Wong FHA, See KC. Critical care considerations in rhabdomyolysis-associated acute kidney injury and kidney replacement therapy. World J Nephrol 2026; 15(2): 118309 [DOI: 10.5527/wjn.v15.i2.118309]
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Faith Hui Ai Wong, Department of Medicine, National University Hospital, Level 10 NUHS Tower Block, 119228, Singapore. faithwonghuiai@u.nus.edu
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Urology & Nephrology
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review-article
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Wong FHA, See KC. Critical care considerations in rhabdomyolysis-associated acute kidney injury and kidney replacement therapy. World J Nephrol 2026; 15(2): 118309 [DOI: 10.5527/wjn.v15.i2.118309]
Author contributions: Wong FHA conducted the literature review and wrote the manuscript; See KC conceptualised the review, critically revised the manuscript, and provided academic supervision. Both authors read and approved the final manuscript.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Corresponding author: Faith Hui Ai Wong, Department of Medicine, National University Hospital, Level 10 NUHS Tower Block, 119228, Singapore. faithwonghuiai@u.nus.edu
Received: December 29, 2025 Revised: February 28, 2026 Accepted: March 23, 2026 Published online: June 25, 2026 Processing time: 168 Days and 18.8 Hours
Abstract
Rhabdomyolysis is a frequently seen and potentially severe condition in intensive care, resulting from causes like trauma, infection, drug toxicity, or prolonged immobility. When muscle cells break down, substances such as myoglobin enter the bloodstream, increasing the risk of acute kidney injury (AKI), which greatly affects patient outcomes. Prompt diagnosis, effective fluid management, and supportive care are crucial for reducing kidney-related complications. In more critical situations, standard treatments may not be enough, and kidney replacement therapy (KRT) may be required. This review offers practical, evidence-based guidance on managing AKI associated with rhabdomyolysis, focusing on decision-making in critical care settings. Main topics include understanding disease mechanisms and assessing risk, strategies for fluid resuscitation, managing electrolytes and acid-base balance, and considering additional medications. It also discusses when and how to start KRT, comparing continuous and intermittent methods, and reviews practical aspects of removing myoglobin from circulation. The article highlights new developments, such as early detection biomarkers for AKI and advanced extracorporeal techniques. By combining scientific knowledge with hands-on clinical recommendations, this review helps healthcare professionals provide the best possible care for patients with rhabdomyolysis who develop AKI, including those needing KRT.
Core Tip: Rhabdomyolysis-associated acute kidney injury (AKI) remains a serious concern in critical care, with management strategies often limited by a lack of clinical evidence. This review synthesises underlying pathophysiological mechanisms, current established and novel biomarkers, early AKI risk prediction scores and key management strategies, including fluid resuscitation and addressing debates regarding urine alkalisation and the role of kidney replacement therapy. By integrating a holistic understanding of pathophysiology with evidence-guided clinical practice, this article supports more informed and individualised care for critically ill patients with rhabdomyolysis-associated AKI, while highlighting possible future therapeutic directions.
Citation: Wong FHA, See KC. Critical care considerations in rhabdomyolysis-associated acute kidney injury and kidney replacement therapy. World J Nephrol 2026; 15(2): 118309
Rhabdomyolysis is a clinical syndrome of destruction of skeletal muscle, causing disruption and release of myoglobin, creatine kinase (CK) and lactate dehydrogenase into circulation[1,2]. It is frequently characterised by myalgia, weakness and dark urine, and associated with acute kidney injury (AKI), myoglobinuria and electrolyte imbalances[3]. Often seen in critically ill patients in intensive care units (ICU), the diagnosis of rhabdomyolysis is most commonly made when serum CK levels are five times the upper limit of normal (> 1000 IU/L)[4-6].
From a previous study with 1084 patients in a surgical ICU in Macedonia, the incidence of rhabdomyolysis was 8.58%[2]. In another study from Malaysia, the incidence in the general ICU was found to be 9.2%, of which 36.2% of rhabdomyolysis patients developed AKI[7]. Furthermore, male patients, patients with a greater mean body mass index and prolonged operating times have a higher risk of developing rhabdomyolysis[8]. A retrospective study of 151 ICU patients in China showed significantly poorer clinical outcomes in patients with rhabdomyolysis, with a higher mortality rate than those without[9].
There were also poorer outcomes in patients with rhabdomyolysis-related AKI than those without AKI[9], with a 5-year study finding that patients who had AKI had a mortality rate three times higher than those without AKI[10]. Risk factors of developing AKI following rhabdomyolysis include sepsis, trauma and prolonged surgery[7]. Early vigorous fluid resuscitation can prevent myoglobinuric AKI and reduce mortality in patients with rhabdomyolysis[11].
The mortality rate of rhabdomyolysis-associated AKI at day 28 of a study done in France was 10.9%[12], with another retrospective cohort study stating that number to be 22.5% during hospitalisation, further increasing to 40.0% in patients who require kidney replacement therapy (KRT)[13]. Furthermore, almost 30% of patients had an estimated glomerular filtration rate of less than 60 mL/minute/1.73 m2 at month 3, compared to 11.2% before hospital admission for rhabdomyolysis[12]. Therefore, a comprehensive understanding and early management of rhabdomyolysis and related AKI can change patients’ recovery outcomes. This review aims to discuss the pathophysiology and clinical features of rhabdomyolysis-related AKI and important critical care management strategies.
