CME Slides Forum - F.F. Hou

A joint Congress by ERA-EDTA and ISN

ANTI-PROTEINURIC DOSES OF RAS INHIBITORS: EFFICACY FOR RENOPROTECTION

Fan Fan Hou, Guangzhou, China

Chair: Richard Glassock, Los Angeles, USA

Thierry Hannedouche, Strasbourg, France

Hou

Prof F.F. Hou
Division of Nephrology
Nanfang Hospital
Southern Medical University
Guangzhou, P.R.China

Mr Chairmen, Ladies and Gentlemen thank you for inviting me and my topic today is anti-proteinuric doses of RAS inhibitors: efficacy for renoprotection.

Hypertension and hyperproteinuria are the major risk factors for progressing of CKD. High levels of proteinuria predict a renal deterioration in both diabetic and non-diabetic nephropathy. Lowering the blood pressure will reduce the proteinuria, however reduction in blood pressure and the proteinuria may occur discordantly and it has been shown that the residual albuminuria is a risk factor for developing ESRD. So proteinuria should be an independent therapeutic target for renoprotection.

Over the past 20 years ACE inhibitors and ARBs have become the cornerstone in the treatment of the CKD because numerous lines of evidence have shown that they have a blood pressure lowering independent anti-proteinuric effect. However, despite the benefit of ACE inhibitors or ARB therapy, CKD is delayed but not prevented and a substantial proportion of patients still experience renal morbidity.
It has been hypothesised that limited renoprotection offered by ACE inhibitors and ARBs is a result of the fact that they are unable to provide complete suppression of the RAAS.

Actually, there are two options for improving RAAS inhibition, one is the combination of ACE inhibitors and ARBs or the combined use of ACE inhibitors or ARB plus the -- inhibitor or aldosterone antagonist and an alternative option is to use higher doses of ACE inhibitors or ARBs. I will summarise the data from studies that have been taken with this approach.

So generally doses of ACE inhibitors and ARBs are based on the dose-response for blood pressure. As I have mentioned the response of BP and proteinuria are not necessarily concordant. Angiotensin 2 mediated hemodynamic effects as well as inflammation and the fibrosis in the kidney, the heart and in the vasculature and benefit beyond the hemodynamic effects of an ACE inhibitor or an ARB has been seen in the treatment of heart failure. Data from animal studies have indicated that anti-fibrotic benefits of RAS blockade in the kidney seems to require dosages much higher than antihypertensive dosages.

So in a recent study that evaluated lisinopril for renoprotection in this double blind randomised trial 49 patients with type 1 diabetes and nephropathy received three treatment periods with 20, 40 and 60 mg of lisinopril daily in a randomised order. Each period lasted for 2 months.

In the -- the reduction of urinary albumin excretion rate from baseline was 63%, 71% and 70% with increase in the dose of lisinopril. Then compared with lisinopril 20 mg/daily there was a further reduction in albuminuria with lisinopril 40 mg but 60 mg did not offer further renoprotection. More important the difference in urinary albumin excretion between 20 and 40 mg/daily of lisinopril was still significant after adjustment for changes in ambulatory blood pressure.

So another two small trials with limited number of patients that are treated with lisinopril from 10-40 mg came to a different conclusion. As in one, titration of lisinopril was associated with the further decrease of urinary albumin excretion but such effect was not seen in the others.

In a recent multicentre double blind randomised trial, the DROP study 391 hypertensive patients with type 2 diabetes and microalbuminuria were treated with valsartan at 3 doses.

So in the DROP study all the patients received valsartan 160 mg daily for the first 4 weeks, and doses of valsartan increased in 2 of 3 groups for 30 weeks.

So as we see in the results that comparable albuminuria dosing can be seen in 3 groups at week 4 and subsequently a high significant albumin fall occurred with valsartan 320 mg and 640 mg.

At week 30 twice as many patients returned to normal albuminuria with valsartan 640 mg in comparison with 160 mg.

