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Dick de Zeeuw, M.D., Ph.D. Dr. de Zeeuw is Professor and Head of Clinical Pharmacology at the University of Groningen, The Netherlands. He obtained both his MD and PhD degrees at the University of Groningen, where he also did his postgraduate work as a Research Fellow in the Department of Medicine. He is Treasurer of the Dutch Society of Nephrology and of the European Dialysis and Transplant Association. His research interests include the anti-proteinuric and renoprotective effects of ACE-inhibitors and angiotensin receptor blockers, as well as methods of measurement of renal blood flow. He is the author of more than 140 international scientific publications in these and related fields. |
Introduction of Dr. de Zeeuw
Dr. Weber: Well we've dealt with the arteries, we've dealt with blood pressure, we've dealt with the heart, and I guess that leaves us with kidneys. We have now as part of our program Dr. Dick de Zeeuw. Dick and I have been together on many programs over the years; and it's a real pleasure, Dick, to welcome you again to New York. Dr. de Zeeuw is on the faculty of the department of medicine at the State University Hospital in Groningen in the Netherlands. He is going to tell us about renal effects of angiotensin II pathology and physiologic issues. Dick, welcome.
Renal Effects of AII: Physiology and Pathology
Dr. Dick de Zeeuw
28.8 modem
14.4 modemReal Audio recording of Dr. de Zeeuw's Presentation
Introductory remarks
Thank you, Michael; and also thank you for inviting me to this nice meeting, which I am ashamed to say I have never been attending before, but it will certainly not be the last time.
Effects of angiotensin in renal injury: hemodynamic mechanisms vs. a role of growth factors
As Michael said, I will focus my talk on the renin angiotensin system in the kidney. As the previous speakers, particularly the previous three speakers have been discussing, I think from the preclinical data there are at least a couple of very interesting hypotheses emerging. First of all, what is the role of angiotensin II in progression of disease, where it applies to the heart, vessels, and kidney? And the second one is, I think: Is this progression phenomenon something that is involved with the hemodynamic effects of angiotensin II or are growth effects adding to that or even replacing that hypothesis?
I will submit to you the data that we have gathered in the past decade in our group. It is intriguing to me to see that with the interpretation of the mostly clinical data and some animal data, we can tap into this new hypothesis of...on the one hand the hemodynamic effects and on the other hand, the relation to growth promoting. The current scheme that we look at when we deal with the kidney and disease is the ability for all of us dealing with patients with renal insufficiencies to keep them from progressing further and losing their renal function. And the particular role of this event, this vicious circle that is present between renal insufficiency after an initial pathogenetic insult and loss of renal tissue... and in the progress of this decline, apparently there is a particular role of the renin angiotensin system in this setting. The role of it has been, as many have said, focused on glomerular hypertension part, and that is the hemodynamic part of functional adaptations within the kidney using angiotensin II, sodium retention, blood pressure increases, to rise the pressure within the glomerulus to keep up with the loss of function due to loss of nephrons. And this, on the one hand, functional adaptation, has also a down side to it and that is an increased loss of nephrons due to this increased pressure, interestingly also accompanied with factors also known in hypertension to be important--that is hyperlipidemia and also changes in the permeability of the vasculature in the kidney, particularly identified by changes in loss of proteins.
I think that at this time point the hypothesis is valid to put forward to state that these hemodynamic changes on the one hand, induced by the renin angiotensin system, are the working hypothesis of angiotensin II and its role in maybe decline of function of organs. And for the kidney, the slower pathway may be the proteinuria pathway in which, and I will demonstrate this to you in the next couple of slides, in which the proteinuria represents the growth pathway of the kidney and the damage that it does--possibly also through angiotensin II although those relations have been hard to identify, at least in the human situation.
Effects of ACE-inhibition on progression of renal insufficiency
Now it is clear that if we intervene in the renin angiotensin system, and there have been many studies that have been demonstrating that elegantly... is that if we intervene in the renin angiotensin system by the only method available to us long-term, which is ACE inhibition, that we can prevent the progressive loss of renal function here indicated by the survival curve of the kidney in this French study compared to when we give in this case an ACE inhibitor enalapril where we were able to protect the kidney from further damage. This has been demonstrated both in nondiabetics, as this slide demonstrates, as well in diabetic renal disease. It shows you that for angiotensin converting enzyme inhibition the involvement of the renin angiotensin system is there, although there is still debate whether other parameters are of importance except the renin angiotensin system, and I'll come back to that.
