Examining rhabdomyolysis-related acute kidney injury in COVID-19 patients and its comparison to other acute kidney injury types

Abstract

Rhabdomyolysis (RM) is characterized by disrupting muscle cells and releasing intracellular components into circulation. Some symptoms associated with RM include muscle weakness, discolored urine, and myalgia. RM can be caused by coronavirus disease 2019 (COVID-19) causing exaggerated immune response leading to muscle damage. Acute kidney injury (AKI), when presented with RM, leads to increased mortality. Examining RM-related AKI and its comparison to other AKI types in COVID-19 patients could improve the management of viral infections developing RM and AKI. RM potentially complicated COVID-19 infection course and is a major etiology of AKI. RM-related AKI had higher severity and mortality than other AKI types, with increased hypercoagulopathy and inflammatory markers. Findings also express procalcitonin use in follow-ups with severe COVID-19 patients. Study limitations include small sample size, absence of kidney biopsies, and focus on the first wave of the pandemic, which should be addressed in future research to generate accurate and relevant findings.

Key Words: Rhabdomyolysis; Acute kidney injury; Rhabdomyolysis-associated acute kidney injury; COVID-19; Creatine kinase; Procalcitonin; Rhabdomyolysis treatment

Core Tip: The study explored differences between rhabdomyolysis (RM)-related acute kidney injury (AKI) and other AKI types in coronavirus disease 2019 (COVID-19) patients. RM patients had high inflammation, procalcitonin, C-reactive protein, and ferritin. The prognosis of RM-related AKI was considered worse in comparison to developing AKI from other causes in COVID-19 patients. RM is a risk factor for AKI in COVID-19 patients. Hence, follow-ups are essential to monitor RM development. Study limitations include small sample size, absence of kidney biopsies, and focus on the 1^st wave of the pandemic. Addressing these limitations leads to accurate result generation, potentially improving viral infection management for RM and AKI development.

TO THE EDITOR

Rhabdomyolysis (RM) syndrome is characterized by the integral disruption of the skeletal muscle cell, leading to an outflow of intracellular components into the bloodstream[1,2]. Causes of RM are diverse, such as direct injury, trauma, infections, or muscle ischemia[3,4]. RM is clinically characterized by three symptoms: Myoglobinuria, myalgia, and weakness[3]. In contrast, less than 10% of patients exhibit these symptoms in a triad, while above 50% exhibit initial symptoms as discolored urine without weakness or muscle pain[3,5]. RM-specific laboratory marker is the sign of elevated serum creatine kinase (CK) levels, valuing 5-10 times greater than the normal upper limit that establishes RM in a patient[6].

Injury to muscle cells and rapid energy depletion are the main pathways to muscle necrosis in RM[7]. An increase in calcium in the muscle fibers leads to activation of phospholipase enzyme alongside other calcium-activated enzymes, causing excess breakdown of phospholipids, leading to degradation of cellular and organelle membranes and ion channel disturbance[7,8]. Free fatty acids are associated with oxidative stress led by free radicals such as reactive oxygen species (ROS). Oxidation of ROS molecules on muscle cell components and organelles leads to reduced cellular function. The sarcoplasmic reticulum is the organelle involved in calcium storage vital for controlled muscle contraction through actin-myosin cross-bridge formation and is an adenosine triphosphate dependent process. Its membrane holds the sodium (Na⁺)/calcium (Ca²⁺) exchanger and the Na⁺/potassium (K⁺) pump, maintaining high K⁺ and low Na⁺ and Ca²⁺ concentrations in the cell[7].

Hence, ROS activity on the sarcoplasmic reticulum membrane increases calcium concentration in the cytoplasm. The presence of excess calcium alongside the activity of ROS leads to continued muscle contraction and rapid adenosine triphosphate depletion[8]. These outcomes, alongside water retention due to the influx of Na⁺ and Ca²⁺ causing cell swelling and disruption of cellular structures, cause muscle cell degradation[7,8]. Other deteriorating processes include the increase of mitochondrial calcium and activation of cytochrome c and apoptosis-inducing factor, leading to cellular death and tissue necrosis[8]. The release of cellular components from the damaged cell leads to hyperkalemia, elevated anion gap, hyperuricemia, and hyperphosphatemia[6]. Calcium deposition is these damaged muscle cells that can also lead to hypercalcemia. Aciduria caused by metabolic acidosis could exacerbate the tubules’ damage due to lowered urine pH, globin formation through myoglobin dissociation, and ferrihemate having nephrotoxic activity[6].

