The Control of Chronic Renal Failure by ARBs and ACE Inhibitors
The Control of Chronic Renal Failure by ARBs and ACE Inhibitors
Introduction
It's long been known that use of a renin-angiotensin-aldosterone system (RAAS) antagonist slows the progression of kidney disease and specifically slows progression of advanced kidney disease, primarily in patients with proteinuria who have greater than 300 mg/day and have lost at least half of their kidney function. That's basically the composition of the trial demographic that has been looked at, and in those settings, achieving blood pressure control and using a RAAS blocker as part of that, either an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin receptor blocker (ARB), have been shown to slow nephropathy progression compared with controlling blood pressure with the absence of these agents. The data in nonproteinuric kidney disease, people with microalbuminuria, or people with no albuminuria who have renal insufficiency are actually very limited, and the data that do exist are not very compelling as far as renal outcomes looking at doubling of creatinine end-stage renal disease (ESRD). However, looking at the changes in progression to macroalbuminuria is also consistent with what has been seen in the more advanced nephropathy patients, a reduction in progression to macroalbuminuria, which is a clear indication of nephropathy -- that's information up to about 2002. What do we know since 2002? Has anything been more crystallized? What additional data do we have?
Recent Data on Use of ACE Inhibitors
We have 10-year follow-up data in the African-American study of kidney disease, in which the ACE inhibitor ramipril was used compared with the dihydropyridine calcium antagonist amlodipine as well as the once-daily beta-blocker metoprolol to really evaluate whether we're affecting doubling of creatinine, ESRD, or death. As most of the audience knows, in 2002 there was a publication in JAMA that showed that these inhibitors conferred the greatest benefit to these people with hypertensive kidney disease. They did not have diabetes. They did not have other immunologic diseases. The important part of this is that two thirds of them had microalbuminuria and only one third had macroalbuminuria greater than 300 mg/day. Moreover, there are only about 52 out of 1094 patients who actually had 1 g of proteinuria or more. It turns out that when you look at progression of disease going out to 10 years in the follow-up that we just completed, the ACE inhibitor group exhibited slow nephropathy progression, but it was unable to halt nephropathy progression. This is important, because blood pressure control in this follow-up period was exceedingly good, better than any other kidney trial to date, with an average mean systolic blood pressure of 126-127 mm Hg. Therefore, at least in black hypertensive nephrosclerosis, the ability to stop nephropathy progression -- even with an ACE inhibitor as part of the cocktail for lowering blood pressure -- was limited. Yes, we slowed progression, but we were unable to stop it. That's an important point, and that's a new piece of information that will be published very shortly in the Archives of Internal Medicine.
Aldosterone Blockade
An additional piece of information that we have is the use of aldosterone blockade. Aldosterone blockade, using either eplerenone or spironolactone in concert with ACE inhibitors or ARBs, has been found to further lower proteinuria by an average of 25% to 30% in people who have more than 30 mg of proteinuria. This is important because this reduction in proteinuria has been seen to correlate with additional slowing of nephropathy progression. This has been shown in the RENAAL Trial, in the IDNT Trial, and in the AASK (African American Study of Kidney disease). I think it's also important for the leadership to know that the COOPERATE trial has had some data discrepancies, and this has been written both in the American Journal of Nephrology and alluded to in the recent meta-analysis by Regina Kunz, MD, in the Annals of Internal Medicine. For that reason, it's not included in their analysis. Suffice it to say that use of aldosterone blockade when combined with other RAAS blockers lowers proteinuria and does so with only small additional reductions in blood pressure. I think that's an important point. Additionally, we have the direct renin inhibitors. The direct renin inhibitors, as many of the readers know, are represented by the prototype aliskiren, and this drug inhibits the enzyme and reduces the generation of angiotensin II and reduces aldosterone. There have certainly been a number of blood pressure studies, and that's what the drug is indicated for. There is a very large trial starting in diabetic nephropathy, the ALTITUDE trial, which is still recruiting but will be proof of concept if we can slow nephropathy progression with this class of drugs. Additionally, data were presented at the American Society of Nephrology last year using this agent with angiotensin receptor blockade to see whether proteinuria can still be blocked much like what was described earlier with the aldosterone antagonist. In fact, that was the case. Specifically looking at these data, the AVOID trial is the study that I'm referring to. This is a study that really looked -- in a double-blind, placebo-controlled manner -- at the use of this agent in the presence or absence of losartan 100 mg and showed proteinuria reductions that, at least at 6 months out, compared with placebo, resulted in an additional 20% further reduction in proteinuria. This was not related to dramatic differences in blood pressure, although blood pressure was somewhat better in the group that received aliskiren with losartan. This is a new piece of information consistent with what I think most of us would have expected with this class of agent as further reducing proteinuria. Apart from this, another trial was published by Hou FF, et al, from China looking at benazepril in nondiabetic kidney disease. The data were similar to what you would have expected with the APRI trial that was published back in The New England Journal of Medicine in 1996 with the same drug. That is a clear benefit in slowing nephropathy progression as it says by doubling of creatinine progression, ESRD, or death. The latest data are actually, when you take the data together with the previous data, further evidence that use of RAAS blockade slows progression of advanced nephropathic proteinuric nephropathy regardless of the ideology whether it's hypertensive disease, diabetic nephropathy, or related to some other nondiabetic ideology. The outcome studies that are now pending are actually looking at changes in proteinuria with sulodexide in the presence of RAAS blockade to see whether there's any further benefit offered there. Those data are pending and remain to be analyzed.
