1. Description of the problem
Pigment nephropathy is an abrupt decline in renal function as a consequence of the toxic action of endogenous hem-containing pigment on the kidney. Such pigments include myoglobin, released from skeletal muscle in rhabdomyolysis, and hemoglobin, released during intravascular hemolysis.
Once released into the systemic circulation they are filtered by the kidney where they may cause tubular obstruction, vasoconstriction and free-radical generation. They are excreted, and may be detected in the urine. Etiological factors predisposing to myoglobinemia and hemoglobinemia are detailed in Table I.
|PIGMENT||ETIOLOGICAL MECHANISM||SPECIFIC CAUSE|
|Crush injury||Electrical injury|
|Burns||Acute vascular insufficiency|
|Exhaustive, normal muscle||Extreme exertion||Seizures|
|Heat exhaustion||Status asthmaticus|
|Sickle cell trait|
|Exhaustive, abnormal muscle||Malignant hyperthermia||Neuroleptic malignant syndrome|
|Mitochondrial myopathies||Glycogen storage diseases|
|Infective, bacterial||Legionella||Streptococcus pneumoniae|
|Drugs||See Table II|
|Toxins||Illicit drug use (Table II)||Mushroom poisoning|
|Snake bites||Spider bites|
|Hemoglobin||Extracorporeal RBC damage||ECMO||Aging blood products|
|Intravascular RBC destruction||Hemolytic uremic syndrome||Prosthetic heart valve|
|Major transfusion reaction||Severe aortic stenosis|
|Snake bite||Foot-strike hemolysis|
|Paroxysmal cold hemoglobinuria||Paroxysmal nocturnal hemoglobinuria|
|Infusion of hypotonic solutions|
|Intrinsic RBC defects||G-6-PD deficiency||Pyruvate kinase deficiency|
|Sickle cell anemia||Thalassemia|
|Extrinsic RBC defects||Liver disease||Intravenous immunoglobulin|
|Hypersplenism||Autoimmune hemolytic anemia|
|Snake bite||Spider bite|
Rhabdomyolysis is the dissolution of skeletal muscle and is a common condition with multiple precipitants including crush injury, polytrauma, pressure myonecrosis, and poisoning, all commonly seen by the intensivist. Electrolyte disturbances and infections may cause rhabdomyolysis in patients admitted to the intensive care unit (ICU) with other pathologies. AKI may develop in up to 50% of cases of traumatic rhabdomyolysis. It may be account for up to 10% of cases of AKI.
Massive intravascular hemolysis is uncommon, but critically ill patients in the ICU may be specifically at risk of idiosyncratic drug reactions, intravenous immunoglobulin therapy, or hemolytic transfusion reactions as a result of ABO incompatibility, than the general population. The incidence of a major incompatibility reaction has been reported as 1 in 100,000 units of PRC transfused.
Cardiac Surgery-Associated Acute Kidney Injury (CSA-AKI) is undoubtedly a complex manifestation of the syndrome of AKI with a multifactorial pathogenesis.
There is mounting evidence that the generation of free hemoglobin and subsequent hemoglobinuria as a result of mechanical damage to the erythrocytes during cardiopulmonary bypass plays a role in the development of renal impairment after major cardiovascular surgery requiring extracorporeal support. CSA-AKI is the most common cause of AKI after sepsis and pigment nephropathy could be a much larger problem than previously thought.
There are no biochemical or consensus definitions of what constitutes pigment nephropathy. Critically ill patients are exposed to multiple insults which may result in AKI, but there are multiple opportunities for pigment exposure in the ICU. Many of the conditions which may result in myoglobinemia or free hemoglobinemia have few symptoms and subtle, if any, diagnostic signs.
A high degree of suspicion is required and appropriate biochemical tests should be performed urgently; pigment nephropathy is potentially one of the few ameliorable causes of AKI and if not sought, cannot be found.
The classical symptoms of rhabdomyolysis are muscular pain, out of proportion to clinical signs, and dark urine. Loss of function and paresthesia are symptoms of compartment syndrome. The symptoms of a transfusion reaction vary from fevers, chills and loin pain, to complete cardiovascular collapse. These, and the subtle symptoms of other causes of intravascular hemolysis, may be impossible to ascertain in the critically ill patient.
The events surrounding admission to hospital and to intensive care need to be scrutinised. One of the most common causes of rhabdomyolysis is pressure-induced myonecrosis due to prolonged surgical, drug-induced or traumatic immobility and these presentations should prompt biochemical investigation, as should drug overdose, illicit drug ingestion, animal envenomation and prolonged seizures.
All patients undergoing operative procedures requiring cardiopulmonary bypass should be carefully observed for evidence of acute renal impairment.
Adverse drug reactions can cause both rhabdomyolysis and hemolysis. Table II lists known drug precipitants. These conditions should be suspected in the event of a sudden deterioration in renal function after the initiation of a new medication. Some degree of myositis is a very common side effect of the almost ubiquitous statin drugs. Some drugs and foodstuffs colour urine, but cause no appreciable increased risk of AKI. These are detailed in Table III.
|Statins||Tricyclic antidepressants||Amphotericin B|
|Fibrates||Selective serotonin re-uptake-inhibitors||SIMPLE ANALGESICS|
|Penicillamine||Lithium||DRUGS OF ADDICTION|
|Barbiturates||DRUGS USED IN ANESTHESIA||Cocaine|
Alcohol can alter muscle metabolism and electrolyte balance; in association with prolonged inebriation this can lead to rhabdomyolysis.
Even careful clinical examination may yield no findings in eliciting the cause of an AKI if the underlying cause is pigment nephropathy. However, some findings on clinical examination should prompt further investigation to assess the risk of a subsequent renal insult from pigmentemia.
Damaged muscle may be tender, woody, or associated with pressure blisters or erythema of the overlying skin. Trauma to the closed compartments of the forearm or lower limb may cause compartment syndrome.
There may be evidence of impaired tissue perfusion. This may be a consequence of hypovolemia due to fluid sequestration in rhabdomyolytic muscle or the anaphylactic state which may result from a hemolytic transfusion reaction.
Pallor, jaundice and splenomegaly may be seen in underlying hemolytic conditions.
Pigment nephropathy, typified by rhabdomyolysis, normally presents with oliguria and an abrupt loss of excretory function. 7-21 days after the initial insult a polyuric phase will occur, normally with recovery of excretory function.
Pallor, jaundice and splenomegaly may be the only features of hemolytic anemia found on clinical examination. Acute hemolytic transfusion reactions may present with increased ventilatory requirements, fever, or marked signs of circulatory collapse.
Damage to 150 g of muscle can release enough potassium to elevate serum levels by 1 mmol/litre. Significantly more damage can occur in crush injury victims. Serum levels also rise in hemolysis. The management of both conditions – drug and fluid administration and transfusion – can further increase serum potassium.
Serum levels should fall through increased urinary excretion, but AKI leads to an abrupt reduction in potassium excretion, making the development of hyperkalemic arrhythmias a significant concern.
Phosphate is also released by both myocyte necrosis and erythrocyte lysis and serum concentrations mirror serum potassium concentrations for many of the same reasons.
The intracellular influx of calcium into damaged muscle in leads to hypocalcemia in rhabdomyolysis in 20-100% of patients, potentiated by the direct and indirect effects of hyperphosphatemia.
Calcium supplementation should only be given for dangerous hyperkalemia as a late feature of rhabdomyolysis in 20-30% of cases is hypercalcemia with a release of calcium from recovering myocytes, recovery of vitamin D synthesis by the kidney and an increase in PTH prompted by the initial hypocalcemia. The uptake of calcium by damaged muscle can also lead to heterotopic calcification.
Urea and creatinine
Creatine is an important metabolic substrate for skeletal muscle energy production and when released from damaged myocytes it is converted into creatinine in the circulation. Urea clearance is reduced in AKI and its production increased in any catabolic state.
