CME Slides Forum - W. Van Biesen

BASIC PHYSIOLOGY IS THE SALT FOR PD TREATMENT

Wim Van Biesen, Ghent, Belgium

Chair: Giovanni Cancarini, Brescia, Italy

Rafael Selgas, Madrid, Spain

vanbiesen

Dr W. van Biesen
Dept of Nephrology
University Hospital Ghent
Ghent, Belgium

Good afternoon everybody. Instead of sitting outside in the sun and enjoying Barcelona, you will have an opportunity here to have a post lunch nap and sleep a bit while I tell you a bit about the basic physiology and how salt should interfere with that.

Now, the first question of course, if you have to talk about a topic like salt in PD is the question, is it really as bad as everybody tells us? Is it really a demon in the axis of evil or is it just an innocent bystander in what we’re doing in our PD patients?

Of course, this was debated already a long time ago some people saying that indeed there is something to say that sodium is dangerous but other people saying no it’s not dangerous at all and one of the basic differences between these two approaches, why some people think it’s very important to have salt very well regulated and others do not think it to be important is of course, that we have the problem of what we call sodium sensitivity. Some people tend to be salt sensitive some people tend to not be.

If you’re a normal human being not being in your mind but in your body, if you have normal kidneys, then it’s very clear that if you have a higher salt intake well then you have just a higher salt output. But if you have an impaired kidney function, if you have for example, renal disease and most of our PD patients have some form of renal disease, this is quite clear, well then it might be a completely different picture. It might be that indeed you’re salt sensitive and that indeed if you increase your salt intake, that your blood pressure will go up and that a lot of nasty things will happen. Formerly it was thought that if you increase your salt intake, then of course your plasma sodium will go up a little bit and then your plasma osmolarity will go up a bit and you then will induce thirst and because of that you will start drinking and because of the drinking you will increase your extracellular volume and because of that there will be some blood pressure increase and everybody was convinced that this was the main mechanism why patients with a high salt intake had a worse outcome because of volume overload and because of the hypertension.

Now, we know that there is even more than that going on even in patients with normovolemia if you increase the salt intake and their volume status is not altered, we know that there are direct effects on the hypothalamus, we know that there is local activation of the RAS system and indeed there are direct effects on the vascular system, on the cardiac hypertrophy that occur in these patients. So there is more going on than just volume. But start at the bottom line, start with the most easy to grasp that this indeed is their volume overload induced by the patients by taking salt.

Here you can see that indeed if you increase the sodium intake over the patients and you can see these patients started with a low sodium intake and then they increased their sodium intake all of a sudden and you can see that the intake always lacks before the excretion meaning that there is some retention of the salt, meaning indeed that in patients with impaired kidney function that the salt is retained inside of the body and of course, because of that it’s very clear that also the water will be kept inside of the body.

So the urinary volume will decrease and as a consequence of that indeed there will be volume overload in these patients. It’s very good to understand, it’s very important to understand that this is an osmolarity driven process, meaning that if you increase the osmolarity of the patient’s blood, this is a very strong driving force to increase indeed the intake of free water and indeed to result in fluid overload in these patients.

Here you can see that if you have isotonic volume depletion, meaning if you just lose as much salt as water, well it takes a long time before you get activation of your thirst access here expressed as EVP in your plasma, but in contrast if you have isovolemic osmotic increase, so if you increase the osmolarity of your blood, you have a steep and very rapid increase in your thirst feeling meaning that you get hypovolemic that you will start to take in free water to compensate the hyperosmolarity.

That it’s not only salt that is driving this process can be seen from this study by Ramdeen and coworkers where you can see that if you compare the post dialysis sodium levels in non-diabetics and diabetics well, they’re quite comparable but if they come back to haemodialysis the next session, you can see that in diabetics well, the sodium has decreased a bit because these patients have taken some free water because of thirst and you can see that the diabetics gained more weight despite the fact that their sodium in the plasma decreased and the reason is of course that in the diabetics there is already some hyperosmolality, there is already because of the hyperglycaemia an increased thirst effect meaning that they will drink more during the session and in this case of course, this will result in a hyponatremia. So, yes hyperosmolality is a problem, it can be induced by salt, it can be induced by glucose so only already for those reasons PD patients where the glycaemia might be somewhat higher might be at risk of hypervolemia.

So, so far I’ve tried to prove to you that in patients with impaired salt excretion, we call them salt sensitive and there are very good reasons to understand that in patients with PD, with ESRD that they should be salt sensitive, well salt intake in these patients will lead to volume overload and we all know, we all are aware that volume overload by itself is very dangerous.

