Interstitial Nephritis

The kidney has two main compartments:

• The GLOMERULI — the filters (involved in glomerulonephritis)
• The TUBULES + INTERSTITIUM — handle reabsorption and concentration

INTERSTITIAL NEPHRITIS is inflammation of the interstitium, usually with damage to surrounding tubules.

Two Forms

1. Acute Interstitial Nephritis (Ain)

• Sudden-onset AKI
• Usually allergic/immune mediated
• Eosinophils present on biopsy
• Reversible if caught early

2. Chronic Interstitial Nephritis (Cin)

• Slow progressive damage
• Fibrosis and tubular atrophy
• Usually irreversible
• Causes: analgesic nephropathy (long NSAIDs/paracetamol), lithium, chronic urinary obstruction, reflux nephropathy, sickle cell, sarcoidosis, Sjögren's, lead, Balkan endemic nephropathy, aristolochic acid

Causes Of Acute Ain

• DRUGS (most common — 70-80%):
• PPIs: omeprazole, lansoprazole, esomeprazole, pantoprazole
• Antibiotics: penicillins, cephalosporins, ciprofloxacin, co-trimoxazole, rifampicin, vancomycin
• NSAIDs: ibuprofen, naproxen, diclofenac (often less classic 'allergic' picture)
• Allopurinol
• 5-aminosalicylates (mesalazine, sulfasalazine)
• Diuretics (furosemide, thiazides)
• Anticonvulsants (phenytoin, carbamazepine)
• Cancer immunotherapy: checkpoint inhibitors (pembrolizumab, nivolumab)
• INFECTIONS: Legionella, Leptospira, EBV, CMV, Hantavirus, TB, HIV
• AUTOIMMUNE: sarcoidosis, Sjögren's syndrome, lupus, IgG4-related disease
• TIN-U (tubulointerstitial nephritis + uveitis): young women, eye inflammation + AIN
• Idiopathic

Typical Presentation

• Rising creatinine over days to weeks
• Often picked up on routine blood test
• Started a new drug in the previous 2 days to 6 weeks
• Flank pain or general malaise
• Less commonly: fever, rash, joint pain ('classic triad' — present in < 10%)
• Eosinophilia on FBC
• Reduced urine output (occasionally)
• Tubular dysfunction signs:
• Low potassium or low phosphate
• Low bicarbonate (acidosis)
• Glycosuria with normal blood sugar (proximal tubule)
• Sodium wasting

Urine Findings

• White cells without infection (sterile pyuria)
• White cell casts
• Eosinophiluria (Hansel stain) — supportive but not specific
• Mild proteinuria (usually < 1 g/day, not nephrotic)
• Bland sediment otherwise

Investigations

• Drug history — go back 6 weeks; include OTC, supplements, herbal
• FBC (eosinophilia in 30%)
• U&E (rising creatinine)
• Urine ACR
• Urine microscopy (white cells, casts)
• Urine eosinophils
• ANA, ANCA, complement, ACE (sarcoid)
• Serum IgG4
• HIV, hepatitis screen
• Slit lamp eye exam (TIN-U)
• Renal ultrasound (usually normal-sized or enlarged)
• KIDNEY BIOPSY — interstitial inflammation with eosinophils; granulomas in sarcoid; IgG4+ cells in IgG4-RD

STEP 1 — IDENTIFY AND STOP THE CULPRIT:

• Single most important intervention
• Stop ALL non-essential medications and supplements
• Restart only what is truly needed
• Document allergy alert — avoid lifelong

STEP 2 — STEROIDS:

• Recommended for biopsy-proven AIN with persistent AKI
• IV methylprednisolone 250-500 mg ×3 days (for severe cases)
• Then oral prednisolone 1 mg/kg (max 60-80 mg) daily for 2-4 weeks
• Then taper over 8-12 weeks total
• Earlier steroids = better chance of avoiding chronic kidney damage

STEP 3 — SUPPORTIVE:

• Treat acidosis (sodium bicarbonate)
• Replace potassium/magnesium if low
• Avoid further nephrotoxins (no NSAIDs lifelong)
• Adequate hydration
• Dialysis if severe AKI (temporary)

Special Situations

• Checkpoint inhibitor AIN: stop checkpoint inhibitor; steroids; sometimes can resume cancer drug; oncology + nephrology liaison
• Sarcoid: prednisolone — often dramatic response; consider methotrexate as steroid-sparing
• Sjögren's, IgG4-RD: prednisolone + rituximab
• TIN-U: steroids + topical/systemic for eyes
• Infection-related: treat infection (avoid nephrotoxic antibiotics if possible)

DRUG-INDUCED — when AIN is biopsy-confirmed and drug stopped, kidney function usually improves within 2-12 weeks. Failure to recover may mean chronic damage has set in.

Proton pump inhibitors (omeprazole, lansoprazole, esomeprazole, pantoprazole, rabeprazole) are now the COMMONEST drug cause of AIN in UK practice.

Why

• Used by ~15% of UK adults — many long-term without indication
• PPI-AIN often subclinical: gradual slow creatinine rise
• Chronic PPI use linked to CKD progression in observational studies
• Mechanism: delayed hypersensitivity — usually weeks to months after starting (sometimes years)

REVIEW PPI USE if:

• On for > 8 weeks without ongoing reflux/ulcer indication
• Started 'just in case' without clear reason
• Creatinine has risen unexplainedly

Deprescribing

• Step down to H2 blocker (famotidine) or alginate (Gaviscon)
• Treat true reflux with lifestyle (weight, alcohol, late meals, head of bed)
• Test for H. pylori — eradicate if positive
• Some patients genuinely need lifelong PPI (Barrett's, severe oesophagitis, NSAID + risk factors)

If Ppi-ain Diagnosed

• Stop the PPI permanently
• Avoid ALL PPIs (cross-reactivity)
• Switch to H2 blocker if acid suppression still needed
• Document allergy

Recovery

• Best if drug stopped early
• Steroids improve renal recovery in biopsy-confirmed cases
• Most regain function within 4-12 weeks
• Some are left with chronic interstitial damage and CKD

Factors Predicting Worse Outcome

• Delay in stopping culprit drug
• Older age
• Pre-existing CKD
• Extensive interstitial fibrosis on biopsy
• Granulomas on biopsy
• No steroid treatment

Follow-up

• 1-3 monthly bloods until recovered
• 6-monthly long-term for those with residual CKD
• Document drug allergy clearly
• Allergy alert bracelet/wallet card
• Inform GP, pharmacist, dentist
• Avoid the entire drug class (e.g. avoid ALL PPIs if PPI-AIN)

Chronic Interstitial Nephritis

• Long-term avoidance of nephrotoxins (NSAIDs especially)
• BP control < 130/80
• ACE inhibitor or ARB if proteinuria
• Treat underlying autoimmune disease
• Standard CKD management
• Specialist input if cause unclear