How does amphotericin cause renal toxicity

The analysis considered all comparative studies published in the literature between January and May The outcome data reviewed herein focused on renal toxicity as measured by serum creatinine S-Cr and the doubling or the mean difference in S-Cr levels from baseline to the end of therapy or the need for dialysis.

No studies compared ABCD nephrotoxicity to the other lipid formulations. Based on our review we conclude that lipid formulations of amphotericin B are an important strategy to preserve renal function and improve survival in critically ill patients who require treatment for systemic fungal infections.

Invasive fungal infections IFI frequently occur in patients receiving haematopoietic stem cell transplants HSCT , solid organ transplants SOT , chemotherapy for solid tumours, and inpatients having graft-versus-host disease, serious neutropenia, haematological malignancies, and AIDS 1—5.

Other filamentous mould infections with high mortality rates, e. Patients receiving antifungal therapies for IFI are usually immunocompromised and critically ill, with complex co-morbid conditions.

Renal impairment has been shown to affect morbidity and mortality in such individuals 8—11 and several studies have demonstrated that acute renal failure ARF is an independent risk factor contributing to the death of patients 12— Declining renal function is caused, in part, by the underlying pathophysiological condition of the patient, but it may also be brought about by the widespread use of nephrotoxic compounds.

Of particular note is the antifungal agent, conventional amphotericin B deoxycholate c-AmB which, despite its known nephrotoxicity, remains the treatment of choice for invasive fungal infections IFI in many centres.

Nephrotoxicity of the c-AmB frequently necessitates dose reduction or treatment discontinuation Various lipid-based formulations of amphotericin B AmB have been developed in recent years in order to improve efficacy, safety and in particular to reduce its nephrotoxicity 16— This paper tries to clarify the clinical issues concerning the use of c-AmB and its lipid formulations by reviewing the literature on their nephrotoxicity, the risk factors for renal impairment, the definitions of renal insufficiency and the consequences of decreased renal function.

Renal failure is one of the most common forms of organ dysfunction occurring in patients admitted to intensive care units ICUs and is a strong indicator of early mortality 12— Ojo and colleagues 26 estimated the incidence of CRF in non-renal transplants patients at 60 months post-transplant to be 6. Moreover, they calculated that as a whole, the occurrence of CRF in this group of patients was associated with a more than four-fold greater risk of death.

Until recently, long-term renal toxicity has not been considered a major late complication in bone marrow transplant BMT. Renal insufficiency results essentially from a combination of factors such as radiation injury, liver failure, graft-versus-host disease and drug toxicity previous chemotherapy, antibiotics, antiviral or anti-fungal agents, calcineurin inhibitors and radiocontrast agents; see Table 1 The development of renal failure has been associated with poor patient outcomes 28 , Despite better renal tolerance in children, two studies showed high incidence of renal impairment after BMT.

Kist-van Holthe and colleagues investigating the effect of BMT on renal function in children, identified risk factors for ARF as being i high pre-BMT serum creatinine, and ii transplantation with either a non-HLA-identical related or a marched unrelated donor In turn, renal failure or initiation of haemodialysis resulted in an increase rate of serious infections due to the subsequent and profound reduction in T-cell response Thus, renal impairment could be an emerging risk factor for the development of IFI, as well as invasive aspergillosis 33 , 34 and candidiasis The most widely used indicators in clinical practice are serum creatinine S-Cr levels and creatinine clearance Cr-Cl as based on steady-state S-Cr dosage.

Other markers such as the serum clearance of inulin 36 , nonradioactive iodine contrast media i. Iohexol, iopromide or Iothalamate 37 , and radioactive 51Cr-EDTA clearance 38 are more reliable estimates of glomerular filtration rate GFR but are not used in routine patient care.

The surrogate marker, serum cystatin C, may be used to detect ARF earlier than creatinine but it is still considered experimental S-Cr level is a limited indicator of GFR since a variety of patient-specific variables such as age, sex, race, muscle-mass, weight, drugs, etc.

