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

Drug-Induced Kidney Disease (DIKD)

Drugs are associated with about one-third of AKI cases in the hospital. The concept of “nephrotoxin

stewardship” has been proposed. Nephrotoxin stewardship is a term taken from antimicrobial

stewardship that generally refers to “coordinated interventions to improve and measure the appropriate

use of drugs by promoting the selection of the optimal drug regimen, including dosing, duration of

therapy, and route of administration” (Clin Infect Dis 2016;62:e51-77). Kane-Gill has proposed 3 goals

for nephrotoxin stewardship—medication safety, kidney health, and avoidance of unnecessary costs—

kidney dysfunction according to three primary factors:

Phenotype of kidney injury: AKI (ATN, acute interstitial nephritis [AIN], osmotic nephrosis),

glomerular disorder (hematuria, proteinuria), nephrolithiasis (crystalluria, nephrolithasis,

obstruction), and tubular dysfunction (renal tubular acidosis, Fanconi syndrome, syndrome of

inappropriate diuretic hormone, diabetes insipidus, phosphate wasting)

Mechanism: Type A (dose-dependent toxicities), type B (unpredictable, not dose-dependent)

Time course: Acute (1–7 days), subacute (8–90 days), chronic (more than 90 days)

More recently, a group of experts proposed a more contemporary DIKD schema that incorporates

“dysfunction without damage”, “damage without dysfunction”, “both dysfunction and damage,” and

“neither dysfunction nor damage”.

Extrarenal: Drugs that alter renal perfusion or influence intraglomerular hemodynamics can heighten a

patient’s risk of AKI. Examples include the following:

Loop diuretics: Intravascular volume depletion leading to loss of effective arterial blood volume

Negative inotropes or vasodilatory antihypertensives that reduce renal perfusion

Nonsteroidal anti-inflammatory drugs (NSAIDs) and angiotensin-converting enzyme inhibitors/

angiotensin receptor blockers (ACEIs/ARBs)

Normally, glomerular pressure is maintained, in part, by vasodilation of the afferent arterioles

or vasoconstriction of the efferent arterioles.

ii.

Vasodilation of the afferent arteriole is partly controlled by the effects of prostaglandins.

Medications that decrease prostaglandin synthesis such as NSAIDs decrease the ability of the

afferent arteriole to vasodilate and thus increase the risk.

iii.

Vasoconstriction of the efferent arteriole, which helps maintain transcapillary pressure, is

mediated through angiotensin II. Drugs that block angiotensin II such as ACEIs and ARBs

prevent effective efferent vasoconstriction and thus increase the risk.

iv.

The so-called “triple whammy” of NSAIDs/diuretics/ACEIs or ARBs has been described

as having a uniquely high risk of AKI because of the multiplicity of the intraglomerular

hemodynamic impact (BMJ 2013;346:e8525). Information from an adverse drug event report

database showed that the median time to AKI onset was 20 days with a single triple whammy

drug, 44 days for two drugs, and 8 days for three drugs. The onset of AKI is generally early

and decreases over time, especially if an NSAID is part of the combination therapy (Plos One

2022;17:e0263682).

Use of calcineurin inhibitors, particularly in the setting of other risk factors for AKI, is thought

to interfere with renal hemodynamics.