Understanding rhabdomyolysis induced acute kidney injury in patients with COVID-19

Abstract

This work comments on an article published in the recent issue of the World Journal of Virology. Rhabdomyolysis is a complex condition with symptoms such as myalgia, changes to urination, and weakness. With the potential for substantial kidney impairment, it has also been shown to be a severe complication of coronavirus disease 2019 (COVID-19). To date, various theoretical explanations exist for the development of rhabdomyolysis induced acute kidney injury (RIAKI) in COVID-19 infection, including the accumulation of released striated muscle myoglobin in the urine (myoglobinuria). In their article, they (2024) demonstrate in a retrospective study that RIAKI in COVID-19 patients tended to have elevated levels of C-reactive protein, ferritin, and procalcitonin. These patients also had poorer overall prognoses when compared to COVID-19 patients who have acute kidney injury (AKI) due to other causes. It is clear from these findings that clinicians must closely monitor and assess for the presence of rhabdomyolysis in COVID-19 patients who have developed AKIs. Moreover, additional research is required to further understand the mechanisms behind the development of RIAKI in COVID-19 patients in order to better inform treatment guidelines and protocols.

Key Words: COVID-19; Rhabdomyolysis; Acute kidney injury; Mortality; Complication

Core Tip: The article published in the recent issue of the World Journal of Virology (2024) has shown that patients with rhabdomyolysis induced acute kidney injury (RIAKI) as a complication of coronavirus disease 2019 (COVID-19) infection tend to show elevated levels of specific biomarkers. Additionally, patients with RIAKI in COVID-19 infection have worse outcomes compared to patients who have acute kidney injury due to other causes in COVID-19 infection. To improve overall outcomes, there is a need to better understand the mechanism for RIAKI development in COVID-19, and to create evidence-based treatment protocols for this condition. To determine which approaches are most effective, more research on the outcomes for patients with differing treatment regimens is required.

TO THE EDITOR

Rhabdomyolysis is a complex disease characterised by extensive skeletal muscle damage and the sequestration of intracellular contents into the bloodstream. Increased levels of contents such as uridine acid, myoglobin, creatine kinase (CK), and potassium reflect early structural changes and complications of rhabdomyolysis[1]. Whilst common symptoms include myalgia, muscle weakness, and red/brown urine, they are typically absent in almost 50% of patients[2]. Diagnosis is instead defined as per biochemical markers, namely, a CK level more than 5 times the upper limit of normal with an associated increased in transaminase and lactate dehydrogenase (LDH)[3]. Trauma, strenuous exercise, hyperthermia, toxin exposure, infection, and sepsis, as well as hypoxaemia-induced metabolic disequilibrium are predominating aetiologies[4]. One such recent infectious agent contributing in 2% of hospitalised patients is coronavirus disease 2019 (COVID-19) disease, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)[5]. With a postulated incidence of 15%-20% of rhabdomyolysis in the course of COVID-19, a possible contributor to the poor prognosis and over 40% mortality seen in this cohort is the development of an acute kidney injury (AKI)[6]. Different theoretical mechanisms explain rhabdomyolysis induced AKI (RIAKI) in the course of COVID-19. One explanation for RIAKIs are the accumulation of released striated muscle myoglobin in the urine (myoglobinuria), resulting in the formation of pigment casts. These casts deposit within the nephron resulting in intratubular obstruction, with the resulting endothelial damage ultimately causing an acute tubular injury[7]. Whilst this is considered the main aetiology, additional pathological mechanisms of AKIs in COVID-19 include pre-renal azotaemia, glomerular disease, thrombotic microangiopathy, and treatment related AKI[8].

AKI IN COVID-19 PROGNOSTICATION

Whilst RIAKIs may be associated with higher rates of morbidity and mortality, Murt and Altiparmak[3], sought to compare the outcomes of COVID-19 patients with RIAKIs and AKIs of differing aetiologies. Previously, due to the difficulty in accurately determining the exact aetiology of AKIs particularly in COVID-19, there has been a scant presence in the literature of studies comparing the prognostic outcomes of varying AKI aetiologies.