Very important to understand and to tell your trainees and the people that are in training in nephrology is that most of the time we tell our patients you should not drink so much, this is not a driving process. It’s not the drinking that is terribly wrong, it’s the sodium and the hyperglycaemia that make the people drink that are terribly wrong. So you should restrict on salt and not per se on volume in these patients.

Well, there are some very good reasons for that. One of the reasons might be that as I’ve already told you at the beginning it’s not per se because of the volume overload by itself or alone that these patients are jeopardised or that these patients are at risk when they increase their salt intake. Here you see in the X axis the intracellular sodium concentration which at the end will result in the increase in vascular tone in your cells and here you see the sodium flux over the cell, the transmembranous self intracellular flux in relation to the concentration of the intracellular sodium. You can see that in patients where there is a decrease in the influx as, for example, which you can induce by ouabain and other related substances which we call the Digoxin-like substances which are increased in patients with ESRD because they are changing in their distribution volume. You can see that in these patients that there will be an increase in the level at which these sensors will start to work and as a result of that there will be an increased in intracellular sodium and in these patients there will be a higher vascular tone if you sodium load them, so if they increase their sodium intake. So indeed once again in ESRD patients even besides the volume effects there is a vascular tone effect induced by the accumulation of substances like ouabain and DLS like substances.

There is a second thing, normally if you have a normal subject well you can see that if you increase the sodium reabsorption, there will also be some form of vasodilation and at the end in the patients besides the fact that they will excrete the extra sodium, they will because of the vasodilation have no change in blood pressure but in our patients, in patients on PD and ESRD there is a hampering, there is a inhibition of this vasodilation and because of that if these patients are salt sensitive it will result in a blood pressure elevation and at the end in hypertension.

That this is the case can be deducted from these studies published in Hypertension recently by Ohashi and coworkers where you can see that in normal circumstances if you have an increased adiponectin level, you can see that these patients are protected from salt sensitivity, whereas if they are knocked out for adiponectin, if you don’t give them adiponectin, you can see that if you salt load them then again they will react with hypertension, an increase in blood pressure. This mechanism is completely regulated. The vasodilation is completely regulated by an NO oxidase system. So it’s an NO mediated system. People that are not asleep at this moment will say but, wait a minute Van Biesen you’re completely wrong because in patients on PD adiponectin is increased so our PD patients should be protected for salt sensitivity.

Well this is not the case. Why not? Well, I agree, adiponectin is increased in PD patients but we also know that their NO system is completely defective in most of our PD patients and because of that we react or our uremic patients will react as adiponectin knockout because of the inhibition of the NO system and in these patients you will see that indeed if you salt load them that they will be become hypertensive patients. So PD patients, ESRD patients for these reasons are in danger or jeopardised indeed for salt sensitivity and salt loading. There is even more.

There is a very clear relation between what we call the metabolic syndrome and the components of it and the insulin resistance and the insulin resistance and the salt sensitivity. The first step, relation between metabolic syndrome and insulin resistance. Well you see here that indeed the patients that are salt sensitive expressed here in the Y axis well they are increased if you have the metabolic syndrome, if you have reduced HDL cholesterol, if you have raised triglycerides, if you have elevated free plasma glycerides, if you have central obesity. This is a bit the prescription or the explanation for most of our patients because many patients on PD indeed have raised triglycerides. Many patients on PD indeed have some central obesity.

Indeed most of our patients have some components of the metabolic syndrome and for that reason they might be indeed having some form of insulin resistance because of the glucose loading. Here you can see that there is a clear relation between the systolic blood pressure during the night and during the salt intake in these patients in relation to the nocturnal blood pressure.

So, you can see that there is a very clear insulin sensitivity in relation to sodium sensitivity. If you have increased insulin resistance, you will also have increased sensitivity for sodium in these patients. Of course, our patients on PD are especially at risk because they indeed have all those components of the metabolic syndrome. Once again in this study, you can see that well age not per se but of course, gender reduced HDL cholesterol, raised triglycerides, elevated free plasma glycerides and central obesity, indeed they all will work against salt sensitivity in these patients.

Remember the group that is most in danger on PD as compared to HD are the older diabetic patients and there is a reason for that because the older diabetic patients are especially prone to the metabolic syndrome and for that reason there might be a relation with the salt sensitivity and there might be a relation with the worst outcome in these patients.

