|Year : 2002 | Volume
| Issue : 4 | Page : 481-491
|Amphotericin B Nephrotoxicity
Corinne Isnard Bagnis, Gilbert Deray
Department of Nephrology, Pitié – Salpêtrière Hospital, Boulevard de L’hôpital, Paris, France
Click here for correspondence address and email
|How to cite this article:|
Bagnis CI, Deray G. Amphotericin B Nephrotoxicity. Saudi J Kidney Dis Transpl 2002;13:481-91
The frequency of fungal infections is increasing. The mean reason for this rising incidence of mycotic diseases is the higher number of hospitalized patients with risk factors for opportunistic and fungal infections, i.e. compromised immune defense mechanisms. ,
After more than 30 years of clinical use, amphotericin B (AmB) remains the reference treatment for invasive fungal infections. As a result, the drug is widely used despite toxic properties that in other circumstances would render it unacceptable. The most limiting of these side effects and a reportedly common one, is renal toxicity.
This article reviews the clinical aspects, histopathological changes, pathophysiology and prevention of AmB nephrotoxicity with emphasis on the renal tolerance of the new lipid formulation.
| Clinical Aspects of Amphotericin B Nephrotoxicity|| |
The clinical manifestations include renal insufficiency, urinary potassium wasting and hypokalemia, urinary magnesium wasting and hypomagnesemia, metabolic acidosis due to type 1 (or distal) renal tubular acidosis, and polyuria due to nephrogenic diabetic insipidus.
| Azotemia|| |
An increase in blood urea nitrogen (BUN) and serum creatinine (SCr) levels have been reported to occur in over 80% of patients receiving AmB at the time of introduction of this agent.  In more recent studies, 40 to 60% of the patients had at least a doubling in serum creatinine. ,, Azotemia secondary to AmB is usually considered as reversible. However, the incidence of persistent damage has been shown to be dose-dependent. Chronic renal failure was observed in 44% of patients receiving more than a total of 4 g of AmB, whereas only 17% of patients receiving less than 4 g had persistent azotemia.  In another study, only 8% of patients who received less than 1 g had chronic renal insufficiency.  Furthermore in most clinical studies, renal function has been assessed from SCr which provides a rather imprecise measure of glomerular filtration rate. In an old and unique paper, Butler et al  in 1964, have evaluated inulin and paraamino-hippurate (PAH) clearances before, during, and up to 17 months after AmB treatment. Total dosage of treatment varied from 1,536 to 3,511 mg. Glomerular filtration rate (GFR) and renal blood flow (RBF) decreased in all patients during treatment. Glomerular filtration rate remained altered in three out of five patients at least five months after stopping AmB.
| Tubular Defects|| |
It has been clearly documented that AmB induces renal potassium wasting and can produce substantial potassium deficit. Levels below 3 mmol/L have been reported in 12 to 40% of the patients in recent publications. ,, Potassium and magnesium should be routinely monitored during AmB therapy as depletion of these electrolytes can predispose the patient to adverse effects, such as generalized weakness, which can progress to an ascending paralysis with severe depletion, metabolic disorders, neurologic dysfunction, and life threatening arrhythmias. Electrolyte abnormalities may persist for weeks following the discontinuation of AmB therapy. An event more dangerous and rarely reported side effect of rapid infusion of AmB is hyperkalemia , Hyperkalemia can occur because of a serum AmB concentration dependent shift of potassium from the intracellular compartment.
The risk of hyperkalemia appears greatest in patients with renal failure, probably due to decreased ability to excrete a renal load of potassium and possibly aggravated by increased body stores of potassium.
Renal tubular acidosis
The development of renal tubular acidosis during AmB treatment was first reported by Sanford, Rasch and Stonehill. , It is now considered a common dose-related manifestation of the nephrotoxicity of AmB. ,
Acidification defect usually precedes a significant fall in GFR and is generally reversible within a few months of the end of therapy. The incidence of clinically apparent acidosis with a moderate dose of AmB (< 1 g) is quite low (< 2%). All six patients studied by Patterson et al had abnormal response to acid loading when receiving > 1g AmB. 
Hypomagnesemia is a common feature of AmB therapy. ,,, In Barton's study, renal magnesium wasting resulting in mild to moderate hypomagnesemia was demonstrated by the second week of therapy and maximal by the fourth week of treatment with AmB. Although hypomagnesemia is usually mild, a severe decrease in plasma magnesium levels requiring magnesium supplements may develop in some patients. Furthermore, the therapy of hypokalemia associated with AmB can be quite resilient unless hypomagnesemia is corrected. Therefore, routine monitoring of the serum magnesium levels is useful during AmB therapy.
