Myoglobinuria

Myoglobinuria is usually the result of rhabdomyolysis or muscle destruction. Any process that interferes with the storage or use of energy by muscle cells can lead to myoglobinuria. The release of myoglobin from muscle cells is often associated with an increase in levels of creatine kinase (CK), aldolase, lactate dehydrogenase (LDH), serum glutamic-pyruvic transaminase (SGPT), and other enzymes. When excreted into the urine, myoglobin, a monomer containing a heme molecule similar to hemoglobin, can precipitate, causing tubular obstruction and acute kidney injury.

A clinician caring for a patient with crush injuries or other causes of muscle destruction must recognize the presence and severity of myoglobinuria and initiate aggressive hydration to prevent acute kidney injury.

The most common causes of myoglobinuria in adults are trauma, alcohol and drug abuse, usually in relation to muscle necrosis from prolonged immobilization and pressure by the body weight. Prolonged ethanol consumption and seizure activity, similar to excessive physical activity, can produce an imbalance between muscle energy consumption and production, resulting in muscle destruction. In children and adolescents, the most common causes of rhabdomyolysis and myoglobinuria are viral myositis, trauma, exertion, drug overdose,[1] seizures, metabolic disorders, and connective tissue disease.

Myoglobin is released from muscle tissue by cell destruction and alterations in the permeability of the skeletal muscle cell membrane.[2, 3, 4] Under normal conditions, the sodium potassium ATPase pump maintains a very low intracellular sodium content. A separate sodium-calcium channel then serves to pump additional sodium into the cell in exchange for calcium extrusion from the cell. In addition, most intracellular calcium is normally sequestered within organelles. Damage to muscle cells interferes with both mechanisms, leading to an increase in free ionized calcium in the cytoplasm. The high intracellular calcium activates numerous calcium-dependent enzymes that further break down the cell membrane, leading to the release of intracellular contents such as myoglobin and creatine kinase into the circulation. A model of the helical domains of myoglobin is shown in the image below.

Myoglobin is a dark-red, 17,8-kDa, monomeric heme protein that contains iron in its ferrous (Fe+2) form.[3] It is easily filtered by the glomerulus and is rapidly excreted into the urine. Plasma levels of myoglobin rapidly fall after its release. When large amounts of myoglobin enter the renal tubule lumen, it interacts with the Tamm-Horsfall protein and precipitates; this is a process favored by acidic urine. Tubule obstruction principally occurs at the level of the distal tubule. In addition, reactive oxygen species generated by damage to both muscle and kidney epithelial cells promote the oxidation of ferrous oxide to ferric oxide (Fe+3), thus generating a hydroxyl radical. Both the heme moieties and the free iron-driven hydroxyl radicals may be critical mediators of the direct tubule toxicity, which mainly occurs in the proximal tubule.

Thus, the precipitation of myoglobin in the renal tubules with secondary obstruction, tubular toxicity, or both constitutes the primary causes for acute kidney injury during myoglobinuria. A higher volume of urine flow and a higher urine alkalinity prevent myoglobin from precipitating as readily as it otherwise does.

Trauma and compression

Trauma is one of the most common cause of myoglobinuria. Patients who experience crush injuries, such as those that occur when individuals are buried after earthquakes, have rhabdomyolysis and myoglobinuria. Volume depletion from fluid sequestration in damaged tissues and poor fluid intake accentuate the possibility of acute renal insufficiency. Electric shock can cause enough muscle damage to precipitate myoglobinuria.

Exertion

Exertional myoglobinuria occurs in most athletes but rarely becomes symptomatic unless combined with poor training, inadequate oral intake, dehydration, and heat exhaustion. Trauma from repeated blows to the muscle always releases myoglobin into the system. The treatment is prevention, which includes plentiful fluid, limited exercise during particularly hot periods, and avoiding muscle trauma. Athletes have more myoglobin in their muscles than other individuals and are prone to symptoms when small amounts of muscle tissue are damaged.[5, 6]

Viral myositis

Viral infections from a wide variety of organisms can cause myositis and myoglobinuria. Viral myositis is one of the most common causes of rhabdomyolysis in children.[7] Influenza is the predominant viral agent associated with rhabdomyolysis. The patient usually presents with generalized weakness and myalgias, particularly in the back and proximal extremities. Children with influenza A and influenza B viral infections can present with tenderness in calves and lower extremities.[8]

Electrolyte disorders

Metabolic diseases, particularly those involving muscle metabolism, may be associated with myoglobinuria. Males are affected more often, and symptomatology is exacerbated by exercise and heat injuries. Potassium depletion has been particularly associated with myoglobinuria.