Closing Comments
I believe that the data that have existed since 2002, when all of these other trials were already published, are consistent with what we already knew: The RAAS blockade needs to be part of the antihypertensive cocktail of any patients with nephropathy, especially if they have proteinuria. Combinations of aldosterone antagonists or direct renin inhibitors with either ACE inhibitors or ARBs will further lower proteinuria. This additional reduction in proteinuria has been shown at least in post hoc analyses of 3 separate large outcome trials to be consistent with the better or greater slowing on nephropathy progression in these individuals. This was, in part, related to better blood pressure control, but not totally related to this. I think that's an important point. Lastly, many physicians are worried about the information on hyperkalemia that is out there, so it's important to know. This is actually an abstract that we are now writing up as a formal paper. In the study that we did looking at level of kidney function and predictors of who's going to develop hyperkalemia defined as greater than or equal to 6 in people already on an ACE inhibitor or an ARB, it turns out that we've done an analysis of the AASK study. We've done an analysis of the EPHESUS trial, which is a heart failure study. In the EPHESUS trial, aldosterone antagonist was given with either an ACE inhibitor or an ARB in heart failure patients. There was a benefit on mortality reduction up to a potassium level of 5.7. That was with glomerular filtration rates (GFRs) less than 60. In all studies that have been evaluated, if your estimated GFR is less than 30, you will more than likely have a problem with potassium. Regardless of your GFR, if your baseline potassium on good doses of RAAS blockade before you add the other RAAS blocking agents is greater than 4.8 mEq/L, then the probability of getting into trouble with hyperkalemia regardless of the GFR is pretty high, because you get on average about a 0.6-mEq rise in potassium when you add these agents. Depending on the diet, it can be as high as a 1-mEq increase. I think one has to keep in mind that this is an issue. However, patients should not be denied these agents, so I would encourage good use of diuretics. I would encourage good use of appropriately dosed ACE inhibitors or ARBs. With this caveat, which we found in our study and which we've presented to the American Society of Nephrology -- and will be publishing soon -- baseline potassium greater than 4.8 will predict development of hyperkalemia if a second RAAS blocking agent is added. An estimated GFR of less than 30, especially if the potassium level is anywhere above 4.5, will also predict development of hyperkalemia, defined as greater than 5.5.
It's long been known that use of a renin-angiotensin-aldosterone system (RAAS) antagonist slows the progression of kidney disease and specifically slows progression of advanced kidney disease, primarily in patients with proteinuria who have greater than 300 mg/day and have lost at least half of their kidney function. That's basically the composition of the trial demographic that has been looked at, and in those settings, achieving blood pressure control and using a RAAS blocker as part of that, either an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin receptor blocker (ARB), have been shown to slow nephropathy progression compared with controlling blood pressure with the absence of these agents. The data in nonproteinuric kidney disease, people with microalbuminuria, or people with no albuminuria who have renal insufficiency are actually very limited, and the data that do exist are not very compelling as far as renal outcomes looking at doubling of creatinine end-stage renal disease (ESRD). However, looking at the changes in progression to macroalbuminuria is also consistent with what has been seen in the more advanced nephropathy patients, a reduction in progression to macroalbuminuria, which is a clear indication of nephropathy -- that's information up to about 2002. What do we know since 2002? Has anything been more crystallized? What additional data do we have?
Recent Data on Use of ACE Inhibitors
We have 10-year follow-up data in the African-American study of kidney disease, in which the ACE inhibitor ramipril was used compared with the dihydropyridine calcium antagonist amlodipine as well as the once-daily beta-blocker metoprolol to really evaluate whether we're affecting doubling of creatinine, ESRD, or death. As most of the audience knows, in 2002 there was a publication in JAMA that showed that these inhibitors conferred the greatest benefit to these people with hypertensive kidney disease. They did not have diabetes. They did not have other immunologic diseases. The important part of this is that two thirds of them had microalbuminuria and only one third had macroalbuminuria greater than 300 mg/day. Moreover, there are only about 52 out of 1094 patients who actually had 1 g of proteinuria or more. It turns out that when you look at progression of disease going out to 10 years in the follow-up that we just completed, the ACE inhibitor group exhibited slow nephropathy progression, but it was unable to halt nephropathy progression. This is important, because blood pressure control in this follow-up period was exceedingly good, better than any other kidney trial to date, with an average mean systolic blood pressure of 126-127 mm Hg. Therefore, at least in black hypertensive nephrosclerosis, the ability to stop nephropathy progression -- even with an ACE inhibitor as part of the cocktail for lowering blood pressure -- was limited. Yes, we slowed progression, but we were unable to stop it. That's an important point, and that's a new piece of information that will be published very shortly in the Archives of Internal Medicine.
