Acute Interstitial Nephritis
Acute inflammatory condition of the renal interstitium and tubules, most commonly triggered by drugs, infections, or autoimmune processes, leading to a rapid decline in kidney function.
Acute Interstitial Nephritis (AIN)
Acute interstitial nephritis (AIN) is characterised by acute inflammatory infiltrates affecting the renal interstitium and tubular cells, leading to a rapid decline in kidney function (acute kidney injury) over days to weeks [1][2]. The inflammation is primarily localised to the tubulointerstitium — the compartment of extracellular matrix, cells, and fluid that surrounds the renal tubules — rather than the glomeruli or vasculature.
Breaking down the name:
- "Acute" = rapid onset (days to weeks, as opposed to chronic which is months)
- "Interstitial" = affecting the interstitium (the supporting tissue between the tubules)
- "Nephritis" = nephros (Greek: kidney) + -itis (inflammation) → kidney inflammation
The interstitium comprises ~95% of the renal parenchyma, so any pathology here has detrimental effects on renal function [1].
AIN is distinct from acute tubular necrosis (ATN), which involves death/injury of tubular epithelial cells typically from ischaemia or direct nephrotoxins. AIN is an immune-mediated or hypersensitivity-driven inflammatory process in the surrounding interstitial tissue, although the tubules are secondarily damaged by the inflammatory infiltrate.
Key Distinction: AIN vs ATN
- ATN: Tubular epithelial cell death → muddy brown/granular casts. Onset in minutes to hours. Usually ischaemic or nephrotoxic.
- AIN: Interstitial inflammation → sterile pyuria, WBC casts. Onset in days to weeks. Usually drug hypersensitivity, infection, or autoimmune. Both are intrinsic renal causes of AKI, but the mechanism, timeline, and urinalysis findings differ.
- AIN accounts for 5–15% of all AKI cases [1][3]
- It is an under-recognised cause of AKI because:
- Many cases are subclinical or have non-specific presentations
- The "classic triad" is present in only ~10% of cases
- Definitive diagnosis requires renal biopsy, which is not performed in every AKI patient
- In biopsy series of unexplained AKI, AIN is found in 15–27% of cases — suggesting it is far more common than clinically suspected
- Drug-induced AIN is the most common form (~71%) [2]
- Higher risk in the elderly (polypharmacy, more drug exposure, reduced renal reserve) [4]
- TINU syndrome (tubulointerstitial nephritis and uveitis) is more common in children and young women [3]
Hong Kong Context
- High use of PPIs (widely available over-the-counter) — increasingly recognised as a common cause of AIN
- Traditional Chinese medicines (herbal nephropathy) may cause interstitial nephritis
- NSAIDs are frequently used for musculoskeletal pain in the ageing population
- Allopurinol-induced AIN is relevant given the high prevalence of gout and the HLA-B*5801 allele in the Chinese population (associated with severe allopurinol hypersensitivity including AIN, SJS/TEN, and acute hepatitis) [5]
- Immune checkpoint inhibitors (anti-PD-1/PD-L1) are increasingly used in oncology, and immune checkpoint inhibitor-associated AKI (typically AIN) is an emerging problem [5]
3. Anatomy and Functional Review
The tubulointerstitium is the space between the nephrons (glomeruli + tubules) and the renal vasculature. It consists of:
| Component | Function |
|---|---|
| Interstitial cells (fibroblasts, dendritic cells, macrophages) | Structural support, immune surveillance, erythropoietin production (cortical fibroblasts) |
| Extracellular matrix (collagen, glycosaminoglycans) | Scaffolding for tubular architecture |
| Interstitial fluid | Medium for solute exchange between tubules and peritubular capillaries |
| Peritubular capillaries | Supply O₂ and nutrients to tubules; receive reabsorbed solutes |
The interstitium participates in fluid and electrolyte exchange as well as endocrine functions of the kidney [6]. It is not just passive scaffolding.
The tubules are embedded in the interstitium. Any interstitial inflammation will:
- Compress tubules → ↓ tubular flow → oliguria
- Disrupt peritubular capillary blood supply → tubular ischaemia
- Impair solute and water reabsorption/secretion → electrolyte disturbances, concentrating defect, acidosis
- Damage tubular basement membranes → tubular dysfunction (Fanconi syndrome, RTA)
- Impair erythropoietin production → anaemia (if chronic)
| Tubular Segment | Key Functions Affected in AIN |
|---|---|
| Proximal convoluted tubule (PCT) | Reabsorption of Na⁺, HCO₃⁻, glucose, amino acids, phosphate, uric acid → Fanconi syndrome if damaged |
| Loop of Henle | Countercurrent multiplication, Na⁺/K⁺/2Cl⁻ reabsorption → concentrating defect if damaged |
| Distal convoluted tubule (DCT) | Na⁺/Cl⁻ reabsorption, Ca²⁺ reabsorption |
| Collecting duct | ADH-mediated water reabsorption (AQP2), H⁺/K⁺ secretion → nephrogenic DI, RTA if damaged |
4. Aetiology
The causes of AIN can be broadly categorised into: (1) Drugs (~71%), (2) Infections (~16%), (3) Autoimmune/systemic diseases (~5–10%), (4) TINU syndrome (~5%), and (5) Idiopathic (~8%) [2][3].
This is overwhelmingly the most common cause. The reaction is typically idiosyncratic (unpredictable, not dose-dependent) and represents a type IV delayed hypersensitivity reaction (T cell–mediated).
Drug-induced AIN is usually an idiosyncratic reaction, occurring 3–5 days after drug intake (but can be several weeks after exposure) [2].
| Drug Class | Key Examples | Notes |
|---|---|---|
| Antibiotics | Penicillins (esp. methicillin — historically the "classic" cause), cephalosporins, co-trimoxazole (TMP-SMX), quinolones, rifampicin | Methicillin-induced AIN was where the "classic triad" was first described [3] |
| NSAIDs | All NSAIDs, including COX-2 selective | NSAIDs can also cause minimal change disease or membranous nephropathy concurrently → nephrotic syndrome + AKI [4] |
| Proton pump inhibitors (PPIs) | Omeprazole, lansoprazole, pantoprazole | PPIs cause acute tubulointerstitial nephritis → AKI, and chronic tubulointerstitial nephritis → CKD [7]. Increasingly recognised; may have delayed onset (weeks to months) |
| Diuretics | Loop diuretics (furosemide), thiazides | |
| Allopurinol | May have other allergic features → SJS/TEN, acute hepatitis, acute TIN. HLA-B5801* [5] | |
| Immune checkpoint inhibitors | Anti-PD-1 (nivolumab, pembrolizumab), anti-PD-L1, anti-CTLA-4 | Immune checkpoint inhibitor–associated AKI — emerging cause; often requires immunosuppression [5] |
| Mesalazine (5-ASA) | Used in IBD; often delayed onset (months to years) [2] | |
| Rifampicin | Known to cause tubulointerstitial nephritis [5]. Can cause AIN even on re-exposure after a gap | |
| Others | Phenytoin, carbamazepine, lithium, acyclovir, indinavir |
High Yield: NSAID-Induced Renal Disease Is Multifaceted
NSAIDs can cause multiple forms of kidney injury:
- Haemodynamic AKI (↓ prostaglandin → afferent arteriolar vasoconstriction → ↓ GFR) — this is the most common
- Acute tubulointerstitial nephritis (immune-mediated)
- Minimal change glomerulopathy or membranous nephropathy (may coexist with AIN → nephrotic syndrome + AKI) [4]
- Papillary necrosis (chronic use)
- Salt and water retention → hypertension, oedema
The slide explicitly notes: "NSAID-induced Nephrotic Syndrome + AKI" involves minimal change glomerulopathy and acute tubulointerstitial nephritis with T lymphocytes and eosinophils (40%) [4].
Infections can cause AIN through direct invasion of the interstitium or immune-mediated mechanisms [2][3].
| Pathogen Type | Examples |
|---|---|
| Bacteria | All species associated with pyelonephritis (e.g. E. coli), Staphylococcus, Streptococcus, Enterococcus, Legionella, Corynebacterium diphtheriae, Treponema pallidum, Leptospirosis, Mycobacteria (TB) |
| Viruses | EBV, CMV, Polyomavirus (BK virus), Hantavirus (rat urine–related) |
| Fungi | Candida, Histoplasmosis |
| Parasites | Toxoplasmosis |
In Hong Kong, consider leptospirosis (rat urine exposure, especially after typhoons/flooding) and TB (relatively endemic).
| Disease | Mechanism/Notes |
|---|---|
| Sjögren's syndrome | Autoimmune lymphocytic infiltration of the interstitium; can cause distal RTA (type 1) and nephrogenic DI. May be associated with Graves' disease [8] |
| SLE (Lupus nephritis) | Lupus can cause both glomerulonephritis AND tubulointerstitial nephritis |
| Sarcoidosis (~1%) | Granulomatous interstitial nephritis; also causes hypercalcaemia (↑ 1,25-dihydroxy vitamin D from macrophages) |
| IgG4-related disease | Dense lymphoplasmacytic infiltrate rich in IgG4⁺ plasma cells; increasingly recognised; may affect kidneys, pancreas, salivary glands |
| GPA (Granulomatosis with polyangiitis) | ANCA-associated vasculitis; can cause RPGN and TIN |
| IBD (Crohn's, UC) | TIN may be drug-related (mesalazine) or disease-related |
| PBC (Primary biliary cholangitis) | Rare association |
Tubulointerstitial nephritis and uveitis (TINU) syndrome: combination of tubulointerstitial nephritis and uveitis, more common in children and young women [3].
- Presents with anterior uveitis (eye pain, photophobia, redness) + AKI from TIN
- Systemic symptoms: fever, weight loss, fatigue
- Important to check eyes (slit-lamp exam) in any young patient with unexplained AIN
- No identifiable cause after thorough workup
- May represent an unrecognised drug or autoimmune trigger
5. Pathophysiology
Understanding the pathophysiology of AIN requires thinking about it as fundamentally an immune-mediated inflammatory process in the renal interstitium.
Drug-induced AIN is a Type IV (delayed-type) hypersensitivity reaction — this is the same mechanism as contact dermatitis or tuberculin skin test reaction.
Step-by-step mechanism:
-
Hapten formation: The drug (or its metabolite) acts as a hapten — a small molecule that is not immunogenic by itself but becomes so when it binds to a carrier protein (e.g., tubular basement membrane proteins, or Tamm-Horsfall protein).
-
Antigen presentation: The hapten-carrier complex is taken up by antigen-presenting cells (dendritic cells, macrophages) in the renal interstitium and presented to T lymphocytes via MHC molecules.
-
T cell activation: CD4⁺ and CD8⁺ T lymphocytes are activated and infiltrate the interstitium. This is the dominant cell type in the inflammatory infiltrate.
-
Eosinophil recruitment: In many drug-induced cases (up to 40% in NSAID-induced AIN [4]), eosinophils are recruited, reflecting the allergic/hypersensitivity nature.
-
Inflammatory cascade: Activated T cells release cytokines (TNF-α, IFN-γ, IL-2, IL-4, IL-5) → further recruitment of inflammatory cells → interstitial oedema → tubular compression and injury.
-
Tubular damage: The inflammatory infiltrate directly damages tubular epithelial cells → tubular dysfunction (electrolyte wasting, concentrating defect, acidosis).
-
If unresolved → fibrosis → chronic interstitial nephritis → CKD.
This explains why AIN is idiosyncratic — it depends on the individual's immune response to the drug-protein complex, not on drug dose. The same drug at the same dose may cause AIN in one patient but not another.
The classic triad (fever + rash + eosinophilia) was originally described in methicillin-induced AIN. Methicillin is a particularly potent hapten that triggers a robust systemic hypersensitivity response. Modern causative drugs (PPIs, NSAIDs) tend to cause a more indolent, localised immune response without prominent systemic manifestations — hence the triad is now rarely seen [3].
- Direct mechanism: Organisms invade the interstitium → inflammatory response (e.g., ascending bacterial pyelonephritis)
- Immune-mediated mechanism: Infection triggers an immune response that cross-reacts with interstitial antigens (molecular mimicry) or causes immune complex deposition in the interstitium
- In conditions like Sjögren's syndrome, autoreactive lymphocytes directly infiltrate the renal interstitium (similar to how they infiltrate salivary and lacrimal glands)
- In sarcoidosis, non-caseating granulomas form in the interstitium
- In IgG4-related disease, IgG4⁺ plasma cells and fibrosis dominate the infiltrate
NSAIDs can cause concurrent glomerular disease (minimal change disease or membranous nephropathy) PLUS AIN [4]. This is because:
- The T lymphocytes activated in the interstitium also release cytokines that injure podocytes → podocyte foot process effacement → minimal change disease → nephrotic-range proteinuria
- This explains why nephrotic syndrome occurs in < 1% of AIN overall, but is more common in NSAID-induced AIN [3]
Pathophysiology Summary for Exams
Drug-induced AIN = Type IV hypersensitivity (T cell–mediated) → interstitial inflammatory infiltrate (lymphocytes ± eosinophils) → tubular compression & damage → AKI.
