Acute Tubular Necrosis for ABIM

Acute Tubular Necrosis for the American Board of Internal Medicine Exam

Acute tubular necrosis (ATN) is a form of acute kidney injury (AKI) characterized by damage to the renal tubular epithelial cells, leading to acute renal dysfunction. It is the most common cause of AKI in hospitalized patients and results from ischemic or nephrotoxic insults to the kidneys.

Ischemic Acute Tubular Necrosis:
Caused by prolonged or severe reductions in renal perfusion, leading to tubular cell injury due to hypoxia. This can occur in conditions such as:
Septic Shock: Severe infections causing systemic vasodilation and hypotension, reducing renal blood flow.
Hypovolemic Shock: Severe dehydration, hemorrhage, or fluid losses from burns or gastrointestinal causes.
Cardiogenic Shock: Reduced cardiac output in heart failure or myocardial infarction.
Surgical Complications: Major surgeries, particularly involving cardiopulmonary bypass, which can cause ischemic insults to the kidneys.

Nephrotoxic Acute Tubular Necrosis:
Results from direct tubular damage by toxic substances, including:
Medications: Aminoglycosides, amphotericin B, cisplatin, radiocontrast agents, and nonsteroidal anti-inflammatory drugs (NSAIDs).
Endogenous Toxins: Myoglobin (from rhabdomyolysis), hemoglobin (from hemolysis), uric acid (tumor lysis syndrome), and light chains (multiple myeloma).
Exogenous Toxins: Heavy metals (e.g., lead, mercury), contrast agents, and certain poisons.

Tubular Cell Injury:
In ATN, ischemic or toxic injury leads to the loss of tubular epithelial cell integrity. Cells lose their polarity, leading to impaired sodium and water reabsorption. Damaged cells slough off into the tubular lumen, causing obstruction and further reducing the glomerular filtration rate (GFR).
Intrarenal Vasoconstriction:
Ischemia or nephrotoxic agents cause intrarenal vasoconstriction by activating the renin-angiotensin-aldosterone system (RAAS), the sympathetic nervous system, and endothelin release. This decreases renal blood flow and exacerbates hypoxia in the tubules.
Backleak of Filtrate:
With tubular damage, filtrate leaks back from the tubules into the interstitium, further impairing kidney function. The combination of tubular obstruction, cell injury, and backleak leads to a significant reduction in GFR.

Oliguria or Anuria:
A reduction in urine output (oliguria <400 mL/day) is a common finding in ATN, though non-oliguric ATN may occur. Anuria (<50 mL/day) suggests severe injury.
Signs of Volume Overload:
Due to impaired kidney function, patients may present with peripheral edema, pulmonary edema, hypertension, and jugular venous distention.
Electrolyte Abnormalities:
Hyperkalemia: Due to impaired renal potassium excretion.
Metabolic Acidosis: Accumulation of acid from reduced excretion of hydrogen ions and decreased bicarbonate reabsorption.
Hyperphosphatemia: Reduced phosphate excretion.
Hyponatremia: From fluid overload or impaired water excretion.
Uremia:
Symptoms of severe renal failure, including nausea, vomiting, confusion, asterixis, and, in severe cases, pericarditis, can develop if ATN progresses without treatment.

Initiation Phase:
The initial insult (ischemia or nephrotoxicity) leads to tubular injury, with a decline in GFR and urine output. This phase lasts hours to days.
Maintenance Phase:
Sustained reduction in GFR, oliguria or anuria, electrolyte disturbances, and uremia. This phase typically lasts 1 to 3 weeks.
Recovery Phase:
As tubular cells regenerate, GFR increases, and urine output improves. Polyuria may occur, potentially leading to dehydration or electrolyte imbalances. Full recovery may take weeks to months.

History and Clinical Presentation:
Important factors include recent hypotension, shock, nephrotoxic drug use, or exposure to toxins. A history of muscle injury or hemolysis may suggest rhabdomyolysis or hemoglobinuria as the cause.
Urinalysis:
Granular ("muddy brown") casts: Pathognomonic for ATN, formed by necrotic tubular cells.
Epithelial Cell Casts: Indicative of tubular cell injury.
Low Specific Gravity: Reflects the kidney’s inability to concentrate urine.

Blood Tests:
Elevated serum creatinine and blood urea nitrogen (BUN) levels, which indicate decreased GFR.
Hyperkalemia, hyperphosphatemia, and metabolic acidosis.
Fractional Excretion of Sodium (FeNa):
FeNa >2% is typical in ATN, reflecting impaired sodium reabsorption.
Imaging:
Renal ultrasound may show normal kidney size and structure but can help rule out obstruction.

Supportive Care:
Volume Management: Careful management of fluid balance is essential. Hypovolemia should be corrected with isotonic fluids, while hypervolemia may require diuretics (e.g., furosemide) or dialysis.
Electrolyte Management: Hyperkalemia, acidosis, and hyperphosphatemia should be addressed. Potassium-lowering therapies include diuretics, calcium gluconate (for cardioprotection), insulin with glucose, and sodium polystyrene sulfonate.
Nutrition: Adequate caloric intake is important, but potassium, phosphorus, and fluid restrictions are often necessary.
Removal of Nephrotoxic Agents:
Discontinue nephrotoxic drugs (e.g., aminoglycosides, NSAIDs). Radiocontrast-induced ATN can be prevented with intravenous hydration and possibly N-acetylcysteine.
Renal Replacement Therapy (RRT):
Indications for dialysis include refractory hyperkalemia, severe metabolic acidosis, volume overload unresponsive to diuretics, and uremic complications (e.g., pericarditis, encephalopathy). RRT can be delivered as intermittent hemodialysis or continuous renal replacement therapy (CRRT), particularly in critically ill patients.

Recovery:
Most patients recover renal function if the underlying cause of ATN is addressed and adequate supportive care is provided. However, in severe cases or those associated with prolonged ischemia or extensive nephrotoxic exposure, some patients may develop chronic kidney disease (CKD).
Mortality:
Mortality in ATN depends on the underlying cause and the presence of comorbid conditions. Mortality rates are higher in critically ill patients, particularly those with sepsis or multi-organ failure.

Key Points

Acute tubular necrosis is the most common cause of acute kidney injury in hospitalized patients and is due to ischemic or nephrotoxic insults.
Key causes include hypotension (shock), sepsis, nephrotoxic drugs (e.g., aminoglycosides, radiocontrast), and endogenous toxins (e.g., myoglobin in rhabdomyolysis).
Clinically, ATN presents with oliguria or anuria, volume overload, hyperkalemia, metabolic acidosis, and uremia.
Diagnosis is supported by the presence of granular ("muddy brown") casts in the urine, elevated creatinine, and a FeNa >2%.
Management involves supportive care, correction of electrolyte imbalances, and removal of nephrotoxic agents. Renal replacement therapy may be necessary in severe cases.
Recovery is possible with appropriate care, but mortality is high in critically ill patients.