There are even more interesting things that you can find. There is a direct relation between increased salt intake and the production of TGF-β. This is a non-haemodynamic effect. It’s not related to volume overload. It’s not related to anything with volume, it’s just direct if you increase the salt intake, you will have an increase in TGF-β production. There is a very good relation and this is a very recent paper published by the group of Achim Jorres in Lab Investigation 2007 some weeks ago where they found that TGF-β is one of the regulators that regulates the glucose induced senescence of mesothelial cells in dialysis patients. Remember it has always been said well high transporters are particularly at risk to have a decreased peritoneal function and a bad outcome and it was thought that it was because of the glucose. Well it might be that it’s more than just the glucose because especially in these patients there is a bad salt output for reasons I will explain later. So, if they have more salt loading, it might be that they have an upregulation of TGF-β and because of that a far more rapid deterioration of their peritoneal membrane. So once again, if you salt load the patient, not only will there be hypervolemia which urges you to use more glucose in these patients, but also per se by the salt loading you will induce a more rapid deterioration of your peritoneal membrane.

So in conclusion so far I think that salt indeed is a dangerous poison in PD patients because first of all the uremic toxicity by itself, it already induces disturbances that induce the vascular reactivity. The salt enhances the insulin resistance, there are effects of salt that are enhanced in patients with metabolic disturbances like our patients on PD and salt might even have a direct link to the deterioration of peritoneal membrane through enhanced TGF-β production. So if you think about the physiology of salt and how it relates to cardiovascular disease, you might come to the conclusion that indeed our patients are jeopardised and should be treated very carefully with regards to salt intake.

So having said this, how can we manage to have a low body sodium in our patients? Well, most important diet. Dietary sodium restriction is the key to the success in the salt management of our patients.

This has been shown in this study for example, by Gunal and coworkers where you can see that by simply instructing the patients to get a lower salt intake, you were able to reduce 2 kg of body weight, they were able to reduce the hypertension in these patients. They were able even to reduce the cardiothoracic index even despite the fact that it’s only an indirect marker of cardiac hypertrophy still they were able to show that this was different.

Here once again, if you salt restrict the patient, you can see that indeed if you go from a 10 g of salt per day to a 4-5g of salt per day you can see that there is a decrease in blood pressure despite the fact that your volume, that the dry weight of the patient doesn’t change once again pleading for the effect of the non-volume mediated salt induced hypertension in these patients.

Not only the blood pressure changes there are also other things that we consider as very nasty like for example, left ventricular hypertrophy. Well if you place patients on a salt restriction, you can see that in most of the patients there is a good reduction of left ventricular mass at least in only one of the patients there was an increase, all the others fair better if you put them on a salt restriction.

There is only one study that I found but it’s only a very limited number of patients, 20 patients and it’s only a very short-term follow up where they found so-called ‘no difference’, this was the conclusion of the paper but if you look more carefully, then you can see that even in this so-called negative study there was an increase in blood pressure both systolic and diastolic, if you increase the salt with 200 meq per day in these patients even in the short-term, even in the days following this experiment. So indeed dietary sodium restriction might be the clue to a good successful salt restriction in our PD patients.

Other ways, of course, are to enhance the diuresis in the patients and to enhance the excretion of salt with the use of diuretics.

This is a study by the group of Ray Krediet, by Van Holden and coworkers where they gave short-term, so one single shot of diuretics, loop diuretics to the patients and you can see that indeed if you give diuretics, you enhance the sodium excretion in these patients and this relates the better your residual renal function well the more sodium you will be able to remove. This is of course an open door for nephrologists, I agree with that but it’s important to realise that if your residual renal function goes down, well it also will mean that your sodium excretion capacity and the reactivity to diuretics will go down. It’s not dangerous to give diuretics, it will not impair on your urinary excretion over time and it will not impair your glomerular filtration, your residual renal function over time, the only difference will be that indeed your body sodium will go down so it will be having a good effect on the patient.

There is one caveat for this. It has been shown in different studies that the superiority of salt restriction by diet is clearly very much more powerful in fact, than the removal of salt by diuretics. So, it’s very easy to say to the patient well you should not follow a sodium restrictive diet, I will give you some loop diuretics and the effect will be the same, the effect will not be the same.

Superiority of salt restriction has been shown in very good and well-performed studies already more than 20 years ago. So, it’s not equal to give loop diuretics instead of a salt restricted diet.

What about PD self and the removal of salt by PD? Well, I’ll give you this slide and it says, enjoy the water because this is what we really measure in our patients. We measure ultrafiltration and we express that as ml of water that come out of our patients.

