Perazella MA. Clin J Am Soc Nephrol. 2018;doi:10.2215/CJN.00150118

April 12, 2019
2 min read

Nephrotoxic AKI typically caused by a combination of three risk factors


Perazella MA. Clin J Am Soc Nephrol. 2018;doi:10.2215/CJN.00150118

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A published review outlined drug-induced nephrotoxicity, a common cause of acute kidney injury, and its associated factors surrounding medications, drugs and other ingested substances.

“Importantly, the general population is exposed to a large number of prescribed and over-the-counter drugs as well as a variety of substances available at health food stores,” author Mark A. Perazella, MD, the director of the acute dialysis unit at Yale Medicine, said in the review. “Various imaging agents used for diagnostic purposes are also associated with nephrotoxicity. However, not all patients exposed to the various potential nephrotoxins develop kidney disease. Thus, the nephrotoxicity of medications, drugs, and other ingested substances is a complicated process that involves a combination of factors.”

Perazella stated that the introduction to a potentially toxic offending agent is primarily the initial step toward AKI. Drugs and metabolites can cause acute crystalline nephropathy, obstructing urinary flow, leading to AKI. According to the study, products associated with crystalline nephropathy include methotrexate, acyclovir, indinavir/atazanavir, sulfadiazine, vitamin C, foscarnet, oral sodium-phosphate and triamterene.

Perazella also included that many alternative/complimentary products that aren’t FDA approved could be nephrotoxic. This includes herbal remedies, natural products and nutritional supplements, as they interact with conventional drugs producing another potential avenue of nephrotoxicity, according to Perazella.

Patient related factors should also be considered as a potential cause for nephrotoxicity and AKI. Risk factors can include older age and female sex, a combination associated with decreased body fat and water, leading to excess drug dosing. In conjunction, Perazella said elderly patients have a greater tendency for vasoconstriction from increased endothelin and circulating angiotensin II levels, increasing the patient’s risk to excess drug concentration exposure.

“Along the lines of nonmodifiable risk factors is the patient’s underlying genetic makeup,” wrote Perazella. “In fact, the role of pharmacogenetics as an explanation for the heterogeneous patient response to drugs (underdosing, therapeutic dosing and overdosing) reflects genetic makeup and supports the need for ‘personalized’ or ‘precision’ medicine. As such, underlying host genetic makeup can enhance vulnerability of the kidney to potential nephrotoxins.”

Perazella added that a higher rate of renal blood flow can also be attributed to nephrotoxicity due to significant drug concentrations. Tubular cells reside in an almost hypoxic environment and an excessive cellular workload of these cells increases the risk of a nephrotoxic-related injury.

“For kidney injury to occur, some combination of these three risk factors is generally present,” Perazella wrote. “More often than not, more than one is present. It is the differences in structure of the ingested drug, underlying patient characteristics and alterations in kidney handling of the ingested substance that likely explain the variability and heterogeneity observed with drug-induced nephrotoxicity.” – by Scott Buzby



Disclosure: Perazella reports no relevant financial disclosures.