Key points:
- Idiosyncratic, NOT dose-dependent
- T lymphocytes are the dominant cell
- Eosinophils present in ~40% (especially NSAID)
- If prolonged/untreated → fibrosis → CKD
6. Classification
| Acute TIN | Chronic TIN | |
|---|---|---|
| Timeline | Days to weeks (< 90 days) | > 90 days (weeks to months) |
| Histology | Inflammatory infiltrate (lymphocytes, eosinophils), interstitial oedema | Fibrosis, tubular atrophy, less inflammation |
| Reversibility | Often reversible if cause removed | Usually irreversible |
| Outcome | AKI | CKD |
Drug-induced kidney disease can be classified temporally: Acute (< 7 days), Subacute (7–90 days), Chronic (> 90 days) [7]
As above: Drugs, Infections, Autoimmune, TINU, Idiopathic.
Entities within tubulointerstitial nephritis [1]:
- Acute interstitial nephritis — drugs, infections, autoimmune disease
- Chronic interstitial nephritis — etiology often not well known
- K⁺-wasting tubular disorders
- Renal tubular acidosis
AIN is classified as an intrinsic renal cause of AKI (specifically tubulointerstitial) [9]:
- Pre-renal → hypovolaemia, shock
- Intrinsic renal → glomerular (GN), tubulointerstitial (ATN, AIN), vascular
- Post-renal → obstruction
7. Clinical Features
AIN is mostly clinically silent [2]. The presentation depends on:
- The severity of the interstitial inflammation
- The cause (drug vs infection vs autoimmune)
- Whether there is a systemic hypersensitivity response
| Symptom | Pathophysiological Basis | Frequency |
|---|---|---|
| Non-specific malaise, anorexia, nausea, vomiting | Uraemia from AKI — accumulation of nitrogenous waste products (urea, creatinine) → GI irritation and CNS effects | Common |
| Oliguria | Interstitial oedema compresses tubules → ↓ tubular flow; also ↓ GFR from interstitial inflammation disrupting peritubular capillary flow | ~51% of patients [2] |
| Polyuria (in some cases) | Tubular damage → concentrating defect (nephrogenic DI) → inability to reabsorb water in collecting duct; if damage is predominantly medullary, concentrating mechanism fails before GFR drops significantly | Less common than oliguria |
| Flank/loin pain | Renal capsule stretching from interstitial oedema → capsular nociceptor stimulation | Variable |
| Gross haematuria | Inflammation extending to involve tubular basement membranes and small vessels → RBCs leak into tubular lumen | Very unusual, only ~5% of patients; microscopic haematuria is more common [3] |
| Frothy urine | Proteinuria from tubular damage (unable to reabsorb filtered low-molecular-weight proteins) or concurrent glomerular disease (NSAIDs) | Variable |
| Fever | Systemic hypersensitivity reaction; cytokine release (IL-1, IL-6, TNF-α) from activated T cells and macrophages → hypothalamic set point elevation | ~27% of patients [2] |
| Arthralgia | Part of the systemic hypersensitivity/drug allergy reaction | Uncommon |
| Symptoms of underlying disease | e.g., dry eyes/mouth (Sjögren's), eye pain/photophobia (TINU uveitis), joint pain (SLE), cough/dyspnoea (sarcoidosis) | Depends on cause |
| Sign | Pathophysiological Basis | Frequency |
|---|---|---|
| Skin rash (maculopapular, urticarial, or morbilliform) | Drug hypersensitivity — same immune mechanism causing the AIN also targets the skin (Type IV hypersensitivity → dermal T cell infiltration) | ~15% of patients [2] |
| Fever | As above | ~27% |
| Costovertebral angle tenderness | Renal capsule distension from interstitial oedema | Variable |
| Peripheral oedema, hypertension | If AKI causes significant fluid retention (↓ GFR → ↓ Na⁺/water excretion) | Variable |
| Signs of underlying disease | e.g., parotid swelling (Sjögren's), malar rash (SLE), erythema nodosum (sarcoidosis), uveitis (TINU — red eye, photophobia, pain) | Depends on cause |
Classic triad of drug hypersensitivity (seen in only ~10% of patients): Fever + Eosinophilia + Skin rash ± Arthralgia [2][3][6]
Not commonly seen nowadays due to the absence of cases of methicillin-induced AIN in which this triad originates from [3]
Why is the triad rare now?
- Methicillin is essentially never used clinically anymore
- Modern causative drugs (PPIs, NSAIDs, checkpoint inhibitors) tend to produce a more indolent, organ-limited immune response without robust systemic hypersensitivity
Classic Triad: A Red Herring for Diagnosis
Do NOT wait for the classic triad of fever + rash + eosinophilia before suspecting AIN. It is present in only ~10% of cases. The absence of these features does NOT exclude the diagnosis. A high index of suspicion is required in any patient with unexplained AKI and recent drug exposure.
These are not strictly "clinical features" in the traditional sense, but are often the first clue to AIN:
| Finding | Pathophysiological Basis |
|---|---|
| ↑ Serum creatinine (virtually all patients) | ↓ GFR from interstitial inflammation and tubular compression [2] |
| Eosinophilia (peripheral blood, ~23%) | Systemic allergic/hypersensitivity response; IL-5 release from Th2 cells promotes eosinophil production and survival [2] |
| ↑ ESR/CRP | Non-specific markers of systemic inflammation |
| Mild anaemia | Combination of: ↓ EPO production (interstitial fibroblasts damaged), haemodilution (fluid retention), and anaemia of inflammation |
| FENa > 1% | Tubular damage → impaired Na⁺ reabsorption → higher fractional excretion of sodium (distinguishes intrinsic renal AKI from pre-renal) [2] |
| Finding | Pathophysiological Basis |
|---|---|
| Sterile pyuria | WBCs in urine WITHOUT bacterial infection — reflects interstitial inflammation with WBCs crossing into tubular lumen [2][9] |
| WBC casts / tubular casts | WBCs trapped in Tamm-Horsfall protein matrix within the tubular lumen — pathognomonic of tubulointerstitial inflammation |
| ± Eosinophiluria | Eosinophils in urine — suggestive but NOT specific for AIN (can also be seen in UTI, cholesterol emboli, GN). Sensitivity only ~67%, specificity ~83% [2] |
| ± RBCs | From tubular/interstitial capillary damage. Usually non-dysmorphic (i.e., not from glomerular origin) |
| Variable proteinuria: usually < 1 g/day, typically tubular (low molecular weight proteins) | Tubular damage → impaired reabsorption of filtered low-MW proteins (β2-microglobulin, retinol-binding protein). Glomeruli are structurally intact in most cases [2] |
| ± Glycosuria (with normal blood glucose) | Proximal tubular damage → impaired glucose reabsorption (part of Fanconi syndrome) |
Urine Dipstick vs Spot UACR in AIN
Standard urine dipstick detects albumin primarily. In AIN, the proteinuria is often tubular (low-molecular-weight proteins like β2-microglobulin), which the dipstick may miss. If dipstick is negative but you suspect proteinuria, check spot UACR or urine protein electrophoresis (UPE). This is similar to the myeloma scenario where Bence Jones proteins are not detected by dipstick.
A relatively bland urinalysis does NOT exclude the diagnosis [2].
| Disturbance | Mechanism |
|---|---|
| Hyperkalaemia | ↓ GFR → ↓ K⁺ excretion; also, if distal tubule is damaged → impaired K⁺ secretion (Type 4 RTA) |
| Hypokalaemia (paradoxical, in some cases) | If predominantly proximal or loop tubular damage → K⁺ wasting |
| Metabolic acidosis (non-anion gap) | Renal tubular acidosis (RTA) — Type 1 (distal, impaired H⁺ secretion) or Type 2 (proximal, impaired HCO₃⁻ reabsorption) depending on which segment is damaged [1] |
| Fanconi syndrome | Proximal tubular damage → wasting of glucose, phosphate, amino acids, uric acid, bicarbonate |
| Nephrogenic diabetes insipidus | Medullary interstitial inflammation → damage to collecting duct → impaired ADH response → polyuria, hypernatraemia. Seen especially in Sjögren's and lithium-induced TIN [8] |
| Feature | Why? |
|---|---|
| AKI (↑ creatinine) | Interstitial oedema → compresses tubules and peritubular capillaries → ↓ GFR |
| Oliguria | Tubular compression → ↓ urine flow |
| Sterile pyuria | Inflammatory WBCs cross from interstitium into tubular lumen — no bacteria |
| WBC casts | WBCs trapped in Tamm-Horsfall protein in tubules |
| Eosinophiluria | Eosinophils (from hypersensitivity) migrate into tubular lumen |
| Low-grade proteinuria (< 1 g/d) | Tubular damage → failure to reabsorb filtered low-MW proteins |
| Fever, rash, eosinophilia | Systemic Type IV hypersensitivity (drug-protein complex triggers immune response) |
| Non-AG metabolic acidosis | Tubular damage → impaired H⁺ secretion (Type 1 RTA) or HCO₃⁻ reabsorption (Type 2 RTA) |
| Electrolyte wasting | Damaged tubules cannot properly reabsorb Na⁺, K⁺, Mg²⁺, PO₄³⁻ |
| Nephrogenic DI | Medullary damage → loss of AQP2 expression → ADH resistance |
| Nephrotic syndrome (NSAID only) | Concurrent minimal change disease or membranous nephropathy from T-cell cytokine injury to podocytes |
9. Key Associations and Special Scenarios
Graves' disease can be associated with autoimmune interstitial nephritis, especially in the context of Sjögren's syndrome [8]
- Sjögren's → lymphocytic infiltration of renal interstitium → distal RTA (Type 1) and nephrogenic DI
- Chronic interstitial nephritis with positive rheumatoid factor and positive anti-Ro → Sjögren syndrome [8]
- May present with polyuria, polydipsia (nephrogenic DI), hypokalaemia, non-AG metabolic acidosis
- Increasingly recognised cause of AIN with dense storiform fibrosis and IgG4⁺ plasma cell infiltrate
- Often multi-organ involvement (autoimmune pancreatitis, sclerosing cholangitis, sialadenitis)
- Responds to corticosteroids
- Anti-PD-1/PD-L1 and anti-CTLA-4 agents → removal of immune "brakes" → T cells attack self-antigens including renal interstitial antigens
- Immune checkpoint inhibitor–associated AKI requires immunosuppression (corticosteroids), unlike most drug-induced AIN where simply stopping the drug suffices [5]
- Allopurinol may cause SJS/TEN, acute hepatitis, acute TIN [5]
- HLA-B5801* allele (prevalent in Chinese/Southeast Asian populations) confers high risk
- Pre-prescription HLA testing is now standard of care before starting allopurinol in Chinese patients
High Yield Summary
Acute Interstitial Nephritis (AIN) — Key Points for Exams:
-
Definition: Acute inflammatory infiltrate of the renal interstitium → AKI. The interstitium is ~95% of renal parenchyma.
-
Most common cause: Drugs (~71%) — antibiotics, NSAIDs, PPIs, allopurinol, checkpoint inhibitors, rifampicin.
-
Mechanism: Type IV (T cell–mediated) hypersensitivity — idiosyncratic, NOT dose-dependent. Drug acts as hapten.
-
Classic triad: Fever (27%) + Eosinophilia (23%) + Rash (15%) — present in only ~10% of cases. Do NOT rely on this for diagnosis.
-
Urinalysis: Sterile pyuria, WBC/tubular casts ± eosinophiluria. Proteinuria usually < 1 g/day (tubular pattern). Bland urinalysis does NOT exclude AIN.
-
NSAID special: Can cause concurrent minimal change disease + AIN → nephrotic syndrome + AKI. Infiltrate contains T lymphocytes and eosinophils (40%).
-
PPIs: Cause both acute TIN → AKI and chronic TIN → CKD.
-
Allopurinol: HLA-B5801* — SJS/TEN + AIN + hepatitis. Pre-test in Chinese patients.
-
Checkpoint inhibitor AIN: Requires immunosuppression (steroids), not just drug cessation.
-
Sjögren's: Autoimmune AIN → distal RTA + nephrogenic DI.
-
TINU: AIN + uveitis → young women/children.
-
AIN accounts for 5–15% of all AKI cases.
-
Management principle: Stop the offending drug → most patients improve. Immunosuppression only for severe/refractory cases.
Active Recall - Acute Interstitial Nephritis
[1] Lecture slides: GC 057. Glomerular and Tubulo-interstitial Diseases and Acute Kidney Injury.pdf (p59–60) [2] Senior notes: Ryan Ho Urogenital.pdf (p91, Section 4.1 Acute Interstitial Nephritis) [3] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (p1028–1030) [4] Lecture slides: GC 043. Drugs and the Kidney.pdf (p27) [5] Senior notes: Block A - Drugs and the Kidney.pdf (p8) [6] Senior notes: Block A - Nephrotology Teaching Clinic RTD.pdf (p1) [7] Senior notes: Block A - Chronic Kidney Disease and its Complications.pdf (p11–12) [8] Senior notes: Block A - Two cases of polyuria and polydipsia.pdf (p4–5) [9] Senior notes: Ryan Ho Critical Care.pdf (p25, 27)
Differential Diagnosis of Acute Interstitial Nephritis
When a patient presents with AKI — rising creatinine, abnormal urinalysis, ± systemic features — the clinical challenge is to determine whether AIN is the culprit or whether one of its many mimics is responsible. The differential diagnosis operates on two levels:
- Level 1: Differentiating AIN from other causes of AKI (i.e., where does AIN sit within the AKI framework?)