Released by the lysis of both muscle and red blood cells high levels of uric acid can contribute to the renal insult of AKI by propagating cast formation. Crystals may be visible in the urine.
Bilirubin is the breakdown product of both hemoglobin and myoglobin. Unconjugated bilirubin will be elevated in both conditions, and has itself been theorised to be tubulotoxic.
Full blood count
Stress response or underlying infection can provoke a leucocytosis in rhabdomyolysis or crush injury. Diminishing platelet counts may herald the onset of DIC. Anemia can occur as a consequence of injury and bleeding, or red cell loss in hemolysis.
Both transfusion reactions and rhabdomyolysis can precipitate disseminated intravascular coagulopathy due to the release of intracellular contents. Monitoring fibrinogen will allow early detection of this complication and monitoring coagulation studies can help guide supportive therapy.
Blood film abnormalities
The blood film in any cause of hemolysis will show spherocytosis and may show elliptocytes, and microspherocytes. The presence of other features, such as schistocytosis, can point to specific underlying diagnoses.
Key management points
Pigment nephropathy is the abrupt loss of renal function as a consequence of the toxicity of the endogenous hem-based pigments hemoglobin and myoglobin on the kidney.
Traumatic and non-traumatic rhabdomyolysis, massive intravascular hemolysis and cardiac surgery are all probable causes of pigment nephropathy, and may all be forms of renal sideropathy, with labile iron playing an important role in the development of AKI.
CSA-AKI and rhabdomyolysis are significant causes of AKI; if they have a common pathogenic mechanism related to hem-pigment toxicity then pigment nephropathy would be the most common cause of AKI after sepsis.
The most important step in the management of pigment nephropathy is prevention. It may be preventable. Maintain a high degree of clinical suspicion and perform urine and biochemical investigations promptly in an attempt to identify the risk of the condition before AKI ensues.
Aggressive fluid resuscitation, urinary alkalinisation and forced osmotic diuresis may prevent pigment nephropathy due to myoglobinemia; their use is unreported in hemoglobinemia. Standard treatment of established AKI should be initiated.
Bicarbonate may reduce oxidative stress in pigment nephropathy and CSA-AKI. Clinical trials are being performed and the results awaited.
Standard hemodialysis does not remove hem pigments from the blood effectively. High flux membranes can remove myoglobin from the blood, though the effectiveness of this therapy is undetermined.
If oliguric AKI does ensue then close clinical and biochemical monitoring is required to limit secondary-AKI and provide the optimum milieu for renal recovery. Renal replacement therapy may be required for control of fluid, electrolyte or acid-base balance, uremia, or the other complications of AKI.
In rhabdomyolysis removal of the causative agent and restoration of blood to ischemic muscle can lead to reperfusion injury, with significant systemic release of vasoactive substances, profound fluid shifts, and sudden, malignant increases in serum electrolyte concentration. High dose vasoconstrictive agents and emergent renal support may be required.
Exogenous potassium should be avoided if possible. Exogenous calcium can result in heterotopic calcification in cases of rhabdomyolysis.
2. Emergency Management
Emergency management of PI-AKI
The basics.All assessment should begin by assessing Airway, Breathing and Circulation in a systematic manner with early establishment of intravenous access and invasive monitoring in the critical care environment.
Early identification.If pigment nephropathy is not suspected, it cannot be diagnosed and the opportunity to ameliorate the insult lost. Urinalysis and serum CK are useful in the identification of patients at risk of the condition. Immediate treatment for hyperkalemia may be required.
Early fluid resuscitation. This should ideally begin in the field in patients with crush injury and on identification with others. Rapid volume expansion with 1000 ml of normal saline followed by sufficient fluid to maintain a 200-300 ml/hr diuresis limits secondary renal injury and may reduce cast nephropathy.
Alkalinisation of the urine. With a urinary pH > 6.5 hem pigment cast formation is inhibited. Alternating normal saline with 1.26% sodium bicarbonate during fluid resuscitation and maintenance can alkalinise the urine.
Maintenance of urine output. An osmotic diuresis can maintain the desired urine output. 0.5 g/kg of mannitol should be administered as over 15-30 minutes, followed by an infusion of 0.1 g/kg/hr if desired, titrated to urine output.
Identify and treat the precipitating cause.This may require electrolyte replacement in non-traumatic rhabdomyolysis, fasciotomy for compartment syndrome or treatment for an acute hemolytic transfusion reaction.
Prevent further damage to the kidney. Maintenance of the intravascular volume, favourable flow and pressure hemodynamics, prevention of anemia and sepsis and avoidance of other nephrotoxins are all important in limiting secondary AKI.
Continue treatment until the urine is clear. The urine in PI-AKI will generally be red-brown; clearing of this colouration over 1-4 days provides visual evidence of the clearing of pigment.
Anticipate complications.These can be early – hyperkalemia as a consequence of crush syndrome; late – hypercalcemia; as a result of the underlying precipitant – shock in acute transfusion reactions; as a consequence of oligo-anuric AKI; or due to therapy – fluid overload.
Consider early renal replacement therapy.Patients with significant muscle injury are at risk of sudden overwhelming hyperkalemia. Intractable acidosis, electrolyte abnormalities, fluid balance issues or progressive azotemia may all prompt the early initiation of RRT, even in the absence of anuria.
Creatine kinase is the most sensitive marker of muscle injury. It catalyses ATP formation from ADP and is released into the circulation with muscle cell injury. Normal serum CK levels are 45-260 units/litre, and high levels are not an uncommon finding in critically ill patients. CK rises within 12 hours of muscular insult, peaks within 24 hours of injury and has a half-life of 36-48 hours, declining 1-3 days after the cessation of muscle damage.
There is no biochemical definition of rhabdomyolysis, but 1000 units per litre or 5 times the upper limit of normal is often used as a pragmatic definition. Subtypes specific to skeletal, myocardial and brain tissue exist.
Levels greater than 5000 units/litre are associated with an increased risk of AKI.
Rising CK levels despite therapy should prompt an urgent search for ongoing muscle damage.
Myoglobin, hemoglobin and haptoglobin
Serum myoglobin concentration is normally less than 100 micrograms/litre but can rise to >10,000 micrograms/litre or more in severe rhabdomyolysis. The half-life, assuming normal glomerular filtration, is 1-3 hours, making it an impractical diagnostic marker in many cases.
There is some evidence that peak myoglobin concentration may be predictive of the development of AKI and the need for RRT.
Free plasma concentrations of hemoglobin greater than 0.1 g/litre have been shown to adversely affect nitric oxide-mediated hemodynamics. Significant episodes of hemolysis are associated with much higher levels of extracellular hemoglobin – 10 g/litre in severe hemolytic episodes of paroxysmal hemoglobinuria and 3-21 g/litre in acute hemolytic reactions in long term dialysis patients.
It would seem reasonable to assume that the risk of developing the condition increases with extracellular hemoglobin concentration.
At physiological concentrations hemoglobin is normally scavenged by, and irreversibly bound to, haptoglobin. The binding capacity of haptoglobin for hemoglobin is approximately 0.7-1.5 g/litre which is rapidly exceeded in significant hemolysis, and plasma haptoglobin concentrations fall.
Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) concentrations are elevated in rhabdomyolysis. Lactate dehydrogenase (LDH) is elevated in both hemolysis and rhabdomyolysis. Carbonic anhydrase III is a very specific marker of skeletal muscle injury but is an impractical diagnostic test, relying on costly and lengthy radioimmunoassay.
Urea and creatinine
Creatine is an important metabolic substrate for skeletal muscle energy production. When released from damaged myocytes it is converted into creatinine in the circulation. In patients with rhabdomyolysis-induced AKI the rate of rise of creatinine is said to outstrip that of urea, altering the normal physiological ratio urea:creatinine of 1:10-15 to closer to 1:6. Recent evidence from crush syndrome sufferers suggests this may not always hold true.
