INTRODUCTION — Amphotericin B is used in the treatment of often life-threatening fungal infections (see "Pharmacology of amphotericin B"). Impaired kidney function is a relatively common complication of amphotericin B, as are other kidney manifestations, including urinary potassium wasting and hypokalemia, urinary magnesium wasting and hypomagnesemia, metabolic acidosis due to type 1 (or distal) renal tubular acidosis (RTA), and polyuria due to nephrogenic diabetes insipidus [1-5].
An overview of amphotericin B nephrotoxicity is presented here. The management of hypokalemia, hypomagnesemia, distal RTA, and nephrogenic diabetes insipidus is discussed in detail elsewhere:
●(See "Clinical manifestations and treatment of hypokalemia in adults", section on 'Treatment'.)
●(See "Hypomagnesemia: Evaluation and treatment".)
●(See "Treatment of nephrogenic diabetes insipidus".)
ACUTE KIDNEY INJURY
Incidence with conventional amphotericin B — Conventional amphotericin B (ie, not the lipid formulations) causes renal vasoconstriction and can reduce the glomerular filtration rate (GFR) by more than one-half [1-4,6,7]. In the two largest reviews, a 50 percent or greater increase in serum creatinine was observed in 138 of 494 and 174 of 643 patients (28 and 27 percent), respectively [4,6].
The risk of amphotericin-induced kidney injury is influenced by other factors:
●Concurrent therapy with other nephrotoxins, such as an aminoglycoside, cyclosporine, or foscarnet, increases the risk of acute kidney injury (AKI) [4,6-8]. In one report, the incidence of a twofold or greater increase in serum creatinine was 15 percent in patients taking no or one concurrent nephrotoxic drug and 41 percent in those taking two or more concurrent nephrotoxic drugs [7].
●Chronic kidney disease at baseline and the severity of the underlying illness also increase the risk [4,6]. In one series, the incidence of moderate to severe nephrotoxicity (defined as a doubling of the serum creatinine to a level greater than 2 mg/dL) was 4 percent in patients with no risk factors for AKI and 8 to 29 percent in those with chronic kidney disease [6].
●The likelihood of kidney disease is also dose dependent, with the risk of kidney dysfunction being low at doses of less than 0.5 mg/kg per day and a cumulative dose of less than 600 mg [4,6,8].
A prediction rule risk stratified patients based upon the following clinical data available during the course of therapy: location of care (general medical unit versus intensive care unit), concurrent use of cyclosporin, and maximum daily amphotericin B dose (<60 mg versus ≥60 mg daily). In the lowest risk group (12 percent of patients), the risk of nephrotoxicity was 4 percent, while in the highest risk group (10 percent of patients), the risk of AKI was 80 percent [4].
In most cases, the serum creatinine increases by no more than 2.5 mg/dL (220 micromol/L) above baseline [1,4,6,9]. More severe kidney injury due to amphotericin B alone is uncommon but can occur with diuretic-induced volume depletion or the concurrent administration of another nephrotoxin.
Issues related to prevention of amphotericin B nephrotoxicity, including the use of lipid-based formulations, are discussed below. (See 'Lipid-based formulations' below.)
Pathogenesis — The mechanism of amphotericin-induced nephrotoxicity is incompletely understood. It has been proposed that both tubular injury and renal vasoconstriction play an important role [10,11]. Amphotericin B inserts into cell membranes, resulting in the creation of pores that increase membrane permeability [10]. Proximal tubular cells and medullary interstitial cells respond with programmed cell death when treated with therapeutic doses of amphotericin B. In animal models, the number of apoptotic tubular cells correlates with the degree of hypokalemia and loss of renal concentrating ability; administration of insulin-like growth factor-1, an antiapoptotic agent, prevents hypokalemia and preserves concentrating ability [12]. In addition to this direct effect, in vitro studies suggest that approximately one-half of the tubular toxicity of amphotericin B may be mediated by deoxycholate, a detergent used as a solubilizing agent for amphotericin B [10].
