key: cord-1009822-fwox2pwp
authors: Kodama, Kentaro; Imai, Toru; Asai, Yasuo; Kozu, Yutaka; Hayashi, Kentaro; Shimizu, Tetsuo; Gon, Yasuhiro; Ootsuka, Susumu
title: Incidence and risk factors for hyperkalaemia in patients treated for COVID‐19 with nafamostat mesylate
date: 2022-03-21
journal: J Clin Pharm Ther
DOI: 10.1111/jcpt.13646
sha: 958d2ebdf83a76ea1d6bff9b764d878afadc5dd2
doc_id: 1009822
cord_uid: fwox2pwp

WHAT IS KNOWN AND OBJECTIVE: Nafamostat mesylate (NM) is used clinically in combination with antiviral drugs to treat coronavirus disease (COVID‐19). One of the adverse events of NM is hyperkalaemia due to inhibition of the amiloride‐sensitive sodium channels (ENaC). The incidence and risk factors for hyperkalaemia due to NM have been studied in patients with pancreatitis but not in COVID‐19. COVID‐19 can be associated with hypokalaemia or hyperkalaemia, and SARS‐CoV‐2 is thought to inhibit ENaC. Therefore, frequency and risk factors for hyperkalaemia due to NM may differ between COVID‐19 and pancreatitis. Hyperkalaemia may worsen the respiratory condition of patients. The objective of this study was to determine the incidence and risk factors for hyperkalaemia in COVID‐19 patients treated with favipiravir, dexamethasone and NM. METHODS: This retrospective study reviewed the records of hospitalized COVID‐19 patients treated with favipiravir and dexamethasone, with or without NM, between March 2020 and January 2021. Multivariable logistic regression analysis was performed to identify the risk factors for hyperkalaemia. RESULTS AND DISCUSSION: Of 45 patients who received favipiravir and dexamethasone with NM for the treatment of COVID‐19, 21 (47%) experienced hyperkalaemia. The duration of NM administration was a significant predictor of hyperkalaemia (odds ratio: 1.55, 95% confidence interval: 1.04–2.31, p = 0.031). The receiver‐operating characteristic curve analysis determined that the cut‐off value for predicting the number of days until the onset of hyperkalaemia was 6 days and the area under the curve was 0.707. WHAT IS NEW AND CONCLUSION: This study revealed that the incidence of hyperkalaemia is high in patients treated for COVID‐19 with NM, and that the duration of NM administration is a key risk factor. When NM is administered for the treatment of COVID‐19, it should be discontinued within 6 days to minimize the risk of hyperkalaemia.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a Betacoronavirus that causes severe pneumonia similar to that caused by severe respiratory syndrome coronavirus and Middle East respiratory syndrome coronavirus. 1, 2 It is highly contagious, with more than 276 million cases worldwide and more than 5.37 million deaths as of 23

December 2021. 3 SARS-CoV-2 infection causes coronavirus disease , 4 and antiviral drugs and steroids are used as therapy. 5 However, their therapeutic effect is limited, and various drug screening systems are being used to search for new therapeutic agents.

It has been suggested that the spike protein expressed on the surface of SARS-CoV-2 is primed by transmembrane protease serine 2 (TMPRSS2) and enters host cells via angiotensin-converting enzyme 2 receptors. 6 In order to inhibit the entry of SARS-CoV-2 into the host, screening of inhibitors targeting TMPRSS2 has been conducted, and nafamostat mesylate (NM) has been identified as a candidate. 7, 8 Basic studies suggest that NM inhibits SARS-CoV-2 entry into lung epithelium-derived calu-3 cells by inhibiting TMPRSS2. 7, 9 In addition, NM has been reported to be effective against COVID-19 in clinical practice, 10, 11 and its use in combination with antiviral drugs may improve the therapeutic outcome because of its ability to inhibit the entry of SARS-CoV-2 into host cells. 10 Nafamostat mesylate inhibits proteolytic enzymes 12 and has been used for treating acute pancreatitis and disseminated intravascular coagulopathy (DIC). 13, 14 Although NM is generally safe, 13, 14 it can cause hyperkalaemia due to inhibition of the amiloridesensitive sodium channel (ENaC). 15 SARS-CoV-2 may inhibit the activation of ENaC, 16 and hyperkalaemia is a common complication of COVID-19. 17 Conversely, SARS-CoV-2 may increase the activity of the renin-angiotensin system, resulting in hypokalaemia, 18 and hypokalaemia has also been reported as a complication of COVID-19. [18] [19] [20] As SARS-CoV-2 infection may affect serum potassium regulation, the incidence of hyperkalaemia due to NM may differ in COVID-19 patients from that in patient with other conditions. NM has been reported to be a risk factor for hyperkalaemia in patients with acute pancreatitis. 21 There have been two case reports of NMinduced hyperkalaemia in patients with COVID-19, 22,23 but the incidence and risk factors for NM-induced hyperkalaemia in patients with COVID-19 are unknown.

