Enzymuria following amphotericin B application in the rat

Abstract

The effect of amphotericin B application on urinary renal tubule enzyme excretion was investigated in rats treated with amphotericin B (1.5 mg kg-1 b.i.d., i.v.) for 4 days. Application of amphotericin B induced a significant higher daily urinary enzyme activity of the renal tubular enzymes N-acetyl-beta-glucosaminidase (NAG), beta-glucuronidase (GRS), alanine-aminopeptidase (AAP) and gamma-glutamyltransferase (GGT) in comparison with controls and sodium deoxycholate treated animals as well. A significant increase in the renal excretion of NAG, GRS, AAP and GGT occurred after the first day of amphotericin B treatment and continued until the fourth day. Following treatment for 4 days with amphotericin B urine AAP activity amounted to 69 +/- 19 U g-1 creatinine, control: 39 +/- 7 U g-1 creatinine (P < 0.05). After 4 days GGT excretion increased to 803 +/- 238 U g-1 creatinine, control: 445 +/- 106 U g-1 creatinine (P < 0.05). At the fourth day NAG excretion was 80 +/- 39 U g-1 creatinine, control: 23 +/- 5 U g-1 creatinine (P < 0.05) and GRS 724 +/- 604 U g-1 creatinine (amphotericin B), control: 276 +/- 158 U g-1 creatinine (P < 0.05). Treatment with amphotericin B decreased the creatinine clearance significantly: 0.94 +/- 0.16 ml-1 min-1 vs. control 1.35 +/- 0.29 ml-1min-1 (P < 0.05). Fractional sodium and potassium excretion was not influenced by amphotericin B. The application of sodium deoxycholate had no influence on urinary renal tubular enzyme activity. The results show that amphotericin B application induces early enzymuria of renal tubule enzymes suggesting damage of proximal renal tubules.

COMMUNICATION: Pharmacokinetics and Nephrotoxicity of Amphotericin B-Incorporated Poly(Ethylene Glycol)-Block-Poly(N-Hexyl Stearate l-aspartamide) Micelles

“…10,11,12 Previous reports have shown that AmB-D significantly increases urinary NAG levels in rats. 13 Similarly, AmB-D increased urinary NAG level after a single injection, increasing NAG levels by 3-fold. In contrast, AmB-incorporated PEG- b -PHSA micelles did not significantly alter urinary NAG output relative to control rats, despite similar biodistribution of AmB into the kidneys for AmB-incorporated PEG- b -PHSA micelles and AmB-D (Figure 1).…”

“…have shown that AmB-D treatment also induces a significant increase in urinary GGT output following treatment. 13 In the kidney, GGT is located on the external surface of the brush border membrane of the proximal tubule and is shed into the urine rather than the blood when cell injury occurs. In this study, AmB-D has also been found to significantly increase urinary GGT activity in comparison to control rats (p < 0.05).…”

Urinary Aminopeptidase Activities as Early and Predictive Biomarkers of Renal Dysfunction in Cisplatin-Treated Rats

“…In consequence, AlaAp activity has been widely used as a marker of renal dysfunction in animal models of nephrotoxicity induced with vancomicine [24] or amphotericin B [25], or in human diseases like glomerulopathies [26], IgA nephropathy [27], rheumatoid arthritis [28] or diabetes [29], and there are contradictory results about its utility as a marker in kidney transplanted patients [30], [31].…”

Reformulation of Fungizone by PEG-DSPE Micelles: Deaggregation and Detoxification of Amphotericin B

“…AmB tends to self-aggregate, a property that contributes to loss of binding specificity and consequential toxicity (2). Severe nephrotoxicity has limited its clinical use, prompting researchers to focus on safely solubilizing and reducing toxicity of the drug (3–7). Attempts to reduce toxicity have resulted in formulations that are less nephrotoxic in comparison to the original AmB formulation, Fungizone ® (AmB-SD).…”