The definition of nephrotoxicity varies in different studies. Significant renal toxicity is usually taken to be a doubling of S-Cr from baseline but may also be 1. Consequently, we indicated for each study the definition of renal failure Table 2A , 3A and 4A.

This is frequently induced by septic shock 9 , 23 , haemodynamic conditions cardiogenic shock or hepatorenal syndrome , or toxicity haemolysis, drugs and radiocontrast agents in association with such general patient factors as age, male gender, diabetes, pre-existing renal disease 47 , 49— The nephrotoxicity induced by c-AmB therapy, on the other hand, appears to have both tubular and glomerular components, with a direct toxic effect on epithelial cell membrane causing ATN and vasoconstriction in the glomeruli from basement membrane fibrosis.

These combine to reduce blood flow and filtration rate 53— AmB-induced nephrotoxicity may begin very early during therapy, long before any renal insufficiency becomes clinically apparent Even in patients with normal GFR, rapid change in electrolyte levels can occur, leading to significant potassium loss as a result of tubular injury. Saline infusion may blunt or delay nephrotoxicity but its use has been rarely reported.

Percentage of patients who developed acute renal failure according to total dose of amphotericin B. Adapted from Bates The use of concomitant nephrotoxic therapies significantly increases the risk of AmB-related nephrotoxicity and the use of these among immunocompromised patients is particularly frequent.

By virtue of their increased hydrophobicity, these lipid formulations of AmB appear not only to have lower nephrotoxicity, but to target delivery more effectively to the sites of fungal infection or inflammation. Lipid formulations are also believed to deliver less drug to the kidney, accounting for their reduced nephrotoxicity 58— Overall, not only did the definitions and assessment of renal function vary from one study to another, but the doses of lipid formulations of amphotericin B differed considerably in these investigations and this could be a possible reason for the variations reported in renal impairment rates.

Numerous prospective studies have been conducted comparing the efficacy and safety of c-AmB with the various lipid AmB formulations, mainly as used empirically for febrile neutropenia and in treatment of proven IFI.

Two of these were randomized 46 , 62 , two were non-randomized prospective studies 63 , 64 , and the recent prospective study by Miller and colleagues 65 was the only one to compare two lipid formulations with c-AmB.

In the recent randomized investigation by Subira et al. In two recent systematic reviews, i. Macaulay and colleagues 66 and Martino et al. In each one, L-AmB was found to have a renal safety profile that was significantly superior to that of c-AmB. Walsh et al. Indeed, whereas the incidence of S-Cr doubling in patients receiving no or one concomitant nephrotoxic drug was 6. Prentice et al. Treatment and outcome. Up to now, only three clinical studies comparing ABCD to c-AmB have been conducted in patients with invasive fungal infections 72— Two of these investigations were double-blinded randomized trials 73 , 74 and one was a comparison with a historical control group In all of them, ABCD appeared to have equivalent efficacy and superior renal safety as compared to c-AmB but more frequent infusion-related reactions than the c-AmB treated patients.

Regarding renal safety, Bowden et al. Despite the switch, the patients who were initiated on c-AmB continued to have an increased risk of nephrotoxicity of 1. There have been ten clinical studies from to comparing the various lipid AmB formulations see Table 4A and Table 4B. A similar rate of nephrotoxicity 7. These data could reflect the heterogeneity in the severity of the underlying clinical condition among study groups and might explain the difference of nephrotoxicity rates observed between ABLC and L-AmB treated patients 79 , The classification system includes separate criteria for creatinine and urine output UO.

This classification allows detection of patients in whom renal function is markedly affected high specificity for true renal dysfunction but limited sensitivity and patients in whom renal function is mildly affected high sensitivity for detection of kidney malfunction but limited specificity for its presence.