Damaged muscle will be evident as areas of abnormal technetium-99 and gallium-67 uptake on bone scanning. MRI in both T1 and T2 weighted images will show significant abnormalities of signal intensity in rhabdomyolytic muscle. Nonspecific changes will be present on CT scan. Ultrasound has also been used to detect damaged muscle, but the sensitivities for the modalities are significantly different: 100% for MRI, 62% for CT and 42% for ultrasonography.
Renal ultrasound should be carried out to ensure that there is no evidence of renal obstruction in any case of new onset AKI.
Compartment pressure testing can be performed in suspected cases of rhabdomyolysis using either specialist equipment or a pressure transducer attached to a needle which can be inserted into the suspicious area to measure and monitor compartment pressure. Pressures of 30-50 mmHg are associated with ischemia and should prompt surgical intervention.
Muscle biopsy is rarely conclusive. Tests for underlying abnormalities can be carried out on muscle tissue, but the histology is often on-specific showing only patchy myonecrosis.
Bone marrow biopsy may be indicated for the further investigation of hemolytic anemia.
Normal lab values
CK: normal values 26-250 units/litre in most units.
Myoglobin: reported normal and pathological values vary and the kinetics of myoglobin make it an unreliable biomarker.
There are no consensus, pathological or biochemical definitions of pigment nephropathy. The diagnosis of AKI is well described elsewhere. The typical presentation of oliguric AKI followed some 7-14 days by polyuria with subsequent recovery of renal function is not helpful in early diagnosis or prevention. This is important as pigment nephropathy may be a potentially preventable insult in critically-ill populations exposed to multiple precipitants for the development of AKI.
Early recognition of potential etiological factors is the most important step in the management of pigment nephropathy. AKI occurs as a consequence of both hemoglobinemia and myoglobinemia. Hematuria, hemoglobinuria and myoglobinuria all give positive urinalysis dipstick tests for blood due to the presence of hem.
In over 80% of cases of microscopic hematuria urgent urinary microscopy could be expected to show intact red blood cells prompting imaging of the renal tract rather than assessment for pigment nephropathy.
Discriminating between hemoglobinuria and myoglobinuria may be more difficult. In rhabdomyolysis the urine will be reddish-brown, often with pigmented casts and there will be a marked elevation in plasma CK. The rise in serum creatinine may be significantly greater than the rise in urea. Direct myoglobin measurement is difficult, in part because the protein is freely filtered by the kidney. However, recent evidence exists that it may be a useful biomarker in predicting AKI.
In the absence of pre-existing renal failure the plasma in rhabdomyolysis will retain its normal colour. In hemoglobinuria the plasma appears red-brown as the larger molecule is relatively poorly filtered and a higher concentration remains in the circulation.
In hemolysis the presence of an elevated LDH and low haptoglobin has been described as 90% specific for the diagnosis of hemolysis. The presence of haptoglobins >250 mg/litre and a normal LDH excludes hemolysis with 92% sensitivity.
Novel biomarkers, such as neutrophil gelatinase-associated lipocalin, which can effectively predict the risk of AKI after a renal insult are being evaluated in a variety of situations. It is hoped that by elucidating the mechanism by which these substances are released in response to renal injury we may develop an early warning system for AKI and find specific targets for therapeutic intervention.
None of these have been validated specifically in the prediction of pigment nephropathy, but recent evidence suggests that the role of labile iron is central to their physiology. Their exact role is unclear, but they offer an exciting opportunity to refine our understanding of the syndrome.
Table I summarises the possible etiologies of myoglobinemia and hemoglobinemia. Table III summarises the differential diagnosis of coloured urine.
The most important distinction to make is between pigmenturia and hematuria. The presence of intact blood cells in the urine may indicate damage to the renal tract in cases of trauma, an intrinsic cause of renal failure such as glomerulonephritis or a malignancy.
All of these diagnoses have substantially different requirements for investigation and further management.
Figure 2 describes a potential pathway for the investigation and confirmation of the cause of pigmentemia and pigmenturia, beginning with urinalysis.
4. Specific Treatment
Prevention of pigment nephropathy
Depending on the etiology of the pigmentemia and pigmenturia there is mixed evidence for the benefits of specific prophylactic intervention. The prevention of tubular cast formation and maintenance of intravascular volume are the main goals of preventative therapy.
In patients with traumatic rhabdomyolysis, particularly those with crush injury, aggressive fluid resuscitation may restore intravascular volume, improve renal and other tissue perfusion and maintain the glomerular filtration rate. Substantially more fluid than may be required over initial estimates. In all causes of pigmentemia fluid administration can increase urine fluid rate, reduce tubular pigment concentration and reduce cast formation.
There is no evidence-based regimen which has been validated, but 1000 ml of normal saline given over the first hour has been recommended as initial therapy. This should be commenced prior to extrication in crush injury. Solutions containing lactate or potassium should be avoided.
Published advice recommends sufficient fluid administration to maintain a urine output of 200-300 ml/hr. An increasing body of evidence exists to suggest that fluid overload is implicated in a number of pathophysiological processes in the critically ill patient and is unlikely to protect against AKI. Fluid resuscitation should be tailored to clinical end-points determined by invasive monitoring and patient review.
Urinary alkalinisation and mannitol-bicarbonate diuresis
The release of intracellular contents promotes acidemia and requires renal clearance of a large acid load. Tubular cast formation is enhanced in an acidic environment. A urinary pH >6.5 inhibits the tubular precipitation of myoglobin with a pH > 7 inhibiting uric acid precipitation, and may help to prevent injury.
Traditionally, bicarbonate has been used to alkalinise the urine, though some experts argue that large volume administration of crystalloid may achieve sufficiently alkaline urine for the inhibition of tubular cast formation.
Bicarbonate is a potent scavenger of hydroxyl ions and could conceivably act to reduce oxidative stress on a cellular level. It can ameliorate hyperkalemia and systemic acidosis as a consequence of PI-AKI, but may contribute to fluid overload and hypocalcemia, so its use should be carefully, and invasively, monitored.
The use of mannitol, assuming the patient is not in established oligo-anuria, can prompt an osmotic diuresis, minimising tubular pigment concentrations. It may scavenge free-radicals, reducing oxidative stress, and reduce compartment pressures by pulling extracellular water into the intravascular space. Mannitol also acts as a renal vasodilator but can cause adverse effects through volume depletion, hyperosmolality, and can contribute to volume overload.
An initial bolus of 0.5 g/kg of 20% mannitol can be given over 15-30 minutes with a subsequent infusion commenced at 0.1 g/kg/hr titrated to maintain a urine output of 200-300 ml/hr. 1.26% sodium bicarbonate solution can be alternated with normal saline during fluid resuscitation and maintenance. More complex regimes involving diluting mannitol and bicarbonate in normal saline exist, but are unlikely to offer any significant benefit.
This regime is pragmatic; there is no evidence base. Though bicarbonate-mannitol forced diuresis is considered the current standard of care in the management of rhabdomyolysis and may be beneficial in other forms of pigment nephropathy, there is little high level evidence to support their use over and above aggressive fluid resuscitation.
Treatment should be continued until there is resolution of myoglobinuria, practically identified by clearing of the urine, which takes 1-4 days in most cases.
The management of established pigment nephropathy
If AKI results from pigment nephropathy then its management is the same as other forms of the clinical syndrome. Removal of the precipitants, maintenance of favourable hemodynamic and clinical conditions, prevention of further renal insult and the standard supportive therapy should all be employed.