- Level 2: Once AIN is suspected, differentiating the specific cause of AIN (drug vs infection vs autoimmune vs TINU vs idiopathic)
AKI is defined by an abrupt decrease in kidney function. Various aetiologies include ATN, acute interstitial nephritis, acute glomerular and vasculitic renal diseases, prerenal azotaemia, and acute postrenal obstructive nephropathy. More than one of these conditions may coexist. [1]
The classic framework for AKI is pre-renal → intrinsic renal → post-renal [9]. AIN sits within the intrinsic renal category, specifically in the tubulointerstitial compartment. The key differentials are:
Recognising pre- and post-renal disease is particularly important because these are often rapidly reversible compared to renal intrinsic disease [9].
| Feature | Explanation | How to Differentiate from AIN |
|---|---|---|
| Mechanism | Inadequate renal perfusion → ↓ GFR without structural parenchymal damage | No tubular/interstitial inflammation |
| Causes | Dehydration, haemorrhage, sepsis, heart failure, liver failure (hepatorenal) | History of fluid loss, hypotension, poor intake |
| Urine findings | Concentrated urine (high osmolality > 500 mOsm/kg), low urine Na⁺ (< 20 mmol/L), FENa < 1% | AIN: FENa > 1% (tubular damage impairs Na⁺ reabsorption) [2] |
| Urine sediment | Bland — no cells, no casts (or only hyaline casts) | AIN: sterile pyuria, WBC casts |
| Urea:Creatinine ratio | Urea >> Creatinine (disproportionately elevated urea due to increased reabsorption in slow-flowing tubules) [9] | AIN: both rise proportionally |
| Response to fluids | Rapid improvement in creatinine with IV fluid resuscitation | AIN: does NOT improve with fluids alone |
Why the distinction matters: Pre-renal AKI is the most common cause of AKI (> 50%). It is rapidly reversible with volume resuscitation. However, prolonged pre-renal disease will progress to become ATN (ischaemic injury to tubules) [9] — so prompt correction is critical.
This is the most important differential for AIN because both are intrinsic renal, tubulointerstitial causes of AKI.
| Feature | ATN | AIN |
|---|---|---|
| Mechanism | Direct tubular epithelial cell death from ischaemia or nephrotoxin | Immune-mediated interstitial inflammation |
| Timeline | Decline in RFT in minutes to hours [10] | Decline in RFT in days [10] |
| Causes | Ischaemic (prolonged pre-renal), nephrotoxins (aminoglycosides, contrast, paracetamol) | Drugs (hypersensitivity), infection, autoimmune |
| Urine sediment | Muddy brown granular casts (pathognomonic), epithelial cell casts [6] | Sterile pyuria, WBC/tubular casts ± eosinophiluria [2] |
| Systemic features | Absence of hypersensitivity manifestations [3] | Classic triad (fever + rash + eosinophilia) in ~10% |
| Proteinuria | Usually minimal | Usually < 1 g/day, tubular pattern |
| FENa | > 1% (also impaired tubular reabsorption) | > 1% |
| Reversibility | Self-limited if cause removed; tubular regeneration occurs | Usually reversible if drug stopped; may need steroids |
High Yield: ATN vs AIN — The Exam Distinction
The key differentiating features between ATN and AIN are:
- Urine sediment: Muddy brown casts (ATN) vs sterile pyuria with WBC casts (AIN)
- Systemic hypersensitivity: Absent in ATN, present in ~10% of AIN (fever, rash, eosinophilia)
- Timeline: ATN is more abrupt (minutes–hours after insult); AIN develops over days–weeks after drug exposure
- Absence of pyuria argues against AIN; absence of hypersensitivity manifestation argues against AIN [3]
Glomerulonephritis presents with the nephritic syndrome: haematuria, hypertension, oliguria, oedema, and proteinuria. The urinalysis pattern is the key distinguishing feature from AIN.
| Feature | Acute GN | AIN |
|---|---|---|
| Urine sediment | Dysmorphic RBCs, RBC casts (diagnostic of glomerular bleeding) [11] | WBC casts, sterile pyuria, ± non-dysmorphic RBCs |
| Proteinuria | Often heavy (can be nephrotic range) | Usually < 1 g/day, tubular type |
| Hypertension | Common (fluid retention from ↓ GFR + RAAS activation) | Less prominent |
| Complement levels | May be low (IC-mediated GN: PSGN, lupus, MPGN, cryoglobulinaemia) or normal [11] | Normal (not complement-mediated) |
| Serology | ANCA, anti-GBM, ANA/anti-dsDNA, ASLO, C3/C4 all useful | Not typically relevant (unless autoimmune cause of AIN itself) |
Differential diagnosis of haematuria on the GC lecture slide [1] includes: urologic conditions (stones, tumour), renal conditions (glomerulonephritis, acute interstitial nephritis, polycystic kidney disease), and infection (cystitis, TB, schistosomiasis).
Why this matters: If you see dysmorphic RBCs and RBC casts, think glomerular disease. If you see WBC casts and sterile pyuria, think AIN. The urinalysis is your single most useful bedside tool for localising the lesion.
| Feature | RPGN | AIN |
|---|---|---|
| Tempo | Rapid decline in GFR over days to weeks (similar to AIN!) | Days to weeks |
| Urine | Active sediment: dysmorphic RBCs, RBC casts, heavy proteinuria | Sterile pyuria, WBC casts |
| Systemic features | Depends on type: haemoptysis (anti-GBM/Goodpasture's), purpura (vasculitis), joint pain (SLE) | Fever, rash, eosinophilia (drug-related) |
| Serology | ANCA, anti-GBM, ANA/dsDNA — one of these is usually positive | Usually negative (unless autoimmune AIN) |
| Biopsy | Crescents on glomerular histology | Interstitial infiltrate, sparing of glomeruli |
RPGN is an emergency — untreated, it leads to irreversible renal failure within weeks. Distinguishing it from AIN is critical because management is completely different (immunosuppression + plasmapheresis for RPGN vs drug cessation ± steroids for AIN).
Multiple myeloma can cause AKI through cast nephropathy — an important mimic of AIN [12].
| Feature | Myeloma Cast Nephropathy | AIN |
|---|---|---|
| Mechanism | Clonal free light chains exceed proximal tubular reabsorption capacity → combine with Tamm-Horsfall protein → waxy myeloma casts obstruct distal tubules → tubulointerstitial nephritis [12] | Immune-mediated interstitial inflammation |
| Population | Elderly (> 60), bone pain, anaemia | Any age |
| Urine dipstick | May be NEGATIVE (dipstick detects albumin, not light chains) but ↑↑ UACR on quantification [9] | Low-grade proteinuria (< 1 g/day) |
| Urine protein electrophoresis (UPE) | Monoclonal band (Bence Jones protein) | No monoclonal band |
| Bloods | Anaemia, ↑ calcium, ↑ total protein, ↑ β2-microglobulin, ↑ LDH | RFT derangement, ± eosinophilia |
| Serum protein electrophoresis (SPE) | M-spike / paraprotein | Normal |
Myeloma kidney is an emergency — must act immediately to save the kidney [12].
Myeloma and the Urine Dipstick Trap
Standard urine dipstick detects albumin primarily. In myeloma cast nephropathy, the protein in the urine is light chains (Bence Jones protein), which the dipstick does NOT detect. A patient can have massive proteinuria from myeloma with a negative dipstick. Always request spot UACR or UPE if myeloma is suspected. This is analogous to AIN where proteinuria is tubular (low-MW proteins) and may also be under-detected by dipstick.
| Feature | Post-Renal Obstruction | AIN |
|---|---|---|
| Mechanism | Bilateral ureteric or bladder outlet obstruction → back-pressure → ↓ GFR | Interstitial inflammation |
| Causes | BPH, prostate/bladder CA, bilateral stones, retroperitoneal fibrosis | Drugs, infections, autoimmune |
| USG kidneys | Hydronephrosis (dilated pelvicalyceal system) [8] | Large, echogenic kidneys (interstitial oedema) [6] or normal |
| Urine sediment | Usually bland | Sterile pyuria, WBC casts |
| Management | Urgent decompression (catheter, nephrostomy) | Stop offending drug ± steroids |
Prolonged obstruction → chronic interstitial nephritis and tubular dysfunction (nephrogenic DI) [8][9]. This is why post-renal disease, if untreated, eventually causes the same histological picture as chronic TIN.
This is an important differential because it can mimic AIN with eosinophilia + AKI + skin findings — especially after a vascular procedure or anticoagulation.
| Feature | Cholesterol Emboli | AIN |
|---|---|---|
| Setting | Post-catheterisation, post-vascular surgery, anticoagulation in elderly with aortic atherosclerosis | Drug exposure, infection, autoimmune |
| Skin | Livedo reticularis, blue toe syndrome (cool, blue, painful toes with palpable pulses) | Maculopapular or urticarial rash |
| Eosinophilia | YES — can be prominent | YES |
| Eosinophiluria | YES | YES |
| Complement | Low (consumed by cholesterol crystal–activated complement pathway) | Normal |
| Renal biopsy | Biconvex clefts ("cholesterol clefts") in arcuate/interlobular arteries | Lymphocytic/eosinophilic interstitial infiltrate |
| Tempo | Subacute — worsening over weeks (stepwise decline) | Days to weeks |
Why this is a trap: Both AIN and cholesterol emboli can present with AKI + eosinophilia + eosinophiluria + skin findings. The key distinction is the clinical setting (post-procedural, atherosclerotic risk factors) and complement levels (low in cholesterol emboli, normal in AIN).
| Feature | Acute Pyelonephritis | AIN |
|---|---|---|
| Fever | High spiking | May be present (~27%) |
| Flank pain | Prominent, with CVA tenderness | Variable |
| Urine culture | Positive (significant bacteriuria ≥ 10⁵ CFU/mL) | Sterile (pyuria WITHOUT positive culture) |
| Pyuria | Present WITH bacteriuria | Sterile pyuria (WBCs without bacteria) [2] |
| WBC casts | Can be present | Present |
| Response | Responds to antibiotics | Responds to drug withdrawal ± steroids |
The critical distinction is that pyelonephritis has positive urine cultures with significant bacteriuria, while AIN has sterile pyuria — WBCs without organisms. If urine culture is negative despite pyuria, think: AIN, TB, nephrolithiasis, or non-bacterial infection [11].
Certain drugs can cause AKI through haemodynamic mechanisms rather than interstitial inflammation. This distinction is critical because management differs.
| Drug | Haemodynamic AKI Mechanism | AIN Mechanism |
|---|---|---|
| NSAIDs | Inhibit prostanoid production → afferent arteriolar vasoconstriction → ↓ renal blood flow → ↓ GFR [13] | Type IV hypersensitivity → interstitial inflammation |
| ACEI/ARB | Efferent arteriolar vasodilatation → ↓ intra-glomerular pressure → ↓ GFR | Rarely cause AIN (more commonly haemodynamic) |
| Calcineurin inhibitors | Afferent arteriolar vasoconstriction → ↓ GFR | Can cause chronic TIN |
NSAIDs can cause renal impairment by inhibiting prostanoid production in the kidneys → impaired regulation of renal blood flow. NSAIDs can also cause TIN and GN. [13]
The haemodynamic AKI from NSAIDs is dose-dependent and rapidly reversible on cessation, whereas NSAID-induced AIN is idiosyncratic and may take longer to resolve.
Once you have established that the AKI is likely AIN (based on urinalysis pattern, clinical setting, and exclusion of other causes), the next step is identifying the specific aetiology.
| Clue | Likely Cause |
|---|---|
| Recent drug started 3–5 days to weeks ago | Drug-induced AIN |
| Fever + generalized rash + eosinophilia + hepatosplenomegaly + lymphadenopathy after anti-TB drugs | TB drug–induced ATIN [6] |
| Nephrotic syndrome + AKI + eosinophilia | NSAID-induced (minimal change + AIN) [4][5] |
| Dry eyes, dry mouth, positive anti-Ro/anti-La | Sjögren's syndrome |
| Malar rash, arthralgia, positive ANA/anti-dsDNA | SLE / Lupus nephritis |
| Bilateral hilar lymphadenopathy, hypercalcaemia, ↑ ACE level | Sarcoidosis |
| Eye pain, photophobia, red eye (uveitis) in young woman | TINU syndrome |
| Multi-organ fibrosis, elevated IgG4 | IgG4-related disease |
| On immune checkpoint inhibitor for cancer | Anti-PD-1/PD-L1 associated AIN |
| On lithium for bipolar disorder | Lithium-induced chronic TIN (nephrogenic DI, CKD) [14] |
| Haemoptysis + AKI | Unlikely AIN — think RPGN (anti-GBM, ANCA vasculitis) |
TB Drug–Induced AIN: A Classic Teaching Case
A 74-year-old lady with fever + generalized rash + hepatosplenomegaly + lymphadenopathy, started on anti-TB medications 10 days ago. WBC 17,800 with eosinophilia, serum creatinine 560 μmol/L, urinalysis shows WBC casts. Renal USG shows large echogenic kidneys (enlarged by oedema). Top differential = TB drug–induced ATIN. [6]
This case illustrates the classic presentation beautifully: temporal relationship with drug (10 days), systemic hypersensitivity features (fever, rash, eosinophilia, hepatosplenomegaly), AKI (creatinine 560), characteristic urine (WBC casts), and renal imaging (large echogenic kidneys from interstitial oedema).
