INTRODUCTION — Acute kidney injury (AKI) can occur in patients who have rhabdomyolysis and, less commonly, in patients with hemolysis [1,2]. In both groups of patients, AKI is caused by the nonprotein heme pigment that is released from either myoglobin or hemoglobin and is toxic to the kidney.
The prevention and treatment of heme pigment-induced AKI due to nontraumatic rhabdomyolysis or hemolysis will be reviewed here. The clinical features and diagnosis of this disorder, AKI due to traumatic muscle injury, overviews of rhabdomyolysis and hemolysis, and the general management of oliguric AKI and its complications are discussed elsewhere:
●(See "Clinical features and diagnosis of heme pigment-induced acute kidney injury".)
●(See "Crush-related acute kidney injury".)
●(See "Clinical manifestations and diagnosis of rhabdomyolysis".)
●(See "Diagnosis of hemolytic anemia in adults".)
PREVENTION — In addition to treating the underlying rhabdomyolysis or hemolysis, the general goals for prevention of AKI in all patients at risk for heme pigment-induced AKI are twofold:
●Correction of volume depletion if present
●Prevention of intratubular cast formation
The underlying conditions and factors that have led to rhabdomyolysis or hemolysis must also be addressed to avoid continued heme pigment release.
These issues are reviewed here. The prevention of AKI in patients who have suffered trauma and are entrapped at the site of trauma are discussed separately. (See "Crush-related acute kidney injury", section on 'Prevention'.)
The general approaches to the treatment of the factor(s) causing rhabdomyolysis (including an acute compartment syndrome) or hemolysis are discussed in detail elsewhere. (See "Clinical manifestations and diagnosis of rhabdomyolysis" and "Acute compartment syndrome of the extremities" and "Drug-induced hemolytic anemia".)
Volume administration — The prevention of AKI requires early and aggressive fluid resuscitation. The goals of volume repletion are to maintain or enhance kidney perfusion, thereby minimizing ischemic injury, and to increase the urine flow rate, which will limit intratubular cast formation by diluting the concentration of heme pigment within the tubular fluid, wash out partially obstructing intratubular casts, and increase urinary potassium excretion.
Intravenous isotonic saline should be administered as soon as possible after the onset of injury (even while the patient is being rescued) or detection of hemolysis and continued until the muscle injury or hemolysis has resolved. The evidence to support this strategy is largely based upon studies of traumatic crush injuries that have resulted from large-scale natural or manmade disasters. Although these studies are predominantly retrospective and underpowered, they are believed to be broadly applicable to AKI that is due to nontraumatic rhabdomyolysis and to hemolysis as well, given their common underlying pathogeneses. These studies are discussed elsewhere. (See "Crush-related acute kidney injury".)
The optimal fluid and rate of repletion are unclear. No studies have directly compared the efficacy and safety of different types and rates of fluid administration in this setting. In particular, no studies have directly compared the use of chloride-restricted (bicarbonate, lactate, or acetate as the accompanying anion) versus chloride-liberal fluid resuscitation strategies in the prevention of heme pigment-induced AKI due either to rhabdomyolysis or hemolysis. (See "Treatment of severe hypovolemia or hypovolemic shock in adults", section on 'Buffered crystalloid'.)
In addition, the total amount and rate of volume repletion will vary depending on the underlying cause of rhabdomyolysis and hemolysis.
As an example, attempted aggressive volume resuscitation in the setting of massive hemolysis may result in volume overload and pulmonary edema, especially in patients with compromised cardiac function. In contrast, volume overload is less likely to occur in patients with rhabdomyolysis, at least during its initial stages, due to the sequestration of significant amounts of fluid within damaged muscle.
For patients who are at risk for heme-associated AKI due to rhabdomyolysis from any cause, we suggest initial fluid resuscitation with isotonic saline at a rate of 1 to 2 L/hour. The plasma creatine kinase (CK) concentration correlates with the severity of muscle injury, and concentrations >5000 unit/L identify patients who are at risk for the development of AKI. CK levels typically rise within 12 hours of the onset of muscle injury, peak within 24 to 72 hours, and normalize around five days after the cessation of muscle injury. However, it may be difficult to identify patients who are at high risk for AKI based upon the initial plasma CK value since the CK level may still be rising from ongoing muscle injury. Thus, sequential CK measurements are critical in tailoring therapeutic interventions.
