Dose adjustment in chronic kidney disease

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I'm Dhineli Perera, your host for this episode and it's a pleasure to be speaking to Associate Professor Darren Roberts. Darren is a nephrologist and clinical pharmacologist with research interest areas including pharmacokinetics and drug dosing in renal impairment. Darren writes about the different ways to assess renal function and the factors to be considered when adjusting drug doses in chronic kidney disease. Darren, welcome to the program.

Thanks, Dhineli. Great to be here.

So Darren, can you start by giving us a little refresher on why we need to adjust drug doses in chronic kidney disease?

Yeah, sure. The kidneys have a very important role in terms of pharmacology because a lot of drugs are excreted by the kidneys. And so, quite simply, if the kidney function is reduced and so therefore there is less drug being excreted, then unless we adjust the dose of the drug that we're giving someone, then they'll actually receive a relative overdose. So concentration will go high and that may be associated with toxicity and other adverse drug reactions.

Therefore, we need to be able to change the way we dose drugs to suit someone's kidney function. And that then becomes where it becomes a very tricky area because every person is different. They're different sizes and they've got different degrees of kidney function. And so, for any individual we need to tailor their dosing to suit their kidney function.

Right, okay. So I think most health professionals are pretty familiar with the term glomerular filtration rate, but your article sort of explains that there are lots of different ways we can quantify it. I guess one of the main ways is the estimated GFR or eGFR based on the CKD-EPI formula. Is that correct?

Yeah. Because it's so readily available.

Yeah. And so, what would be some of the pros and cons with this approach?

So I guess just to double check, just to clarify that everyone is sort of understanding the same terminology as I'm speaking about it, eGFR is that measurement that comes on the pathology results. It's a calculated value which is performed by the laboratory. Because it knows the gender of the patient and the age, then it's able to make some assumptions and do some calculations to estimate what the GFR is. And this is based on a study which was a very large study where they did lots of mathematics and they think that it's a useful measure of understanding what the actual kidney function is.

And so, the best advantage of this is that this is already calculated, but it's certainly not perfect. There's a few assumptions that come from this. So the pathology company doesn't know how large the patient is, and so we then need to be able to... So a problem with the eGFR is that we need to adjust it based on some people who have extremes of weight and height. The other issue that happens in general is that because it's based on creatinine there's always going to be a lot of variability. Creatinine is a measurement that fluctuates around the place, and it doesn't matter what formulas you apply to that. And that may be based on current health or the medications that you're taking, volume status, if you're dehydrated, for example.

Right, okay. And then the other serum creatinine-based approach that you've mentioned is the Cockcroft-Gault equation or eCrCl, e-creatinine clearance. What are some positives and negatives with this estimate?

Yeah. I think this is a formula that a lot of us were taught during our undergraduate, whatever that might be.

Yeah, definitely.

And we call it the e-creatinine clearance because it was validated against a 24-hour urine collection. So that's part of the reason why we use a different terminology for it. It's based on different tests. A key advantage of creatinine clearance is that it incorporates the patient's weight. So there is some more personalisation of the kidney function based on who that individual is. But the same problems apply in that it is still based on the creatinine concentration in the blood, and that in itself is an imperfect measure. The other thing is it does involve calculations to be performed and therefore it's prone to errors. And then the next question or tricky thing is what weight do we use? There's a whole lot of different weights that we can use to consider a person, lean body weight, ideal body weight, actual body weight, and various sorts of adjustments. And which one you use may depend in part on who the patient is.

You've got a table in your article that actually goes through that quite nicely. So I'd recommend listeners to definitely check it out if this is a question that you're constantly asking in your daily practice. Okay, so let's move on to the measured GFR. Can you tell us a little bit more about what this gold standard is and when would it have been used?

Yeah, sure. So the measured GFR is considered a gold standard for a simple reason. The substance that we're using to measure the kidney function is only filtered. As you know, GFR is glomerular filtration rate. It's a measure that tells us what the filtration is going through the kidney. But many other compounds may have some degree of secretion, for example, creatinine. This is one of the areas why creatinine falls down because some of it is secreted in the proximal tubule. So when we do a measured GFR, it's where we inject a substance that is only filtered and then we can measure how quickly it goes through the kidney and then that can be used to calculate the GFR. But there's problems with the measured GFR as you can imagine.

First of all, it needs to be performed under specialist conditions, and when I say specialist conditions, I mean going to a nuclear medicine laboratory to be able to have this performed. And therefore, there's going to be cost and inconvenience associated with it. It is still a useful test to do if there's a good clinical indication, but by and far this is not going to be a test that many prescribers are going to consider. But it is used as the standard upon which things such as eGFR have been compared.

Okay. And I think similar to Cockcroft-Gault, a lot of us would have been taught along the way that the 24-hour urine collection is actually the gold standard. But would you say that this is sort of now outdated using this approach?

I think it depends on the question in many ways. So I think at 24-hour creatinine clearance can have some benefit. When we're trying to understand specifically what someone's kidney function is like, if they've got extremes of weight. But the problem with a 24-hour creatinine clearance is a few things. First of all, as mentioned, some creatinine is excreted into or secreted into the proximal tubule and therefore the measurement will overstate the actual GFR. Maybe only by about 20%, but there's a lot of interpatient variability with how much that occurs.