PATHOPHYSIOLOGY OF RHABDOMYOLYSIS-ASSOCIATED AKI
In the ICU, rhabdomyolysis can develop and is often multifactorial. The predominant causes vary greatly, but most commonly include previous prolonged surgery, resuscitation and ischemia by vascular obstruction[10,14]. Due to its peripheral location, skeletal muscle is more susceptible to hypoxia and vascular compromise. Immobilisation during unconsciousness and prolonged surgeries also increases the risk of ischemia and vascular obstruction[3]. Aggressive resuscitation can be very traumatic, resulting in rhabdomyolysis[15]. These causes, along with the other aetiologies of rhabdomyolysis, which must also be considered, can be divided into two major categories: Acquired and genetic[16] (Table 1).
In normal function within a myocyte, sodium and potassium levels are regulated by the sodium-potassium ATPase pump, which transports 3 sodium ions out and 2 potassium ions into the cell using ATP. The high sodium concentration extracellularly works in favour of the sodium-calcium exchanger, driving calcium extracellularly in exchange for sodium. Intracellularly, an active calcium ATPase, which also requires ATP, regulates calcium levels by controlling its entry into the sarcoplasmic reticulum and mitochondria[17].
Regardless of aetiology, the underlying pathophysiology follows a common mechanism (Figure 1). When muscle perfusion is reduced in rhabdomyolysis, intracellular ATP is depleted, resulting in the deregulation of the sodium-potassium ATPase pump and the calcium ATPase. Calcium is no longer moved extracellularly or into the sarcoplasmic reticulum, resulting in high intracellular calcium levels[17]. This activates cytolytic enzymes such as hydroxylases, proteases and nucleases, impairing cell organelles, especially the mitochondria. Eventually, ATP levels decrease, free oxygen radicals are produced, and ultimately, cell damage occurs. Intracellular contents, including potassium, phosphate, myoglobin, CK and lactate dehydrogenase, among others, are released into circulation[1].
Figure 1 Different aetiologies leading to ATP depletion and cellular breakdown.
Furthermore, in aetiologies where there is direct injury to the myocyte, a disruption in the muscle cell membrane will lead to an influx of calcium, alongside further release of calcium due to damage to the sarcoplasmic reticulum and mitochondria[3]. Myoglobin has been known as the nephrotoxin most directly implicated in rhabdomyolysis-related AKI[18]. Several mechanisms working in conjunction have been discussed in various papers on how myoglobin causes renal injury.
Direct tubular toxicity and oxidative stress
One of the most important mechanisms is that of oxidative injury through reactive oxygen species (ROS) (Figure 2). As myoglobin passes through the nephrons, it is internalised in the proximal convoluted tubule. Within tubular epithelial cells, myoglobin is broken down into iron, carbon monoxide and biliverdin via heme-oxygenase-1. Iron builds up, and excess iron combines with hydrogen peroxide to produce hydroxyl radicals and ferric iron through the Fenton reaction. This process of iron cycling amplifies the formation of ROS[1]. In parallel, ferric myoglobin is oxidised to ferryl-myoglobin, which initiates large amounts of lipid peroxidation, further increasing oxidative stress[19]. Overproduction of ROS can damage cells via peroxidation of fatty acids and production of malondialdehyde, which can cause polymerisation of protein and DNA[1].
Myoglobin also causes problems of tubular obstruction in the ascending loop of Henle, where it combines with Tamm-Horsfall protein, forming a pH-dependent precipitate. The tubular casts formed occlude the distal renal tubule, increasing intratubular pressure. Vascular flow and perfusion are reduced, promoting inflammation, and glomerular filtration rate falls through the altered Starling’s forces[19].
Renal hemodynamic changes
Hemodynamically, third spacing occurs due to damaged muscle, resulting in a drop in intravascular fluid volume. This stimulates the renin-angiotensin-aldosterone system, vasopressin production and the sympathetic nervous system, all contributing to renal vasoconstriction[20]. Lipid peroxidation also produces isoprostanes, which, along with other vascular mediators such as endothelin-1, thromboxane-A2 and tumour necrosis factor a, cause vasoconstriction and contribute to renal arteriolar dysregulation and hypoperfusion[3,20].
These mechanisms do not work in silo, and there are many factors in play, including volume status and pH levels. Tubular cast formation increases with volume depletion, renal vasoconstriction and a more acidic urine. Stronger and more rapid bonds are formed between the Tamm-Horsfall protein and myoglobin, and myoglobin is progressively less soluble with decreasing urinary pH, resulting in a higher percentage of precipitation, causing more tubular obstruction[1,21]. Furthermore, a lower pH leads to increased production of lipid radicals, initiating more myoglobin-induced lipid peroxidation by making ferryl-myoglobin more reactive towards lipids and lipid hydroperoxides. This worsens oxidative stress, exacerbating the tubular injury[1].
