In an adult with new‑onset acute kidney injury, interstitial nephritis, electrolyte abnormalities, uric‑acid nephropathy, and suspected drug‑induced nephrotoxicity, what is the most likely cause and recommended management?

Management of Acute Kidney Injury with Suspected Drug-Induced Interstitial Nephritis

Immediately discontinue all potentially nephrotoxic medications—particularly NSAIDs, antibiotics (especially beta-lactams), and proton pump inhibitors—as drug-induced acute interstitial nephritis (DI-AIN) is the most likely cause and accounts for 70-90% of biopsy-proven interstitial nephritis cases, with prompt drug withdrawal being the single most critical intervention to prevent progression to chronic kidney disease. 1, 2

Immediate Diagnostic and Therapeutic Actions

Identify and Remove the Offending Agent

• Stop all nephrotoxic drugs immediately, including NSAIDs, antibiotics (particularly beta-lactams and sulfonamides), proton pump inhibitors, diuretics, ACE inhibitors/ARBs, and any other potential culprits 1, 3
• Drug-induced AIN accounts for 20-25% of community-acquired AKI requiring hospitalization and up to 25% of ICU-acquired AKI 1
• Each additional nephrotoxic medication increases AKI odds by 53%, and combining three or more nephrotoxins results in AKI in 25% of non-critically ill patients 1
• The "triple whammy" combination of NSAIDs, diuretics, and renin-angiotensin system inhibitors dramatically increases AKI risk and must be avoided 1, 3

Assess Volume Status and Hemodynamics

• Immediately evaluate for hypovolemia versus volume overload, as prerenal azotemia from NSAIDs or ACE inhibitors can coexist with intrinsic kidney injury 1, 3
• Place a urinary catheter to monitor hourly urine output if severe oliguria is present 3
• Initiate aggressive intravenous fluid resuscitation with isotonic saline if hypovolemic, but avoid overhydration in established AKI 3

Obtain Kidney Biopsy for Definitive Diagnosis

• Kidney biopsy should be strongly considered to confirm DI-AIN, differentiate from acute tubular necrosis, and guide corticosteroid therapy 1, 2, 4
• Biopsy reveals extensive interstitial lymphocytic infiltrate, interstitial edema, and tubular injury in DI-AIN 4
• DI-AIN typically presents 7-10 days after drug exposure as a delayed hypersensitivity reaction 5
• Classic triad of fever, rash, and eosinophilia occurs in <10% of cases; most patients present with isolated AKI 2, 4

Corticosteroid Therapy

Indications and Timing

• Initiate oral prednisone 1 mg/kg/day (maximum 80 mg/day) or pulse methylprednisolone 500-1000 mg IV daily for 3 days in biopsy-confirmed DI-AIN or when clinical suspicion is high and biopsy cannot be obtained 1, 5
• Corticosteroids exert potent anti-inflammatory effects on T cells and eosinophils, which mediate the immune response in DI-AIN 5
• Early corticosteroid initiation (within 7-14 days of AKI onset) improves renal recovery, though evidence remains limited 4
• For Stage 3 AKI (creatinine ≥3× baseline or oliguria <0.3 mL/kg/hr for ≥24 hours), consider pulse-dose methylprednisolone 1

Tapering Strategy

• After 3 days of IV methylprednisolone, convert to oral prednisone 1 mg/kg/day if creatinine is improving 1
• Taper by 10 mg/week while monitoring creatinine and electrolytes 1
• Total treatment duration typically 4-6 weeks, though optimal duration is not well-established 4

Differential Diagnosis and Specific Considerations

Distinguish DI-AIN from Other Drug-Induced Nephropathies

Acute Tubular Necrosis (ATN) from aminoglycosides, vancomycin, cisplatin, or amphotericin B:

• ATN typically presents with nonoliguric renal failure 10 days after aminoglycoside initiation 6
• Vancomycin can cause acute tubular injury through cast nephropathy, distinct from interstitial nephritis 7, 8
• Vancomycin-associated AKI risk increases with higher serum levels and concomitant nephrotoxins 7
• ATN requires supportive care and drug discontinuation but not corticosteroids 6, 8

