Drug Induced Interstitial Nephritis

Drug induced interstitial nephritis is an immune mediated hypersensitivity injury of the kidney interstitium and tubules caused by a medicine. It accounts for about 60 to 70% of biopsy proven acute interstitial nephritis and about 1 to 3% of kidney biopsies overall, rising to 5 to 15% of biopsies for unexplained acute kidney injury.

The commonest triggers are:

• Antibiotics (penicillins, cephalosporins, fluoroquinolones, sulphonamides including co-trimoxazole, rifampicin, vancomycin).
• Proton pump inhibitors.
• NSAIDs and cyclo oxygenase 2 inhibitors.
• Allopurinol.
• Loop and thiazide diuretics (sulphonamide derivatives).
• 5-aminosalicylates.
• Anticonvulsants (phenytoin, carbamazepine).
• Immune checkpoint inhibitors (about 2 to 5% of treated patients).
• Some antivirals (atazanavir).

Older age, polypharmacy and proton pump inhibitor use are the main risk factors.

Pathophysiology

The drug or a hapten attached to tubular proteins triggers a delayed type IV (T-cell mediated) response with infiltration of T cells, macrophages and eosinophils, tubulitis, interstitial oedema and later fibrosis, which explains why prolonged exposure reduces recovery.

• Rise in creatinine 7 to 10 days after first exposure (days after re-exposure), or after months to years for proton pump inhibitors, NSAIDs and checkpoint inhibitors (median about 3 months, with a range of weeks to over a year).
• The classic triad of fever, rash and eosinophilia occurs in under 10 to 15% of patients; arthralgia, flank pain and rash occur less often.
• Non-oliguric acute kidney injury is typical; oliguria in about 30%.
• Tubular dysfunction: distal renal tubular acidosis, hyperkalaemia, glycosuria, Fanconi syndrome, salt wasting and polyuria.
• Proteinuria is usually under 1 g daily (low molecular weight); nephrotic range proteinuria in NSAID associated disease (with minimal change disease).

Red flags

• Creatinine doubling within days, or oliguria.
• Fever, rash and eosinophilia after starting a new drug.
• Previous reaction to the same drug or class.
• Checkpoint inhibitor therapy with a creatinine rise: do not assume pre-renal.
• Persistent kidney injury more than 3 to 7 days after stopping the suspected drug.

• Medication review across the previous 3 to 6 months (including over-the-counter proton pump inhibitors and NSAIDs); timing against onset of kidney injury.
• Creatinine, urea, electrolytes, bicarbonate, full blood count with eosinophil count (raised in 30 to 40%), C-reactive protein, liver tests, urinalysis.
• Urine microscopy: sterile pyuria, white cell casts, mild haematuria (absence of red cell casts); urine protein:creatinine ratio (usually under 100 mg/mmol).
• Urine eosinophils (poor sensitivity and specificity; do not use for decision making), urine beta-2 microglobulin.
• Kidney ultrasound: normal or enlarged echogenic kidneys; exclude obstruction.
• Kidney biopsy when the diagnosis is uncertain, creatinine does not improve in 3 to 7 days after withdrawing the drug, or before starting corticosteroids.
• Biopsy findings are interstitial oedema and infiltrate of lymphocytes, plasma cells and eosinophils, tubulitis, with granulomas in some; fibrosis predicts poor recovery.
• Exclude other causes: infection, systemic autoimmune disease (anti-nuclear antibodies, ANCA, complement), sarcoidosis, IgG4 related disease, tubulointerstitial nephritis with uveitis, light chain disease.

Differential diagnosis

• Acute tubular injury, pre-renal injury, glomerulonephritis, infection associated interstitial nephritis, sarcoid interstitial nephritis, IgG4 related disease, tubulointerstitial nephritis with uveitis, urinary tract obstruction, crystal nephropathy.