Effects of ACE-inhibitors on renal hemodynamics
What makes an ACE inhibitor so different from conventional treatment, in this case, beta blockers? First of all, it has been long known that ACE inhibitors indeed show what you would expect if you deprive the kidney of angiotensin II, that is that they increase effective renal plasma flow, vasodilate the kidney, despite the fact that there is blood pressure reduction. This is probably done post-glomerulus as indicated by the fall in filtration fraction that occurs with an ACE inhibitor and that shows that there is probably reduction in intra-glomerular pressure occurring because there is a slight but much less significant fall in GFR occurring compared to the rise in effective renal plasma flow.
Effects of ACE-inhibitors vs. other antihypertensives on proteinuria
Apart from this short-term very important hemodynamic phenomenon, there is also the effect of ACE inhibitors on proteinuria, here indicated by a double blind study from our group [1], where you see that with the similar effect on diastolic and systolic blood pressure of a beta blocker and an ACE inhibitor in a group of non-diabetic subjects with proteinuria that the anti-proteinuric effect is considerably more present with the ACE inhibitor and makes it different from conventional treatment strategies. This is not only true for beta blockers, it also holds true, as we recently demonstrated in a meta analysis for other anti-hypertensive agents, calcium antagonists, beta blockers, and vasodilators and hydrochlorothiazide-like drugs show that they have a minimal effect on proteinuria, about a 15 percent reduction... compared to ACE inhibitors that have about a 40 to 50 percent reduction in proteinuria despite the fact that these drugs all had a similar reduction in blood pressure. The intriguing part is that this particular phenomenon and characteristic of ACE inhibitors applies to both diabetics and nondiabetics and applies to both micro- albuminuria and full blown proteinuria to the same extent. For the first part diabetes and non-diabetes, I will show you that in this slide, is that indeed there is this phenomenon of ACE inhibition being anti-proteinuric in the diabetic and non-diabetic and not for the other anti-hypertensives. So it looks like that with the ACE inhibitors we have drugs intervening in the renin angiotensin system differentiating themselves from not only reducing the blood pressure effectively but also changing the renal hemodynamics, possibly lowering inter-glomerular pressure and, on the other hand, lowering proteinuria.
Role of proteinuria in progression of renal disease
What is the importance of this proteinuria lowering per se? We already know that the reduction of intra-glomerular pressure, certainly from the animal experiments, is very important. But also the reduction in proteinuria appears to be very important and predictive, as shown in the study from our group here but by many others recently, that the reduction of this proteinuria that you can obtain initially with ACE inhibitor study, if this reduction is around 80 to 100 percent, which is the case in some patients, you will see that these patients in the subsequent years of follow up have less of a fall in this case in creatinine clearance and creatinine clearance slope than those where you were not able to reduce the proteinuria as effectively. And this indicates at least that the treatment and the intervention in the renin angiotensin system that you do with the ACE inhibitors protects the kidney in those cases where you are able to reduce proteinuria; or similar relations have been put forward, for instance, for the effect on filtration fraction and on renal hemodynamics.
AII vs. non-AII effects of ACE inhibitors
The question comes forward whether this intervention with the ACE inhibitors now is related to the angiotensin II part that we all are so aware of, ACE inhibitors preventing the formation of angiotensin II, or that it is related to the hypothesis of an increase in the levels of bradykinin or to other phenomena that we are still not yet aware of. I think that in the clinical situation there is evidence for both of these hypotheses. I will in the next couple of slides show you some examples.
First of all, I think that the relation with the renin angiotensin system and the anti-proteinuric effect of ACE inhibitors becomes clear when we look at the phenomenon that the effect of these agents is only clear when we use low-sodium diets in these patients to stimulate the renin angiotensin system and then make the intervention. Now what do we do with the low-sodium diet? Or for that matter by using a high-sodium diet and using hydrochlorothiazide? What we actually do then is make the kidney dependent, at least hemodynamically as we know of it, on angiotensin II and circulating angiotensin II levels and maybe even on tissue with angiotensin II levels for its function. And if we make them dependent on the renin angiotensin system by either low-sodium diet or by hydrochlorothiazide, we see that the anti-proteinuric effect is much less during the high-sodium diet of the ACE inhibitor period than during the low-sodium diet or during the adding of the hydrochlorothiazide. I think that this demonstrates that there is involvement of the renin angiotensin system at least in the anti- proteinuric effect itself. However, whether it is truly only angiotensin is still not known.
