Rhabdomyolysis-related acute kidney injury in patients with COVID-19

Abstract

BACKGROUND

Viral and bacterial infections may be complicated by rhabdomyolysis, which has a spectrum of clinical presentations ranging from asymptomatic laboratory abnormalities to life-threatening conditions such as renal failure. Direct viral injury as well as inflammatory responses may cause rhabdomyolysis in the course of coronavirus disease 2019 (COVID-19). When presented with acute kidney injury (AKI), rhabdomyolysis may be related to higher morbidity and mortality.

AIM

To compare rhabdomyolysis-related AKI with other AKIs during COVID-19.

METHODS

A total of 115 patients with COVID-19 who had AKI were evaluated retrospectively. Fifteen patients had a definite diagnosis of rhabdomyolysis (i.e., creatine kinase levels increased to > 5 times the upper normal range with a concomitant increase in transaminases and lactate dehydrogenase). These patients were aged 61.0 ± 19.1 years and their baseline creatinine levels were 0.87 ± 0.13 mg/dL. Patients were treated according to national COVID-19 treatment guidelines. They were compared with patients with COVID-19 who had AKI due to other reasons.

RESULTS

For patients with rhabdomyolysis, creatinine reached 2.47 ± 1.17 mg/dL during follow-up in hospital. Of these patients, 13.3% had AKI upon hospital admission, and 86.4% developed AKI during hospital follow-up. Their peak C-reactive protein reached as high as 253.2 ± 80.6 mg/L and was higher than in patients with AKI due to other reasons (P < 0.01). Peak ferritin and procalcitonin levels were also higher for patients with rhabdomyolysis (P = 0.02 and P = 0.002, respectively). The mortality of patients with rhabdomyolysis was calculated as 73.3%, which was higher than in other patients with AKI (18.1%) (P = 0.001).

CONCLUSION

Rhabdomyolysis was present in 13.0% of the patients who had AKI during COVID-19 infection. Rhabdomyolysis-related AKI is more proinflammatory and has a more mortal clinical course.

Key Words: Rhabdomyolysis; Acute kidney injury; COVID-19; SARS-CoV-2; Creatine kinase

Core Tip: This study investigated rhabdomyolysis-related acute kidney injury (AKI) in patients with coronavirus disease 2019 (COVID-19) and compared it with COVID-19-related AKI due to other causes. Patients with rhabdomyolysis had more inflammation with higher levels of C-reactive protein, procalcitonin, and ferritin. The prognosis of rhabdomyolysis-related AKI was worse than for other forms of COVID-19-related AKI. Patients with inflammatory viral infections such as COVID-19 should be closely followed up for life-threatening conditions such as rhabdomyolysis.

INTRODUCTION

Rhabdomyolysis is characterized by extensive muscular injury and the release of intracellular components into the systemic circulation. The severity of rhabdomyolysis may range from asymptomatic enzyme elevations to electrolyte abnormalities and even life-threatening conditions. Symptoms of rhabdomyolysis include myalgia, muscle weakness, and red/brown urine.

Trauma, strenuous exercise, hyperthermia, and toxin exposures are the main etiologies of rhabdomyolysis, but it can also be caused by infections and sepsis[1]. Among infectious agents, viruses constitute a considerable part. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can also cause rhabdomyolysis. There are different theoretical mechanisms of rhabdomyolysis in coronavirus disease 2019 (COVID-19). One theory is direct muscle injury by SARS-CoV-2. Also, metabolic disequilibrium between energy needs and production, especially in patients with hypoxemia, can cause rhabdomyolysis[2]. The real incidence and outcome of rhabdomyolysis in the course of COVID-19 are not known. However, previous studies found the incidence at around 15% to 20%. Additionally, the mortality of patients with COVID-19 with rhabdomyolysis was found to exceed 40%[3].

Independent of rhabdomyolysis, acute kidney injury (AKI) may be seen in the course of COVID-19, and it is related to poor prognosis[4]. Rhabdomyolysis may further complicate the clinical course as an additional risk factor for AKI. Rhabdomyolysis was found as the background etiology for 7% of patients who had AKI in the course of COVID-19[5].

This study aimed to compare rhabdomyolysis-related AKI with other types of AKI in COVID-19. Such analysis may provide insights for physicians to manage different viral infections that may cause AKI and rhabdomyolysis.