In addition, the McMahon score, which can be calculated at the time of presentation, predicts the risk of AKI requiring kidney replacement therapy (KRT) [3,4]. Variables in this risk prediction model include age, sex, underlying etiology of rhabdomyolysis, and initial laboratory values (ie, calcium, CK, phosphate, and bicarbonate). A McMahon score <5 indicates a 2 to 3 percent risk of KRT or death, whereas a score >10 indicates roughly a 50 to 60 percent risk of KRT or death.
All patients should be initially treated with vigorous fluid repletion until it is clear from sequential laboratory values that the plasma CK level is stable and not increasing. Patients who have a stable plasma CK level <5000 unit/L do not require intravenous fluid, since studies have shown that the risk of AKI is low among such patients [5-8].
Fluid requirements may be less among patients with hemolysis, who are generally less volume depleted than patients who have rhabdomyolysis. In patients who are at risk for heme-associated AKI due to hemolysis, we suggest isotonic saline at an initial rate of 100 to 200 mL/hour. The degree of hemolysis that is associated with the risk of AKI is not known. All patients should be initially treated with intravenous saline, providing volume overload is not present. Fluid administration should continue until hemolysis is controlled unless the patient develops signs of volume overload.
The volume status of the patient should be carefully assessed and urine output monitored. The initial rate is continued until the systemic blood pressure normalizes and the patient starts to produce urine or there is evidence of volume overload. Volume overload is defined by signs of pulmonary congestion or via central hemodynamic monitoring since peripheral edema may be present, even in the absence of volume overload, due to third space sequestration. If an adequate diuresis is established, fluids are titrated to maintain a urine output of 200 to 300 mL/hour.
Among patients with rhabdomyolysis, fluid repletion should be continued until plasma CK levels decrease to <5000 unit/L and continue to fall. Studies have shown that there is a low likelihood of AKI when peak CK levels are under 5000 to 10,000 unit/L [5-8]. Among patients with hemolysis, lactate dehydrogenase (LDH) and hemoglobin levels should be monitored to guide intravenous fluid therapy and indicate when to stop fluid administration. (See "Clinical features and diagnosis of heme pigment-induced acute kidney injury", section on 'Other laboratory findings'.)
Bicarbonate — Patients with rhabdomyolysis who are appropriately monitored may benefit from bicarbonate therapy. We generally administer a bicarbonate infusion to patients who have severe rhabdomyolysis, such as those with a serum CK above 5000 unit/L or clinical evidence of severe muscle injury (eg, crush injury) and a rising serum CK, regardless of the initial value. In such patients, bicarbonate may be given, providing the following conditions are met:
●Hypocalcemia is not present
●Arterial pH is less than 7.5
●Serum bicarbonate is less 30 mEq/L
We generally do not administer bicarbonate to patients with hemolysis, unless another indication is present (such as concurrent rhabdomyolysis, which may occur in the settings of envenomation and poisonings). The use of bicarbonate has not been evaluated in patients with hemolysis. (See "Clinical features and diagnosis of heme pigment-induced acute kidney injury", section on 'Causes of hemolysis'.)
Among patients with rhabdomyolysis, we infuse approximately 130 mEq/L of sodium bicarbonate (150 mL [3 amps] of 8.4 percent sodium bicarbonate mixed with 1 L of 5 percent dextrose or water) via an intravenous line separate from that used for the isotonic saline infusion. The initial rate of infusion is 200 mL/hour; the rate is adjusted to achieve a urine pH of >6.5.
If bicarbonate is given, the arterial pH and serum calcium should be monitored every two hours during the infusion. The bicarbonate infusion should be discontinued if the urine pH does not rise above 6.5 after three to four hours, if the patient develops symptomatic hypocalcemia, if the arterial pH exceeds 7.5, or if the serum bicarbonate exceeds 30 mEq/L. If the bicarbonate solution is discontinued, volume repletion should be continued with isotonic saline.
If a diuresis is established, we suggest continuing bicarbonate therapy until plasma CK decreases to less than 5000 unit/L or symptomatic fluid overload develops.
A forced alkaline diuresis, in which the urine pH is raised to above 6.5, may diminish the kidney toxicity of heme pigments. In theory, urine alkalinization prevents heme-protein precipitation with Tamm-Horsfall protein and therefore intratubular pigment cast formation. Alkalinization may also decrease the release of free iron from myoglobin, the formation of vasoconstricting F2-isoprostanes, and the risk for tubular precipitation of uric acid [1,2,9].
