• 04 Aug 2020
  • 15 min
  • 04 Aug 2020
  • 15 min

What do current guidelines recommend? Ashlea Broomfield interviews Akshay Athavale about current treatment guidelines for proteinuria, in particular albuminuria. Combined renin­–angiotensin­–aldosterone inhibition is not recommended. Read the full article in Australian Prescriber.


Welcome to the Australian Prescriber Podcast. Australian Prescriber, independent, peer-reviewed and free.

Welcome to the Australian Prescriber Podcast. My name is Ashlea Broomfield, and I'm here with Dr Akshay Athavale, who's a clinical pharmacology registrar with a special interest in renal medicine. In this episode we are talking about his recent article and this is on proteinuria. Welcome Akshay.

Hi Ashlea. Thanks for having me on.

So basically today we're talking about the presence of proteins in the urine. So for our listeners out there, let's start with some semantics. Does albuminuria equal proteinuria?

That's a good question, no, not exactly. Proteinuria would be sort of officially or technically defined as all proteins found in the urine, which would include albumin, but would also include other proteins. And albuminuria would specifically refer just to the measurement of albumin in the urine, excluding all other proteins that may be found. The terms are often used interchangeably, and for the most part it doesn't really matter all that much. I guess proteinuria is more of a general term and it may include other conditions such as multiple myeloma and things which may also have non-albumin proteins in the urine. And a lot of the interchangeability relates to historical studies that were done. And so the early studies that we're looking at, ACE inhibitors or angiotensin receptor blockers for reducing proteinuria, only measured total proteinuria, whereas the more recent studies have started to measure only albuminuria.

But for today, we’re looking at the conditions that are more likely to cause albuminuria and how we might treat that. So keeping that in mind, how can we case find patients that have albuminuria?

Generally we would advocate screening for patients to assess for the presence of albuminuria. And the reason for that is that it's a fairly strong predictor of cardiovascular risk as well as risk factor for cerebrovascular events, and also for progression to later stage chronic kidney disease or end stage kidney disease. And generally we would say that screening for albuminuria should be done in any patients with one or more risk factors for chronic kidney disease, whether that be, I guess, most commonly diabetes, but also hypertension, smoking, previous history of cardiovascular disease, family history of kidney disease, obesity, or people from high-risk populations, such as indigenous or Torres Strait Islander people.

And how often should that screening occur?

That's a really good question as well. I don't think there's necessarily a clear guideline as to how often it should occur. I guess one of the things we would look at would be if you have a particular patient with one or more of those risk factors, then they should be screened at least at some point, either in an ambulatory hospital clinic or in primary practice with their general practitioner. And then they should be assessed serially, probably every six to 12 months, to assess the effect of treatment on albuminuria more so than anything else.

So my understanding from the RACGP Red Book and Guide for detection, preventing disease and promoting health for Aboriginal and Torres Strait Islanders, and the Chronic kidney disease guidelines, is that we're asked to screen people annually and then thereafter the monitoring will depend on what's going on there. So in the article you outlined that treatment of albuminuria includes the use of an ACE inhibitor or an angiotensin receptor blocker. What's the evidence for improved outcomes with these, and are they different for the two different classes of medication?

There's good evidence that both angiotensin converting enzyme inhibitors and angiotensin receptor blockers are beneficial in reducing both total proteinuria and albuminuria and are useful in reducing the rates of progression of chronic kidney disease in particular. There also is some evidence that reducing proteinuria and albuminuria is beneficial in reducing overall cardiovascular risk. And so, for example, in some of the early ACE inhibitor studies they found that reducing proteinuria delayed rate of progression to later stages of chronic kidney disease but most importantly, to end stage kidney disease, and reduce the risk of dialysis in the future, as well as the risk or requirement for renal transplantation. And it can do that by a rate of almost half, so it can almost halve that risk in the long term. Angiotensin receptor blockers are much the same and there's fairly good evidence that it reduces albuminuria in both diabetic and non-diabetic populations. It's kind of hard to say which one of those two drugs is superior in terms of reducing the overall degree of proteinuria or albuminuria, but overall they would both be beneficial in reducing albuminuria.

Let's say that a lot of these populations may already be on an ACE inhibitor or an angiotensin receptor blocker. What needs to change once we find albuminuria in people that might already be on one of these medications?

In terms of their overall treatment I guess one of the things to determine is whether there's a requirement for escalation in their actual treatment dose of either an ACE inhibitor or an angiotensin receptor blocker. Often patients are on a low dose of an ACE inhibitor or an angiotensin receptor blocker for hypertension, but for achieving the best outcomes with regard to albuminuria, patients should be up-titrated to the maximum tolerable dose of either of those medications. And that often comes as a bit of a trade-off and things like blood pressure need to be monitored fairly closely in order to prevent adverse effects. I guess if a patient is on an ACE inhibitor and they're identified as having albuminuria, then they should probably also be screened for underlying causes of the albuminuria, probably most notably diabetes or to ensure that they receive adequate and appropriate treatment for that as well.

You mentioned that we get better outcomes in proteinuria when we aim for the highest effective dose of an ACE inhibitor or an angiotensin receptor blocker. And in the current hypertension guidelines, they suggest that instead of titrating up one medication first to the maximal dose to minimise the side effects, to utilise combination therapy and then titrate up each one at a time, rather than getting to the highest dose effectively for treatment. In a setting of someone who may be newly diagnosed with chronic kidney disease or hypertension and have proteinuria, how do we reconcile that need for a maximal dose of the ACE inhibitor with the guidelines in hypertension suggesting that we use combination therapy to reduce the side effects?

