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American Society of Nephrology
American Society of Nephrology Annual Scientific Meeting
November, 1999


Are Angiotensin-II Receptor Antagonists
Better than ACE Inhibitors?


Dr. Anderson

Sharon Anderson, M.D.
Professor of Medicine, University of Oregon Health Sciences Center, Portland, OR.

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Moderator:
The next speaker is Dr. Sharon Anderson. She trained with Dr. Barry Brenner at the Brigham and undertook some of the classic studies we are all so aware of about the pathophysiology of progressive renal disease and the role of angiotensin. So she is very qualified to tackle this topical subject: "Are angiotensin type-1 blockers better antihypertensives than angiotensin converting enzyme inhibitors?" Sharon is presently at the Portland, Oregon, Division of Nephrology.

Dr. Anderson
Thank you. With the permission of the ASN, I have taken the liberty of changing the title of my talk and the focus somewhat. As a nephrologist, I am much more interested in the question of whether AII receptor antagonists (AIIRA) are better renal protective agents than ACE inhibitors (ACEI) as compared to the question of whether they are better antihypertensive agents. And so, having said that, I will move right on.

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Relevant areas of comparison
In terms of theoretical differences, most of us know that ACE inhibitors are currently the gold standard when it comes to protecting against the progression of renal disease. When the angiotensin-II receptors were characterized and compounds to block these receptors began to come available, there began a very lively discussion and debate as to potential theoretical differences between these compounds, the question being: Would the new AII receptor antagonist be as good as ACE inhibitors? Perhaps better? Perhaps not as good?

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Theoretical differences
And that debate took the form of several questions, which are summarized here. There were some people who argued that angiotensin- II receptor antagonists might prove to be superior to ACE inhibitors.

AII formation via non-ACE pathways
The reason for that would be that we know that ACE inhibitors do not completely block the formation of angiotensin-II; and furthermore, there are a number of alternative pathways, non-ACE pathways, by which the body can make angiotensin-II. And so by going through these alternative pathways, which would not presumably be touched by the presence of an ACE inhibitor, it might be more effective to use an AII receptor antagonist, which would come along and mop up all the AII however it was formed.

Bradykinin
There were others who said ACE inhibitors might be superior to AII receptor antagonists. We know, for example, that ACE inhibitors actually increase bradykinin levels, whereas AII receptor antagonists do not. And whether or not that is important depends upon whether or not you believe that bradykinin is important.

Plasminogen activator inhibitor - 1 factor
We know that ACE inhibitors reduce the level of PAI-1, plasminogen activator inhibitor 1 factor, which is a known mediator now of progressive renal disease. There was some evidence early on that AII receptor antagonists might not have that beneficial effect. That may be due to species differences, and I will talk a little more about it later.

Serum AII levels
Finally, we know that angiotensin-II receptor antagonists actually increase angiotensin-II levels. And so perhaps these higher levels of angiotensin-II floating around might have adverse effects through effects on other AII receptors or other pathways we don't know so much about. So that laid the question.

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Comparative efficacy in treating hypertension
I am going to go through now and talk briefly about the efficacy in hypertension and then most of the rest of the talk will be on the topic of renal protection.

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Source: Willenheimer R et al, Eur Heart J. 1999 Jul;20(14):997-1008.

Published studies in the literature: informal analysis
There are a couple of pieces of information out there that do address the question of whether these drugs are equally effective as antihypertensive drugs. A little earlier this year, Dr. Willenheimer published a review article in The European Heart Journal. It wasn't really a meta-analysis, but he did in fact describe a number of published studies involving hundreds of patients, in which the antihypertensive efficacy of various AII receptor antagonists had been compared to that of the ACE inhibitor enalapril. Basically his conclusion was that a large number of these studies found equal antihypertensive effect. But that wasn't really a formal meta- analysis.

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Source: Gansevoort RT et al, J Clin Invest. 1992 Sep;90(3):766-71.

Comparative efficacy in hypertension: meta-analysis
More recently and published in the abstract book for this meeting we are at today, is a more formal meta-analysis from Gansevoort and colleagues in the Netherlands. They did a meta-analysis of AII receptor antagonists, which was designed to first relate dose- response curves to starting doses; secondly, to look for within class differences; and thirdly, to compare them with a couple of other classes of drugs. They examined all randomized clinical trials that had lasted 4 to 12 weeks and consisted of monotherapy.