AII infusion during ACE inhibition: Effect on glomerular hemodynamics and proteinuria
What we tried to do is see whether angiotensin II itself plays an important role by adding exogenous angiotensin II in patients in whom we used ACE inhibitors for reduction of proteinuria. Now, such a scheme, and I will show you a couple of slides on this... such a scheme is only executed in the clinical setting by using low doses of angiotensin II for only a short period of time. So this particular setting in which we used it was where we could infuse angiotensin for a couple of hours at several different doses. And what we did is we infused 5, 10, and 20 percent doses of angiotensin, the dose that would increase blood pressure by 20 mm of mercury [2]. So 5, 10, or 20 percent of that pressure dose was infused for each one hour consecutively. And the effects of that in a patient group that was not treated with ACE inhibitors are that it raises blood pressure slightly as you would expect. Now intriguingly if these same patients were treated for four weeks with an ACE inhibitor, thus lowering their blood pressure at the baseline level here, then subsequently giving these patients exogenous angiotensin II would again cause a rise in blood pressure that was close to the pre-ACE treatment levels. But more interesting, obviously, is what happens to the renal hemodynamics and the proteinuria. First of all, renal hemodynamics here, exemplified by renal vascular resistance and filtration faction. As expected without the ACE inhibitor, angiotensin II increases the filtration fraction. The ACE inhibitor, given for four weeks, reduces the filtration fraction. Subsequent low doses of angiotensin II already restore filtrating fraction to pre-ACE treatment levels, suggesting that indeed angiotensin II is an important factor in the effect of ACE inhibitors on renal hemodynamics. Now what was the intriguing part of this particular study is that there is no effect of angiotensin II on proteinuria at baseline, there is a clear decrease with the ACE inhibitor at four weeks, but the subsequent couple of hours of infusing of angiotensin II were not able to change proteinuria at all.
Time dissociation between ACEi effects on hemodynamics vs. proteinuria
This suggests that first of all there was a differentiation between the hemodynamic and the anti-proteinuric effect of ACE inhibitors; and secondly that these short-term infusions of angiotensin II were not able to restore the anti-proteinuric effect... maybe even showed us that it was not angiotensin II related, this anti-proteinuric effect. Moreover, the disassociation between the hemodynamic and the anti-proteinuric effect is also shown in the time course when we look at effects of ACE inhibitors [3]. Here you see that, and let's focus on the yellow line here which indicates the filtration fraction, that on the first hours of using an ACE inhibitor, you will see a full-blown effect on renal hemodynamics, effect on renal plasma flow and GFR (...here indicated by the filtration fraction), which does not change during the subsequent 30 days of treatment in these patients. Whereas if we look at the proteinuria, you see that there is only a small effect, only about 10 percent, anti-proteinuric effect in the first hours of angiotensin converting enzyme inhibition, but that subsequent tests on the following days, you see that there is a slow onset of the maximum effect of anti-proteinuric effect. So there is a disassociation between the hemodynamic and the anti-proteinuric effect of ACE inhibitors, indicating that either the two are... effects of two different actions of this inhibitor being angiotensin II on the one hand and the bradykinin system on the other hand... or that, and that will be the good alternative, that the short-term infusions of angiotensin II are not able to restore something that takes a long time to be present.
So what we did is we were looking for a model in which we could infuse the angiotensin for a much lower period of time and see if we still could link the anti-proteinuric effect to angiotensin II. And this was done in an animal model because, as you all know, problems in the human setting for long-term, and I mean for a more than couple of weeks infusion of angiotensin II is too hazardous. This model is an adriamycin rat model which shows a stable proteinuria after induction of disease, which happens here. The stable proteinuria... and with response to ACE inhibition, the same that we see in the human setting--that is a clear fall in proteinuria with a slow onset of this fall with the ACE inhibitor. And it's also linked to prevention of glomerulosclerosis in this model. Now in this model we were able to infuse angiotensin II for, in this case, two weeks at a dose that had restored blood pressure to pretreatment levels of the ACE inhibitor.
As you see in this model, in the top panel proteinuria is depicted, there is again the slow onset of the anti-proteinuric effect. And then with the infusion of angiotensin II, you see that there is in the first couple of days no response to angiotensin II as far as proteinuria is concerned. In the following days, you see a slow attenuation of the effect of the ACE inhibitor, not reaching completely the pre-ACE inhibitor treatment level but certainly indicating that angiotensin II does play a role... and then a subsequent, after withdrawal, a subsequent return to the full efficacy of the ACE inhibitor. After withdrawing the ACE inhibitor, again a slow effect back to pretreatment levels. And this indicates that indeed angiotensin II may be important in ...but on a longer term for the anti-proteinuric effect of ACE inhibitors. This has substantiated that bradykinin does not play a particularly important role since a bradykinin antagonist does not have any effect on proteinuria whatsoever in this particular model. Whereas if we use an angiotensin II antagonist in this model, we were able to reduce proteinuria to the same extent as we were doing with an ACE inhibitor. So I think in this model it clearly shows that the anti-proteinuric effect of ACE inhibitors, in an animal model at least, appears to be related to the angiotensin II effect albeit on a much longer time scale and probably more growth related than hemodynamically related.