In another study the evaluated actual high doses with irbesartan for renoprotection in this double marked randomised trial 52 hypertensive type 2 diabetes patients with microalbuminuria were treated randomly with irbesartan 300, 600 and 900 mg once daily with each dose for 2 months.

As shown in the results, reduction in urinary albumin excretion rate from baseline was 52%, 49% and 59% with increasing dose of irbesartan and albuminuria was reduced significantly more by irbesartan 900 mg compared with the lower doses. Increasing the dose up to 900 mg lead to a more complete RAAS blockade evidence by decreased urinary aldosterone level with additional reduction of urinary albumin excretion rate. This effect seems different, independent of changes in systolic blood pressure and GFR.

Very recently a multicentre Canadian study, the SMART trial evaluated whether the Supramaximal dosages of candesartan would reduce the proteinuria to a greater extent than the maximum proved antihypertensive dosage.

So in this randomised double blind study 269 patients who had persistent proteinuria despite 7 weeks of treatment with the highest approved dosage of candesartan that is 16 mg/daily treated with 16, 64 and 128 mg of candesartan for 30 weeks.

So shown in the results the percentage of protein urine reduction was 60% in patients receiving 64 mg of candesartan and 33% in patients receiving the 124 or 128 mg in comparison with those treated with 16 mg candesartan. So the three largest trials that evaluated high doses of ARB all suggest a blood pressure lowering independent anti-proteinuric dosage of this process.

We know that albuminuria is a surrogate marker of renal endpoints. So whether the increase of the dose of ACE inhibitors or ARB improve the renal outcome, the studies with -- are currently lacking.

In our recent study in the ROAD trial we demonstrated in the first study that uptitration of benazapril and losartan against the proteinuria -- for the benefit of renal outcome. So in this randomised blinded endpoint trial 360 non-diabetic patients with mean serum creatinine 2.8 mg/dl and overt proteinuria were randomly assigned to 4 groups receiving either the conventional dosage of benazapril or losartan or individual uptitration of these two drugs to optimal anti-proteinuric and tolerant dosages.

During the 8 week run-in period patients in group 1 and group 2 received 10 mg of benazapril and those in group 3 and in group 4 received 50 mg losartan. Those who continuously showed inadequate blood pressure control received an additional conventional anti-hypertensive drug. During the titration period patients in group 2 received the monthly uptitration of benazapril from a starting dose of 10 mg and then 20 and 30 and 40 mg and those in group 4 received an increase in dose of losartan from a 50-100 mg and 150 and 200 mg. The uptitration will be stopped if the anti-proteinuric effect of ACE inhibitor or ARB has reached its -- that’s the urinary protein excretion did not fall by greater than 10% or that systolic blood pressure lower than 120 mmHg despite the withdrawal of all additional and conventional antihypertensive drugs. This optimal anti-proteinuric dose was maintained for a mean of 3.7 years.

The primary endpoint of the ROAD study is time to the composite of the doubling of serum creatinine, ESRD or death.

The optimal anti-proteinuric dose of benazapril and losartan is compared with the conventional dose was associated with 51 and 53 reduction in the primary renal endpoint.

The optimal anti-proteinuric doses of benazapril and losartan at comparable blood pressure control obtained a greater reduction in proteinuria as compared with the conventional doses.

The dose titration study in the ROAD trial indicates that there might be an individual difference in the responsiveness to the anti-proteinuric effect of ACE inhibitors or ARBs. Optimal anti-proteinuric efficacy was obtained in about half of the patients with losartan 100 mg or benazapril 20 mg daily. However, about 25% of patients need even higher doses for proteinuria control and above 7-6% of patients did not respond to the uptitration increases in the dosages to the maximal licensed dose seems not to overcome the therapeutic resistance.

In summary other studies with increasing dose of ACE inhibitor we can see the optimal anti-proteinuric doses of ACE inhibitors do not seem greatly beyond the recommended doses.