CLINICAL FEATURES OF RHABDOMYOLYSIS AND ASSOCIATED AKI
Early recognition of rhabdomyolysis is important so that timely treatment can be started. Rhabdomyolysis can be differentiated from other diagnoses, even if they have overlapping features (Table 2). Rhabdomyolysis is known for its classic triad of muscle pain, weakness and tea-coloured urine. However, a comparative study by Gabow et al[22] found that only half of rhabdomyolysis patients present with the triad. The most common symptom is that of muscle pain, seen in 50% of adults with rhabdomyolysis, while dark-coloured urine is seen in 30% to 40%. Muscle weakness tends to affect proximally. Other clinical features may be non-specific, with systemic features such as fever, fatigue, nausea, confusion, delirium, agitation or anuria. Local signs and symptoms of muscle bruising, swelling and tenderness may also be seen[23]. While dark-coloured urine is commonly associated with rhabdomyolysis and suggests significant myoglobin excretion, it is neither a specific nor sensitive feature, and it is important to note that its absence does not rule out rhabdomyolysis[3].
Table 2 Differential diagnoses of rhabdomyolysis[1,20,21,24].
Diagnostic laboratory testing of serum CK is well-known, with elevated CK being more specific for the diagnosis than other biomarkers. Many papers state that CK being more than 1000 IU/L or five times the upper limit of normal is diagnostic of rhabdomyolysis[3-5,16,24]. CK of more than 5000 IU/L should also be noted, due to more significant muscle injury and increased risk of AKI[3,23].
Other laboratory tests should also be sent, including a full blood count, comprehensive metabolic panel, urinalysis and serum myoglobin. While serum myoglobin can be detected before CK elevation, it has a shorter half-life and rapid metabolism. Hence, it is not always detectable and is not used for diagnosis[3,23]. However, there have been recent studies showing that serum myoglobin was found to be the best predictor of AKI development, ahead of serum CK and urinary myoglobin, showing that serum myoglobin is still a significant biomarker[14,25].
Initially, serum calcium might be low due to the excessive influx of calcium into myocytes[23]. Later on in the recovery phase of rhabdomyolysis and AKI, calcium mobilisation may lead to hypercalcemia[3]. Hyperuricemia may be seen due to excessive cell breakdown and release of muscle purines[3,23]. High creatinine levels with a blood urea nitrogen (mg/dL)-to-creatinine (mg/dL) ratio of less than 10:1 may be due to metabolism of released muscle creatine[3]. The release of intracellular contents, including phosphates and organic acids such as lactic acid, leads to metabolic acidosis with an anion gap[3,23]. As disseminated intravascular coagulation (DIC) may occur with rhabdomyolysis, a coagulation panel should be done[3,24].
Other tests include an electrocardiogram (ECG) to rule out hyperkalemia, which would present with tall, tented T waves, widened QRS complexes with or without conduction blocks, prolonged PR intervals, ventricular tachycardia or even asystole[3,23]. Hypocalcemia may also present on the ECG as QTC prolongation[23]. Further imaging, such as plain radiographs, may be done to rule out differential diagnoses of bone fractures, joint dislocations and visualise soft tissue swelling. Computed tomography scans may also identify compartment syndrome, which should be clinically correlated if suspected[23].
Traditionally, serum myoglobin and CK have long been used to predict the development of AKI, with a serum myoglobin level ≥ 1000 ng/mL having worse outcomes. This was seen in an over 10-year intensive care survey done by Wu et al[26], showing higher acute physiology and chronic health evaluation II and sequential organ failure assessment scores, lower Glasgow Coma Scale scores and a higher incidence of acute myocardial infarction and 90-day mortality in post-exertional heat stroke patients. While CK is a more reliable marker for the diagnosis of rhabdomyolysis due to its longer half-life, it does not correlate with any severity of renal failure. Peak serum myoglobin was more predictive of rhabdomyolysis-induced AKI than CK, with the threshold being around 4000 ng/mL[27].
Liver function tests may also suggest renal injury, as higher levels of aspartate aminotransferase and alanine aminotransferase are associated with AKI. In rhabdomyolysis, these liver enzymes are elevated due to muscle release of aminotransferases, and not from liver disease, as there is a lack of correlation between CK and other liver biomarkers, such as bilirubin, alkaline phosphatase and g-glutamyl transferase. McMahon et al[28] have reported that low calcium levels and high phosphate levels are biomarkers of AKI risk in rhabdomyolysis, with increased risk observed at calcium levels < 1.88 mmol/L (7.5 mg/dL) and phosphate levels > 1.29 mmol/L (4.0 mg/dL).
Metabolic acidosis is another predictive factor of AKI in rhabdomyolysis, which was defined as blood pH < 7.35, HCO3- < 19 mmol/L or lactate > 2.25 mmol/L in Lim’s article[24]. When pH is low, myoglobin is less soluble, increasing the risk of precipitation of myoglobin and forming casts in kidney tubules. Severe and persistently elevated lactate in the first 48 hours of admission to the ICU in any patient was reported to be an independent risk factor of AKI[29].
