What is the treatment approach for acute interstitial nephritis (AIN)?

Acute Interstitial Nephritis: Comprehensive Overview for Provider Theory Examination

Definition and Epidemiology

Acute interstitial nephritis (AIN) is an immune-mediated inflammatory disease of the renal interstitium that accounts for 15-20% of all acute kidney injury cases and represents the most common histologic finding (80-90%) in immune-related renal dysfunction. 1, 2

• AIN is diagnosed in 2.8% of all kidney biopsies and 13.5% of biopsies performed specifically for acute renal failure 2
• The incidence of immune-related renal dysfunction is 2-7%, with highest prevalence (5%) in patients receiving anti-PD(L)1/anti-CTLA-4 combination immunotherapy 1
• Median onset of immune-related AIN occurs at 3-4 months after initiating checkpoint inhibitor therapy 1

Etiology and Pathophysiology

Drug-induced AIN accounts for 60-70% of all cases, with medications triggering an antigen-initiated, cell-mediated immune response in the renal interstitium. 3, 4, 2

Primary Drug Culprits (in order of frequency):

• Antibiotics (49% of drug-induced cases): Amoxicillin (8%), ciprofloxacin (8%), and other beta-lactams 4
• Proton pump inhibitors (14% of drug-induced cases): Omeprazole is the single most common offending agent (12% of all drug-induced AIN) 4, 5
• NSAIDs (11% of drug-induced cases) 4
• Immune checkpoint inhibitors: Anti-PD(L)1 and anti-CTLA-4 agents 1

Non-Drug Etiologies:

• Autoimmune diseases (20% of cases) 4
• Infections (4% of cases) 4
• Idiopathic (remaining cases) 2

Pathophysiologic Mechanism:

• Cell-mediated immune injury with interstitial inflammation, tubulitis, and edema 3
• Lymphocytic infiltrate with neutrophils and eosinophils in the interstitium 1, 5
• Progressive interstitial fibrosis if untreated 3
• Primary tubular dysfunction precedes decline in glomerular filtration rate 2

Risk Factors

Concomitant use of PPIs and NSAIDs during checkpoint inhibitor therapy significantly increases AIN risk. 1

• Pre-existing chronic kidney disease does NOT predispose to immune-related AIN 1
• Older age correlates with increased risk, particularly for PPI-induced AIN 4
• Most patients (majority) will have concurrent extra-renal immune-related adverse events 1

Clinical Presentation

AIN typically presents with non-oliguric acute kidney injury characterized by modest but gradual increments in serum creatinine, often without classic symptoms. 2

Key Clinical Features:

• Slowly progressive azotemia with creatinine elevation to 1.5-3× baseline or upper limit of normal 1
• Often asymptomatic or presenting with nonspecific symptoms: fatigue, malaise, nausea, vomiting 2, 5
• Oliguria, hematuria, peripheral edema, anorexia may occur but are not universal 6

Classic Triad (Present in <10% of cases):

• Fever, rash, and eosinophilia are UNCOMMON and should not be relied upon for diagnosis 3

PPI-Induced AIN Characteristics:

• Patients are older and less symptomatic than those with antibiotic-induced AIN 4
• Longer duration of drug exposure (median 30-130 days vs. 15 days for antibiotics) 4
• Longer delays in diagnosis and treatment initiation 4

Diagnostic Approach

Renal biopsy remains the gold standard for definitive diagnosis of AIN, showing interstitial inflammation with lymphocytic infiltrate, tubulitis, and edema. 1, 7, 3

Mandatory Initial Exclusions:

Before diagnosing AIN, systematically rule out: 1, 8

• Hypovolemia and dehydration
• Urinary tract obstruction (via renal ultrasound ± Doppler)
• Recent IV contrast exposure
• Urinary tract infection (urine culture)
• Medication-induced acute tubular necrosis
• Hypotension or hypertensive emergency

Laboratory Evaluation:

• Serum creatinine and BUN: Monitor baseline and serial measurements 1, 6
• Urinalysis with microscopy: Phase contrast microscopy for dysmorphic RBCs 1
• Urine protein-to-creatinine ratio (UPCR) or 24-hour protein collection if proteinuria present 1
• Eosinophiluria: Limited diagnostic utility; neither sensitive nor specific 3
• Glomerulonephritis screen (if hematuria present): ANA, complement C3/C4, ANCA, anti-GBM, hepatitis B/C, HIV, immunoglobulins, protein electrophoresis 1

