4- ACUTE TUBULAR NECROSIS

• Most common cause of hospital-acquired acute kidney injury


  Damage and destruction of renal tubular epithelial cells
• Features of acute tubular necrosis (ATN)


  • BUN:creatinineratio=10:1
  • Urineosmolality=300(isosthenuria)
  • UrineNa>40
  • FENa>2%
  • Specific gravity 1010
  • Urinalysis and microscopy show pigmented granulation (muddy brown) casts and tubular epithelial cells
• Management of acute tubular necrosis


  1. Supportive

  2. Dialysis
• Recovery from acute tubular necrosis depends on


  • Severity
  • Co morbidities
  • Oliguric vs non-oliguric renal failure (Non-oliguric has better prognosis)
• Duration of acute tubular necrosis is 1-4 weeks
• Ischemic ATN


  Caused by prolonged pre-renal AKI, unlike Pre-renal AKI, GFR doesn't improve with restoration of renal blood flow
• Pathophysiology of ischemic ATN

  1. Renalvasoconstriction

  2. Tubular obstruction from sloughed cellular material

  3. Back leak of glomerular ultrafiltrate across the exposed tubular basement membrane
• Types of ischemic ATN


  • With hypotension (blood pressure less than 90/60)
  • Without hypotension (occurs when normal adaptive responses of the kidney to maintain renal perfusion (autoregulation) are impaired)
• Risk factors for ischemic ATN without hypotension


  • Old age
  • Atherosclerotic or renovascular disease
  • Hypertension
  • DM
  • CKD
  • Multiple myeloma
  • Medications (NSAID, ARBs, ACEI)
• Prognosis of ischemic ATN


  Usually reversible unless severe prolonged ischemia, when irreversible injury may occur
• Drug induced ATN


  Caused by the cumulative effect of the drug (after at least 5 days), not after the first dose. There is no fever or rash.
• Risk factors for drug induced ATN


  • Older age
  • Decreased effective blood volume
  • Chronic kidney disease
  • Concomitant nephrotoxic exposure
• Drugs causing ATN


  • NSAIDs
  • Aminoglycosides
  • Cisplatin, carboplatin
  • Amphotericin B
• Pathophysiology of drug induced ATN


  1. Intra-renal vasoconstriction ex: calcineurin inhibitor

  2. Direct toxic effect to proximal tubular epithelial cells ex: aminoglycosides (gentamycin), anti-cancer agents (Cisplatin, Carboplatin)

  3. Osmotic nephrosis: vacuolization and swelling of renal proximal tubular cells, ex: mannitol, immunoglobulins

  4. NSAIDs: disrupt the compensatory vasodilation response of renal prostaglandins to vasoconstrictor hormones via their inhibition of COX-1 and COX-2
• Drugs need 5 to 10 days to cause nephrotoxicity (unlike contrast)
• Differentiate from AIN: drug induced ATN occurs from the cumulative effect of the drug (after at least 5 days), not after the first dose. There is no fever or rash.
• Treatment of drug induced ATN

  Identify and stop the drug causing ATN
• Pigment Nephropathy


  Rhabdomyolysis: Myoglobinuria
• Causes of Rhabdomyolysis


  • Trauma to muscles or excessive exercise
  • Metabolic and electrolyte disorders
  • Endocrinopathies
  • Drugs/toxins, seizures
  • Hyper/hypothermia
  • Compartment syndrome
  • Infections
• Pathophysiology of Rhabdomyolysis


  1. Damage to muscles à release of myoglobin & K

  2. Intravascular volume depletion from fluid sequestration within damaged muscles à renal vasoconstriction à direct and ischemic tubular injury

  3. Tubular obstruction from intraluminal cast formation
• Lab findings in Rhabdomyolysis

  • Hyperkalemia
  • Hyperphosphatemia (released from myocytes)
  • Hyperuricemia (from high cell breakdown)
  • Hypocalcemia (myoglobin binds Ca)
  • Metabolic acidosis
  • Elevated CK, LDH, AST and ALT
• Management of Rhabdomyolysis


  1. Protect the heart from hyperkalemia. Do ECG, if signs of hyperkalemia à immediate Ca gluconate

  2. Generous IV fluid hydration, maintain urine output > 300 ml/hr

  3. Osmotic diuretics (mannitol)

  4. Correct the cause

  5. Dialysis
• Hemolysis: Hemoglobinuria


  Less common cause of pigment nephropathy than myoglobins
• Both myoglobinuria and hemoglobinuria can cause tea colored urine and urine dipstick +ve for blood
• Differentiating myoglobinuria and hemoglobinuria