The reduction in GFR associated with amphotericin B-induced tubular toxicity may be mediated in part by the tubuloglomerular feedback (TGF) system [1,9]. Normally, when sodium chloride delivery to the distal tubule increases, a greater quantity of sodium chloride enters the macula densa cells located in the early portion of the distal tubule. This results in a feedback loop (TGF), which triggers afferent arteriolar vasoconstriction and a fall in GFR [1,9]. Under most circumstances, this TGF response is physiologically appropriate: high rates of sodium chloride delivery out of the proximal tubule are restored to near-normal levels by the appropriate reduction in GFR, and this prevents excessive sodium chloride losses in the urine [13].
However, amphotericin B nephrotoxicity increases the permeability of the macula densa cells. This may inappropriately activate the TGF system and lead to excessive afferent arteriolar vasoconstriction and a fall in GFR [1,9].
Alternatively, the renal vasoconstriction and fall in GFR may reflect a direct action of amphotericin B on blood vessels, rather than TGF [14]. In experimental animals, administration of a calcium channel blocker prevents amphotericin-induced vasoconstriction and the resultant decline in GFR [15].
Prevention — The risk of nephrotoxicity can be reduced by using lower doses of amphotericin and by avoiding concurrent therapy with other nephrotoxins, such as an aminoglycoside or cyclosporine [4,6]. Two other preventive measures are salt loading and the use of lipid formulations of amphotericin B. In addition, for some fungal infections, non-amphotericin B agents are now available.
N-acetylcysteine has been shown to protect against amphotericin-induced nephrotoxicity in animal models, preserving GFR and reducing apoptosis of renal tubular cells [16,17]. Evidence for a protective role in humans, however, has been inconclusive [18].
Salt loading — The proposed importance of TGF in amphotericin B nephrotoxicity has led to the use of salt loading since volume expansion has been shown to reduce the sensitivity of the TGF system. Studies in both humans and animals have shown that saline administration can protect against or ameliorate the amphotericin B-induced decline in GFR [1,2,9,19] but not the signs of tubular dysfunction described below [19].
The beneficial effect of salt loading was best shown in a controlled study of patients with mucocutaneous leishmaniasis who received a 10-week course of amphotericin B (average dose 50 mg per day, given three times per week) [19]. The serum creatinine concentration was stable with salt loading (1 liter of isotonic saline over the 60 minutes prior to amphotericin B administration) but rose from 0.6 to 1 mg/dL (53 to 88 micromol/L) in patients given only water. The minor degree of kidney function impairment in the relatively healthy control group probably reflects in part the absence of potentiating factors, such as volume depletion or concurrent aminoglycoside therapy.
However, this benefit of salt loading does not prove that TGF, rather than vasoconstriction, is the major mechanism underlying the reduced GFR. Increases in the secretion of vasoconstrictors (angiotensin II and norepinephrine) and decreases in the secretion of the vasodilator atrial natriuretic peptide might modulate the constrictive effect of amphotericin B [14]; volume expansion could prevent these hormonal changes.
Lipid-based formulations — Experimental [20] and human studies (including both observational [21-24] and randomized trials [25,26]) suggest that the incidence and severity of nephrotoxicity can be minimized, though not eliminated, by administering amphotericin B in a lipid-based formulation. Several lipid-based amphotericin B products exist. Lipid complex (Abelcet) and liposomal (AmBisome) are available in the United States. Colloidal dispersion (Amphocil) is not currently widely available.
The best comparative data are reported in a meta-analysis of randomized trials that compared conventional amphotericin B with both liposomal amphotericin B (five trials, 1233 patients) and lipid emulsion amphotericin B (nine trials, 459 patients) [25]. Compared with conventional amphotericin B, the incidence of nephrotoxicity was significantly reduced with the use of liposomal amphotericin B (14.5 versus 32.5 percent) or lipid emulsion amphotericin B (12.2 versus 30.6 percent).