Role of AII in proteinuria reduction: human studies with remikiren and losartan
What is the evidence of angiotensin II playing an important role in anti-proteinuric effect in the human model? First of all, if we look at the data that are available, there are two interventions that are optional for us to look at this. The first is the renin inhibitor of an oral... renin inhibitor remikiren, which was only available at the time of this study for eight days' continuous treatment. But it certainly shows that this renin inhibitor lowers proteinuria in non-diabetic disease as we would expect in the first couple of days with ACE inhibitors, indicating that indeed the renin angiotensin system is important in the anti-proteinuric effect of an ACE inhibitor.
The intriguing studies come from the angiotensin II antagonists, in this case losartan, which shows that again 50 and 100 mg consecutively for four weeks given to patients with non-diabetic disease shows an anti-proteinuric effect that has a slow onset of action, reaching plateau after about four weeks, and averages about 50 percent at the highest dose in this case [4]. It's intriguing to see that there is a dose response. It appears to be a dose response, although we were not able to see whether this was still a time effect in this particular study. So it shows that the anti-proteinuric effect at least comes to a level of which we would expect it to be from ACE inhibitors.
ACE inhibitors vs. receptor blockers: renal hemodynamics and proteinuria
How does it compare to the ACE inhibitor? Well, first of all, the hemodynamic profile of losartan looks very much the same as that of an ACE inhibitor given in these non-diabetic patients consecutively in the doses of 10 and 20 mg for enalapril in this case [5]. You see that there is, with the angiotensin II antagonist, a rise in effective renal plasma flow, and a clear fall infiltration fraction, as we were also seeing with the ACE inhibitor and also seeing in this case with the ACE inhibitor. And similarly with the anti- proteinuric effect, you see that this anti-proteinuric effect in this particular population reaches again about 45 percent, similar to that that you see with an ACE inhibitor. It, in my opinion, brings forward an intriguing discussion, and that is it looks like angiotensin II, if we intervene at least with an ACE inhibitor and with an angiotensin II antagonist, it appears to play a very crucial role both in the hemodynamic and the anti-proteinuric effect and that these two, known to be related to the protective effect... and a damaging effect on the one hand and a protective effect on the other hand of intervention in the renin angiotensin system... does seem to link the renin angiotensin system very decisively to progressive renal function loss in at least the surrogate endpoints that we are looking at here.
Losartan is specific in reducing proteinuria as with a very recently finished study from the Norwegian group of Holdaas, who show that losartan compared to amlodipine, lowers proteinuria where it did not change with the calcium antagonist. I think that the future will be very intriguing to see whether angiotensin II antagonists are more specific tools to intervene in the renin angiotensin system on the receptor level ...prove to be as protective as we've seen with ACE inhibitors to date.
RENAAL Study
The study that is starting at the moment is called...and is funded by Merck... is called the RENAAL Study, which stands for Reduction of Endpoints in Non-insulin dependent diabetes mellitus with the Angiotensin II Antagonist Losartan. This is an international study of around 1,500 patients and which will be looking at primary endpoints for kidney, all-cause mortality, doubling of serum creatinine, end stage renal disease and death; and the secondary endpoints of CV morbidity and mortality and proteinuria , treating with losartan versus placebo. There is conventional treatment in both arms, with a treatment duration of about four years in these patients with somewhat higher risks of progressive renal function loss because of their presence of albuminuria and some higher creatinine levels. I think this and other studies in this area, will definitely show whether it is still angiotensin II, its hemodynamic and its trophic effects that are of importance in progressive renal function loss or that still other parameters are there that we have not teased out.
Thank you for your attention.QUESTIONS AND DISCUSSION Dr. Weber:
That was a great presentation, Dick. Is there any way that the effect of losartan or ACE inhibitors or the other anti-angiotensin II drugs ...their effect on proteinuria directly has an effect on glomerular or renal pathology or is proteinuria basically a marker of something else?