The indications for commencing RRT remain the same and are discussed at length in other sources. Electrolyte disturbances are common, may be severe, and if dealing with a massive cellular injury, overwhelming. They may require very early initiation of RRT, more frequent or more intense treatment to clear the solute load and this will require some form of dialytic therapy if a filtration modality is chosen.
The modality of RRT chosen may depend on local expertise, the need to limit anticoagulant exposure in some patients, co-morbid conditions and the severity of illness.
Drugs and dosages
0.9% sodium chloride solution: 1000 ml over 1 hour then infusion rate tailored to clinical assessment and urine output (maintain 200-300 ml/hr).
1.26% sodium bicarbonate solution: alternate with saline during fluid resuscitation and maintenance to keep urinary pH 6.5-8.
20% mannitol solution: 0.5 g/kg given over 15-30 minutes initially, then infusion of 0.1 g/kg/hr titrated to effect.
Renal replacement therapies
Standard hemodialysis membranes do not remove myoglobin. High-flux membranes can efficiently clear myoglobin, though the effect on outcome is not clear and no recommendations can be made as to its use. In units with sufficient expertise and in patients with massive myoglobin loads it may be a beneficial therapy.
Other prophylactic therapeutic measures
Loop diuretics have not been shown to improve outcome in AKI. They may acidify the urine and potentiate cast formation. They can induce calciuria and hypocalcemia. There is no evidence for their use, but they may be required for the pragmatic treatment of fluid overload. There is no evidence for direct calcium or iron manipulation, removal of uric acid, other methods of urinary alkalinisation or other antioxidant pharmacotherapy.
The management of compartment syndrome and muscle injury
Relief of muscle ischemia can result in a significant reperfusion injury and lead to the systemic dissemination of pro-inflammatory molecules and a systemic inflammatory response. However prolonged muscle ischemia can lead to infarction and significant disability. It can also provide a continuing source of pigment to drive PI-AKI.
Management of compartment syndrome is controversial, with routine fasciotomies increasing the risk of infection, and carrying a morbidity of their own. Routine measurement of compartment pressures with needle pressure transduction also increases the risk of infection. Persistent elevation or a sudden increase in plasma CK levels 48-72 hours after the initial insult should prompt urgent investigation for the source.
Surgical intervention can be advocated in the case of obvious distal ischemia or compartment pressures greater than 30 mmHg or within 30 mmHg of diastolic blood pressure.
Muscle injury in malignant hyperpyrexia or neuroleptic malignant syndrome may be ameliorated by dantrolene in a 1 mg/kg intravenous bolus though evidence for its efficacy in ameliorating the consequent renal injury is lacking.
5. Disease monitoring, follow-up and disposition
Expected response to treatment
It is difficult to recommend either myoglobin or CK be used to guide ongoing therapy. CK is the most pragmatic choice as myoglobin is rapidly filtered by the kidney and so plasma levels falls rapidly, and it is unstable in urine, making it a poor biomarker, despite its etiological role in pigment nephropathy.
Using CK may lead to a prolonged course of treatment where the myoglobin has already been cleared by the kidney. Urine colour can be used as a visual marker of clearing hemoglobinuria or myoglobinuria. CK can be used to monitor for ongoing muscle necrosis.
The indications for cessation of renal replacement therapy are discussed in detail elsewhere, but increasing urine output and falling serum creatinine while RRT is ongoing are the best indicators of renal recovery.
The prognosis of the precipitating condition requires consideration, but AKI of any cause has been shown to have a profound effect on mortality. In-hospital and ICU mortality is significantly increased over that expected by illness severity scoring in patients developing any degree of renal impairment. Hospital mortality varies from 25 – 80% and ICU mortality varies from 20 – 70% with the mortality for AKI requiring RRT reaching 50 – 60%.
Several studies have shown significant increases in the risk of mortality with even modest increases in serum creatinine. The development of AKI seems to prime other organ systems for failure and AKI is strongly, independently, associated with the development of multiple organ failure.
Survival from AKI is associated with reduced duration of RRT and rates of RRT dependence, the absence of pre-existing renal disease, the maintenance of urine output, younger age, reduced need for inotropic support and other organ support. 10-20% of survivors will require on-going renal support after discharge from hospital.
Large randomised controlled trials and meta-analysis have failed to show any effect of RRT treatment modality on either mortality or renal recovery. Long-term survival of patients with AKI requiring RRT is impaired, with 50-60% surviving to 28 days and 20-53% surviving 1 year. This is independent of the underlying etiology.
A normal CK in the presence of pigmented urine, AKI and significant muscle injury should prompt repeat testing. Ensure laboratory values are exact – some centres use a dilutional method for analysing very high plasma levels of CK and will report an approximate figure which can take a significant time to report.
If CK is being used to identify patients with ongoing myonecrosis a delay in analysis or an approximate value being quoted can lead to irretrievable muscle damage, disability and a missed opportunity to prevent progression to AKI.
On-going evaluation of polytrauma, areas at risk of compartment syndrome and open fasciotomies will be required of the surgical team. Referral to nephrology is indicated if there is no evidence of renal recovery once the patient is otherwise fit for discharge from ICU. The neurology and hematology teams can play a useful role in identifying the etiology of the pigment nephropathy if not obvious, as can clinical geneticists.
The pathophysiology of AKI in pigment nephropathy is complex and is related to both the toxic action of the pigment and the pathophysiology of the antecedent condition. There is a failure of the normal homeostatic pigment-scavenging mechanisms leading to circulating free hemoglobin or myoglobin.
AKI is believed to result as a consequence of hem-mediated oxidative stress, tubular obstruction with cast formation, and nitric oxide-mediated renal vasoconstriction. Acute hypovolemia, hemodynamic disturbances or a systemic inflammatory response propagated by the antecedent condition can exacerbate the renal insult.
Rhabdomyolysis is the breakdown of striated muscle. This tissue is at significant risk of trauma due to its lack of bony protection, and is very susceptible to ischemic and metabolic insults due to its highly variable energy requirements. Whatever the insult, the process of rhabdomyolysis seems to be initiated by intracellular calcium influx, up to 10 times the normal intracellular concentration.
This leads to sustained muscle contraction and depletion of intracellular ATP which, combined with the calcium-induced activation of intracellular autolytic enzymes and oxidant stress from calcium-damaged mitochondria, leads to myocyte necrosis and the release of intracellular components into the extra-cellular milieu.
These intracellular contents – phosphates, potassium, uric acid, myoglobin and other proteins, and creatine kinase and other enzymes – propagate an inflammatory response. The damaged muscle sequesters fluid as a consequence of inflammation-provoked localised capillarial leak which leads to edema, local pressure increases and a worsening of ischemia.
The restoration of blood flow to ischemic muscle leads to reperfusion injury – an influx of fluid and neutrophils which exacerbate the inflammatory response by releasing enzymes and inflammatory mediators and provoking further oxidative injury. It also releases the intracellular contents and inflammatory mediators into the systemic circulation leading to the electrolyte disturbances associated with the condition, a systemic inflammatory response and downstream injury to other organ systems.
Compartment syndrome occurs when, due to bleeding, edema, burns or other injury, the pressure within one of the closed body compartments begins to rise. This includes the posterior compartment of the thigh containing the gluteal muscles, the forearm, and the compartments created by the fascial planes of the lower leg.
Once local pressure exceeds that of capillary drainage venous outflow is compromised, increasing local pressure further. Without surgical release arterial supply can be compromised leading to significant muscle ischemia.
When freeing victims of crush injury after major disasters crush syndrome can occur. The pressure of the debris on skeletal muscle induces rhabdomyolysis. On removal of the debris a reperfusion injury occurs. This causes AKI, but may also cause fatal cardiac arrhythmias due to electrolyte disturbance, disseminated intravascular coagulation due to thromboplastin release and acute respiratory distress syndrome. Compartment syndrome is a common consequence of crush injury.
