Navigating Medication Challenges in Kidney Disease, Updating Prior Drug Dosing Consensus

In a discussion with Pharmacy Times, Linda Awdishu, PharmD, FASN, professor and division head of clinical pharmacy, University of California San Diego Skaggs School of Pharmacy and Pharmaceutical Sciences, discusses the challenges and considerations that are necessary for prescribing and de-prescribing medications in patients with advanced chronic kidney disease, as well as the potential for reevaluating previous methods of drug dosing for this population. Awdishu will be presenting at the panel “Drug Dosing in Kidney Diseases and Dialysis: Factors That Affect Drug Clearance” during ASN Kidney Week in Philadelphia, Pennsylvania (November 2, 2023, to November 5, 2023).

Pharmacy Times: What are some key challenges and considerations when prescribing and de-prescribing medications for patients with advanced chronic kidney disease (CKD)?

Linda Awdishu: Yeah, that's a really excellent question. So, it's actually been an area of interest in multiple studies now. Dr. Rashida Hall, Wendy St. Peter, and other colleagues looked at what are some of the qualitative factors that impact de-prescribing in patients on dialysis. Some of the issues that have come up are really interconnectability between different electronic health records, and that really is problematic because if the electronic health record in the dialysis unit is different from the health record for the patient—in the health system in which they received their other care—then 1 of the biggest interventions is medication reconciliation.

Some other challenges include time constraints, whose role is it, defining roles amongst the different providers and taking the responsibility. So, when de-prescribing is implemented, it is significant and it may impact about 17%, 20% of patients, and there were some Canadian studies done 1 by—I believe Marissa Battistella and colleagues—where they were able to show that after de-prescribing a certain number of target medications, that patients remained off of those medications, 50% of them remained off medications at 6 months. Which is great, it's long lasting interventions.

Pharmacy Times: How do thiazide diuretics come into play for patients with advanced CKD or end-stage kidney disease (ESKD) who are on dialysis, and what is the current understanding of their efficacy and safe use?

Awdishu: This has been an exciting development for us. So, back many years ago when I was taught about thiazide diuretics, I was taught that they're not as efficacious when the kidney function, or glomerular filtration rate (GFR), is below 30 [milliliters] per minute—and back then it was creatinine clearance was below 30 mLs per minute, and it's because they don't get to the full site of action, they weren't secreted enough in the tubules. And that, thought process, that classical training has been challenged, so the CLICK study—which was done by Dr. Agarwal and colleagues—showed that in advanced CKD—so patients with a GFR of 15 to 30 mLs per minute—they could implement chlorthalidone on top of the patient's antihypertensive regimen and they were able to show further reductions in blood pressure. I think the magnitude of blood pressure reductions was about 10 to 12 millimeters of mercury, so it was significant. And a majority of those patients—I think it was 50% or 60%—had already been on loop diuretics as part of their regimen, so adding in chlorthalidone really gave benefit to blood pressure control in a population that we didn't think would achieve benefit.

In terms of, advancing to dialysis, I think that's still a question that—hopefully—Dr. Agarwal will address [during his session] at the ASN [conference].

Pharmacy Times: When it comes to drug dosing in kidney diseases, are there specific drug classes or medications that pose greater challenges in terms of balancing therapeutic effects and avoiding toxic accumulation? Could you provide examples or strategies for managing such medications in patients with advanced CKD and those on dialysis?

Awdishu: So, when we think about medications that could pose challenges in patients with reductions in their kidney function or those on dialysis, I think about high-risk drugs. So, the first group of drugs that comes to mind is pain medications. And then, of course, anticoagulants and other high-risk medications. But I’ll talk about pain medicines, and really, pain medications are problematic because patients, a lot of [them] are in pain…when they're in end-stage renal disease on dialysis, 60% of them are maybe prescribed an opiate, and we do know that certain opiates can accumulate in kidney disease—like morphine—and cause [adverse effects (AEs)] of sedation and respiratory depression. And there were a couple of studies that actually showed that the prescription of an opiate was associated with an increased risk of altered mental status, increased risk of…falls and fractures. And that risk was over 50% for altered mental status and falls, and over 30% for fractures. So it's something that we have to be mindful of balancing pain management and the reduction of risks of these really serious AEs.

Other pain meds, like gabapentin and pregabalin were also studied from the [United States Renal Data System], and they showed similar [AEs], and what was surprising is that even super low doses of gabapentin—less than 100 milligrams a day, which is the renally-adjusted dose—was associated with an increased risk of falls. So, really pain management needs more attention, more research for finding kind of optimal drugs for our patients.

Pharmacy Times: What are some of the recent advancements or research findings in the field of drug dosing for patients with advanced CKD and ESKD on dialysis? Have there been any notable developments or breakthroughs that are improving the management of medication regimens in these populations?

Awdishu: So, probably the most notable breakthrough was the implementation of a new GFR estimating equation that did not include the race variable. So, the CKD-EPI 2021 equation removed race as a variable, and subsequently, different health systems across the country are implementing that new equation. And for drug dosing, historically, pharmacists were using the Cockcroft-Gault [equation] of creatinine clearance, and we are currently working on recommendations for switching to the new CKD-EPI equation. So, the National Kidney Foundation has put together a task force of pharmacists, nephrologists, and other care providers to put out recommendations on how to use the CKD-EPI 2021 equation. And 1 of the biggest challenges is that those GFR estimating equations are adjusted to a patient's normalized body surface area of 1.73 meters squared. But for drug dosing, we can't use normalized or indexed values of GFR, it's really important to de-index, the value and use the patient's actual body surface area. And so, those are some of the new issues that we're dealing with now for drug dosing. And then working with the FDA to come up with some consensus around drug dosing, because these older drugs were studied using different estimating equations, and so, we want to make sure that we're providing good guidance to pharmacists and physicians on how to appropriately dose drugs in kidney disease.