A U of A researcher is leading a study that could help save the lives of people in intensive care whose kidneys work too well, flushing out critical medications before they can do their job.
"The patients I study have neurological injuries, often life-threatening ones. And in my research, I found that approximately 70 per cent of those patients have a phenomenon called augmented renal clearance (ARC)," says Sherif Mahmoud, associate professor and associate dean academic in the Faculty of Pharmacy & Pharmaceutical Sciences.
As Mahmoud explains, people with ARC have "super kidneys" that eliminate everything very quickly — the exact opposite of people with kidney failure or renal disease, whose kidneys are inefficient and struggle to filter out toxins. The problem is that patients with ARC may also filter out critical medications like antibiotics or anti-seizure medications before they can take effect.
"We can't afford to have something like an antibiotic working ineffectively in a critically ill patient," says Mahmoud, citing a study done in sepsis patients that showed there was an increased risk of death for every hour that an antibiotic's full effect is delayed because of inappropriate dosage.
To make matters worse, the most common method to assess kidney function largely fails to detect ARC. Typically, a blood sample is taken and clinicians measure the serum creatinine level, estimating the kidney's function from that number. However, this approach "grossly underestimates the true prevalence of augmented renal clearance because these equations were developed and validated in non-ICU patients," says Mahmoud.
The optimal method to accurately diagnose ARC involves eight to 24 hours of urine collection, but that isn't practical in many clinical settings, he adds.
This knowledge gap is what Mahmoud, who was named Canadian Pharmacist of the Year in 2024, is looking to address with Augmented Renal Clearance in Neurocritical Care Population: A Prospective Multicenter Study (Neuro-ARC). The five-year study, done in collaboration with the University of Kentucky, began enrolling patients in 2022. About 300 patients have been enrolled so far, and researchers are aiming to include about 500 in total. The Neuro-ARC study is funded by the University Hospital Foundation and the Faculty of Pharmacy and Pharmaceutical Sciences.
"Hopefully the end result will be a new prediction tool so when a patient comes into the ICU, based on their characteristics and some risk factors, we'll be able to accurately determine whether they have augmented renal clearance."
Identifying ARC is only part of the challenge, Mahmoud notes. Clinicians also need to know the optimal dosage for these patients with super kidneys.
To look at dosage requirements, Mahmoud and his collaborators selected seven medications to begin analyzing in detail — the antibiotics vancomycin, meropenem, piperacillin, tazobactam and acyclovir, along with two anti-seizure medications, levetiracetam and lacosamide.
"We intentionally chose those seven because they are commonly used in the ICU and failure of them is often life-threatening, so we really need to make sure we dose them appropriately."
Recently, Mahmoud developed a simple, quick and environmentally friendly way to determine vancomycin concentration in patients' blood using high-performance liquid chromatography (HPLC). He has already used the same HPLC technology to assess levetiracetam, piperacillin/tazobactam and acyclovir, gaining insight on how best to determine the concentration of these particular medications.
Mahmoud notes that while a technique called liquid chromatography mass spectrometry is more sensitive, it requires very expensive equipment. HPLC is more widely available, particularly in resource-limited countries, making it a more accessible option.
Analysis of the remaining medications is already underway, and Mahmoud has a publication forthcoming that includes recommendations for levetiracetam dosage. To determine whether the dosage of a particular medication is ideal, Mahmoud explains, "we developed a model that uses computer simulation to simulate 10,000 patients with the new dosing and find the dose that best achieves the right concentration.
"This way, we can create actual guidelines for clinicians."