Despite these potential benefits, there is no clear clinical evidence that an alkaline diuresis is more effective than a saline diuresis in preventing AKI [10]. The only data in support of an alkaline diuresis are derived from uncontrolled case series in which a benefit was demonstrated among patients with severe rhabdomyolysis. These data are discussed elsewhere. Data on the combination of bicarbonate and mannitol are presented below. (See "Crush-related acute kidney injury", section on 'Use of bicarbonate' and 'Mannitol' below.)
In addition to a lack of clear evidence of benefit, maintaining the urine pH above 6.5 is difficult in patients with AKI. There are also potential risks to alkalinization of the plasma, such as promoting calcium phosphate deposition (which is more likely if hyperphosphatemia is present) and inducing or worsening the manifestations of hypocalcemia by both a direct membrane effect and a reduction in ionized calcium levels [1]. Manifestations of severe hypocalcemia include tetany, seizures, and cardiac arrhythmias. (See "Clinical manifestations of hypocalcemia".)
The alkalinization of urine could increase the risk of intratubular deposition of calcium-phosphate in the setting of rhabdomyolysis-induced hyperphosphatemia.
Mannitol — We do not routinely administer mannitol. The benefit of mannitol in rhabdomyolysis is not established. Experimental studies suggested that mannitol might be protective by causing a diuresis, which minimizes intratubular heme pigment deposition and cast formation, and/or by acting as a free radical scavenger, thereby minimizing cell injury [11,12]. However, mannitol did not ameliorate proximal tubular necrosis, suggesting that the induced diuresis was of primary importance [11].
The available retrospective series in humans reported conflicting results regarding the effectiveness of combined administration of bicarbonate and mannitol in preventing heme pigment-induced acute tubular necrosis (ATN) [13-16]. In a series of 382 patients with serum CK concentration >5000 unit/L, 154 (40 percent) were treated with bicarbonate and mannitol [16]. There was no statistically significant difference in the incidence of kidney failure (defined as serum creatinine >2.0 mg/dL [177 micromol/L]; 22 versus 18 percent), dialysis (7 versus 6 percent), or death (15 versus 18 percent) in patients who were or were not treated with bicarbonate and mannitol, respectively. However, there was a trend toward improved outcomes in patients with extremely high serum CK levels (greater than 30,000 unit/L) treated with bicarbonate and mannitol.
Unless the patient is carefully monitored and losses replaced when appropriate, mannitol can lead to both volume depletion and, since free water is lost with mannitol, hypernatremia [11]. Mannitol administered in very high doses, or to patients with reduced renal excretion due to kidney function impairment, can cause hyperosmolality, volume expansion, and hyperosmolar hyponatremia. The increase in plasma osmolality can also cause passive movement of potassium out of cells and raise the plasma potassium concentration. AKI may occur if patients are treated with more than 200 g of mannitol per day. (See "Complications of mannitol therapy".)
The use of mannitol administration may be of benefit in patients with marked elevations in CK (>30,000 unit/L); however, even in these patients with severe rhabdomyolysis, the true benefit associated with mannitol administration remains undefined. (See "Crush-related acute kidney injury", section on 'Use of mannitol'.)
If mannitol is given, adding 50 mL of 20 percent mannitol (1 to 2 g/kg per day [total, 120 g], given at a rate of 5 g per hour) to each liter of fluid is suggested. Mannitol is contraindicated in patients with oligoanuria, and patients should have adequate urine outputs (>20 mL/hour).
If mannitol is given, the plasma osmolal gap should be measured and mannitol discontinued if the osmolal gap rises above 55 mosmol/kg (calculator 1 and calculator 2). Mannitol should be discontinued if the desired diuresis of approximately 200 to 300 mL/hour cannot be achieved since there is a risk of hyperosmolality, volume overload, and hyperkalemia with continued mannitol administration under these conditions. (See "Complications of mannitol therapy".)
Loop diuretics — We do not give loop diuretics unless volume overload is present. Loop diuretics have no impact on outcome in AKI [17,18]. In the context of rhabdomyolysis, loop diuretics may worsen the already existing trend for hypocalcemia since they induce calciuria and may increase the risk of cast formation [19,20]. (See "Possible prevention and therapy of ischemic acute tubular necrosis".)
