Medicine chapters
Acute tubular necrosis and acute interstitial nephritis
The two main tubular causes of intrinsic acute kidney injury: ischaemic or toxic acute tubular necrosis, and drug-induced allergic interstitial nephritis, with their urine findings and treatment.
- ATN is the commonest cause of intrinsic AKI: tubular cells die from prolonged ischaemia or toxins (aminoglycosides, contrast, myoglobin); urine shows muddy brown granular casts, urine Na >20 and FENa >1%.
- ATN passes through oliguric, maintenance and polyuric recovery phases over about 1–3 weeks; treatment is supportive.
- Acute interstitial nephritis is mostly a drug allergy (penicillins, NSAIDs, PPIs): fever, rash, eosinophilia, eosinophiluria, sterile pyuria; stop the drug, consider prednisolone.
On this page
Overview
Intrinsic AKI means damage within the kidney itself. The two big tubular causes are:
- Acute tubular necrosis (ATN): death of tubular cells from ischaemia or toxins. It causes about 80–90% of intrinsic AKI.
- Acute interstitial nephritis (AIN): inflammation of the interstitium and tubules, usually an allergic reaction to a drug.
Both cause a rising creatinine, but their history, urine and treatment differ. Exams love to make you tell them apart from each other and from prerenal AKI.
Acute tubular necrosis
Aetiology
| Type | Causes |
|---|---|
| Ischaemic (commonest) | Any prolonged prerenal state: haemorrhage, burns, severe vomiting and diarrhoea, pancreatitis, septic shock, cardiogenic shock, major surgery, abruptio placentae, pre-eclampsia, hepatorenal syndrome |
| Exogenous toxins | Aminoglycosides (gentamicin), iodinated contrast, amphotericin B, cisplatin, NSAIDs, ACE inhibitors (with hypoperfusion), heavy metals, ethylene glycol (oxalate crystals), snake bite |
| Endogenous toxins | Myoglobin (rhabdomyolysis, crush injury), haemoglobin (intravascular haemolysis, e.g. falciparum "blackwater fever", mismatched transfusion), uric acid (tumour lysis), light chains (myeloma) |
Prerenal AKI and ischaemic ATN are a continuum. If poor perfusion lasts long enough for autoregulation to fail, a reversible prerenal state becomes established ATN that no longer responds to fluid.
Risk factors
- Older age and pre-existing CKD.
- Diabetes (especially for contrast), heart failure, liver disease.
- Hypovolaemia and hypotension, sepsis.
- Combining nephrotoxins (e.g. gentamicin + furosemide, NSAIDs + ACE inhibitor).
- High or prolonged drug doses (aminoglycosides), large contrast volumes.
- Myeloma (paraprotein) and major vascular or cardiac surgery.
Pathophysiology (just enough for the exam)
- The proximal tubule and the thick ascending limb in the outer medulla use a lot of energy and receive little oxygen, so they die first in ischaemia. The proximal tubule is also the main target of toxins.
- Dead cells slough into the lumen, form casts and block the tubules; filtrate leaks back across damaged epithelium.
- Afferent arteriolar spasm lowers glomerular pressure, so GFR falls.
- Because the basement membrane often survives, tubular cells can regenerate. This is why ATN is reversible.
Muddy brown granular casts are the urine signature of ATN; red cell casts point to glomerulonephritis and white cell casts to interstitial nephritis or pyelonephritis.
Casts by site: red = glomerulus, white = interstitium, muddy brown = dead tubules, fatty = nephrotic leak.
Clinical course
| Phase | What happens |
|---|---|
| Initiation | The insult; urea and creatinine begin to rise |
| Maintenance (oliguric) | Oliguria common (non-oliguric if insult milder); hyperkalaemia, metabolic acidosis, fluid overload, uraemia; lasts about 1–3 weeks |
| Recovery (polyuric) | GFR returns before tubular reabsorption recovers: large urine volumes with loss of sodium, potassium and water (risk of hypokalaemia, dehydration) |
Recovery usually takes 7–21 days and is delayed by continuing sepsis.
Aminoglycoside and contrast ATN are often non-oliguric: creatinine rises while urine output is maintained. Non-oliguric AKI has a better outcome than oliguric AKI.
Diagnosis
- Urine microscopy: muddy brown granular casts and renal tubular epithelial cells and casts.
- Urine indices: tubules cannot conserve sodium or concentrate urine.
- Urine sodium >20 mmol/L.
- FENa >1% (often >2%).
- Urine osmolality <350 mOsm/kg; specific gravity about 1.010 (isosthenuria).
- Dipstick: little protein or blood (unlike glomerulonephritis).