Biomarkers of inflammation, such as lymphocytes and neutrophil counts, and an abnormal coagulation panel with elevated prothrombin time (PTT) and D-dimers could also predict AKI in patients with high serum myoglobin[26]. However, DIC should be ruled out, as PTT may be prolonged due to typical DIC presentation. In the initial stages of DIC, PTT may even be normal or shortened, and hence, PTT may not be the most reliable for predicting AKI[24]. Other markers, such as K+, which has shown inconsistent predictive value for AKI[24], and uric acid, which has only been studied in a specific cause of rhabdomyolysis[30], should not be considered reliable predictors of rhabdomyolysis-associated AKI in the ICU. Many novel biomarkers have been studied, especially in recent years, to improve detection and risk prediction.
Following a 24-hour ultramarathon, levels of miR-1, miR-133, miR-208 and miR-499, which are microRNAs released by injured myocytes and secreted into the bloodstream, were significantly raised in participants who developed exertional rhabdomyolysis, with an average CK of 50000 IU/L[31]. Similarly, elevations in urinary protein markers fatty acid binding proteins 1 and 3 (FABP1 and FABP3) have been proven to be diagnostic and prognostic markers for KRT initiation in patients with AKI[32].
Besides microRNAs and FABP, the use of neutrophil gelatinase-associated lipocalin (NGAL) levels, a protein upregulated in ischemic or nephrotoxic AKI in the kidney, has been contradictory. Previously, a review by Devarajan[33] showed that both plasma and urine NGAL were excellent predictors of AKI, with initial NGAL at the time of presentation accurately predicting AKI with an area under the curve of 0.95. However, more recently, a multicentre prospective study by Pommet et al[34] resulted in the poor ability of NGAL to predict AKI in rhabdomyolysis patients admitted to the Emergency Department, even after adjustments for age, sex and SpO2. Furthermore, Berlin et al[35] found that NGAL was not statistically better at predicting the development of AKI than serum creatinine, conflicting with earlier studies. NGAL is also released during systemic inflammation, which is often seen in critically ill patients, resulting in its inability to specifically measure NGAL released by tubular cells and hence reducing its use as a specific marker for AKI[36]. Meanwhile, high levels of kidney injury molecule-1, a transmembrane protein expressed at high levels in proximal tubule epithelial cells after ischemic or toxic injury, have been shown to accurately predict AKI, with high sensitivity and specificity[37].
Amongst these, tissue inhibitors of metalloproteinase-2 (TIMP-2) and insulin-like growth factor-binding protein-7 (IGFBP7) are key novel biomarkers to note. They are cell-cycle arrest proteins released by renal tubular cells during cellular injury or stress, including during AKI, where G1 cell cycle arrest occurs. In BigpAK-2, a multicentre randomised controlled trial (RCT) done across 34 countries in Europe, TIMP-2 × IGFBP7 was used to identify patients at high-risk of AKI[38]. TIMP-2 × IGFBP7 of 0.3 (ng/mL)2 or more showed high sensitivity but poor specificity to identify critically ill patients at high risk of developing moderate to severe AKI within 12 hours in a Topaz study[39]. Rather than looking at each biomarker individually, studies suggest that using them as part of a panel, often incorporating these novel biomarkers, provides better discrimination of AKI and performs more reliably than any single biomarker alone, including traditional markers[40].
On the whole, many of these novel biomarkers, while well-studied for various causes of AKI, are lacking in the literature for rhabdomyolysis-specific contexts[24,41]. These biomarkers, which are effective in predicting AKI from other causes, can also be applicable and used for rhabdomyolysis-associated AKI. However, close monitoring of these patients remains essential. In clinical practice, many of these biomarkers are also not widely commercially available and are currently not routinely used in clinical practice, due to mixed evidence and the lack of validation of their utility as standard diagnostic tests for AKI[42]. Currently, only urinary TIMP-2 × IGFBP7 has been approved by the Food and Drug Administration and European Medicines Agency to predict the risk of AKI, showing good progress in achieving regulatory recognition[43]. However, TIMP-2 × IGFBP7 and NGAL biomarker tests are not cost-effective compared to standard care, and therefore have not been incorporated into routine clinical practice[44].
There are also several risk prediction scores and models of AKI in patients with rhabdomyolysis, proposed to guide management and monitoring intensity, each varying in statistics. The McMahon risk score has been widely studied, incorporating clinical and laboratory variables such as age, serum creatinine, CK and other factors, to produce a score predicting the need for KRT or mortality in rhabdomyolysis. A McMahon risk score ≥ 6 has a relatively high sensitivity of 86% and moderate specificity of 68% for predicting KRT, with another study reporting that a cut-off of ≥ 7.8 has a sensitivity of 71.4% and a specificity of 77.8%[45,46]. In contrast, peak CK levels of at least 5000 IU/L used to predict the need for KRT have a specificity of 55% and a sensitivity of 83%, limiting its utility as a predictive marker[46]. Emerging models such as the GDF-TRACK-AKI model, which integrates serum biomarkers (growth differentiation factor-15), CK and occurrence of rhabdomyolysis with trauma. It has a very high specificity of 98%, showing potential for high utility in ruling in high-risk patients. However, it still requires more external validation and studies across various clinical scenarios before application[47].
