Dysnatremia and its Clinical Significance in COVID-19 Era

• Dysnatremia is common with COVID-19 infection.
• Hyponatremia is the most common form of dysnatremia.
• Hypernatremia is linked to an elevated risk of serious illness and mortality in the hospital. In patients with SARS-COV2 infection, hypernatermia was linked to a greater risk of mortality.

Table (1) : Demographic data of all patients.

The angiotensin-converting enzyme 2 (ACE2) [10] receptor, which is extensively expressed in the kidneys, particularly in the proximal tubule, may bind to SARS-CoV-2. SARS-CoV-2 enters cells coupled with the membrane receptor, which is effectively eliminated from the membrane's external site, after binding. [11].

Surface ACE2 is further downregulated once the viral complex is endocytosed, leading to unopposed angiotensin II buildup. Angiotensin II may suppress ACE2 expression even further. [12]. Angiotensin II promotes sodium reabsorption in the kidney's proximal convoluted tubule by promoting sodium-hydrogen exchange. Renal sodium reabsorption is followed by renal chloride reabsorption and potassium excretion, possibly leading to hyperchloremia and hypokalemia. These changes occured considerably more often in hyponateremia patients than in those without hypernatremia, indicating that enhanced angiotensin II activity is a potential [13].

The often-observed electrolyte abnormalities during COVID-19 might have an impact on therapy, hospital stay duration, and death. As a result, we set out to investigate whether dysnatremia affects the severity, mortality, or COVID-19 outocme in patients hospitalized with SARS-COV2.

A total of 163 individuals with SARS-CoV-2 infection were admitted to Ain Shams University for the present research. 80 of them had abnormal sodium levels in their blood, with 71 hyponatremic patients and 9 hypernatremic patients. Hyponatremia was more common upon admission, with a frequency of 8 to 28 percent [14], whereas hypernatremia was considerably less common, with a prevalence of 5.3 percent [15]. Jin et al. found that hyponatremia was more commonly in COVID-19 patients than hypernatremia (9.9% vs. 2.4%), similar to our findings (44.5 percent vs. 5.5 percent) [16]. In another research by Hirsch et al., dysnatremias were observed in over half of COVID-19 patients (51.7%) upon admission, with hyponatremia being the most prevalent. [17]. Hyponatremia was also common in Ruiz-Sánchez et al. where COVID-19 infected 4,664 individuals in hospitals, Hyponatremia was found in more than 20% of patients for a total of 957 cases. Hypernatremia, on the other hand, was found in just 3.7 percent of the people (174 in total) [18].

Due to syndrome of inappropriate antidiuresis (SIADH), which is a major cause of hyponatremia, particularly in viral pneumonia, euvolemic hyponatremia is the most prevalent dysnatremia in hospitalized patients. A case series of COVID-19-related SIADH has also been published earlier [19, 20]. Patients with hyponatremia and fever were shown to be a strong predictor of COVID-19 infection in this case study. Inflammatory cytokine production, ventilation–perfusion mismatch, intravascular volume depletion, stress, discomfort, and emotions are all possible causes of SIADH in COVID-19 infection. Positive-pressure ventilation (PPV) is another common cause of SIADH and hyponatremia. [21].

Laboratory and radiographic data indicated substantial variations between hypernatremia and normonatremia patients in the Hu et al research. Additionally, hyponatremia patients needed more oxygen support than normonatremia patients [22]. In our study, 53.5% of hyponatremia patients and 11.1 percent of hypernatremia patients had a mild or moderate type case, with lower ratios than normonatremia patients (38.5%). However, a total of 47.5% of hyponatremia patients and 88.9% of hypernatremia patients had serious or critical diseases with higher ratios than normonatremia patients (61.5 %). Patients with salt balance problems had a greater death rate than those with normonatremia.

Fever (71.3%), shortness of breath (69.6%), cough (56.4%), disrupted conscious level (14.1%), weariness (12.3%), and diarrhea were among the hospitalized patients' clinical complaints (10.4 %). The most prevalent concomitant clinical condition was hypertension (74.8 %). In relation to clinical importance, 90 patients (55.2%) and 63 patients (38.7%) of those hospitalized had diabetes and chronic kidney failure (CKD), respectively. In addition, 37 patients (22.7 %), 25 patients (15.3%), and 21 patients (12.9%) had cardiac disease, neurological illness, and chronic liver disease, respectively. Other comorbidities were present in 33 individuals (20 %). Except for respiratory distress, which occurs in 88.9% of hypernatremic patients and 59.2% of hyponatremic patients compared to 77.1% in normanatremic patients with statistically substantial difference, there were no substantial differences in demographic and clinical features between hypernatremic, hyponatremic, or normonatremic patients. Furthermore, no substantial variations in comorbidities were seen amongst the three groups analyzed.

