Experimental studies on nephrotoxicity of aminoglycosides at low doses. Mechanisms and perspectives

Abstract

The nephrotoxicity of aminoglycosides is an important consideration in the clinical use of these agents. The underlying biochemical and cytologic mechanisms have, therefore, been the subject of many extensive studies. Few experimental studies, however, have employed doses relevant to those used in clinical practice. This article focuses on data obtained using such a "low-dose" approach. Aminoglycosides accumulate specifically in the lysosomes of proximal tubular cells by a process of adsorptive pinocytosis; in the lysosomes, they induce a phospholipidosis that has been studied in vivo and in vitro (e.g., by computer-aided conformational analysis). A similar phospholipidosis is also observed in humans. The overall nephrotoxicity of aminoglycosides results from a combination of their intrinsic ability to bind to phospholipids and the extent of their renal uptake. The development of phospholipidosis is accompanied by focal necroses, tubular regeneration, and interstitial proliferation, even at low, therapeutic doses of these agents. These changes are related to the nephrotoxic potential of the aminoglycosides. Of all 2-deoxystreptamine-containing aminoglycosides tested so far, and by all criteria, amikacin is associated with the least dramatic alterations. Together, these approaches may provide a rational basis to study and compare the nephrotoxicity of aminoglycosides at clinically relevant dosages. They may also serve for the screening and design of aminoglycosides with lower toxicity than those currently available.