They found some 13,000 patients who fit those criteria of patients with diastolic blood pressures in the range of 95 to 115. The looked at the maximal effect, E-max, and the dosage at which 50 percent of the E-max was obtained. The overall result, some of which I will show you in the next slide, is that there was no statistical difference in the maximal effect among the different AII receptor antagonists but that these drugs did appear to have slightly less blood pressure lowering efficacy than either diuretics or ACE inhibitors as monotherapy.

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Maximum efficacy may be slightly higher with ACE inhibitors
That is shown here. This slide shows you E-max, which is the reduction in blood pressure with these drugs. As you can see, among several commercially available AII receptor antagonists, there was really no difference in the maximal effect, but monotherapy with diuretics or ACE inhibitors was a little bit more significantly effective.

So I think that is pretty much the state of that information. I think as clinical nephrologists, we rarely can get away with monotherapy for anything, and I think many of us believe that when we use either ACE inhibitors or AII receptor antagonists, we should be adding in a diuretic. There certainly is data that adding a diuretic will increase the antihypertensive efficacy of the AII receptor antagonists.

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Comparative renoprotective effects
I am going to turn now to the topic of renal protection and tell you a little bit about what we have learned about mechanisms, protection and evidence from experimental models. I will tell you right now that there is a large amount of data on this. In the interest of time, I am only going to be able to show you selected studies. I will apologize to the many investigators whose work I won't be able to mention.

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Mechanisms of AII-induced renal injury
In terms of the mechanisms of injury, we now know that there are many mechanisms by which angiotensin-II can initiate or perpetuate renal injury. Angiotensin-II increases blood pressure, efferent arteriolar resistance and glomerular capillary pressure, and in the process we have an increased mesangial influx of macromolecules, which is felt to stimulate cytokines, macrophages, and other disease mediators.

Angiotensin-II and glomerular hypertension are both also associated with an increase in proteinuria. We now believe that increased urinary protein excretion is not only a sign of renal disease but a pathogenetic mechanism in that heavy amounts of proteinuria passing through the proximal tubule on a chronic basis can actually promote tubulointerstitial injury.

Angiotensin-II has many other effects, including stimulation of a number of growth factors, stimulation of apoptosis, oxidant stress, and stimulation of the release or formation of endothelin, TGF-beta, PDGF, PAI-1, a huge long list of mediators of the sclerosing process. So we believe that ACE inhibitors, which have been shown in at least animal models to block all of these--ACE inhibitors probably work by reversing some or many of these mechanisms in the kidney. The question is whether AII receptor antagonists will be equally effective.

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Source: Lafayette RT et al, J Clin Invest. 1992 Sep;90(3):766-71.

Comparative effects: glomerular capillary pressure
There have been a number of studies looking at the effects and comparing the effects of AII receptor antagonists to ACE inhibitors and their effects on glomerular hemodynamics and perm selectivity. What we know, as I just mentioned, is that ACE inhibitors reduce efferent arteriolar pressure and glomerular capillary pressure. In a number of models, we now know that that is also true for the AII receptor antagonist.

This is data from one of the earlier studies by Richard Lafayette and Tim Meyer et al. looking in the chronic renal failure remnant kidney model looking at glomerular capillary pressure. On the left are rats with chronic renal failure receiving no therapy, and they have severe glomerular capillary hypertension.

The AII receptor antagonist, losartan, was basically equivalent to enalapril in reducing glomerular pressure to the normal range. A more standard, older regimen, combination regimen of triple therapy (TRX in the figure), was ineffective. And this ability of the AII receptor antagonist to normalize glomerular capillary pressure has been shown in a number of other models--diabetes and many others. Not shown here, but it has also been shown by these investigators and others, that AII receptor antagonists share with ACE inhibitors the ability to improve glomerular permselectivity as assessed by studies of dextrans and so forth.

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Source: Lafayette RT et al, J Clin Invest. 1992 Sep;90(3):766-71.

Comparative protection against proteinuria
Another endpoint or another important point we would like to look for is protection in glomerular diseases, protection against the development of proteinuria, glomerular sclerosis, and structural injury.