First line: stop the drug immediately

• Withdraw the suspected agent and avoid the whole class where relevant (for example, any proton pump inhibitor; penicillin class reactions); choose a structurally unrelated alternative for the original indication.
• Supportive care: avoid nephrotoxins (NSAIDs, contrast, aminoglycosides, vancomycin); maintain euvolaemia.
• Correct hyperkalaemia (calcium gluconate 10% 10 mL intravenously over 10 minutes, insulin 10 units with glucose 25 g, salbutamol 10 to 20 mg nebulised).
• Sodium zirconium cyclosilicate 10 g three times daily for up to 48 hours, then 5 to 10 g daily, maximum 15 g.
• Treat acidosis with sodium bicarbonate 500 mg to 1 g two to three times daily to bicarbonate at least 22 mmol/L.
• Observe for 3 to 7 days after stopping; about 50% improve without steroids.

Corticosteroids (start when no improvement in 3 to 7 days, or when function is severely impaired, or the biopsy shows significant active inflammation without extensive fibrosis)

• Prednisolone 1 mg/kg daily (maximum 60 mg) for 1 to 2 weeks, then taper over 4 to 6 weeks (total 6 to 8 weeks); start within 2 weeks of onset because delayed treatment (over 3 weeks) is associated with poorer recovery.
• Severe disease (creatinine above 300 micromol/L, or dialysis requirement): methylprednisolone 250 to 500 mg intravenously daily for 3 days, then prednisolone 1 mg/kg daily (maximum 60 mg) tapered over 4 to 6 weeks.
• Steroid non-response or contraindication: mycophenolate mofetil 1 g twice daily for 3 to 6 months (limited evidence); stop if no response after 4 weeks of steroids.
• Give pneumocystis prophylaxis with co-trimoxazole 480 mg daily unless the trigger was a sulphonamide (then atovaquone 1500 mg daily).
• Give gastric protection with famotidine 20 mg daily (reduced when eGFR is under 50) rather than a proton pump inhibitor when that was the trigger; monitor glucose, blood pressure and infection.

Immune checkpoint inhibitor interstitial nephritis

• Grade 2 (creatinine 2 to 3 times baseline): hold the drug; prednisolone 0.5 to 1 mg/kg daily.
• Grade 3 or 4 (creatinine above 3 times baseline, or dialysis): stop the drug permanently; methylprednisolone 1 to 2 mg/kg daily intravenously, then prednisolone 1 mg/kg tapered over 4 to 6 weeks.
• Mycophenolate mofetil 1 g twice daily or infliximab 5 mg/kg when refractory.
• Rechallenge may be considered in selected patients after recovery with oncology input, with or without continued prednisolone 10 mg daily.
• Concurrent proton pump inhibitors are a major risk factor; stop them.

Kidney replacement therapy. Indications: potassium above 6.5 mmol/L refractory to treatment, pH under 7.15, fluid overload unresponsive to diuretics, uraemic complications; need is uncommon (about 10 to 30% of severe cases); dialysis independence is expected in most.

Long term care.

• Record the drug allergy; recheck creatinine and urine protein:creatinine ratio at 1 week, 4 weeks, 3 months and 12 months.
• About 40 to 50% have some residual loss of function and 5 to 10% progress to chronic kidney disease (higher with fibrosis above 25% at biopsy, older age and prolonged exposure).
• Manage chronic kidney disease as usual.

Monitoring. Creatinine, potassium and bicarbonate daily during acute injury, then twice weekly until stable; blood pressure, glucose and weight during steroids.

Referral and escalation. Nephrology for any acute kidney injury with suspected drug trigger; urgent for oliguria, hyperkalaemia above 6.5 mmol/L, or severe acidosis; oncology for checkpoint inhibitor injury.

Special groups

• Older adults: highest risk from proton pump inhibitors and NSAIDs; slower recovery; use the lowest effective steroid dose.
• Children: antibiotics and NSAIDs; weight based prednisolone 1 to 2 mg/kg daily (maximum 60 mg).
• Transplant recipients: distinguish from rejection by biopsy; steroids carry a risk of infection.
• Pregnancy: avoid mycophenolate; prednisolone is acceptable.