| Condition | Key Distinguishing Feature from AIN |
|---|---|
| Pre-renal AKI | FENa < 1%, bland sediment, responds to fluids |
| ATN | Muddy brown casts, no hypersensitivity features, onset in minutes–hours |
| Acute GN / RPGN | Dysmorphic RBCs, RBC casts, heavy proteinuria, active serology |
| Myeloma cast nephropathy | Negative dipstick but ↑ UACR, M-spike on SPE, bone pain, anaemia, hypercalcaemia |
| Post-renal obstruction | Hydronephrosis on USG, bland sediment |
| Cholesterol emboli | Post-procedural, livedo reticularis, blue toes, low complement |
| Acute pyelonephritis | Positive urine culture (NOT sterile pyuria) |
| NSAID haemodynamic AKI | Dose-dependent, reversible on cessation, bland sediment, no eosinophilia |
High Yield Summary — Differential Diagnosis of AIN
Three critical distinctions to make in AKI:
-
Pre-renal vs Intrinsic vs Post-renal → Use volume assessment, FENa, USG
-
ATN vs AIN (both intrinsic tubulointerstitial):
- ATN: muddy brown casts, no systemic features, onset minutes–hours
- AIN: sterile pyuria + WBC casts, ± fever/rash/eosinophilia, onset days–weeks
-
AIN vs GN (both intrinsic renal):
- AIN: WBC casts, low-grade proteinuria, sterile pyuria
- GN: RBC casts, dysmorphic RBCs, heavy proteinuria, active serology
Don't forget the mimics: Cholesterol emboli (post-procedural, livedo reticularis, low complement), myeloma (negative dipstick, M-spike), pyelonephritis (positive urine culture — NOT sterile pyuria)
Active Recall - Differential Diagnosis of AIN
References
[1] Lecture slides: GC 057. Glomerular and Tubulo-interstitial Diseases and Acute Kidney Injury.pdf (p16, p59–60) [2] Senior notes: Ryan Ho Urogenital.pdf (p91, Section 4.1 Acute Interstitial Nephritis) [3] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (p1028–1031) [4] Lecture slides: GC 043. Drugs and the Kidney.pdf (p15, p27) [5] Senior notes: Block A - Drugs and the Kidney.pdf (p8, p14) [6] Senior notes: Block A - Nephrotology Teaching Clinic RTD.pdf (p1, p19) [7] Senior notes: Block A - Chronic Kidney Disease and its Complications.pdf (p11–12) [8] Senior notes: Block A - Two cases of polyuria and polydipsia.pdf (p4–5) [9] Senior notes: Ryan Ho Critical Care.pdf (p25, p27) [10] Senior notes: Maksim Medicine Notes.pdf (p234) [11] Senior notes: Ryan Ho Fundamentals.pdf (p360) [12] Senior notes: Block A - An old man with bone pain and anaemia_ multiple myeloma; monoclonal gammopathy.pdf (p20) [13] Senior notes: Block A - Nephrology Data Interpretation.pdf (p11) [14] Senior notes: Ryan Ho Psychiatry.pdf (p53)
Diagnostic Criteria, Algorithm and Investigations for Acute Interstitial Nephritis
1. Diagnostic Criteria — Conceptual Framework
Unlike many conditions in medicine, AIN does not have a universally standardised set of diagnostic criteria akin to the Jones criteria (rheumatic fever) or the SLICC criteria (SLE). The diagnosis is made through a combination of clinical suspicion, laboratory findings, and — when needed — histopathological confirmation by renal biopsy. Think of it as a probabilistic exercise: the more pieces of the puzzle you assemble, the more confident you are.
Before diagnosing AIN, you first need to confirm that the patient has AKI. The universally accepted framework is the KDIGO 2012 criteria [15][16]:
AKI is diagnosed if ANY ONE of the following is present [16]:
- ↑ Serum creatinine ≥ 26.5 μmol/L within 48 hours
- ↑ Serum creatinine to ≥ 1.5× baseline within 7 days
- Urine output < 0.5 mL/kg/h for ≥ 6 hours
KDIGO AKI Staging [16]:
| Stage | Serum Creatinine | Urine Output |
|---|---|---|
| I | 1.5–1.9× baseline within 1 week | < 0.5 mL/kg/h for 6–12 h |
| II | 2.0–2.9× baseline within 1 week | < 0.5 mL/kg/h for ≥ 12 h |
| III | ≥ 3.0× baseline within 1 week | < 0.3 mL/kg/h for 24 h OR anuria ≥ 12 h |
In Hong Kong we use μmol/L for creatinine, whereas other parts of the world use mg/dL [15]. (Conversion: 1 mg/dL ≈ 88.4 μmol/L)
Creatinine Is an Insensitive Early Marker
GFR has already fallen by ~50% by the time serum creatinine begins to rise [16]. This means AIN can be causing significant interstitial inflammation before the lab "catches up." Always maintain a high index of suspicion in the right clinical setting, even if creatinine is only mildly elevated.
Once AKI is confirmed, you must determine where the injury is:
AKI aetiology is classically separated into [1][9]:
- Pre-renal ( > 1/2): ineffective perfusion
- Intrinsic renal ( < 1/2): intrinsic renal disease
- Tubular necrosis (ischaemia, toxins)
- Interstitial nephritis
- Acute GN / RPGN
- Post-renal ( < 10%): obstructive uropathy
The diagnostic workup systematically excludes pre-renal and post-renal causes first, then differentiates between the intrinsic renal compartments.
A clinical (presumptive) diagnosis of AIN can be made when the following constellation is present:
| Criterion | Detail |
|---|---|
| 1. AKI | Rising creatinine meeting KDIGO criteria |
| 2. Temporal relationship | Recent exposure to a known causative drug (3–5 days to several weeks), infection, or known autoimmune disease [2] |
| 3. Suggestive urinalysis | Sterile pyuria, WBC/tubular casts ± eosinophiluria [2][3][6] |
| 4. Supportive systemic features | Fever, rash, eosinophilia (present in only ~10%) |
| 5. Exclusion of alternatives | Pre-renal (responds to fluids, FENa < 1%), post-renal (no hydronephrosis on USG), ATN (no muddy brown casts), GN (no RBC casts/dysmorphic RBCs) |
| 6. Response to drug withdrawal | Improvement in RFT after stopping the suspected drug supports the diagnosis retrospectively |
Renal biopsy is usually required to confirm the diagnosis [6].
However:
Renal biopsy is the definitive diagnosis but is often NOT necessary [3]:
- NOT needed if diagnosis is likely, if the presumed precipitating drug can be easily withdrawn, and if the patient improves after withdrawal of a potentially offending drug
- Indicated when diagnosis is unclear (non-characteristic urinalysis), if patient is not improving, or if glucocorticoid treatment is being considered [3]
The following algorithm represents the systematic approach to a patient with suspected AIN, integrating all the steps above:
The Decision to Biopsy — A Practical Framework
Biopsy NOT needed if:
- Clear temporal drug relationship
- Drug easily discontinued
- RFT improves within 3–7 days of drug cessation
Biopsy IS needed if:
- No obvious causative drug
- Diagnosis uncertain (atypical urinalysis, features overlapping with GN)
- No improvement after drug cessation (within 5–7 days)
- Glucocorticoid therapy is being considered (want histological confirmation before committing to immunosuppression)
- Advanced/severe AKI (to assess degree of fibrosis — this determines reversibility and prognosis)
3. Investigation Modalities — Detailed Breakdown
3.1 Bedside Investigations
Review of medications: ALWAYS done in AKI [9]
This is the single most important "investigation" in AIN. You are essentially looking for a temporal relationship between starting a new drug and the onset of AKI.
- Assess for hypovolaemia (dry mucous membranes, tachycardia, hypotension, poor skin turgor) → favours pre-renal
- Assess for fluid overload (peripheral oedema, raised JVP, basal crackles) → fluid retention from AKI
- Assessment of volume status: volume contraction vs volume overload [9]
- Drug rash may suggest acute interstitial nephritis [9]
- Maculopapular rash → drug hypersensitivity
- Livedo reticularis → cholesterol emboli (differential, not AIN)
- Anterior uveitis (red eye, photophobia) → TINU syndrome
- Dry eyes/mouth → Sjögren's syndrome
3.2 Urinalysis and Urine Studies
This is the cornerstone investigation for localising the cause of AKI. The GC lecture on renal investigations and AKI workup emphasises a layered approach [9][15]:
| Parameter | Expected in AIN | Interpretation |
|---|---|---|
| Protein | Trace to 1+ (mild) | Dipstick detects albumin ≥ 300 mg/day (macroalbuminuria) only; cannot detect low-MW tubular proteins or Bence Jones protein [16] |
| Blood | Trace to 1+ | Microscopic haematuria in up to 2/3; gross haematuria uncommon (~5%) [3] |
| Leukocyte esterase | Positive | Reflects inflammation — infection (UTI) or inflammation (e.g. AIN) [16] |
| Nitrites | Negative | Negative nitrites with positive leukocyte esterase = sterile pyuria → supports AIN over UTI |
Sterile Pyuria — The Diagnostic Pearl
Sterile pyuria = presence of WBCs in urine but negative urine culture. This is the hallmark finding that should make you think of AIN. The differential for sterile pyuria [16]:
- AIN (most common in the context of AKI)
- Renal TB (always request early morning urine × 3 for AFB if suspected)
- Nephrolithiasis
- Interstitial cystitis
- Partially treated UTI
This is where the diagnosis often becomes clear. You are looking at casts and cells under the microscope.