Shown on the right again is data from the paper by Lafayette and Meyer looking at proteinuria in those four groups of animals. The untreated animals have substantial proteinuria, the AII receptor antagonist was just as effective as the ACE inhibitor in limiting the development of proteinuria, whereas the triple therapy (TRX) was ineffective. This capacity of the two classes of drugs to reduce proteinuria and glomerular sclerosis also has been shown in a number of different experimental models.

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Source: Zoja C et al, Am J Kidney Dis. 1997 Feb;29(2):254-64.

Protection against proteinuria in passive Heymann nephritis
Another model that it has been shown in is this one, which is a glomerular disease model, passive Heymann nephritis (PHN in the figure). The data are from Zoya and coworkers, where they studied four groups of animals: In the light grey bars, which you can barely see, are control animals. The tall red bars are animals with passive Heymann nephritis. On the right are two groups that were treated with either the ACE inhibitor lisinopril (Lis) or the AII receptor antagonist L158,809.

This slide shows you proteinuria which is very high in this model, but as you can see, very equivalently reduced with both classes of drugs. This has been shown in a number of other models of glomerular disease. Perhaps not surprising, and very reassuring I think, in glomerular models the two classes of drugs appear to be equivalent.

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Source: Shihab FS et al, Kidney Int. 1997 Sep;52(3):660-73.

Comparative protection against tubulo-interstitial injury
Cyclosporin nephrotoxicity
I think somewhat more surprising and interesting is that there have been some studies now showing that these drugs may be effective in tubulointerstitial forms of renal disease, a category of diseases that we have always though of as a little bit more resistant to the effect of AII blockade.

This is data from Fouad Shibab and our esteemed Dr. Bennett and colleagues, in a model of cyclosporin nephrotoxicity in the rat. They had a number of different groups. All of these groups got cyclosporin except the group on the far left which got vehicle. In red are cyclosporin. Over here are groups receiving antihypertensive therapy. What they were looking at here was the degree of morphologic tubulointerstitial fibrosis.

Fibrosis was substantial in the cyclosporin group, which is in red. The next two bars are animals that received either enalapril or losartan. As you can see, there was a statistically significant and equivalent reduction in tubulointerstitial injury with both of these classes of drugs that block the renin angiotensin system. They also looked at a calcium channel blocker, nilvadapine (Nilv), a combination of hydralazine and hydrochlorothiazide (H/H), and those were ineffective.

So we are now talking in terms of limiting not only glomerular disease, but there are now studies suggesting that in tubulointerstitial disease these drugs may have an equivalent beneficial effect.

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Areas where renal protection is comparable with AIIRA vs. ACEI:
In fact, this slide just summarizes some of the models in which an equivalent beneficial effect has been seen: All of the standard glomerular models, renal ablation and diabetes, but also some more tubulointerstitial models such as cyclosporin nephrotoxicity and chronic rejection, as well. In fact, in almost but not quite every model that has been looked at, the drugs appear to be equivalent in terms of experimental renal disease.

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Protection against sclerosing mediators
What about effects on pro-sclerosing mediators? I showed you a long list of things that angiotensin-II stimulates and there has been a lot of investigating looking to see whether these two classes of drugs are equally able to block the mediators. I will just show you some representative examples.

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TGF-beta-1
This is again data from the Shihab study on cyclosporin nephrotoxicity looking at renal TGF-beta-1 mRNA. TGF-beta, of course, is considered to be one of the leading mediators of progressive renal injury. The TGF-beta levels are very high in the cyclosporin rats and equivalently reduced with the two drugs that block the renin angiotensin system. They also saw a small reduction with nilvadapine (Nilv) in this study.

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Source: Shihab FS et al, Kidney Int. 1997 Sep;52(3):660-73.

Protection against plasminogen activator inhibitor
They also looked at another mediator, which is PAI-1, which was significantly increased in the cyclosporin rats and modestly but significantly reduced with the two drugs. There are a number of studies in experimental models that do suggest that these drugs reduce PAI-1, and that is a of hot topic of investigation right now. There may be some species differences. And it may be that the effects on PAI-1 in humans, or at least in human serums where it has been measured, are a little different than in experimental animals. But, in general, most of the studies do find some reduction in PAI-1, both with the ACE inhibitor and with the AII receptor antagonists.

