Literature search and review of mechanism of renal toxicity foramphotericin B.

Fråga: Literature search and review of mechanism of renal toxicity foramphotericin B.

Sammanfattning: Amphotericin B binds to sterols in the fungal cell membrane, thereby damaging its function and increasing permeability. This mechanism is responsible not only for the fungicidal effect but also for its kidney toxicity. The tubulo-glomerular feedback is activated because of increased ion delivery. Thus, GFR and blood flow are reduced. In the distal tubule, defects in hydrogen excretion is characteristic, with resulting metabolic acidosis.

Renal lesions are usually reversible, but the acidification defect may last as long as a year after discontinuation of therapy.

Svar: Amphotericin B is a polyene antibiotic with a large molecular weight of 924. The term polyene refers to the presence of double bonds. In amphotericin B there are seven conjugated double bonds along the hydrophobic side of the circular molecule. There are also several hydroxyl groups along the hydrophilic side and a mycosamine side chain (1). The drug is insoluble in water, has a poor absorption, and 95 per cent of drug in plasma is bound to lipoproteins (1). Amphotericin B is slowly excreted. Only insignificant amounts are recovered as unchanged drug and impaired renal function does not significantly alter the serum concentration (1,2). Amphotericin B binds to fungal cell membrane sterols, mainly ergosterol, increasing cell membrane permeability (2,3). Bacteria that lack sterols as components of their membranes are not affected by polyenes (3) but mammalian cells that possess cholesterol are also disrupted by polyenes (3). The binding of amphotericin B to microorganisms appears to result in a leakage of small intracellular molecules (e.g. potassium) and larger molecules eventually leading to cell death.

Amphotericin B has profound effects on cell membrane functions. Amphotericin B and cholesterol complexes in membranes forms aqueous pores large enough to allow the passage of cations, anions, and neutral solutes smaller than the size of sucrose (3). This membrane alteration may induce two different mechanisms of nephrotoxicity: renal vasoconstriction and direct toxic effect on renal tubules.

The nephrotoxicity of antifungal agents has been reviewed recently (2). The effect of amphotericin B on the proximal tubular function might modify membrane permeability, increasing thedelivery of monovalent ions to the macula densa. This activates tubuloglomerular feedback and GFR and renal blood flow arereduced (2). These effects have been described in man, dogs, andrats, as a doserelated phenomenon, although renal plasma flow is reduced to a greater extent than GFR, suggesting a disproportionate afferent arteriolar vasoconstriction (2,5). This can be antagonized by dopamine and saralasin, which antagonize renal vasoconstriction (2). In a clinical study where special action was taken to treat sodium depletion by increased sodium intake, the signs of renal toxicity were reversed (6).

The characteristic clinical picture of renal toxicity consists of proteinuria, haematuria, urinary sediment changes, elevated BUN and creatinine, altered urine concentrating ability with renal potassium wasting and subsequent hypokalemia, distal renal tubular acidosis and subsequent metabolic acidosis, and in some cases, ADH-resistant nephrogenic diabetes insipidus (1-4). Histologically, proliferative glomerular and degenerative tubular changes are common. In man, histological examination of renal tissue following amphotericin B treatment has revealed intracellular calcium deposits with necrosis of the proximal and distal convoluted tubules and thickened tubular basement membranes, but only minor changes in glomeruli. Tubular damage with nephrocalcinosis is the most frequently reported kidney pathology associated with amphotericin B administration. In humans nephrocalcinosis has been described in both the proximal anddistal tubule.

Lesions of distal tubular transport capacity predominate in early toxicity. Amphotericin B induces a distal renal tubular acidosis characterized by a decrease in net acid excretion and impaired urinary concentrating ability. As the permeability for hydrogen and potassium ions is greatly increased, the influx of hydrogen ions into cells is accelerated by the presence of amphotericin B when the external medium is more acid than the interior of the cell. Cell components are then damaged by autolytic enzymes activated by the increased hydrogen ion concentration (3). Another mechanism of cell lesion is the increased amount of oxygen consumed in active electrolyte transport. This results in a hypoxic lesion in the medullary thick ascending limb of Henle´s loop, a nephron segment with a relatively low oxygen supply (2,3,5). Nephrogenic diabetes insipidus, or renal potassium wasting with hypokalemia are clinical consequences. In patients with normal renal function the increase in potassium excretion will yield hypokalemia. In anuric patients hyperkalemia may occur, due to the liberation of intracellular potassium, and insufficient elimination. In these cases, the risk of ventricular fibrillation due to hyperkalemia is high, and potassium levels should be monitored carefully. Rapid infusion of amphotericin B should not be used in patients with impaired potassium excretion (7).

Thetoxic effects are closely related to the total cumulative dose of the drug. Under 600 mg, few clinical renal abnormalities have been observed. Renal abnormalities appear in up to 80 per cent of patients treated with 2-3 g, and almost always when the dose is greater than 5 g (1-4). Serum electrolytes, BUN, and creatinine levels should be followed closely during therapy, and these parameters, rather than the therapeutic response, dictate the daily dosage and the duration of therapy.

Some measures to diminish amphotericin B nephrotoxicity have been attempted. Mannitol infusion can prevent a rise in blood urea nitrogen concentration and serum creatinine, possibly because of itscapacity to increase renal perfusion and urinary flow. Data in humans are controversial. Bullock et al (8) demonstrated that mannitol was not effective, but Rosch et al (9) reported a less nephrotoxic but equally therapeutic candicidal effect in patients treated with amphotericin B and mannitol. Different dosage schedules could explain those differences. Sodium supplementation waspreviously mentioned as being important to decrease the sensitivity of the kidney (6).

The tubular transport defects are usually reversible but the defect in acidification may last as long as a year after discontinuation of therapy. Potassium wasting diminishes relatively rapidly after treatment is stopped. The decline in GFR is usually at least partially reversible, but permanent renal failure has been described with prolonged high doses or multiple courses of amphotericin B therapy (1-4). 1 Goodman and Gilman, The pharmacological basis of therapeutics. 1985; 7th ed: 1219-1223 2 Yang DJ, Rankiny GO: Nephrotoxicity of antifungal agents. Adv Drug React Acute Poisoning Rev 1985; 4: 37-49 3 Humes HD, Weinberg JM: Toxic nephropathies. In: The Kidney. Ed by:Brenner BM, Rector FC. Third ed. 2 vol. WB Saunders, Philadelphia, 1986. pp 1491-1507 4 Meyler´s, Side effects of drugs. Ed by MNG Dukes, Elsevier, Amsterdam. 1984; 10th ed: 518 5 Kavlock RJ, Rehnberg BF, Rogers EH: Amphotericin B- and folic acid-induced nephropathies in developing rats. Toxicol Appl Pharmacol 1985; 81: 407-415 6 Heidemann HT, Gerkens JF, Spickard WA, Jackson EK, Branch RA: Amphotericin B nephrotoxicity in humans decreased by salt depletion. Am J Med 1983; 75: 476-481 7 Craven PC, Gremillion DH: Risk factors of ventricular fibrillation during rapid amphotericin B infusion. Antimicrob Agents Chemother 1985; 27: 868-871 8 Bullock WE, Luke RG, Nuttall CE, Bhathena D: Can mannitol reduce amphotericin B nephrotoxicity? Double-blind study and description of a new vascular lesion in kidneys. Antimicrob Agents Chemother 1976; 10: 555-563 9 Rosch JM, Pazin GJ, Fireman P: Reduction of amphotericin B nephrotoxicity with mannitol. JAMA 1976; 235: 1995-1996