📋 Key Information Summary
- Acute interstitial nephritis (AIN) accounts for approximately 15–27% of unexplained acute kidney injury (AKI) cases in Australian hospital settings and is frequently underdiagnosed.
- Drugs are the most common aetiology in adults, responsible for 70–80% of cases — proton-pump inhibitors (PPIs), NSAIDs, and antibiotics (penicillins, cephalosporins, trimethoprim) are the leading culprits.
- The classic triad is: (1) rising serum creatinine, (2) sterile pyuria, and (3) eosinophiluria — though the full triad is present in fewer than one-third of cases.
- Early identification and withdrawal of the offending agent is the single most important management step; delays correlate with increased risk of chronic kidney disease (CKD).
- Urine eosinophils (Hansel stain preferred over Wright stain) are supportive but not pathognomonic; the sensitivity of urine eosinophiluria is approximately 40–60%.
- Kidney biopsy remains the gold standard for diagnosis when the clinical picture is uncertain or when there is no improvement after drug withdrawal.
- Corticosteroids are indicated in drug-induced AIN where renal function fails to recover within 5–7 days of offending agent cessation.
- Typical corticosteroid regimen: prednisolone 0.5–1 mg/kg/day (max 60 mg) orally for 2–4 weeks, followed by a taper over 4–6 weeks.
- Infectious AIN (bacterial pyelonephritis, leptospirosis, CMV) requires treatment of the underlying infection rather than immunosuppression.
- Sarcoid-associated and IgG4-related tubulointerstitial nephritis are important immune-mediated causes requiring specialist rheumatology/nephrology co-management.
- Nephrology referral is indicated for all patients with AIN and AKI Stage ≥2 (KDIGO criteria), biopsy-proven disease, or when dialysis may be required.
- Aboriginal and Torres Strait Islander peoples have higher rates of renal disease generally; consider AIN in the differential of unexplained AKI in remote settings where polypharmacy is common.
Introduction & Australian Epidemiology
Acute interstitial nephritis (AIN) is an inflammatory disorder of the renal tubulointerstitium characterised by interstitial oedema, tubular injury, and infiltration by inflammatory cells — predominantly lymphocytes, macrophages, eosinophils, and occasionally plasma cells. It is an important and potentially reversible cause of acute kidney injury (AKI).
Historically considered a rare entity, AIN is now recognised as the cause of 15–27% of intrinsic AKI cases in hospital-based cohorts, with autopsy and biopsy series suggesting it is significantly underdiagnosed. The rising incidence parallels increased use of implicated medications, particularly proton-pump inhibitors (PPIs), which have emerged over the past decade as one of the most common offending agents.
In Australia, data from the ANZDATA registry and tertiary centre renal biopsy series (including Westmead Hospital and Royal Adelaide Hospital series) confirm that drug-induced AIN predominates in adult practice, while post-infectious and immune-mediated causes are important in paediatric and immunocompromised populations. The condition affects all age groups but is most common in adults aged 40–75 years, with a slight male predominance (M:F ≈ 1.5:1).
Early recognition and prompt withdrawal of the causative agent are critical, as delayed diagnosis is associated with irreversible tubular atrosis, interstitial fibrosis, and progression to CKD requiring dialysis. This guideline covers the aetiology, clinical features, investigation, and management of AIN in the Australian setting.
