Etiology

Intrinsic acute kidney injury

Intrinsic causes include any condition that leads to severe direct kidney damage (∼ 35% of cases of AKI).

• Acute tubular necrosis (causes ∼ 85% of intrinsic AKIs)
  • Ischemia: e.g., due to prolonged hypotension
  • Nephrotoxic drugs: e.g., radiographic contrast agents, aminoglycosides, cisplatin, methotrexate, ethylene glycol, amphotericin B
  • Endogenous toxins: e.g., hemoglobin in intravascular hemolysis, myoglobin in rhabdomyolysis, uric acid in TLS, Bence-Jones protein light chains in multiple myeloma
• Acute interstitial nephritis
  • Medication: e.g., antibiotics , phenytoin, interferon, PPIs, NSAIDs, cyclosporine
  • Infection
    • Bacterial: e.g., Legionella spp., Streptococcus spp.
    • Fungi: Candida, Histoplasma
    • Viral: e.g., hepatitis C virus, cytomegalovirus, HIV
  • Infiltrative diseases: e.g., sarcoidosis, amyloidosis
• Vascular diseases
  • Hemolytic uremic syndrome (HUS)
  • Thrombotic thrombocytopenic purpura (TTP)
  • Hypertensive emergency
  • Vasculitis, scleroderma renal crisis
  • Renal vein thromboses, renal atheroemboli, renal infarction
• Glomerulonephritis:e.g., rapidly progressive glomerulonephritis

Pathophysiology

Prerenal

• Decreased blood supply to kidneys (due to hypovolemia, hypotension, or renal vasoconstriction) → failure of renal vascular autoregulation to maintain renal perfusion → decreased GFR → activation of renin-angiotensin system → increased aldosterone release → increased reabsorption of Na⁺, H₂O → increased Urine osmolality → secretion of antidiuretic hormone → increased reabsorption of H₂O and urea
• Creatinine is still secreted in the proximal tubules, so the blood BUN:creatinine ratio increases.

Intrinsic

• Damage to a vascular or tubular component of the nephron → necrosis or apoptosis of tubular cells → decreased reabsorption capacity of electrolytes (e.g., Na⁺), water, and/or urea (depending on the location of injury along the tubular system) → increased Na⁺ and H₂O in the urine → decreased Urine osmolality

Postrenal

Four phases of AKI

1. Initiating event (kidney injury) (Duration: Hours to days)
   • Symptoms of the underlying illness causing AKI may be present.
2. Oliguric or anuric phase (maintenance phase) (Duration: 1-3 weeks)
   • Progressive deterioration of kidney function
     • Reduced urine production (oliguria), < 50 ml/24 hrs = anuria
     • Increased retention of urea and creatinine (azotemia)
   • Complications: fluid retention (pulmonary edema), hyperkalemia, metabolic acidosis, uremia, lethargy, asterixis
3. Polyuric/diuretic phase (Duration: ~ 2 weeks)
   • Glomerular filtration returns to normal, which increases urine production (polyuria), while tubular reabsorption remains disturbed.
   • Complications: loss of electrolytes and water (dehydration, hyponatremia, and hypokalemia)
4. Recovery phase (Duration: Months to years)
   • Kidney function and urine production normalize.

Clinical features

Subtypes and variants

Acute tubular necrosis

• Epidemiology: causes ∼ 85% of intrinsic AKIs
• Location
  • The straight segment of the proximal tubule and the straight segment of the distal tubule (i.e., the thick ascending limb) are particularly susceptible to ischemic damage.
    • Blood flow in the renal medulla is relatively low compared to that in the renal cortex.
      • Facilitates the development of an osmolality gradient that allows for effective urine concentration
      • Causes medullary vulnerability to hypoxia when renal blood flow is decreased (renal ischemia)
  • The convoluted segment of the proximal tubule is particularly susceptible to damage from toxins (but can also damage from ischemia).
    • First encounters toxins
  • Descending and ascending limbs are not, as their function is primarily passive.
• Etiology
  • Ischemic: Injury occurs secondary to decreased renal blood flow.
    • Severe hypotension, especially in the context of shock: hypovolemic (e.g., hemorrhage, severe dehydration), septic, cardiogenic (e.g., heart failure), or neurogenic shock
    • Cholesterol embolism (atheroemboli)
  • Toxic: Injury occurs directly due to nephrotoxic substances.
    • Contrast-induced nephropathy
    • Medication: aminoglycosides, cisplatin, amphotericin, lead, ethylene glycol
    • Pigment nephropathy
      • Myoglobinuria due to rhabdomyolysis (crush syndrome)
      • Hemoglobinuria associated with hemolysis
• Pathophysiology: necrotic proximal tubular cells fall into the tubular lumen → debris obstructs tubules → decreased GFR → sequence of pathophysiological events similar to prerenal failure
• Diagnostic

Diagnostics

Urine sediment

• Prerenal: hyaline casts due to concentrated urine in the setting of low renal perfusion
• Intrinsic: renal tubular epithelial cells or granular, muddy brown, or pigmented casts
• Postrenal: none

Treatment