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Myoglobinuria


Myoglobinuria

Article Author:
Muhammad Yasir Anwar
Article Editor:
Vikas Gupta
Updated:
10/5/2020 10:03:53 AM
For CME on this topic:
Myoglobinuria CME
PubMed Link:
Myoglobinuria

Introduction

Myoglobin is an iron-containing heme protein that is present predominantly in the sarcoplasm of skeletal and cardiac muscles. Due to the presence of heme moiety, myoglobin serves as a carrier and store for oxygen in muscle cells of the body. Myoglobin has more affinity for oxygen as compared to hemoglobin. As a result of that, it can acquire oxygen from hemoglobin, hence transferring it from the blood to the muscle tissues.[1]

As the name suggests, myoglobinuria means the presence of an abnormally excessive amount of myoglobin in the urine. As myoglobin is present in the muscle cells, myoglobinuria is almost invariably associated with damage to the cell membranes of myocytes. This breakdown of the muscle cells is also known as rhabdomyolysis. It leads to the release of myoglobin in the blood from where it is ultimately filtered by the glomerulus and enters the renal tubule.[2]

In this article, we will look into the etiology, pathophysiology, evaluation, management and complications of myoglobinuria.

Etiology

As myoglobin is present in the muscle cells, myoglobinuria is associated with damage to the cell membranes of myocytes. Numerous etiologies can lead to the rupture of the myocytes' cell membranes. We can categorize them broadly into physical and non-physical causes.[3]

1. A few examples of physical causes are trauma, crush injury, heatstroke, hypothermia, malignant hyperthermia, extensive burns, seizures, strenuous exercise, and prolonged immobility.

2. The non-physical causes include hypoxic injury, metabolic disturbances, genetic disorders, infections, drugs, and toxins.

  • Some examples of hypoxic injury are carbon monoxide poisoning, vascular thrombosis, and vasculitis.
  • Metabolic disturbances leading to myoglobinuria include hypokalemia, hypophosphatemia, hyponatremia, hypocalcemia, and hypernatremia.
  • Genetic disorders leading to muscle cell breakdown include disorders of carbohydrate metabolism (e.g., McArdle's disease, phosphofructokinase deficiency), disorders of lipid metabolism (e.g., carnitine deficiency), muscular dystrophy, dermatomyositis, and polymyositis.
  • Infections mostly causing rhabdomyolysis include coxsackie virus, malaria, herpes virus, influenza virus, HIV, legionella, and salmonella.
  • Drugs and toxins which cause rhabdomyolysis are alcohol, sedative-hypnotics, cocaine, methadone, antilipemic drugs, and many others.

Epidemiology

Since myoglobinuria is directly related to muscle injury, it is difficult to assess its stand-alone incidence. However, it is mostly seen in young population due to more incidences of infection as well as trauma. The athletic population is also much more prone to injuries and rhabdomyolysis, hence the increased incidence of myoglobinuria in that population. Similarly, in the young population, there is an increased incidence of infections leading to myositis, ultimately increasing the cases of myoglobinuria in that population. Rhabdomyolysis and crush syndromes are also common results of natural disasters like earthquakes, so myoglobinuria is also more commonly seen in the affected population of these disasters.[4][5]

Pathophysiology

Myoglobinuria occurs due to excess myoglobin in the blood resulting from the damage to the cell membrane of myocytes. It can be caused by a direct injury that damages the cells. The intracellular contents, including myoglobin, enters the bloodstream. Alternatively, this damage to the cell membrane can be a result of metabolic disturbances.

In the case of metabolic factors, the damage to myocytes occurs mostly due to the lack of ATP. Adenosine Triphosphate (ATP) is critical to the myocytes, and its levels should be maintained above a certain level to keep the cell viable. The common substrates for ATP production are glycogen and triglycerides. Therefore, any defect in the metabolism of these substrates leads to rhabdomyolysis, especially when the person is involved in ATP requiring activities like strenuous exercise.[6]

In addition to the release of myoglobin, during this process of cell death, the myocytes can accumulate large amounts of fluid, which can lead to hypovolemia as well.

After cell death, other intracellular contents like creatine kinase (CK), phosphate, and potassium are also released into the blood along with myoglobin, which can lead to electrolyte abnormalities, most important of which is hyperkalemia as it can lead to cardiac rhythm abnormalities if not corrected appropriately.

Myoglobin, normally circulating in the blood, is mainly bound to Haptoglobin and Alpha2- immunoglobulin. However, at levels higher than 0.5 – 1.5mg/dL, the haptoglobins are saturated, and the excess free myoglobin is filtered by the glomerulus.[7] 

Although small amounts of myoglobin are normally filtered and quickly excreted by the kidneys, the large amount of myoglobin can damage the kidneys and even cause acute renal failure.[8] The proposed mechanisms for myoglobin induced nephropathy are:

  1. Renal vasoconstriction as the damaged myocytes sequester fluid and lead to hypovolemia, which activates the renin-angiotensin system leading to renal vasoconstriction.
  2. Heme protein, especially myoglobin, has a direct toxic effect on renal tubule, especially on the proximal tubules.
  3. Excessive myoglobin can interact with Tamm-Horsfall protein in the distal tubules and result in cast formation in the presence of acidic urine. It leads to tubular obstruction.

History and Physical

The classic history of myoglobinuria points towards rhabdomyolysis and includes the triad of weakness, muscular pain, and dark urine. However, many cases of myoglobinuria present only with dark urine without any other physical symptoms. Patients may complain of some mild non-specific symptoms like tiredness, body aches with dark urine.

