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.