I think the trickiest thing though with the 24-hour creatinine clearance is actually doing the test properly. So it means you actually need to collect all urine within a 24-hour period. And so, for people who are passing urine, just as we all do in an ambulatory sense, means that you need to empty the bladder at the start and empty the bladder at the end, and most of us don't just empty our bladder on demand. So a 24-hour creatinine clearance may be readily performed in someone who's got a catheter. But it's a bit harder, particularly for ward-based patients. And so, we often say start it the next morning because most people past urine some time soon after rising. But that means that it may take then two or three days until you get your 24-hour creatinine clearance result, and that's a pretty long time to wait until you are able to start thinking about how you dose your medicine.

Yeah. And I guess in a CKD setting that may not be too long, but in an acute setting then their creatinine clearance has changed well and truly within those few days, and so it's not always that useful by the time you get the results anyway.

That's true. Although all of these formulas are only for people with chronic kidney disease. They only apply to someone who's got a stable creatinine and so if someone is in the hospital and they've got changing kidney function then none of these formulas would apply. That's a good point to raise actually.

Okay. All right, so what is the de-indexed eGFR and when should that be used? Now, this is a... I will point out this is a newer concept as well that a lot of us hadn't heard of. So it'll be good to hear your opinion on that.

Again, it's one of these things that's not that new, but it's actually something that's not well spoken about. When you look at the results on a pathology system, you'll always notice that it says mL/minute/1.73 m². The reason for that is that the result that's there is thought to relate to a person who has a body surface area of 1.73 m². Very few of us do. Most of the time it's larger than that, more like 1.9. And therefore, our actual GFR is higher than the eGFR. So it's the de-indexing of the eGFR which allows to know exactly what someone's eGFR is. And it's actually a very straightforward process. You just calculate someone's body surface area, divide that by 1.73 and then multiply that by the eGFR. So it's not complicated, but it's something that very few of us do. It's something I do only on occasion and that depends on the individual that's involved. This is not something we all have to do as part of our routine care.

There is, for the listeners, there is a box in the article that has the equation for the de-indexed eGFR. So if you wanted to revisit that, I'd suggest you go back to check that out in the article itself. But I guess knowing which equation to use as you've already suggested in your answers before is it really just gets more and more complicated in patients at the extremes of your demographics, so the very old, the very young, the obese, the underweight. You've summarised these in Table 2 of your article. Could you walk us through it briefly?

Yeah, sure. I think the main thing to remember is most people are going to be fine. The key points that listeners should take home from this is that if someone is particularly heavy, and just to give you a number, because I think we need a number and this is an imprecise number, but if they're more than 120 kg as an adult or they're less than 60 kg as an adult, then these would be seen as extremes of weight based on the studies that were used to determine this formula, and I think this is where we should start to make changes to the eGFR and do some de-indexing. Height also is important, although as you know, height plateaus out. In general, I think some with a BMI greater than 30 or less than 18.5, this would make you think, "I'm going to actually calculate this person's eGFR by doing a de-indexing of the eGFR that's reported."

So that takes me to my next question, which was you've suggested that the eGFR is a reasonable estimate to use in drug dosing, but there are possibly drug types where a more careful approach is warranted. What would those be?

I think it's a difficult question to answer because it depends on the drug that is being prescribed, the person's being prescribed from what you're treating. If we take the example of amoxicillin, it is almost all excreted by the kidney and therefore you think it would be the sort of drug where we should say we must be careful about dose reducing. However, it is a drug that is very well tolerated. Very few side effects, even if you overdose someone. Giving it to someone orally, for example, the concentrations that that will be achieved won't be extremely high and it's the sort of drug that's given for the short course. And it's a drug which we need a minimum concentration to achieve a benefit. So it's not the sort of drug which I'd get particularly concerned about for dose adjusting for someone with impaired kidney function.

In contrast though, there are other anti-infectives, for example, the antivirals, so valganciclovir, or particularly relevant to those in the communities, aciclovir. This is a drug that certainly needs to be dose adjusted and a lot of care should be taken. We've seen many cases of people coming in with confusion because they've been prescribed too high dose of aciclovir. There's other medicines which we would know well because we do therapeutic drug monitoring on them. So that's drugs such as digoxin, lithium and immunosuppressives. These are medicines whereby we do need some care with dosing on the basis of kidney function.

But overall, I think if someone is uncertain, then they should be looking up in some sort of product information to see what dose adjustments are required, and asking for help if they're still uncertain.

So on that note, Darren, just to direct our listeners, do you have a preference or a place that is your go-to reference for adjustments?

It depends on what I'm looking it up for. So I think AMH or Therapeutic Guidelines. Generally, these would be the two sources that I would go to first. And I think if you had to choose one, I would choose Australian Medicines Handbook because it covers drug dosing of all drugs. But if uncertain, the product information is still useful.

Okay, fantastic. Well, that's unfortunately all the time we've got for this episode. Thanks so much for joining us today, Darren.

No worries. Thanks, Dhineli. Appreciate it.

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