The history of the patient typically includes some pointers towards the cause of rhabdomyolysis like trauma, drug use, strenuous exercise, coma, or some muscle tissue disorder.

Physical examination may reveal muscle weakness, tenderness, or signs of trauma, but in most of the non-trauma cases, it yields nothing. If the muscle tenderness is present, it is usually more prominent in the proximal muscle groups in case of inflammatory etiologies.

Evaluation

Diagnostic tests typically performed in the case of dark urine starts with a urine dipstick. The urine dipstick test turns out positive for heme in these patients. It is followed by microscopic analysis of the urine, which reveals no red blood cells. This points to the presence of myoglobin in the urine. There are quantitative and more precise tests available to measure myoglobin in the urine like immunohistochemistry, spectrophotometry, and radioimmunoassay, but they are not commonly required in clinical practice. Creatine kinase levels are also measured, and its high level in blood confirms muscle injury as the cause of myoglobinuria.

Baseline studies of blood electrolytes and renal function tests are also done as these patients are at increased risk for hyperkalemia and acute kidney injury.

Patient's medication history should be reviewed to find out if they are taking any medication which is related to rhabdomyolysis.

Later on, further investigations are carried out to find out the cause of rhabdomyolysis, and some of these investigations include urine toxicology screen, ESR (Erythrocyte Sedimentation Rate) for inflammatory myopathies like dermatomyositis and polymyositis.

Treatment / Management

The primary goal of treatment in the case of myoglobinuria is to prevent acute kidney injury (AKI), and for that, the initial therapy is mainly focused on rehydration to facilitate the renal clearance of myoglobin. The patient is started on normal saline or Ringer's lactate, and it is titrated to maintain a urine output of 200 to 300 mL/hour.[9] The electrolyte abnormalities like hyperkalemia are managed using a conservative approach.

As we know, acidic urine facilitates the cast formation; therefore, some specialists recommend alkalinization of urine by using intravenous sodium bicarbonate. It is hypothesized to prevent cast formation and crystallization of uric acid.[10]

Similarly, the use of diuretics in such patients is debatable. There is no substantial evidence in favor of their use.[11] Mannitol and furosemide are sometimes used in some selective patients to prevent non-oliguric renal failure.

If the patients do not respond to rehydration, hemodialysis is used as a last resort. It removes the nephrotoxic substances as well as corrects the electrolytic abnormalities. There is some evidence that the early initiation of dialysis in patients with rhabdomyolysis may improve the outcome of kidney injury.[12]

Differential Diagnosis

There are a few other causes of dark or red-coloured or dark urine, also known as pigmenturia. Myoglobinuria should be differentiated from them.[13]

Other causes of pigmenturia include:

  • Acute intermittent porphyria
  • Hematuria
  • Hemoglobinuria
  • Bilirubinuria
  • Alkaptonuria

Prognosis

In most of the cases, the prognosis of myoglobinuria is good. Although it can lead to AKI, most of the time the damage to the kidney is minimal and reversible.[14]

Complications

Acute Kidney Injury (AKI) is the most common complication of myoglobinuria. Studies suggest that up to 50 % of the cases of rhabdomyolysis can cause AKI depending on the cause.[15][16] Rhabdomyolysis is responsible for approximately 10% of AKI cases.[17][18]

The other most common complication is electrolyte disturbance, especially hyperkalemia due to the spillage of intracellular contents from the damaged myocytes.

Deterrence and Patient Education

After appropriate management, patients should be educated properly regarding the causes of myoglobinuria. They should be given specific instructions to prevent any such incidence in the future depending on their respective underlying diagnoses. 

Firstly, the patients should be educated that it can happen in the future as well. If something like this happens in the future like they experience dark urine or muscle pain, they should make an appointment with their doctor. Myoglobinuria can be easily checked by a urine sample, and it should be tested in time. 

If the patient is having myoglobinuria due to the prescription medications, they should be given proper education about it and if possible, the culprit drug should be changed.

If it has occurred due to rigorous exercise, the patients should be educated to modify their exercise routine and intensity. They should also be advised to maintain proper hydration during their activities.

And if it is related to some recreational drug use or excessive alcohol consumption, they should be comprehensively counseled about it and should be given proper information about rehabilitation centers if they want to get rid of the use of such substances. They should be given the contact information of such centers as well. 

Enhancing Healthcare Team Outcomes

Myoglobinuria can lead to acute renal failure and can cause permanent damage if not managed appropriately and efficiently. So, in order to prevent morbidity and mortality, it is best to be managed by an interprofessional team. It involves the initial management by an emergency physician and a hospitalist so that appropriate earlier hydration can be managed.

Upon discharge, the patient should be educated about the causes of rhabdomyolysis. College students who present with frequent myoglobinuria due to their athletic activities should be educated about it and may be asked to change their exercise routine and intensity, and also should be advised to hydrate themselves regularly in order to prevent any renal damage. If the patients are on any prescription medications that can cause muscle breakdown, the pharmacists should also educate the patients about them. They may consult the physician to recommend any alternative drug without any such side effects.

The main goal is to identify the problem early and maintain communication among the team for early intervention. Early intervention and later on educating the patient about the problem yields the best clinical outcome.[19][4][5] (Level 5).


References

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[3] David WS, Myoglobinuria. Neurologic clinics. 2000 Feb;     [PubMed PMID: 10658177]
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