Nephropharmacology

for the Clinician

Pharmacology behind Common Drug Nephrotoxicities

Mark A. Perazella

Abstract
Patients are exposed to numerous prescribed and over-the-counter medications. Unfortunately, drugs remain
a relatively common cause of acute and chronic kidney injury. A combination of factors including the innate
nephrotoxicity of drugs, underlying patient characteristics that increase their risk for kidney injury, and the
metabolism and pathway of excretion by the kidneys of the various agents administered enhance risk for drug- Section of
induced nephrotoxicity. This paper will review these clinically relevant aspects of drug-induced nephrotoxicity for Nephrology,
Department of
the clinical nephrologist. Medicine, Yale
Clin J Am Soc Nephrol 13: 1897–1908, 2018. doi: https://doi.org/10.2215/CJN.00150118 University, New
Haven, Connecticut
and Veterans Affairs
Medical Center, West
Introduction potentially nephrotoxic medication is an obvious re- Haven, Connecticut
Medications are a relatively common cause of kid- quirement. Drugs may be modestly nephrotoxic or
ney injury (1–12). The epidemiology of drug-induced maintain high risk to cause kidney injury on the basis Correspondence:
nephrotoxicity is currently based on literature focus- of their structure, dose, metabolic handling, excretory Dr. Mark A. Perazella,
ing on AKI. Drug-induced nephrotoxicity in adults is pathway through the kidney, and other characteris- BB 114, 330 Cedar
approximately 14%–26% in prospective cohort studies tics (5–9). Underlying patient characteristics, such as Street, New haven, CT
06410. Email: mark.
of AKI, whereas 16% of hospitalized AKI is due to drugs comorbid conditions, genetic determinants of drug perazella@yale.edu
in the pediatric population (1–4). Drug-induced neph- metabolism and transport, and immune response genes,
rotoxicity is more common in hospitalized patients, in are also important in drug nephrotoxicity (5–9). As the
particular intensive care unit patients (2,5). kidney metabolizes and excretes (through filtration and
Importantly, the general population is exposed to tubular secretion) many ingested drugs, the interaction
a large number of prescribed and over-the-counter of these substances with various parts of the nephron
drugs as well as a variety of substances available at may be associated with nephrotoxicity (5–9). For kidney
health food stores (natural products, supplements, injury to occur, some combination of these three risk
herbal remedies) (6–20). Various imaging agents used factors is generally present. More often than not, more
for diagnostic purposes are also associated with neph- than one is present. It is the differences in structure of
rotoxicity (21–23). However, not all patients exposed the ingested drug, underlying patient characteristics,
to the various potential nephrotoxins develop kidney and alterations in kidney handling of the ingested sub-
disease. Thus, the nephrotoxicity of medications, drugs, stance that likely explain the variability and heteroge-
and other ingested substances is a complicated process neity observed with drug-induced nephrotoxicity.
that involves a combination of factors. These include the
inherent nephrotoxic potential of the drug, underlying
patient characteristics that enhance their risk for kidney The Drug
injury, and the metabolism and excretion of the poten- The initial step in the development of kidney in-
tial offending agent by the kidney (6–9). jury involves exposure to a potentially toxic offending
As part of the Clinical Journal of the American Society agent. The general population is exposed to a variety
of Nephrology series “Nephropharmacology for the of potential nephrotoxic substances including pre-
Clinician,” this review will cover some of the common scribed therapeutic agents, over-the-counter products,
nephrotoxic drugs that the kidney is exposed to in clin- diagnostic agents, and environmental substances
ical practice, the factors that increase vulnerability of the (Table 1). Examples of potentially nephrotoxic drugs
kidney to these potential toxins, provide insight into the that are utilized to treat various disease processes
mechanisms by which kidney injury occurs, and cover include antimicrobial agents, anticancer drugs, anal-
some of the associated clinical kidney syndromes that gesics, and immunosuppressive agents (1–34). Fur-
develop in response to these agents (1–33). thermore, a large number of new medications with
unknown nephrotoxic potential make it through clin-
ical trials and are subsequently released into clinical
Factors Associated with Drug-Induced practice where they cause kidney injury. This is likely
Nephrotoxicity related to exposure of these new drugs in patients
The development of drug-induced nephrotoxicity who have comorbidities or other characteristics that
can be best understood by examining the factors increase nephrotoxic risk that were not included in
that contribute to nephrotoxicity (1–9). Exposure to a clinical trials. Although clinicians prescribe the vast

www.cjasn.org Vol 13 December, 2018 Copyright © 2018 by the American Society of Nephrology 1897