Acute Kidney Injury and Kidney Replacement Therapy in the Critically Ill Patient

Intrarenal toxicity: There are several types of kidney toxicity from xenobiotics. These include direct

tubular toxicity, AIN, glomerular diseases, osmotic nephrosis, crystalluria/nephrolithiasis, and altered

electrolyte handling.

Direct tubular toxicity: Drugs can be associated with direct tubular damage, cell apoptosis, and

necrosis. ATN may be suggested by the presence of granular casts (“muddy brown casts”) or renal

tubular epithelial cells on a urinalysis.

Examples of drugs that contribute to ATN: Intravenous contrast, aminoglycosides, amphotericin

B, vancomycin, colistin, antiviral agents, platinum chemotherapy

ii.

Direct tubular toxicity is often a type A injury that responds to dose adjustment or drug

discontinuation and supportive care.

AIN: Drug-associated AIN is thought to be a cell-mediated immune response, analogous to a

type 4 hypersensitivity reaction. Microscopic hematuria, sterile pyuria, and nonnephrotic range

proteinuria are features of AIN on urinalysis. Other features of AIN can include urine and/or

peripheral eosinophilia with clinical symptoms of fever, rash, and joint pains. Although commonly

cited in the literature, these may not be universally present; in fact, only 10%–30% of patients

with this diagnosis have the “classic triad” of eosinophilia, fever, and rash. A kidney biopsy can be

considered but, in the acute setting, is rarely performed until other causes are ruled out.

Drug causes have been implicated in up to 75% of AIN cases. Other separate or concurrent

contributors to AIN include infections (5%–10%), idiopathic causes (5%–10%), and causes

associated with systemic diseases (10%–15%).

ii.

Examples of drugs that contribute to AIN: Penicillins, cephalosporins, sulfonamides,

ciprofloxacin, vancomycin, NSAIDs and cyclooxygenase-2 [COX-2] inhibitors, proton pump

inhibitors, immune checkpoint inhibitors, phenytoin, valproic acid, ranitidine, diuretics, and

cocaine

iii.

Management of AIN includes discontinuation of the offending agent. These injuries are

often subacute and take weeks to months to resolve. Steroids may be used, but this remains

controversial.

iv.

Recently, the combination of piperacillin/tazobactam and vancomycin received specific

attention for its risk of nephrotoxicity. In ICU patients, observational studies suggest that

empiric courses of less than 72 hours are no more nephrotoxic than other such combinations.

Preclinical models in rats using histopathology and novel urinary kidney biomarkers suggest

no evidence of heightened risk with the combination (J Antimicrob Chemother 2020;75:1228-

an increased risk of creatinine-defined AKI with piperacillin/tazobactam and vancomycin

combination compared with the cefepime and vancomycin combination, but not changes in

cystatin C, blood urea nitrogen, mortality, or need for KRT. This finding supports the idea

that the piperacillin/tazobactam and vancomycin effects on creatinine may represent a pseudo-

toxicity rather than true AKI. In observational data in humans, evidence still favors a potential

increased risk of AKI with the combination and remains an ongoing area of research; thus,

the risk-benefit of other combinations should be considered in conjunction with other potential

toxicities or antibiotic stewardship efforts.

Glomerular diseases: DIKD rarely manifests as glomerular disease. Glomerular diseases

from medication can include immune-mediated glomerular diseases, including antineutrophil

cytoplasmic antibody (ANCA)-associated vasculitis with necrotizing and crescentic/pauci-immune

glomerulonephritis, drug-induced lupus, and drug-associated membranous nephropathy. In

addition, drugs may cause direct glomerular toxicity, resulting in minimal change disease or focal

segmental glomerulosclerosis. Depending on the type of injury, suggestive diagnostics of drug-

associated glomerular diseases may include proteinuria, hematuria, positive antibody tests, rash,

fever, myalgias, and polyarthritis. A kidney biopsy is often pursued.