Toxins, drugs, and diet

Snakebites and other venoms can cause muscle necrosis and myoglobinuria.[9]

Some drugs predispose individuals to rhabdomyolysis, including AZT (used to treat acquired immunodeficiency syndrome [AIDS]) and lovastatin (used to treat hypercholesterolemia). However, statin-induced rhabdomyolysis is rare and occurs in less than 0.1% of all users.

Alcohol, cocaine, amphetamines, phencyclidine, ecstasy, and some dietary supplements can lead to myoglobinuria.[10]

Ingestion of ethylene glycol, isopropyl alcohol, and phencyclidine has been associated with myoglobinuria.

Overindulgence in quail can also cause myoglobinuria in some patients.

Infection or sepsis syndromes

Syndromes involving muscle destruction include gas gangrene, tetanus, Legionnaire disease, or shigellosis. Coxsackie viral infections with myositis may be the most common cause of mild myoglobinuria.

Endocrine disorders

Diabetic ketoacidosis, myxedema, and nonketotic hyperosmolar comas can disrupt muscle energy.

Malignant hyperthermia and high fevers

These may be contributors.

Hereditary myopathies

Hereditary myopathies, such as McArdle syndrome and muscular dystrophy, can precipitate myoglobinuria.

The differential diagnosis for myoglobinuria must include metabolic myopathies. This diverse and complex list of disorders is long, with new additions each year.

In general, patients with myopathies report exercise intolerance, muscle pain, and cramps rather than weakness. Patients with some types of muscular dystrophy or inflammatory myositis (eg, dermatomyositis, polymyositis) may present with progressive weakness.

Metabolic disorders

Patients with defects of carbohydrate metabolism (eg, myophosphorylase, phosphofructokinase, phosphohexoisomerase deficiency) have symptoms of easy fatigability or cramping induced by dynamic isometric exercise, such as heavy lifting, or prolonged exercise, such as swimming or running. Acute muscle breakdown can lead to myoglobinuria. These patients typically present after participating in high-intensity exercise, such as weight lifting.

Defects in lipid metabolism include carnitine deficiency, beta-oxidation enzyme deficiency, or disorders of fatty acid transport. Prolonged fasting or prolonged activity induces muscle pain and myoglobinuria. Fever, sepsis, and exposure to cold can also induce muscle fatigue in this set of disorders. These patients typically develop symptoms after prolonged low-intensity exercise, such as walking.

Patients with mitochondrial disorders (beta-oxidation disorders) usually present with static and progressive muscular weakness. Failure to thrive, floppy-baby syndrome, and generalized muscle weakness are present in most of these children. Patients usually present with chronic muscle cramping and weakness rather than episodic muscle cramping and weakness. Patients with some types of muscular dystrophy or inflammatory myositis may present with progressive weakness.

A case study reinforced the idea that myoglobinuria should be considered a manifestation of a primary sarcoglycanopathy, even as the only recognizable sign at the debut of the disease.[11]

Heat exhaustion and cold exposure

These conditions induce abnormal muscle metabolism by means of various mechanisms, including poor perfusion and decreased oxygenation, acidosis, rhabdomyolysis, or glucose and/or glycogen depletion.[12] Reye syndrome may also be included in this group. Patients with recurrent exercise-induced myoglobinuria may have defective carnitine palmitoyltransferase activity.[13]

Frequency

United States

The frequency of myoglobinuria varies with the incidence of natural disasters and environmental trauma. Epidemics of viral myositis may temporarily increase the incidence in local areas. In urban areas with a high incidence of drug and alcohol abuse, many patients with myoglobinuria may present to emergency departments. Hot weather increases the incidence of stress induced rhabdomyolysis, especially in young athletes.