Aldosterone Blockade
An additional piece of information that we have is the use of aldosterone blockade. Aldosterone blockade, using either eplerenone or spironolactone in concert with ACE inhibitors or ARBs, has been found to further lower proteinuria by an average of 25% to 30% in people who have more than 30 mg of proteinuria. This is important because this reduction in proteinuria has been seen to correlate with additional slowing of nephropathy progression. This has been shown in the RENAAL Trial, in the IDNT Trial, and in the AASK (African American Study of Kidney disease). I think it's also important for the leadership to know that the COOPERATE trial has had some data discrepancies, and this has been written both in the American Journal of Nephrology and alluded to in the recent meta-analysis by Regina Kunz, MD, in the Annals of Internal Medicine. For that reason, it's not included in their analysis. Suffice it to say that use of aldosterone blockade when combined with other RAAS blockers lowers proteinuria and does so with only small additional reductions in blood pressure. I think that's an important point. Additionally, we have the direct renin inhibitors. The direct renin inhibitors, as many of the readers know, are represented by the prototype aliskiren, and this drug inhibits the enzyme and reduces the generation of angiotensin II and reduces aldosterone. There have certainly been a number of blood pressure studies, and that's what the drug is indicated for. There is a very large trial starting in diabetic nephropathy, the ALTITUDE trial, which is still recruiting but will be proof of concept if we can slow nephropathy progression with this class of drugs. Additionally, data were presented at the American Society of Nephrology last year using this agent with angiotensin receptor blockade to see whether proteinuria can still be blocked much like what was described earlier with the aldosterone antagonist. In fact, that was the case. Specifically looking at these data, the AVOID trial is the study that I'm referring to. This is a study that really looked -- in a double-blind, placebo-controlled manner -- at the use of this agent in the presence or absence of losartan 100 mg and showed proteinuria reductions that, at least at 6 months out, compared with placebo, resulted in an additional 20% further reduction in proteinuria. This was not related to dramatic differences in blood pressure, although blood pressure was somewhat better in the group that received aliskiren with losartan. This is a new piece of information consistent with what I think most of us would have expected with this class of agent as further reducing proteinuria. Apart from this, another trial was published by Hou FF, et al, from China looking at benazepril in nondiabetic kidney disease. The data were similar to what you would have expected with the APRI trial that was published back in The New England Journal of Medicine in 1996 with the same drug. That is a clear benefit in slowing nephropathy progression as it says by doubling of creatinine progression, ESRD, or death. The latest data are actually, when you take the data together with the previous data, further evidence that use of RAAS blockade slows progression of advanced nephropathic proteinuric nephropathy regardless of the ideology whether it's hypertensive disease, diabetic nephropathy, or related to some other nondiabetic ideology. The outcome studies that are now pending are actually looking at changes in proteinuria with sulodexide in the presence of RAAS blockade to see whether there's any further benefit offered there. Those data are pending and remain to be analyzed.
Closing Comments
I believe that the data that have existed since 2002, when all of these other trials were already published, are consistent with what we already knew: The RAAS blockade needs to be part of the antihypertensive cocktail of any patients with nephropathy, especially if they have proteinuria. Combinations of aldosterone antagonists or direct renin inhibitors with either ACE inhibitors or ARBs will further lower proteinuria. This additional reduction in proteinuria has been shown at least in post hoc analyses of 3 separate large outcome trials to be consistent with the better or greater slowing on nephropathy progression in these individuals. This was, in part, related to better blood pressure control, but not totally related to this. I think that's an important point. Lastly, many physicians are worried about the information on hyperkalemia that is out there, so it's important to know. This is actually an abstract that we are now writing up as a formal paper. In the study that we did looking at level of kidney function and predictors of who's going to develop hyperkalemia defined as greater than or equal to 6 in people already on an ACE inhibitor or an ARB, it turns out that we've done an analysis of the AASK study. We've done an analysis of the EPHESUS trial, which is a heart failure study. In the EPHESUS trial, aldosterone antagonist was given with either an ACE inhibitor or an ARB in heart failure patients. There was a benefit on mortality reduction up to a potassium level of 5.7. That was with glomerular filtration rates (GFRs) less than 60. In all studies that have been evaluated, if your estimated GFR is less than 30, you will more than likely have a problem with potassium. Regardless of your GFR, if your baseline potassium on good doses of RAAS blockade before you add the other RAAS blocking agents is greater than 4.8 mEq/L, then the probability of getting into trouble with hyperkalemia regardless of the GFR is pretty high, because you get on average about a 0.6-mEq rise in potassium when you add these agents. Depending on the diet, it can be as high as a 1-mEq increase. I think one has to keep in mind that this is an issue. However, patients should not be denied these agents, so I would encourage good use of diuretics. I would encourage good use of appropriately dosed ACE inhibitors or ARBs. With this caveat, which we found in our study and which we've presented to the American Society of Nephrology -- and will be publishing soon -- baseline potassium greater than 4.8 will predict development of hyperkalemia if a second RAAS blocking agent is added. An estimated GFR of less than 30, especially if the potassium level is anywhere above 4.5, will also predict development of hyperkalemia, defined as greater than 5.5.