Renal concentrating defect and polyuria,,
This abnormality is almost invariably present in all patients and occurs early (1-2 weeks) in the course of therapy. It is temporally unrelated to azotemia. It is not responsive to vasopressin and is generally reversible a few months after therapy is discontinued.
| Histopathologic Changes|| |
Renal histopathologic changes due to AmB are variable and presumably dose related. Glomerular lesions include thickened or fragmented basement membranes, hypercellularity, fibrosis and hyalinization. Tubular lesions include focal and generalized degeneration and atrophy involving primarily the ascending limb of the loop of Henle and the distal convoluted tubules where the concentration of unreabsorbed solute and the urine acidity are greatest. Nephrocalcinosis occurs in both the proximal and distal convoluted tubules with divalent calcium ion found intraluminaly, intracellularly and interstitially but in the greatest concentration at the corticomedullary junction.
Changes as a result of AmB nephrotoxicity take place both in areas known to be most vulnerable to hypoxia (medullary ray and medulla), and in areas rich in oxygen (adjacent to glomeruli).
| Clinical Consequences of Amphotericin B Nephrotoxicity|| |
AmB nephrotoxicity is not a benign complication. It is not just a "reversible increase in serum creatinine". Amphotericin B nephrotoxicity increases both patient's cost of treatment and mortality.
Pharmaco-economic analysis of liposomal AmB versus AmB-lipid complex (ABLC) in the empirical treatment of persistently febrile neutropenic patients was recently performed by Greenberg et al.  Hospital billing data were collected on 89 of 244 patients enrolled in a randomized, double blind, comparative, multicenter trial.  In both the clinical and cost study samples, ABLC patients had a higher incidence of nephropathy. Hospital costs were higher in patients who developed nephrotoxicity across all treatment groups (37,246 US dollars for no renal toxicity versus 62,004 US dollars for renal toxicity, p < 0.05).
Furthermore, patients who developed renal toxicity in the cost study sample were more likely to require dialysis. Hospital costs excluding drug costs were highest in the renal toxicity and dialysis groups.
Wingard et al  have shown that AmB nephrotoxicity increases patients' mortality. The records of 239 immunosuppressed patients, aged 13 or older, receiving AmB for suspected or proven aspergillosis were reviewed in five transplant and cancer centers between 1990 and 1993 to determine nephrotoxicity, dialysis and fatality rates. During AmB treatment or within 30 days of cessation, the creatinine doubled in 53%, exceeded 221 µmol/L in 29%, dialysis was used in 14.5% and death occurred in 60% of patients.
Dialysis was necessary in 38% of patients in whom the creatinine exceeded 221 µmol/L. In a multivariate Cox proportional hazards analysis, allogenic bone marrow transplant (BMT) patients (HR = 6.34, p < 0.001), autologous BMT patients (HR = 5.06, p = 0.024) and patients in whom the SCr exceeded 221 µmol/L (HR = 42.02, p < 0.001) were at greater risk for requiring hemodialysis. In a multivariate Cox proportional hazards analysis after adjustment for duration of AmB treatment factors significantly associated with mortality were: the use of hemodialysis (HD) (HD = 3.089, p < 0.001) and the use of nephrotoxic agents (HR = 1.96, p = 0.017) while solid organ transplant (SOT) patients were at lower risk (HR = 0.46, p = 0.002). In this study, nearly 90% of BMT patients underwent hemodialysis if their SCr level exceeded 221 µmol/L and nearly half received hemodialysis, if their SCr exceeded 176.8 µmol/L. Thus, it is clear that when treating BMT patients, switching to alternative treatments may be proposed at lower levels of increased SCr than they would when treating SOT patients or nontransplantation-immunocompromised patients.
| Mechanisms of Nephrotoxicity|| |
It has been proposed that both tubular injury and renal vasoconstriction play an important role in AmB nephrotoxicity. 
Polyenes antibiotics exert their antifungal effect by altering the membrane permeability of the fungal cell, leading to the loss of intracellular elements. However AmB also binds to cholesterol molecules found in mammalian cell membranes. AmB is inserted into cell membranes, resulting in the creation of pores that increase membrane permeability in the renal vasculature and renal epithelial cells. Vascular and tubular effect of AmB are thought to be secondary to these effects on cell membranes.