Normal erythrocytes have a lifespan of 120 days. Hemolysis is the destruction of red blood cells before their allotted span. This can be extracorporeal during cardiopulmonary bypass, intravascular due to changes in tonicity, infective agents, valvular disease or complement fixation, or extracellular in the reticuloendothelial system by macrophages, in response to inherent or acquired structural alterations of the cellular membrane preventing passage through this system.
Major incompatibility transfusion reactions occur when ABO-incompatible red cells are transfused into a patient with a reacting antibody. The presence of the antibodies in the plasma of the transfusion recipient leads to complement activation and fixation of the C5b-9 membrane attack complex. This punches holes in the erythrocyte membrane leading to osmolysis.
The fixation of the attack complex also generates C3a, which produces the classic bronchospastic and cardiovascular collapse of anaphylaxis, and C5a, which causes ventilation-perfusion mismatching through pulmonary migration of granulocytes.
The lysed red cell corpses induce renal vasoconstriction, the free hemoglobin has a number of systemic effects detailed below, and complement activation and the release of intracellular contents activates other components of the inflammatory cascade including interleukin-1B, -6 and -8 and tumour necrosis factor-a, leading to a systemic inflammatory response.
Cardiac surgery-associated AKI
CSA-AKI is a well recognised clinical syndrome, but significant argument exists as to the nature of the renal insult sustained during cardiopulmonary bypass-requiring surgeries and there is no clear preventative or therapeutic strategy to ameliorate this condition, which is associated with significant morbidity and mortality.
The likely pathophysiology of CSA-AKI is multifactorial with ischemia-reperfusion, toxins, a systemic inflammatory response, hemodynamic disturbance and oxidative stress all playing a role. Ischemia-reperfusion is intimately related to the generation of oxidative stress and its associated free radical injuries, and with the propagation of a systemic inflammatory response.
CPB has several stages during which profound hemodynamic upset may occur. It is associated with microembolisation and low output states are common post-procedure.
During CPB there are also significant increases in serum free hemoglobin and myoglobin. Free hemoglobin is an independent risk factor for the development of CSA-AKI and correlates with post-operative tubular injury. Studies have shown elevated markers of skeletal muscle breakdown and found serum myoglobin to be predictive of the development of AKI after CPB. This, along with the elevated CK seen post-operatively, would indicate that rhabdomyolysis also plays a role in the pathogenesis of CSA-AKI.
Increasing duration of CPB is independently associated with an increased risk of AKI and it would follow that longer bypass times would be associated with more mechanical trauma to the erythrocytes and higher levels of free pigment.
It is likely that CPB-AKI may be due, certainly in part, to the toxic effects of the hem containing pigments released during CPB.
Myoglobin is a major hem protein of the sarcoplasm of skeletal and cardiac muscle. It is a folded 153-amino acid polypeptide chain with a molecular weight of 17,500 daltons. It contains an iron-porphyrin moiety and as such acts as a store and transportation medium for oxygen.
It has a greater affinity for oxygen than hemoglobin; it can therefore act to provide oxygen for energy production during times of increased metabolic demand by stripping oxygen from circulating hemoglobin and supplying it to muscle mitochondria.
In rhabdomyolysis and other conditions resulting in myoglobinemia, circulating myoglobin is scavenged by haptoglobin and alpha2-globulin. The binding capacity of haptoglobin is overwhelmed by serum concentrations of myoglobin in excess of 0.5-1.5 mg/decilitre. Excess myoglobin is freely filtered by the kidney to enter the urinary space.
Hemoglobin is normally a tetrameric molecule with two pairs of unalike polypeptide chains. Each of these sub-units is associated with an iron-containing hem group responsible for oxygen-binding. The interaction of these chains determines the quaternary structure of the molecule which in turn influences the ability of the tetramer to function as an oxygen transport medium.
The tetramer is large, approximately 64,000 daltons in size. Free hemoglobin is filtered by the kidney, though not as readily as myoglobin. It normally dimerizes in the plasma and is, under normal circumstances, scavenged by haptoglobin. The haptoglobin-hemoglobin complex is readily bound and phagocytosed by monocytes and macrophages which depletes the circulating haptoglobin concentration but leads to the generation of anti-inflammatory cytokines.
Other scavenging mechanisms for hemoglobin include the oxidisation of ferrous hem to ferric hem, which dissociates from the hemoglobin molecule to bind to hemopexin, a plasma glycoprotein. The hem moiety is pro-oxidant and pro-inflammatory. It is broken down by hem oxygenase 1 into carbon monoxide, biliverdin and iron.
The iron is deactivated by the acute phase protein ferritin while biliverdin and carbon monoxide have beneficial anti-inflammatory and anti-oxidant effects. Biliverdin is metabolised to bilirubin.
The capacity of these systems is finite; once overloaded the urinary and plasma concentrations of hemoglobin and free iron rises. Hemoglobin scavenges nitric oxide to produce methemoglobin and nitrate which can lead to marked endothelial dysfunction. Hem produces toxic effects in several ways.
The mechanism of AKI in pigment nephropathy
Current understanding of the pathogenesis of pigment nephropathy suggests a three-fold renal insult and there is an expanding experimental and clinical evidence suggesting that free iron has a significant role in the process.
Hem pigments are concentrated in the renal tubules leading to precipitation, a situation enhanced by the acidic milieu created by the shocked states which may result from massive hemolysis or significant rhabdomyolysis and potentiated by the kidneys attempt to restore circulating volume by the retention of salt and water.
Tamm-Horsfall protein, a ubiquitous endogenous substance, reacts with the pigment to form pigmented casts. The original hypothesis of direct renal tubular obstruction and dilatation is in doubt since micropuncture experiments have shown the casts to be easily removable with low pressure perfusion and intratubular pressures to be low. This would suggest cast formation as a consequence of reduced flow of urine through the tubules rather than complete obstruction.
This is a natural response to the activation of the renin-angiotensin-aldosterone system to maintain intravascular volume if the underlying condition induces hypovolemia. The inflammatory mediators released on cell lysis or generated by reperfusion injury cause renal vasoconstriction.
Nitric oxide is an endogenous vasodilatory agent. Inhibitors of nitric oxide synthesis worsen AKI while agents generating nitric oxide help to preserve renal function. Myoglobin and hemoglobin are direct scavengers of nitric oxide. Other agents released on cellular disruption, including erythrocyte arginase, work in a myriad of ways to reduced nitric oxide concentrations or regeneration, all contributing to endothelial disruption and inappropriate vasoconstriction.
Direct infusion of hemoglobin solutions has shown systemic evidence of vasoconstriction and reduced creatinine clearances in experimental and clinical models.
Several studies have shown evidence of free radical-mediated cellular injury in pigment nephropathy, with high intracellular concentrations of malondialdehyde and progressive signs of cytotoxicity. Ferrous (Fe 2+) iron can be oxidised to ferric (Fe 3+) iron with the generation of a highly reactive hydroxyl ion which then initiate lipid peroxidation. Hem moieties may be able to directly catalyse lipid peroxidation. Radical formation is propagated by the acidic milieu of the renal tubule.
Hem oxygenase is an important mediator of oxidant stress. It catalyses the rate limiting step in hem degradation. Its production is upregulated in many models of AKI. Inhibition worsens renal dysfunction while pre-emptive induction improves outcome in experimental models of AKI, and multiple studies have shown a renoprotective role for this enzyme suggesting that it may be an important therapeutic target in the prophylaxis and treatment of pigment nephropathy.
The role of labile free iron
Iron is released from hem molecules in both hemoglobinemia and myoglobinemia during their breakdown. If normal scavenging mechanisms are overwhelmed or there is a significant concentration of reactive species then it will be released into the systemic circulation.