International

Acute kidney injury due to rhabdomyolysis was first described by Bywaters and Beall during World War II; they noted the hypovolemic shock, dark urine, and kidney failure that developed in survivors from the rubbles of the London bombings. Crush injuries related to earthquakes and other natural disasters are the major cause of cases reported internationally. Any person dug from the rubble of such disasters should be considered to have rhabdomyolysis, myoglobinuria, and potential acute renal failure and, therefore, should be given rapid fluid resuscitation.

Race

Race is a factor only when natural disasters and economic shortfalls increase the rates of drug and alcohol abuse and the mortality rate among certain racial groups.

Sex

Myoglobinuria tends to affect males more than females because of the former group's predisposition to trauma and participation in strenuous physical exercise. Persons who exercise and have increased muscle mass have an increased intracellular myoglobin content.

Age

In a recent large retrospective review, the median age was 11 years.[14] The leading cause of rhabdomyolysis in the 0-9 year age range was viral myositis, whereas the leading diagnosis in the 9-18 year age range was trauma.

Patients with uncomplicated cases of myoglobinuria recover without sequelae.

Myoglobinuria causes little or no morbidity or mortality unless it is associated with the secondary complications of rhabdomyolysis, including hyperkalemia, hypocalcemia, and acute kidney injury.[2] However, when it is associated with severe rhabdomyolysis, myoglobinuria-induced acute renal failure is a potentially lethal complication.

In adults, rhabdomyolysis can be complicated by acute kidney injury in approximately 30% of patients,[15] with about 5% of those requiring hemodialytic support. In the pediatric age group, although previous small case series reported acute renal failure rates of 40-50%, a large retrospective review indicates that only about 5% of subjects with rhabdomyolysis develop acute kidney injury (defined as a serum creatinine level >97.5 percentile for age and gender).[14] Rhabdomyolysis accounts for or contributes to about 7% of all causes of acute kidney injury in the United States.[16] In both adults and children, the overall mortality rate of acute severe rhabdomyolysis is reported to be 7-8% and is primarily related to acute renal failure and multiorgan failure.

Patients who develop exercise-induced rhabdomyolysis need education in maintaining adequate fluid intake, in oral rehydration, and in pacing their exercise in hot weather or extreme conditions.

The classical triad of symptoms of rhabdomyolysis includes myalgia, muscle weakness, and dark urine. The typical history may include drug use, coma, trauma, or strenuous exercise. Patients who use diuretics and develop severe potassium deficiency may be predisposed to rhabdomyolysis.

Some patients may provide a history of viral illnesses, fever, convulsions, electric shock, burns, crush injuries, or trauma of any type. Patients may have a history of sepsis, especially sepsis that affects muscle tissue, such as gas gangrene. Others may give a history of participation in organized athletics during the summer or in strenuous exercise during athletic events, such as bicycle races or mountain climbing.

The use of some prescription drugs, such as azidothymidine (AZT) or lovastatin, or the ingestion of ethylene glycol may predispose individuals to myoglobinuria. Other drugs associated with myoglobinuria include heroin, codeine, barbiturates, amphetamines, licorice, diazepam, amphotericin-B, phencyclidine, and some dietary supplements.

Acute tumor lysis syndrome may be associated with myoglobinuria.

Snakebites, bites from recluse spiders, and multiple insect stings can cause muscle necrosis.

Ingestion of quail can precipitate myoglobinuria.

Autoimmune vesiculitis, such as dermatomyositis, may destroy muscle tissue.

Recurrent myoglobinuria was reported in a 14-year-old girl with Becker muscular dystrophy.[17]

Physical examination reveals generalized muscle weakness, often with painful muscle groups, trauma, and/or areas of ischemic pressure necrosis when the patient has laid down for extended periods.

Expect any patient with extensive trauma to have some myoglobinuria.

The volume status of the patient should be carefully and quickly determined because volume depletion necessitates rapid correction in order to prevent acute renal failure.

The most serious complication of myoglobinuria is acute renal failure.

Other complications can result from renal shutdown or from the intracellular products released into the system by rhabdomyolysis.