Biomarker Differentiation:

• NGAL (Neutrophil Gelatinase-Associated Lipocalin): Levels >220-244 μg/g creatinine suggest acute tubular necrosis rather than AIN 7
• Utility of urinary biomarkers for early AIN diagnosis remains under investigation 2

Imaging:

• Renal ultrasound ± Doppler: First-line to exclude obstruction/clot; typically shows normal kidney size with possible increased echogenicity (30-40% of cases) 1, 6
• Gallium-67 scintigraphy: Limited diagnostic utility and not recommended 3

Renal Biopsy Indications:

• Consider on case-by-case basis to confirm diagnosis, especially in: 1, 8
  • Severe cases (Grade 3-4 AKI with creatinine >3× baseline)
  • Uncertain etiology requiring differentiation from other pathologies
  • Cases where steroid therapy decision depends on histologic confirmation
  • Patients with confusion or altered mental status suggesting severe uremia 8

Staging and Severity Grading

Use KDIGO (Kidney Disease: Improving Global Outcomes) criteria for AKI staging, which differs from CTCAE version 5.0 criteria. 1

KDIGO Staging:

• Stage 1 (Grade 1): Creatinine 1.5-1.9× baseline or >0.3 mg/dL increase 1
• Stage 2 (Grade 2): Creatinine 2.0-2.9× baseline 1
• Stage 3 (Grade 3): Creatinine ≥3× baseline or ≥4.0 mg/dL or initiation of renal replacement therapy 1
• Grade 4: Creatinine >6× upper limit of normal 1

Treatment Algorithm

Grade 1 (Creatinine 1.5× Baseline or >ULN-1.5× ULN):

Continue checkpoint inhibitor therapy while monitoring; no steroids required. 1

• Review hydration status and all medications 1
• Perform dipstick urinalysis and assess for proteinuria (UPCR) 1
• Repeat creatinine weekly 1
• Renal ultrasound ± Doppler if obstruction suspected 1
• Escalate management if worsening 1

Grade 2 (Creatinine 1.5-3× Baseline or 1.5-3× ULN):

Withhold checkpoint inhibitor; initiate oral prednisolone 0.5-1 mg/kg daily after excluding other causes. 1, 7

• Hydrate patient and recheck creatinine in 48-72 hours 1
• Discuss with nephrologist regarding need for biopsy 1
• Perform renal ultrasound ± Doppler to exclude obstruction 1
• If proteinuria: obtain 24-hour collection or UPCR 1
• If hematuria: perform phase contrast microscopy and glomerulonephritis screen 1
• Repeat creatinine/potassium every 48 hours 1
• Recommence checkpoint inhibitor only when returns to Grade 1/baseline AND if on steroids, only once <10 mg prednisolone daily 1
• Advise patient to notify immediately if oliguria develops 1

Grade 3 (Creatinine >3× Baseline or 3-6× ULN):

Withhold checkpoint inhibitor; admit patient for monitoring; initiate IV methylprednisolone 1-2 mg/kg daily. 1, 7, 8

• Admit for inpatient monitoring with careful fluid balance 1, 8
• Repeat creatinine every 24 hours 1, 8
• Early discussion with nephrologist regarding biopsy 1, 8
• Consider pulse methylprednisolone for severe cases 1
• After stabilization, transition to oral prednisone 1 mg/kg/day (maximum 80 mg/day) 7, 8
• Monitor electrolytes, acid-base status, and mental status daily 8

Grade 4 (Creatinine >6× ULN):

Manage as Grade 3 in hospital with renal replacement therapy availability; permanently discontinue checkpoint inhibitor. 1, 8

• Patient requires facility capable of providing dialysis 1
• Consider more aggressive immunosuppression if steroid-refractory 8

Critical Management Principles:

The single most important intervention is immediate discontinuation of the offending agent; failure to do so worsens outcomes regardless of steroid therapy. 7, 8, 3

• Discontinue ALL nephrotoxic medications: PPIs, NSAIDs, antibiotics causing AIN 1, 8
• Checkpoint inhibitor management: 1
  • Grade 1: Continue
  • Grade 2: Withhold temporarily
  • Grade 3-4: Permanently discontinue