| Finding | Significance in AIN | Pathophysiological Basis |
|---|---|---|
| Sterile pyuria (WBCs, no bacteria) | Characteristic feature [2][3] | Inflammatory WBCs migrate from the inflamed interstitium across the tubular epithelium into the tubular lumen |
| WBC casts | Suggestive of AIN, but absence does not exclude the diagnosis [3][11] | WBCs become trapped in Tamm-Horsfall protein secreted by thick ascending limb cells; proves the WBCs originate from the KIDNEY (not bladder/lower tract) |
| Eosinophiluria | Suggestive but NOT diagnostic [3][11] | Eosinophils from hypersensitivity reaction migrate into tubular lumen. Requires special staining: Wright's or Hansel's stain [3]. Sensitivity ~67%, specificity ~83% — can also be seen in cholesterol emboli, UTI, GN |
| RBCs (non-dysmorphic) | Present in up to 2/3 of patients [3] | Capillary damage in inflamed interstitium; non-dysmorphic because they do NOT pass through the glomerulus |
| RBC casts | Uncommon [3] | More typical of glomerulonephritis, but can occasionally occur in AIN [11] |
| Renal tubular epithelial (RTE) cells and casts | Non-specific [3] | Desquamation of tubular epithelium; seen in ATN, AIN, and proliferative GN [11] |
| Granular casts (muddy brown) | AGAINST AIN — suggests ATN instead [9] | Represent degenerated tubular cells; pathognomonic for ATN |
A bland sediment with few cells or casts, or a relatively normal urinalysis, does NOT exclude the diagnosis of AIN [2][3]
Urinalysis interpretation patterns [17]:
- Proteinuria + Haematuria + Dysmorphic RBC + RBC casts → Proliferative GN (nephritic pattern)
- Heavy proteinuria + No haematuria → Non-proliferative GN (nephrotic pattern) / DM nephropathy / Amyloidosis
- Granular or epithelial cell casts + RTE cells → Tubulointerstitial nephritis / ATN
- Pyuria → UTI / Interstitial nephritis / Nephrolithiasis
| Test | Expected in AIN | Rationale |
|---|---|---|
| Spot urine ACR | Mildly elevated, usually < 1 g/day equivalent | Tubular proteinuria (low-MW proteins); glomeruli intact |
| Urine protein:creatinine ratio (PCR) | < 100 mg/mmol (generally modest and tubular in type) [6] | |
| 24-hour urine protein | < 1 g/day | Heavy proteinuria (> 3.5 g/day) → think glomerular disease or concurrent NSAID-induced MCD |
| Urine protein electrophoresis (UPE) | Tubular pattern (β₂-microglobulin, retinol-binding protein) | Confirms tubular origin of proteinuria if needed |
| Test | Expected in AIN | Interpretation |
|---|---|---|
| FENa (Fractional excretion of sodium) | > 1% [2] | Tubular damage → impaired Na⁺ reabsorption. Differentiates from pre-renal AKI (FENa < 1%) |
| Urine Na⁺ | > 20 mmol/L (often > 40) | Same reasoning — damaged tubules cannot avidly reabsorb Na⁺ |
| Urine osmolality | < 350 mOsm/kg | Impaired concentrating ability — the medullary interstitium is inflamed → disrupted countercurrent mechanism [16] |
Differentiating pre-renal from intrinsic renal AKI [16]:
| Parameter | Pre-renal | ATN/AIN (Intrinsic) |
|---|---|---|
| FENa | < 1% | > 2% |
| Urine Na⁺ | < 20 | > 40 |
| Urine osmolality | > 500 | < 350 |
| Plasma Urea/Cr | > 100 | < 40 |
| Urine/Plasma Cr | > 40 | < 20 |
- Essential to exclude UTI/pyelonephritis
- In AIN: urine culture is negative (sterile pyuria)
- If positive → treat the infection; the pyuria is from the infection, not AIN
3.3 Blood Investigations
| Test | Expected in AIN | Interpretation |
|---|---|---|
| Serum creatinine | Elevated (virtually all patients) [2] | ↓ GFR from interstitial inflammation |
| Serum urea (BUN) | Elevated | Rises with creatinine; urea:creatinine ratio helps differentiate from pre-renal (where urea rises disproportionately) |
| eGFR | Reduced | Calculated from creatinine using CKD-EPI formula |
| Electrolytes | Variable: ↑K⁺ (↓ secretion), ↓K⁺ (if proximal/loop damage), non-AG metabolic acidosis (RTA) | Reflects which tubular segment is predominantly damaged |
Components of renal function test: Sodium, chloride, potassium, urea, creatinine, creatinine clearance [15]
| Finding | Expected in AIN | Significance |
|---|---|---|
| Eosinophilia (peripheral) | Present in ~23% [2] | Systemic hypersensitivity; Th2-driven IL-5 release → eosinophil production. Occurs commonly in hypersensitivity reactions; occurs less commonly in NSAIDs-induced AIN [3] |
| Leukocytosis | Variable | Non-specific inflammation |
| Normocytic anaemia | If AKI is prolonged | ↓ EPO production from damaged interstitial fibroblasts |
LFT is indicated in patients with drug-induced AIN to look for associated drug-induced liver injury [3]
- Particularly relevant for allopurinol (can cause concurrent acute hepatitis, SJS/TEN, and AIN) [5]
- Rifampicin can also cause drug-induced hepatitis
- Immune checkpoint inhibitors can cause multi-organ immune-related adverse events (irAEs)
| Marker | Expected | Note |
|---|---|---|
| ESR | Elevated | Non-specific |
| CRP | Elevated | Non-specific; may help gauge degree of systemic inflammation |
These are ordered when autoimmune AIN is suspected (no clear drug cause, systemic features present):
| Test | Target Condition | Rationale |
|---|---|---|
| ANA (Anti-nuclear antibodies) | SLE [3] | Lupus can cause both GN and TIN |
| Anti-Ro/SSA, Anti-La/SSB | Sjögren's syndrome [3] | Autoimmune TIN → distal RTA, nephrogenic DI |
| ANCA (c-ANCA, p-ANCA) | GPA, MPA | If vasculitis suspected (RPGN differential) |
| Anti-GBM | Anti-GBM disease | If pulmonary-renal syndrome suspected |
| Complement (C3, C4) | Lupus, MPGN, cryoglobulinaemia | Low in immune complex–mediated disease; normal in AIN |
| IgG4 levels | IgG4-related disease | If multi-organ fibroinflammatory disease suspected |
| Serum ACE level | Sarcoidosis | Elevated in ~60% of sarcoidosis cases |
| Serum calcium | Sarcoidosis | Hypercalcaemia from ↑ 1,25-dihydroxy vitamin D production by granulomas |
| Test | When to Order | Purpose |
|---|---|---|
| SPE + immunofixation | Elderly with AKI, bone pain, anaemia | Exclude myeloma cast nephropathy [9] |
| Serum free light chains | Same | κ:λ ratio abnormality in myeloma |
| β₂-microglobulin | Myeloma workup | Prognostic marker |
| LDH, haptoglobin, reticulocyte count | If haemolysis suspected | TMA/HUS/TTP (differential of AKI) |
| Blood cultures | If febrile | Exclude infective endocarditis, bacteraemia |
| HLA-B*5801 | Before starting allopurinol (prevention) or if allopurinol-induced AIN suspected | High prevalence in Chinese population [5] |
3.4 Imaging
USG kidneys/ureters as 1st line for any hydronephrosis ± stones [9]
This is the first-line imaging in any AKI workup. In the context of suspected AIN:
| Finding | Interpretation |
|---|---|
| Normal-sized or enlarged kidneys | Supports acute process (interstitial oedema causes swelling). Large, echogenic kidneys — enlarged by oedema is a characteristic finding in AIN [6] |
| Small, contracted kidneys | Suggests chronic kidney disease (fibrosis + tubular atrophy); less likely to be pure AIN unless superimposed on pre-existing CKD |
| No hydronephrosis | Excludes post-renal obstruction |
| Hydronephrosis | Post-renal cause — NOT AIN |
| Bilateral large polycystic kidneys | ADPKD (differential for haematuria, not AIN) |
| Increased cortical echogenicity, loss of corticomedullary differentiation | Non-specific finding of parenchymal disease [15] |
In the presence of renal impairment, try avoiding a contrast CT to prevent toxicity [8]
| Modality | When | Purpose |
|---|---|---|
| Non-contrast CT KUB | If stones suspected | Identify obstructing calculi |
| CXR | If sarcoidosis/TB suspected, or pulmonary-renal syndrome | Bilateral hilar lymphadenopathy (sarcoidosis), cavitation/infiltrates (TB), alveolar haemorrhage (Goodpasture's/ANCA vasculitis) |
| DTPA scan | Renal perfusion and drainage | Rarely needed in AIN |
| DMSA scan | Renal scarring | Chronic pyelonephritis/reflux nephropathy |
3.5 Renal Biopsy — The Gold Standard
Renal biopsy is usually required to confirm the diagnosis. This typically shows evidence of intense inflammation, with infiltration of the tubules and interstitium by polymorphonuclear leukocytes and lymphocytes. Eosinophils may also be observed, especially in drug-induced AIN. [6]
Indicated in patients when diagnosis is unclear such as non-characteristic urinalysis, if patient is not improving, or if glucocorticoid treatment is being considered [3]
Specific scenarios:
- Doubtful diagnosis (no obvious drug cause) [2]
- Under consideration for steroid treatment [2] — you want histological proof before committing to immunosuppression
- Advanced AKI [2] — to assess degree of fibrosis (which predicts irreversibility)
- No improvement in RFT by 3–7 days after drug cessation [2]
- Suspicion of concurrent GN (e.g., NSAID-induced MCD + AIN)
Consider renal biopsy if prerenal cause or ATN unlikely, or persistent oliguria > 6 weeks [16]
[15]:
- Contracted kidneys — hard to target, may just get fibrous tissue
- Large cysts — cannot stop bleeding
- Solitary kidney — risk of losing the only functioning kidney
- Uncontrolled bleeding diathesis
- Uncontrolled hypertension
- Active UTI (risk of seeding)
| Component | Finding | Interpretation |
|---|---|---|
| Light Microscopy | Interstitial oedema [3] | Fluid accumulation from inflammation |
| Inflammatory cell infiltration: predominantly lymphocytes (T cells) and monocytes/plasma cells in the tubules and interstitium [2][3] | T cell–mediated (Type IV) hypersensitivity | |
| Eosinophils may be found [2] | Especially in drug-induced AIN; supports hypersensitivity mechanism | |
| Sparing of glomeruli and blood vessels [3] | This is what distinguishes AIN from GN (glomerular) and vasculitis (vascular) | |
| Tubulitis (lymphocytes invading tubular epithelium) | Direct tubular injury by immune cells | |
| Granulomas (~6% overall; up to 25% in drug-induced) [2] | Consider drug reaction, sarcoidosis, TB, GPA, histoplasmosis | |
| Immunofluorescence | Usually negative (or non-specific) | AIN is T cell–mediated, NOT immune complex–mediated, so no immune deposits |
| Electron Microscopy | No electron-dense deposits | Confirms absence of immune complex deposition |
| Fibrosis assessment | Degree of interstitial fibrosis and tubular atrophy | Critical for prognosis — extensive fibrosis = irreversible damage = less likely to recover |
High Yield: Biopsy Findings That Distinguish AIN from Its Mimics
| Biopsy Finding | Diagnosis |
|---|---|
| Interstitial lymphocytic infiltrate + eosinophils + spared glomeruli | AIN |
| Muddy brown casts + tubular epithelial necrosis | ATN |
| Crescents (proliferating epithelial cells in Bowman's space) | RPGN |
| Mesangial IgA deposits | IgA nephropathy |
| Biconvex cholesterol clefts in arcuate arteries | Cholesterol emboli |
| Non-caseating granulomas + interstitial inflammation | Sarcoidosis or drug-induced granulomatous AIN |
| Caseating granulomas with AFB | Renal TB |
| Dense IgG4⁺ plasma cell infiltrate with storiform fibrosis | IgG4-related disease |
| Investigation | Purpose | Key Finding in AIN |
|---|---|---|
| Drug history | Identify temporal culprit | New drug 3 days to weeks before AKI |
| Urine dipstick | Screen | Leukocyte esterase +, protein ±, blood ± |
| Urine microscopy | Localise lesion | Sterile pyuria, WBC casts ± eosinophiluria |
| Urine culture | Exclude UTI | Negative (sterile pyuria) |
| Urine PCR/ACR | Quantify proteinuria | PCR < 100 mg/mmol, tubular pattern |
| FENa | Pre-renal vs intrinsic | > 1% |
| RFT | Quantify AKI | ↑ Creatinine, ↑ urea |
| CBC with differential | Eosinophilia | Present in ~23% |
| LFT | Drug-induced liver injury | Especially with allopurinol, rifampicin |
| Autoimmune markers | Exclude autoimmune cause | ANA, anti-Ro/La, ANCA, C3/C4, IgG4 |
| Renal USG | Exclude obstruction; assess kidney size | Normal/enlarged echogenic kidneys, no hydronephrosis |
| Renal biopsy | Definitive diagnosis | Lymphocytic interstitial infiltrate ± eosinophils, sparing glomeruli, ± granulomas |
Imagine you have a 65-year-old patient started on omeprazole 3 weeks ago, now presenting with rising creatinine (150 → 280 μmol/L over 5 days):
- AKI confirmed: Creatinine > 1.5× baseline → KDIGO Stage I at minimum
- Drug history: PPI started 3 weeks ago → temporal relationship ✓
- Urine dipstick: Protein trace, blood trace, leukocyte esterase positive, nitrites negative
- Urine microscopy: WBCs (no bacteria), WBC casts, occasional eosinophils on Hansel stain
- Urine culture: Negative → sterile pyuria ✓
- FENa: 2.5% → intrinsic renal (not pre-renal) ✓
- Renal USG: Normal-sized kidneys, no hydronephrosis → post-renal excluded ✓
- CBC: Mild eosinophilia (0.8 × 10⁹/L)
- No rash, no fever → classic triad absent (expected — only 10%)
Conclusion: Clinical diagnosis of PPI-induced AIN. Stop omeprazole. Monitor creatinine. If improves → diagnosis confirmed. If no improvement in 5–7 days → proceed to renal biopsy and consider glucocorticoids.
PPIs cause acute tubulointerstitial nephritis → AKI, and chronic tubulointerstitial nephritis → CKD [7]
High Yield Summary — Diagnosis of AIN
-
No formal diagnostic criteria — diagnosis is clinical + laboratory ± histological
-
First confirm AKI (KDIGO criteria), then localise (pre-renal vs intrinsic vs post-renal), then differentiate intrinsic causes by urinalysis
-
Cardinal urinalysis findings: Sterile pyuria + WBC casts ± eosinophiluria. A bland urinalysis does NOT exclude AIN.
-
Eosinophiluria requires Wright's or Hansel's stain — routine microscopy will not detect it. Sensitivity ~67%, specificity ~83% — suggestive but NOT diagnostic.
-
FENa > 1% distinguishes intrinsic renal from pre-renal AKI
-
Renal biopsy is the gold standard but is not always needed. Reserve for: unclear diagnosis, no improvement with drug withdrawal, considering steroids, advanced AKI.
-
Biopsy hallmarks: Lymphocytic interstitial infiltrate ± eosinophils, interstitial oedema, sparing of glomeruli and blood vessels, ± granulomas (~6%)
-
Always check LFT in drug-induced AIN — multi-organ hypersensitivity may be present
Active Recall - Diagnosis of AIN
References
[1] Lecture slides: GC 057. Glomerular and Tubulo-interstitial Diseases and Acute Kidney Injury.pdf (p59–60, p65) [2] Senior notes: Ryan Ho Urogenital.pdf (p91–92) [3] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (p1028–1031) [4] Lecture slides: GC 043. Drugs and the Kidney.pdf (p15–16, p27) [5] Senior notes: Block A - Drugs and the Kidney.pdf (p8, p14) [6] Senior notes: Block A - Nephrotology Teaching Clinic RTD.pdf (p1, p19) [7] Senior notes: Block A - Chronic Kidney Disease and its Complications.pdf (p11–12) [8] Senior notes: Block A - Two cases of polyuria and polydipsia.pdf (p4) [9] Senior notes: Ryan Ho Critical Care.pdf (p25, p27) [11] Senior notes: MBBS Final MB (Pediatrics) (Felix PY Lai).pdf (p418) [15] Senior notes: Block A - Introduction to Renal Investigations (RFT, urine tests and US kidneys).pdf (p1, p5) [16] Senior notes: Maksim Medicine Notes.pdf (p205, p216) [17] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (p928–930)
Management of Acute Interstitial Nephritis
The management of AIN is conceptually straightforward and rests on a few core principles — but the nuance lies in when to escalate beyond simple drug withdrawal. Think of management in three tiers:
| Tier | Action | Rationale |
|---|---|---|
| Tier 1 | STOP the incriminated drug | Remove the antigenic stimulus driving the Type IV hypersensitivity reaction |
| Tier 2 | Supportive care for AKI | Manage the consequences of ↓ GFR while awaiting recovery |
| Tier 3 | Immunosuppression (glucocorticoids ± steroid-sparing agents) | Dampen the immune-mediated inflammation if removal of the trigger alone is insufficient |
Management — STOP the incriminated drug. Immunosuppression (usually not necessary, except in drug-induced vasculitis, immune CPI-associated AKI?) [4]
Stop the incriminated drug → usually patients get better [5]
The question mark on the GC slide after "immune CPI-associated AKI?" is deliberate — it highlights that this is an evolving area of practice. Current evidence (2025–2026) supports glucocorticoids for checkpoint inhibitor–induced AIN, but the data are not from large randomised trials.