However the optimal anti-proteinuric doses of ARBs particularly the candersatan, irbesartan and valsartan are greatly beyond the currently recommended doses. Optimal anti-proteinuric doses for telmisartan is 80 mg/bid and for losartan is 100mg/d high.

So one must consider whether administration of such high doses of ACE inhibitors or ARBs is safe?

So the high doses of ACE inhibitor or ARBs seem well tolerated. Headache and dizziness has been observed in patients with very high doses of ARB. About 7-5% of patients had elevated serum potassium but it doesn’t seem dose-related and really it was apparent even in patients with -- or chronic renal insufficiency.

So in conclusion most studies performed with higher doses of either ACE inhibitor or particularly ARB suggest that this approach is associated with a further decrease in proteinuria. Most patients may obtain their optimal response at standard doses, but some patients may do so at higher doses of RAS inhibitors. Patients who would benefit from higher doses are not prior identifiable, so titration for maximal anti-proteinuric effects would be a logical step during treatment. Higher doses of ACE inhibitor and ARB seem well tolerated.

So we recommended that increasing doses of ACE inhibitor or ARB should be considered in patients who have not reached optimal response for proteinuria reduction with their conventional doses.

Chairman: Thank you Doctor Hou for sharing this new concept of optimal dosing. I’m sure there will be some questions or comments. Yes?

Question: Thank you for your lecture I have two questions actually. First, what about combination of ACE and ARBs to avoid higher doses of each combination? Second question is, do you think there is a role of endothelin antagonists? Because there have been notions that both ACEs and ARBs actually by inhibiting the endothelin release and this is a measure of course of many states like this. What do you think about the role of endothelin antagonist in these proteinuric cases?

Dr. Hou: So the first question you asked was combination. The combination of ACE inhibitors and ARBs is the most frequently used combination but most studies that are not performed with this approach suffer from a confounding factor of further blood pressure lowering particularly when the dose used in the combination therapy group is the same as that used in the monotherapy group. However, a carefully performed meta-analysis combination of ACE inhibitors and ARBs does provide a more robust anti-proteinuric effect. The CORPORATE study employs the doubling of serum creatinine and the ESRD as a primary endpoint and the risk for reaching the primary endpoint is certainly low in combination therapy. Some controversies surround this study as with regards to the interpretation of the ambulatory blood pressure. A new study that has been initiated where combination of ACE inhibitors and ARBs in comparison with the monotherapy in treatment of patients with diabetic nephropathy and the data from this study may complicate or perhaps validate the observations made by the CORPORATE study. I understand because untargeted study, a trial performed in patients with high risk of cardiovascular events suggest that combination therapy worsens the renal outcome in comparison with the monotherapy. However, this is not a study of patients with underlying kidney disease and only 13% of patients in each group have a microalbuminuria and second the presence of large excluded patients with hypotension, hyperkalemia and the acute decrease in renal function questions the doses of the study drugs. So furthermore death is the most frequent event in untargeted which accounts for 85% of total events. It has been shown that an decrease of blood pressure too aggressively is associated with increased mortality. So it is possible to exclude the possibility that in other words renal outcome untargeted are missing combination therapy group might be induced by a high potential inducing high renal perfusion. This hypothesis is supported by the fact that substantial proportion of dialysis events on target is acute dialysis. So in general I think the combination of ACE inhibitors and ARBs may reduce the proteinuria further. But the more studies may be required to confirm the long term benefit of renal outcome. Although lack of long term evidence for renal outcome but this approach has been adopted for most nephrologists as standard care in the treatment of proteinuric coronary kidney disease.

Question: How was kidney function -- did they have normal renal function? Second in some patients did you have increase in creatinine even when controlling proteinuria? Third, did you have hypotension as a side effect when using high doses?

Dr. Hou: So actually we included the changes in eGFR as a secondary endpoint and the decrease of eGFR in patients with high doses of ACE inhibitors and ARBs is slow in comparison with those with low doses. Second question?