CME Slides Forum - B. Rodriguez-Iturbe

A joint Congress by ERA-EDTA and ISN

MANAGEMENT OF THE CKD PATIENT: SALT RESTRICTION, DIURETICS OR BOTH?

Bernardo Rodriguez-Iturbe, Maracaibo, Venezuela

Chair: Nathan Levin, New York, USA

Stanley Shaldon, Fontvieille, Monaco

rodrigueziturbe

Prof B. Rodriguez-Iturbe
Hospital Universitario de Maracaibo
Centro de Investigaciones Biomedicas
Maracaibo, Venezuela

Thank you very much doctor Shaldon. I don’t know if I’ll bring you down to earth or not.

Well, my task this evening is actually to talk a little bit about management in the CKD patient: salt restriction, diuretics or both. I’m going to address this subject by taking these particular subheadings in succession.

First of all, I will briefly go over salt retention and renal disease and why there is a tendency to salt retention and what are the proinflammatory effects of salt retention, sodium retention.
Then I will talk briefly about salt restriction and the control of hypertension and proteinuria.
Then what data there is that diuretic treatment and proteinuria, what is the potential beneficial effect of diuretic treatment and then end up with perhaps some considerations more suggestions as to what to do in the CKD patient with this.

Now the first part, which is the tendency to salt retention, very briefly to remind you all that the upper limit of the renal capacity to excrete NaCl is about perhaps 6% of the GFR. So if you drop the GFR to about 10% of normal and you give that patient a 10 g of salt per day, then he’s going to have real trouble to excrete that salt.

In second place is that the intrarenal oxidative stress, inflammation and Angiotensin II activity within the kidney drive a tendency to sodium retention and finally, that the pressure natriuresis is impairing CKD because actually --- you have decreased capillary network, you have increased fibrosis, you have more distance between the blood vessel and the tubules so that’s impaired.

Let me first start with this particular diagram to remind you all that there is a three legged stool if you will in which you have immune cell infiltration, oxidative stress and intrarenal angiotensin II activity. I’m not going to go into the details on all these specific areas here within the picture but just to tell you that it’s practically impossible to have one of them without actually recruiting the other two into action.

So just to show you an example, if you have immune cell infiltration, you have direct superoxide production both in the infiltrating cell and from the resident cells that generate oxygen species that in turn produce intercellular adhesion molecules, proinflammatory cytokines and bring this back. In other words these 3 things are basically involving chronic kidney disease of practically whatever nature you want to think. So the proinflammatory effects of sodium retention I would like to look at it from this view point. This high salt intake what does it do to this triad if you will? One of the things it does is to increase fibrosis and TGF-beta and Doctor Sanders has already spoken extensively about that and superbly as usual. You have inflammation and there are a number of papers that indicate that a high sodium diet will produce inflammation. You have in addition an increase in intrarenal angiotensin activity both by an increase of two effects that are easily demonstrated. If you have increased receptors in the arterioles and you have increased renal angiotensin II content and you have oxidative stress which is manifested as shown there by superoxide production, increased NADPH oxidase and decreased nitric oxide generation. Let me go briefly through some of these just to remind you of some of these papers.

This is a paper by Meng showing how superoxide is increased with a high salt diet over a low salt diet and of course, in every one of these instances the addition of peroxide dismutase by -- in this particular case when it is down both in the cortical and in the medullary area.

Then of course, this is a paper by Doctor Wilcox’s group showing how the NADH and NADPH both are increased with a high salt diet and some of the subunits are also increased.

A paper by Doctor Vaziri’s group showing how different isotypes of nitric oxide synthase are actually decreased both in the aorta and in the kidney when you give a high salt diet.

I will not talk about the effects of -- but just to mention to you that if you give a high salt diet as in this case, you increase the production of a proinflammatory transcription factor, nuclear factor KB and your TNF

and of course you get this kind of a picture within the kidney showing that it’s a proinflammatory thing.

Finally, to discuss with you a little bit about intrarenal angiotensin activity,

Doctor Ruan and his co-workers showed how a high salt diet will increase not only the binding to the H2 receptor but actually an increase in the receptor with increasing doses if you will of salt in the diet. This is just to show you a little bit that we’re talking about angiotensin within the kidney not in the plasma. If you have one model of salt-sensitive hypertension and in this particular case it was induced by angiotensin infusion and then subsequently giving a high salt diet

and compare this to what happens if you reduce the inflammation with mycophenolate and controls with high and normal salt diet, you can see that as expected as the blood pressure goes up the plasma angiotensin actually comes down you will suppress the plasma angiotensin but the image that you see within the kidney is exactly the opposite. As the systolic pressure goes up, the renal angiotensin goes up.

Actually there is a very nice correlation as well and this is part of the same experiments between the infiltrating cells in these particular cases macrophages within the kidneys very nicely relate with the amount of renal angiotensin II in this model that I have just described.

Now what happened to a model of CKD in this particular case, a remnant kidney model if you treat them with a high salt diet? Well if you give them the high salt diet, the one thing that happens is that the creatinine goes higher and the proteinuria goes higher. So you say a general effect that will make things worse definitely.

So salt restriction and control of hypertension and proteinuria as a next point in there.

I’m not going to go into this because you all know that hypertension and renal function loss have been demonstrated to be associated in the general population, as well as in patients with CKD. These studies are all very well known.

But I do want to emphasise a couple of points on control of blood pressure in CKD. The first one is that in non-proteinuric patients you have a little bit more leeway when you have proteinuria the recommendation is you go as low as possible and certainly below 125/75 mmHg. But those are the goals and a significant number of patients that vary between 61% and 46% of the patients depending on who you read have trouble going below this value of 140/90 mmHg and certainly getting to the desired levels only between 15-11% of the patients can do that. I bring up this point because I want to emphasise that among the causes for poor hypertension control in CKD, there are a number of them but I’m interested in the context of this afternoon’s talk that there is an insufficient compliance of patients to a dietary salt restriction.

