In the clinical situation, and in long term models of nephrotoxicity in the rat, salt loading protects against deterioration in renal function; recommendations are made for the optimisation of amphotericin B therapy by salt loading.
New preparations of the drug, such as liposomal amphotericin B, may also prove useful in minimising nephrotoxicity while maintaining antifungal activity, but further research is needed with both salt loading and liposomal amphotericin B to confirm or deny their protective effect on kidney function.
Abstract The frequency of fungal infections is increasing. Amphotericin B is thought to have several mechanisms by which it precipitates nephrotoxicity, including arteriolar vasoconstriction and direct tubular injury [ 19 ]. It would be expected that the course of recovery would differ between these two phenotypes. To complicate matters further, most research characterizing amphotericin B-induced renal injury is derived from patients who received amphotericin B deoxycholate.
Deoxycholate, a bile salt derivative used to solubilize amphotericin B, has been shown to be nephrotoxic even in the absence of amphotericin B [ 11 , 20 ]. The relatively rapid course of at least partial recovery suggests that many of these patients who recovered may have had a prerenal mechanism of injury, though not directly studied in this work.
The authors state that there were no cases of irreversible nephrotoxicity. Unfortunately, Luber and colleagues did not report the duration of follow-up, nor the amphotericin B formulation used in their study population, making direct comparisons difficult.
Although high rates of nephrotoxicity have been reported in patients who receive a cumulative total dose of 5 grams or more of amphotericin B deoxycholate [ 13 ], we are not aware of any published data that has established a reliable cumulative dose threshold associated with irreversible renal injury for liposomal amphotericin B.
Though one-third of the cohort received cumulative doses greater than 5 grams and average cumulative doses were 2. It has previously been reported that male sex, higher weight, and concomitant use of cyclosporine, vancomycin, and angiotensin converting enzyme inhibitors are all independently associated with a higher risk of LAmB-associated nephrotoxicity [ 12 , 18 , 21 ].
Definitions of renal recovery after AKI are evolving and no specific one has been used consistently in the context of LAmB-associated nephrotoxicity [ 22 ]. In fact, the majority of existing literature does not elaborate on the employed definition of recovery, making a direct comparison impossible. The definition used in the present study has been employed previously, primarily in research pertaining to renal recovery after the use of continuous renal replacement therapy [ 23 — 25 ].
The Acute Disease Quality Initiative consensus statement describes a poorer prognosis for patients whose renal injury fails to rapidly improve and suggests assessing renal recovery at 90 days following AKI to determine if chronic renal injury has resulted [ 26 ].
Unfortunately, due to limited follow-up data available at 90 days, this was not feasible in the present study. Our study is not without limitations. First, the issue of prescriber bias is inherent in an analysis of this nature. Physicians may be more predisposed to treat sicker patients with higher doses of LAmB due to a perceived risk of treatment failure.
These events occurred infrequently and thus were not included in the multivariable modeling, potentially limiting the applicability of these findings to the most critically ill patients. We also captured exposure to nephrotoxic medications commonly used in this population. While unlikely, we cannot rule out that administration of other rarely utilized nephrotoxins may have contributed to study findings.
Additionally, adherence to salt loading was not explicitly collected therefore we cannot confirm the magnitude of influence, if any, of this practice on the outcome of renal recovery.
The definition of AKI in the current investigation was chosen based on those used in prior studies of LAmB nephrotoxicity in an attempt to enhance generalizability of the data.
Also, it is possible that full recovery of LAmB-associated nephrotoxicity may take longer than 30 days in some patients and their recovery would not have been captured in this analysis.
This time frame was chosen based on widely available follow-up data and adds value to existing literature by providing the first defined length of follow-up, furthering our understanding of the clinical course of LAmB-associated nephrotoxicity. Despite the limitations mentioned above, this is, to our knowledge, the largest investigation of the reversibility of LAmB-associated nephrotoxicity performed to date.
More efforts should be made to describe the course of renal recovery in patients with LAmB-associated AKI and the factors which influence it. Further investigation is needed to confirm these findings when aggressive dosing strategies are utilized. Additional research is also warranted to further characterize the course of recovery after LAmB-associated nephrotoxicity, including the comprehensive spectrum of renal recovery and long-term renal outcomes.
An earlier version of this work has been presented in abstract form at the Society of Critical Care Medicine Annual Congress in Supplementary Appendix. Supplemental Figure S1.
Flowchart visualizing enrollment, dose-group assignment, and follow-up. They would then be followed until complete recovery, death, or discharge, or for 30 days after LAmB-associated nephrotoxicity, whichever occurred first. Outcomes were subdivided according to study definitions into no recovery, partial recovery, and complete recovery. Supplementary Materials. Personett et al. This is an open access article distributed under the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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Journal overview. Special Issues. Personett , 1 Bryce M. Kayhart, 1 Erin F. Academic Editor: Frank Park. Received 18 Oct Accepted 02 Jan Published 28 Jan Abstract Background. Introduction Amphotericin B is a broad spectrum antifungal agent with over half a century of use in the treatment of invasive fungal infections [ 1 ]. Methods 2. Follow-Up and Endpoints The primary outcome was complete recovery of kidney injury within the first 30 days after nephrotoxicity.
Results 3. Baseline Patient Characteristics A total of unique patients with any exposure to LAmB were screened and 98 included after application of eligibility criteria. In animals exposed to amphotericin B, sodium loading interferes with this response. Mounting clinical evidence also supports the usefulness of sodium supplementation to prevent as well as to reverse amphotericin B—induced nephrotoxicity.
These preliminary observations merit confirmation in a prospective, randomized clinical trial. The incidence of mycotic disease is increasing. The major risk factor is impaired host defense mechanisms due to underlying disease eg, acquired immunodeficiency syndrome or therapeutic maneuvers eg, cancer chemotherapy, radiotherapy, iatrogenic immunosuppression for organ transplantation.
Despite the availability of newer antifungal agents, amphotericin B Fungizone remains the broad-spectrum antifungal antibiotic of choice for the treatment of deepseated mycotic infections.
Unfortunately, this drug causes a variety of adverse effects, including fever, chills, nausea,. Branch RA. This review will concern amphotericin B-induced nephrotoxicity, whose mechanisms are not completely clear. Nephrotoxicity seems related to direct amphotericin B action on the renal tubules as well as to drug-induced renal vasoconstriction. The main mechanisms of nephrotoxicity suggested in the literature are presented.
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