What are the clinical features of acute tubular necrosis (ATN) in patients with a history of exposure to nephrotoxic substances or recent major surgery?

Clinical Features of Acute Tubular Necrosis

Acute tubular necrosis (ATN) presents with acute kidney injury characterized by rising serum creatinine, often with oliguria, muddy brown granular casts on urinalysis, and fractional excretion of sodium >1%, typically occurring in the setting of ischemic injury, nephrotoxic exposure, or sepsis. 1

Clinical Presentation and Risk Factors

ATN is the most common cause of intrinsic acute kidney injury in hospitalized patients, accounting for approximately 68% of AKI cases in patients with decompensated cirrhosis and about 76% of ARF cases in critical care units. 2, 3

Common Precipitating Factors

• Ischemic injury from hypotension, sepsis, major surgery, or prolonged renal hypoperfusion 1, 4
• Nephrotoxic exposures including aminoglycosides, NSAIDs, contrast agents, cisplatin, ifosfamide, and other chemotherapeutic agents 5, 2
• Mixed etiologies combining both ischemic and nephrotoxic insults, which account for approximately 38% of ATN cases in ICU patients 6
• Post-transplant setting, particularly in cadaveric grafts where ATN occurs frequently in the immediate post-transplant period 1

Clinical Characteristics by Etiology

The three forms of ATN exhibit distinct clinical profiles. Ischemic and mixed ATN demonstrate higher rates of multiple organ failure (46% and 55% respectively) compared to pure nephrotoxic ATN (7%). 6 Complications such as gastrointestinal bleeding, severe acidosis, oliguria, and hypervolemia are more prevalent in ischemic and mixed ATN. 6

Laboratory and Urinary Findings

Urinalysis

The hallmark urinary findings include muddy brown granular casts, tubular epithelial cells, and renal tubular epithelial cell casts. 1

• Proteinuria is typically <500 mg/day without significant albuminuria, helping exclude glomerular diseases 1
• Absence of significant hematuria (<50 RBCs per high-power field) distinguishes ATN from glomerulonephritis 1
• Urinary sediment shows tubular debris and cellular elements 1

Fractional Excretion Indices

Fractional excretion of sodium (FENa) >1% indicates tubular damage in ATN, distinguishing it from prerenal causes which typically show FENa <1%. 5, 1 However, this cutoff has limitations:

• In cirrhotic patients, FENa <1% has 100% sensitivity but only 14% specificity for prerenal causes 5
• Diuretic use confounds FENa interpretation; in these cases, fractional excretion of urea (FEUrea) >50% suggests ATN while <35% suggests prerenal causes 1
• In hepatorenal syndrome differentiation, FEUrea <28.16% has 75% sensitivity and 83% specificity for separating HRS from non-HRS 5

Serum and Urinary Biomarkers

Urinary sodium concentration in ATN is typically >20 mEq/L, compared to <10 mEq/L in prerenal AKI. 1

Emerging biomarkers provide earlier and more specific diagnosis:

• Neutrophil gelatinase-associated lipocalin (NGAL) with urinary cutoff of 220-244 mg/g creatinine best differentiates ATN from prerenal azotemia or hepatorenal syndrome 5, 1
• NGAL levels in HRS-AKI are always much lower than in ATN, even when HRS has not responded to treatment 5
• Other tubular injury markers include kidney injury molecule-1 (KIM-1), interleukin-18, and N-acetyl-β-D-glucosaminidase 5, 1
• The more biomarkers that are elevated, the more likely the diagnosis is ATN 5

Clinical Course and Oliguria

Oliguria is a critical prognostic indicator and the only variable universally associated with mortality across all ATN types (OR 2.53,95% CI 1.60-3.76). 6 Daily urine output monitoring is essential as oliguria is associated with poor prognosis. 2

Interestingly, tubular cell shedding occurs with significant viability (up to 100% in some cases), indicating that tubular cell detachment can occur before cell death. 7 This dissociation between cell detachment and cell death challenges traditional concepts of ATN pathophysiology.

Imaging Findings

Ultrasound of kidneys is the first-line imaging modality, showing: 1

• Normal-sized kidneys with preserved corticomedullary differentiation, suggesting acute rather than chronic kidney disease 1
• Absence of hydronephrosis to exclude post-renal obstruction 1
• Normal renal ultrasound helps differentiate ATN from hepatorenal syndrome 1

Tc-99m MAG3 renal scan may show a persistent nephrogram without excretion, suggesting ATN. 1 MRI may show loss of corticomedullary differentiation, though this finding is nonspecific. 1

Differential Diagnosis

Key Distinguishing Features

Prerenal azotemia differs from ATN by:

• Response to volume expansion 1
• FENa <1% 1
• Benign urinary sediment without casts or tubular cells 1

Hepatorenal syndrome differs from ATN by:

• Absence of proteinuria and hematuria 1
• Normal urinary sediment despite severe AKI 1
• Normal renal ultrasound 1
• No response to volume expansion with albumin 1

Acute glomerulonephritis presents with dysmorphic RBCs, RBC casts, and significant proteinuria, which are absent in ATN. 1

Histopathological Features

When kidney biopsy is performed (not routinely required), ATN demonstrates: 1

• Loss of brush border in proximal tubules
• Tubular epithelial flattening and detachment
• Tubular casts and debris in tubular lumina
• Minimal glomerular or vascular changes

Prognosis and Mortality

Mortality rates vary significantly by clinical setting and ATN etiology:

• Overall hospitalized patients: 37.1% mortality 3
• ICU patients: 78.6% mortality 3
• Ischemic ATN: 66% mortality 6
• Mixed ATN: 63% mortality 6
• Nephrotoxic ATN: 38% mortality 6

The cause of ATN profoundly impacts both short- and long-term outcomes. 8 Complete renal recovery at discharge occurs in 100% of surviving patients with pure nephrotoxic ATN, 74% with pure ischemic ATN, but only 30% with mixed ATN. 8 After 7 years, 60% of pure ATN survivors remain alive compared to only 22% of mixed ATN survivors. 8

Special Clinical Contexts

In transplant patients, ATN must be distinguished from acute rejection, which requires different management approaches. 1 In cirrhotic patients, differentiating ATN from hepatorenal syndrome is crucial as treatment approaches differ significantly. 1 In patients with acute liver failure, ATN may coexist with hepatorenal syndrome, complicating diagnosis and management. 1