What is the difference between Acute Interstitial Nephritis (AIN) and Acute Tubular Necrosis (ATN)?

Differences Between Acute Interstitial Nephritis (AIN) and Acute Tubular Necrosis (ATN)

AIN and ATN are distinct forms of acute kidney injury with different pathophysiology, causes, clinical presentations, and treatment approaches. ATN primarily affects tubular epithelial cells through ischemia or toxins, while AIN involves inflammation of the renal interstitium typically caused by immune-mediated reactions to medications. 1

Pathophysiology

Acute Tubular Necrosis (ATN)

• ATN is characterized by damage to the tubular structures with necrosis of tubular epithelial cells 1
• It primarily affects the tubular epithelial cells due to ischemia (reduced blood flow) or direct toxin exposure 1
• ATN is the most common cause of intrinsic acute kidney injury in hospitalized patients, accounting for approximately 29% of renal biopsies in patients with acute kidney injury 1, 2
• In critical care settings, ATN accounts for about 76% of cases of acute renal failure 2

Acute Interstitial Nephritis (AIN)

• AIN is characterized by inflammation within the kidney interstitium 1
• It involves inflammatory cell infiltration (T-lymphocytes, monocytes, and occasionally eosinophils) in the renal interstitium 1, 3
• AIN represents 80-90% of immune-related renal dysfunction in patients on immunotherapy 1
• The inflammatory process in AIN can lead to edema and tubular damage through inflammatory mediators rather than direct cellular injury 3, 4

Etiology

ATN Causes

• Ischemic causes: hypotension, shock, sepsis, major surgery, trauma 1, 5
• Nephrotoxic causes: antibiotics (aminoglycosides), contrast media, chemotherapeutic agents (cisplatin), heavy metals 1, 5
• Mixed etiology (combination of ischemic and nephrotoxic factors) is common in clinical practice 5
• ATN can be classified as ischemic (51%), nephrotoxic (11%), or mixed (38%) based on causative factors 5

AIN Causes

• Drug-induced (most common): antibiotics (beta-lactams, sulfonamides), NSAIDs, proton pump inhibitors 1, 4
• Immune checkpoint inhibitors can trigger AIN through immune system activation 1
• Infections: pyelonephritis, viral infections (CMV, EBV), leptospirosis 3, 4
• Autoimmune disorders: Sjögren's syndrome, lupus nephritis, IgG4-related disease 3
• Idiopathic causes where no specific trigger is identified 3

Clinical Presentation and Diagnosis

ATN Presentation

• Often occurs in the setting of known risk factors (hypotension, sepsis, nephrotoxin exposure) 1, 5
• Presents with rapid rise in serum creatinine, often with oliguria 6, 5
• Acid-base or electrolyte disturbances may be present even without significant changes in kidney function 1
• Multiple organ failure is frequently associated with ischemic (46%) and mixed ATN (55%) 5
• Mortality is significantly higher in ischemic (66%) and mixed ATN (63%) compared to nephrotoxic ATN (38%) 5

AIN Presentation

• Often presents with acute or subacute kidney injury, sometimes with incomplete recovery 3, 4
• Classic triad (fever, rash, eosinophilia) is present in less than 10% of cases 3
• May have sterile pyuria, white blood cell casts, mild proteinuria 3
• Eosinophiluria may be present but has poor sensitivity and specificity 3
• Definitive diagnosis requires kidney biopsy showing interstitial inflammation 1, 3

Diagnostic Differentiation

• Fractional excretion of sodium (FENa) has traditionally been used to differentiate prerenal causes from structural causes like ATN, but has limited specificity in cirrhosis 6
• Fractional excretion of urea (FEUrea) may better discriminate between different causes of AKI 6
• Biomarkers like NGAL (neutrophil gelatinase-associated lipocalin) can help differentiate ATN from AIN and other causes of AKI 6, 1
• NGAL levels in ATN are significantly higher than in AIN or prerenal azotemia, with a cutoff value of 220-244 μg/g of creatinine suggested for differentiation 6
• Gallium-67 scintigraphy has shown efficacy in experimental studies for differentiating AIN from ATN, with significantly higher uptake in AIN 7
• Kidney biopsy remains the gold standard for definitive diagnosis and differentiation between ATN and AIN 1, 3

Treatment Approaches

ATN Management

• Supportive care with focus on fluid management is the primary treatment approach 1
• Removal of nephrotoxic agents is crucial 1
• Renal replacement therapy may be required in severe cases 2
• Despite advances in treatment, mortality remains high, especially in ICU settings (up to 78.6%) 2

AIN Management

• Primary intervention is discontinuation of the offending agent 1
• Corticosteroids are often used, especially in drug-induced cases 1
• For immune checkpoint inhibitor-related AIN, high-dose methylprednisolone (1 mg/kg) is recommended 1
• Early diagnosis and treatment improve prognosis and reduce risk of progression to chronic kidney disease 4

Prognosis

• ATN generally has a worse prognosis than AIN, with higher mortality rates, especially in critically ill patients 5, 2
• Oliguria is a universal independent predictor of mortality in ATN (odds ratio 2.53) 5
• AIN has better recovery potential if the offending agent is promptly removed and appropriate treatment initiated 3, 4
• Both conditions can progress to chronic kidney disease if not properly managed 3, 4