The major mechanism causing damage to the kidneys in RM patients is the huge release of myoglobin into the bloodstream and subsequent myoglobinuria[6]. It is a key component released in the bloodstream that gets filtered in the glomeruli. It is then passed into the tubules, interacting with the Tamm-Horsfall protein in acidic urine[9]. Myoglobin in the urine exceeds 100 to 300 mg/dL, causing proximal accumulation and formation of an iron cast in the tubules, tubular obstruction, and injury[6]. Hence, myoglobinuria is an important indicator when diagnosing RM[10].

A frequent complication of RM is acute kidney injury (AKI), which is associated with an increase in mortality by about 19.2%-59.0%[1]. A retrospective study conducted by Park et al[11] that involved 1023 patients having RM due to blunt trauma observed a 47.6% incidence of AKI in the severe RM patients with a 14.3% mortality rate among hospitalizations. AKI pathogenesis is not fully understood. However, experimental evidence suggests the main mechanisms include tubular obstruction, intrarenal vasoconstriction, and ischemic or direct tubule injury[12,9]. RM is also caused by coronavirus disease 2019 (COVID-19) disease. Implications from researchers are that an exaggerated immune response causes damage to the muscle during the viral infection[13,14]. RM can be considered a risk factor for the development of AKI in the clinical course of COVID-19 infections[15]. In critically ill COVID-19 patients having RM, the risk of mortality increases to around 30%, while 40.4% developed AKI and only 13% recovered[16]. AKI is also observed to be the strongest predictor of mortality in patients with COVID-19 and RM[16].

Murt and Altiparmak[17] aimed to compare RM-AKI and other AKI types in COVID-19 patients to provide insights to physicians to manage viral infections leading to RM and AKI. They conducted their study at the Cerrahpasa Medical Faculty in Istanbul, Türkiye. They included the first wave of COVID-19 patients who presented between 15 March to 15 June 2020, excluding patients with past chronic kidney disease while involving patients having RM-related ‘in-hospital’ AKI. COVID-19 infections were diagnosed through reverse transcription-polymerase chain reaction and oral and nasal swab tests. Diagnosis and categorization of AKI were according to the Kidney Diseases Improving Global Outcomes criteria, and baseline CK was established. Detection was done through a nationwide electronic health record system. Patients were diagnosed with RM if their CK levels were ‘higher than five times the upper normal level’ with ‘concomitant increases’ in lactate dehydrogenase and transaminases. Patients diagnosed with AKI and COVID-19 infection were admitted into COVID-19 wards, and vitals were closely monitored. Admissions to intensive care units were done when required. Patient follow-up endpoints were either discharge from the hospital or death. Statistical analysis involved normal distribution and assessment through the Kolmogorov-Smirnov test. Analysis between groups was conducted using the Mann-Whitney U-test or independent samples. Students’ t-tests and usage were based on distribution normality. Percentages were used to present categorical variables, and comparison was done through the χ²-test. Statistical analysis was performed using the IBM SPSS version 22.0. Significance was accepted for two-sided P < 0.05.

Results of the study show that out of the 115 COVID-19-infected patients having AKI, 15 had concomitant RM, with two patients possessing AKI upon admission to the hospital, while the rest 13 followed with new-onset AKI during admission to the hospital. Upon comparing patients with RM-AKI and patients with other AKI types, high peak CK levels, C-reactive protein, procalcitonin, and peak procalcitonin levels were observed. Upon admission, patients with RM had higher peak ferritin levels, indicating a more pronounced inflammatory response. Patient follow-up showed peak CK levels significantly higher in patients with RM, implying severity of AKI increased for patients with RM to AKI stage II or III. AKI presenting patients without RM was considerably milder. Patients with RM and AKI had significantly higher levels of pro-B-type natriuretic peptide (proBNP), admissions to the intensive care units, and mortality rate between the groups. In contrast, hyperkalemia was seen as similar in both groups.