Dr. de Zeeuw:
I think that's a very important point that you bring up, Michael. It certainly is a marker. Proteinuria is certainly a marker of that what happens within the kidney, and that is clear from at least the studies where you look at essential hypertension and microalbuminuria where you look at diabetes and microalbuminuria in the early stages where you see that lowering of pressure, lowering of intraglomerular pressure is accompanied by appropriate changes in microalbuminuria. However, I think that there is accumulating evidence that by itself proteinuria also has a role in causing the damage either through glomerular cell effects, uptaking them as mesangial cells or through uptake in the proximal tubule interstitium. I think that by just intervening in that particular mechanism you also protect the kidney. And not only that, I think that it is clear that if angiotensin II is indeed related in the kidney to growth, and it looks that way at least in the human model, that changes in the glomerular basement membrane are actually that what happens when we intervene re angiotensin II. That shows the slow onset of the anti-proteinuric effect to be directly related to the effect of the drug on angiotensin II more than to the pathology that is behind it.
Dr. Weber:
Okay, Professor McGregor?
Dr. McGregor:
Thanks. Very nice studies. It is actually nice to see some interesting clinical studies with losartan for once. What I wanted to ask you was you almost have a paradox in terms of trying to associate angiotensin II with proteinuria that as you and you others have shown, if you put people on a low-salt diet and the renin angiotensin system goes up, you actually get a reduction in proteinuria. It seems to me that perhaps the way to look at this is rather like with left ventricular hypertrophy where again if you salt restrict people, you get a reduction in left ventricular hypertrophy and yet a rise in angiotensin II. Therefore, the relationship between sodium balance and the level of angiotensin II seems to be important in whether angiotensin II is having a trophic and deleterious effect on say LVH or on proteinuria or whether it is not. And I wondered if you would like to comment on that, specifically the inter-relation to proteinuria, because you have a paradox which needs explaining if you're going to say it is all due to AII, and I think sodium balance and the level of angiotensin II is critical in that interpretation.
Dr. de Zeeuw:
I think you touched on a very good point. We have often wondered why ...if we put patients on a low-sodium diet, thereby stimulating their renin angiotensin system and rising the levels of angiotensin II, why we did not see an increase in proteinuria in that particular setting. In fact, as I showed you, even exogenous angiotensin II infusion did not show what ...in some rat studies has been demonstrated... that you could increase proteinuria by just exogenous angiotensin II. I think it may have to do with your explanation. The other option that I would like to bring forward is the intra-renal renin angiotensin system because I think what we do when we infuse angiotensin II, exogenous angiotensin II at least, is that it reaches the pre-glomerular vessel, the afferent arteriole has some effect there that we cannot control for and then passes to the efferent arteriole and has its effect on intra-glomerular pressure. Now with the intra-renal renin-angiotensin system that has been demonstrated to be present, that effect on the afferent arterial, the pre-glomerular vessel, may not necessarily be there and there may only be this effect on the post-glomerular vessel. I think that is one of the things that may partly but certainly not fully explain the discrepancy between the rise in the angiotensin system and not seeing effects on proteinuria.
Dr. Weber:
One last quick question.
Speaker:
In many clinical settings when we use an ACE inhibitor, we know that some patients do not bring down their protein excretion. Is there any way of predicting, either with ACE inhibitors or AII receptor antagonists, which patients might respond by reducing the proteinuria?
Dr. de Zeeuw:
I think that there will always be some patients who will not respond. But in our hands, there are at least two important predictors that are there. The first is whether or not you have been able to stimulate the renin angiotensin well enough. In some cases when you are in a state of nephrotic syndrome, and with all the events being there that are part of that, and with low albumin levels you certainly need to increase the albumin levels to get your full-blown effect. This probably has to do with kinetics more than it has to do with the effects. But I think first of all, sodium restriction to be an important predictor; secondly, serum albumin being an important predictor; and I think thirdly, and that may be an important issue for the future, there may be just a genetic mechanism involved here. For instance, ACE polymorphism has been implicated in this particular phenomenon where your genetic makeup may be such that the relation between the effect of an ACE inhibitor and your genetic makeup, for instance, may be related to the anti-proteinuric effect [6]. We are conducting these studies now, have no data yet. But that may be an important issue.
Dr. Weber:
Well, thank you, Dick.
References
1. Aperloo et al. Brit Med J 303:821-824, 1991.
2. Heeg et al. Kidney Int 40:734-741, 1991.
3. Gansevoort et al. Kidney Int 44:579-584, 1993.
4. Gansevoort et al. J Hypertens 12: S37-S42, 1994.
5. Gansevoort et al. Kidney Int 45:861-867, 1994.
6. Essen et al. Lancet 347: 94095, 1996.
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