Aetiology: Drug-Induced, Infectious, Immune
Drug-Induced AIN (70–80% of cases)
Drug-induced AIN is a type IV (delayed-type) hypersensitivity reaction. It is typically not dose-dependent, may occur after days to months of exposure, and can recur upon re-challenge. The most commonly implicated drug classes in Australia include:
| Drug Class | Examples | Approximate Relative Risk |
|---|---|---|
| Proton-pump inhibitors | Omeprazole, esomeprazole, pantoprazole, lansoprazole | High — now the most common single-class cause |
| Antibiotics | β-lactams (penicillins, cephalosporins), trimethoprim-sulfamethoxazole, fluoroquinolones, rifampicin | High — β-lactams historically the most recognised |
| NSAIDs | Ibuprofen, naproxen, diclofenac, indomethacin, COX-2 inhibitors | Moderate — may also cause minimal-change nephrotic syndrome |
| Diuretics | Thiazides, frusemide, ethacrynic acid | Low–Moderate |
| Anticonvulsants | Carbamazepine, phenytoin, lamotrigine, valproate | Low–Moderate |
| Immune checkpoint inhibitors | Nivolumab, pembrolizumab, ipilimumab | Emerging — checkpoint inhibitor-related nephrotoxicity |
| Other | Allopurinol, 5-ASA (mesalazine), cimetidine, indinavir | Low |
Infectious AIN
Infection-related AIN may result from direct renal parenchymal invasion or immune-mediated injury:
- Bacterial: Escherichia coli, Proteus, Klebsiella (ascending pyelonephritis); Leptospira spp. (tropical regions including northern Australia); Streptococcus (scarlatina-associated AIN); Brucella
- Viral: CMV (especially immunocompromised), HIV-associated nephropathy, hantavirus, polyomavirus (BK virus), Epstein–Barr virus (EBV)
- Fungal: Candida spp., Aspergillus spp. — predominantly in immunosuppressed patients
- Rickettsial: Q fever (Coxiella burnetii) — relevant in rural Australia
- Parasitic: Leishmania, Toxoplasma — imported cases
Immune-Mediated AIN
Systemic autoimmune conditions may present with isolated or predominant tubulointerstitial inflammation:
- Sarcoidosis: Non-caseating granulomatous interstitial nephritis; may cause hypercalcaemia-related renal impairment
- IgG4-related tubulointerstitial nephritis: Part of IgG4-related systemic disease; characteristic storiform fibrosis and IgG4+ plasma cell infiltration on biopsy
- Sjögren syndrome: Tubulointerstitial nephritis in up to 30% of patients, though often subclinical
- Systemic lupus erythematosus: Lupus interstitial nephritis (class III/IV often have interstitial component)
- Tubulointerstitial nephritis with uveitis (TINU) syndrome: Idiopathic; predominantly in young females
PPI-associated AIN is increasing: PPIs are now the single most common cause of drug-induced AIN in Australian tertiary centres. All PPIs carry this risk. Maintain a high index of suspicion in any patient on long-term PPI therapy presenting with unexplained AKI and bland urinary sediment.
Clinical Features & Classic Triad
The Classic Triad
The classic triad of AIN — fever, rash, and arthralgia — was originally described with methicillin-associated AIN. However, the full triad is present in fewer than 10% of contemporary cases. In practice, AIN more commonly presents insidiously with:
- Rising serum creatinine (unexplained AKI) — the most consistent finding
- Sterile pyuria — white blood cells on urine microscopy with negative culture
- Eosinophiluria — present in only 40–60% of cases
Symptoms & Signs
| Feature | Frequency | Notes |
|---|---|---|
| Oliguria / rising creatinine | 80–100% | Usually non-oliguric initially; AKI may progress |
| Sterile pyuria | 70–80% | WBC casts or free WBCs; urine culture negative |
| Fever | 30–50% | May be low-grade; often absent with NSAIDs |
| Maculopapular rash | 15–30% | Typically truncal; coincides with drug exposure |
| Arthralgia | 15–25% | Non-specific; may accompany rash |
| Flank pain | 10–20% | Dull, bilateral; renal capsule stretching |
| Peripheral eosinophilia | 25–40% | Blood eosinophil count >0.5 × 10⁹/L |
| Eosinophiluria | 40–60% | Hansel stain >1% eosinophils of urinary WBCs |
Clinical Pearl: Drug-induced AIN from NSAIDs often lacks the classic hypersensitivity features (fever, rash, eosinophilia) and presents as isolated AKI — sometimes with nephrotic-range proteinuria due to concurrent minimal-change disease. Maintain a high index of suspicion in any patient with unexplained AKI on NSAIDs.
Timing of Onset
Drug-induced AIN typically presents 7–21 days after drug initiation, but may occur within days (antibiotics) or months to years (PPIs, NSAIDs). Re-exposure to a previously offending agent may produce symptoms within 24–48 hours.
Investigations
Laboratory Investigations
Essential
Serum Creatinine & eGFR
Serial monitoring to establish AKI trajectory. KDIGO staging guides urgency of intervention.
Essential
Full Blood Count with Differential
Peripheral eosinophilia (≥0.5 × 10⁹/L) present in 25–40% but absence does not exclude AIN.
Essential
Urinalysis & Urine Microscopy
Sterile pyuria (WBC >5/HPF); WBC casts pathognomonic but uncommon; haematuria in ~30%. Send urine culture to exclude infection.
Available
Urine Eosinophils (Hansel Stain)
Request specifically — Hansel stain is more sensitive than Wright stain. >1% eosinophils of urinary WBCs is supportive. Sensitivity 40–60%, specificity ~80%. Not pathognomonic (also seen in rapidly progressive GN, atheroembolic disease, prostatitis).
Available
IgE Level
May be elevated in drug-induced AIN; non-specific but supportive of hypersensitivity mechanism.
Available
Serum IgG4 (if IgG4-related disease suspected)
Elevated in IgG4-related tubulointerstitial nephritis. Available through major pathology providers (Sonic, Healius).