An acute renal vasoconstrictive effect of AmB has been well established in animals and humans. ,, Infusions of AmB intravenously or into the renal artery, induce short-term reduction in renal blood flow and glomerular filtration rate and an increase in glomerular afferent arteriolar and renal vascular resistance. The role of decreased renal blood flow as a major contributor to the decreased glomerular filtration rate is suggested by the lack of correlation between azotemia and the severity of morphologic changes. The mechanism(s) of the contractile response to AmB has been the focus of many studies. The drug may act either directly on the vascular smooth muscle or through release of secondary mediators. A role for tubulo glomerular feedback in acute AmB nephrotoxicity was derived from early studies, which showed inhibition of the acute renal effects of AmB by physiological and pharmacological interventions that also blocked tubuloglomerular feedback. ,,
However, recent studies did not provide support for a role of the tubulo glomerular feedback mechanism in the AmB-induced reduction of glomerular filtration rate.  Neither renal denervation, angiotensin II receptor blockade,  ganglionic or adrenergic blockade  nor selective dopamine DA1 agonist , prevented the renal effects of AmB.
Potent vasodilators such as dopamine, , hydralazine and nitroprusside , were also ineffective in preventing AmB-induced vasoconstriction. Endothelin does not appear to be involved in the acute renal responses to AmB. Indeed, in vivo and in vitro studies have shown that AmB does not alter plasma endothelin levels in rats and does not stimulate endothelin release from cultured bovine aortic endothelial cells.
Finally, there is evidence that AmB activates the synthesis of arachidonic metabolites. In a recent in vitro study, supernatant levels of thromboxane B2 were found significantly elevated in the presence of AmB versus buffer alone. Furthermore in the same study, a specific thromboxane A2 receptor antagonist was found to reverse AmB-induced renal vasoconstriction.  Direct vasoconstriction may be a possible cause for AmB-induced nephrotoxicity. AmB may act as a calcium ionophore and/or alters calcium fluxes by changing membrane potential.
Increased tubular permeability, mainly in the distal tubule but also in the proximal tubule, has been related to increase in the solute permeability of plasma membranes produced by interaction of the antibiotic with membrane bound sterols. ,, AmB binds to ergosterol in fungal cell walls and with lesser affinity to cholesterol in mammalian plasma membranes. Thus, pores or ion channels are created allowing transmembrane ion and metabolite fluxes. Sodium influx is a dominant consequence, resulting in Na +K + -adenosine triphosphatase (ATPase)-driven sodium extrusion and adenosine triphosphate (ATP) use. To maintain cellular ATP levels, dramatic dose increments in mitochondrial respiration and hence, oxygen consumption results. If energy demand outstrips ATP production, energy depletion, free radical generation and cell calcium overload may result. These processes can culminate in cell death. Recently, evidence for a fundamental change in plasma membrane sphyngomyelin and ceramide expression during the early stages of polyene-mediated tubular toxicity has been reported. That both sphyngomyelin and ceramide content can critically alter tubular injury responses strongly suggests that these changes are not simply epiphenomena but rather potential determinants of polyene-induced tubular cell attack.
Tubular abnormalities mostly arise from the direct effect of the drug on distal cellular membranes. Impaired acidification is caused by increased passive permeability of the luminal membrane and back diffusion of hydrogen ion. Renal concentrating defect is secondary to an alteration in the normally urea-impermeable membrane of the cortical duct. Finally, an increase in the passive fluxes of potassium down its electrochemical gradient may explain potassium wasting.
| Prevention of Amphotericin B Nephrotoxicity|| |
Therapeutic interventions that decrease AmB nephrotoxicity are of critical importance. They include the detection and suppression of risk factors, salt supplementation, pharmacological agents and the use of new liposomal formulations.
Risk factors for AmB nephrotoxicity include higher average daily dose (approximately a doubling for each 0.16 mg/kg/day increment), diuretic use, concomitant use of nephrotoxic drugs and abnormal baseline renal function. ,
Diuretics have been employed extensively as co-therapy with AmB and protective effect have been claimed from one small uncontrolled clinical study and from experimental works in the dog.  Only one double blind controlled study has been performed in 11 patients to evaluate the capacity of mannitol to diminish the nephrotoxicity of AmB in man. This study has failed to confirm a beneficial effect of mannitol in this indication. 
More recent studies have shown that diuretics administered during the course of AmB until three days prior to nephrotoxicity conferred a 12.5 fold increase in the risk for nephrotoxicity.  Diuretics given before the initiation of AmB therapy did not confer an increased risk. Furthermore, furosemide and mannitol may aggravate AmB induced electrolytes abnormalities.
There has been concern over shortening the infusion time because of fear that there may be an increase in infusion related toxicity. In one randomized, double blind trial of 45 min versus four hours infusions of AmB, no difference was found in the renal tolerance of AmB.  Chills, nausea and vomiting were more common in those who received AmB rapidly.