I give you the next case to consider and to think about and remember when you look at patients. It’s a young female polycystic kidney disease and she complains of itching, she has a lot of complaints fatigue, faible, weak and she feels a bit like a centrifuged towel. She’s on an ICPD regimen, she has 5 cycles of two hours with 2.5 L of 1.36% glucose. She has a good residual renal function and she has a good peritoneal ultrafiltration of 1.5 L/day. Despite that she comes with hypertension, a blood pressure of 160/100 mmHg and she has oedema. These are her numbers. She has a Kt/V of 2, she has a residual renal Kt/V of 0.3, 1.8 peritoneal and this is her lab biochemistry.

She has a very good peritoneal ultrafiltration and despite that she has oedema and she has hypertension. Well, the clue of this patient is that in fact she’s on the completely wrong regimen because this is the question of course you can think about while I continue, because this patient is in fact a slow transporter and because the fact she’s a slow transporter, this will mean that she’s very good at ultrafiltering because her glucose gradient is maintained all over her dwell. So she produces a lot of water and if you look to the ultrafiltration, this is very good, it’s 1.5 L after the over night. The only problem is that she’s removing water not salt. At the end of the night she retains her salt, she has lost the water, she has become hyperosmolar, remember the physiology at the beginning of my talk she became hypertonic and she will drink and if she drinks, nothing has happened. So she lost 1.5 L of water on the paper sheet but she has not lost her salt.

This is evaluated in this study by Aanen and coworkers from the group of Simon Davies where you can see that indeed if you go and these are patients being treated with a 1.36 going to a 3.86% glucose, you can see that if you look to the predicted ml as the observed ml, well there is a fairly good correlation and it doesn’t differ between the different glucose concentrations.

But if you look to what happens in the sodium excretion in the short dwell, you will see that the line for the low glucose is completely different than the line for the higher glucose and will be completely different for the 3.86. This means that if you increase the water excretion by enhancing or by elevating the glucose concentration in your bag, well you’re able to remove more water but not more salt.

If you have a short dwell this is more expressed than if you have a long dwell because in a long dwell you can see that the lines coincide more easily, more correctly so being the fact that indeed there is a compensation for that.

There might be large differences if you go from a 1.36 to a 3.86 you can see that the mean difference between what you expect in terms of water and what you really get in terms of salt might even end up to be something like 30 mmol/L times 8 L it’s 250 mmol/day, it’s a huge difference.

The reason for that is the effect of what we call sodium sieving. Because of the presence of the aquaporins it means that in the beginning of the dwell you will have a very good removal of free water but not of sodium and because of that in the beginning of the dwell you will have a drop in the sodium concentration in your dialysate, you remove free water but no sodium transport. There is a discrepancy, a great difference in concentration between the plasma sodium and the dialysate sodium and because of that in the second part of the dwell there will be diffusive transport of the sodium meaning that only in the second part of the dwell there will be removal of sodium in these patients. So if you restrict these patients to very short dwells, you will remove a lot of water but not of sodium. At the end of the day or at the end of the night the patient becomes hypertonic and he will start drinking again and there will be no pure ultrafiltration. This is of course because of the presence of the aquaporins which are only permeable for water and not for any other solutes.

For reasons of time I’ll just skip. Indeed you can see in this slide that the more aquaporin expression there is in the peritoneal membrane, the more the patient will be likely to remove free water. So if you only look to the water, you remove water but not salt and this is of course, not very good.

It’s not only if the aquaporins are not working that you can see that sodium sieving disappears, you can also have that if you have announced diffusion like, for example, in a peritonitis patient. If you have peritonitis, the sodium diffusion goes so fast that you have a complete abolishment of the sodium sieving curve and that you can see also the fast removal of sodium in these patients.

The second determinant of the sodium removal in peritoneal dialysis besides the sodium sieving is of course, the drained volume and here you have to keep in mind that in high transporters.

Well there might be a high sodium diffusion already from the beginning of the dwell but because of the fact that the glucose disappears they will all only have a very low intraperitoneal volume and at the end of the dwell they will have probably even negative infiltration meaning that less water comes in than goes out, meaning once again that they reabsorb sodium instead of losing sodium. Therefore, you have to be very careful and you have to be very careful in prescribing your treatment regimens. If you have a patient with a high transport status or a fast transport status, it should be on short dwells to avoid problems with this, with negative volume. If you have a patient with a slow or slow average membrane, you should have him on longer dwells to avoid the negative effects of sodium sieving.

So, for your volume status it’s extremely important that the patient is on the right treatment that is good for him.

