Acute Tubular Injury

Acute tubular injury is damage to the renal tubular epithelium, caused by ischaemia, sepsis or nephrotoxins, that reduces glomerular filtration. It is the most common cause of intrinsic acute kidney injury in hospitalised patients, and the clinical syndrome is commonly called acute tubular necrosis, although frank necrosis is often limited and many cells show sublethal injury such as brush border loss, vacuolation, loss of polarity and cast formation.

The proximal straight tubule (S3 segment) and the medullary thick ascending limb are most vulnerable because of high oxygen consumption and low oxygen tension in the outer medulla.

Mechanisms:

• ATP depletion, oxidative stress and mitochondrial injury in tubular epithelial cells
• Sloughed cells and Tamm-Horsfall protein forming obstructing casts, raising intratubular pressure
• Backleak of filtrate through damaged epithelium
• Tubuloglomerular feedback with afferent vasoconstriction
• Inflammation and endothelial injury

Course:

• Initiation: hours to days, injury reversible if perfusion is restored
• Extension: ongoing hypoxia and inflammation
• Maintenance: stable low GFR for 1 to 2 weeks (oliguric or non-oliguric)
• Recovery: tubular regeneration, then polyuria; function returns over 1 to 3 weeks, with a minority progressing to chronic kidney disease

• Oliguria (below 400 mL daily) in 50% of cases; non-oliguric injury is common, especially with aminoglycosides
• Features of the cause: shock, sepsis, surgery, contrast, drugs, rhabdomyolysis
• Volume overload, hyperkalaemia, metabolic acidosis, hyperphosphataemia, hypocalcaemia, uraemia
• Polyuric recovery phase with risks of hypokalaemia, hypomagnesaemia and volume depletion
• No haematuria or significant proteinuria in uncomplicated cases

Red flags: potassium above 6.5 mmol/L, pH below 7.15, pulmonary oedema, uraemic pericarditis or encephalopathy, anuria (complete obstruction or cortical necrosis), failure to recover by 3 weeks.

• Creatinine, urea, electrolytes, bicarbonate, phosphate, calcium, creatine kinase, lactate
• Urinalysis and microscopy: muddy brown granular casts and tubular epithelial cells (sensitive and specific); a cast score improves diagnostic accuracy
• Urine indices: fractional excretion of sodium above 2%, urine sodium above 40 mmol/L, urine osmolality below 350 mOsm/kg, fractional excretion of urea above 50% (indices are unreliable after diuretics or in sepsis)
• Failure to improve within 48 to 72 hours of restored volume and perfusion confirms intrinsic injury
• Renal ultrasound: normal or slightly enlarged kidneys, to exclude obstruction
• Urinary biomarkers where available: NGAL, TIMP-2 multiplied by IGFBP7 above 2.0 (ng/mL)2/1000, indicating high risk
• Biopsy if features suggest another diagnosis (haematuria, proteinuria above 1 g daily, rash, systemic disease) or recovery is delayed beyond 3 weeks

Differentials: prerenal azotaemia, acute interstitial nephritis, glomerulonephritis, thrombotic microangiopathy, obstruction, cortical necrosis.

There is no specific therapy that reverses established injury; the aim is to remove the insult and support the patient until recovery.

Supportive

• Optimise haemodynamics: mean arterial pressure at least 65 mmHg, euvolaemia, adequate oxygen delivery (haemoglobin at least 70 g/L).
• Stop nephrotoxins; withhold ACE inhibitors, angiotensin receptor blockers, NSAIDs and metformin; adjust renally cleared drugs.
• Loop diuretic only for overload: furosemide 40 to 80 mg intravenously, titrated to effect; do not use to convert oliguria in the hope of improving outcome. Dopamine, mannitol and fenoldopam have no benefit.
• Avoid fluid overload: net positive balance of 10% of body weight or more is associated with higher mortality.
• Nutrition: energy 20 to 30 kcal/kg daily, protein 0.8 to 1.0 g/kg daily without renal replacement, 1.0 to 1.5 g/kg daily on renal replacement; restrict potassium and phosphate if elevated.
• Hyperkalaemia: calcium gluconate 10% 10 mL intravenously, insulin 10 units with glucose 25 g, salbutamol 10 to 20 mg nebulised, sodium zirconium cyclosilicate 10 g three times daily for up to 48 hours.
• Acidosis: sodium bicarbonate 500 mg to 1 g orally two to three times daily; intravenous 8.4% sodium bicarbonate 50 to 100 mmol when pH is below 7.1 while preparing renal replacement.
• Hyperphosphataemia: calcium carbonate 500 mg with meals or sevelamer 800 mg three times daily.

Renal replacement therapy for refractory hyperkalaemia, pH below 7.15, overload unresponsive to diuretics, uraemic complications (pericarditis, encephalopathy, bleeding) or dialysable toxins. Early initiation without these indications is not beneficial. Haemodialysis 3 to 4 hours daily or on alternate days, or continuous therapy at 20 to 25 mL/kg/h in unstable patients.

Recovery phase. Replace urinary losses with oral fluids or 0.45% saline; monitor potassium, magnesium and phosphate; avoid over treating polyuria.

Follow up. Creatinine, eGFR and albumin:creatinine ratio at 3 months and annually for patients with severe injury or incomplete recovery; blood pressure control; avoid nephrotoxins.

Refer to nephrology if no recovery by day 7 to 14, when renal replacement is considered, or when the cause is uncertain.