Amphotericin B Nephrotoxicity

Abstract

The frequency of fungal infections is increasing. Amphotericin B remains the anti-fungal drug of choice for most systemic infections, but a limiting factor for its use is the development of nephrotoxicity. Amphotericin B-induced nephrotoxicity is manifested as azotaemia, renal tubular acidosis, impaired renal concentrating ability and electrolyte abnormalities like hypokalaemia and sodium and magnesium wasting. All these abnormalities occur to varying degrees in almost all patients receiving the drug. Upon withdrawal of therapy renal function gradually returns to baseline, although in some instances permanent damage is sustained, especially when the cumulative dose exceeds 5g. Salt depletion enhances the development of nephrotoxicity. The mechanism of nephrotoxicity involves direct cell membrane actions to increase permeability, as well as indirect effects secondary to activation of intrarenal mechanisms (tubuloglomerular feedback) and/or release of mediators (thromboxane A2). The latter effects are presumably responsible for the observed acute decreases in renal blood flow and filtration rate, responses that are inhibited by several physiological and pharmacological interventions. Changes in intracellular calcium levels may also contribute to the observed effects. 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.

Amphotericin B Is Cytotoxic at Locally Delivered Concentrations

“…This drug complexes with cell membrane sterols of host cells, forming pores that leak electrolytes similar to its antifungal action. This drug's mechanism of action can lead to systemic toxicity, including renal, hepatic, cardiac, and blood dyscrasia and death [1,18]. Concentrations of amphotericin in the blood and renal system are highly dependent on their formulation and delivery mechanism [6].…”

Ventajas y desventajas de los distintos tipos de anfotericina en pediatría: revisión de la bibliografía

“…3,4,6 Los primeros incluyen escalofríos, fiebre, náuseas, vómitos, flebitis, dolores generalizados, convulsiones, cefaleas. 3,6 La nefrotoxicidad es el efecto adverso más relevante, 1,3,4,7,8,13 por estar asociada con mayor morbimortalidad, requerimiento de hemodiálisis, prolongación de la estadía hospitalaria y mayores costos. 4,7.18-21 Se ha descripto que los pacientes pediátricos tienen menor toxicidad renal que los adultos, 1,5,,6,13 pero las series difieren en cuanto a la gravedad y la incidencia.…”

“…La anfotericina también interactuaría con los esteroides de las membranas de las células renales y aumentaría la permeabilidad a diferentes moléculas intracelulares. 3 Finalmente, podría producir apoptosis de las células tubulares y de las células intersticiales de la médula renal. El desoxicolato también sería tóxico.…”

“…El desoxicolato también sería tóxico. 3,12 Existen factores que aumentan la morbilidad renal de la anfotericina, como la presencia de hipoflujo renal, hiponatremia y el uso de otros fármacos nefrotóxicos (por ej., inhibidores de la calcineurina, furosemida, aminoglucósidos, cisplatino e ifosfamida, entre otros).…”

“…3 Asimismo, el espectro de especies de hongos causantes de patología en seres humanos también se ha modificado. 4 Desde el siglo pasado el desoxicolato de anfotericina B ha sido el fármaco de elección para tratar las infecciones fúngicas sistémicas.…”