Slide 1

Madam, Chairman, thank you very much for your very nice introduction. It’s a pleasure that I’ve been invited to give this mini lecture on how to measure peritoneal transport.

Slide 2

Before talking about that I would like to show a few data showing that it is important to measure peritoneal transport because it provides information for the prescription of PD. You will use a different prescription based on transport status. More importantly perhaps is that peritoneal transport changes during the time course of PD, it’s not a static property of the peritoneum and then transport status has changed and ultrafiltration failure has developed. Measurement of peritoneal transport can identify the presence for instance and also the causes of ultrafiltration failure.

Slide 3

Well, it was Doctor Tardowsky who published the first paper on measurement of peritoneal function in 1987 the famous PET, peritoneal equilibration test you will all know I think that it’s a 4 hour dwell time with 2.27% or 2.5% in the States glucose-based dialysis solution. Preceding exchange is 1.36%. One blood sample is taken for creatinine and glucose and dialysate samples at 2 hours and 4 hours for creatinine and glucose. So it’s rather simple and it was simplified even further in the fast PET where the sample at 2 hours was omitted.

Slide 4

This is the PET as it has been promoted very much and is still the most useful test. This is the kind of data that you can get, we may look at creatinine here for instance after 4 hours. You see that the dialysate of the plasma ratio of creatinine varies enormously among individuals and you will know that this category is called ‘high transporters’ and this category ‘low transporters’ and for glucose you see a kind of mirror image; the high transporters are here in the low region of the 0 and this of course, because glucose gets absorbed very rapidly in these patients.

Slide 5

That might create some confusion because the removal of urea is very much dependent on the drained volume and these patients are likely to have impaired ultrafiltration and therefore a low drained volume. So they might in fact have low urea clearances. That’s exactly what happen. So 2 studies, one from Sweden and here’s the CANUSA study from Canada and the United States. You see that the high transporter patients had a lower Kt/V urea than the other categories and it was the case in both studies. That’s a bit confusing and I think therefore, that the term ‘high transporters’ should better be replaced by the term ‘fast transporters’ because that’s really what happens. Another thing to keep in mind is that the presence of a fast transport status means the presence of a large vascular surface area.

Slide 6

So far the PET at the moment. The next one that has been described is the personal dialysis capacity test, the PDC test. It was developed by Doctor Haraldson from Sweden published in 1995 and this is quite a different approach, it uses 5 exchanges with different glucose concentrations and different dwell times. What it does is that it gives, of course, let’s say the adequacy parameters but in addition, it models parameters for peritoneal transport characteristics and I’ll come back to that in a moment.
What’s also different when you compare it to the PET, is that it includes the measurement of plasma and dialysate albumin concentration. That is rather important I think.

Slide 7

So here are the differences between the PET and the PDC. The PET uses one exchange, the PDC 5. This is 2.7% here it’s variable. Dwell time here is 4 hours and here we have a wide range of dwell times. The number of dialysate samples is also different, I’ve shown you this one of two it 6 in the PDC. Serum albumin and dialysate albumin are determined in the PDC not in the PET. Both tests do not use a volume marker, calculating the PET is very simple, D/P creatinine but for a PDC you need kinetic modelling. 

Slide 8

So it’s quite a different approach. What are the parameters that are modelled in the PDC test? Well, first of all there is an area parameter Ao/Δx and so this is kind of surface area and it appears that it is proportional to the MTAC for instance, of creatinine. It also models a fluid absorption rate, JV absorption rate which consists of 2 mechanisms namely lymphatic flow and reabsorption of the fluid by the colloid osmotic pressure gradient. Then in third place it models the large pore fluid flux, JV large and that is calculated from albumin clearances because albumin is the only solute determined here that passes through the large pore system.
Well, it has been claimed that the PDC is superior to the PET but I’m not quite sure whether that is really the case and I’ll discuss that issue.

Slide 9

Comparison of Ao/Δx has been done with iohexol intraperitoneally and with D/P creatinine, a limited number of patients in this study and it appeared that iohexol was better than D/P creatinine and that’s a bit odd because iohexol was given here intraperitoneally. That’s of course another transport direction and it also includes lymphatic flow.
A study from Denmark from Doctor Heaf and colleagues, a multicentre study showed that JV large was related to hypoalbuminemia and also to mortality.
The last study by Doctor Van Biesen here is the most recent one. It’s a large study also showed that this parameter was superior to discriminate inflammation as the cause of fast transport status.

