ANNALS OF CLINICAL AND LABORATORY SCIENCE, Vol. 12, No. 1 Copyright © 1982, Institute for Clinical Science, Inc. Mechanisms of Antibiotic-Induced Nephrotoxicity THOMAS W. SEALE, Ph .D. and OWEN M. RENNERT, M.D. Departments of Pediatrics and Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73190 ABSTRACT Each of the major classes of clinically useful antibiotics can cause neph­ rotoxicity. Major differences exist among classes, and these are reviewed with regard to the frequency of occurrence of nephrotoxicity, the direct or indirect toxic effects of the drugs, their site(s) of action within the kidney, current views of their pathophysiological effects and observations which provide clues to the biochemical mechanisms underlying their adverse effects on kidney structure and function. Even for a single abnormal kidney function, such as non-oliguric reduction of glomerular filtration rate by gentamicin, the physiological and biochemical mechanisms may be com­ plex. In no instance has the biochemical mechanism underlying antibiotic- induced nephrotoxicity been definitely established. Introduction of antibiotics with relatively low Nephrotoxicity has long been recog­ therapeutic indices and significant neph­ nized as a serious complication resulting rotoxic potential. In addition, some from antibiotic administration. The vast widely employed antibiotics with low po­ array of antibiotic types and derivatives tential for inducing renal disease will in­ available to the clinician and the in­ frequently have significant detrimental creased monitoring for early signs of renal effects on the kidneys of certain patients. impairment have reduced the risk of kid­ These idiosyncratic drug responses may ney damage compared to the early days of reflect intrinsic or environmentally- sulfonamide and neomycin therapy. induced changes in renal function or drug However, the improved technical capac­ metabolism. The intent of this paper is to ity to maintain the severely debilitated review concisely current insights into the patient who is markedly more susceptible mechanisms underlying the most fre­ to a variety of opportunistic pathogens and quently encountered types of antibiotic- the increasing incidence of microbial induced nephrotoxicity. The aminoglyco­ drug resistance often necessitate the use sides, amphotericin, and the polymixins 0091-7370/82/0100-0001 $01.50 © Institute for Clinical Science, Inc. 2 SEALE AND RENNERT are reviewed in detail based on a litera­ As shown in table I, these antibiotics ture search complete through December, include a diverse group of chemically dis­ 1980. Additional aspects of this topic can similar compounds which exert their be found in excellent reviews by Appel antimicrobial effects through site-specific and Neu1 and Sanders and Sanders.56 action on several distinct biological targets. The structural and functional dis­ General Features of Antibiotic- similarities among these agents, e.g., Induced Nephrotoxicity polymyxin and penicillin, suggested the likelihood that differences would occur in Several general considerations help to their target sites within the kidney, in provide an overview of the patho­ their biochemical mechanisms of action physiological effects of antibiotics on on renal tissue, and in their frequencies of the kidney. (1) Toxicity has been doc­ inducing renal damages. The order of ar­ umented to occur upon administration of rangement of the antibiotics listed in table the major classes of therapeutically use­ I reflects in general their propensity for ful antibiotics. (2) The frequency of occur­ impairing renal function. Thus, most pa­ rence of antibiotic-induced nephrotox­ tients receiving amphotericin B have icity varies greatly and depends upon the evidence of some degree of nephrotox­ class of antibiotic, the properties of par­ icity.7,13,68 The high frequency (approxi­ ticular derivatives within one antibiotic mately 20 percent) of occurrence of renal class, and the physiological status of the damage associated with colistimethate patient. (3) Several anatomically and func­ (polymyxin E)35 and other polymyxins51 tionally distinct kidney sites are suscep­ limits their clinical application to situa­ tible targets for the adverse effects of tions in which other antibiotics cannot be antibiotics. (4) Antibiotic-induced nephro­ employed. Nephrotoxicity associated toxicity may be indirectly or directly with the aminoglycosides ranges from 2 to mediated. 