A sensitivity and specificity of at least 90% are typically ideal to ensure that high-risk patients are accurately ruled out, preventing unnecessary aggressive treatment, while reliably identifying patients who need close monitoring or early intervention. Most currently available scores for predicting rhabdomyolysis-associated AKI risk demonstrate only moderate sensitivity and specificity, making them useful adjuncts in clinical practice rather than definitive decision thresholds.
MANAGEMENT OF RHABDOMYOLYSIS-ASSOCIATED AKI
The main goals of management of rhabdomyolysis-associated AKI are: (1) Correct hypovolemia; (2) Prevent intratubular cast formation; (3) Management of complications, e.g., electrolyte abnormalities, AKI, acute liver injury, DIC; and (4) Treat cause of rhabdomyolysis.
Correct hypovolemia
A well-accepted mainstay of management of rhabdomyolysis-associated AKI is early fluid resuscitation. Intravenous (IV) fluids help promote renal tubule flow, dilute nephrotoxins (such as myoglobin) and supply adequate renal perfusion[3,17,48]. Fluid resuscitation targets hypovolemia and corrects electrolyte and acid-base imbalances, particularly in hyperkalemia and acidosis. Alkalisation of urine helps protect the kidneys from nephrotoxic damage from hyperuricosuria and myoglobinuria, while relieving intramuscular edema can decompress muscle compartments and preserve muscle integrity. Additionally, by correcting acidosis and hyperkalemia and through neutralising the vasodilatory effects of nitric oxide in injured muscles, arteriolar contractility is restored, and inappropriate arteriolar vasodilation may be reversed[11].
While the main principles of treatment have been well-agreed on, specific aspects, such as the choice of fluids and the optimal timing of administration, have been debated. While there is no difference between outcomes after the usage of crystalloids and non-hyperoncotic colloids[49], crystalloids are more commonly given, especially lactated Ringer’s solution or normal saline[48]. Hyperoncotic colloids should be avoided to prevent further renal dysfunction[49]. Only one RCT has been done comparing lactated Ringer’s solution and normal saline. Through that trial, it was found that urine and serum pH after administering lactated Ringer’s solution were higher than that of normal saline 12 hours after infusion, but there was no significant difference in median time to CK normalisation between the two solutions[50]. Hence, both solutions are acceptable in early fluid resuscitation in the treatment of rhabdomyolysis.
Another point of debate is the amount of fluid to give. Through various studies and case reports, different volumes have been reported in various regimens, ranging from 6 L to 24 L of fluid per day[11]. On one hand, Kim et al[51] reported in their retrospective propensity score-matched cohort study that patients who received high-volume fluid therapy of more than or equal to 3 mL/kg/hour had worse renal outcomes and a lower survival rate than those who received low-volume fluid therapy of less than 3 mL/kg/hour. However, Iraj et al[52] recommend at least 3 L/day for mild rhabdomyolysis, and at least 6 L/day for severe rhabdomyolysis (CK ≥ 15000 IU/L), as volumes greater than 3 L/day for mild rhabdomyolysis have little appreciable change. Adding on to that, reports studying Hanshin-Awaji earthquake casualties in 1995 showed that those who received less than 6 L/day developed myoglobinuric AKI[53,54]. Overall, more studies advocate for larger volumes of fluid replacement[11,21,55,56], with Better and Abassi[11] finding that these aggressive regimens will invariably result in positive fluid balance of 12 kg to 20 kg, but are typically well-tolerated and do not cause pulmonary congestion or raised central venous pressure. Regardless of which regimen is best, each patient should be evaluated individually, with the severity of rhabdomyolysis, AKI, clinical course and medical background taken into consideration[48]. Caution must also be taken via close monitoring to avoid fluid overload in patients once hypovolemia has resolved[57].
The timing of administration has fewer debates, with the consensus being that earlier fluid resuscitation is better. This would preferably be before substantial cast formation, heme endocytic uptake and tubular necrosis[21]. The longer it takes for reperfusion to occur, the higher the chance of renal failure, as the damage caused by free radicals is most easily corrected in the early stages of reperfusion[56]. Patients whose fluid resuscitation was initiated earlier had better outcomes, and there was less need for dialysis, as seen in crush victims in the Bingol earthquake in 2003[58]. A good sign of recovery would be urine output, targeted at 1 to 3 mL/kg/hour, up to 300 mL/hour[48].