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Source: Ishidoya S et al, Kidney Int. 1995 May;47(5):1285-94.

Comparative protection in an obstructive nephropathy model
There is one interesting exception to the rule. That is obstructive tubulointerstitial disease. There have been a series of very elegant studies by Ishidoya, Morrissey, Saulo Klahr, and coworkers in the model of unilateral ureteral obstruction, which is just what it sounds like it would be. They have looked at many indices of injury in this model.

In this slide here, they have looked at the number of ED-1 positive cells, which is an index of the number of macrophages flooding the interstitium. In the white, on the left, is the control, which is actually the contralateral, unobstructed kidney; in red are the findings in the obstructed kidney. On the left the rats that received no treatment. There was a marked increase in the number of ED-1 positive cells. In the middle, enalapril significantly reduced that macrophage influx, whereas an AII receptor (SC 51316 in the figure) antagonist was without effect.

So this appears to be an exception and may be one model in which the AT1 receptor antagonists are not quite as effective. There is a lot of important work going on to look at the mechanisms. It doesn't appear as though there is a difference in MCP1.

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Source: Thomas SE et al, Kidney Int. 1998 Apr;53(4):897-908.

Protection against apoptosis
Another mechanism has to do with the inhibition of apoptosis, which we now know is somewhat stimulated or regulated by angiotensin-II. This is data from Susan Thomas, Takashi Andoh, Bill Bennett and their group again in an experimental cyclosporin nephrotoxicity model where they had groups of rats, cyclosporin rats, that either received no treatment, losartan or a combination of hydralazine and furosemide (H/F in the figure).

Here they were looking at apoptosis in the interstitium by the number of TUNEL-positive cells, which was significant in the cyclosporin rats, markedly reduced with losartan, but not with the other combination of drugs. So there are not a whole lot of studies yet in this field, but it does appear as though the AII receptor antagonist can indeed inhibit apoptosis, as well.

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Similar mechanisms of protection
So there are many, many mechanisms of protection by which at least it appears that in general the AII receptor antagonists are pretty much equivalent to ACE inhibitors in our animal models. They both control systemic and glomerular hypertension; they both suppress TGF-beta, improve glomerular permselective, reduce proteinuria; I didn't show you, but they both seem to improve endothelial cell function, suppress PAI-1 and limit apoptosis and undoubtedly others. So many, many areas of similarity between these drugs.

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Clinical studies
What about clinical studies? This is the way it always works. We always have a wealth of animal data before we have any clinical data. The clinical data is starting to emerge with these drugs. I have to say up front, there are no long-term outcome studies yet of AII receptor antagonists in clinical renal disease. There are a number of trials in progress as we speak, but none have been completed or reported. We are in some ways far behind our cardiology colleagues who have been all of this question for quite a while.

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Source: Gansevoort RT et al, Kidney Int. 1994 Mar;45(3):861-7.

Dose-effect of AIIRA on blood pressure vs. proteinuria
I am going to show you a little bit of the clinical data that is available, with the caveat again that it is all short-term and not yet definitive outcome data. This is a now classic study, I think. It was the first one that was published and widely cited that looked at the hemodynamic and antiproteinuric effects of losartan in patients with substantial nondiabetic proteinuria.

This slide shows you the percent change from baseline in blood pressure, which is in yellow, and proteinuria, which is in red, at different doses. At a dose of 50 mg of losartan, there was a significant reduction in blood pressure and a significant reduction in proteinuria, as well. In this study when the increased the losartan to 100 mg a day, there was no further blood pressure effect, but there was an additional antiproteinuric effect.

In the same study (data not shown), they compared the effects to those of an ACE inhibitor and found that losartan had an equal antiproteinuric efficacy in these patients as compared with an ACE inhibitor.

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Source: Parving HH et al.

Crossover study: AIIRA vs. ACEI in diabetic nephropathy
There is very little additional data available yet. I would like to show you some data from a couple of abstracts which have been published in the abstract book for this meeting and are going to be presented at this meeting in a very important clinical disease, which is diabetic nephropathy. The first one, from Dr. Parving's group, was a study in Type I diabetes, a randomized, crossover trial of 16 patients, Type I patients with overt nephropathy. They were studied in a crossover design, several periods--each of two months, losartan or enalapril at various doses.

