Amphotericin B Nephrotoxicity

Jun-Ki Park
5/17/11

Invasive fungal infections are an important cause of

morbidity and mortality in pts with neutropenia, who
are receiving chemotherapy.

As standard of care, patients with persistent fever and

neutropenia, despite ABXs and without apparent
etiology of fever, receive empirical antifungal therapy.

Amphotericin is treatment of choice for most deepseated mycoses.

1997GuidelinesfortheUseofAntimicrobialAgentsinNeutropenicPatients
withUnexplainedFever.Hughesetal.CID1997

Incidence of Ampho B Nephrotoxicity

Authors

Rate of Nephrotoxicity

White et al. CID 1998

64 %

Walsh et al. NEJM 1999

49 %

Wingard et al. CID 1999

53 %

Clinical Manifestations

Renal insufficiency

Hypokalemia, urinary K wasting

Hypomagesemia, urinary Mg wasting

Metabolic acidosis d/t type 1 RTA

Polyuria d/t nephrogenic DI

Risk Factors

Dose dependence:
(low risk at doses less than 0.5mg/kg per day and
cumulative dose of less than 600mg

Chronic renal insufficiency

Concomitant nephrotoxins (e.g. tacro, cyclsporine, AG)

Dehydration

Severity of underlying disease / patient category

FigureA.Cumulative
probabilityofdeveloping
modseverenephrotoxicity,
stratifiedbymeandaily
amphotericinBdosage.

FigureB.Cumulative
probabilityofdeveloping
modseverenephrotoxicity,
stratifiedbyNr.Of
independentriskfactors
(amikacinorcyclosporine
treatment,meandaily
amphotericinBdose35mg,
weight90kg,malesex,and
chronicrenaldisease).

Harbarthetal.AmJMed.2001

Wingardetal.CID2001

Pathogenesis
Direct toxic effects:
Amphotericin inserts into cell membranes, creating
pores that increase cell permeability, leading to
hypoerkalemia, hypomagnesemia, distal RTA.
Deoxycholate toxicity (bile salt, traditional Ampho B
solubilizing agent)
Vasoconstriction of afferent arterioles
Indirect effect:
Decreased GFR via Tubuolglomerular Feetback
mediated vasoconstriction.

Andreolietal.KI1973

Zietzeetal.Nat.Rev.Nephrol.2009

Steinmetzetal.JCI1970

Steinmetzetal.JCI1970

Steinmetzetal.JCI1970

Kimetal.JLabClinMed2001

Toxic Effect of Deoxycholate

Zageretal.KI1992

Sawayaetal.JClinInvest1991

Sawayaetal.JClinInvest1991

Prevention

Salt loading

Use of lipid formulations of Ampho B

Avoidance of concurrent nephrotoxins

Effect of Salt Loading

Llanosetal.KI1991

Effect of Salt Loading

Llanosetal.KI1991

Lipid Formulations of Ampho B

AmBisome a true liposome sturcture

Abelcet (amphotericin B lipid complex

(ABLC) with a ribbon-like structure)

Amphocil/Amphotec (amphotericin B
colloid dispersion (ABCD)) with a disclike structure)

Whiteetal.ClinicalInfectiousDiseases1998

AmBisome

Walshetal.NEJM1999

Nephrotoxicitydefinedby:
sCrtwoormoretimesthe
baseline
Concomitantnephrotoxicdrugs:
Aminoglycosides
Cyclosporine
Foscarnet
Thefollowingnumbersofpatients
tookvariousnumbersofdrugs:
0or1:79patientsreceiving
Ambisomeand92AmpB
2ormore:264and252,resp.
3ormore:120and119,resp.
Walshetal.NEJM1999

Walshetal.NEJM1999

THANK YOU!