Management of complications
Hemodynamics should be closely monitored, especially for patients in shock. Certain parameters to note would be mean arterial pressure, which is suggested to be more than 65 mmHg[59], with some recommending > 70 mmHg to 75 mmHg[60]. For patients with chronic hypertension, mean arterial pressure should be higher, at > 80 mmHg to 85 mmHg, to ensure adequate perfusion. Diastolic blood pressure of more than 55 mmHg, mean perfusion pressure of more than 60 mmHg and renal perfusion pressure ≥ 60 mmHg have also been recommended to prevent further progression of AKI[60,61]. Patients in circulatory shock should be closely monitored, and vasopressors can be administered along with IV fluids[13], with the use of norepinephrine deemed beneficial over other vasopressors in AKI[59].
Electrolyte imbalances may also be seen, most commonly: Hyperkalemia, hyperphosphatemia, hypocalcemia and hypomagnesemia. As hyperkalemia could cause cardiac arrhythmias, potassium should be monitored closely. Any patient with a high K+ level of more than 6 mmol/L should have cardiac monitoring and have an ECG obtained for manifestations of hyperkalemia. This typically happens early in the course of the disease process, requiring timely correction with insulin and glucose.
Hypocalcemia also occurs early and may aggravate the electrical effect of hyperkalemia. However, treatment with calcium chloride or calcium gluconate is only indicated if the patient is symptomatic or if there is severe hyperkalemia, as early correction of hypocalcemia can cause calcium deposition in injured muscle. Calcium may eventually return to normal levels during the recovery phase, and might even be high, causing hypercalcemia, due to the release of calcium from injured muscle and mild secondary hyperparathyroidism from the AKI.
Hyperphosphatemia is largely due to phosphate release from injured cells, which can bind to calcium and deposit in soft tissues, while also inhibiting calcitriol and vitamin D formation. As phosphate is excreted in urine over time, early hyperphosphatemia decreases. However, treatment of hyperphosphatemia should be used with caution, as calcium chelators may increase calcium phosphate precipitation in injured muscle while decreasing phosphate levels[48].
Prevent intratubular cast formation
The alkalisation of urine through the addition of sodium bicarbonate to IV fluids is theoretically sound, but it remains relatively unsupported by robust clinical evidence. The mechanism of action of sodium bicarbonate is to alkalinise urine and prevent acidic precipitation of myoglobin[17], as well as to reduce redox cycling and lipid peroxidation, overall decreasing oxidative stress, tubular damage and renal vasoconstriction[62]. Unfortunately, there has not been a study comparing the administration of IV fluids with sodium bicarbonate to fluid administration alone[62,63]. There are even arguments against the use of bicarbonate, with Bosch et al[20] finding that this might cause a reduction in ionised calcium, worsening initial hypocalcemia and may result in more harm than benefit to the patient. Along with this, the retrospective propensity score-matched cohort study done by Kim et al[51] in 2022 found that bicarbonate therapy increased AKI risk, the need for dialysis and even mortality. Hence, sodium bicarbonate should be avoided if hypocalcemia, alkalemia, or metabolic alkalosis is already present, and its role in the treatment of rhabdomyolysis-related AKI remains controversial.
Mannitol is another proposed addition, with multiple benefits, including being a rapid-acting osmotic diuretic and working as a renal vasodilator to improve glomerular filtration rate, inducing diuresis and hence excretion of excess myoglobin, preventing myoglobin cast formation. It is also a free radical scavenger with antioxidant effects on renal parenchyma[20,62,64]. However, if mannitol is given immediately after a renal injury or in the early stages of AKI, it can cause a sudden drop in renal cortical ATP and worsen renal function[21].
Evidence for the use of bicarbonate and mannitol has been limited, with the few simply comparing the combined effects of bicarbonate and mannitol with normal saline, not individually[63]. These studies were also small, with sample sizes of 7 to 24 patients[65-67]. In a bigger study, it was found that even with the combined effects of sodium bicarbonate and mannitol, there was no difference in rates of renal failure, dialysis or mortality compared to when normal saline was given[68]. Homsi et al[65] corroborated with Brown et al[68], establishing that the addition of bicarbonate and mannitol was unnecessary and there were no beneficial effects.
Finally, diuretics, specifically loop diuretics, have also been discussed in various papers. Theoretically, loop diuretics (e.g., furosemide) reduce ischemic injury by inhibiting sodium transport and decreasing oxygen consumption, as well as excreting tubule-blocking debris, increasing blood flow. Despite this, there have been limited studies supporting this theory, with more data showing some harm from the use of furosemide. Prophylactic loop diuretics were found to be harmful or ineffective in the prevention of AKI, and did not reduce the need for KRT or shorten the duration of AKI[69]. Ho and Sheridan[70] report that furosemide is not effective in preventing and treating AKI, did not reduce in-hospital mortality, need for dialysis, number of dialysis sessions required, proportion of oliguric patients or length of hospital stay. The risk of ototoxicity was instead increased with higher doses of furosemide, and it is unlikely to improve renal function[71]. Although these studies do not cover rhabdomyolysis-associated AKI specifically, it might still be wise to avoid loop diuretics, except for cases of fluid overload, and they are not recommended to prevent or treat AKI[72]. Overall, Table 3 summarises all the above-mentioned management strategies of rhabdomyolysis-associated AKI and their individual recommendations.
Table 3 Summary of management strategies of rhabdomyolysis-associated acute kidney injury.