Available
Autoimmune Serology (ANA, ENA, dsDNA, ANCA)
To exclude lupus nephritis or ANCA-associated vasculitis if immune-mediated cause suspected.
Renal Biopsy — Gold Standard
Percutaneous renal biopsy is the definitive diagnostic test and should be performed when:
- Clinical suspicion is high but the diagnosis remains uncertain
- No improvement in renal function 5–7 days after cessation of suspected offending agent
- Immune-mediated aetiology is suspected (sarcoidosis, IgG4-related disease, lupus)
- To exclude alternative diagnoses (ANCA vasculitis, anti-GBM disease, acute tubular necrosis)
| Biopsy Finding | Interpretation |
|---|---|
| Dense interstitial lymphocytic infiltrate (CD4+ and CD8+ T cells) | Most common pattern in drug-induced AIN |
| Eosinophilic infiltrate | Characteristic of drug-induced; may also be seen in parasites |
| Non-caseating granulomas | Sarcoidosis; also consider mycobacterial/fungal infection |
| Storiform fibrosis + IgG4+ plasma cells | IgG4-related tubulointerstitial nephritis |
| Tubulitis (lymphocyte invasion of tubular basement membrane) | Confirms active interstitial inflammation |
| Interstitial fibrosis >50% | Chronicity — poor prognostic indicator; less likely to respond to steroids |
Imaging
- Renal ultrasound: First-line imaging; kidneys may be enlarged with increased echogenicity (oedema). Helps exclude obstruction and assess renal size.
- CT abdomen (non-contrast): If biopsy planned — evaluates kidney position and excludes cystic/mass lesions.
Renal biopsy risks: Major complication rate (requiring intervention) is approximately 1–2%. Contraindications include uncontrolled hypertension, uncorrected coagulopathy, solitary kidney (relative), and morbid obesity making safe percutaneous access difficult. Discuss with interventional radiology.
Management: Drug Withdrawal, Steroids
Principle 1: Immediate Withdrawal of Offending Agent
Critical first step: Cease ALL suspected nephrotoxic agents immediately upon clinical suspicion of AIN. Do not wait for biopsy confirmation. Every day of continued drug exposure increases the risk of irreversible interstitial fibrosis and permanent CKD.
In most drug-induced AIN cases, renal function begins to improve within 5–14 days of drug cessation. If no improvement is seen by day 5–7, corticosteroid therapy should be initiated (see below). Document the offending drug clearly in the patient's allergy/adverse drug reaction list and notify their GP.
Principle 2: Supportive Care
- Fluid balance management — avoid nephrotoxins (contrast, aminoglycosides)
- Electrolyte monitoring and correction (hyperkalaemia, metabolic acidosis)
- Dialysis if indicated — severe AKI Stage 3 (KDIGO), refractory hyperkalaemia, fluid overload, uraemic symptoms
- Medication dose adjustment for renal impairment (renal dosing)
- Blood pressure control; avoid ACEi/ARB during acute phase if haemodynamically unstable
Principle 3: Corticosteroids
Corticosteroids are the mainstay of immunosuppressive therapy for drug-induced AIN when withdrawal of the offending agent alone is insufficient. The optimal timing, dose, and duration remain debated, but the following regimen is consistent with Australian nephrology practice and international consensus:
Prednisolone
Solone® · Generic · Corticosteroid
Adult dose
0.5–1 mg/kg/day (max 60 mg) PO daily for 2–4 weeks, then taper by 5–10 mg/week over 4–6 weeks (total course 6–10 weeks)
Paediatric dose
1–2 mg/kg/day (max 60 mg) PO daily; taper as per nephrology advice
Route
Oral
Renal adjustment
No dose adjustment required for renal impairment
Key monitoring
Blood glucose (risk steroid-induced diabetes), BMD if >3 weeks, PJP prophylaxis if prolonged
PBS status
✔ PBS General Benefit
Intravenous pulse methylprednisolone (500 mg–1 g IV daily for 3 days) may be considered for severe AIN with dialysis-dependent AKI or biopsy showing minimal fibrosis, followed by oral prednisolone taper. This should be initiated in consultation with nephrology.