Slide 10

I’ll go into that study a little bit more so that you get some feeling of what really happens. So these are 2 tables from that study, in fact general inflammation as defined by a CRP more than 10 was compared to signs of peritoneal inflammation and that’s what you see over here. A peritoneal inflammation was defined as a circulation where the large pore flux was more than you would expect based on the surface area parameter. The absence of inflammation was a situation where JVL was about where you would expect based on the surface area. What came out was very significant. So patients with general inflammation also had peritoneal inflammation but not all of them of course, as you see over here. Also some patients without general inflammation had some signs of peritoneal inflammation but in the χ-square the difference was highly significant. Note that JVL is based on albumin kinetics. Then in the same patient one of the dwells, the 4-hours dwell was used to calculate PET parameters and that’s shown here where the PET parameter for peritoneal inflammation is of course, the presence of a fast transport status, so that’s here against the other categories. Here you see that the discrimination is less because patients who had signs of general inflammation, not all of them had a fast transport status and therefore, a difference and resulted in inflammation and a number of them had a fast transport status so the difference was not significant anymore. But what is missing in this paper is what would have happened when the albumin data were used in the PET. It might have been that a discrimination of the PET would have been much better then because it’s all dependent here on the albumin.

Slide 11

So I think the main conclusion from these studies is that JVL gives more information on the PET data but when you extend the PET with albumin measurements it might be possible to get exactly the same results.

Slide 12

So the question is then should the PET then be replaced by the PDC?
Well, 5 exchanges are needed so there’s a risk of more inaccuracies. Much more lab investigations so higher costs. Assumptions have to be made for kinetic modelling and there are no sodium kinetics included. On the other hand, it is necessary to do something about the PET because there is no sodium and there’s no albumin in it.

Slide 13

So what have been developed are tests here like a modified PET, the mini PET a modified PET with a temporary drainage and the standard peritoneal permeability analysis and I’ll discuss them with you shortly and I’ll start with the SPA.

Slide 14

The SPA is a kind of PET modification using 3.86% glucose preceded and followed by a rinsing procedure, it uses dextran 70 as a volume marker. At various time points dialysate samples are taken and here you see that small solutes are determined, electrolytes, dextrans of course and a number of serum proteins.

Slide 15

So it’s a very complete test and what’s calculated are things like MTAC, D/P ratios of small solutes, glucose absorption, sodium sieving, protein clearances and fluid transport includes ultrafiltration rate, transcapillary ultrafiltration rate, net UF rate, effective lymphatic absorption rate, free water transport and residual volume. If you use this data to model it, it’s also possible to model the osmotic conductance to glucose.

Slide 16

Well, some of the results obtained are shown here. For instance it appeared that the MTAC creatinine was related to body surface area, statistically significant but you see there’s a very wide variation. Nevertheless when you do studies comparing patients with each other, then it would be wise to normalise for that.

Slide 17

Here are the intra-individual coefficients of variation. Recumbent and upright position. They’re below 10% for small – and between 10 and 20% for fluid transport. Fluid transport is always worse with reproducibility done solute transport.

Slide 18

This is the kind of data that the SPA gives you. A 4-hours dwell, transcapillary ultrafiltration, effective lymphatic absorption and the difference between the two, the intraperitoneal volume.

Slide 19

Another interesting thing and there was a poster on that today was that using this technique we found a U-shaped solute transfer in time. So this is MTAC creatinine, this is the first year, second year, third year, the years these SPAs are done in our patient population and you see an interesting U-shape over here but this might represent let’s say an increased surface area due to vasoactive mediators and this might be the beginning of structural changes in the peritoneal membrane.

Slide 20

Also what you could expect as relationship between MTAC creatinine and the clearance of β2 microglobulin both pass through the small pores and that is absent when you replace β2 with α2 macroglobulin because it’s a very large protein and only passes through the large pores.

Slide 21

Advantages of the SPA are that it’s the most complete assessment, disadvantage of course that it is too complicated for routine clinical practice. So that was the reason to work again on the PET.

Slide 22

The modified PET has been described in the guidelines on ultrafiltration failure by the International society for PD already in 2000. It is just a PET but there’s a 3.86% glucose solution, an additional dialysate sample at 60 minutes for the assessment of sodium sieving. Well you might think then well doesn’t that influence my D/P creatinine? the answer is it does not and I will show you that over here. Here are patients where simultaneous measurements were done with 1.36% glucose and 3.86% glucose.