3. Tier 1: Withdraw the Offending Agent
This is the single most important step and the mainstay of treatment for drug-induced AIN.
Discontinue causative agent: mainstay. Majority recover if short-term drug exposure only [2]
Drug-induced AIN is a Type IV hypersensitivity reaction. The drug (acting as a hapten) is the ongoing antigenic stimulus. Remove the antigen → the immune response winds down → inflammation resolves → tubular and interstitial recovery begins.
| Point | Detail |
|---|---|
| Identify the culprit | Review ALL medications; focus on drugs started in the preceding 3 days to weeks. If multiple suspects, consider stopping all non-essential drugs simultaneously |
| Substitute the drug | If the patient needs the therapeutic effect of the stopped drug, substitute with an alternative from a different class. Example: if PPI caused AIN, switch to H₂ receptor antagonist (ranitidine/famotidine) |
| Document allergy | Once AIN is attributed to a specific drug, label the patient as allergic to that drug. Cross-reactivity within the same drug class is possible (e.g., cross-reactivity among penicillins) but not universal |
| Do NOT re-challenge | Re-exposure to the same drug can cause recurrent AIN, often more severe and with faster onset (anamnestic immune response). Exception: rifampicin re-challenge protocols under specialist supervision with very slow dose escalation |
High Yield: GC Lecture Slide — Drug-Induced TIN Management
Drug-induced tubulointerstitial nephritis:
- Acute kidney injury
- May lead to permanent damage
- Management — STOP the incriminated drug
- ? Immunosuppression (usually not necessary, except in drug-induced vasculitis, immune CPI-associated AKI?) [4]
This is the core exam-answer framework for management of drug-induced AIN. "Stop the drug" is the first-line answer. Immunosuppression is second-line and specifically indicated for vasculitis and checkpoint inhibitor AKI.
4. Tier 2: Supportive Management of AKI
While awaiting recovery after drug withdrawal, the patient still has acute kidney injury and requires meticulous supportive care. The approach mirrors general AKI management [9]:
Ensure and manage ABC: "A dead person has no renal function" [9]
| Action | Rationale |
|---|---|
| Treat hypoxaemia with O₂ | Tissue oxygenation supports renal recovery |
| Treat hypotension with IV fluid resuscitation | Ensure adequate renal perfusion pressure. However, in AIN the issue is NOT pre-renal — fluids correct any co-existing volume depletion but will NOT reverse the interstitial inflammation itself |
| Do NOT give diuretics initially — "Takes time for UO to respond" [9] | Diuretics will not treat AIN and may cause further electrolyte disturbances. Only use diuretics if there is overt fluid overload |
Avoid nephrotoxins, e.g. NSAIDs, potential nephrotoxins [2]
| Drug to Avoid | Why |
|---|---|
| NSAIDs | Can worsen AKI via haemodynamic mechanism (↓ PG → ↓ renal blood flow) AND can cause further AIN |
| Aminoglycosides | Direct tubular toxicity |
| IV contrast | Contrast nephropathy risk. In the presence of renal impairment, try avoiding a contrast CT to prevent toxicity [8] |
| ACEI/ARB | Can worsen GFR by reducing intra-glomerular pressure (efferent arteriolar dilatation). Temporarily hold during AKI, resume once creatinine has stabilised |
| Metformin | Risk of lactic acidosis with ↓ GFR. Must monitor kidney function for many drugs → metformin, ACEI/ARB [7] |
| Complication | Mechanism | Management |
|---|---|---|
| Fluid overload (oedema, hypertension, pulmonary oedema) | ↓ GFR → ↓ Na⁺/water excretion → volume expansion | IV loop diuretics (e.g. furosemide); dialysis if refractory [9] |
| Hyperkalaemia (K⁺ > 6 mmol/L) | ↓ GFR → ↓ K⁺ excretion; if distal tubular damage → ↓ K⁺ secretion | IV calcium gluconate (cardioprotection) → NaHCO₃ infusion → dextrose/insulin drip → PO polystyrene sulfonate → dialysis if refractory [9] |
| Metabolic acidosis | Tubular damage → impaired H⁺ secretion (Type 1 RTA) or HCO₃⁻ reabsorption (Type 2 RTA); also ↓ GFR → ↓ acid excretion | IV bicarbonate infusion; dialysis if severe (pH < 7.1) |
| Hyperphosphataemia, hypocalcaemia | ↓ GFR → ↓ PO₄³⁻ excretion → ↑ PO₄ → binds Ca²⁺ → ↓ Ca | Phosphate binders (calcium carbonate/acetate), dietary restriction |
| Parameter | Frequency | Purpose |
|---|---|---|
| RFT (Na, K, Urea, Cr, eGFR) | Daily (or twice daily if critically ill) | Track trajectory of renal recovery vs decline |
| Urine output | Hourly (if catheterised) | Oliguria is an early sign of worsening; polyuria may indicate recovery |
| Fluid balance | Daily | Guide fluid therapy; prevent overload |
| Weight | Daily | Objective measure of fluid status |
| ECG | If K⁺ > 6 | Detect hyperkalaemic ECG changes (peaked T waves → widened QRS → sine wave) |
Temporary dialysis if necessary [2]
Dialysis is the last resort when conservative medical management fails. Use the AEIOU mnemonic [9]:
| Letter | Indication | Threshold |
|---|---|---|
| A | Acidosis | Metabolic acidosis with pH < 7.1 refractory to bicarbonate infusion |
| E | Electrolyte imbalance | Hyperkalaemia > 6.5 mmol/L or rapidly rising K⁺ refractory to medical Rx |
| I | Intoxication | Drug removal in overdose (less relevant in AIN specifically) |
| O | Overload | Fluid overload refractory to diuretics |
| U | Uraemia | Features of uraemia: pericarditis, neuropathy, ↓ mental status |
Most patients with AIN do not require dialysis. Those who do typically have severe AIN with prolonged oliguria or dialysis-dependent AKI at presentation.
5. Tier 3: Immunosuppression — Glucocorticoids
This is the most debated aspect of AIN management. The evidence base is limited (no large randomised controlled trials), but current consensus and clinical practice provide reasonable guidance.
AIN is an immune-mediated inflammatory process (Type IV hypersensitivity with T cell activation). Glucocorticoids:
- Suppress T cell activation (reduce IL-2 production, inhibit T cell proliferation)
- Reduce cytokine release (TNF-α, IFN-γ, IL-1, IL-6) → less inflammatory infiltrate
- Reduce interstitial oedema → less tubular compression → faster GFR recovery
- Prevent long-term scarring — by stopping the inflammation before it progresses to fibrosis [2]
Immunosuppression: usually not necessary, except for severe cases / systemic manifestations [5]:
- Drug-induced vasculitis
- Drug-induced muco-cutaneous manifestations
- Immune checkpoint inhibitor–associated AKI
- Drug-induced hepatitis
Immunosuppression: usually require confirmation by renal biopsy [2]
Specific indications:
| Indication | Rationale |
|---|---|
| No improvement in RFT by 3–7 days after drug withdrawal | The inflammation is not self-resolving; active immunosuppression may accelerate recovery and prevent fibrosis |
| Biopsy-confirmed active inflammation with minimal fibrosis | Active inflammation is steroid-responsive; established fibrosis is NOT |
| Severe AKI / dialysis-dependent AKI | Higher stakes — want to prevent irreversible damage |
| Immune checkpoint inhibitor–associated AIN | Responsive to steroids; those not given steroids did not improve [5] |
| TINU syndrome | Dual pathology (TIN + uveitis) often requires steroids for both components |
| Autoimmune AIN (Sjögren's, SLE, sarcoidosis) | Steroids treat the underlying autoimmune disease AND the AIN simultaneously |
| Drug-induced vasculitis / systemic hypersensitivity | Multi-organ involvement warrants immunosuppression |
Glucocorticoids: ? accelerates recovery, prevents long-term scarring [2]
| Severity | Regimen | Rationale |
|---|---|---|
| Moderate AIN (not dialysis-dependent) | Prednisolone 1 mg/kg/day × 2–3 weeks, then taper over 3–4 weeks [2] | Gradual taper prevents rebound inflammation |
| Severe / dialysis-dependent AKI | IV pulse methylprednisolone 250–500 mg daily × 3 days, then switch to oral prednisolone 1 mg/kg/day and taper [2] | Pulse therapy achieves rapid high-dose immunosuppression in critical situations |
Early steroid treatment within 7 days of drug withdrawal improves outcome in drug-induced AIN [3]
This is a critical teaching point: timing matters. The longer you wait, the more likely the inflammation has progressed to fibrosis, which steroids cannot reverse.
Steroids are indicated in all patients with suspected drug-induced AIN EXCEPT NSAIDs, which is less likely to respond to steroids [3]
Efficacy: controversial, ? less efficacious in NSAID-related AIN [2]
Why might NSAIDs respond less to steroids?
The mechanism of NSAID-induced AIN may involve additional non-immune pathways (direct prostaglandin inhibition → haemodynamic component) alongside the immune-mediated component. The concurrent minimal change disease (which itself IS steroid-responsive in primary MCD) adds complexity — but in NSAID-MCD, the underlying trigger is the drug, and removing the NSAID is the primary treatment.
NSAID-Induced AIN: Stop the Drug, Don't Rush to Steroids
For NSAID-induced AIN:
- Stop the NSAID — this alone may be sufficient
- Allow 1–2 weeks for improvement after drug cessation
- Steroids are less effective compared to other drug-induced AIN
- If nephrotic syndrome is present (concurrent MCD), the proteinuria often resolves with NSAID withdrawal ± steroids
This is an increasingly important clinical scenario as immunotherapy use expands in oncology.
Immune checkpoint inhibitor–associated AKI: most of the time this side effect is an off-target effect, due to the excessive stimulation of the immune system [5]
Responsive to steroids → those not given steroids did not improve [5]
| Aspect | Approach |
|---|---|
| Drug cessation | Withhold the CPI (not always permanently discontinued — depends on oncology benefit-risk) |
| Steroids | Prednisolone 1 mg/kg/day; earlier and more aggressive use than standard drug-induced AIN |
| Biopsy | Strongly recommended before steroids (to confirm AIN and exclude other pathologies like TMA or GN) |
| Re-challenge | May cautiously re-challenge the CPI after renal recovery, under close nephrology-oncology co-management. Recurrence rate ~20–30% |
| Second-line | If steroid-refractory: mycophenolate mofetil (MMF) or cyclosporine may be considered |
| Underlying Disease | Treatment Approach |
|---|---|
| Sjögren's syndrome | Glucocorticoids; may need long-term immunosuppression (MMF, azathioprine) to control the autoimmune process |
| SLE (lupus TIN) | Part of overall lupus nephritis management — corticosteroids + MMF or cyclophosphamide depending on class |
| Sarcoidosis | Glucocorticoids (first-line); consider methotrexate or azathioprine as steroid-sparing agents |
| IgG4-related disease | Glucocorticoids (excellent initial response); rituximab for relapsing/refractory disease |
| TINU syndrome | Systemic glucocorticoids for TIN + topical/systemic steroids for uveitis |
For steroid-refractory or steroid-dependent AIN, limited data support:
| Agent | Evidence | When to Consider |
|---|---|---|
| Mycophenolate mofetil (MMF) | Small case series | CPI-associated AIN refractory to steroids; autoimmune AIN requiring steroid-sparing |
| Azathioprine | Case reports | Steroid-sparing for autoimmune AIN (Sjögren's, SLE) |
| Cyclophosphamide | Very limited | Severe lupus TIN (Class IV lupus nephritis with TIN component) |
| Rituximab | Growing evidence | IgG4-related disease, refractory Sjögren's |
| Aetiology | Primary Treatment | Steroids? | Special Considerations |
|---|---|---|---|
| Drug-induced (antibiotics, PPIs, diuretics, allopurinol) | Stop the drug | If no improvement by 3–7 days OR biopsy shows active inflammation | Early treatment within 7 days improves outcome [3] |
| NSAID-induced | Stop the NSAID | Less efficacious; try drug withdrawal first [2][3] | May have concurrent MCD → nephrotic syndrome |
| Immune checkpoint inhibitor | Stop the CPI | Usually required; responsive to steroids [5] | Co-manage with oncology; may re-challenge |
| Infection-related | Treat the underlying infection | Generally NOT indicated (treat infection) | Ensure adequate antibiotic coverage; avoid further nephrotoxic antibiotics |
| Sjögren's syndrome | Steroids ± steroid-sparing agent | Yes | Long-term co-management with rheumatology |
| SLE | Steroids + immunosuppression (MMF/CYC) | Yes | Part of comprehensive lupus nephritis protocol |
| Sarcoidosis | Steroids | Yes | Monitor serum Ca²⁺, ACE levels |
| TINU syndrome | Steroids (systemic + topical ophthalmic) | Yes | Ophthalmology co-management for uveitis |
| Idiopathic | Consider steroids if biopsy-confirmed | Case-by-case | May have self-limited course |
Prognosis: not well-described; mean recovery time 1.5 months but may be incomplete [2]
| Factor | Better Prognosis | Worse Prognosis |
|---|---|---|
| Duration of drug exposure | Short exposure (days) | Prolonged exposure (weeks–months, e.g. PPIs) |
| Time to drug withdrawal | Early recognition and cessation | Delayed recognition |
| Time to steroids | Within 7 days of drug withdrawal [3] | Delayed treatment is similar to supportive care [3] |
| Biopsy findings | Active inflammation, minimal fibrosis | Significant interstitial fibrosis and tubular atrophy |
| Baseline kidney function | Normal pre-existing kidneys | Pre-existing CKD (less renal reserve) |
| Cause | Drug-induced (most reversible) | NSAID-induced (less responsive to steroids), chronic TIN |
Even mild, reversible AKI has important clinical consequences, e.g. CKD transition [1]. This is why AIN must be taken seriously — even if creatinine recovers, the patient is at increased risk of developing CKD.