MATERIALS AND METHODS

Setting and the patients

The study was conducted at Cerrahpasa Medical Faculty, Istanbul, Türkiye, which serves as a tertiary healthcare center. During the pandemic, the university hospital was designated as a pandemic control hospital. The first wave of patients with COVID-19 from the pandemic was between 15 March to 15 June 2020. To study the sole relation between COVID-19 and AKI, those who had prior chronic kidney disease (CKD) were excluded from the study. Patients who had rhabdomyolysis-related in-hospital AKI were involved in the study.

Definitions

COVID-19 was diagnosed using real-time polymerase chain reaction test from combined nasal and oral swabs.

AKI was diagnosed according to the Kidney Diseases Improving Global Outcomes (KDIGO) criteria: An absolute increase in creatinine levels by 0.3 mg/dL in the last 48 h or a 50% increase in creatinine levels in the last 7 d. AKI was also categorized according to the KDIGO criteria: A 1.5–1.9 times increase was classed as stage I, a 2.0–2.9 times increase was considered as stage II, and > 3.0 times or increase to > 4.0 mg/dL was accepted as stage III. Baseline creatinine was defined as the lowest creatinine level in the last 6 mo, excluding the last 7 d. This was detected via a nationwide electronic health record system. Rhabdomyolysis was diagnosed in patients who had creatine kinase (CK) levels that were higher than five times the upper normal level with concomitant increases in transaminases and lactate dehydrogenase (LDH).

Patient follow-up

Patients who were diagnosed as having COVID-19 and had AKI were admitted to the designated COVID-19 wards in the hospital. They received all supportive care according to the guidelines released and regularly updated by the Turkish Ministry of Health COVID-19 Scientific Steering Committee. Hemogram, C-reactive protein (CRP), procalcitonin, pro-brain natriuretic peptide (proBNP), urea, creatinine, electrolyte levels, and oxygen saturation were checked daily. When needed, patients were admitted to intensive care units, receiving all necessary medical care. The endpoint for patient follow-up was either hospital discharge or death.

Statistical analysis

The normality of the distribution of continuous data was assessed using the Kolmogorov–Smirnov test. Continuous data with normal distribution are presented as mean ± SD and those with non-normal distribution are presented as median and interquartile range. Between-group analysis of continuous data was performed using the independent samples Students’ t test or Mann–Whitney U test depending on the normality of the distribution. Categorical variables are presented as percentages and compared using the χ² test. IBM SPSS version 22.0 was used for statistical analysis. A two-sided P < 0.05 was accepted as statistically significant.

RESULTS

Among 115 patients who had AKI in this first wave of the pandemic, 15 had concomitant rhabdomyolysis. Two patients had AKI on the day of hospital admission and the remaining 13 developed new-onset AKI during hospital admission. The mean day of AKI was 7.4 days ± 3.1 d for these 13 patients.

In the comparison of patients with rhabdomyolysis-related AKI and other patients with AKI, age, baseline creatinine levels, and sex distribution were similar. In addition, the rates of both hypertension and diabetes between these two groups were also similar (Table 1).

Table 1 Baseline characteristics of acute kidney injury patients with rhabdomyolysis and other acute kidney injury, n (%).

	Rhabdomyolysis (n = 15)	Other AKI (n = 100)	P value
Age, yr	61.00 ± 19.10	62.60 ± 13.50	0.70
Baseline creatinine (mg/dL)	0.86 ± 0.13	0.92 ± 0.15	0.25
Gender (%, male)	73.3	75.0	0.86
Hypertension	6 (40.0)	28 (28.0)	0.34
Diabetes	5 (33.3)	21 (21.0)	0.30

Data are given as mean ± SD when normally distributed. χ² test is used for categorical variables and Mann-Whitney U test is used for non-normally distributed data. AKI: Acute kidney injury.

The complete blood count and hemoglobin levels of patients were comparable (Table 2). The mean arterial pressure of both groups was also similar. Peak creatinine levels of patients with rhabdomyolysis were higher. In addition, patients with AKI and rhabdomyolysis had lower lymphocyte counts and higher CRP levels. Procalcitonin and peak procalcitonin levels were also higher for patients with both AKI and rhabdomyolysis. Although on-admission ferritin levels were similar for both groups, patients with rhabdomyolysis had higher peak ferritin levels indicating a greater inflammatory response.