Labile iron has been shown to be a biomarker of vascular injury. It is a highly reactive species capable of catalysing hydroxyl ion formation and stimulating lipid peroxidation. It is capable of directly inducing changes in renal tubular epithelium.
Experimental evidence suggests that the nephrotoxic effects of gentamicin may be due to the release of iron-gentamicin complexes from the renal cell mitochondria with subsequent oxidative stress. Deferoxamine treatment in experimental models of myoglobinuric renal failure may be renoprotective, suggesting that chelation of free iron may be therapeutic, with a mechanism of action similar to endogenous ferritin.
Evidence is mounting for free iron playing a central role in the pathogenesis of many forms of AKI. CSA-AKI, pigment and gentamicin nephropathy may all be forms of renal sideropathy. Further work regarding the nephrotoxic mechanisms of cisplatin associated AKI, contrast-induced AKI and CKD support the importance of free iron as a major causative factor in the development of renal pathology.
AKI is common in intensive care units – it complicates between 30 and 70% of admissions to critical care. 4-5% of ICU admissions will require RRT. As regards the hospital population, in one study of emergency attendances to hospital AKI complicated 18% of cases. Other work has shown that it complicates up to 20% of inpatient admissions.
Over the last 10 years the incidence of AKI in ICU has been increasing, likely as a consequence of the evolution of the patient demographic over the last decade. This may also explain why, despite increasing information on the pathophysiology of the condition, mortality remains greater than 50% in patients requiring RRT. In addition only recently, with the introduction of the RIFLE and AKIN criteria, has there been an established definition for AKI allowing accurate reporting of the condition.
It is thought that myoglobinuria-associated AKI may account for up to 10% of cases of AKI and that AKI may develop in up to 50% of cases of traumatic rhabdomyolysis. There seems to be a relationship between CK titres and the development of AKI, with CK > 5000 IU/litre having a 50% chance of developing AKI. The risk of requiring RRT also increases with increasing CK – 84% of patients presenting after the Kobe earthquake in Japan with a CK > 75,000 IU/litre required RRT.
Up to 26,000 cases of rhabdomyolysis may be reported yearly in the USA, with 1 in 1000 patients admitted to hospital having an elevated CK. The lack of a biochemical definition for rhabdomyolysis or myoglobinuria means that the true incidence of the disease is difficult to gauge, particularly given the myriad of possible causes and the likelihood of under-reporting of mild cases.
It is difficult to identify the characteristics of the population most at risk of the condition, but alcohol may well be the most common etiological factor. During mass disasters the condition is much more common. Up to 5% of the local population may suffer a crush injury in an earthquake zone.
The epidemiology of AKI as a consequence of hemoglobinuria is not well described in the literature. There is a paucity of information regarding the epidemiology of hemolysis in the intensive care unit. In a case review of 10 patients with massive hemolysis subsequent to the infusion of a hypotonic solution five developed some degree of AKI.
Data from transfusion reporting bodies suggest that 1 major incompatibility reaction occurs for every 100,000 units of PRC transfused with mortality from major incompatibility approximately 1 per 1.8 million PRC transfused. In a confidential enquiry into errors in transfusion practice in the UK there were 366 reported hazards, 62 of which were ABO incompatible transfusion errors. Six of those patients died.
Cardiac surgery associated AKI
AKI complicates 19-45% of the more than 1,000,000 operations utilising cardiopulmonary bypass each year in the developed world. It is thought to be the second most significant contributor to the burden of AKI after sepsis. The RIFLE criteria have been validated in this patient population and show a clear relationship between RIFLE grade and mortality.
Acute kidney injury
In pigment nephropathy the prognosis of the precipitating condition requires consideration, but AKI of any cause has been shown to have a profound effect on mortality. In-hospital and ICU mortality is significantly increased over that expected by illness severity scoring in patients developing any degree of renal impairment.
Hospital mortality varies from 25 – 80% and ICU mortality varies from 20 – 70% with the mortality for AKI requiring RRT reaching 50 – 60%. Several studies have shown significant increases in the risk of mortality with even modest increases in serum creatinine. The development of AKI seems to prime other organ systems for failure and AKI is strongly, independently, associated with the development of multiple organ failure.
Survival from AKI is associated with reduced duration of RRT and rates of RRT dependence, the absence of pre-existing renal disease, the maintenance of urine output, younger age, reduced need for inotropic support and other organ support. 10-20% of survivors will require on-going renal support after discharge from hospital.
Large randomised controlled trials and meta-analysis have failed to show any effect of RRT treatment modality on either mortality or renal recovery. Long-term survival of patients with AKI requiring RRT is impaired, with 50-60% surviving to 28 days, 24-45% surviving for six months, 20-53% surviving 1 year and only 15-52% alive at 5 years. This is independent of the underlying etiology.
The prognosis of rhabdomyolysis appears to be good from the sparse literature, with one study reporting an overall survival rate of almost 80%. In the ICU rhabdomyolysis will typically be associated with multiple co-morbid conditions and this and the severity of resultant pigment nephropathy will undoubtedly affect both patient and renal survival.
Those patients requiring renal support only purely as a consequence of rhabdomyolysis may require ongoing RRT for up to three months after the insult, but most make a functional recovery.
The prognosis of crush syndrome varies throughout the literature. Immediate mortality occurs as a result of massive trauma, head injury, or asphyxiation. Early deaths are caused by electrolyte abnormalities and untreated shock. AKI is a significant cause of death in patients suffering from crush syndrome, as is the propensity to develop sepsis.
Outcome data following significant episodes of hemolysis is sparse in the literature; data regarding the outcome of PI-AKI as a consequence is even scarcer. It is likely that co-morbid conditions, the overall severity of illness and the severity of AKI are more associated with outcome than the fact that the AKI results from hemoglobinuria.
In severe hemolytic transfusion reactions the mortality approaches 4%; however it is unreported how contributory the acute renal insult is given the state of profound circulatory collapse which often accompanies a major incompatibility reaction.
Cardiac surgery-associated AKI
Current evidence suggests that the prognosis of CSA-AKI mirrors that of AKI of other causes. Patients developing AKI post-cardiac surgery display an increased risk of mortality with increasing creatinine concentration. There is a higher incidence of post-operative complications including sepsis, bleeding and neurological injury. ICU and hospital stays are prolonged; readmission rates higher and quality of life reportedly lower after the development of CSA-AKI.
Special considerations for nursing and allied health professionals.
What's the evidence?
Description of the problem
Zager, RA. “Rhabdomyolysis and myohemoglobinuric acute renal failure”. Kidney Int. vol. 49. 1996. pp. 314-326. (Though this review is fourteen years old it includes an excellent review of the conditions and, in particular, the experimental basis of the current understanding of their etiology and pathophysiology.)
Grossman, RA, Hamilton, RW, Morse, BM. “Nontraumatic, rhabdomyolysis and acute renal failure”. New Engl J Med. vol. 291. 1974. pp. 807-811. (A detailed description of the syndrome of acute renal failure as a consequence of nontraumatic myoglobinuria, as well as the changes in calcium homeostasis unique to rhabdomyolysis.)
Dhaliwal, G, Cornett, PA, Tierney, LM. “Hemolytic anemia”. Am Fam Physician. vol. 69. 2004. pp. 2599-2606. (This is a useful review article summarising the different types of hemolytic anemia and discussing the further investigation of the condition.)
David, WS. “Myoglobinuria”. Neurol Clin. vol. 18. 2000. pp. 215-243. (This excellent review article includes a detailed description of the etiology and potential complications of myoglobinuria.)
Knochel, JP. “Catastrophic medical events with exhaustive exercise “White collar rhabdomyolysis.””. Kidney Int. vol. 38. 1990. pp. 709-719. (This provides an overview of exhaustive rhabdomyolysis in as much detail as one could wish.)
