Version May 2024
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 "Rhabdomyolysis: Clinical manifestations and diagnosis".)
●(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 is 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 "Rhabdomyolysis: Clinical manifestations and diagnosis" and "Acute compartment syndrome of the extremities" and "Drug-induced hemolytic anemia".)
Who needs prevention — For patients with rhabdomyolysis who have plasma creatine kinase (CK) values >5000 units/L and those who have CK values that are increasing regardless of baseline value, we suggest the administration of intravenous (IV) fluid. IV fluids to prevent AKI should be administered until it is clear from sequential laboratory values that the plasma CK level is ≤5000 units/L and not increasing. (See 'Volume administration' below.)
The plasma CK concentration correlates with the severity of muscle injury, and concentrations >5000 units/L identify patients with rhabdomyolysis who are at risk for the development of AKI [3-6]. However, it may be difficult to identify patients who are at high risk based upon the initial plasma CK value since the CK level may still be rising from ongoing muscle injury. 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.
The degree of hemolysis that is associated with the risk of AKI is not known. Given that the risk of AKI associated with hemolysis is uncertain, the decision to use IV crystalloid for the prevention of AKI should be individualized and based upon the degree of hemolysis, likelihood of ongoing hemolysis, and presence of other AKI risk factors, such as preexisting chronic kidney disease or hemodynamic instability. As an example, many experts would administer isotonic saline in the setting of a suspected acute hemolytic transfusion reaction to prevent AKI due to severe hemolysis.
Volume administration — The mainstay of AKI prevention in patients with rhabdomyolysis or hemolysis is early and aggressive volume administration with crystalloid fluids. IV crystalloid maintains or enhances kidney perfusion, thereby minimizing ischemic injury, and increases the urine flow rate, which will limit intratubular cast formation by diluting the concentration of heme pigment within the tubular fluid and wash out partially obstructing intratubular casts.
Choice of IV fluids — For patients with rhabdomyolysis or hemolysis, we suggest initial volume administration with isotonic saline rather than other intravenous (IV) fluids. However, the optimal type of fluid in this setting is not established. 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.
Rate of fluids — Isotonic saline should be administered as soon as possible after the onset of muscle injury/rhabdomyolysis or detection of hemolysis.
●Initial rate – The rate of initial fluid administration differs depending on whether the patient has rhabdomyolysis or hemolysis. Initial fluid requirements are generally more for patients with rhabdomyolysis, who often present with substantial volume depletion due to the sequestration of significant amounts of fluid within damaged muscle.
•In patients with rhabdomyolysis, we initiate isotonic saline at a rate of 1 to 2 L/hour.
•In patients with hemolysis, we initiate isotonic saline at a rate of 100 to 200 mL/hour. A higher initial rate (200 to 300 mL/hour) may be appropriate in patients with more severe hemolysis.
●Titrating fluids – The initial fluid rate should be titrated according to the patient's volume status and urine output, parameters which must be carefully monitored during treatment.
Fluid titration should be directed at correcting volume depletion if present. If volume depletion is not present, subsequent adjustments to the fluid prescription vary according to the clinical scenarios below:
•Volume replete and producing urine – For patients with rhabdomyolysis or hemolysis who are volume replete and are producing urine, we titrate the rate of intravenous fluids to target a goal urine output of approximately 200 to 300 mL/hour while avoiding volume overload. For patients with rhabdomyolysis, this usually means decreasing the amount of administered fluid.
Unless the patient develops signs of volume overload, intravenous fluids should be continued until the muscle injury or hemolysis has largely resolved. Among patients with rhabdomyolysis, fluid repletion should be continued until plasma CK levels decrease to ≤5000 units/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 units/L [3-6]. Among patients with hemolysis, we continue fluids until the lactate dehydrogenase level decreases to <1.5 times the upper limit of normal and the hemoglobin is stable over at least a six-hour period, although there are no data to support these or any other thresholds.