Management therapy
Recommendation
Fluid resuscitation
Early initiation; use crystalloids (lactated Ringer’s or normal saline); volume of 6 L/day or more
Bicarbonate, mannitol and antioxidant use
Based on clinician’s judgement; limited evidence with little difference in outcomes
In the event that early fluid resuscitation has not been sufficient to aid recovery, KRT must be considered. This is especially in patients with AKI and various complications, but the exact indications and thresholds for electrolyte imbalances and other remain disputed. There are still some indications that have been generally agreed upon, divided into absolute and relative indications (Table 4), but this is non-exhaustive. Importantly, there is currently no convincing evidence that removal of myoglobin via KRT resolves rhabdomyolysis itself[73], therefore, KRT should be initiated based on standard AKI indications rather than for myoglobin clearance only.
Table 4 Indications of kidney replacement therapy in rhabdomyolysis-associated acute kidney injury[78,107,108].
Indications for kidney replacement therapy
Absolute indications
Refractory hyperkalemia (K+ > 6.5 mmol/L, rapidly increasing or associated with cardiac arrhythmias)
Refractory pulmonary edema (diuretic resistant)
Refractory metabolic acidosis (pH < 7.2)
Blood urea nitrogen concentration of > 40.0 mmol/L
Uremia with signs and symptoms (e.g., pericarditis, encephalopathy, bleeding)
Refractory fluid overload with organ dysfunction
Concomitant drug/toxin intoxication that is dialysable
Relative indications
Severe non-renal organ dysfunction from AKI/fluid overload
Progressive/persistent AKI (serum creatinine > 3 times baseline and/or profound oliguria)
Many studies have reviewed the optimal time for KRT initiation, but a clear consensus has not been established. The effects of early and standard KRT initiation were assessed, and found that early KRT initiation has little to no difference in terms of risk of death at day 30, after 30 days or non-recovery of kidney function at 90 days[74-76]. Based on RCTs, early, pre-emptive KRT initiation is not supported, but instead, initiation should be based on the patient’s individualised clinical background, context and condition[77]. In the RCT AKIKI2, in severe AKI patients with oliguria for > 72 hours or blood urea nitrogen concentration > 40.0 mmol/L (112 mg/dL), KRT should be initiated, with further delay of KRT resulting in more potential harm[78]. Thus, KRT should not be initiated pre-emptively or early, but rather should be decided upon based on the patient’s current condition.
The choice of modality for KRT is largely between continuous and intermittent therapies, each with their own benefits and disadvantages. Intermittent hemodialysis allows for rapid solute clearance and volume removal in 3 hours to 4 hours, and can be used in electrolyte derangements and drug poisoning that requires rapid correction, for example, severe hyperkalemia, acidosis and lithium, salicylate and non-volatile alcohol poisonings. Continuous KRT (CKRT) is preferred in patients with hemodynamic instability, raised intracranial pressures and severe dysnatremia. However, one risk of CKRT is the possibility of filter clotting, which thus requires the use of anticoagulants. Somewhere in between is prolonged intermittent renal replacement therapy, which has slow clearance and ultrafiltration over 6 hours to 12 hours, and is used in patients who cannot tolerate hemodialysis but require frequent interruptions of CKRT[77].
There are differences between each modality, with CKRT being the most commonly used in the treatment of rhabdomyolysis-associated AKI. Normal diffusion-based hemodialysis is usually not able to effectively eliminate middle molecular weight molecules, such as myoglobin, which has a molecular weight of 17 kDa[79]. If intermittent hemodialysis is the only available option, high cut-off (HCO) filters allow for rapid and effective removal of plasma proteins up to 45 kDa, which would include myoglobin, compared to standard filters[80]. Medium cut-off membranes are also able to clear myoglobin and have the added benefit of being more cost-effective[81].
Various CKRT modalities are available, including continuous venovenous hemofiltration, continuous venovenous hemodiafiltration, continuous venovenous hemofiltration with HCO filters, and the integration of an adsorber (CytoSorb®) into the extracorporeal circuit. All of them have been shown to allow for faster clearance of myoglobin in the treatment of rhabdomyolysis-associated AKI[82-84]. Nonetheless, it is important to monitor for hypoalbuminemia, especially when using HCO filters, as albumin is also lost through these filters[85]. Overall, while CKRT has been proven to be an effective modality, more robust RCTs are needed for better clinical evidence as to the best choice for use in myoglobinuria.
In patients where CKRT is indicated, there are specific measures taken to optimise its effectiveness. As clots may form in the extracorporeal circuits, which may interrupt CKRT and thus limit its benefits, anticoagulation is necessary. The two most commonly used anticoagulants include regional citrate anticoagulation (RCA) and unfractionated heparin. RCA is reportedly more effective in prolonging filter lifespan and reducing the risk of bleeding[86,87]. Although previously thought to be unsafe, RCA is safe in liver failure, but the patient’s acid-base status and electrolyte levels have to be monitored closely[88]. In cases of hypocalcemia, calcium can be supplemented[89]. An initial dose of 2.5 mmol/L of RCA in blood has fewer citrate-related complications compared to higher conventional doses of 3 mmol/L to 5 mmol/L, but dosing protocols may vary[90]. Complications such as citrate accumulation have to be watched for, as it is a rare but potentially fatal condition. This can be identified via electrolyte imbalances of hypocalcemia and a total calcium to ionised calcium ratio of more than 2.5[89]. Thus, if close monitoring of the patient is not possible, unfractionated heparin is a good alternative, as it is more cost-efficient and has had a long history of relatively safe use, with the biggest concern for it being heparin-induced thrombocytopenia and bleeding[91].
