Vancomycin‐Induced Kidney Injury: Animal Models of Toxicodynamics, Mechanisms of Injury, Human Translation, and Potential Strategies for Prevention

Abstract

Vancomycin is a recommended therapy in multiple national guidelines. Despite the common use, there is a poor understanding of the mechanistic drivers and potential modifiers of vancomycin-mediated kidney injury. In this review, historic and contemporary rates of vancomycin-induced kidney injury (VIKI) are described, and toxicodynamic models and mechanisms of toxicity from preclinical studies are reviewed. Aside from known clinical covariates that worsen VIKI, preclinical models have demonstrated that various factors impact VIKI, including dose, route of administration, and thresholds for pharmacokinetic parameters. The degree of acute kidney injury (AKI) is greatest with the intravenous route and higher doses that produce larger maximal concentrations and areas under the concentration curve. Troughs (i.e., minimum concentrations) have less of an impact. Mechanistically, preclinical studies have identified that VIKI is a result of drug accumulation in proximal tubule cells, which triggers cellular oxidative stress and apoptosis. Yet, there are several gaps in the knowledge that may represent viable targets to make vancomycin therapy less toxic. Potential strategies include prolonging infusions and lowering maximal concentrations, administration of antioxidants, administering agents that decrease cellular accumulation, and reformulating vancomycin to alter the renal clearance mechanism. Based on preclinical models and mechanisms of toxicity, we propose potential strategies to lessen VIKI.

A Risk Prediction Flowchart of Vancomycin-Induced Acute Kidney Injury to Use When Starting Vancomycin Administration: A Multicenter Retrospective Study

“…In preclinical studies, VCM-induced AKI is presumed to be a result of the accumulation of the drug in proximal tubule cells, which triggers cellular oxidative stress and apoptosis. However, the underlying mechanism of VCM-induced AKI remains poorly understood [ 7 ]. To prevent a deteriorated prognosis, early detection of nephrotoxicity is crucial for patients treated with VCM [ 6 ].…”

Cefepime Neurotoxicity in a Patient With Acute Tubular Necrosis

“…We started our patient on vancomycin and piperacillin/tazobactam on admission. Vancomycin is a nephrotoxic drug [ 5 ]. The nephrotoxicity of vancomycin and piperacillin/tazobactam combined is higher than that of vancomycin alone [ 7 ].…”

“…It causes dose-dependent acute tubular necrosis (ATN) secondary to oxidative stress in proximal tubule cells, autophagy, and obstructive cast formation. It can also cause acute interstitial nephritis [ 5 ].…”

Vancomycin Area Under the Curve‐guided Dosing and Monitoring: “Is the Juice Worth the Squeeze”?

“…Data show that vancomycin accumulates in proximal renal tubular cells and causes oxidative stress, which results in acute tubulointerstitial damage. 4 In animal and clinical studies, the totality of data demonstrate that the extent of vancomycin-induced AKI increases as a function of the intensity and duration of vancomycin exposure. [4][5][6][7][8] Consistent with nonimmunologic drug-related AKI events (e.g., acute tubular necrosis vs acute interstitial nephritis), most events occur after 4-5 days of vancomycin therapy.…”

“…4 In animal and clinical studies, the totality of data demonstrate that the extent of vancomycin-induced AKI increases as a function of the intensity and duration of vancomycin exposure. [4][5][6][7][8] Consistent with nonimmunologic drug-related AKI events (e.g., acute tubular necrosis vs acute interstitial nephritis), most events occur after 4-5 days of vancomycin therapy. 7,9,10 It is important to recognize that when the 2009 consensus guidelines were written, there was limited data to support the efficacy and safety of maintaining trough levels between 15 and 20 mg/L 2 .…”