AKI may lead to permanent damage [4]
High Yield: The Window of Opportunity in AIN
There is a critical time window in AIN management:
- Stop the drug immediately — every day of continued exposure worsens prognosis
- Assess response by day 3–7 — if creatinine is not improving, escalate
- Start steroids within 7 days of drug withdrawal if no improvement — delayed treatment has outcomes similar to supportive care alone [3]
- Biopsy fibrosis = the point of no return — once significant fibrosis has set in, steroids will not reverse it
Think of it as analogous to stroke thrombolysis: there is a therapeutic window, and delays in treatment lead to irreversible damage.
Even after recovery from AIN, patients require ongoing monitoring:
| Action | Rationale |
|---|---|
| Serial RFT monitoring | Ensure complete recovery; some patients have incomplete recovery and transition to CKD |
| Drug allergy documentation | Prevent re-exposure; label in electronic health record |
| Avoid same drug class | Cross-reactivity is possible (e.g., within beta-lactams), though not universal |
| Annual eGFR check | AKI is a risk factor for future CKD, even if initial recovery appears complete |
| PPI deprescription | Try to discontinue long-term PPI therapy as much as possible — PPIs can induce acute interstitial nephritis and chronic TIN → CKD [7][18] |
| Address underlying cause | For autoimmune AIN: ongoing rheumatology follow-up; for TINU: ophthalmology surveillance for uveitis relapse |
High Yield Summary — Management of AIN
The Three Pillars of AIN Management:
-
STOP THE DRUG — this is THE answer. Most patients improve with drug cessation alone.
-
Supportive AKI care — fluids, electrolyte correction, avoid nephrotoxins, monitor RFT daily, dialysis if AEIOU indications met.
-
Glucocorticoids if needed:
- Indication: no improvement in 3–7 days, biopsy-confirmed active inflammation, severe/dialysis-dependent AKI, CPI-associated AIN, autoimmune AIN
- Regimen: prednisolone 1 mg/kg/day × 2–3 weeks, taper over 3–4 weeks; pulse methylprednisolone if severe
- Early treatment within 7 days improves outcome; delayed treatment = supportive care
- Less efficacious in NSAID-induced AIN
- CPI-associated AIN: responsive to steroids; those not given steroids did not improve
Immunosuppression is USUALLY NOT necessary except for:
- Drug-induced vasculitis
- Drug-induced muco-cutaneous manifestations
- Immune checkpoint inhibitor–associated AKI
- Drug-induced hepatitis
Prognosis: Mean recovery 1.5 months. May be incomplete. Even mild AKI → increased CKD risk.
Active Recall - Management of AIN
References
[1] Lecture slides: GC 057. Glomerular and Tubulo-interstitial Diseases and Acute Kidney Injury.pdf (p60) [2] Senior notes: Ryan Ho Urogenital.pdf (p92–93) [3] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (p1030–1032) [4] Lecture slides: GC 043. Drugs and the Kidney.pdf (p16) [5] Senior notes: Block A - Drugs and the Kidney.pdf (p8–9) [6] Senior notes: Block A - Nephrotology Teaching Clinic RTD.pdf (p1) [7] Senior notes: Block A - Chronic Kidney Disease and its Complications.pdf (p12) [8] Senior notes: Block A - Two cases of polyuria and polydipsia.pdf (p4) [9] Senior notes: Ryan Ho Critical Care.pdf (p25–27) [18] Senior notes: Block A - Indigestion and 'heartburn'_ nausea and vomiting; gastric motility problems; benign esophageal lesions.pdf (p11)
Complications of Acute Interstitial Nephritis
The complications of AIN arise from two broad sources: (1) the AKI itself and its metabolic consequences, and (2) the long-term sequelae of interstitial damage if the inflammation is not promptly reversed. Thinking about complications from first principles, the kidney is responsible for waste excretion, fluid/electrolyte balance, acid-base homeostasis, and endocrine functions (EPO, vitamin D activation, RAAS). When the tubulointerstitium — which constitutes ~95% of the renal parenchyma [19] — is inflamed, ALL of these functions can be compromised.
1. Acute Complications (During the AKI Episode)
These are direct consequences of diminished kidney function during the active inflammatory phase. They mirror the general complications of AKI from any cause but are worth understanding in the specific context of AIN.
| Mechanism | Clinical Manifestation | Why It Happens |
|---|---|---|
| ↓ GFR → ↓ Na⁺ and water excretion | Peripheral oedema, hypertension, pulmonary oedema [9] | The inflamed interstitium compresses peritubular capillaries and tubules → ↓ filtration and impaired excretion of the daily fluid and salt load. The patient retains fluid that they cannot excrete. |
| Iatrogenic fluid administration without matching output | Worsening oedema, ↑ JVP | In-hospital IV fluids given to "support kidneys" can paradoxically worsen fluid status if the kidneys cannot excrete them |
| Mechanism | Why It Is Dangerous |
|---|---|
| ↓ GFR → ↓ K⁺ excretion by the kidney | K⁺ is the most immediately life-threatening electrolyte derangement in AKI |
| Distal tubular damage → ↓ K⁺ secretion (Type 4 RTA mechanism) | Even if GFR is only moderately reduced, damaged distal tubules cannot secrete K⁺ normally |
| Metabolic acidosis → H⁺/K⁺ exchange → K⁺ shifts out of cells | Acidosis worsens hyperkalaemia by driving intracellular K⁺ into the extracellular space |
- Symptoms usually only when K⁺ > 6 mmol/L: arrhythmia, weakness [9]
- ECG changes: peaked T waves → flattened P waves → widened QRS → sine wave → cardiac arrest
- Requires urgent treatment: IV calcium gluconate (cardioprotection), NaHCO₃ infusion, dextrose/insulin drip, PO polystyrene sulfonate, dialysis [9]
Hyperkalaemia in AIN: A Double Hit
AIN causes hyperkalaemia through two mechanisms simultaneously: (1) reduced GFR (less K⁺ filtered) AND (2) direct tubular damage (less K⁺ secreted at the distal tubule). This is why hyperkalaemia can be disproportionately severe relative to the degree of creatinine elevation in AIN, compared to pre-renal AKI where tubular K⁺ secretion is preserved.
| Type | Mechanism | Features |
|---|---|---|
| Non-anion gap metabolic acidosis (RTA) | Damaged distal tubules → impaired H⁺ secretion (Type 1 distal RTA); or damaged proximal tubules → impaired HCO₃⁻ reabsorption (Type 2 proximal RTA) [1][19] | Normal anion gap, hyperchloraemia. May present early even before creatinine is markedly elevated |
| High anion gap metabolic acidosis | Severe ↓ GFR → accumulation of uraemic toxins (sulphate, phosphate, organic acids) that are normally excreted by the kidney | Occurs when AKI is advanced (Stage III); anion gap > 12 |
When GFR drops sufficiently, nitrogenous waste products (urea, creatinine, and other "uraemic toxins") accumulate:
| Uraemic Complication | Mechanism | Clinical Features |
|---|---|---|
| Uraemic encephalopathy | Uraemic toxins cross the blood-brain barrier → neuronal dysfunction | Confusion, asterixis, seizures, drowsiness → coma |
| Uraemic pericarditis | Toxin-mediated inflammation of the pericardium | Chest pain (pleuritic, positional), pericardial friction rub, pericardial effusion → tamponade |
| Uraemic nausea/vomiting | GI mucosal irritation from uraemic toxins | Anorexia, nausea, vomiting (common presenting symptom) |
| Uraemic bleeding | Uraemic toxins impair platelet function (↓ adhesion and aggregation) | Prolonged bleeding time despite normal platelet count, GI bleeding, easy bruising |
- Features of uraemia (pericarditis, neuropathy, ↓ mental status) are indications for dialysis [9]
- Patients with AIN are immunocompromised at multiple levels:
- The AKI itself impairs immune function (uraemia → leukocyte dysfunction)
- If treated with glucocorticoids → further immunosuppression
- If on dialysis → catheter-related bloodstream infections
- In particular, patients with drug hypersensitivity–associated AIN who are also febrile must be carefully evaluated to distinguish the fever of hypersensitivity from a superimposed infection
NSAID-induced nephrotic syndrome + AKI: minimal change glomerulopathy + acute tubulointerstitial nephritis, with T lymphocytes and eosinophils (40%), higher risk in elderly [4]
The concurrent nephrotic syndrome introduces additional complications:
- Severe oedema / anasarca — from massive proteinuria → hypoalbuminaemia → ↓ oncotic pressure
- Thromboembolism — nephrotic syndrome is a hypercoagulable state (loss of antithrombin III, protein S, protein C in urine; increased hepatic synthesis of clotting factors)
- Increased infection risk — urinary loss of immunoglobulins
- Hyperlipidaemia — hepatic response to hypoalbuminaemia → increased VLDL and LDL synthesis
2. Subacute and Chronic Complications
These develop when AIN is not promptly diagnosed and treated, allowing the inflammation to persist and transition to fibrosis.
This is the single most important long-term complication of AIN.
Even mild, reversible AKI has important clinical consequences, e.g. CKD transition [1]
AKI may lead to permanent damage [4]
Chronic TIN is the major pathway leading to chronic kidney disease [19]
Why does AIN lead to CKD?
The pathophysiological sequence is:
- Persistent interstitial inflammation (if the drug is not stopped, or the autoimmune process is not controlled)
- Fibroblast activation → deposition of collagen and extracellular matrix in the interstitium
- Interstitial fibrosis → replaces normal interstitial tissue with scar tissue
- Tubular atrophy → chronically compressed and damaged tubules lose their epithelial lining and function
- Loss of peritubular capillaries → chronic ischaemia → further fibrosis (a vicious cycle)
- Nephron loss → ↓ functioning nephron mass → ↑ workload on remaining nephrons → hyperfiltration → secondary glomerulosclerosis → further nephron loss
Classification of chronic TIN on histology [6]:
- Interstitial inflammation — lymphocytes + plasma cells + macrophages
- Interstitial fibrosis
- Tubulitis with focal tubular atrophy
This is in contrast to acute TIN histology which shows interstitial oedema (reversible) rather than fibrosis (irreversible).
PPIs cause acute tubulointerstitial nephritis → AKI, and chronic tubulointerstitial nephritis → CKD [7]
If AIN progresses to CKD, the patient develops all the systemic manifestations of CKD [7]:
| CKD Complication | Pathophysiology |
|---|---|
| Metabolic acidosis | ↓ nephron mass → ↓ H⁺ excretion and ↓ HCO₃⁻ regeneration |
| Hypertension and LVH | Fluid retention, RAAS activation, ↓ renal vasodilatory prostaglandins → chronic volume overload and ↑ SVR. "Good practice for a patient presenting with HT to get a urine dipstick" [7] |
| Congestive cardiac failure → systolic HF, HFrEF | Chronic volume overload + hypertension + anaemia → cardiac remodelling |
| Anaemia: Normochromic normocytic anaemia → lack of erythropoietin [7] | The interstitial fibroblasts that produce EPO are destroyed by the inflammatory and fibrotic process. Anaemia in CIN may be more severe than expected for the degree of ↓ GFR because the interstitium (where EPO is produced) is specifically damaged [19] |
| CKD-MBD (Mineral and bone disorder) | ↓ GFR → ↓ phosphate excretion → ↑ PO₄ → ↓ Ca²⁺ → secondary hyperparathyroidism → high or low PTH, bone biochemistry abnormality, vascular calcification [7] |
Anaemia in CIN: Disproportionately Severe
In chronic interstitial nephritis, anaemia may be more severe than ↓ GFR would predict [19]. This is because the interstitial fibroblasts that produce EPO are specifically targeted and destroyed by the inflammatory/fibrotic process. In glomerular CKD, the interstitium is relatively spared until late stages, so EPO production is better preserved for the same level of GFR loss.