The major results are shown over here, which show the percent decrease in baseline. All the drugs reduced blood pressure, of course. This column shows you the reduction in urinary albumin excretion. What they concluded is that the highest doses of losartan, 100, enalapril, 20--that the reduction in albuminuria was equivalent with the two drugs. So a very short-term study in Type I diabetes indicating efficacy.

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Source: Castelao AM et al

AIIRA vs. ACEI on proteinuria in type 2 diabetes
A somewhat similar study is also in the abstract book of this meeting by another group of investigators looking at Type II diabetes, again a small study of 24 patients with hypertension and overt nephropathy followed for 18 months. They were treated with either losartan or enalapril.

They found equivalent effects on the serum creatinine. On the right is shown urinary protein excretion with the white bars being the pre- values and the red being post-values. As you can see, enalapril lowered the proteinuria, and losartan was equivalent in its ability to reduce proteinuria.

So at least using this short-term surrogate marker, if you will, of a reduction of proteinuria, the early indications are that these drugs are looking pretty good. Again, we desperately need long-term studies with harder outcomes to be able to answer that question.

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AIIRA and ACEI: Combination therapy
I think one of the most exciting concepts that comes about with these drugs is the idea of use in combination regimens. Again, the cardiologists are way ahead of us. Many of you may know that they are already doing major trials, either an ACE inhibitor versus an AII receptor antagonist or a combination of the two versus either one alone. In nephrology we haven't really come around to that as much as we perhaps should. But I think we need to think about it. People, of course, have tried to do this in animal models; but the problem in animal models is that either one of those drugs alone works so well it is hard to show an additive benefit.

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Source: Ots M et al, J Am Soc Nephrol 1998;9:224-230.

Renal ablation model
This, for example, is a study that was published by Ots a couple of years ago in the renal ablation model. They had four groups of animals. The group in red received no therapy; in yellow is a group that got enalapril; green, a group that got losartan; and white is a group that got the combination. This slide shows you proteinuria, which, as you would expect, was progressively increasing in the untreated animals, was equivalently reduced in all of the other groups, but there was no statistical difference among these groups. So in animal studies, it is really hard to show (increased efficacy with) the combination.

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Source: Russo D et al, Am J Kidney Dis. 1999 May;33(5):851-6.

Combination therapy for IgA nephropathy
There are no major studies in patients, but I want to show you a small study that was recently published. It is a very small study. It is kind of anecdotal, but I think it is intriguing and gives us some thoughts for the future. This is a study that was published in the "American Journal of Kidney Disease" earlier this year, a study of IgA nephropathy--very small study, eight patients, who had normal blood pressure, stable proteinuria of 1 to 3 grams/day, and normal or mildly impaired renal function.

The patients were all on an ACE inhibitor to start with. They then added losartan and took away the ACE inhibitor; did a sequential design; kept the blood pressure constant on all the regimens. And what they found, I thought was very interesting, again, in a very small trial.

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Source: Russo D et al, Am J Kidney Dis. 1999 May;33(5):851-6.

Combination therapy in IgA nephropathy: results
This slide shows you proteinuria at baseline. The patients had about 2 grams. Proteinuria came down, as you would expect, with an ACE inhibitor; it came down even further with a combination of an ACE inhibitor and losartan. When they withdrew the ACE inhibitor, losartan alone was as effective as the ACE inhibitor, and again the combination was better.

I hate to have to show such a small study, but to my knowledge, it is the only one out there. I think it really suggests the intriguing possibility that there may be a real benefit to adding these two drugs together when it comes to treating our patients with chronic renal failure.

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Closing remarks
In summary, as compared with ACE inhibitors, the angiotensin-II AT-1 receptor antagonists show nearly equivalent antihypertensive efficacy, perhaps not equivalent; show similar renal protection in most experimental models; show similar short-term antiproteinuric efficacy in clinical studies. I think the role of combination therapy merits further testing in slowing the progression of chronic renal failure, as well as the treatment of congestive heart failure.

I am going to stop there and thank you for your attention.

Discussion

Moderator:
Thank you very much, Sharon. We've got time for perhaps one or two questions now. Just while people are coming up, what do you think, Sharon, might be the mechanism of this additive effect of the two drugs on reducing proteinuria if indeed it is really true and it is not just a flawed study because the doses weren't high enough?