The most important laboratory test is measurement of creatine kinase (CK) levels to assess for rhabdomyolysis. Myoglobin is the first enzyme that increases, but it returns to normal levels within the first 24 hours after the onset of symptoms. This is because myoglobin is rapidly cleared from the serum into the urine. However, serum CK levels may remain elevated after serum and urine test results for myoglobin have become negative. Serum CK levels typically peak about 3 days after the onset of symptoms, and remain elevated for several days. Thus, although the detection of myoglobin in the serum is considered pathognomonic for rhabdomyolysis, the serum CK level is a more useful marker for the diagnosis and assessment of severity because of its delayed clearance from the plasma. A CK level of more than 1000 U/L is characteristically seen in patients with rhabdomyolysis.[4, 7]  Levels of other muscle enzymes, such as aldolase, lactate dehydrogenase (LDH), or aspartate aminotransferase (AST), may also be elevated.

Electrolyte abnormalities may cause or result from rhabdomyolysis, including hyperkalemia and hyperphosphatemia from the damaged muscle cells. Hypocalcemia may develop from the hyperphosphatemia or as result of calcium deposition in the damaged muscles. Uric acid values may be elevated, and metabolic acidosis may develop.

Acute renal insufficiency (elevated BUN and creatinine levels) is a consequence of severe myoglobinuria in which the globulin precipitates and blocks the urinary tubules. Creatinine levels may be elevated out of proportion to BUN levels due to excessive leak of creatine from damaged muscle cells. Alkalinization of the urine and increased urine flow facilitates myoglobin excretion.

Although both myoglobinuria and hemoglobinuria may cause a tea-colored appearance of the urine, and although both cause positive results on the urine dipstick for blood, myoglobinuria may be differentiated from hemoglobinuria by performing a series of simple tests.[18]  Myoglobinuria is brown, and often only a few RBCs are present in the urine. Hematuria produces a reddish sediment in spun urine samples. Red or brown urine with a negative dipstick result for blood indicates a dye in the urine. Hemoglobin produces a reddish or brown coloration in the spun serum, whereas myoglobin does not discolor the serum. CK levels are markedly elevated in myoglobinuria. Results of radioimmunoassays for the specific measurement of serum or urine myoglobin can be delayed by several days and are not useful in immediate diagnosis and treatment.

Other electrolytic abnormalities associated with rhabdomyolysis result from the extrusion of intracellular contents into the plasma and include hyperkalemia, hypercalcemia or hypocalcemia, hyperphosphatemia, and hyperuricemia.

Imaging studies are rarely of use in this metabolic disorder.

Intravenous (IV) pyelograms may reveal a dense renogram, but most are normal.

Tests for sickle cell disease (eg, sickle preparations, hemoglobin electrophoresis) may reveal patients who are prone to rhabdomyolysis. A study by Nelson et al found that sickle cell trait was associated with a higher risk of exertional rhabdomyolysis (similar to the risk associated with tobacco use) among 47,944 soldiers who had undergone testing for hemoglobin AS.[19]

A drug and metabolic screen of the urine, blood, or both may indicate illicit drug use.

Complements and antinuclear antibodies may help in differentiating autoimmune polymyositis from other conditions.

In patients with acute renal insufficiency due to myoglobinuria, fractional excretion of sodium (FENa) is less than 1%, probably because tubular obstruction and damage is the cause of oliguria rather than glomerular damage.

Muscle biopsy may be of use when a metabolic myopathy is suspected.

All patients with suspected myoglobinuria or rhabdomyolysis should be admitted for intravenous (IV) hydration and management of complications. A creatine kinase (CK) level of more than 5000 U/L is considered to be an absolute indication for hospitalization and vigorous IV hydration. Initial treatment focuses on preventing myoglobin precipitation in the urine by inducing and maintaining a brisk diuresis. Immediately administer saline to patients with suspected myoglobinuria or rhabdomyolysis because early hydration is the key to ameliorate acute kidney injury. Isotonic saline boluses of 20 mL/kg should be initially administered, with repeat boluses depending on the hydration status of the patient. This should be followed by continued hydration with IV fluids given at a rate of 2-3 times maintenance.[4, 20]

Achievement of a urine output goal of 2-3 mL/kg/h is recommended. IV hydration should be continued until the CK level is consistently less than 1000 U/L, the urine clears, and the patient is able to maintain adequate oral hydration.

