Melatonin, a commonly used sleep aid, may significantly reduce the risk for acute kidney injury (AKI) in patients treated with vancomycin, according to a new observational study published in Antimicrobial Agents and Chemotherapy.
In a retrospective cohort study at a large community medical center, researchers examined 303 hospitalized adult patients treated with vancomycin from January 2016 to September 2020. After controlling for potential confounders, melatonin use was significantly associated with 63% decreased odds of AKI.
The cohort consisted of 101 patients treated with melatonin as part of ordinary care and 202 control patients. The melatonin and control groups had a mean age of 60.9 and 64.4 years, respectively. The primary endpoint was development of AKI, defined as an absolute increase in serum creatinine of 0.3 mg/dL or higher or a 50% or greater increase in serum creatinine level. Both groups had similar characteristics, but the treatment group had a significantly higher incidence of bacteremia/sepsis (37.6% vs 25.2% for controls).
“Our findings were surprising. However, there is biologic plausibility,” said the study’s lead author, Luigi Brunetti, PhD, an associate professor at the Rutgers Ernest Mario School of Pharmacy in New Brunswick, New Jersey. Previous studies have shown that vancomycin induces AKI through oxidative stress and mitochondrial damage. Melatonin is an antioxidant, and several preclinical studies demonstrated its renoprotective properties against oxidative stress-induced nephrotoxicity, including secondary to vancomycin, Dr Brunetti explained.
“We also suspect that melatonin alleviates mitochondrial stress. There are data that suggest damaged mitochondrial function in early AKI. Perhaps melatonin functions to alleviate oxidative stress and restore mitochondrial balance,” Dr Brunetti said.
On univariate analysis, concomitant use of piperacillin-tazobactam and loop diuretics was significantly associated with 3.9-fold and 3.4-fold increased odds of AKI, respectively.
Patients who experienced AKI had a significantly longer median length of stay in the hospital compared with patients who did not (11.0 vs 6.0 days). The authors noted that each case of AKI increases the hospitalization costs significantly, so melatonin could reduce overall health care costs in addition to lowering the risk for vancomycin-related AKI.
Dr Brunetti and colleagues explained that the oral bioavailability of melatonin varies widely in human beings, depending on clinical factors. In the current study, the doses and frequency of melatonin administration were not consistent among the patients in the treatment group. Most patients (68.3%) received 5 mg of melatonin, whereas other patients (31.7%) received 3 mg.
Given the relatively benign profile of melatonin, his team plans to conduct a randomized controlled trial, Dr Brunetti said. For now, the optimal dose and frequency of melatonin needed for its renoprotective effects are unknown. “Drugs, especially antibiotics such as vancomycin, are a frequent cause of acute kidney injury,” Dr Brunetti said. “Besides drug discontinuation or avoidance, there are few if any options that serve as nephroprotectants. Melatonin may fill this void, but confirmatory studies are needed.”
“Vancomycin-induced AKI is a clinically important issue, particularly in people with [chronic kidney disease]. As melatonin is relatively benign, it might be a useful renoprotective agent,” said Srinivasan Beddhu, MD, chief of the renal section at the Salt Lake VA Healthcare System and professor of internal medicine at the University of Utah School of Medicine in Salt Lake City.
Prospective, randomized clinical trials (RCTs) are warranted to prove the efficacy of melatonin in this setting, Dr Beddhu said. “There have been multiple interventions that have been promising in observational studies and pre-clinical animal experiments, which have not panned out in RCTs,” he said.
Anjay Rastogi, MD, PhD, professor and clinical chief of nephrology at the David Geffen School of Medicine at UCLA, said the appearance of “long COVID” and its adverse effects on kidney function has created an even more urgent need to find nephro-protective agents. “I find this study very intriguing and interesting,” Dr Rastogi said. He noted, however, the study has its limitations and, in his opinion, “it is more of a hypothesis-generating study.”
Nephrologist Catherine Clase, MB BChir, professor of medicine at McMaster University in Hamilton, Ontario, Canada, agrees that the findings are encouraging, but they should not influence clinical practice. She pointed out that the study was relatively small and melatonin’s beneficial effect just barely achieved statistical significance.
“In preclinical studies in rats, melatonin looks promising at reducing nephrotoxin-induced rises in creatinine and biomarkers, and changes in histology,” Dr Clase said. “But these studies are typically done with very large doses of melatonin. For example, doses used in rats have been 5-10 mg/kg; where a night-sedation dose for a human is typically 1-5 mg.”
There are other agents that have shown preclinical evidence for preventing vancomycin-induced nephrotoxicity, Dr Clase said. Ginkgo biloba extract 761, amrinone, and other compounds are also being investigated. A recent review of preclinical evidence from 2014 to 2019 regarding new strategies for prevention of vancomycin-induced nephrotoxicity found that antioxidants, including vitamin C, vitamin E, cilastatin, melatonin, zingerone, rutin, naringenin, saffron, silymarin and dexmedetomidine protected kidneys from vancomycin-induced nephrotoxicity.
Hong TS, Briscese K, Yuan M, et al. Renoprotective effects of melatonin against vancomycin-related acute kidney injury in hospitalized patients: a retrospective cohort study. Antimicrob Agents Chemother. 2021;65(9):e0046221. doi:10.1128/AAC.00462-21. Published online August 17, 2021.