Table 2 Comparison of rhabdomyolysis related acute kidney injury and other acute kidney injury.

	Rhabdomyolysis (n = 15)	Other AKI (n = 100)	P value
Peak creatinine (mg/dL)	2.47 ± 1.17	1.62 ± 0.58	0.000
Mean arterial pressure (mmHg)	89.75 ± 8.63	88.63 ± 14.38	0.790
Hemoglobin (g/dL)	12.59 ± 1.83	12.26 ± 1.83	0.560
Lymphocytes (μL)	941.60 ± 311.70	1362.30 ± 676.10	0.010
Nadir lymphocytes (μL)	533.30 ± 280.60	957.90 ± 618.80	0.020
CRP (mg/L)	111.12 ± 69.91	77.45 ± 78.41	0.140
Peak CRP (mg/dL)	253.24 ± 80.67	156.95 ± 111.20	0.000
Procalcitonin (ng/mL)	0.28 [0.12-0.75]	0.10 [0.06-0.28]	0.018
Peak procalcitonin (ng/mL)	1.61 [0.40-10.60]	0.16 [0.08-1.03]	0.002
Creatine kinase (U/L)	260.00 [123.50-1057.20]	94.50 [58.0-203.70]	0.005
Peak CK (U/L)	1929.30 ± 1282.20	238.10 ± 237.0	0.000
	Median: 1514.0	Median: 126.50
Ferritin (ng/mL)	669.0 [195.90-1403.50]	366.00 [192.50-884.0]	0.360
Peak ferritin (ng/mL)	1320.10 ± 590.0	967.10 ± 1038.70	0.020
	Median: 1267.50	Median: 657.0
LDH (U/L)	469.40 ± 162.70	408.00 ± 350.0	0.550
Peak LDH (U/L)	964.90 ± 409.60	654.70 ± 61.80	0.030
Albumin (g/dL)	3.15 ± 0.49	3.44 ± 0.49	0.057
D-dimer (μg FEU/mL)	1.62 ± 1.34	1.93 ± 3.17	0.730
Peak d-dimer (μg FEU/mL)	23.40 ± 22.50	7.90 ± 11.07	0.030
Uric acid (mg/dL)	4.85 ± 2.18	5.81 ± 2.18	0.160
HCO3- (mmol/L)	21.51 ± 8.71	24.98 ± 4.53	0.220

Data are given as mean ± SD when normally distributed and as median (interquartile range) when non-normally distributed. Student’s t-test is used for normal distributed data and Mann-Whitney U test is used for non-normally distributed data. AKI: Acute kidney injury; CK: Creatine kinase; CRP: C-reactive protein; LDH: Lactate dehdyrogenase.

Peak creatinine levels in the follow-up were significantly higher for patients with rhabdomyolysis. In other words, AKI was more severe for patients with rhabdomyolysis, with 80% of them having stage II or III AKI. In contrast, AKI without rhabdomyolysis was milder (84.4% of these patients had stage I AKI) (Table 3). Patients with AKI and rhabdomyolysis had significantly higher proBNP levels, higher intensive care unit admissions, and higher mortality than patients with AKI due to other causes. Mortality of rhabdomyolysis-related AKI was 73.3%, whereas it was 18.0% for other patients with AKI. However, the rate of hyperkalemia was not different for both groups.

Table 3 Acute kidney injury stages and outcome of rhabdomyolysis patients and others, n (%).

	Rhabdomyolysis (n = 15)	Other AKI (n = 100)	P value
AKI stage I, II, III (%)	20.0; 33.3; 46.7	85.0; 10.0; 5.0	0.000
ICU admission	12 (80.0)	27 (27.0)	0.002
Mortality	11 (73.3)	18 (18.0)	0.001
Pro-BNP (pg/mL)	7460 [1451.0-34624.0]	583 [99.7-4203.0]	0.003
Hyperkalemia	8 (53.3)	39 (39.0)	0.270

χ² test is used for categorical variables and Mann–Whitney U test is used for non-normally distributed data. Data are given as median (interquartile range) when non-normally distributed. AKI: Acute kidney injury; ICU: Intensive care unit; BNP: Brain natriuretic peptide.