The reduced risk of nephrotoxicity found in this meta-analysis is consistent with two large retrospective series of 3514 patients treated with lipid-based formulations of amphotericin B [23]. A doubling of the serum creatinine concentration occurred in 13 percent of patients, and 3 percent required dialysis.
The reason why lipid-based formulations are associated with less AKI is incompletely understood. However, two possibilities have been proposed:
●The liposomal preparation does not contain deoxycholate, which (as noted above) has direct tubular toxicity [10].
●The liposomes may be preferentially distributed to the reticuloendothelial system, where amphotericin B can be transferred directly to trapped fungi with less delivery to other cholesterol-containing cells, such as those in the kidney.
Among the lipid preparations, liposomal amphotericin B may be less nephrotoxic than the amphotericin B lipid complex [27].
As with conventional amphotericin B, the risk of nephrotoxicity with lipid-based formulations is higher among patients concurrently treated with other potentially nephrotoxic drugs, including aminoglycosides, cyclosporine, foscarnet, angiotensin-converting enzyme (ACE) inhibitors, and angiotensin receptor blockers (ARBs) [7,23,28,29].
Lipid-based formulations have largely supplanted the use of conventional amphotericin B in countries with adequate resources. However, the conventional formulation is still widely used for HIV-associated cryptococcal meningitis, as recommended by the Infectious Disease Society of America and the World Health Organization. A modified regimen of conventional amphotericin B may lessen kidney disease in such patients. In a trial of 368 patients with HIV-associated cryptococcal meningitis, for example, a shorter course (five to seven days) of amphotericin B, with isotonic saline prehydration and cessation of therapy if the serum creatinine increased to 2.5 mg/dL (220 micromol/L) produced equal efficacy, less nephrotoxicity, and greater reversibility of nephrotoxicity as compared with a standard 14-day course without prehydration [30]. The long-term half-life of amphotericin (up to two weeks) provides ongoing fungicidal activity after discontinuing the drug, which may have accounted for the equal efficacy in patients treated with a shorter course.
ELECTROLYTE DISORDERS — The increase in membrane permeability caused by amphotericin B is also thought to contribute to the electrolyte abnormalities that often occur. This defect results in the reduction of ion concentration gradients, which normally exist between the cytoplasm of distal tubule cells and the tubule lumen. In these cases, potassium leaks from the cytoplasm down a favorable concentration gradient into the lumen. Similarly, hydrogen ions diffuse down their gradient from the lumen into the cytoplasm of distal tubule cells [31]. Thus, an increase in tubular permeability will promote the back-diffusion of secreted hydrogen ions (or of carbonic acid formed by the combination of hydrogen with filtered bicarbonate), thereby limiting acid excretion [32-34]. Hypomagnesaemia and renal magnesium wasting also occur as a result of amphotericin kidney toxicity [34,35]. Amphotericin B is one of three drugs (the other two are cyclosporin and cis-platinum) associated with major renal magnesium loss and magnesium depletion [34]. (See "Hypomagnesemia: Causes of hypomagnesemia".)
The loss of magnesium and potassium may also be related in part to the systemic toxicity of the amphotericin B that causes these intracellular ions to leak into the extracellular fluid space and then be lost into the urine [2].
The net effect of these changes is that both hypokalemia due to potassium loss and a normal anion gap metabolic acidosis (ie, a distal renal tubular acidosis [RTA]) due to hydrogen retention are commonly seen [2,7,31,33]. Hypomagnesemia, though somewhat less common, is also reported. The distal RTA generated by amphotericin B, unlike most other forms of distal RTA, is associated with a normal urine-blood partial pressure of carbon dioxide (PCO2) after alkaline loading [36,37]. This likely results from the previously mentioned back-diffusion of secreted hydrogen ions, but a loss of polarity of the chloride-bicarbonate exchanger is also consistent with this finding [36]. Treatment of the hypokalemia and RTA consists of administering alkali with potassium. (See "Treatment of distal (type 1) and proximal (type 2) renal tubular acidosis", section on 'Distal (type 1) renal tubular acidosis'.)