•Volume replete with oligoanuria – For patients with rhabdomyolysis or hemolysis who are volume replete but remain oligoanuric after an aggressive course of initial IV fluid administration (eg, 6 liters for rhabdomyolysis or 3 liters for hemolysis), we decrease intravenous fluids to a rate sufficient only to maintain circulatory support. Fluid administration totals may need to be adjusted in patients with heart failure, and signs and symptoms of volume overload should be assessed frequently in such patients. Patients who are volume replete but do not produce urine after an adequate volume challenge should be considered to have established acute kidney injury. These patients should be closely followed for indications to initiate dialysis. (See 'Established AKI' below.)
•Volume overload – Fluids should be stopped in any patient who develops volume overload. In rhabdomyolysis, substantial peripheral edema may be present in the absence of volume overload due to third-space fluid sequestration. Volume overload in these patients is better assessed by signs of pulmonary congestion or via central hemodynamic monitoring. Loop diuretics may be employed to control volume overload.
The optimal fluid regimen to prevent heme pigment-induced AKI is unclear. The evidence to support an aggressive volume administration 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".)
Bicarbonate in selected patients — Patients with rhabdomyolysis may benefit from urinary alkalinization with bicarbonate therapy with appropriate monitoring. After an adequate diuresis has been established with isotonic saline (see 'Volume administration' above), we generally administer a bicarbonate infusion to patients who have severe rhabdomyolysis, such as those with a serum CK level above 5000 units/L or clinical evidence of severe muscle injury (eg, crush injury) and a rising serum CK level, regardless of the initial value. In such patients, bicarbonate may be given, provided that the following conditions are met:
●Hypocalcemia is not present
●Arterial pH is less than 7.5
●Serum bicarbonate is less than 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'.)
Our approach to bicarbonate administration and monitoring is as follows:
●Administration – Among patients with rhabdomyolysis, we infuse isotonic sodium bicarbonate (150 mEq of sodium bicarbonate added to 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.
Because sodium bicarbonate represents a volume load, the rate of concurrent isotonic saline infusion (see 'Rate of fluids' above) should be decreased by an amount equivalent to the rate of isotonic sodium bicarbonate administered. We continue bicarbonate therapy until the plasma CK level decreases to less than 5000 units/L or until the development of alkalemia, hypocalcemia, or symptomatic fluid overload.
●Monitoring – 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.
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 [1,2,7].
Despite these potential benefits, there is no clear clinical evidence that an alkaline diuresis is more effective than a saline diuresis in preventing AKI [8]. 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'.)
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.
Approaches we do not use
Mannitol — We do not routinely administer mannitol. Mannitol does not have an established benefit in rhabdomyolysis and may cause harm. However, some experts use mannitol as an adjunct to intravenous crystalloid in nonoliguric patients with traumatic rhabdomyolysis, provided close monitoring is possible. (See "Crush-related acute kidney injury", section on 'Use of mannitol'.)
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 [9,10]. However, mannitol did not ameliorate proximal tubular necrosis, suggesting that the induced diuresis was of primary importance [9]. Human studies examining mannitol for prevention of heme pigment-induced AKI are retrospective, limited by coadministration of bicarbonate, and/or report conflicting results [11-14].
Unless the patient is carefully monitored and losses are replaced when appropriate, mannitol can lead to both volume depletion and, since free water is lost with mannitol, hypernatremia [9]. Mannitol administered in very high doses, or to patients with reduced renal excretion due to kidney function impairment, can cause hyperosmolality and volume expansion. 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".)
Loop diuretics — We do not give loop diuretics to prevent AKI in patients with rhabdomyolysis or hemolysis. Loop diuretics have no impact on outcome in AKI [15,16]. 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 [17,18]. (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.
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 [3,19].
