KDIGO Clinical Practice Guideline for Acute Kidney Injury
Amphotericin B nephrotoxicity: Recommendations and Rationale

Amphotericin b nephrotoxicity

Amphotericin B has been the standard of treatment for lifethreatening systemic mycoses for over 50 years. This polyene antifungal agent is insoluble in water and needs to be solubilized with deoxycholate and given i.v. in the absence of electrolyte solutions to maintain solubility. Despite its broad-spectrum fungicidal activity against a large number of invasive systemic mycoses, drug-induced nephrotoxicity is common and remains the principal dose-limiting toxicity of amphotericin B.^328-330 Amphotericin B has numerous other significant toxicities, including thrombophlebitis, electrolyte disturbances, hypoplastic anemia, and systemic toxicity associated with fever, chills, hypotension, and cytokine release.^331,332 AKI related to amphotericin B is clinically significant and is associated with higher mortality rates, increased LOS, and increased total costs of health care when managing patients with systemic fungal infection.^328,330

Over the past two decades, three major advances in antifungal therapy have become clinically available: i) the lipid formulations of amphotericin B; ii) the introduction of the echinocandin class of antifungal agents; and iii) an expanding number of azoles with extended activity against a variety of fungal pathogens. Therapeutic alternatives to amphotericin B have been a welcome addition in the management of systemic mycoses and selected, protozoan, parasitic infections, but their incremental costs and tradeoffs in spectrum of activity against fungal pathogens need to be considered, in addition to their favorable toxicity profiles and reduced potential for nephrotoxicity. A number of therapeutic options are now available to the clinician when deciding upon the choice for empiric or directed antifungal therapy. Avoidance of risk of nephrotoxicity is one of the major, but not the only, determinants when selecting antifungal therapy at present.

• 3.8.6: We suggest using lipid formulations of amphotericin B rather than conventional formulations of amphotericin B. (2A)

Rationale

The broad-spectrum, polyene, antifungal agent amphotericin B deoxycholate has been the mainstay of treatment for systemic mycoses for decades. Despite its well-known toxicity profile, the potent antifungal activity of amphotericin B, in addition to its activity against certain protozoan parasites (Plasmodium spp., Leishmania spp., Naegleria spp.), indicates that this therapy will remain a standard agent in clinical medicine for the foreseeable future.

Amphotericin B–induced nephrotoxicity is related to multiple mechanisms, including ischemic injury and direct tubular- and glomerular-cell membrane toxicity. Amphotericin causes vasoconstriction of the afferent renal arteriole along with a systemic inflammatory response that may reduce renal blood flow. Amphotericin B also directly inserts into human cellular membranes, where it disrupts membrane permeability and physiology.^331,332 Tubular epithelial cells residing in the deep medullary regions of the kidney are particularly susceptible to injury where considerable osmotic stress exists across cell membranes even under physiologic conditions. The end result is enzymuria, loss of renal tubular concentrating ability, renal tubular acidosis, increasing urinary losses of potassium and magnesium, and decreased glomerular function, resulting in azotemia and decreased synthesis of erythropoietin. Amphotericin B–induced nephrotoxicity is often accompanied by concomitant administration of other potentially nephrotoxic agents such as cyclosporine A, aminoglycosides, chemotherapeutic agents, and a number of other potentially nephrotoxic agents.^328,329,333

Considerable efforts have been undertaken to try to limit nephrotoxicity and permit the continued use of amphotericin B deoxycholate for the management of systemic mycoses. Simple maneuvers, such as salt repletion and provision of adequate amounts of potassium, are beneficial in animal models in the prevention of amphotericin B nephrotoxicity. These measures have a mixed record in clinical practice, and their capacity to prevent AKI when treating severe fungal infections remain unclear. The relative ease and simple logic of volume repletion and potassium supplementation during amphotericin B therapy supports their routine use, despite the relative lack of compelling clinical evidence to recommend these maneuvers.

Various dosing strategies have also been instituted in an attempt to limit amphotericin B–induced nephrotoxicity. One strategy is to give amphotericin B as a continuous infusion rather than a 2- to 4-hour infusion to limit nephrotoxicity.^329,334 While there is some suggestion that a continuous infusion may limit nephrotoxicity, enthusiasm for this strategy is tempered by the potential loss of some antifungal activity. Amphotericin B exhibits concentrationdependent antifungal activity, and continuous infusion of low-doses of amphotericin B could result in suboptimal protection for some patients with invasive fungal infections.³³⁴

Another common strategy is the administration of alternate-day doses of amphotericin B, rather than daily doses.^335,336 This strategy is better tolerated and might reduce nephrotoxicity without sacrificing efficacy in stable patients. However, clear evidence that this strategy reduces nephrotoxicity is not supported by large, adequately controlled clinical trials as yet.

One of the major innovations in amphotericin B therapy over the last 15 years has been the introduction of lipid formulations of amphotericin to limit the problem of nephrotoxicity associated with conventional amphotericin B deoxycholate. Three lipid formulations are available including: amphotericin B colloidal dispersion, amphotericin B lipid complex, and liposomal amphotericin B. Amphotericin B colloidal dispersion is formulated by amphotericin B complexed with cholesteryl sulfate. Amphotericin B lipid complex is composed of amphotericin B complexed with dimyristoyl phosphatidylcholine and dimyristoyl phosphatidylglycerol. Liposomal amphotericin consists of amphotericin B complexed with hydrogenated soy phosphatidylcholine, distearoylphosphatidylcholine, and cholesterol.^337-340 Other formulations that might further reduce the risk of AKI from amphotericin B include nanoparticle packaging in micelles with polyaspartic acid.³⁴⁰

The safety and efficacy (in incidence of nephrotoxicity) of lipid formulations of amphotericin have been studied in numerous experimental and clinical trials with conventional amphotericin B deoxycholate as the comparator.^{337–339,341–350} A detailed analysis of these various trials, and a number of meta-analyses that have analyzed this clinical question, concluded that the lipid formulations are less nephrotoxic than amphotericin B deoxycholate.^344,346 When feasible, we recommend that lipid formulations supplant the use of conventional amphotericin B deoxycholate to reduce the risk of nephrotoxicity.

The incremental costs associated with the lipid formulations and their relative efficacy for systemic mycoses remains the subject of considerable debate. The existing evidence would suggest that the overall risk-benefit ratio and costeffectiveness with these lipid formulations is essentially cost-neutral with amphotericin B deoxycholate.^337,339 Attempts to increase the doses of lipid formulations of amphotericin further to improve efficacy have resulted in mixed results and are not recommended at present.^342,343

Lipid formulations of amphotericin are less nephrotoxic but require different dosing strategies (three- to five-fold higher doses than deoxycholate formulations of amphotericin B). Some of these agents continue to induce general systemic toxicity reactions similar to those observed with the deoxycholate formulation (e.g., amphotericin B colloidal dispersion).