DISCUSSION

While AKI may develop due to a variety of reasons during COVID-19[6], rhabdomyolysis is one of the specific risk factors. In patients with rhabdomyolysis, non-protein heme pigment is mainly responsible for the occurrence of AKI[7]. Although some drugs may cause rhabdomyolysis, it was not attributed to any medication in our patient cohort. In the pathophysiology of rhabdomyolysis-related AKI, vasoconstriction, tubular injury, and/or tubular obstruction can be responsible factors. Avoiding volume depletion is the main strategy to prevent AKI in rhabdomyolysis. Also, prescribing relevant fluid treatments decreases intratubular cast formation. However, fluid administration during COVID-19 was advised to be restricted, with a fear that it may result in lung edema[8].

Previously, our group and other researchers have shown that, when complicated with AKI, COVID-19 has a worse prognosis[9,10]. However, the prognosis of different etiologies for AKI was not compared in the vast majority of studies. This is mainly because of the difficulty in finding the exact etiology of AKI in the course of COVID-19. Because of the respiratory nature of the disease, acute tubular necrosis due to hypoxemia has been accepted as the main factor of AKI in COVID-19. Hypercoagulopathy and the inflammatory nature of the disease may result in intrarenal injuries including microangiopathies. The exact etiology is seldom defined because performing a kidney biopsy is not possible for most patients with unstable clinical conditions. However, rhabdomyolysis can generally be diagnosed with clinical signs, symptoms, and laboratory findings. We identified 15 patients with rhabdomyolysis among our patients with COVID-19-related AKI.

AKI was more severe in patients with rhabdomyolysis. This was apparent with higher mean creatinine levels and more patients having stage II and III AKI (33.3% and 46.7%, respectively). In contrast, the majority of AKIs in the other group were stage I (84.4%). Rhabdomyolysis-related AKI generally occurs concurrently with hyperkalemia, which may be another reason for the higher mortality. We also found that mortality was significantly higher for patients with rhabdomyolysis; however, the rate of hyperkalemia was similar for both groups. Thus, the higher mortality of rhabdomyolysis could not be attributed to hyperkalemia. Accordingly, there must be other factors that increase mortality in patients with COVID-19 with rhabdomyolysis.

Similar to prior reports, rhabdomyolysis in our patients with AKI either started late or worsened during follow-up[11]. Thus, CK, urea, and creatinine levels, as well as electrolytes should be closely monitored in viral infections with inflammatory characteristics. We performed daily laboratory checks because patients could rapidly deteriorate. We found much higher peak ferritin and D-dimer levels in patients with both AKI and rhabdomyolysis. This may point to increased coagulation and inflammation in cases of COVID-19 with rhabdomyolysis. Higher hypercoagulopathy and systemic inflammation may be drivers of additional muscular injury.

We found higher proBNP levels in patients with AKI with rhabdomyolysis. N-terminal pro-BNP may be elevated in cardiac stress. It may also be elevated due to increased pulmonary tension in hypoxemia. Higher proBNP is independently related to a worse prognosis for COVID-19[12]. As seen in our patients, AKI may result in higher proBNP levels as a result of volume overload. Rhabdomyolysis causes more severe AKI[13] and thus results in higher proBNP levels.

Procalcitonin levels were also higher in patients with both AKI and rhabdomyolysis. Previous reports have underlined procalcitonin as a prognostic biomarker for severe COVID-19[14]. Procalcitonin is released in the inflammatory state as a response to proinflammatory cytokines. Higher peak CRP, LDH, and ferritin levels in rhabdomyolysis may show a worse inflammatory state in patients with rhabdomyolysis compared with other AKIs. Our findings show the utility of procalcitonin in the follow-up of patients with severe COVID-19.

This study had some limitations. First, the sample size was small. This is because of the exclusion of patients who already had CKD and applying strict clinical criteria to diagnose rhabdomyolysis. Nevertheless, such an approach ensured the exact accuracy of diagnosis. Secondly, kidney biopsies could not be performed due to the disease severity and scarcity of such resources during the first wave of the pandemic. Lastly, this study focused on the first wave of the pandemic.

CONCLUSION

Rhabdomyolysis may complicate the clinical course of COVID-19 and it is one of the major etiologies for AKI. When compared with AKI due to other causes, patients with rhabdomyolysis had higher inflammatory and hypercoagulopathy markers. The prognosis of rhabdomyolysis-related AKI is worse than for other AKIs.