Nephrotoxic and ototoxic agents

It is well established that many drugs, such as the aminoglycoside antibiotics and the chemotherapeutic drug cisplatin, are capable of inducing both nephrotoxicity and ototoxicity. The factors that selectively predispose the kidney and inner ear to the toxic effects of these agents as well as the mechanism by which damage is produced are not well defined. The two organs differ greatly in their exposure to these toxic agents. The kidney has an abundant vascular supply and tends to selectively concentrate a number of drugs within the renal cortex or medulla, often to toxic levels. The vascular supply of the inner ear is not as extensive. In addition, the stria vascularis of the cochlea may act as a functional regulator of drug entry into inner ear fluids. The absorption of drugs into perilymph and endolymph is poorly understood. Selective accumulation theories of drug accumulation in the inner ear must be questioned because of the results of recent pharmacokinetic studies, which give contrary data. Drug-induced ototoxicity and nephrotoxicity can be explained on a cellular level. Studies using radiolabeled gentamicin suggest that binding mechanisms of the drug to the plasma membrane of the outer hair cells of the cochlea and vestibular apparatus and to the brush border receptors of the renal proximal convoluted tubules are similar. This suggests the same receptor sites for aminoglycosides occur in otic and renal organs. Calcium channels are implicated because of the reversibility of aminoglycoside-induced changes in the cochlear microphonic by calcium and other divalent cations. Calcium channel blockers, such as verapamil, reduce the nephrotoxicity of a number of drugs that are also ototoxic. Studies are needed to assess potential prevention of ototoxicity by use of these same calcium channel blocking agents. Aminoglycosides concentrate within the lysosomes of renal proximal tubular cells. Possibly, they also may concentrate in lysosomes within the cells of cochlear and vestibular structures. Nephrotoxic heavy metals concentrate within proximal tubular cells and, some, such as lead or bismuth, specifically concentrate within intracytoplasmic or intranuclear inclusion bodies. Studies are necessary to determine if the same metals accumulate within the cochlear and vestibular cells, inclusion bodies, or both. These questions and others must be answered before it can be determined why many nephrotoxic drugs and agents are also ototoxic.