What are the causes of acute kidney injury (AKI)?

Causes of Acute Kidney Injury

Acute kidney injury results from three major pathophysiologic categories—prerenal (>60% of cases), intrarenal (~35%), and postrenal (<3%)—with prerenal causes from hypoperfusion being the most common, followed by intrinsic damage (most often acute tubular necrosis), and rarely obstruction. 1

Prerenal Causes (Hypoperfusion)

Prerenal AKI occurs when renal perfusion decreases without initial structural kidney damage, accounting for more than 60% of all AKI cases. 1, 2

Volume Depletion States

• Absolute hypovolemia from hemorrhage, gastrointestinal losses (vomiting, diarrhea), burns, or excessive diuresis causes prerenal AKI 1, 2
• Third-space sequestration in pancreatitis, peritonitis, or severe hypoalbuminemia from nephrotic syndrome reduces effective circulating volume 1, 2

Cardiac Dysfunction

• Decreased cardiac output from heart failure, cardiogenic shock, or arrhythmias impairs renal perfusion 1, 2

Vasodilation States

• Systemic vasodilation from sepsis, anaphylaxis, or cirrhosis leads to relative hypoperfusion 1, 2

Vascular Occlusion

• Renal artery thrombosis or embolism causes prerenal AKI 1, 3

Medication-Induced Hemodynamic Changes

• NSAIDs reduce renal perfusion through prostaglandin inhibition, causing dose-dependent reduction in renal blood flow and precipitating overt renal decompensation 4
• ACE inhibitors and ARBs impair autoregulation of glomerular filtration, particularly dangerous when combined with NSAIDs and diuretics (the "triple whammy") 5, 2
• Diuretics cause volume depletion and prerenal azotemia 2

Critical pitfall: The "triple whammy" combination of NSAIDs, diuretics, and renin-angiotensin system inhibitors dramatically increases AKI risk. 5 Patients at greatest risk include those with impaired renal function, heart failure, liver dysfunction, and the elderly. 4

Intrarenal Causes (Parenchymal Damage)

Intrarenal AKI involves direct damage to renal parenchyma and accounts for approximately 35% of cases. 1

Acute Tubular Necrosis (Most Common Intrinsic Cause)

• Ischemic ATN results from prolonged or severe prerenal states 1, 6
• Nephrotoxic ATN from medications including aminoglycosides, vancomycin, amphotericin B, polymyxins, cisplatin, methotrexate, and tenofovir 3
• Contrast-induced injury through decreased glomerular filtration, renal hypoperfusion, and direct tubular toxicity, though modern agents carry lower risk than previously thought 5, 3
• Rhabdomyolysis with myoglobin-induced tubular injury 2

Glomerular Disease

• Glomerulonephritis from autoimmune conditions or infections 1, 2
• Thrombotic microangiopathy 2

Interstitial Disease

• Acute interstitial nephritis from medications (particularly proton pump inhibitors with 4.35-fold adjusted risk) or infections 1, 3

Vascular Disease

• Vasculitis affecting renal vessels 1

Viral-Mediated Injury

• Direct tubular cell injury from viral infections (e.g., COVID-19) with potential for proximal tubular injury and Fanconi syndrome 2

Critical consideration: Drug-associated AKI occurs in 20% of community-acquired cases requiring hospitalization and 25% of critically ill patients. 5 Each additional nephrotoxin increases AKI odds by 53%, with risk more than doubling when patients receive three or more nephrotoxins simultaneously. 5

Postrenal Causes (Obstruction)

Postrenal AKI results from urinary tract obstruction and accounts for less than 3% of cases. 1

Upper Tract Obstruction

• Ureteral obstruction from stones, blood clots, or external compression 2, 3

Lower Tract Obstruction

• Bladder outlet obstruction from prostatic hypertrophy, bladder stones, or neurogenic bladder 2, 3
• Urethral obstruction from strictures or external compression 2

Important note: Postrenal obstruction is very uncommon in cirrhotic patients, so routine pelvic ultrasound is not needed unless specific risk factors are present. 1

High-Risk Populations

Certain patient populations face substantially elevated AKI risk:

• Age >65 years represents an independent risk factor 1, 2, 3
• Pre-existing chronic kidney disease significantly increases susceptibility 1, 2, 3
• Diabetes mellitus increases risk through multiple mechanisms 1, 2, 3
• Liver disease increases risk through altered hemodynamics and hepatorenal syndrome 1, 2
• Critical illness with 30-60% of ICU patients developing AKI 1

Drug Stewardship and Prevention

The most important prevention strategy is drug stewardship, balancing the risk of toxicity from excessive doses versus therapeutic failure from under-dosing. 5

Key Prevention Principles

• Avoid nephrotoxin combinations, particularly the "triple whammy" 5
• Each additional nephrotoxic drug presents 53% greater odds of developing AKI 5
• Electronic health record systems identifying patients exposed to ≥3 nephrotoxic drugs have led to sustained decreases in AKI incidence 5

Contrast-Associated AKI Management

• Modern contrast agents carry far fewer risks than previously thought, and significant kidney injury is unusual in patients with normal or mildly reduced baseline kidney function 5
• Intravenous contrast should not be withheld due to AKI concern in life-threatening conditions where the diagnostic information could have important therapeutic implications 5
• Volume expansion with sodium bicarbonate and oral N-acetylcysteine lack efficacy based on the PRESERVE and POSEIDON trials 5

Medication Management During AKI

• Discontinue nephrotoxins when possible, as early reversal of AKI leads to improved survival 5
• NSAIDs are not recommended in patients with advanced renal disease; if initiated, close monitoring is required 4
• Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state 4