Follow-up with mannitol to induce diuresis, supported by adequate IV fluids, has been advocated. Mannitol causes diuresis, which minimizes intratubular myoglobin deposition, acts as a free radical scavenger and reduces tubule cell damage, and may act as a direct renal vasodilator. However, the clinical benefit of this therapy remains unproven. In retrospective studies, volume expansion with saline alone prevented acute renal failure, and mannitol had no additional benefit.[21]

Raising the pH of the urine to 6.5 or more can be facilitated by adding sodium bicarbonate to the fluids. Alkalinization of the urine has been postulated to minimize the breakdown of myoglobin into its nephrotoxic metabolites and to reduce crystallization of uric acid, thereby decreasing damage to tubule cells. However, this modality of therapy remains somewhat controversial because large volumes of crystalloid alone may be sufficient to alkalinize the urine and because bicarbonate therapy can aggravate the hypocalcemia. No large randomized trials have demonstrated that alkalinization of urine is superior to early aggressive hydration with crystalloid in the management of rhabdomyolysis.

Hyperkalemia and hypocalcemia may require emergent treatment.

Patients with crush injuries and trauma require treatment for the soft tissue and bony injuries.

Patients with compartment compression due to muscle edema may require fasciotomy.

CK levels generally peak on day 3 and then rapidly decrease by half every 24-48 hours.

Further inpatient care

Hemodialysis or continuous veno-veno hemodialysis (CVVHD) may be needed to treat acute renal insufficiency in patients with myoglobinuria. Recovery often occurs in 10-14 days.

Electrolyte complications of rhabdomyolysis, including hyperkalemia and hypocalcemia, may need immediate treatment.

In the recovery phase, patients may develop hypercalcemia as calcium precipitated in damaged tissue returns to the circulation.

Long-term diuresis may cause hypokalemia.

Surgical debridement may be needed if muscle damage or necrosis is extensive. Fasciotomy may be required to manage compartment compression syndrome.

Nephrologists may facilitate the safe initiation of diuresis to avoid dialysis. If dialysis is needed, consultation with a nephrologist is necessary.

Activity is restricted by the extent of muscle damage. Persons who have had exertional myoglobinuria must limit their future activity and maintain adequate hydration.

Patients with metabolic muscle diseases must avoid trauma, overexertion, dehydration, and heat injuries.

Patients may need extensive rehabilitation for muscle damage.

In patients with myoglobinuria, administer a sodium chloride solution for volume depletion as 0.9% NaCl solution, lactated Ringers solution, or a solution of 0.45% NaCl and sodium bicarbonate 50 mEq/L. Mannitol may be administered to facilitate osmotic diuresis. Diuretics such as furosemide are less desirable because they may accentuate intravascular volume depletion.

Class Summary

These agents raise the osmolality of plasma and renal tubular fluid, which creates an osmotic inhibition of water transport in the proximal tubule. This effect subsequently decreases the gradient for passive sodium absorption in the ascending limb of the loop of Henle. The increased urinary flow is achieved by means of nonelectrolyte solute diuresis. Increased glomerular filtration rate may also be observed.

Mannitol (Osmitrol)

Osmotic diuretic. Inhibits tubular reabsorption of electrolytes by increasing osmotic pressure of glomerular filtrate. Increases urinary output.

Class Summary

Sodium bicarbonate is used as a gastric, systemic, and urinary alkalinizer. Sodium bicarbonate is administered IV to alkalinize the urine in patients with rhabdomyolysis because it may prevent the toxicity that can result from the presence of myoglobin in acidic urine and prevent the crystallization of uric acid.

Sodium bicarbonate

Useful in alkalizing urine to prevent acute myoglobinuric renal failure. Titrate dose to increase pH >7, usually available as 1 mEq/mL. Add to 0.45% NaCl to deliver 1-2 mEq/kg/d.