Despite these concerns, however, judicious use of loop diuretics may be justified in patients with rhabdomyolysis or hemolysis if there is evidence of volume overload.
Patients who remain oliguric or anuric despite aggressive volume resuscitation should be considered to have established AKI. Among such patients, the rate of fluid administration should be decreased to a rate sufficient to maintain circulatory support. Such patients should be closely followed for indications to initiate dialysis. (See 'Treatment of established AKI' below.)
Dialysis — The use of dialysis to remove myoglobin, hemoglobin, or uric acid in order to prevent the development of kidney injury has not been demonstrated [5,21].
TREATMENT
Treatment of metabolic abnormalities — Patients should be closely followed for the development of metabolic abnormalities including hyperkalemia, hypocalcemia, hyperphosphatemia, and hyperuricemia. (See "Clinical features and diagnosis of heme pigment-induced acute kidney injury", section on 'Clinical manifestations'.)
To minimize the late occurrence of hypercalcemia as well as the risk of calcium-phosphate precipitation, calcium supplementation for hypocalcemia should be avoided unless significant signs and symptoms of hypocalcemia develop or calcium administration is required for the management of hyperkalemia.
Hyperkalemia should be anticipated and may occur even in the absence of severe AKI. Hyperkalemia should be aggressively treated with standard medical management. Dialysis may be required to treat severe hyperkalemia. (See "Treatment and prevention of hyperkalemia in adults".)
Patients who develop hyperuricemia should be treated with allopurinol. Allopurinol should be given orally at 300 mg if uric acid levels are >8 mg/dL (476 micromol/L) or if there is a 25 percent increase from baseline. Allopurinol is not indicated in the treatment of hemolysis in the absence of hyperuricemia.
We do not give rasburicase (recombinant xanthine oxidase) to hyperuricemic patients with rhabdomyolysis or hemolysis, as it has not been sufficiently studied in these circumstances. However, rasburicase is effective to rapidly lower serum uric acid concentrations in tumor lysis syndrome and was effective in two children with hyperuricemia and AKI from rhabdomyolysis [22].
Treatment of established AKI — Other than maintenance of fluid and electrolyte balance and tissue perfusion, there is no specific therapy once the patient has developed AKI. The initiation of dialysis may be necessary for control of volume overload, hyperkalemia, severe acidemia, and uremia. A detailed discussion of the indications for dialysis is presented elsewhere. (See "Kidney replacement therapy (dialysis) in acute kidney injury in adults: Indications, timing, and dialysis dose".)
Peritoneal dialysis may not be sufficient to achieve adequate metabolic control in patients with severe rhabdomyolysis, which may necessitate frequent hemodialysis or the use of high-dose continuous kidney replacement therapy (KRT) [2,21].
PROGNOSIS — The overall prognosis for patients with heme-induced AKI is favorable as most survivors recover sufficient kidney function to be dialysis independent, and many will recover to normal or near-normal kidney function [23].
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Chronic kidney disease in adults".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topic (see "Patient education: Rhabdomyolysis (The Basics)")
SUMMARY AND RECOMMENDATIONS
●Patients with rhabdomyolysis are at risk for heme-induced acute kidney injury (AKI). Early and aggressive fluid resuscitation is the major preventive therapy. We recommend that all patients with rhabdomyolysis who have plasma creatine kinase (CK) values >5000 unit/L and those who have CK values that are increasing regardless of baseline value be administered intravenous fluid (Grade 1B). (See 'Volume administration' above.)
●The optimal fluid for the prevention of heme-induced AKI is not known. For patients with rhabdomyolysis who are to receive intravenous fluid, we suggest initial volume repletion with isotonic saline rather than other fluids (Grade 2C). (See 'Volume administration' above.)
●The optimal rate of repletion for the prevention of heme-induced AKI is not known. For patients with rhabdomyolysis who are to receive intravenous fluid, we suggest initial volume repletion at a rate of 1 to 2 L/hour rather than lower or higher rates (Grade 2C). The rate is adjusted to maintain the desired diuresis of approximately 200 to 300 mL/hour. (See 'Volume administration' above.)
●Heme-induced AKI from hemolysis may also be prevented by volume repletion. The volume requirements for patients with hemolysis are generally less than the volume requirements of patients with rhabdomyolysis. For patients at risk for heme-induced AKI from hemolysis, we suggest initial volume repletion with isotonic saline at a rate of 100 to 200 mL/hour rather than lower or higher rates (Grade 2C). (See 'Volume administration' above.)
