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 from acute tubular necrosis, nephrotoxins, or glomerular disease. 1, 2

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 despite normal total body water. 1, 2

Cardiac Dysfunction

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

Vascular Causes

• Systemic vasodilation from sepsis, anaphylaxis, or cirrhosis leads to relative hypoperfusion. 1, 2
• Renal artery occlusion from thrombosis or embolism causes acute prerenal injury. 1, 2

Medication-Induced Hemodynamic Changes

• NSAIDs reduce renal perfusion through prostaglandin inhibition, causing dose-dependent reduction in renal blood flow and precipitating overt renal decompensation, particularly in patients with impaired renal function, heart failure, liver dysfunction, or those taking diuretics and ACE inhibitors. 3
• ACE inhibitors and ARBs impair autoregulation of glomerular filtration by dilating efferent arterioles. 4, 2
• The "triple whammy" combination of NSAIDs, diuretics, and renin-angiotensin system inhibitors dramatically increases AKI risk through combined hemodynamic effects. 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 that progress to structural tubular injury. 1, 5
• Nephrotoxic ATN occurs from direct tubular toxicity by filtered substances. 1, 5

Nephrotoxic Medications

• Aminoglycosides, vancomycin, amphotericin B, and polymyxins cause direct tubular toxicity. 6
• Contrast media causes injury through decreased glomerular filtration, renal hypoperfusion, and direct tubular toxicity, though modern agents carry lower risk than previously thought, and contrast should not be withheld in life-threatening conditions. 4, 6
• Proton pump inhibitors (particularly omeprazole) carry a 4.35-fold adjusted risk for AKI. 6
• Chemotherapeutic agents including cisplatin, methotrexate, and tenofovir cause tubular injury. 6

Drug Burden and Combinations

• Each additional nephrotoxin increases AKI odds by 53%, and receiving three or more nephrotoxins more than doubles the risk, with 25% of non-critically ill patients developing AKI. 4
• Pharmacokinetic interactions such as macrolide antibiotics (clarithromycin, erythromycin) combined with statins increase rhabdomyolysis-induced AKI through CYP3A4 inhibition. 4

Glomerular and Vascular Causes

• Glomerulonephritis from autoimmune conditions or infections causes intrarenal AKI. 1, 2
• Vasculitis affecting renal vessels leads to intrinsic injury. 1
• Thrombotic microangiopathy including thrombotic vascular processes causes intrinsic AKI. 2

Interstitial Disease

• Acute interstitial nephritis from medications (especially antibiotics, PPIs, NSAIDs) or infections causes intrarenal AKI. 1

Other Intrinsic Causes

• Rhabdomyolysis with myoglobin-induced tubular injury causes intrinsic AKI. 2
• Viral-mediated tubular injury from direct kidney infection (e.g., COVID-19) can cause intrinsic AKI with proximal tubular injury manifesting as Fanconi syndrome. 2

Postrenal Causes (Obstruction)

Postrenal AKI results from urinary tract obstruction and accounts for less than 3% of cases. 1, 6

Upper Tract Obstruction

• Ureteral obstruction from stones, blood clots, or external compression (tumors, retroperitoneal fibrosis) causes postrenal AKI. 1, 2

Lower Tract Obstruction

• Bladder outlet obstruction from prostatic hypertrophy, bladder stones, or neurogenic bladder leads to postrenal AKI. 1, 2
• Urethral obstruction from strictures or external compression causes postrenal AKI. 1, 2

Important caveat: 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 have dramatically increased susceptibility to AKI from any cause:

• Age >65 years represents an independent risk factor. 1, 2, 6
• Pre-existing chronic kidney disease significantly increases susceptibility. 1, 2, 6
• Diabetes mellitus increases risk through multiple mechanisms. 1, 2, 6
• Liver disease increases risk through altered hemodynamics and hepatorenal syndrome. 1, 2
• Critical illness with 30-60% of ICU patients developing AKI. 1
• Patients at greatest risk from NSAIDs include those with impaired renal function, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors, and the elderly. 3

Drug-Associated AKI: Critical Clinical Context

Drug-associated AKI accounts for 20% of community-acquired AKI requiring hospitalization and approximately 25% of ICU-acquired AKI, with mortality rates of 40-50% similar to other AKI etiologies. 4

Key principle for drug stewardship: The framework distinguishes between drugs causing functional kidney dysfunction (hemodynamic effects) versus structural kidney injury (direct toxicity), with many drugs causing both. 4

Risk mitigation strategies:

• Evaluate nephrotoxic causality by assessing temporal sequence, excluding other causes, and observing response to drug removal. 4
• Select less nephrotoxic alternatives whenever possible. 4
• Avoid nephrotoxin combinations, as escalating from two to three nephrotoxins more than doubles AKI risk. 4
• Electronic health record systems identifying patients exposed to three or more nephrotoxic drugs have led to sustained decreases in AKI incidence. 4