Amphotericin B may also cause resistance to antidiuretic hormone, leading to polyuria and polydipsia [2,5,7,37]. (See "Clinical manifestations and causes of nephrogenic diabetes insipidus".)
As with acute kidney injury (AKI), electrolyte abnormalities and nephrogenic diabetes insipidus may be less common with liposomal amphotericin B [7,38]. In the randomized trial cited above, liposomal amphotericin B was associated with a significantly lower rate of hypokalemia (serum potassium concentration ≤2.5 mEq/L) but no significant change in the rate of hypomagnesemia (serum magnesium concentration ≤1.5 mg/dL [0.6 mmol/L]) [7]. When conventional amphotericin B is used, patients without significant kidney function impairment should receive daily preemptive administration of potassium, which may prevent serious hypokalemia [30].
In contrast to AKI, the manifestations of tubular dysfunction do not appear to be ameliorated by volume expansion [19]. Treatment of the magnesium wasting consists of the administration of magnesium supplements. However, the efficacy of this regimen is limited by the urinary excretion of most of the supplemental magnesium. (See "Hypomagnesemia: Evaluation and treatment".)
COURSE — The nephrotoxicity associated with amphotericin B is usually reversible with discontinuation of therapy [9,39]. However, recurrent kidney dysfunction can occur if treatment is reinstituted [39].
SUMMARY AND RECOMMENDATIONS
●Amphotericin B commonly causes kidney function impairment, including decreased glomerular filtration rate (GFR), urinary potassium wasting and hypokalemia, urinary magnesium wasting and hypomagnesemia, metabolic acidosis due to distal (or type 1) renal tubular acidosis (RTA), and polyuria due to nephrogenic diabetes insipidus.
●Possible mechanisms for decreased GFR include (1) renal vasoconstriction, due to a direct effect of amphotericin B on the vasculature or to tubular glomerular feedback mediated by the drug's effect on sodium entry into juxtaglomerular cells and (2) tubular toxicity, which alters ion permeability. This is probably mediated in part by binding of the drug to cholesterol in mammalian cell membranes and in part by deoxycholate, a detergent used as a solubilizing agent for the original formulation of amphotericin B. Deoxycholate is not contained in the liposomal preparation.
●The risk of amphotericin B nephrotoxicity is increased by higher daily doses and concurrent therapy with other nephrotoxins, such as an aminoglycoside or cyclosporine.
●The decline in GFR caused by amphotericin B, but not the manifestations of tubular dysfunction, is ameliorated by volume expansion with saline.
●The incidence and severity of nephrotoxicity can be minimized by administering amphotericin B in lipid-based formulations; liposomal amphotericin B may be less nephrotoxic than the amphotericin B lipid complex.
●An increase in membrane permeability induced by amphotericin B is thought to account for the electrolyte abnormalities that often occur: (1) back-diffusion of secreted hydrogen ion and/or carbonic acid from the tubular lumen to the plasma best explains RTA, and (2) enhanced diffusion of potassium from the renal tubular cell to the tubular lumen down a favorable concentration gradient explains renal potassium wasting and hypokalemia. Renal magnesium wasting and hypomagnesemia may develop.
●Amphotericin B may also cause resistance to antidiuretic hormone (nephrogenic diabetes insipidus), leading to polyuria and polydipsia.
●Liposomal preparations of amphotericin B are associated with a lower incidence of acute kidney injury (AKI) and electrolyte abnormalities. The nephrotoxicity associated with amphotericin B is usually reversible with discontinuation of therapy. However, recurrent kidney dysfunction can occur if treatment is reinstituted.