It is important to prevent hyperkalaemia because fluctuations in serum potassium levels may increase the risk of respiratory failure requiring ventilator management. 24 Thus, clarification of the frequency and risk factors of NM-induced hyperkalaemia in COVID-19 would be beneficial for patient management. Therefore, in this study, we investigated the incidence and risk factors of hyperkalaemia in COVID-19 patients who were treated with NM.

We conducted a retrospective study using electronic medical records.

Patients hospitalized with COVID-19 at Nihon University Itabashi Hospital in Tokyo, Japan, between March 2020 and January 2021 were included in the study.

In our institution, the standard treatment for patients hospitalized with COVID-19 was a combination of favipiravir and dexamethasone. Patients who received favipiravir (3600 mg/day on the first day, and 1600 mg/day on the second and subsequent days) for up to 14 days and dexamethasone (6.6 mg/day) for up to 10 days were included in the standard treatment group. Patients who received favipiravir and dexamethasone in the same doses as the standard treatment group and NM were included in the combination treatment group. NM was administered at a dose of 0.2 mg/kg/hour by continuous intravenous infusion. The combination treatment group included patients who were treated with NM because of persistent fever or no reduction in oxygen demand within 3 days after starting standard treatment. In patients with COVID-19, non-invasive positive pressure ventilation and ventilator management are risk factors for acute kidney injury, 25 and are considered to be risk factors for hyperkalaemia. In addition, it has been reported that the incidence of hyperkalaemia is higher in patients with fatal COVID-19 than in patients who recover. 17 For these reasons, patients who received positive pressure ventilation (nasal high flow or ventilator); patients who died during drug treatment; and patients with hyperkalaemia before the start of treatment were excluded. Hyperkalaemia was defined as a serum potassium level of ≥5 mEq/L, according to the definition of the American Heart Association. 26 

The following data were extracted from electronic medical records: patient background: age, sex, weight, body mass index and body temperature; dosing parameters: duration of NM administration (days) and dose (mg/kg/day); laboratory parameters on admission: blood urea nitrogen, serum creatinine, total bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), sodium, potassium, lactate dehydrogenase, ferritin and C-reactive protein levels;

white blood cell count and eGFR. In addition, serum potassium levels during drug administration, history of present illness, medical history and concomitant medications were recorded. Creatinine clearance was calculated using the Cockcroft-Gault equation.

We compared the characteristics of the patients in the standard and combination therapy groups before the start of treatment. Next, we compared the incidence of hyperkalaemia from the start of treatment and the number of days of hyperkalaemia from the onset of infection to the end of treatment in each group. In addition, we compared the pre-treatment backgrounds of the patients who did not have hyperkalaemia and those who had hyperkalaemia in the combination treatment group. The groups were compared using Fisher's exact test for comparison of categorical variables, and the Mann-Whitney U-test or Student's t-test for comparison of continuous variables.

Among patients in the combination treatment group, risk factors for hyperkalaemia were identified using multivariable logistic regression. The independent variables were factors that have been suggested as independent risk factors in previous studies (age, presence of fever, duration of NM administration and serum potassium level before NM administration). 21 In addition, Pearson's correlation coefficient was used to screen variables for multicollinearity. If two factors showed a strong correlation (r > 0.8), one of the two factors was excluded from the model. The receiver-operating characteristic (ROC) curve was used to calculate the cut-off value for predicting hyperkalaemia for factors with a p value < 0.05 in the univariate analysis, using multivariable logistic regression analysis. Two-sided p-values < 0.05 were considered statistically significant. JMP 14 (SAS Institute Inc.) was used for the analyses.

This study protocol complied with the Japanese ethical guidelines for medical research involving human subjects and was approved by the Nihon University Itabashi Hospital Institutional Ethics Committee (approval number: RK-210608-06).

Of the 96 patients who received standard or combination therapy during the study period, 82 were eligible for inclusion in the analysis. Of these, 37 patients were in the standard treatment group and 45 patients were in the combination treatment group. Fourteen patients were excluded because they had received positive pressure ventilation, died during the drug treatment period and had a serum potassium level of ≥5 mEq/L before the start of treatment ( Figure 1 ).

The clinical characteristics of the patients in the standard treatment and combination treatment groups before the start of treatment are shown in Table 1 . There were significantly more males (p = 0.004) in the combination treatment group, and patients in the combination treatment group had significantly higher ALT (p = 0.043) levels than patients in the standard treatment group. 

Of the 45 patients in the combination treatment group, 21 developed hyperkalaemia. The patients who developed hyperkalaemia were significantly older (p = 0.027) and had a significantly longer NM administration period (p = 0.016) than the patients without hyperkalaemia (Table 3 ). (Table 4 ).

Receiver-operating characteristic curve analysis of the relationship between the duration of NM treatment and the occurrence of hyperkalaemia revealed that the area under the curve was 0.707. The optimal cut-off value for predicting the time to the onset of hyperkalaemia was 6 days, with a sensitivity of 85.7% and the specificity of 45.8% (Figure 2 ).