In determining the mortality and morbidity of these groups, physicians treating AKIs may be better placed to accurately prognosticate patients experiencing an AKI or rhabdomyolysis as a result of a viral illness. Their paper found that patients when comparing aetiologies of AKIs in COVID-19 patients, those with RIAKIs had higher inflammatory and hypercoagulopathy markers as well as poorer prognoses. Through understanding these markers, challenge current treatment paradigms of RIAKIs in COVID-19 patients which currently struggle to rationalise potential stigmata of fluid restriction protocols such as pulmonary oedema could be challenged[9]. Commonly rhabdomyolysis treatment prioritises the removal of the cause and the reversal of any associated metabolic aberrations such as hypokalaemia, hypophosphatasemia, hypocalcaemia, hyponatraemia or hypernatraemia, and hyperglycaemic states[10]. Similar to much of the surrounding literature outlining the treatment challenges which are posed by poorly understanding the pathophysiology of RIAKIs in COVID-19, Murt and Altiparmak[3], look to provide an explanation for the additional factors which increased RIAKI mortality. Therefore, to substantiate alternative targeted treatment paradigms, monitoring biomarkers may prove useful.

Their paper sought to closely monitor biomarkers due to the possibility for rapid deterioration-RIAKI patients had higher mean creatinine levels and more patients with Kidney Diseases Improving Global Outcomes stage II and stage III AKIs than those of other aetiologies. Interestingly, the higher mortality in RIAKI patients could not be attributed to hyperkalaemia due to the similarities observed in the groups levels. COVID-19 may however uniquely provide additional drivers of muscular injury through and an inflammatory state with increased coagulation as higher peak ferritin and D-dimer levels were observed in the RIAKI group. Other increased markers such as C-reactive protein, LDH and ferritin were found to corroborate these findings of the RIAKI group. Additionally, researchers observed higher pro-brain natriuretic peptide levels in the RIAKI group which may reflect additional cardiac stress resulting from pulmonary tension or volume overload. As rhabdomyolysis independently causes more severe AKIs, this may account for the higher levels observed. However, they too are indicator of a poorer prognosis in COVID-19[11].

CLINICAL IMPLICATIONS

With concerns for exacerbation of stigmata of COVID-19 such as pulmonary oedema hampering RIAKI treatment mainstays-it becomes increasingly difficult to accurately account for the poorer prognosis in COVID-19 patients complicated by AKIs. Treatments such as fluid prescription to decrease the propensity for intratubular cast formation are foregone here as instead hypoxaemia is touted as the main driver of acute tubular necrosis. Regardless, clearer evidence-based treatment guidelines and protocols need to be developed for patients with COVID-19 who develop RIAKI.

Currently, like the much of the existing literature, with an overreliance on clinical signs, symptoms, and laboratory findings due to patients being too unwell to biopsy, the lack of definition of exact aetiology further impedes our understanding of RIAKI disease progression[3,12]. As a result, additional confounding variables make it increasingly difficult to account for differences in morbidity and mortality when typically indicative biomarkers such as hyperkalaemia are not found to be dissimilar. A call may therefore be made for others to investigate alternative treatment paradigms in COVID-19 when RIAKI occurs, as this may entail deviating from regular treatment mainstays to improve overall health outcomes. This needs to occur alongside further research to more clearly determine the basis of the development of RIAKI in COVID-19. This will allow for faster diagnosing of this life-threatening complication, which can further improve the outcomes for patients with RIAKI.

CONCLUSION

In their work, Murt and Altiparmak[3] have shown that RIAKI is a major, life-threatening complication that can occur in a proportion of COVID-19 patients. These patients tend to have some biomarkers that may indicate the presence of RIAKI. Concerningly, patients with RIAKI during COVID-19 infection tend to have worse outcomes compared to patients who have developed AKI due to other causes in COVID-19 infection. More research is needed to determine the mechanisms for RIAKI development. Furthermore, to improve overall outcomes, there remains a clear need to determine the most effective treatment regimens for this life-threatening problem.