May 15th, 2023
Incidence of acute kidney injury in dogs with systemic mycotic infections treated with amphotericin B (1996-2020)
Systemic mycoses, including histoplasmosis, blastomycosis, aspergillosis, cryptococcosis, and coccidioidomycosis, are rare but important infections of dogs. Dogs affected with systemic mycoses could present with disseminated disease that requires aggressive antifungal therapy. Amphotericin B (AmB), a polyene macrolide antibiotic, has been used in the treatment for invasive mycoses because of its rapid action and broad-spectrum fungicidal activity.1 Amphotericin B has high affinity for ergosterol in fungal cell membranes, where it binds and creates a defect in the membrane. It has poor oral bioavailability (0.2%-0.9%) necessitating parenteral administration to reach therapeutic plasma concentrations. Adverse effects associated with AmB parenteral administration include infusion reactions and more delayed effects, such as nephrotoxicosis.
There are several formulations of AmB, each with unique pharmacokinetic and toxicokinetic properties. Conventional AmB is complexed with sodium deoxycholate (AmB-D; Fungizone, Xediton Pharmaceuticals Inc., Ontario, CA). It can cause cytotoxicosis to the distal renal tubules and potentially vasoconstriction that alters renal blood flow, leading to an increased risk of acute kidney injury (AKI). To minimize nephrotoxicosis, AmB-D is generally administered to dogs three times weekly, spaced at least 48 hours apart, as a 1 to 2 hour infusion with IV fluid diuresis. Newer, lipid-based amphotericin B formulations have a superior safety profile and have largely replaced the use of AmB-D in people. Amphotericin B lipid complex formulation (ABLC; Abelcet, Lediant Biosciences, Gathersburg, MD) has fungicidal activity that is equal to that of AmB-D and has reduced nephrotoxicosis in rats. This formulation allows for drug delivery in a ribbon-like phospholipid suspension that increases tissue uptake of ABLC by the reticuloendothelial system. ABLC is delivered primarily to sites of inflammation, resulting in reduced plasma concentrations and thereby, reduced nephrotoxicosis.13 In people, there is a reduction in mean serum creatinine (Cr) in patients receiving ABLC,11 and ABLC does not significantly affect serum Cr in people with pre-existing renal disease. Other lipid-based formulations such as liposomal amphotericin B (AmBisome, Astella Pharma, Northbrook, IL) have superior safety profiles to even ABLC; however, veterinary use is limited because of cost. Limited data are available assessing the risk of kidney injury in clinical cohorts of dogs receiving AmB to treat systemic mycoses and factors that might increase the odds of developing an AKI. In one clinical trial that included 11 dogs with blastomycoses treated with ABLC, AKI was not reported.
The goal of our study was to determine the incidence of AKI in dogs with systemic mycoses treated with AmB and to assess differences in AKI incidence for dogs administered AmB-D or ABLC. We hypothesized that AmB-D would be associated with a greater incidence of AKI than ABLC. We hypothesized that dogs with pre-existing kidney disease, recent anesthesia, or coadministration of nephrotoxic drugs would have greater odds of developing an AKI.
Background: Amphotericin-B (AmB) is an essential medication for the treatment of life-threatening systemic mycoses but the incidence and risk factors for acute kidney injury (AKI) after its administration are not known in dogs.
Objective: Determine the incidence of and risk factors for AKI in dogs receiving AmB.
Animals: Fifty-one client owned dogs receiving AmB for the treatment of systemic mycoses.
Methods: Retrospective study. Signalment, potential risk factors, AKI development (creatinine ≥0.3 mg/dL from baseline), drug formulation (deoxycholate [AmB-D] or lipid complex [ABLC]), dose, and treatment duration were recorded. The probability of an AKI diagnosis was evaluated using a log-rank test. The incidence of AKI and odds ratios were calculated for potential risk factors.
Results: Incidence of AKI was 5/12 (42%) for dogs receiving AmB-D and 14/39 (36%) for dogs receiving ABLC. Of the 19 dogs that developed AKI, 16 (84%) continued treatment after a pause in the planned dosing protocol. Fifty percent of dogs received a cumulative dose of 6.9 mg/kg for AmB-D and 22.5 mg/kg for ABLC (P < .01) at time of AKI diagnosis. ICU hospitalization (odds ratio [OR] 0.21, 95% confidence interval [CI]: 0.58-0.87) and inpatient status (OR 0.25, 95% CI: 0.07-0.86) were associated with decreased odds of AKI.
Conclusions and Clinical Importance: Incidence of AKI with AmB is common but does not always preclude continued treatment. The incidence of AKI is similar between AmB-D and ABLC, but dogs receiving ABLC tolerated a higher cumulative total dose before AKI diagnosis.