Steroid Therapy Specifics:

Early initiation of corticosteroids (within 8 days of diagnosis) improves recovery rates in drug-induced AIN. 4

• Timing matters: Delays in steroid initiation (35 days vs. 8 days) correlate with no recovery vs. complete recovery 4
• Duration of drug exposure matters: Longer exposure (130 days vs. 15 days) correlates with worse outcomes 4

Steroid Tapering Protocol:

• Grade 2 severity: Taper over 2-4 weeks once creatinine returns to Grade 1 1
• Grade 3-4 severity: Taper over 4 weeks 1, 8
• Begin taper only after creatinine improvement to Grade 1 1

Supportive Care for Steroid Therapy >4 Weeks:

• PJP prophylaxis (trimethoprim-sulfamethoxazole) 1, 8
• Calcium and vitamin D supplementation 1, 8
• Gastric protection (H2-blocker preferred over PPI given PPI association with AIN) 1, 8
• Monitor afternoon glucose for hyperglycemia 1, 8

Monitoring Requirements

Acute Phase (Grade 2-4):

• Creatinine and electrolytes: Every 24-48 hours depending on severity 1, 8
• Mental status: Daily assessment, as confusion may indicate severe uremia or electrolyte disturbances 8
• Fluid balance: Strict intake/output monitoring in hospitalized patients 1, 8
• Urine output: Oliguria should prompt immediate escalation 1

Recovery Phase:

• Weekly creatinine once stable in Grade 1 1
• Steroid-related complications monitoring throughout treatment course 1, 8

Prognosis and Recovery

At 6 months post-diagnosis, 49% of patients with drug-induced AIN treated with steroids achieve complete recovery, 39% achieve partial recovery, and 12% have no recovery. 4

Recovery Definitions:

• Complete recovery: Creatinine within 25% of baseline or <1.4 mg/dL 1
• Partial recovery: ≥50% decrease from peak creatinine but not within 25% of baseline 1
• No recovery: <50% decrease from peak creatinine 1

Prognostic Factors for Poor Recovery:

• Longer duration of drug exposure (130 days vs. 15 days for complete recovery) 4
• Delayed steroid initiation (35 days vs. 8 days for complete recovery) 4
• Delayed diagnosis and biopsy 4
• PPI-induced AIN has worse prognosis than antibiotic-induced AIN due to longer exposure and diagnostic delays 4

Long-Term Outcomes:

• 20% of patients with checkpoint inhibitor-related AIN may have persistently abnormal renal function 7
• Risk of progression to chronic kidney disease if recognition is delayed 3
• In kidney cancer patients, development of AIN appears to be a good prognostic factor for cancer outcomes, possibly due to shared antigen recognition 1

Critical Pitfalls to Avoid

Failing to identify and remove the offending agent is the most common error and dramatically worsens outcomes regardless of other interventions. 7, 8

Common Errors:

• Using steroids empirically for acute tubular necrosis: Provides no benefit and adds complications; differentiate using NGAL or biopsy 7
• Relying on classic triad (fever, rash, eosinophilia): Present in <10% of cases; absence does not exclude AIN 3
• Overlooking PPI-induced AIN: Patients are often asymptomatic with insidious onset; maintain high index of suspicion 4, 5
• Continuing nephrotoxic medications: Even if not the primary culprit, concurrent PPIs and NSAIDs worsen outcomes 1, 4
• Delaying renal biopsy in uncertain cases: Biopsy prevents unnecessary steroid exposure and confirms diagnosis 1, 8
• Premature checkpoint inhibitor rechallenge: Only restart when Grade 1 AND steroid dose <10 mg prednisolone daily 1
• Inadequate monitoring for oliguria: Should prompt immediate inpatient admission and planning for potential dialysis 1

Special Considerations for Confusion:

Confusion in the setting of AIN indicates severe uremia requiring urgent intervention, or life-threatening electrolyte/acid-base disturbances. 8

• Admit immediately for monitoring and fluid balance 8
• Initiate IV methylprednisolone 1-2 mg/kg daily 8
• Correct electrolyte abnormalities and acid-base disturbances urgently 8
• Consider renal biopsy to confirm diagnosis and guide aggressive therapy 8
• Monitor mental status daily as marker of treatment response 8