1. What is rhabdomyolysis?

Rhabdomyolysis is a condition characterized by muscle injury leading to myocyte necrosis and the release of intracellular contents into the circulation. The term is usually applied when acute kidney injury (AKI) results from the muscle injury, but AKI does not always occur, even following severe muscle injury.

2. How does rhabdomyolysis cause AKI?

Rhabdomyolysis causes AKI through a combination of kidney vasoconstriction, direct oxidant injury, and tubular obstruction.

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  Kidney vasoconstriction: Muscle damage causes interstitial edema at the site of injury. The fluid shift from the intravascular space leads to activation of the renin-angiotensin-aldosterone system (RAAS) and sympathetic nervous system. Vasoconstrictor mediators including endothelin-1, thromboxane-A2, tumor necrosis factor-α, and F2-isoprostanes are also upregulated. The binding of nitric oxide to myoglobin may further contribute to vasoconstriction. The net result is early and prolonged kidney vasoconstriction, which may manifest as oliguria with a low urine sodium concentration prior to progression to acute tubular injury.

  
  
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  Oxidant injury: Free iron released from myoglobin may lead to the formation of oxygen-free radicals as ferrous iron is converted to ferric iron (Fenton reaction). Myoglobin itself has been found to be directly toxic to tubular cells by causing lipid peroxidation of tubular cellular membranes.

  
  
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  Tubular obstruction: Under normal conditions, small amounts of myoglobin are filtered, then endocytosed and metabolized by proximal tubular cells. When myoglobin levels in the tubules exceed the absorptive capacity of the proximal tubular cells, myoglobin may complex with Tamm-Horsfall protein (THP) in the distal nephron to form casts leading to intra-tubular obstruction. An acidic environment (urine pH < 6.5) favors the formation of these complexes.

3. What are some of the common causes of rhabdomyolysis?

Rhabdomyolysis may be caused by a wide range of conditions ( Table 12.1 ). Trauma or direct muscle injury is the most common cause and should be considered in any patient who presents with multiple injuries/trauma.

4. How does alcohol intoxication contribute to rhabdomyolysis?

Alcohol is directly toxic to myocytes (and also proximal tubular cells). Alcoholics are often phosphorus, magnesium, and potassium depleted:

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  Hypokalemia impairs the ability of muscle arterioles to vasodilate, promoting ischemic muscle injury.

  
  
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  Hypomagnesemia can worsen concurrent hypokalemia.

  
  
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  Phosphorus deficiency may result from poor diet, the use of phosphorus-binding medications used for gastrointestinal upset, and urinary phosphorus wasting. Phosphorus is critical in the production of adenosine triphosphate (ATP) and multiple cellular enzymes. Furthermore, alcohol intoxication leading to altered mental status may result in compressive injuries from trauma or to muscle injury from prolonged motionlessness in unconscious individuals.

5. Do statins cause rhabdomyolysis?

Yes. 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) are commonly associated with mild myositis, and, rarely, can progress to severe rhabdomyolysis. This may be more common in those who have other risk factors or with drug–drug interactions that increase statin levels (e.g., calcineurin inhibitors, macrolide antibiotics, antifungals). It has been suggested that statins cause muscle cell damage by inhibiting coenzyme Q and the electron transport chain, interfering with ATP generation. Statin-induced myositis can occur within days of starting the drug but has been described years later. Muscle pain is a common reason to discontinue statin use.

6. Can you get rhabdomyolysis from excessive exercise?

Yes. Exercise-induced muscle injury typically occurs in cases of vigorous exercise, such as in marathon runners or weight lifters. Strenuous exercise may cause thermal injury to the muscle cells combined with ATP depletion. Hypokalemia and volume depletion may also play a role. High temperature and humidity conditions put athletes at increased risk for exercise-induced rhabdomyolysis. Inherited disorders of muscle metabolism may be present in those with recurrent episodes of exercise-induced rhabdomyolysis.

7. Why do some people develop recurrent episodes of rhabdomyolysis?

Behavioral issues should be explored in patients with recurrent rhabdomyolysis. Often recurrent episodes of rhabdomyolysis are linked to alcohol and substance abuse. Toxicology screening can be useful to identify drug or alcohol ingestions as a cause of recurrent muscle injury. The athlete who is abusing diuretics or laxatives is another example. In the latter setting, the combination of strenuous exercise with concurrent diuretic- or laxative-induced hypokalemia can lead to muscle injury.

Less frequently, patients with recurrent episodes of rhabdomyolysis have underlying inherited disorders of cell metabolism (see Table 12.1). These disorders impair cellular energetics as a result of abnormalities in carbohydrate or lipid metabolism. Usually, patients with inherited metabolic myopathies present in childhood, but adult presentation also occurs. The most common inherited disorder causing rhabdomyolysis is carnitine palmitoyltransferase deficiency. Often these inherited disorders of metabolism present with a concurrent precipitating factor, such as strenuous exercise or infection.