The mean creatinine clearance was marginally higher for the slow group throughout the study, but the difference was not significant. It fell progressively with time in both groups. However, in patients with renal insufficiency rapid infusion may be responsible for hyperkalemia and arrythmias.
More recently, Eriksson et al  have compared the effects of AmB deoxycholate infused over 4 or 24 hours in a randomized controlled trial. They found that patients in the continuous infusion group had fewer side effects and significantly reduced nephrotoxicity compared with those in the rapid group.
Experimental animal data  as well as limited uncontrolled trials in humans  have suggested that an emulsion of AmB in 20% lipid solution (Intralipid) can cause less nephrotoxicity than the conventional colloidal suspension in dextrose water. Since then, eight randomized studies have evaluated the safety and toxicity of intravenous AmB deoxycholate prepared in either glucose or intralipid. ,,,,,,, Amphotericin B diluted in a lipid emulsion was found to be less nephrotoxic in five studies and provided no renal benefit in three others. Furthermore, AmB deoxycholate-intralipid was associated with potential pulmonary side effects possibly because of fat overload or an incompatibility of the two drugs. 
The antimycotic efficacy of AmB in intralipid is another controversial issue. Amphotericin lipid mixtures are unstable, show an increase in particle size in emulsion over a short period and do precipitate. Therefore, self made lipid emulsions of AmB should be regarded as unsafe until more pharmacological data are available.
Animal and human studies including prospective and controlled trials, have shown the effectiveness of sodium loading as therapy for AmB nephrotoxicity. Unfortunately sodium loading has not gained wide acceptance as routine practice despite continued substantial reduction of nephrotoxicity. Five human Studies ,,,, of sodium loading therapy, including three prospective randomized trials, have convincingly shown that sodium loading in excess of the usual dietary intake reduces the incidence and severity of AmB-induced nephrotoxicity and may even reverse preexisting nephrotoxicity. The only prospective, double-blind, placebo controlled trial done to assess the protective effects of sodium chloride loading in AmB-induced nephrotoxicity was reported in 1991.  The investigators studied 20 male patients who were being treated with 50 mg of AmB three times per week for 10 weeks for mucocutaneous leishmaniasis. Ten subjects were given one liter of a 5% dextrose solution intravenously before the AmB therapy, and 10 were given one liter of a 0.9% sodium chloride solution intravenously. Serum creatinine levels rose and creatinine clearances decreased significantly in the dextrosetreated group compared with the salinetreated group. A faster loss of acidifying ability occurred in the saline treated group.
Strong circumstantial clinical evidence based on a handful of cases, retrospective and prospective studies and one placebo controlled trial supports the use of sodium chloride supplementation to prevent and to treat AmB-induced nephrotoxicity. Definitive clinical proof of efficacy with a placebocontrolled trial in a representative patients group is probably not forthcoming. The treatment is safe and easy to administer. The best route, dose and timing of sodium chloride therapy to maximize benefit and minimize complications need to be determined. In the meantime, we should probably be administering at least one liter of isotonic saline per day intravenously to patients receiving AmB therapy who can safely tolerate this salt load.
| Lipid Formulations of Amphotericin B|| |
For the past decade, investigators have evaluated the use of lipid formulations of AmB as a target drug delivery system for AmB in an attempt to attenuate its nephrotoxicity and increase its therapeutic potential. Three lipid formulations of AmB are now marketed for clinical use. AmB lipid complex (ABLC, Abelcet) is a concentration of ribbonlike structures of a bilayered membrane formed by combining a 7.3 molar ratio of dimyristoyl phosphatidyl choline and dimyristoyl phosphatidyl glycerol with AmB.
AmB colloidal dispersion (ABCD, Amphocil) is composed of disk like structures of cholesteryl sulfate complexed with AmB. AmBisome, the only true liposomal AmB, consists of small unilamella vesicles made up of bilayer membrane of hydrogenated soy phosphatidylcholine and distearoylphosphatidyl glycerol in a 2:08:1 ratio combined with AmB.
Seven randomized studies have reported on the comparative renal tolerance of AmB lipid formulations with conventional AmB or each other in humans. ,,,,,,,
ABCD was compared to AmB in a randomized double blind study in patients with fever and neutropenia.  Two hundred and thirteen patients were randomized to receive ABCD (4 mg/kg/day) or AmB (0.8 mg/kg/day) for < 14 days. ABCD recipients had significantly less renal toxicity than did AmB recipients whether they were being treated with cyclosporin and aminoglycosides or not. In addition, the absolute and percentage decline in the serum potassium level from baseline to the end of therapy was greater for AmB deoxycholate recipients than for ABCD treatment.