Slide 23

It’s a very short time between those two investigations and you see that there’s a very nice relationship so changing from 2.27% to 3.86% doesn’t influence your follow up of D/P creatinine.

Slide 24

Then more recently the mini path as developed by Doctor La Milia in Italy a very interesting approach especially because it allows you to calculate free water transport. So it’s a 1 hour exchange with 3.86% glucose. Free water transport. The only problem here is and I’ll show you is that D/P ratios of small solutes cannot be compared with those obtained after 4 hours. So you can’t replace the PET with the mini PET.

Slide 25

So this is the principal for the calculation of free water transport. It’s based on the removal of sodium. The removal of sodium is of course, the amount of sodium after 1 hour, so the drained volume times the dialysate concentration minus the instilled amount of sodium so the instilled volume times the sodium concentration in the dialysate. The assumption here is that the small pores offer no hindrance to the transport of sodium. That’s a reasonable assumption I think and if this is the case, the ultrafiltration through small pores can be calculated as sodium removal divided by plasma sodium concentration.

Slide 26

So in ultrafiltration with small pores we also know the total ultrafiltration after 1 hour, so free water transport is just the difference between them so total ultrafiltration minus ultrafiltration through small pores. So that’s a very elegant method and you see that indeed it has effects, a comparison between patients with normal ultrafiltration and patients with ultrafiltration failure, no statistically significant difference here in small pore transport but there were statistically significant differences here in these orange values for free water transport clearly lower than in patients with no ultrafiltration, also for the percentage, 26% versus 35% and also when you just looked at the sieving of sodium.

Slide 27

When you use a volume marker for instance dextran 70, it’s possible to use this principle throughout a 4-hour dwell and you see that here, this is the ultra filtered volume so the change the peritoneal volume due to overall transcapillary ultrafiltration. Small pore transport, free water transport and here it’s expressed as water transport rate and you see that they all go down. You see that free water transport especially goes down during the dwell while in the second half of the dwell small pore transport rates more or less stabilised suggesting that other forces than --- forces are important here.

Slide 28

This is a recently published study by Doctor Anabella Rodrigues from Portugal, it’s a Bland and Altman plot where the difference here between the observed D/P ratio after 1 hour is compared with the one that you would expect based on the circulation after 4 hours. So just assuming an exponential increase in the D/P ratio. You see that there’s a very wide range and there’s no random distribution of these values throughout the total range. So that means that you can’t use it for calculating D/P creatinine. Therefore, you should use a 4-hour dwell.

Slide 29

So what’s the solution here? Well the solution is to modify that with temporary drainage. So that allows the calculation of free water transport at 60 minutes. So 3.86% glucose, a 4-hour dwell developed by Doctor Cnossen from the Netherlands, temporary drainage after 1 hour for the assessment of volume just by weighing and effluent sampling for sodium and after that a re-infusion and a final drainage after 4 hours.

Slide 30

Well what happens then? This is a comparison in 10 patients who underwent modified PET results; temporary drainage and one with temporary drainage in a short interval. They did not influence net ultrafiltration, no effect on the D/P urea, no effect on creatinine, no effect on Dt/Do glucose. But these parameters are not available in the modified PET but you can calculate them over here, here we have small pore transport, free water transport and the contribution of free water transport which was 44% in these patients which was very similar to what has been reported in the literature.

Slide 31

Also when you write a volume curve transcapillary ultrafiltration, small pores and free water transport you find curves that are very similar to the curves that you find when you use a volume marker.

Slide 32

So what is the conclusion of this? How should we measure peritoneal transport in 2008?
Well, I think when you put all these things together and you want to make it clinically feasible in routine clinical practice, you should use a 4 hour dwell with a 3.86% glucose solution, temporary drainage after 1 hour for i.p. volume and sampling followed by re-infusion. Lab investigations should include sodium, creatinine, glucose and albumin. The calculations you can do when you do it this way are of course, D/P creatinine, Dt/Do glucose, a peritoneal albumin clearance, net ultrafiltration and free water transport and I think then you have the kind of maximum information that you can get when you try to measure peritoneal transport which much more information on fluid transport than in the classical PET. I thank you for your attention.