Principle 4: Management of Specific Aetiologies
| Aetiology | First-Line Treatment | Notes |
|---|---|---|
| Drug-induced AIN | Withdraw offending agent + ± corticosteroids | Steroids if no recovery in 5–7 days |
| Bacterial pyelonephritis | IV antibiotics per culture & sensitivity; ceftriaxone 1–2 g IV daily empirically | Do NOT use corticosteroids |
| Leptospirosis | IV benzylpenicillin 1.2 g 4–6 hourly or IV ceftriaxone 1–2 g daily | Early treatment (within 5 days of onset) reduces complications |
| CMV-related AIN | IV ganciclovir 5 mg/kg 12-hourly or oral valganciclovir 900 mg BD | Immunocompromised patients; adjust for renal function |
| Sarcoid-associated AIN | Prednisolone 0.5–1 mg/kg/day; consider steroid-sparing agent (azathioprine, mycophenolate) | Nephrology + rheumatology co-management |
| IgG4-related TIN | Prednisolone 0.6 mg/kg/day × 4 weeks, taper over 3–6 months | Relapse common; rituximab for refractory cases |
| TINU syndrome | Corticosteroids ± NSAIDs for uveitis | Ophthalmology + nephrology co-management |
Second-Line / Steroid-Sparing Agents
For steroid-dependent, steroid-refractory, or chronic interstitial nephritis, consider in consultation with nephrology:
Mycophenolate mofetil
CellCept® · Generic · Antiproliferative immunosuppressant
Adult dose
500 mg–1 g PO BD
Renal adjustment
Caution if eGFR <25 mL/min — specialist dosing required
PBS status
⚠ PBS Authority Required
Azathioprine
Imuran® · Generic · Purine analogue immunosuppressant
Adult dose
1–2 mg/kg/day PO; check TPMT genotype before commencing
Renal adjustment
No specific dose reduction; monitor FBC closely
PBS status
✔ PBS General Benefit
Monitoring & Follow-Up
Daily (inpatient)
Serum creatinine, electrolytes, fluid balance. Monitor for recovery trajectory after drug withdrawal.
Days 5–7
If no creatinine improvement → commence corticosteroids. Consider biopsy if not yet performed.
Weeks 1–2
Expect creatinine to start declining with effective treatment. Continue steroid course.
Weeks 4–6
Taper prednisolone. Recheck creatinine and eGFR. Ensure offending agent documented in allergy list.
3–6 months
Repeat eGFR. Assess for residual CKD. Nephrology follow-up if eGFR <60 mL/min or persistent proteinuria.
12 months+
Annual eGFR and urine ACR monitoring per CKD guidelines. Educate patient regarding drug avoidance.
Special Populations
Pregnancy
Diagnosis: Renal biopsy can be performed in pregnancy but requires multidisciplinary planning (obstetrics, nephrology, interventional radiology).
Steroids: Prednisolone is Category A in Australia; use lowest effective dose. Avoid pulse methylprednisolone unless life-threatening.
Considerations: Pre-eclampsia and HELLP must be excluded as causes of AKI in pregnancy.
Paediatrics
Aetiology: Antibiotics (amoxicillin, ceftriaxone) and NSAIDs are the most common causes in children. TINU syndrome is more common in adolescents.
Steroids: Prednisolone 1–2 mg/kg/day (max 60 mg). Paediatric nephrology should guide management.
Biopsy: May require general anaesthesia in young children; discuss with paediatric nephrology centre (Sydney Children's, RCH Melbourne, Queensland Children's).
Elderly
Polypharmacy: Highest risk group due to multiple concurrent medications. PPIs and NSAIDs are frequently prescribed and often continued unnecessarily.
Steroid risks: Increased risk of steroid-induced diabetes, osteoporosis, and infections (including PJP). Use shorter courses and lowest effective doses. Consider PJP prophylaxis (co-trimoxazole DS 3×/week) if prolonged steroids.
Biopsy: Higher complication risk; weigh diagnostic benefit against procedural risk. May accept presumptive diagnosis if classic presentation with clear drug exposure.
Pre-existing CKD
Baseline: AIN on background CKD may present with disproportionate creatinine rise above baseline. Threshold for investigation should be lower.
Prognosis: Recovery to baseline eGFR is less likely; even partial recovery is clinically meaningful.
Immunocompromised
Differential: Include CMV, BK polyomavirus, fungal infection. Urine CMV/BK PCR should be sent.
Checkpoint inhibitors: AIN is a recognised immune-related adverse event (irAE). Grade 2+ nephrotoxicity requires holding the checkpoint inhibitor and starting prednisolone 1 mg/kg/day.
Transplant patients: Distinguish drug-induced AIN from acute cellular rejection (both show interstitial inflammation on biopsy). Immunohistochemistry is essential.
ATSI Health Considerations
Aboriginal and Torres Strait Islander Health
Aboriginal and Torres Strait Islander peoples experience a disproportionate burden of kidney disease, with rates of end-stage kidney disease (ESKD) approximately 8–10 times higher than non-Indigenous Australians (AIHW 2023). While AIN has not been studied separately in ATSI populations, several factors increase both the risk and diagnostic challenge:
📚 References
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