NephrologyTier 2Disease (DEADMAN)

Acute interstitial nephritis

Description

Immune-mediated inflammation of the tubulointerstitium, sparing glomeruli and vessels
~15-20% of biopsied AKI; the commonest cause of AKI with a bland-ish urine but sterile pyuria
Latency after the culprit drug:
- Antibiotics: 3-14 days (shorter on re-exposure)
- NSAIDs: weeks to months
- PPIs: 10-11 weeks median, up to a year
Not dose-dependent, not predictable - it is a hypersensitivity reaction

T-cell-mediated (type IV) delayed hypersensitivity - drug or metabolite acts as hapten or mimics a tubular antigen
- -> interstitial oedema + lymphocyte, monocyte, plasma cell and eosinophil infiltrate
- -> tubulitis; granulomas in some
- Unchecked -> interstitial fibrosis and tubular atrophy = irreversible

Drugs - the ones that matter

NSAIDs - mediated by increased leukotriene production; no clear risk factors; usually resolves on withdrawal
- Often no fever, no rash, no eosinophilia, and frequently nephrotic-range proteinuria (AIN + minimal change)
Proton pump inhibitors - can begin many months after starting; commonest cause in some series
Beta-lactams (methicillin classically, penicillins, cephalosporins), sulfonamides, rifampicin, ciprofloxacin, vancomycin
Immune checkpoint inhibitors - now a leading cause in oncology; median onset 3 months; steroid-responsive
Allopurinol, 5-ASA/mesalazine, phenytoin, diuretics (thiazides, frusemide), indinavir

Other drug-induced renal injury - do not confuse with AIN

Mechanism	Drugs
Direct tubular toxicity (ATN)	Aminoglycosides, amphotericin B, cisplatin, tenofovir, adefovir, radiocontrast
Crystal nephropathy	Aciclovir, indinavir, sulfonamides, methotrexate
Haemodynamic (dec GFR)	NSAIDs, ACEi/ARB, calcineurin inhibitors
Chronic interstitial nephritis	Calcineurin inhibitors, lithium, chemotherapy, analgesic nephropathy, aristolochic acid
Glomerular	NSAIDs (minimal change), gold/penicillamine (membranous), pamidronate (FSGS)

NSAIDs alone cause four distinct renal lesions: AIN, haemodynamic AKI, chronic interstitial nephritis, and minimal change disease

Non-drug causes

Infection - Legionella, Leptospira, CMV, EBV, hantavirus, streptococcus, TB, BK virus
Autoimmune/systemic - sarcoidosis, Sjogren, SLE, IgG4-related disease, TINU (tubulointerstitial nephritis with uveitis)

Clinical

The classic triad (fever + rash + eosinophilia) is present in <10% - its absence means nothing
- Fever ~35%, rash ~15%, eosinophilia ~25%
Usually non-oliguric AKI found on bloods; flank pain; arthralgia

Urine

Sterile pyuria - white cells without infection
White cell casts (not diagnostic but supportive)
Sub-nephrotic proteinuria (<1 g/day) - nephrotic-range proteinuria suggests NSAID-associated minimal change
Microscopic haematuria; urine eosinophils: poor sensitivity and specificity - do not order
Tubular dysfunction: glycosuria with normal glucose, Fanconi syndrome, type 1 or 4 RTA, hypokalaemia, hypophosphataemia

Other tests

FENa is unhelpful - can be >1% despite hypovolaemia because of tubular dysfunction
Gallium-67 scan - historically used; poor specificity
Renal biopsy is the only definitive test
- Indicated when: diagnosis uncertain, no improvement after withdrawing the suspect drug, considering steroids, or considering continuing an essential drug (e.g. checkpoint inhibitor)
Serology if systemic disease suspected: ACE, calcium, ANA, ENA, IgG4, serology for infection, slit-lamp for uveitis

1. Stop the drug - the single most important step

Review every agent started in the preceding 3 months, including OTC NSAIDs and PPIs
Improvement usually begins within 3-7 days
If no improvement in 5-7 days, biopsy rather than persist

2. Corticosteroids

Biopsy-proven AIN not improving after drug withdrawal -> prednisolone 1 mg/kg (max 60-80 mg) daily for 1-2 weeks, taper over 4-6 weeks
- Some use pulse methylprednisolone 250-500 mg IV for 3 days if severe
*Earlier steroids = better renal recovery - benefit falls sharply after 2-3 weeks and is lost once fibrosis is established*
Evidence is observational; no RCT
NSAID-associated AIN with concurrent minimal change (nephrotic syndrome) does need steroids - withdrawal alone is often not enough

3. Specific situations

Checkpoint-inhibitor AIN - hold the ICI, high-dose steroids; rechallenge is often possible after recovery (discuss with oncology)
Sarcoid - steroids, treat hypercalcaemia
IgG4-related - steroids, then rituximab if relapsing
Infection-related - treat the infection, steroids rarely needed
Mycophenolate for steroid-dependent or steroid-refractory disease

4. Supportive

Avoid further nephrotoxins and contrast; adjust drug doses to eGFR
Document the drug as an allergy - re-exposure causes faster, more severe disease
Dialysis in ~10-40% acutely

Sarcoidosis - granulomatous interstitial nephritis, hypercalcaemia, nephrocalcinosis
Sjogren syndrome - lymphocytic interstitial nephritis, distal (type 1) RTA
IgG4-related disease - storiform fibrosis, low complement, high IgG4, mass lesions
TINU - young females, anterior uveitis, may follow the nephritis by months
SLE, ANCA vasculitis (interstitial nephritis with GN)
Immune checkpoint inhibitor therapy - often with other immune-related adverse events
PPI use - also independently associated with incident CKD
Analgesic nephropathy - papillary necrosis, transitional cell carcinoma

Complete recovery in ~50-60% if the drug is stopped early
Incomplete recovery / residual CKD in ~30-40%; ESKD in ~5-10%
Predictors of poor recovery:
- Duration of exposure after AKI onset (the modifiable one)
- Delay to steroids >2-3 weeks
- Interstitial fibrosis and tubular atrophy on biopsy
- Peak creatinine, need for dialysis, older age, NSAID aetiology
Chronic interstitial nephritis (lithium, CNI, analgesics, aristolochic acid) is progressive and largely irreversible - bland urine, small kidneys, slow eGFR decline
An AIN episode leaves a permanently higher lifetime CKD risk - follow eGFR and BP long-term

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