- Bloods: rising urea and creatinine, high potassium, low bicarbonate, high phosphate.
- Ultrasound: normal-sized, unobstructed kidneys.
- Biopsy is rarely needed; it is done only if recovery is unusually slow or another cause is suspected.
Urine Na 40 mmol/L, plasma Na 135 mmol/L
Urine creatinine 4 mmol/L, plasma creatinine 0.4 mmol/L (400 µmol/L)
FENa = (40 × 0.4) ÷ (135 × 4) × 100 = 3.0% → above 1% → intrinsic (ATN)
Management
There is no drug that reverses ATN. Treatment is supportive until the tubules regrow.
- Restore circulating volume and BP; then avoid overload. Daily intake = urine output + other losses + about 500 mL.
- Stop nephrotoxins; adjust all renally cleared drugs; monitor gentamicin and vancomycin levels.
- Treat sepsis.
- Manage hyperkalaemia (calcium gluconate, insulin–glucose, binders), acidosis and fluid overload.
- Nutrition by mouth or nasogastric tube; restrict potassium and salt.
- Dialysis or haemofiltration for refractory hyperkalaemia, acidosis, overload, uraemic complications (AEIOU).
- In the polyuric phase, replace water, sodium and potassium; check electrolytes daily.
Mannitol, furosemide and "renal-dose" dopamine do not prevent or shorten ATN. Furosemide may be used only to manage fluid overload.
Special causes worth knowing
Rhabdomyolysis (crush syndrome)
- Causes: trauma and crush injury, compartment syndrome, extreme exertion, status epilepticus, prolonged immobility, statins, snake venom, malaria.
- Myoglobin is directly toxic to tubules and forms casts.
- Findings: massively raised CK, high potassium, phosphate and urate, low calcium early, dark (cola) urine; dipstick positive for blood but no red cells on microscopy.
- Treatment: early, aggressive IV fluids; consider sodium bicarbonate to alkalinise urine; look for compartment syndrome (fasciotomy).
Contrast-induced nephropathy
- Iodinated contrast causes renal vasoconstriction and direct tubular toxicity; it is dose-dependent and worst with large-volume angiography.
- Risk factors: CKD, hypovolaemia, heart failure, diabetic nephropathy, nephrotoxins (NSAIDs, ACE inhibitors), myeloma. Diabetes without kidney disease is not itself a risk factor.
- Prevention: IV hydration (0.9% saline or isotonic bicarbonate before and after), the smallest dose of low- or iso-osmolar contrast, stop nephrotoxins. N-acetylcysteine is of doubtful benefit; prophylactic dialysis does not help.
- Metformin should be held around contrast in renal impairment because of lactic acidosis risk.
Tumour lysis syndrome
- After chemotherapy for leukaemia or lymphoma (e.g. Burkitt): high urate, potassium and phosphate, low calcium; uric acid crystals block tubules.
- Prevent with IV hydration and allopurinol (blocks urate formation) or rasburicase (converts urate to soluble allantoin).
Haemoglobinuria: massive intravascular haemolysis (falciparum malaria "blackwater fever", G6PD crisis, transfusion reaction) causes ATN in the same way.
Acute cortical necrosis: severe, prolonged ischaemia (often obstetric: abruption, septic abortion; or HUS) kills the cortex itself. Unlike ATN, it is often irreversible.
Acute interstitial nephritis (allergic interstitial nephritis)
Aetiology
| Cause | Examples |
|---|---|
| Drugs (about 70%) | Penicillins (methicillin classically), cephalosporins, ciprofloxacin, sulphonamides, rifampicin, erythromycin; NSAIDs; proton pump inhibitors; diuretics (furosemide, thiazides); allopurinol, phenytoin, carbamazepine, cimetidine, valproate |
| Infection (about 15%) | Acute pyelonephritis, leptospirosis, Legionella, streptococci, hantavirus, EBV, CMV, HIV, polyoma (BK) virus in transplants |
| Systemic disease | Sarcoidosis (granulomatous), SLE, Sjögren syndrome, IgG4-related disease |
| TINU | Tubulointerstitial nephritis with uveitis, mainly in young people |
It is a type IV (T-cell) hypersensitivity reaction, not dose-related. It usually appears days to weeks after starting the drug (sooner on re-exposure). With NSAIDs it may come months later.
Clinical features
- Often asymptomatic, found as a rising creatinine.
- Classic triad: fever, skin rash and arthralgia (present in only a minority together).
- Oliguric or non-oliguric AKI; sometimes flank pain from swollen kidneys.