Crystalline Nephropathy from methotrexate, acyclovir, or sulfonamides:

• Intratubular crystal deposition causes obstruction and AKI 1, 8
• Requires aggressive hydration and urinary alkalinization (for methotrexate) 1

Uric Acid Nephropathy from tumor lysis syndrome:

• Presents with hyperuricemia, hyperkalemia, hyperphosphatemia, and hypocalcemia 1
• Requires rasburicase or allopurinol, aggressive hydration, and potentially dialysis 1

Drug-Specific Mechanisms

NSAIDs cause AKI through three mechanisms:

• Hemodynamic (afferent arteriole vasoconstriction from prostaglandin inhibition) 1, 6
• Acute interstitial nephritis (delayed hypersensitivity) 1, 2
• Minimal change disease with nephrotic-range proteinuria 1

Antibiotics (beta-lactams, sulfonamides, rifampin):

• Most common cause of DI-AIN, accounting for the majority of cases 2, 4
• Mechanism involves drug-protein conjugate formation triggering T-cell mediated hypersensitivity 5

Proton Pump Inhibitors:

• Second most common cause of DI-AIN after antibiotics 2, 4
• Can present months to years after drug initiation 2

Immune Checkpoint Inhibitors (anti-PD-1, anti-CTLA-4):

• Cause immune-related AIN in 2-7% of patients, most commonly 3-4 months after initiation 1
• Require high-dose corticosteroids (methylprednisolone 500-1000 mg IV daily) and permanent ICI discontinuation for Grade 3-4 toxicity 1

Monitoring and Supportive Care

Laboratory Surveillance

• Daily serum creatinine, BUN, and electrolytes (especially potassium) during acute phase 3
• Urinalysis for sterile pyuria, white blood cell casts, hematuria, and eosinophiluria 4
• Proteinuria is typically mild (<1.5 g/24 hours) in DI-AIN, distinguishing it from glomerular disease 4
• Peripheral eosinophilia supports DI-AIN diagnosis but is present in <30% of cases 2, 4

Electrolyte Management

• Correct hyperkalemia, metabolic acidosis, and other electrolyte disturbances as they arise 1
• Drug-induced tubulopathies (Fanconi syndrome, renal tubular acidosis, salt wasting) may complicate certain agents like cisplatin and ifosfamide 1

Renal Replacement Therapy Indications

• Initiate dialysis for absolute indications: refractory hyperkalemia, severe metabolic acidosis (pH <7.1), uremic symptoms (pericarditis, encephalopathy), or volume overload unresponsive to diuretics 3
• Severe oliguria (<100 mL/24 hours) indicates Stage 3 AKI and may require urgent RRT 1, 3
• Do not delay dialysis if absolute indications are present 3

Critical Pitfalls to Avoid

• Never continue NSAIDs, antibiotics, or PPIs in established AKI—this is the most common preventable error 3
• Do not use dopamine for "renal protection"—this practice is ineffective and outdated 3
• Avoid combining multiple nephrotoxins during recovery phase, as re-injury risk remains elevated 1
• Do not withhold kidney biopsy in elderly patients with unexplained AKI—DI-AIN incidence is increasing in this population, and polypharmacy complicates diagnosis 2
• Recognize that certain drugs (crizotinib, abemaciclib) cause non-injurious creatinine elevation through tubular secretion inhibition—this should not be mistaken for true AKI 1

Prognosis and Long-Term Management

• Approximately one-third of DI-AIN patients progress to chronic dialysis dependence despite treatment 4
• Early drug discontinuation and corticosteroid therapy improve renal recovery, but irreversible fibrosis occurs if treatment is delayed beyond 2-3 weeks 5, 4
• Patients must be counseled that DI-AIN is an idiosyncratic hypersensitivity reaction that recurs on re-exposure, and the offending drug class should be permanently avoided 5
• During AKD recovery phase (days 7-90), maintain caution with nephrotoxin reintroduction to prevent re-injury 1
• NSAIDs should only be reconsidered after complete AKI resolution with return to baseline creatinine 3