Two randomized studies have compared the renal tolerance of Abelcet and AmB deoxycholate. In 1995, Anaissie et al reported, in an abstract, a randomized trial on 231 patients treated with either Abelcet (5 mg/kg/d) or AmB deoxycholate (0.8 to 1.0 mg/kg/d) for hematogenous and invasive candidiasis.  They concluded that the frequency of adverse events was similar between the two treatment groups except for nephrotoxicity which was more common in patients receiving AmB baseline. Serum creatinine doubled in 28% of Abelcet patients and in 47% of AmB deoxycholate patients. Unfortunately, those results were never published as a full paper.
Sharkey et al have compared the renal effects of Abelcet and AmB in the treatment of cryptococcal meningitis in patient with AIDS.  Fifty-five patients were randomized to six weeks therapy with Abelcet (1, 2 or 5 mg/kg/day) with ascending doses for three consequential cohorts or AmB deoxycholate (0.7 to 1.2 mg/kg/day). Mean difference from baseline SCr values over the six weeks duration of the study favored Abelcet over AmB deoxycholate at weeks two and three for the 5 mg/kg/day dose. The true incidence of acute renal failure was not reported in this paper. However, those results were presented two years later in a review on the renal effects of AmB lipid complex.  A doubling in SCr was observed in 50% and 53% of patients treated with Abelcet and AmB respectively. Obviously, a randomized double blind study is necessary to precise clearly the comparative renal tolerance of Abelcet and AmB deoxycholate.
Three randomized studies focused on the comparative renal tolerance of AmBisome and AmB deoxycholate. Those three randomized studies have shown that AmBisome is clearly less nephrotoxic than AmB deoxycholate. In Prentice's trial,  174 adults and 204 children were randomized in two prospective parallel comparative multicentre trials to receive either conventional AmB deoxycholate (1 mg/kg/day) or AmBisome (1 mg/kg/day or 3 mg/kg/day). Nephrotoxicity, in the patient subset not receiving concomitant nephrotoxic agents, defined as a doubling from the patients baseline SCr level, was not observed in the AmBisome 1 mg arm, whereas the incidence was 3% in patients on AmBisome 3 mg and 23% in those on amphotericin B deoxycholate (p < 0.01). Moreover, the time to develop nephrotoxicity was longer and hypokalemia was observed less frequently in both AmBisome arms (p < 0.01).
Leenders et al have reported a randomized multicentre study comparing AmBisome (5 mg/kg/day) to AmB deoxycholate (1 mg/ kg/day) in 66 patients treated for documented or suspected neutropenia-associated invasive fungal infections.  Mean change from baseline SCr was 86% in the AmB deoxycholate and 1.4% in the AmBisome group (p<0.001). Significantly more patients treated with AmB deoxycholate had a 100% increase of their baseline SCr (40% vs 12%, p< 0.001).
Recently, Walsh et al have conducted a randomized double blind multicenter trial comparing AmBisome (3 mg/kg/day) and AmB deoxycholate as empirical therapy for patients with persistent fever and neutropenia.  Significantly fewer patients receiving AmBisome had nephrotoxic effects as indicated by the doubling or tripling of the serum creatinine level (p < 0.001) or by peak serum creatinine values above 309.4 µmol/L. This significant reduction in azotemia was also consistent among subgroups of patients receiving concomitant therapy with nephrotoxic agents. Moreover, there was a decrease in the incidence of hypokalemia.
Wingard et al have recently published a randomized, double blind comparative trial evaluating the safety of AmBisome and Abelcet in the empirical treatment of febrile neutropenia.  A total of 250 patients were randomized to receive either Abelcet 5 mg/kg/day, AmBisome 3 mg/kg/day or AmBisome 5 mg/kg/day. AmBisome had a significantly better safety profile than Abelcet with less chills/rigors, less nephrotoxicity (14.1%, 14.8% vs 42.3%) and fewer toxicity related discontinuation of therapy.
In conclusion, AmB nephrotoxicity is not a benign complication. It results in excess mortality and higher hospital costs. The recognition of risk prevention and early intervention are much more effective than treatment of established acute renal failure.
A change in the creatinine level, however small, should be regarded as consequential and should trigger review and possible intervention. The use of isotonic saline, the suppression whenever possible, of all risk factors and the use of true liposomal formulation should help physicians to decrease the incidence rate of this devastating complication.
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