  1. Microscopic examination: no RBCs seen if myoglobinuria (à do CK level)

  2. Hemoglobin produces a reddish-brown color in centrifuged serum and myoglobins does not discolor the serum
• Contrast Induced Nephropathy


  Most likely due to ATN related to vasoconstriction and cytotoxic effects from contrast, with contributions from prerenal factors or intratubular obstruction
• Pathogenesis of Contrast Induced Nephropathy


  Causes vasospasm of afferent arteriole à renal tubular dysfunction à tremendous reabsorption of NA and water à low urine Na and high osmolality
• Risk factors for Contrast Induced Nephropathy

  • Interventional coronary angiography in the setting of MI
  • eGFR <60 mL/min + albuminuria >300 mg/d, diabetes, or other comorbidities including heart failure, liver failure, or multiple myeloma
  • eGFR <45 mL/min even in the absence of proteinuria, diabetes, or comorbidities
  • Dose and type of contrast agent (low dose, low osmolality preferred)
• Clinical manifestations of Contrast Induced Nephropathy

  • A mild increase in creatinine within 24 to 48 hours after exposure (very fast onset ± immediate oliguria); Cr starts declining within 3-7 days
  • Classic findings of ATN: muddy brown granular and epithelial cell casts and free renal tubular epithelial cells (absence of these doesn't exclude CIN)
  • No evidence of glomerular disease (dysmorphic RBCs or RBC casts) or interstitial nephritis (WBCs or WBC casts)
  • Profoundly low urine Na, FENa <1%, BUN/Cr >20, Uosm >500 (in contrast to AKI due to other causes of ATN)
  • Protein excretion on presentation is absent or mild; However, many radiocontrast agents induce false-positive results (thus, the urine should not be tested for protein for at least 24 hours after a contrast study)
• Diagnosis of Contrast Induced Nephropathy


  Increase in serum Cr within 24 to 48 hours after contrast exposure, and the exclusion of other causes of AKI by urine analysis ± US
• Prevention of Contrast Induced Nephropathy


  1. For all at-risk patients, administer IV isotonic saline (unless contraindicated) prior to and continued for several hours after contrast administration. Saline hydration has the most proven benefit

  2. N-acetylcysteine & sodium bicarb have some benefit, but evidence is not as clear as saline hydration

  3. Withhold NSAIDs for 24 to 48 hours prior to the procedure; unproven data on withholding ACEI/ARBs and statins

  4. Use the lowest effective dose of contrast and avoid performing closely spaced studies (within 48 to 72 hours)
• Management of Contrast Induced Nephropathy


  1. The indications for dialysis are the same as in other forms of AKI

  2. In most cases, the Cr usually starts to decline within 3-7 days, and the patient returns to, or close to, baseline renal function
• Urinalysis


  • Normal or near normal in prerenal disease
  • Classic urinalysis in ATN reveals muddy brown granular, epithelial cell casts, free renal tubular epithelial cells
• FENa


  • Typically less than 1 percent in prerenal disease (indicative of sodium retention)
  • Above 2 percent in ATN
• Response to fluid repletion in patients who have evidence of volume depletion

  • Gold standard for the diagnosis of prerenal disease
  • Does not apply to prerenal disease due to heart failure (cardiorenal syndrome) or cirrhosis (hepatorenal syndrome)
• Complications of ATN


  • Rapid Hyperkalemia
  • Metabolic acidosis
  • Hypocalcemia
  • Hyperphosphatemia
  • Hypoalbuminemia
• Prevention of ATN


  • Recognizing high risk patients: major surgery (esp. cardiac & abdominal aortic aneurysm surgery), sepsis, marked hypovolemia, severe pancreatitis, cardiogenic or hemorrhagic shock
  • Optimizing volume status and maintaining hemodynamic stability
  • Avoiding nephrotoxins — Obvious nephrotoxins, such as aminoglycosides, amphotericin, radiocontrast agents, and NSAIDs
  • Procedure-related measures —Off-pump cardiopulmonary bypass surgery, Pulsatile perfusion via an intra-abdominal balloon pump
• Management of ATN


  1. Largely supportive optimize hemodynamic and IVF infusion

  2. Emergent dialysis in refractory acidemia refractory, hyperkalemia, intoxication (methanol, ethyl glycol), CHF with overload, uremia (pericarditis & encephalopathy)

  3. Diuretic/dopamine/mannitol have no benefit