Causes of Acute Tubular Necrosis (ATN)
ATN results from two primary mechanisms: ischemic injury and nephrotoxic injury, which frequently occur together as mixed causes in hospitalized patients. 1, 2
Ischemic Causes
Ischemic ATN develops when renal perfusion is critically reduced, leading to tubular epithelial cell damage and necrosis. 2, 3
Key ischemic triggers include:
- Hypotension and shock states - particularly cardiogenic shock, which carries significantly worse prognosis than nephrotoxic causes 4
- Sepsis - a major contributor to ischemic tubular injury in critically ill patients 5, 4
- Major surgery - especially cardiac surgery and procedures involving aortic manipulation 1
- Prolonged renal hypoperfusion - from any cause of decreased effective arterial blood volume 6
- Ischemia-reperfusion injury - particularly common in transplant patients, especially with cadaveric grafts and prolonged cold ischemia time 1, 7
Nephrotoxic Causes
Nephrotoxic ATN occurs through direct tubular epithelial cell injury from exogenous or endogenous toxins. 2
Common nephrotoxic agents include:
- Antibiotics - particularly aminoglycosides, which cause direct tubular toxicity 8, 1, 2
- Contrast media - radiocontrast agents used in imaging procedures 8, 1
- Chemotherapeutic agents - various cancer treatments with tubular toxicity 2
- Calcineurin inhibitors - cyclosporine and tacrolimus, especially in transplant recipients 7
- NSAIDs - causing both direct tubular toxicity and renovasoconstriction 8, 2
Mixed Causes
Mixed ischemic and nephrotoxic ATN represents the most common presentation in critically ill patients and carries the worst prognosis. 5, 4
- Mixed-cause ATN accounted for approximately 50% of cases requiring renal replacement therapy in one large cohort, with in-hospital mortality of 55% compared to 39% for pure ischemic and 29% for pure nephrotoxic ATN 5
- Only 30% of mixed ATN survivors achieved complete renal recovery at discharge, compared to 74% with pure ischemic and 100% with pure nephrotoxic ATN 5
- Long-term outcomes are significantly worse, with 38% of mixed ATN survivors developing advanced CKD or ESRD within 7 years 5
Clinical Context and Risk Factors
ATN is the most common cause of intrinsic AKI in hospitalized patients, accounting for approximately 68% of AKI cases in patients with decompensated cirrhosis and 29% of renal biopsies in patients with acute kidney injury. 1, 2
High-risk clinical scenarios include:
- ICU patients with multiple organ dysfunction, where sepsis, hypotension, and nephrotoxin exposure frequently coexist 5
- Post-transplant period - ATN is the leading cause of delayed graft function, particularly with donor hemodynamic instability 1, 7
- Patients with pre-existing vulnerabilities - those already taking multiple nephrotoxic medications or with baseline renal impairment 8
Important caveat: The distinction between pure ischemic, pure nephrotoxic, and mixed causes has profound prognostic implications. Pure nephrotoxic ATN has mortality of only 10% at 21 days with 66% dialysis-free survival, while ischemic ATN has 30% mortality with 41% dialysis-free survival. 4 This underscores the critical importance of identifying and removing nephrotoxic agents while aggressively treating underlying ischemic insults.