25 percent of treated patients, depending TABLE I upon the specific aminoglycoside ad­ Commonly Employed Antibiotics ministered, the criteria for defining Causing Nephrotoxicity toxicity, and the patient population.9,15,59 The remaining classes of antibiotics Antibiotic Class Chemical Structure Microbial Target listed in table I are much less frequently Amphotericin Large double bonded Membrane associated with untoward renal effects. ring structure permeability (polyene)-amino (fungal) From the search for improved therapeutic sugar conjugate indices and more useful antimicrobial ac­ Polymyxins Small cationic Membrane tion spectra, many analogs of classic an­ polypeptides permeability tibiotic types have become available. Aminoglycosides Three covalently Protein bonded amino sugars synthesis These derivatives often differ markedly Sulfonamides Derivatives of Folic acid in their renal effects. For example, the p-aminobenzene- synthesis aminoglycosides, tobramycin and amika­ sulfonic acid cin, are markedly less nephrotoxic than Rifampicin Complex double Ribonucleic acid bonded ring synthesis gentamicin in both animal models20,31,42 structure and in man.59,60,61 The relationship be­ Penicillins Thiazolide (five Cell wall tween empirically determined nephrotox­ membered) - synthesis 0-lactam ring icity and chemical modifications of the conjugates parent antibiotic can help to identify par­ Cephalosporins Thiazolide (six Cell wall membered) - synthesis ticular portions of the antibiotic molecule 3-lactam ring which function in the induction of renal conjugates damage and may suggest possible MECHANISMS OF ANTIBIOTIC-INDUCED NEPHROTOXICITY 3 physiological mechanisms of action of many antibiotics on renal functions, cer­ these drugs. tain antibiotics may act indirectly. In addition to the intrinsic toxicity of an In table II is indicated the association of antibiotic, its nephrotoxicity depends each of the major classes of antibiotics upon physiological influences and phar­ with either immunity-mediated phenom­ macokinetic considerations, such as the ena or direct toxic action. In general, the maximum concentration achieved and the immunity-related nephrotoxic activities duration of significant levels of the an­ of antibiotics occur infrequently. Intersti­ tibiotic. Pre-existing renal dysfunction, tial nephritis brought about by methicillin the disease process rendering the indi­ is a rare complication that appears to be vidual susceptible to infection, changes in associated with prolonged exposure to renal blood flow, electrolyte imbalance high levels of antibiotic.3’10 Fever, and pre- or concomitant administration of eosinophilia, and rash, indicators of an other nephrotoxic drugs, increases the immune reaction, often precede or occur likelihood of deleterious effects of an­ concomitantly with the penicillin- tibiotics on the kidney. These factors and induced renal lesion.3 Penicillins, serving the problem of distinguishing between as haptens, produce allergic reactions the patient’s underlying illness and drug- through their ability to stimulate anti­ induced nephrotoxicity make difficult the body production and to initiate hapten- determination of the incidence of antibody reactions. In patients, circulat­ antibiotic-induced renal disease in pa­ ing antibodies to penicillins are not di­ tients. Such factors further complicate the rected to the intact penicillin molecule determination of the mechanisms respon­ but to its degradation products, e.g., the sible for the deleterious action of antibio­ penicilloyl group, that can form covalent tics on the kidney. bonds to proteins.40’50 With the possible exception of the Loop Target organ specificity, as for example of Henle, each region of the nephron can might be suggested to explain the occur­ be damaged by one or more antibiotic rence of interstitial nephritis, could result classes. The proximal tubule, site of the from at least four biochemical factors. (1) quantitatively most significant reabsorp- The intrinsic activity of the metabolic tive functions, is particularly vulnerable. pathway converting the antibiotic to the If generalized effects, such as phenomena activated hapten may be restricted to a related to hypersensitivity, are excluded, specific tissue and thereby elevate its most antibiotics affect only one or a few local concentration. (2) Conjugation of the targets. For example, the major site of ac­ tion of the aminoglycosides is the proxi­ mal tubule,2,16,32 the site of potential toxic action of the currently used sulfonamides TABLE I I is the collecting duct. Site specificity of Antibiotic - Induced Nephrotoxicity Arises antibiotic-induced nephropathy implies By Two Different Mechanisms several possibilities: (1) there exist cell Indirect Action (Immunity-Medicated) types with distinctly susceptible targets Penicillins (expecially methicillin) Cephalosporins (espec ially cephaloth in) for the deleterious effects of certain Sulfonamides specific antibiotics; (2) the drug may Rifampicin achieve toxic concentrations in only