Benedetto, U, Angeloni, E, Luciani, R. “Acute kidney injury after coronary artery bypass grafting: does rhabdomyolysis play a role?”. J Thorac Cardiov Sur. vol. 140. 2010. pp. 464-470. (This prospective observational study of over 700 consecutive patients showed a significant correlation between serum myoglobin concentration and the development of AKI after cardiopulmonary bypass, suggesting that pigment nephropathy may be an etiological factor in CSA-AKI.)
Sever, MS, Erek, E, Vanholder, R. “Clinical findings in the renal victims of a catastrophic disaster: the Marmara earthquake”. Nephrol Dial Transpl. vol. 17. 2002. pp. 1942-1949. (A retrospective observational study of the victims of a large scale disaster presenting with renal failure, this article usefully summarises the expected clinical features in such presentations.)
Honda, N. “Acute renal failure and rhabdomyolysis”. Kidney Int. vol. 23. 1983. pp. 888-898. (Though this focuses on a single case of non-traumatic rhabdomyolysis in a patient with LDH M-subunit deficiency, it describes the clinical features of rhabdomyolysis well, with a thorough review of pathogenesis.)
Akmal, M, Bishop, JE, Telfer, N. “Hypocalcemia and hypercalcemia in patients with rhabdomyolysis with and without acute renal failure”. J Clin Endoc Metab. vol. 63. 1986. pp. 137-142. (This small study presents the best evidence for the basis of the characteristic changes in calcium homeostasis noted in rhabdomyolysis; most other sources in the literature are offered as case reports.)
Veenstra, J, Smit, WM, Krediet, RT, Arisz, L. “Relationship between elevated creatine phosphokinase and the clinical spectrum of rhabdomyolysis”. Nephrol Dial Transpl. vol. 9. 1994. pp. 637-641. (This 7-year long observational study from the Netherlands describes in detail clinical course, complications and biochemical abnormalities in those patients presenting with CK values greater than 5000 IU/litre.)
Oh, MS. “Does serum creatinine rise faster in rhabdomyolysis?”. Nephron. vol. 63. 1993. pp. 255-257.
Sever, MS, Erek, E, Vanholder, R. “Serum potassium in the crush syndrome victims of the Marmara disaster”. Clin Nephrol. vol. 59. 2003. pp. 326-33. (A retrospective, questionnaire-based observational study performed in the aftermath of a massive earthquake in Turkey. In this analysis of over 600 cases serum potassium was the most significant predictor of the need for RRT and almost 2/3rds of survivors were hyperkalemic on admission to hospital, highlighting the importance of biochemical monitoring in this condition)
Ron, D, Taitelman, U, Michaelson, M. “Prevention of Acute Renal Failure in Traumatic Rhabdomyolysis”. Arch Intern Med. vol. 144. 1984. pp. 277-280. (In this case series of crush injury victims from the Lebanon, treated pre-extrication with aggressive fluid resuscitation, acute renal failure was successfully prevented, providing the rationale for early intervention in rhabdomyolysis.)
Better, OS, Stein, JH. “Early management of shock and prophylaxis of acute renal failure in traumatic rhabdomyolysis”. New Engl J Med. vol. 322. 1990. pp. 825-829. (Pragmatic guidelines for the emergency management of crush syndrome-induced rhabdomyolysis.)
Hamilton, RW, Hopkins, MB, Shihabi, ZK. “Myoglobinuria, hemoglobinuria, and acute renal failure”. Clin Chem. vol. 35. 1989. pp. 1713-20. (An in-depth discussion of the differential diagnosis of myoglobinuria and hemoglobinuria.)
Beetham, R. “Biochemical investigation of suspected rhabdomyolysis”. Ann Clin Biochem. vol. 37. 2000. pp. 581-587. (A review article which clearly describes strategies for early diagnosis and confirmation in suspected cases of rhabdomyolysis.)
Kasaoka, S, Todani, M, Keneko, T. “Peak value of blood myoglobin predicts acute renal failure induced by rhabdomyolysis”. J Crit Care. vol. 25. 2010. pp. 601-604. (This was a small study in a University Hospital utilising an immunochromatography technique of serum myoglobin determination. The unwieldy and specialist nature of this technique means that, while serum myoglobin may be useful for predicting progression to AKI, it is not very practical, and requires further validation.)
Rodriguez-Capote, K, Balion, CM, Hill, SA. “Utility of urine myoglobin for the prediction of acute renal failure in patients with suspected rhabdomyolysis: a systematic review”. Clin Chem. vol. 55. 2009. pp. 2190-2197. (This systematic review identified 8 studies, 295 patients in total, of marked heterogeneity, assessing the predictive value of urinary myoglobin in predicting renal failure in patients with rhabdomyolysis. Though very sensitive the reported sensitivities varied wildly. There is inadequate evidence to recommend the use of urinary myoglobin in this fashion.)
Matsen, FA, Mayo, KA, Sheridan, GW. “Monitoring of intramuscular pressure”. Surgery. vol. 79. 1976. pp. 702-709. (The original description of techniques for monitoring compartment pressure.)
Huerta-Alardín, AL, Varon, J, Marik, PE. “Bench-to-bedside review: rhabdomyolysis – an overview for clinicians”. Crit Care. vol. 9. 2005. pp. 158-69. (A useful review for the critical care physician and the most recently published in the major critical care journals.)
Kendrick, WC, Hull, AR, Knochel, JP. “Rhabdomyolysis and shock after intravenous amphetamine administration”. Ann Intern Med. vol. 86. 1977. pp. 381-7. (This case series describes the successful use of massive fluid resuscitation to prevent renal failure in a small group of patients suffering from amphetamine-induced rhabdomyolysis.)
Eneas, JF, Schoenfeld, PY, Humphreys, MH. “The effect of infusion of mannitol-sodium bicarbonate on the clinical course of myoglobinuria”. Arch Intern Med. vol. 139. 1979. pp. 801-5. (This is the original article describing mannitol-bicarbonate therapy. It draws no clear conclusions but suggests that patients with significant insults, inferred by hyperphosphatemia and significantly higher levels of CK, are likely to progress on to require RRT despite this therapy.)
Zager, RA, Foerder, C, Bredl, C. “The influence of mannitol on myoglobinuric acute renal failure: functional, biochemical, and morphological assessments”. J Am Soc Nephrol. vol. 2. 1991. pp. 848-55. (Though performed in rats, this is describes an interesting series of experiments trying to define the mechanisms by which mannitol appears to reduce the incidence of acute renal failure in pigment nephropathy. Promotion of diuresis seems to be the most important mechanism.)
Brown, CV, Rhee, P, Chan, L, Evans, K, Demetriades, D, Velmahos, GC. “Preventing renal failure in patients with rhabdomyolysis: do bicarbonate and mannitol make a difference?”. J Trauma. vol. 56. 2004. pp. 1191-6. (This relatively large retrospective analysis of over 2,000 adult trauma ICU admissions showed no effect in preventing AKI, dialysis or death in an American University Hospital, confirming the need for further randomised controlled trials in the management of rhabdomyolysis and pigment nephropathy.)
Zager, RA. “Combined mannitol and deferoxamine therapy for myohemoglobinuric renal injury and oxidant tubular stress: Mechanistic and therapeutic implications”. J Clin Invest. vol. 90. 1992. pp. 711-719. (More animal experiments. These confirm that the diuretic effect of mannitol, in rats at least, is the main mechanism by which it is reno-protective in rhabdomyolysis.)
Splendiani, G, Mazzarella, V, Cipriani, S. “Dialytic treatment of rhabdomyolysis-induced acute renal failure: our experience”. Renal Failure. vol. 23. 2001. pp. 183-191. (This retrospective observational study of a small number of markedly heterogeneous patients describes a single centre’s experience with RRT for the condition, as well as outcome.)
