route. This is the EAPOS study so APD, the European APD study. Indeed in this study peritoneal ultrafiltration method but only at baseline. In the NECOSAD study also peritoneal ultrafiltration method in a time-dependant analysis.

Slide 31

This is from the EAPOS study. It appeared that patients who had at baseline a peritoneal removal of more than 750 ml had a better survival than the ones who had at baseline a peritoneal fluid removal of less than 750 ml. This did not hold true through the study. So when they analysed it time-dependently the effect was lost.

Slide 32

This is the NECOSAD study. When peritoneal ultrafiltration was analysed as a continuous variable, it reduced the relative risk significantly. However, it was impossible to give let’s say fixed values among which you would especially have a marked increase in the relative risk of death. So this is an analysis in quintiles although those ones that feel that less than 1150 ml/day had an increased relative risk of death this was not significant. Also when separate cut-off points were analysed like 1.25 L/day or less than 1 L/day significance was not reached. So, it is important to analyse as a continuous variable. So you might say well the higher the peritoneal ultrafiltration, the better the patients will probably do but without the possibility of giving a fixed value.

Slide 33

This slide has already been, at least the study has already been shown by Doctor Van Biesen on the effects of salt restriction. So these were 47 prevalent CAPD patients in Turkey. Their diet was then restricted to 4 g/day and it appeared that only with this salt restriction 20 of them became normotensive. The other 27 patients still needed additional antihypertensive treatment.

Slide 34

Well, what were the parameters in these 20 patients who became normotensive on salt restriction? Well, their body weight decreased, systolic blood pressure was much better. Diastolic blood pressure was much better but also the urine production was lower than before the salt restriction and slightly here the urine production has been influenced by the status of overhydration that they had and really does not represent here residual GFR. There were no measurements done of residual GFR. So this is just probably the correction of overhydration. So what would the approach in anuric patients be? Well, I think it’s important to remember that a higher ultrafiltration is associated with a decreased mortality but when you take this in a very simple way, it would require more 3.86% of glucose solutions which maybe is likely to be detrimental in the long-term because it will damage the peritoneal membrane and by itself lead to ultrafiltration failure.
So what should you do? You should give your patients and especially when they are anuric, a fluid and sodium restriction and use icodextrin for the long-dwell as Doctor Van Biesen has also shown you because that increases ultrafiltration and increases sodium removal.

Slide 35

So in summary then Mr Chairman, Ladies and Gentlemen I have shown you that CAPD patients who were treated with conventional PD solutions may be hypertensive due to fluid overload. There is especially a problem after the development of anuria therefore, preservation of residual urine production is extremely important and I’ve shown you how you can achieve that and it is likely that the fluid and sodium restriction, especially in anuric patients, in combination with an adequate dialysis prescription is likely to be beneficial for the fate of our patients. I thank you for your attention.

Slide 36

Chairman: Thank you Ray for this excellent presentation. I would like to take the home message that I understood that all of us should protect residual renal function in our patients exactly as we do in patients with chronic kidney disease stages II-IV.

Prof. Krediet: Yes, I thank you, you’re absolutely right and in a way it’s amazing that let’s say until 5-10 years ago nobody was really very much interested in residual renal function. That may have been because haemodialysis patients often lose it so quickly.

Chairman: But really the people working on haemodialysis are progressively more considering the protection of residual renal function as well.

Prof. Krediet: Sure.

Chairman: Ok the paper is now open for discussion. Any questions or comments from the floor? Doctor Van Biesen?

Question: I would like to have a bit of a provocative question. If you pretend that PD indeed preserves residual renal function, should that be a clue or a reason to start somewhat more early than we do today or is this just not weighing the balance to the outcome of the patient?

Prof. Krediet: Yes that of course is a bit of a provocative question. What we don’t know at the moment is whether PD preserves residual renal function better than conservative treatment. I mean when that would be the case, I think that problem still has not been solved. We are working on it currently in NECOSAD. It’s impossible to give the right answer but you’re quite right of course, I mean when a PD would be superior to conservative treatment and preservation of residual renal function that could be a reason to start sooner and of course, you have to weigh that, you have to balance that against the side effects of peritoneal dialysis like peritonitis, changes in the peritoneal membrane and so on.

Question: Because there is some evidence or at least a hypothesis, that one of the reasons that PD preserves better residual renal function might be that it removes some substances, uremic toxins that are damaging the glomeruli. For example, in haemofiltration it has been shown that residual renal function is also better preserved than on regular haemodialysis.

Prof. Krediet: Yes sure but I mean there is still no proof. I could show you a slide made in the NECOSAD cohort where it seems that indeed an early start would be better with regards to preservation of residual renal function but the analysis is still not as it should be. So I deliberately chose not to show this slide I think we need more data before we can really be sure about this.

Question: Probably it’s time to reconsider some of the molecules that are now entering the world of preservation of the progression of kidney disease, I mean endogenous substances coming from the bacterial, or intestinal bacterial metabolism and so on, probably involved in the progression of the kidney disease itself. Is anyone aware about any studies on these molecules – of the molecules found in the proteomic analysis of the uremic serum, related with the residual renal function and its preservation? Is anyone aware of this? Not yet.

Prof. Krediet: No I’m not but for instance a simple thing like a high phosphorous increases the loss of residual renal function. So it might be that when you start PD at an earlier phase you have somewhat better phosphate control and that might have an effect but it’s all theory I mean the data are still not there.

Chairman: We have another question from the front.

Question: Laurie McMahon from Australia. Just interested in your thoughts. You showed that patients with furoseimide appeared to do better in terms of volume status than those without. I suppose it’s a slightly provocative question also but would you consider giving all PD patients high dose furosemide to try and encourage that result?

Prof. Krediet: Sure thanks for that question. The answer is rather simple, it’s yes, almost all of our PD patients with residual renal function get on average 500 mg of furosemide once daily.

Question: Do you find you have any metabolic problems with that hypokalemia, low magnesium and so forth?

Prof. Krediet: No, we haven’t seen that. No the therapeutic range of furosemide is extremely wide.

Chairman: Any other questions? Ok thank you Ray, thank you for your provocative presentation.