Even if GFR partially recovers, residual tubular damage can cause chronic tubular dysfunction:
| Syndrome | Tubular Segment Affected | Manifestation | Pathophysiology |
|---|---|---|---|
| Renal tubular acidosis | Distal (Type 1) or Proximal (Type 2) | Non-AG metabolic acidosis, ± hypokalaemia, ± nephrocalcinosis | Damaged tubular cells cannot secrete H⁺ (distal) or reabsorb HCO₃⁻ (proximal) |
| Nephrogenic diabetes insipidus | Collecting duct | Polyuria, polydipsia, nocturia, hypernatraemia | Medullary damage → loss of AQP2 expression → ADH resistance [8] |
| Fanconi syndrome | Proximal tubule | Glucosuria (normal blood glucose), aminoaciduria, phosphaturia, uricosuria, bicarbonaturia | Global proximal tubular dysfunction → failure to reabsorb filtered solutes |
| K⁺-wasting disorders | Loop of Henle / DCT | Hypokalaemia, muscle weakness, arrhythmias | Damaged thick ascending limb or DCT cells cannot reabsorb K⁺ properly |
| Salt-wasting nephropathy | Various | Hyponatraemia, hypotension, volume depletion | Tubular Na⁺ reabsorption impaired → inappropriately high urine Na⁺ |
| Concentration defect (early CIN) | Medullary interstitium / collecting duct | Polyuria/nocturia ± salt wasting [19] | Disrupted medullary interstitial tonicity gradient → impaired countercurrent mechanism |
CIN clinical presentation: concentration defect (early) → polyuria/nocturia ± salt wasting (↓ BP, hypovolaemic hypoNa). Due to tubular damage to medullary area. May have superimposed AKI due to inadequate perfusion [19]
Prognosis: not well-described; mean recovery time 1.5 months but may be incomplete [2]
- Not all patients return to their baseline creatinine
- Risk factors for incomplete recovery:
- Prolonged drug exposure before cessation
- Delayed recognition and treatment
- Significant interstitial fibrosis on biopsy
- Pre-existing CKD (less renal reserve)
- NSAID-induced AIN (less responsive to steroids)
- Older age
- Patients with incomplete recovery carry residual CKD and are at risk for all CKD complications
Chinese herbal medicine and tubulointerstitial nephritis: some traditional Chinese herbal preparations contain the toxin aristolochic acid [6]
Aristolochic acid nephropathy: marked interstitial fibrosis and tubular atrophy, usually few interstitial inflammatory cells. Progression to end-stage renal failure within months [6]
This is a particularly aggressive form of chronic TIN that:
- Progresses rapidly to ESRD requiring dialysis
- Has an increased risk of urothelial carcinomas (transitional cell carcinoma of the bladder, ureter, renal pelvis) [6] — aristolochic acid is a potent mutagen that forms DNA adducts
- The implicated herbs are banned in Hong Kong (關木通, 廣防己, 馬兜鈴, 青木香, 天仙藤) [6]
High Yield: Aristolochic Acid → CKD + Urothelial Cancer
If a patient presents with unexplained CKD and a history of traditional Chinese medicine use, always consider aristolochic acid nephropathy. Beyond the renal complications, these patients need surveillance for urothelial carcinomas (cystoscopy, urine cytology, CT urogram). The implicated herbs are banned in Hong Kong, but patients may have used them before the ban or obtained them from unregulated sources.
3. Complications of Treatment
If steroids are used (prednisolone 1 mg/kg/day for 2–3 weeks, tapered over 3–4 weeks), the short course limits long-term steroid toxicity but can still cause:
| Complication | Mechanism |
|---|---|
| Hyperglycaemia | Steroids → ↑ hepatic gluconeogenesis + ↓ peripheral insulin sensitivity. Particularly problematic in patients with pre-existing diabetes (e.g., the teaching case of diabetic nephropathy + allopurinol-induced AIN [13]) |
| Secondary infections | Immunosuppression → opportunistic infections (PJP, fungal, reactivation of TB/HBV). PJP prophylaxis with co-trimoxazole if prolonged course |
| GI effects | Gastric mucosal irritation → peptic ulceration. Co-prescribe PPI for gastroprotection (but be aware of the irony: PPI itself can cause AIN!) |
| Insomnia, mood changes | CNS effects of corticosteroids |
| Fluid retention, hypertension | Mineralocorticoid effects of prednisolone → Na⁺ and water retention. Compounds the fluid overload from AKI |
| Osteoporosis | If prolonged courses required (autoimmune AIN needing ongoing immunosuppression). Short courses for drug-induced AIN usually not a concern |
If temporary dialysis is required:
| Complication | Detail |
|---|---|
| Catheter-related bloodstream infection (CRBSI) | Central venous catheter → entry point for bacteria (Staph aureus, coagulase-negative staph) |
| Dialysis disequilibrium syndrome | Rapid correction of uraemia → osmotic fluid shifts into brain → cerebral oedema → headache, nausea, seizures. Prevented by starting with short, gentle dialysis sessions |
| Hypotension during dialysis | Rapid fluid removal → ↓ intravascular volume |
| Electrolyte shifts | Rapid correction of K⁺ → cardiac arrhythmias |
| Phase | Key Complications |
|---|---|
| Acute (during AKI) | Fluid overload, hyperkalaemia, metabolic acidosis, uraemia (encephalopathy, pericarditis, bleeding), secondary infection |
| Subacute (recovery phase) | Incomplete recovery, persistent tubular dysfunction (RTA, nephrogenic DI, Fanconi syndrome), residual CKD |
| Chronic (long-term) | CKD progression, CKD-MBD, anaemia (disproportionate to GFR), hypertension/LVH, cardiovascular disease |
| Treatment-related | Steroid side effects (hyperglycaemia, infection, GI), dialysis complications (CRBSI, disequilibrium) |
| Aristolochic acid–specific | Rapid ESRD, urothelial carcinomas |
High Yield Summary — Complications of AIN
The most important complication of AIN is transition to CKD:
- Even mild, reversible AKI has important clinical consequences, e.g. CKD transition [1]
- AKI may lead to permanent damage [4]
- Chronic TIN is the major pathway leading to chronic kidney disease [19]
Acute life-threatening complications of AKI (AEIOU):
- Acidosis, Electrolyte imbalance (hyperkalaemia), Intoxication, fluid Overload, Uraemia
Unique AIN complications:
- Tubular dysfunction syndromes (RTA, nephrogenic DI, Fanconi syndrome) — may persist even after GFR recovers
- NSAID-induced AIN: concurrent nephrotic syndrome → thromboembolism, infection, anasarca
- Anaemia in CIN is disproportionately severe because interstitial fibroblasts (EPO-producing cells) are specifically destroyed
- Aristolochic acid nephropathy: rapid ESRD + urothelial cancer risk
Prevention of complications = early diagnosis + drug cessation + early steroids if indicated
Active Recall - Complications of AIN
References
[1] Lecture slides: GC 057. Glomerular and Tubulo-interstitial Diseases and Acute Kidney Injury.pdf (p59–60) [2] Senior notes: Ryan Ho Urogenital.pdf (p91–93) [4] Lecture slides: GC 043. Drugs and the Kidney.pdf (p16, p27) [5] Senior notes: Block A - Drugs and the Kidney.pdf (p8) [6] Senior notes: Block A - Nephrotology Teaching Clinic RTD.pdf (p1, p6, p9, p11) [7] Senior notes: Block A - Chronic Kidney Disease and its Complications.pdf (p11–12) [8] Senior notes: Block A - Two cases of polyuria and polydipsia.pdf (p4) [9] Senior notes: Ryan Ho Critical Care.pdf (p25–27) [13] Senior notes: Block A - Nephrology Data Interpretation.pdf (p6, p11) [19] Senior notes: Block A - Glomerular and Tubulo-interstitial Diseases and Acute Kidney Injury.pdf (p29) [20] Senior notes: Adrian Lui Pediatrics Notes.pdf (p331)
High Yield Summary
Acute Interstitial Nephritis (AIN) — Key Points for Exams:
-
Definition: Acute inflammatory infiltrate of the renal interstitium → AKI. The interstitium is ~95% of renal parenchyma.
-
Most common cause: Drugs (~71%) — antibiotics, NSAIDs, PPIs, allopurinol, checkpoint inhibitors, rifampicin.
-
Mechanism: Type IV (T cell–mediated) hypersensitivity — idiosyncratic, NOT dose-dependent. Drug acts as hapten.
-
Classic triad: Fever (27%) + Eosinophilia (23%) + Rash (15%) — present in only ~10% of cases. Do NOT rely on this for diagnosis.
-
Urinalysis: Sterile pyuria, WBC/tubular casts ± eosinophiluria. Proteinuria usually < 1 g/day (tubular pattern). Bland urinalysis does NOT exclude AIN.
-
NSAID special: Can cause concurrent minimal change disease + AIN → nephrotic syndrome + AKI. Infiltrate contains T lymphocytes and eosinophils (40%).
-
PPIs: Cause both acute TIN → AKI and chronic TIN → CKD.
-
Allopurinol: HLA-B5801* — SJS/TEN + AIN + hepatitis. Pre-test in Chinese patients.
-
Checkpoint inhibitor AIN: Requires immunosuppression (steroids), not just drug cessation.
-
Sjögren's: Autoimmune AIN → distal RTA + nephrogenic DI.
-
TINU: AIN + uveitis → young women/children.
-
AIN accounts for 5–15% of all AKI cases.
-
Management principle: Stop the offending drug → most patients improve. Immunosuppression only for severe/refractory cases.
High Yield Summary — Differential Diagnosis of AIN
Three critical distinctions to make in AKI:
-
Pre-renal vs Intrinsic vs Post-renal → Use volume assessment, FENa, USG
-
ATN vs AIN (both intrinsic tubulointerstitial):
- ATN: muddy brown casts, no systemic features, onset minutes–hours
- AIN: sterile pyuria + WBC casts, ± fever/rash/eosinophilia, onset days–weeks
-
AIN vs GN (both intrinsic renal):
- AIN: WBC casts, low-grade proteinuria, sterile pyuria
- GN: RBC casts, dysmorphic RBCs, heavy proteinuria, active serology
Don't forget the mimics: Cholesterol emboli (post-procedural, livedo reticularis, low complement), myeloma (negative dipstick, M-spike), pyelonephritis (positive urine culture — NOT sterile pyuria)
High Yield Summary — Diagnosis of AIN
-
No formal diagnostic criteria — diagnosis is clinical + laboratory ± histological
-
First confirm AKI (KDIGO criteria), then localise (pre-renal vs intrinsic vs post-renal), then differentiate intrinsic causes by urinalysis
-
Cardinal urinalysis findings: Sterile pyuria + WBC casts ± eosinophiluria. A bland urinalysis does NOT exclude AIN.
-
Eosinophiluria requires Wright's or Hansel's stain — routine microscopy will not detect it. Sensitivity ~67%, specificity ~83% — suggestive but NOT diagnostic.
-
FENa > 1% distinguishes intrinsic renal from pre-renal AKI
-
Renal biopsy is the gold standard but is not always needed. Reserve for: unclear diagnosis, no improvement with drug withdrawal, considering steroids, advanced AKI.
-
Biopsy hallmarks: Lymphocytic interstitial infiltrate ± eosinophils, interstitial oedema, sparing of glomeruli and blood vessels, ± granulomas (~6%)
-
Always check LFT in drug-induced AIN — multi-organ hypersensitivity may be present
High Yield Summary — Management of AIN
The Three Pillars of AIN Management:
-
STOP THE DRUG — this is THE answer. Most patients improve with drug cessation alone.
-
Supportive AKI care — fluids, electrolyte correction, avoid nephrotoxins, monitor RFT daily, dialysis if AEIOU indications met.
-
Glucocorticoids if needed:
- Indication: no improvement in 3–7 days, biopsy-confirmed active inflammation, severe/dialysis-dependent AKI, CPI-associated AIN, autoimmune AIN
- Regimen: prednisolone 1 mg/kg/day × 2–3 weeks, taper over 3–4 weeks; pulse methylprednisolone if severe
- Early treatment within 7 days improves outcome; delayed treatment = supportive care
- Less efficacious in NSAID-induced AIN
- CPI-associated AIN: responsive to steroids; those not given steroids did not improve
Immunosuppression is USUALLY NOT necessary except for:
- Drug-induced vasculitis
- Drug-induced muco-cutaneous manifestations
- Immune checkpoint inhibitor–associated AKI
- Drug-induced hepatitis
Prognosis: Mean recovery 1.5 months. May be incomplete. Even mild AKI → increased CKD risk.
High Yield Summary — Complications of AIN
The most important complication of AIN is transition to CKD:
- Even mild, reversible AKI has important clinical consequences, e.g. CKD transition [1]
- AKI may lead to permanent damage [4]
- Chronic TIN is the major pathway leading to chronic kidney disease [19]
Acute life-threatening complications of AKI (AEIOU):
- Acidosis, Electrolyte imbalance (hyperkalaemia), Intoxication, fluid Overload, Uraemia
Unique AIN complications:
- Tubular dysfunction syndromes (RTA, nephrogenic DI, Fanconi syndrome) — may persist even after GFR recovers
- NSAID-induced AIN: concurrent nephrotic syndrome → thromboembolism, infection, anasarca
- Anaemia in CIN is disproportionately severe because interstitial fibroblasts (EPO-producing cells) are specifically destroyed
- Aristolochic acid nephropathy: rapid ESRD + urothelial cancer risk
Prevention of complications = early diagnosis + drug cessation + early steroids if indicated
Lupus Nephritis
Lupus nephritis is a serious complication of systemic lupus erythematosus in which immune complex deposition in the kidneys causes glomerular inflammation, potentially leading to renal failure.
Acute Tubular Necrosis
Acute tubular necrosis is the death of renal tubular epithelial cells, most commonly caused by ischemia or nephrotoxins, leading to intrinsic acute kidney injury.