In Hu and colleagues' study, the hospital stays lengths for hypernatremia and normonatremia patients were not statistically variant. [22]. In our research, however, individuals with salt problems had a lengthier hospital stay. When compared to normonatremic individuals, COVID-19 patients with serum sodium abnormalities had a more severe presentation and worse clinical results, particularly hypernatremia.

In the Ruiz-Sánchez et al study, both admitting hyponatremia and hypernatremia were independently related to disease severity in admitted patients with RT-PCR-confirmed COVID-19 CAP [18]. In our study, illness severity was greater in individuals with salt balance abnormalities as compared to the normonatremia group. A total of 53.5 percent of hyponatremia patients and 11.1% of hypernatremia patients had a mild or moderate condition, with lower ratios than normonatremia patients (38.5 %). However, a total of 47.5% of hyponatremia patients and 88.9% of hypernatremia patients had serious or critical diseases with higher ratios than normonatremia patients (61.5%). Patients with salt balance problems had a greater death rate than those with normonatremia.

Among a short retrospective analysis of 29 patients, Berni et al. discovered a more severe result and higher death in patients with hyponatremia admitted for COVID-19. [24]. Some studies have revealed no link between hyponatremia and pneumonia-related in-hospital death. Only a trend toward greater death in the hyponatremia group was seen in Zilberberg et al., retrospective investigation of individuals hospitalized with pneumonia. [25]. However, not all of the patients developed CAP. Cuesta et al. couldnot find more than a trend toward greater mortality in hyponatremia in CAP in their prospective research [26]. Differences in findings might be related to differences in the sample size of patients enrolled.

According to Sjöström et al, within the first two weeks of hospitalization, 65 percent of 223 patients with severe COVID-19 develop hypernatremia, requiring twice as long in the ICU and a greater risk of death than patients without hypernatremia. [27]. They can't rule out the possibility that the high incidence of hypernatremia they discovered was due to iatrogenic causes, but our patients were hypernatremic from the start.

Hyperaldosteronism might be caused by RAAS overactivation due to high angiotensin II levels. Aldosterone operates on the Na/K channels in the distal tubule of the kidney, causing an increase in sodium input and potassium outflow as well as hydrogen ions. This causes hypernatremia. In addition, the hypernatremia group had a longer hospital stay and had a greater fatality rate than the non-hypernatremia group, according to the Sjöström et al research, suggesting that hypernatremia is a sign of serious disease.

Intervention studies examining the impact of active treatment of hyponatremia, on the other hand, are few. In a retrospective analysis of hospitalized patients with an SNa

The response of admitted patients with heart failure and hyponatremia to chronic post-discharge treatment with tolvaptan was analyzed in a subgroup analysis of the Everest trial, and it was discovered that patients with hospitalized SNa concentrations < 130 mmol/L taking tolvaptan had a substantial 40% decrease in readmissions/death after a median follow-up of 8 months, compared to patients taking placebo. In fact, compared to the control group, more than twice as many patients on tolvaptan were discharged with eunatremia in this subgroup of the Everest study [28].

Hyponatremia did not worsen the prognosis of COVID-19 patients in our study, possibly because the majority of our patients had mild hyponatremia, similar to Ruiz-Sánchez et al, who found that mild hyponatremia affects only 3.8 percent of patients with SNa < 130 mmol/L and 0.9 percent with SNa < 125 mmol/L. Hypoxia's involvement with cellular regulatory systems would not apply if there was no cellular edema linked to severe/acute hyponatremia [18].

Our study had some particular limitations such as the absence of some investigations that carry particular importance in hyponatremia such as urine volume, urine sodium, serum osmolarity, and urine osmolarity; those were not feasible in isolation wards that we hope could be further improved in future studies.

CONCLUSION

Patients with salt balance abnormalities had longer hospital stays, had more severe symptoms, and had a greater fatality rate. Despite the fact that the demographic and clinical symptoms were comparable between groups, with the exception of respiratory distress, which was greater in the hypernatremic group, the severity was greater and the ICU stay was substantially longer in patients with sodium disorders, particularly hypernatremia. Hypernatremia may have led to a prolonged need for mechanical breathing, delaying ICU release. Our data imply that COVID-19 may also be complicated with hypernatremia. The electrolyte condition of COVID-19 patients should consequently be given special attention. The actual cause of hypernatremia has yet to be discovered. Given the therapeutic relevance of a disordered blood sodium level, further research into serum sodium disorders in COVID-19 patients is critical.

Funding: None.  

Conflict of interest: None.

Ethical Consideration:

The ethics committee at Ain Shams University accepted the project. An informed consent form was signed by all participants.