Dr. Anderson:
I don't think it is anything fancy. I think that neither one of the drugs completely blocks the renin angiotensin system and that by adding the two together, you are sort of getting an additive effect to block both the amount and the ability of the AII around to act. I don't have a fancier explanation than that. In my mind, that is the most likely.

Audience member:
The group in the Netherlands showed a failure of renal protection in proteinuric renal disease with ACE inhibitors in the patients with DD polymorphism. Are there any studies about AT blockers? Does is matter if they are an alternative in the ACE polymorphism, especially the DD kind?

Dr. Anderson:
That is a really interesting question. The question is whether AII receptor antagonists might be a viable alternative for patients who have the DD genotype and are less responsive to ACE inhibitors. I am not aware of any studies that have looked at that. Just guessing, I would guess there wouldn't be any difference, but I think it is a real important question, but I don't know of any data. It would be worth studying, for sure.

References

1. Willenheimer R, Dahlof B, Rydberg E, Erhardt L. AT1-receptor blockers in hypertension and heart failure: clinical experience and future directions. Eur Heart J. 1999 Jul;20(14):997-1008.

2. Gansevoort RT, Sluiter WJ, de Graeff PA, de Jong PE, de Zeeuw D. Meta-analysis of the antihypertensive effects of angiotensin-II receptor antagonists. J Am Soc Nephrol 1999;10:365A (abstract).

3. Lafayette RA, Mayer G, Park SK, Meyer TW. Angiotensin II receptor blockade limits glomerular injury in rats with reduced renal mass. J Clin Invest. 1992 Sep;90(3):766-71.

4. Zoja C, Donadelli R, Corna D, Testa D, Facchinetti D, Maffi R, Luzzana E, Colosio V, Bertani T, Remuzzi G. The renoprotective properties of angiotensin-converting enzyme inhibitors in a chronic model of membranous nephropathy are solely due to the inhibition of angiotensin II: evidence based on comparative studies with a receptor antagonist. Am J Kidney Dis. 1997 Feb;29(2):254-64.

5. Shihab FS, Bennett WM, Tanner AM, Andoh TF. Angiotensin II blockade decreases TGF-beta1 and matrix proteins in cyclosporine nephropathy. Kidney Int. 1997 Sep;52(3):660-73.

6. Ishidoya S, Morrissey J, McCracken R, Reyes A, Klahr S. Angiotensin II receptor antagonist ameliorates renal tubulointerstitial fibrosis caused by unilateral ureteral obstruction. Kidney Int. 1995 May;47(5):1285-94.

7. Thomas SE, Andoh TF, Pichler RH, Shankland SJ, Couser WG, Bennett WM, Johnson RJ. Accelerated apoptosis characterizes cyclosporine-associated interstitial fibrosis. Kidney Int. 1998 Apr;53(4):897-908.

8. Gansevoort RT, de Zeeuw D, de Jong PE. Is the antiproteinuric effect of ACE inhibition mediated by interference in the renin-angiotensin system? Kidney Int. 1994 Mar;45(3):861-7.

9. Parving HH, Andersen S, Rossing P, Hansen BV, Tarnow L. Renoprotective effects of angiotensin II receptor blockade in type I diabetic patients with diabetic nephropathy. J Am Soc Nephrol 1999;10:132A (abstract).

10. Castelao AM, Ramos R, Sanzhez-Zamorano MA, Alsina J. Comparison of losartan vs. enalapril in type 2 diabetes mellitus patients with diabetic nephropathy. J Am Soc Nephrol 1999;10:127A (abstract).

11. M Ots, HS Mackenzie, JL Troy, HG Rennke, and BM Brenner. Effects of combination therapy with enalapril and losartan on the rate of progression of renal injury in rats with 5/6 renal mass ablation. J Am Soc Nephrol 1998;9:224-230.

12. Russo D, Pisani A, Balletta MM, De Nicola L, Savino FA, Andreucci M, Minutolo R. Additive antiproteinuric effect of converting enzyme inhibitor and losartan in normotensive patients with IgA nephropathy. Am J Kidney Dis. 1999 May;33(5):851-6.




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