Naka, T, Jones, D, Baldwin, I. “Myoglobin clearance by super high-flux hemofiltration in a case of severe rhabdomyolysis: a case report”. Crit Care. vol. 9. 2005. pp. R90-95. (This case report suggests that in the future super high-flux hemofiltration may be a useful additional therapy in oliguric patients to remove circulating myoglobin and attenuate ongoing renal damage. Evidence from trials in free-chain nephropathy in myeloma patients (proteins with a similar molecular size to myoglobin) will be interesting and may prompt randomised controlled trials in the treatment of rhabdomyolysis (Heyne N, Guthoff M, Weisel KC. Rhabdomyolysis and acute kidney injury. New Engl J Med 2009; 361: 1412; author reply 1412-3).)
Köstler, W, Strohm, PC, Südkamp, NP. “Acute compartment syndrome of the limb”. Injury. vol. 35. 2004. pp. 1221-7. (A thorough review of compartment syndrome, the indications and effect of fasciotomy, and the potential complications.)
Disease monitoring, follow-up and disposition
Ward, MM. “Factors predictive of acute renal failure in rhabdomyolysis”. Arch Intern Med. vol. 148. 1988. pp. 1553(In a small group of heterogeneous patients this study examined those factors deemed predictive of renal failure in patients with rhabdomyolysis by multiple logistic regression analysis. CK, hyperkalemia, hyperphosphatemia, hypoalbuminemia and dehydration were shown to be most predictive. The general applicability is questionable, despite the physiological rationale.)
Sharp, LS, Rozycki, GS, Feliciano, DV. “Rhabdomyolysis and secondary renal failure in critically ill surgical patients”. Am J Surg. vol. 188. 2004. pp. 801(This retrospective analysis of trauma patients suggests that CK >5000, BE > -4, and existing renal impairment on presentation with the presence of urinary myoglobin are the strongest predictive factors for the need for RRT in rhabdomyolysis; this has not been prospectively validated.)
Brown, CV, Rhee, P, Chan, L, Evans, K, Demetriades, D, Velmahos, GC. “Preventing renal failure in patients with rhabdomyolysis: do bicarbonate and mannitol make a difference?”. J Trauma. vol. 56. 2004. pp. 1191-6. (This relatively large retrospective analysis of over 2,000 adult trauma ICU admissions also showed a significant correlation between CK > 5000 IU/litre and the incidence of AKI in patients.)
Erek, E, Sever, M, Serdengecti, K. “An overview of morbidity and mortality in the patients with acute renal failure due to crush syndrome”. Nephrol Dial Transpl. vol. 17. 2002. pp. 33-40. (This retrospective questionnaire-based observational study discusses in depth the clinical course and complications experienced by over 600 patients admitted with AKI secondary to crush injury.)
Lappalainen, H, Tiula, E, Uotila, L, Manttari, M. “Elimination kinetics of myoglobin and creatine kinase in rhabdomyolysis: implications for follow-up”. Crit Care Med. vol. 30. 2002. pp. 2212-2215. (Provides a coherent argument for monitoring rhabdomyolysis patients with regular serum myoglobin measurements but not, as would be necessary in clinical practice, a pragmatic method of measuring it)
Zager, RA, Burkhart, KM, Conrad, DS, Gmur, DJ. “Iron, heme oxygenase, and glutathione: Effects on myohemoglobinuric proximal tubular injury”. Kidney Int. vol. 48. 1995. pp. 1624-1634. (Discussion of the role of myoglobin and hemoglobin in the generation of oxidative stress and subsequent renal injury.)
Paller, MS. “Hemoglobin- and myoglobin-induced acute renal failure in rats: role of iron in nephrotoxicity”. Am J Physiol. vol. 255. 1988. pp. F539-F544. (One of the first papers describing the potential pathological effects of free iron on the kidney.)
Llach, F, Felsenfeld, AJ, Haussler, MR. “The pathophysiology of altered calcium metabolism in rhabdomyolysis-induced acute renal failure”. New Engl J Med. vol. 305. 1981. pp. 117-123. (A very small study, though widely referenced, regarding the changes in calcium homeostasis that are described as characteristic of rhabdomyolysis.)
Rother, RP, Bell, L, Hillmen, P, Gladwin, MT. “The clinical sequelae of intravascular hemolysis and extracellular hemoglobin: a novel mechanism of human disease”. Journal American Med Assoc. vol. 293. 2005. pp. 1653-1662. (This interesting review article summarises the toxic effects of hemoglobinemia in vivo and the underlying pathophysiological mechanisms.)
Haase, M, Bellomo, R, Haase-Fielitz, A. “Novel biomarkers, oxidative stress, and the role of labile iron toxicity in cardiopulmonary bypass-associated acute kidney injury”. J Am Coll Cardiol. vol. 55. 2010. pp. 2024-2033. (A thorough and interesting review of the evidence for CSA-AKI being a pigment nephropathy.)
Lopez, JR, Rojas, B, Gonzales, MA, Terzic, A. “Myoplasmic Ca2+ concentration during exertional rhabdomyolysis”. Lancet. vol. 345. 1995. pp. 424-425. (Intracellular calcium measurements in this study helped to elucidate the probable sequence of initiatory events in early rhabdomyolysis.)
Moore, KP, Holt, SG, Patel, RP. “A causative role for redox cycling of myoglobin and its inhibition by alkalinisation in the pathogenesis and treatment of rhabdomyolysis induced renal failure”. J Biol Chem. vol. 273. 1998. pp. 31731-31737. (This series of animal experiments support a causative role for oxidative injury in the renal failure of rhabdomyolysis. They suggest that, in this model, alkalinisation had a protective effect, which may be attributed to inhibition of myoglobin-induced lipid peroxidation rather than inhibition of cast formation.)
Veenstra, J, Smit, WM, Krediet, RT, Arisz, L. “Relationship between elevated creatine phosphokinase and the clinical spectrum of rhabdomyolysis”. Nephrol Dial Transpl. vol. 9. 1994. pp. 637-641. (This 7-year long observational study from the Netherlands describes in detail the clinical course and epidemiology of a large cohort of patients presenting with rhabdomyolysis.)
Atef, MR, Nadjatfi, I, Boroumand, B, Rastegar, A. “Acute renal failure in earthquake victims in Iran: epidemiology and management”. Q J Med. vol. 87. 1994. pp. 35-40. (A detailed analysis of a large cohort of patients suffering from crush injury as a consequence of a massive earthquake in Iran.)
Brown, CV, Rhee, P, Chan, L, Evans, K, Demetriades, D, Velmahos, GC. “Preventing renal failure in patients with rhabdomyolysis: do bicarbonate and mannitol make a difference?”. Journ of Trauma. vol. 56. 2004. pp. 1191-6. (This relatively large retrospective analysis of over 2,000 adult trauma ICU admissions provides useful prognostic data on patients presenting with traumatic rhabdomyolysis in Western ICUs.)
Bagshaw, SM, George, C, Dinu, I, Bellomo, R. “A multi-centre evaluation of the RIFLE criteria for early acute kidney injury in critically ill patients”. Nephrology, Dialysis and Transplantation. vol. 23. 2008. pp. 1203-1210. (In a heterogeneous population of patients with AKI the RIFLE criteria have been validated as a useful prognostic tool and we imagine that the risk of death in pigment nephropathy is similarly stratified.)
Lafrance, JP, Miller, DR. “Acute kidney injury associates with increased long-term mortality”. Journal of the American Society of Nephrology. vol. 21. 2010. pp. 345-52. (This retrospective analysis confirms that, even for patients not requiring RRT, AKI of all causes increases long term mortality significantly.)
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- 1. Description of the problem
- 2. Emergency Management
- 3. Diagnosis
- 4. Specific Treatment
- 5. Disease monitoring, follow-up and disposition
- Special considerations for nursing and allied health professionals.
- What's the evidence?
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