Successful weaning of KRT is the next milestone in the management of patients with rhabdomyolysis-associated AKI. From a study of intensivists in England, the most common reasons for weaning KRT are an increasing urine output, normalisation of pH and achievement of adequate volume status[92]. Klouche et al[93] further suggest that the following conditions be met before initiating weaning of KRT: (1) The cause of AKI and the precipitating factors are identified and resolved; (2) The patient is hemodynamically stable with a stable respiratory status; (3) The patient’s fluid status is optimised; and (4) Initiation of diuresis is observed.
To best predict the success of weaning KRT, a combination of urine output and kinetic estimated glomerular filtration rate should be used[94]. A diuresis threshold of urine volume of more than 500 mL in 24 hours without diuretics, or more than 2000 mL in 24 hours with diuretics, has been suggested to indicate that KRT sessions may be withheld to observe a gradual improvement in renal function[93]. Another approach involves measuring serum creatinine levels and creatinine clearance. A clearance of > 12 mL/minute to 15 mL/minute has been associated with successful weaning, and a daily urinary urea excretion > 1.35 mmol/kg/24 hours and a urine creatinine excretion ≥ 5.2 mmol/24 hours have also been proposed[95].
CONCLUSION
Early, aggressive fluid resuscitation is paramount, typically with lactated Ringer’s solution or normal saline at volumes of more than 6 L/day. Bicarbonate and mannitol therapy have been controversial and have not been proven to have a significant added benefit to the patient, thus should be considered based on the clinician’s judgement. Prompt and early detection of rhabdomyolysis would minimise the risk of renal injury and allow for a better prognosis[58]. In contrast, myoglobin removal via KRT is not shown to be more effective in reducing the risk of AKI or mortality compared to conservative measures[79,96], and therefore should only be used for standard AKI indications, rather than based on CK or myoglobin levels alone.
Various antioxidants have also been discussed, including pentoxyfilline, vitamin C and E, lazaroids and minerals such as zinc, manganese and selenium. These help to minimise nephrotoxic material released from muscle, helping with the treatment of rhabdomyolysis[97,98]. Pentoxyfilline is a xanthine derivative used to improve microvascular blood flow, while decreasing neutrophil adhesion and cytokine release[99]. Free radical scavengers, namely vitamin E, can terminate free radical-initiated lipid peroxidation, protecting the cell membrane from injury and reducing skeletal muscle necrosis[100], which can be beneficial in rhabdomyolysis. Nevertheless, these have not been studied thoroughly, lacking controlled studies evaluating the efficacy of this therapy[20]. Going forward, further studies and research can be conducted to explore the potential use of these antioxidants in clinical practice.
Other novel treatment options that target specific pathophysiological mechanisms are also being explored. For example, inhibition of myoglobin tubular endocytosis through the administration of cilastatin has shown renoprotective effects on mouse models with rhabdomyolysis-induced AKI[101]. In addition, human serum albumin and N-acetyl-L-cysteine polysulfides have been conjugated to create a supersulfide donor with antioxidative properties, which reduced oxidative stress markers in the kidney of mice[102]. Moreover, NOD-like receptor family, pyrin domain containing 3-depleted renal tubular cells in mice demonstrated improved tubular cell viability through attenuation of myoglobin-induced mitochondrial injury and lipid peroxidation[103]. Although these therapies remain in the early stages of research, with time and further studies, they may offer improved treatment options to patients with rhabdomyolysis-associated AKI.
Future clinical trials could further improve accuracy in predicting rhabdomyolysis-associated AKI, especially with the potential of novel biomarkers such as TIMP-2 × IGFBP7, as well as refine management strategies relating to volume of fluid resuscitation, additional therapies and KRT modality of choice. These advancements would determine improvements in renal recovery, dialysis independence and long-term outcomes of critically ill patients in the ICU. With the recent advancements of artificial intelligence and machine learning models, there is great potential for such technology to predict AKI risk with the integration of clinical and laboratory data. With more studies done to support this[104], earlier intervention and more individualised management strategies could be seen.
Rhabdomyolysis-associated AKI is commonly seen in critically ill patients in the ICU, with early diagnosis and management of rhabdomyolysis patients potentially improving clinical outcomes and saving lives. More evidence on the best prediction models and treatment therapies for rhabdomyolysis-associated AKI is needed, eventually allowing for the formulation of a more robust management regimen. Moving forward, the implementation of standardised, evidence-based protocols will be essential to improve care for these patients.
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