Now let me go through the evidence that indicates that salt restriction by itself reduces the proteinuria and blood pressure.

This is a study by Vogt L et al. actually last year and you can see here that if you just compare what the protein excretion is with a high salt diet or with a low salt diet, there is a significant difference. These patients were taking placebo and no other drugs at the time and you can see this reduction both in blood pressure and in proteinuria.

You see the same thing if the patient has already taken in these particular case ACE inhibitors or if they are taking angiotensin II receptor blockers. If you add to that simply a salt restriction, a forced salt restriction in this particular case you see it the other way around. First of all if you give them a high salt diet, the nice response hat you’re getting with low salt diet is lost. You start getting an increase in urinary protein excretion. If you add a low salt diet to the losartan treatment, then you get a movement or a change towards a further reduction in protein excretion right here and a further reduction in blood pressure right around there.

Well two diuretics primarily have been tried: hydrochlorothiazide and furosemide and this is an experimental study by Doctor Zatz’s group in San Paolo and of course this is too small to see so I’m going to highlight some of their findings for you here. This is a 5/6 nephrectomy model and you can see that one month of treatment after 2 months post nephrectomy you see the sham animal with a nice blood pressure and how the nephrectomised animals went up to 204 and if you add in this particular case a low salt diet and you have hydrochlorothiazide here you can see how the addition of both is definitely better than either one of them by themselves, you get practically a normalisation of blood pressure and a normalisation of the intracapillary pressure within the glomeruli. Interestingly if you follow these rats for over 7 months or 8 months post op if you will, the creatinine in the rats with double treatment which is losartan-hydrochlorothiazide and low salt diet as well, you get practically a normal serum creatinine and the survival goes from 29% when you did nothing and 87-86% when you did partially to 100% when you did both treatments. So this is pretty strong evidence that something is cured by adding a diuretic to that.

Let me show another part of the same work by Vogt. Here you have placebo, losartan and losartan and thiazide even to patients that were actually proteinuric urinating about 3.8-4 g of protein a day with a creatinine clearance that was not particularly decreased. They were studied with a 200 or a 90 mmol/day sodium diet. You can see that in any other interventions that were put in there the low salt diet offered an improvement to the previous treatment that was either placebo or the losartan or the losartan-hydrochlorothiazide. This I show here to emphasise the fact that the fact that you’re giving a thiazide doesn’t liberate you from the idea of having a low salt diet because you can get a further improvement if you use both things the same thing goes for arterial pressure.

Furthermore, I think it’s interesting that the effects of this combination with diuretics on top of renin angiotensin system blockade is even more important and more impressive in those patients that were resistant to the blockade alone. So you can see this drop in the protein is more pronounced in the group of patients that they called resistant which were those patients in which the reduction in proteinuria was less than 25%.

Same thing or rather this added effect of a diuretic in the proteinuria you can see with furosemide but this effect is associated in the case of furosemide with an increase in serum creatinine which is more pronounced than when furosemide is not used.

Then from all this I’ll try to make suggestions, I don’t think there are indications or guidelines or anything

but let me show you some studies which I think are interesting because they show the following. Furosemide and hydrochlorothiazide seem to have a little bit higher fractional sodium excretion. Actually you don’t do much better if you use thiazide and furosemide together. As a matter of fact, when you look at the effects that you can get on mean blood pressure or GFR they are not different if you use any of these combinations. So therefore, what would seem to be a reasonable suggestion in CKD you have to restrict dietary sodium, there’s no way out let’s say --- the patient doesn’t run away from your office.

But if you have a patient that with just that added to the angiotensin system blockade keeps a normal blood pressure or certainly below 130/80 mmHg and proteinuria some people say less than 1 g per day what I would argue is that it’s better to have less than 0.5 g/day. Then I think that patients can be managed with dietary restriction alone with this kind.
However, if the patient that you treat has higher blood pressure and you cannot control it well with this combination of proteinuria more than 0.5g/day after you enforce this sodium restriction, he then has normal blood pressure and a very low level of proteinuria then you can go back to this and just watch him and follow him with a low salt diet well, with a relatively low salt diet. But if that doesn’t work and the patient maintains a high protein excretion of hypertension then I think diuretics are worth considering being added and at least without too much evidence based data what we do and what we suggest to do if your GFR is reaching 40 ml/min and 60 ml/min you can start with thiazides. If your GFR is less than 40 ml/min perhaps you try with diuretics. Of course this adds a little bit of complexity to the handling of the patient because you have to test for acidosis, hyperuricemia, weight, post hypertension and electrolytes and you have to check compliance and in compliance it is good to emphasise that the patient should look at sodium in the labels because the cooking and the table salt are the minority of the culprits here and the food acid comes to the kitchen or to the table has about 85% of the total. I think that’s it I thank you very much for your attention.

Chairman: Thank you. Questions for Doctor Iturbe? Please? We have two free communications at the end of this.

Question: -- Poland I have a very short question. What diet would you suggest to a healthy man or a woman of course, without hypertension? What diet would you suggest to a man with permanent hypertension?

Dr. Rodriguez-Iturbe: I better answer the first one which is easier for me I would recommend a diet that is no more than 6 g of NaCl a day so the fight and I’ve just emphasised it here with CKD was to emphasise the point that if you may be a little flexible otherwise with kidney disease you have to be very strict about what you are doing. Now -- hypertension has several reasons and I would investigate a patient very well before saying that what he needs is simply more salt. The patient has autonomic disturbances and there are a lot of other things in there.