Incidence, Predictors, and Impact on Hospital Mortality of Amphotericin B Nephrotoxicity Defined Using Newer Acute Kidney Injury Diagnostic Criteria

Abstract

bStudies on amphotericin B (AmB) nephrotoxicity use diverse definitions of acute kidney injury (AKI). Here, we used the new Kidney Disease Improving Global Outcome (KDIGO) system to describe the incidence, predictors, and impact of AmB-induced AKI on hospital mortality in 162 patients treated with AmB (120 with deoxycholate preparation and 42 with liposomal preparation). KDIGO stage 1 requires an absolute increase of >0.3 mg/dl or >1.5؋ over baseline serum creatinine (SCr), while stage 2 requires >2؋, and stage 3 requires >3؋. A binary KDIGO definition (KDIGObin) corresponds to stage >1. For comparison, we included two definitions of AKI traditionally utilized in nephrotoxicity studies: >0.5 mg/dl (NT0.5) and >2؋ (NT2؋) increase in baseline SCr. The overall incidence of AmB-induced AKI by KDIGObin was 58.6% (stage 1, 30.9%; stage 2, 18.5%; stage 3, 9.3%). Predictors of AKI by KDIGObin were older age and use of furosemide and angiotensin-converting enzyme inhibitor (ACE-I). Traditional criteria detected lower incidences of AKI, at 45.1% (NT0.5) and 27.8% (NT2؋). Predictors of AKI by traditional criteria were older age and use of vancomycin (NT0.5) and use of vancomycin and vasopressors (NT2؋). KDIGObin detected AKI 2 days earlier than the most sensitive traditional criterion. However, only traditional criteria were associated with intensive care unit (ICU) admission, mechanical ventilation, and mortality. In conclusion, the increase in sensitivity of KDIGObin is accompanied by a loss of specificity and ability to predict outcomes. Prospective studies are required to weigh the potential gain from early AKI detection against the potential loss from undue changes in management in patients with subtle elevations in SCr.A mphotericin B (AmB) is a powerful antifungal and antiparasitic agent that binds to the ergosterol component of microbial membranes, creating pores that result in cation leakage and cell death (1). AmB is the drug of choice for the treatment of severe forms of leishmaniasis and remains a lifesaving option for certain invasive fungal infections. Nevertheless, its use is limited by toxicity, including acute kidney injury (AKI).AmB administration leads to direct renal vasoconstriction and causes a profound reduction in renal blood flow (2-4). In addition, AmB alters renal tubular cell membrane permeability (5, 6), allowing back diffusion of hydrogen ions and thereby impairing acid excretion. Recent data suggest that sodium entry through membrane pores activates mitogen-activated protein (MAP) kinases and increases intracellular calcium concentration, culminating in renal tubular cell injury (7). Therefore, AmB-induced AKI appears to result from a combination of ischemic and toxic insults (8). Phenotypically, AmB-induced AKI manifests itself through elevated serum creatinine (SCr) levels that may be accompanied by renal tubular acidosis, characterized by hyperchloremic metabolic acidosis, hypokalemia, and hypomagnesemia.Mistro and coworkers (9) systematically reviewed the literature on AmB-induced AKI and...

Role of Urine Neutrophil Gelatinase-Associated Lipocalin in the Early Diagnosis of Amphotericin B-Induced Acute Kidney Injury

“…Our group has recently shown that the use of newer AKI diagnostic criteria (RIFLE, AKIN, and KDIGO) is able to shorten the time to detection of AmB-induced AKI compared to the use of traditional criteria (34). Herein, we showed that determination of the UrNGAL level has the potential to detect AmB-induced AKI even earlier than use of the most sensitive of the newer SCr-based (KDIGObin) criteria.…”

“…In our recent retrospective study, we showed that the increase in sensitivity of the KDIGObin criterion for the detection of AmBinduced AKI was accompanied by a loss of specificity and the ability to predict hard outcomes, such as intensive care unit admission or mortality (34). Therefore, future studies should be conducted to evaluate if a UrNGAL-oriented treatment strategy will result in a reduction in the incidence of AmB-induced AKI (as defined by SCr-based criteria), as well as reductions in lengths of hospital stay and costs.…”

“…AmB is a highly nephrotoxic drug with antiparasitic and antifungal properties. At the Hospital Universitário Professor Edgard Santos, the main indication for the use of AmB on the hospital wards is leishmaniasis (34). Patients with leishmaniasis usually do not present with an inflammatory response syndrome or renal dysfunction, are hemodynamically stable (and, hence, are not subject to ischemic insults), and require in-house treatment with AmB for prolonged periods.…”

Efficacy and safety of amphotericin B formulations: a network meta-analysis and a multicriteria decision analysis

“…[18] The use of lipid-based formulations reduces the prevalence of AB-induced nephrotoxicity to between 9% and 25%. [70][71][72] (a) Efficacy Rank probabilities sum to one, both within a rank over treatments and within a treatment over ranks. Each drug has a probability of being the best treatment (rank 1) or the worst treatment (rank 5).…”

Retrospective Cohort Analysis of Liposomal Amphotericin B Nephrotoxicity in Patients with Hematological Malignancies

“…Two retrospective Brazilian studies have also examined the incidence of L-AMB nephrotoxicity in mixed patient populations using either the RIFLE criteria (8) or the more sensitive Kidney Disease Improving Global Outcome (KIDGO) staging criteria (16). Of the two, the study by Falci et al (8) is more applicable to our analysis, as they included 105 patients treated with L-AMB and found 22% of the patients fell into the risk category, 3.7% progressed to injury, and 2.4% developed failure.…”