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Drug Classes That Increase AKI Risk in ICU Patients Identified – Renal and Urology News

A new real-world study has identified potentially nephrotoxic drug categories — both known and exploratory — contributing to acute kidney injury (AKI) risk in critically ill adults in the ICU.

Using electronic health record data from 92,616 ICU admissions at 13 Dutch hospitals, investigators found that 13,492 involved AKI (15%) based on serum creatinine criteria alone. After adjustment for confounding factors, 14 of 44 potentially nephrotoxic drug groups were significantly associated with higher AKI risk.

Among 19 drug categories known to be associated with AKI, 8 (42%) were confirmed as being nephrotoxic, Izak A.R. Yasrebi-de Kom, MSc, PhD, of the University of Amsterdam, in The Netherlands, and colleagues reported in Clinical Kidney Journal.1 Opioids were significantly associated with a 1.4-fold increased risk of AKI after adjustment. Antimycotic antibiotics, glycopeptide antibiotics, sulfonamides, aminoglycosides, and penicillins were significantly associated with a 2.1-, 2.0-, 1.9-, 1.9-, and 1.6-fold increased AKI risk, respectively. Immunosuppressants and loop diuretics were both significantly associated with a 1.7-fold increased risk.

Among 25 other drugs that were explored, 6 (24%) were associated with AKI risk. Phosphodiesterase inhibitors, sympathomimetics α- and β-effect, antiarrhythmics, blood and plasma products, antihypertensives, plasma replacement products were significantly associated with a 1.8-, 1.7-, 1.6-, 1.4-, 1.3-, and 1.3-fold higher AKI risk, respectively.

Confounding by indication, specifically hypotension, may be responsible for the association observed with sympathomimetics with α- and β-effect, the investigators noted. After adjustment, nonsteroidal anti-inflammatory drugs (NSAID) excluding salicylates also were associated with AKI.

Across all analyses, 7 drug categories consistently showed an association with increased AKI risk: glycopeptide antibiotics (vancomycin and teicoplanin), sulfonamides (co-trimoxazole), aminoglycosides, penicillins, antiarrhythmics, loop diuretics, and immunosuppressants, the investigators reported.

Iodinated contrast media and proton pump inhibitors did not carry an increased AKI risk, according to the team.

Drug groups associated with a lower hazard of AKI included blood glucose-lowering agents, ACE inhibitors, and anti-epileptics.

These estimated risks reflect the average situation in clinical practice rather than intrinsic nephrotoxicity in the ICU population, the investigators pointed out.  Strategies for lowering AKI risk include dosage adjustments, therapeutic drug monitoring, or better hemodynamic monitoring and support, they noted.

“For many drug groups the nephrotoxicity has been firmly established and is in line with our results,” Dr Yasrebi-de Kom wrote. “For these groups ICUs should implement strategies to prevent or at least reduce severity of AKI due to nephrotoxicity. Clinical decision support systems, implementation of clinical pathways and nephrotoxin stewardship have all shown promising results to attain such improvements in kidney safety in ICU patients.”

A separate study published in Chest2 examined 35,654 ICU admissions involving vancomycin combination treatment. Vancomycin and piperacillin-tazobactam were significantly associated with 1.4-fold increased odds of AKI and 1.3-fold increased odds of initiation of dialysis compared with vancomycin and cefepime and 1.3- and 1.6-fold increased odds of AKI and dialysis, respectively, compared with vancomycin and meropenem.

Managing AKI

The medical community is continuing to look for ways to improve AKI identification and management. In a recent Chinese trial ( Identifier: NCT03736304), investigators randomly assigned 2208 hospitalized patients to an AKI alert group or usual care group with no alert. Clinicians received automated messages to their mobile telephones alerting them to the potential for AKI along with general management measures. The primary outcome was maximum change in estimated glomerular filtration rate (eGFR) within 7 days.

At 7 days, the median absolute change in eGFR did not differ significantly between groups: 3.7 vs 2.9 mL/min/1.73m2 in the AKI alert vs usual care group, Huijuan Mao, MD, PhD, of Jiangsu Province Hospital, The First Affiliated Hospital of Nanjing Medical University in China, and colleagues reported in JAMA Network Open.3Patients in the alert group were significantly more likely to receive intravenous fluids within 2 days of randomization (82.6% vs 61.8%), less likely to be exposed to nonsteroidal anti-inflammatory drugs within 3 days after randomization (5.0% vs 11.0%), and more likely to have AKI documented in the discharge record (49.9% vs 27.3%), however.

In an accompanying editorial,4 Bourne L. Auguste, MD, MSc, of Sunnybrook Health Sciences Centre in Toronto, Ontario, Canada, and colleagues noted that electronic alerts “operate on the premise that real-time surveillance of declining kidney function paired with a prompt notification to the relevant health care practitioner have the potential to trigger timely interventions. Although the majority of literature in this area has attested to the ability of alerts to change physician behaviors in a way that favors earlier intervention as anticipated, most come up short in demonstrating any meaningful effect on patient outcomes.”

The editorialists pointed out that the premise of eGFR calculations “rests on stable serum creatinine levels, an assumption that is rarely met during the acute changes seen in AKI.” In the setting of AKI, “the kinetics of creatinine can lag its true clearance, misrepresenting the real-time state of kidney function and potentially affecting the timing and appropriateness of clinical interventions.”

Most critically ill patients with AKI, however, do not receive appropriate follow-up even once they’re discharged from the hospital. In a separate study of 29,732 ICU patients with AKI who survived to discharge, only 25% had both an outpatient serum creatinine and urinary protein measurement at 3 months, Ngan N. Lam, MD, MSc, of the University of Calgary in Canada, and colleagues reported in Kidney Medicine.5Specifically, 64% had an outpatient creatinine measurement and 28% had a urinary protein measurement. Only 5% saw a nephrologist.


    1. Yasrebi-de Kom IAR, Dongelmans DA, Abu-Hanna A, et al; RESCUE Study Group. Acute kidney injury associated with nephrotoxic drugs in critically ill patients: a multicenter cohort study using electronic health record data. Clin Kidney J. 16(12):2549-2558. doi:10.1093/ckj/sfad160
    1. Chen AY, Deng CY, Calvachi-Prieto P, et al. A large-scale multicenter retrospective study on nephrotoxicity associated with empiric broad-spectrum antibiotics in critically ill patients. Chest. 2023;164(2):355-368. doi:10.1016/j.chest.2023.03.046
    1. Li T, Wu B, Li L, et al. Automated electronic alert for the care and outcomes of adults with acute kidney injury: a randomized clinical trial. JAMA Netw Open. Published online January 19, 2024. doi:10.1001/jamanetworkopen.2023.51710.
    1. Hamidi S, Kim SJ, Auguste BL. Electronic alerts in acute kidney injury – more questions than answers. JAMA Netw Open. Published online January 19, 2024. doi:10.1001/jamanetworkopen.2023.51682
    1. Jeong R, James MT, Quinn RR, et al. Follow-up care of critically ill patients with acute kidney injury: a cohort study. Kidney Med. 2023;5(8):100685. doi:10.1016/j.xkme.2023.100685