As evidenced by the study, RM can be considered a specific risk factor for AKI development in COVID-19 patients. The study expressed difficulty in figuring out the precise etiology of AKI development in COVID-19 infection as AKI prognosis from various etiologies has yet to be previously compared and studied. The generally accepted explanation is acute tubular necrosis by account of hypoxemia. The hyperkalemia rate was similar in both study groups, which contrasts data from previous research, indicating other factors leading to increased mortality in COVID-19 patients with RM. The study also observed AKI’s late development and poor prognosis during the follow-up, which is consistent with prior reports. Peak D-dimer and ferritin levels were high in COVID-19 patients with RM and AKI, which was explained through systemic inflammation and hypercoagulopathy that potentially led to further muscle injury. The high proBNP levels observed in the study were elucidated to be from cardiac stress or higher pulmonary tension seen in hypoxemia. Hence, the study concluded that RM leads to increased severity of AKI, which may have resulted in higher proBNP due to volume overload. Moreover, the study was able to present procalcitonin as a potential tool in the follow-up cases of severe COVID-19 patients.

Limitations to the Murt and Altiparmak[17] study included a small sample size. However, they ensured accuracy through the strict restrictions on the diagnosis of RM and the exclusion of patients previously having chronic kidney disease from the study. Furthermore, kidney biopsies were not performed because of the severity of the disease and scarcity of resources during the first wave; thus, etiology was not defined. Regardless, RM was diagnosed based on patient clinical symptoms and signs, as well as laboratory findings in patients with COVID-19-related AKI, where AKI severity and mortality increased in patients with RM. Moreover, the study only focused on the first wave of the pandemic. Given the consecutive waves during the COVID-19 pandemic, to ensure the study remains relevant, future research could involve analysis of these waves on RM and AKI development to provide reliable and accurate information. For example, future research could consider the impact of COVID-19 based on the severity of the various SARS-CoV-2 infectious strains and whether the infection severity could impact the severity or rate of development of AKI and RM.

Treatment of RM-associated AKI also involves identifying and treating the cause of RM. This consists of the management of traumatic (crush injury) or non-traumatic RM, electrolyte imbalances, diet, and supportive care[7]. RM management intends to avoid volume depletion and intratubular cast formation by prescribing appropriate fluid resuscitation to increase urine output and prevent AKI[7,18]. Aggressive fluid resuscitation should be considered for RM patients to avoid AKI development. However, in patients with AKI, this treatment could lead to volume overload[7]. It is recommended to use isotonic saline with dextrose to reduce hyperkalemia at a rate of 1 L/hour and 500 mL/hour subsequently[7,18]. Alejandro et al[19] outlines the limitation of using aggressive fluid resuscitation in older people for the possible exacerbation of heart failure. Hence, monitoring of creatine phosphokinase and serum creatinine, fluid input, and output are vital for RM management.

Urine alkalization could be considered in cases of alkalosis, allowing for increased solubility of myoglobin and urine excretion, thus reducing the risk of hyperkalemia[7,18]. Alejandro et al[19] reported case study on a COVID-19 patient with RM-AKI discharged after intravenous sodium bicarbonate was applied for urine alkalization with strict observation of creatine phosphokinase and serial serum creatinine concentrations, oxygen, urine output, and respiratory rate. Additionally, due to the potential development of hypocalcemia leading to seizures and tetany through bicarbonate, serum and urine pH concentrations must be monitored, and bicarbonate discontinued once serum pH 7.5 is achieved[7]. Hemodialysis should be considered in cases where aggressive fluid resuscitation proved inefficient in patients remaining oliguric, anuric, or developed AKI[7]. Furthermore, RM is associated with abnormalities in electrolytes such as hyperphosphatemia, hyperkalemia, hyperuricemia, and hyper- and hypocalcemia and, hence, must be monitored and treated accordingly[18].

Currently, there is limited evidence-based research regarding treatment for RM-associated AKI. Future research in this area could aid in developing targeted therapy, thus enhancing patient outcomes. Kwiatkowska et al[20] provides a summary of potential new therapeutic strategies involving anti-inflammatory substances, iron chelators, and antioxidants, and a blood filter mechanism for adsorbing cytokines and myoglobin from blood. However, these techniques require further investigation due to limited human research and data on effectiveness.

In conclusion, Murt and Altiparmak[17] were able to establish a comparison between RM AKI and other AKI types in COVID-19 patients through the study results and establish that RM is a primary etiology of AKI and that it exacerbates the COVID-19 infection. Through comparisons, Murt and Altiparmak[17] were able to define hypercoagulopathy and systemic inflammation to be markers in patients with AKI due to RM and that a worse prognosis was seen in RM-related AKI. However, the limitations of the study, such as small sample size due to selection criteria, absence of kidney biopsies due to scarcity of resources, and severity of the COVID-19 disease, and focus on the 1^st wave of the pandemic, must be acknowledged, and addressed in future research endeavors for the study to remain accurate and relevant.