Often it is fairly common that patients will be started on an ACE inhibitor or an ARB, and then also be started on a peripheral calcium channel blocker or hydrochlorothiazide in order to maintain lower doses of both medications to minimise side effects. One of the trade-offs with that is that adding medications such as a calcium channel blocker won't actually have any beneficial impact on reducing proteinuria in particular. It may be beneficial in reducing overall cardiovascular risk in terms of reducing blood pressure, but in order to achieve the maximum benefit from minimising albuminuria, then the ACE inhibitor or ARB should be up-titrated. So I think it is still reasonable to add for example a low dose of an ACE inhibitor, then add in a stepwise manner a low dose of a peripheral calcium channel blocker. And if any further dose increases are required, then I think that should occur with the ACE inhibitor or ARB if there is evidence of albuminuria before increasing the calcium channel blocker dose.

And so you might aim for the highest effective dose that you can with the ACE inhibitor before increasing the calcium channel blocker thereafter?

Yeah, exactly. And some of that will obviously be limited by side effects like hyperkalaemia or cough associated with an ACE inhibitor. So it may not be necessarily always possible to increase the dose as much as we'd like to.

It was vogue for a while to use both an ACE inhibitor and an ARB. Is that something that we should be doing?

It's not something that I think we should routinely be doing, but there was a lot of research and it was quite trendy at one point to have patients on both of those treatments. But overall, the major studies that have looked at that combination of treatment has found that there's not really any significant advantage in terms of cardiovascular risk reduction, but there are significant harms associated with combination treatment with an ACE inhibitor and an ARB. And those usually relate to hyperkalaemia-related hospitalisations and increased mortality as a result of that. So as a general rule, we wouldn't recommend using both treatments concurrently. However, in certain circumstances for particular patients with careful monitoring, there may be a role for combining treatment. But it would certainly need to be done under very strict supervision.

So this kind of clinical situation, maybe someone with chronic heart failure, where there has been some evidence that that combination may work well together, if that person then develops proteinuria, do we need to change the therapy at all?

I don't necessarily think so. So if a patient's on an ACE inhibitor and spironolactone for example for congestive heart failure and they develop proteinuria, I think if they're not at the maximum tolerable dose of the ACE inhibitor or angiotensin receptor blocker, then certainly up-titration of that dose should be considered with careful monitoring of things such as serum potassium, just to make sure they're not developing significant adverse events.

Akshay, one of the common problems that general practitioners or pharmacists might have is that they come across a patient that is already on an ACE inhibitor/ARB combination and they're not sure whether it's worthwhile continuing this. What steps does a clinician need to go through to determine suitability? And then how could they then deprescribe if it's deemed not suitable?

That's a really good question. And it's certainly a case that's encountered in primary practice in particular I'd imagine where patients may have come from a cardiologist or a nephrologist who's started them on combination treatment with an ACE inhibitor and an angiotensin receptor blocker, and it's kind of left up to the primary practitioner to monitor for all the potential side effects that could occur. I guess the mainstay of trying to determine whether that treatment is appropriate is if there is ongoing evidence of benefit without significant evidence of harms. So for example, if a patient is on combination treatment, but they're having frequent blood tests that show significant hyperkalaemia that requires treatment, then perhaps combination treatment is doing more harm than good.

However, in the circumstance where a patient may be on combination treatment without significant problems such as hypotension or hyperkalaemia, then it might be reasonable to continue combination treatment. In the instance where patients are experiencing more harms than benefits, and I think it is fairly reasonable to deprescribe one of those medications and just continue monotherapy and assess for deterioration in clinical state or worsening of things such as albuminuria. But it is something that's fairly commonly encountered, and it's not an easy decision as to when deprescribing should take place, particularly when the original prescription was performed by another clinician.

So obviously communication with the rest of the team is going to be really important as well?

Yeah, absolutely. And trying to dig out what the specific indication was and what the thresholds for continuing that treatment are particularly important as well. I mean, in certain circumstances there might be clinicians who are happy to tolerate a certain degree of hypotension or a certain degree of hyperkalaemia. And so in those situations it might be reasonable to continue treatment. However, oftentimes the adverse effects are more significant than the benefits that are being derived from the treatment. And in those circumstances, deprescribing is reasonable.

Akshay, are there any final take home messages in relation to proteinuria?

Yeah, I guess the take home messages would be in patients with identified proteinuria in particular albuminuria they should, if there are no contraindications or pre-existing conditions that would prevent it, should be started on supportive measures that would reduce the albuminuria. And that would include either an ACE inhibitor or an angiotensin receptor blocker. As a general overarching principle combination treatment with an ACE inhibitor or angiotensin receptor blocker are associated with more harms than benefits and shouldn't be done in the first instance. And I guess that while a number of research studies have shown that the combination is harmful, there still does seem to be some ongoing research into combination treatment. But so far those studies haven't really shed any additional light onto whether or not combining the two drugs would be of any added benefit.

And you've outlined those in your article for people that are interested in further trials to have a look at?

Yes, exactly. Yep.

That's all the time that we have for this episode. Thank you for joining us on the Australian Prescriber Podcast.

Thanks for having me.


The views of the hosts and guests on the podcast are their own and may not represent Australian Prescriber or NPS MedicineWise. I'm Ashlea Broomfield, and thanks for joining us on the Australian Prescriber Podcast.