One of the other ways that you can use to remove sodium of course besides sodium restriction by diet this is the first step, using diuretics this is the second step. A good prescription adapted to the patient, this is the third step. You can also use of course, icodextrin. Icodextrin is a polymer of glucose and because of that it’s not absorbed and it means that you have a continuous positive ultrafiltration meaning that for every 100 ml that comes out extra you have 0.9 g of salt that you remove out of your patient.

This is indeed a very good and a very elegant way to remove sodium and water out of your patient as has been shown in this study by Simon Davies but there are other studies by Konings and coworkers for example.

You can see that indeed the extracellular fluid after the start of – after 4 months you can see that there is a decrease in extracellular fluid pointing to the fact that indeed you removed extra sodium and extra water in these patients. You can see that it’s not only the extracellular water there is even a decrease in total body water in these patients.

A third way to go potentially would be of course, to reduce the sodium concentration in the dialysate. If you reduce the sodium content in your dialysate, the concentration gradient between the plasma and the dialysate will be higher and because of that you will have a faster and higher transport by diffusion of sodium.

Because of that indeed they were able to show in this study already 10 years ago that indeed if you use these types of hyponatremic solutions, that you can increase the sodium reduction. The only problem with this type of solution and you have to look here is that for reasons of osmolarity you will need higher glucose concentrations which once again, is not very good.

Last slide Mr Chairman. Indeed our PD patients are or should we say were, at least after this lecture they should all be were and not are, often overhydrated as has been shown in this slide. But this is because we didn’t pay enough attention to the basic physiology of what’s going on with our salt.

I think to conclude salt is very important in PD patients and we should take a lot of care of that. Dietary salt restriction is the key. A good understanding of the physiology of the transperitoneal transport of the salt is of importance. High transporters, short dwells, slow or slow average transporters, long dwells and then you will have a successful salt restriction in your patients. I thank you for your attention.

Question: Ian – from – so thank you very much for this wonderful lecture. I was most startled that you showed us there’s internal sodium escape inside the body and an extra renal regulation of sodium which is a key point of blood pressure. So, do you know any concepts of how this salt that is caged inside the body and cannot be mobilised by ultrafiltration, how we could mobilise that?

Dr. Van Biesen: Well, so far there are no tricks as far as I know. There is no medication that works on that because the structures like ouabain are so omnipotent, they are so omnipresent that you can’t work on them. But I’m not a basic physiologist, I’m only a simple PD guy but the only thing that strikes me is that this is literature that has already been available for more than 10 years and people have not paid attention to it like the relation with TGF-β. It’s quite clear to me now that indeed it might be one of the explanations to why the patients with high transport states there is a higher sodium intake in these patients and that might be one of the driving forces of the faster deterioration of their peritoneal membrane. So, I think as a PD community in the future we will have to look more closely to these effects and not attribute everything to the higher glucose per se causing the effects. I’m not saying it’s going to be the answer but at least it’s worth looking at. I’m not sure that there is a medical because this is what you’re pointing at that there is a medical intervention.

Question: Well, some diuretics seem to mobilise or seem to influence the sodium potassium ATPase which is the key player.

Dr. Van Biesen: Yes, as far as I know there is only one medication that worked on the potassium channels but it has been removed from the market because there were too many side effects related to this medication. That’s what I know.

Question: I have a question for you. The first one is how much salt for a patient per day do you suggest? The second one is you showed that the total body water is increased in peritoneal dialysis patients but some papers in the past suggested that not only the extracellular water is increased but also the intracellular water is increased in PD patients.

Dr. Van Biesen: Yes, that’s what I showed in one of the first slides. So because of their ESRD they have an upregulation of their DLS-like structures and because of that their intracellular sodium content will increase and because of that they will become higher water content. With regards to the amount of sodium intake I think for normal PD patients what we say is that they should eat low salt and try to avoid it as much as possible and mostly they end with something like 2, 3, 4 g/day. This is realistic less than that it becomes more torture than real evidence based and probably it’s not good because then if you go lower than that you might risk to also upregulate your RAS system where there’s also not many beneficial things to be expected from that. So I think 3-4 g should be an acceptable range unless Ray you have another opinion on that?

Question: No, but probably the amount of salt that should be taken daily is quite different in general. Patients on APD versus patients on CAPD because these last ones are much more able to eliminate salt. The key in salt elimination is determined by the transference of…

Dr. Van Biesen: Yes that was very clearly shown by some people form Spain, I think Carrera that showed that indeed APD patients get less removal of salt because probably related to the sodium sieving effects. If they have too many short cycles, they remove water but not salt.