●Limited data suggest that alkalinization of urine may benefit patients with severe rhabdomyolysis. The administration of bicarbonate may cause severe alkalosis among anuric patients. For patients with rhabdomyolysis in whom a diuresis is established with volume repletion, we suggest the administration of an alkaline solution rather than isotonic saline, providing the patient is not hypocalcemic and has an arterial pH less than 7.5 and a serum bicarbonate less than 30 mEq/L (Grade 2C). (See 'Bicarbonate' above and "Crush-related acute kidney injury", section on 'Use of bicarbonate'.)
The alkaline solution should be discontinued if the urine pH does not rise above 6.5 after three to four hours of the alkaline solution, if the arterial pH increases to 7.5, if the serum bicarbonate exceeds 30 mEq/L, or if symptomatic hypocalcemia develops. If the bicarbonate solution is discontinued, volume repletion should be continued with isotonic saline. (See 'Bicarbonate' above.)
●Loop diuretics have not been shown to be effective in preventing heme pigment-induced AKI but may be given to patients who develop volume overload as a result of aggressive volume administration. (See 'Mannitol' above.)
●Plasma potassium and calcium should be monitored several times daily until stable. Hyperkalemia should be treated as discussed elsewhere. (See "Treatment and prevention of hyperkalemia in adults".)
●Calcium supplementation should be given only for symptomatic hypocalcemia or severe hyperkalemia. (See "Treatment of hypocalcemia" and "Treatment and prevention of hyperkalemia in adults".)
●Dialysis may be necessary for control of hyperkalemia and correction of acidosis or for the treatment of volume overload. (See 'Treatment of established AKI' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Joseph A Eustace, MB, MHS, MRCPI, who contributed to an earlier version of this topic review.
The UpToDate editorial staff also acknowledges Sinead Kinsella, MD, MBS, MRCPI, now deceased, who contributed to an earlier version of this topic.
1 : Rhabdomyolysis: an evaluation of 475 hospitalized patients.
2 : Rhabdomyolysis.
3 : A risk prediction score for kidney failure or mortality in rhabdomyolysis.
4 : Rhabdomyolysis and acute kidney injury: creatine kinase as a prognostic marker and validation of the McMahon Score in a 10-year cohort: A retrospective observational evaluation.
5 : Prognostic value, kinetics and effect of CVVHDF on serum of the myoglobin and creatine kinase in critically ill patients with rhabdomyolysis.
6 : Serum creatine kinase as predictor of clinical course in rhabdomyolysis: a 5-year intensive care survey.
7 : Epidemiologic aspects of the Bam earthquake in Iran: the nephrologic perspective.
8 : Relationship between elevated creatine phosphokinase and the clinical spectrum of rhabdomyolysis.
9 : Rhabdomyolysis and Myoglobin-induced Acute Renal Failure.
10 : Bench-to-bedside review: Rhabdomyolysis -- an overview for clinicians.
11 : Combined mannitol and deferoxamine therapy for myohemoglobinuric renal injury and oxidant tubular stress. Mechanistic and therapeutic implications.
12 : The role of reperfusion-induced injury in the pathogenesis of the crush syndrome.
13 : Prevention of acute renal failure in traumatic rhabdomyolysis.
14 : Early and vigorous fluid resuscitation prevents acute renal failure in the crush victims of catastrophic earthquakes.
15 : Prophylaxis of acute renal failure in patients with rhabdomyolysis.
16 : Preventing renal failure in patients with rhabdomyolysis: do bicarbonate and mannitol make a difference?
17 : Loop diuretics for patients with acute renal failure: helpful or harmful?
18 : Diuretics, mortality, and nonrecovery of renal function in acute renal failure.
19 : Rhabdomyolysis and myoglobinuric renal failure in trauma and surgical patients: a review.
20 : Management of crush-related injuries after disasters.
21 : Pathogenesis of renal failure in rhabdomyolysis: the role of myoglobin.
22 : Rasburicase improves hyperuricemia in patients with acute kidney injury secondary to rhabdomyolysis caused by ecstasy intoxication and exertional heat stroke.
23 : The clinical and biochemical features of acute renal failure due to rhabdomyolysis.
