Mechanisms of antimicrobial-induced nephrotoxicity in children

Abstract

Drug-induced nephrotoxicity is responsible for 20% to 60% of cases of acute kidney injury in hospitalized patients and is associated with increased morbidity and mortality in both children and adults. Antimicrobials are one of the most common classes of medications prescribed globally and also among the most common causes of nephrotoxicity. A broad range of antimicrobial agents have been associated with nephrotoxicity, but the features of kidney injury vary based on the agent, its mechanism of injury and the site of toxicity within the kidney. Distinguishing nephrotoxicity caused by an antimicrobial agent from other potential inciting factors is important to facilitate both early recognition of drug toxicity and prompt cessation of an offending drug, as well as to avoid unnecessary discontinuation of an innocuous therapy. This review will detail the different types of antimicrobial-induced nephrotoxicity: acute tubular necrosis, acute interstitial nephritis and obstructive nephropathy. It will also describe the mechanism of injury caused by specific antimicrobial agents and classes (vancomycin, aminoglycosides, polymyxins, antivirals, amphotericin B), highlight the toxicodynamics of these drugs and provide guidance on administration or monitoring practices that can mitigate toxicity, when known. Particular attention will be paid to paediatric patients, when applicable, in whom nephrotoxin exposure is an often-underappreciated cause of kidney injury.

Figure 1.

Diagram of the primary types of kidney injury caused by specific antimicrobial agents. Specific agents that have been reported to inflict multiple types of injury are displayed as overlapping.

Figure 2.

Mechanisms of antimicrobial-induced nephrotoxicity. (a) ATN: begins with endocytosis of drug from the urine into tubular epithelial cells (a1). Once inside the cell, the drug causes damage to cell organelles (a2). This initiates the process of cellular apoptosis and death, and release of systemic inflammatory signals (a3). Renal blood flow is then reduced (a4) as a result of tubuloglomerular feedback mechanisms. (b) AIN: antigen from either freely filtered drug or drug that is circulating in the blood is deposited on the basement membrane (b1). The antigen is recognized by dendritic cells (b2), which induce a T cell-mediated immune response (b3) and interstitial inflammation with pyuria (b4). (c) Crystal (obstructive) nephropathy: drug is filtered into the urine (c1). When the urine becomes supersaturated with drug, as in the setting of decreased urine flow, the drug precipitates (often as crystals) and obstructs the tubular lumen (c2). This leads to the release of inflammatory signals into the blood (c3), as well as induction of cellular apoptosis and reduced renal blood flow via tubuloglomerular feedback mechanisms (c4).