Specific lab findings
| Test | Finding |
|---|---|
| Blood count | Eosinophilia |
| Urine dipstick | Leucocytes, mild (sub-nephrotic) proteinuria, microscopic haematuria |
| Urine microscopy | Sterile pyuria, white cell casts |
| Urine eosinophils | Eosinophiluria (supportive but neither sensitive nor specific) |
| Serum IgE | May be raised |
| Ultrasound | Normal or enlarged kidneys |
| Renal biopsy (gold standard) | Interstitial oedema and dense infiltrate of lymphocytes, plasma cells and eosinophils, with tubulitis; granulomas in drug or sarcoid cases |
A patient with AKI, rash and eosinophilia after starting penicillin, an NSAID or a PPI = acute interstitial nephritis.
White cell casts are found in AIN and in acute pyelonephritis. Culture separates them: in AIN the urine is sterile.
NSAIDs can cause AIN together with minimal change disease, so the patient may have nephrotic-range proteinuria as well as AKI.
Diagnosis
Clinical suspicion (new drug, rash, eosinophilia, sterile pyuria) plus exclusion of other causes. Biopsy confirms the diagnosis when it is unclear or before giving steroids.
Management
- Stop the offending drug (the most important step) and avoid the drug class in future.
- Corticosteroids: high-dose prednisolone (60 mg daily), tapered over weeks, may shorten recovery and reduce the need for dialysis, especially if started early.
- Treat infection-related AIN with the right antimicrobial.
- Supportive care and dialysis if needed.
- Most recover, but delay can leave interstitial fibrosis and CKD.
Comparison table
| Feature | Prerenal | ATN | AIN |
|---|---|---|---|
| History | Fluid loss, shock | Prolonged shock, toxins | New drug |
| Fever, rash, eosinophilia | No | No | Yes |
| Urine sediment | Hyaline casts | Muddy brown granular casts | White cells, white cell casts, eosinophils |
| Urine Na / FENa | <20 / <1% | >20 / >1% | >20 / >1% |
| Response to fluids | Yes | No | No |
| Specific treatment | Fluids | Supportive | Stop drug, steroids |
Chronic interstitial nephritis (for contrast)
Long-term analgesic use (especially combinations), lithium, lead, reflux, sickle disease, diabetes and myeloma cause chronic tubulointerstitial disease. Papillary necrosis (analgesics, diabetes, sickle cell disease, severe pyelonephritis) presents with haematuria and loin pain and may shed papillae that block the ureter.
Expect: the commonest cause of intrinsic AKI (ATN); muddy brown granular casts versus red cell casts and white cell casts; urine sodium, FENa and osmolality in ATN versus prerenal AKI; gentamicin and contrast as causes (often non-oliguric); risk factors and prevention of contrast nephropathy; rhabdomyolysis (high CK, dipstick blood without red cells, fluids); tumour lysis prevention; the polyuric recovery phase and hypokalaemia; drug culprits of AIN (penicillins, NSAIDs, PPIs), its fever–rash–eosinophilia picture, eosinophiluria and treatment by stopping the drug and giving steroids.
Quick revision
- ATN: 80–90% of intrinsic AKI; ischaemic or toxic.
- Muddy brown granular casts; urine Na >20; FENa >1%; osmolality <350.
- Phases: initiation → oliguric maintenance → polyuric recovery (watch K+ and water loss).
- Gentamicin ATN: non-oliguric, after several days of use; check levels.
- Rhabdomyolysis: CK very high, blood on dipstick without red cells; aggressive fluids.
- Contrast: hydrate, minimise dose, low-osmolar agent, hold metformin and NSAIDs.
- AIN: drugs (penicillins, NSAIDs, PPIs); fever, rash, eosinophilia; sterile pyuria, white cell casts, eosinophiluria.
- AIN treatment: stop the drug, prednisolone; biopsy is the gold standard.
Written by The House Job from standard references (Kumar and Clark's Clinical Medicine; Fundamentals of Pathology).
FAQ
Why can ATN recover while cortical necrosis does not?
In ATN the tubular basement membrane usually survives and the tubular cells can regrow on it; in cortical necrosis whole glomeruli and tubules die and heal by scarring.
Which drugs most commonly cause acute interstitial nephritis?
Penicillins and other antibiotics, NSAIDs and proton pump inhibitors are the classic culprits.
Are urine eosinophils needed to diagnose interstitial nephritis?
No. They support the diagnosis but are often absent and can occur in other conditions; renal biopsy is the definitive test.
Why does the patient pass so much urine during recovery from ATN?
Filtration recovers before the regenerating tubules can reabsorb salt and water properly, so a temporary salt- and water-losing diuresis occurs.