TREATMENT
Metabolic abnormalities — Patients should be closely followed for the development of metabolic abnormalities including hyperkalemia, hypocalcemia, hyperphosphatemia, and hyperuricemia. Plasma potassium should be monitored several times daily until stable in patients with rhabdomyolysis and hemolysis. Plasma calcium also should be monitored several times daily in patients with rhabdomyolysis. Hypocalcemia and hyperphosphatemia are not significant features of hemolysis in the absence of AKI. (See "Clinical features and diagnosis of heme pigment-induced acute kidney injury", section on 'Clinical manifestations'.)
●Hypocalcemia – To minimize the late occurrence of hypercalcemia in rhabdomyolysis 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 – 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".)
●Hyperuricemia – 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 [20].
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 [2,19].
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 [21].
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
●General principles – Acute kidney injury (AKI) can occur in patients who have rhabdomyolysis and, less commonly, in patients with hemolysis. 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.
●Prevention
•Who needs prevention – For patients with rhabdomyolysis who have plasma creatine kinase (CK) values >5000 units/L and those who have CK values that are increasing regardless of baseline value, we suggest the administration of intravenous fluid (Grade 2C). Intravenous (IV) fluids to prevent AKI should be administered until it is clear from sequential laboratory values that the plasma CK level is ≤5000 units/L and not increasing. The degree of hemolysis that is associated with the risk of AKI is not known. Given that the risk of AKI associated with hemolysis is uncertain, the decision to use IV fluids for the prevention of AKI should be individualized. (See 'Who needs prevention' above.)
•Volume administration – Early and aggressive IV crystalloid administration is the major preventive therapy for patients at risk for heme-induced AKI.
-Choice of fluid – The optimal fluid for the prevention of heme-induced AKI is not known. For patients with rhabdomyolysis or hemolysis who are to receive intravenous fluid for prevention of AKI, we suggest initial volume administration with isotonic saline rather than other intravenous fluids (Grade 2C). (See 'Choice of IV fluids' above.)
-Rate of administration – The optimal rate of IV fluids for the prevention of heme-induced AKI is not known.
For patients with rhabdomyolysis, we initiate isotonic saline at a rate of 1 to 2 L/hour. The rate is adjusted to target a goal urine output of approximately 200 to 300 mL/hour while avoiding volume overload.
For patients with hemolysis, we initiate isotonic saline at a rate of 100 to 200 mL/hour. A higher initial rate (200 to 300 mL/hour) may be appropriate in patients with more severe hemolysis. In general, the volume requirements for patients with hemolysis are less than those of patients with rhabdomyolysis. (See 'Rate of fluids' above.)
•Urinary alkalinization – Limited data suggest that alkalinization of urine may benefit patients with severe rhabdomyolysis. For patients with severe rhabdomyolysis (ie, serum CK level >5000 units/L or clinical evidence of severe muscle injury and a rising serum CK level) in whom a diuresis has been established with volume administration, we suggest IV sodium bicarbonate infusion (Grade 2C). However, sodium bicarbonate should not be administered to patients who have hypocalcemia, alkalemia, or volume overload. Sodium bicarbonate should be discontinued if the urine pH does not rise above 6.5 after three to four hours. (See 'Bicarbonate in selected patients' above.)
•Role of diuretics – 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 'Loop diuretics' above.)
●Treatment
•Metabolic abnormalities – Plasma potassium and calcium should be monitored several times daily until stable. Hyperkalemia should be treated. Calcium supplementation should be given only for symptomatic hypocalcemia or severe hyperkalemia. (See 'Metabolic abnormalities' above.)
•Established AKI – Other than maintenance of fluid and electrolyte balance and tissue perfusion, there is no specific therapy once the patient has developed AKI. Dialysis may be necessary for treatment of hyperkalemia, acidosis, or volume overload. (See 'Established AKI' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Joseph A Eustace, MB, MHS, MRCPI, who contributed to earlier versions of this topic review.
The UpToDate editorial staff also acknowledges Sinead Kinsella, MD, MBS, MRCPI, now deceased, who contributed to earlier versions of this topic.
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