Adapted from Bellomo Imhof et al. Cornely et al. Although the patients were prospectively enrolled, the data were collected retrospectively and for this reason, this registery might have some limitations regarding patient eligibility and selection.

The median daily dose of ABLC of 4. Significant doubling of S-Cr was not found in those patients who received two nephrotoxic agents compared to those with one. Acute renal failure ARF is a common complication in critically ill patients and an independent risk factor for morbidity and mortality.

Clinical Pharmacology and Therapeutics —, Polyene antibiotic-sterol interaction. Sodium status influences chronic amphotericin B nephrotoxicity in the rat. Mitigation of amphotericin B nephrotoxicity with mannitol. British Medical Journal 1: —, Role of adenosine in signal transmission of tubuloglomerular feedback. Kidney International S—S, Adenosine as a possible mediator of metabolic control of glomerular filtration rate.

International Journal of Biochemistry —, Prevention of postoperative acute renal failure with mannitol in cases. Surgery 15—23, Reduction of amphotericin B nephrotoxicity with mannitol. Nephrotoxicity of amphotericin B in dogs: a comparison of two methods of administration. Canadian Journal of Veterinary Research 23—28, Amphotericin B-induced reduction in the glomerular filtration rate: a micro-puncture study. Journal of Pharmacy and Experimental Therapeutics, in press, Effect of mannitol on acute amphotericin B nephrotoxicity.

Research in Experimental Medicine 85—90, A therapeutic dilemma, the treatment of disseminated coccidiomycosis. Schaffner CP, Mechlinski W. Polyene macrolide derivatives, II: Physical-chemical properties of polyene macrolide esters and their water soluble salts.

Journal of Antibiotics Tokyo —, Amphotericin B-induced changes in membrane permeation: a model of nephrotoxicity. Biochemical and Biophysical Research Communications —, Schlondorff D. The glomerular mesangial cell: an expanding role for a specialized pericyte. Schnermann J. Regulation of single nephron filtration rate by feedback: facts and theories.

Clinical Nephrology 3: 75—81, Inhibitory effect of methylxanthines on feedback control of glomerular filtration rate in the rat kidney. Nephrotoxicity in leukemic patients receiving empirical amphotericin B and aminoglycosides. Southern Medical Journal —, Defect in urinary acidification induced in vitro by amphotericin B.

Effect of high concentrations of nystatin upon glycolysis and cellular permeability in yeast. Amphotericin B nephrotoxicity with irreversible renal failure.

The action of piramicin, etruscomycin, and amphotericin B on liposomes with varying sterol content. Thurau K. Modification of angiotensin-mediated tubuloglomerular feedback by extracellular volume. Kidney International 8: S—S, Thurau K, Boylan JW. Acute renal success: the unexpected logic of oliguria in acute renal failure. Tolins JP, Raij L. Chronic amphotericin B nephrotoxicity in the rat, protective effect of prophylactic salt loading. American Journal of Kidney Diseases —, a.

Adverse effect of amphotericin B on renal hemodynamics in the rat: neurohumoral mechanisms and influence of calcium channel blockade. Journal of Pharmacology and Experimental Therapeutics —, b. Winn WA. Coccidiomycosis and amphotericin B. Medical Clinics of North America —, Wright FS, Schnermann J.

Interference with feedback control of glomerular filtration rate by furosemide, triflocin and cyanide. Download references. You can also search for this author in PubMed Google Scholar. Reprints and Permissions. Sabra, R. Amphotericin B Nephrotoxicity.

Drug-Safety 5, 94— Download citation. Published : 04 October Issue Date : March Anyone you share the following link with will be able to read this content:. Sorry, a shareable link is not currently available for this article. Provided by the Springer Nature SharedIt content-sharing initiative.

Skip to main content. Search SpringerLink Search. Summary The frequency of fungal infections is increasing. References Andriole VT. Branch Authors Ramzi Sabra View author publications. View author publications. Rights and permissions Reprints and Permissions. 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.