Nafamostat mesylate inhibits SARS-CoV-2 entry into the body and is expected to be effective in COVID-19 when used in combination with antiviral drugs. 10 We investigated the incidence of hyperkalaemia and risk factors for hyperkalaemia in COVID-19 patients treated with NM. The results showed that the incidence of hyperkalaemia was higher in the combination treatment group using NM and suggested that the duration of NM administration was an independent risk factor.

In this study, the incidence of hyperkalaemia in the standard treatment group (10.8%) was similar to that reported in a metaanalysis investigating the incidence of hyperkalaemia in patients with COVID-19 (0.22%-13.23%). 27 In contrast, the incidence of hyperkalaemia in the combination treatment group was 46.7%.

According to the manufacturer, the incidence of hyperkalaemia in patients with DIC treated with NM is 4.53%, 28 which is far lower than that observed in COVID-19 patients treated with NM in this study. It has been reported that NM inhibits the secretion of prostasin, a serine protease, inhibits the activity of ENaC in renal collecting ducts, 15 inhibits Na + -K + ATPase in renal collecting ducts and inhibits aldosterone secretion, 29,30 resulting in hyperkalaemia.

for SARS-CoV-2 to enter host cells. Furin, a serine protease, has been reported to be involved in this cleavage. 31 As furin cleaves the common amino acid sequence in the extracellular domain of S protein and ENaC, infection with SARS-CoV-2 may cause competition with furin and inhibit the activity of ENaC. 16 ENaC exists in the apical membrane of the distal renal tubules and collecting ducts and reabsorbs sodium, and the renal outer medullary potassium channel, located in the same region, secretes potassium into the tubular lumen for urinary excretion. 32 Therefore, when the activity of ENaC is decreased, urinary excretion of potassium is prevented, and hyperkalaemia occurs as a result. 15 In addition, concomitant dexamethasone use degrades muscle proteins by increasing catabolism. 33 In muscle tissue, the potassium:

nitrogen ratio is 2.7 mEq of potassium per gram of nitrogen. 34 Dexamethasone increases urea nitrogen excretion by degrading Abbreviations: ACE, angiotensin-converting enzyme; ALT, alanine aminotransferase; and WBC, white blood cell; ARB, angiotensin II receptor blocker; AST, aspartate aminotransferase; BMI, body mass index; BUN, blood urea nitrogen; Ccr, creatinine clearance; COPD, chronic obstructive pulmonary disease; CRP, C-reactive protein; eGFR, estimated glomerular filtration rate; LDH, lactate dehydrogenase; Scr, serum creatinine; SMX, sulfamethoxazole; T-Bil, total bilirubin; TMP, trimethoprim. muscle proteins. 35 Therefore, the release of potassium, a component of muscle protein, is expected to be released with urea nitrogen; however, there have been no reports of hyperkalaemia in patients treated with dexamethasone alone. This is because various physiological functions compensate for serum potassium levels during steroid monotherapy. However, the combination of ENaC-inhibiting trimethoprim-sulfamethoxazole (TMP/SMX) and corticosteroids has been reported to increase the incidence of hyperkalaemia more than the administration of TMP/SMX alone. 36 In other words, corticosteroids may cause potassium elevation, and

ENaC inhibition by TMP/SMX interferes with the compensatory function and increases the incidence of hyperkalaemia. In this study, we speculated that the administration of dexamethasone as the standard treatment for COVID-19 may have increased potassiumreleasing protein catabolism, and the combined use of NM may have inhibited potassium excretion from the tubules, contributing to the increased incidence of hyperkalaemia. Furthermore, in the case series of combination treatment of COVID-19 with NM and favipiravir, the incidence of hyperkalaemia due to NM was 9%

(1/11), 10 which was lower than in the present study. In the present study, NM was combined with dexamethasone, and this may have contributed to the development of hyperkalaemia. Based on the above, we consider that the increased incidence of hyperkalaemia is due to a combination of factors, such as potassium release by protein catabolism induced by dexamethasone, in addition to suppression of ENaC activity due to SARS-CoV-2 infection and NM.

However, as we did not measure ENaC activity in each patient in this study, we believe that pharmacological studies are warranted to determine the detailed mechanism by which NM induces hyperkalaemia in patients with COVID-19.

In the comparison of patient characteristics in this study, there were differences between the standard treatment group and the combination treatment group, in the percentage of males and ALT levels. Although it has been suggested that COVID-19 causes electrolyte abnormalities, 27 it has been reported that the incidence of electrolyte abnormalities does not differ by sex. 18, 37 In addition, NM is metabolized by hydrolysis in hepatic microsomes and cytosol. 38, 39 Although the liver is partially involved, the dependence on liver function is low, and mild liver damage is not thought to cause an increase in blood concentration. Therefore, the differences in clinical characteristics between groups are unlikely to have led to the higher incidence of hyperkalaemia in the combination therapy group.

Based on the results of the increased incidence of hyperkalaemia in COVID-19 patients treated with NM, we examined the risk factors for hyperkalaemia. In the combination treatment group, hyperkalaemia was associated with older age and a longer duration of treatment. A previous study also found the age and duration of treatment were risk factors for hyperkalaemia in patients treated for acute pancreatitis with NM. 21 Basic research suggests that the ENaC expression level decreases with age in rats. 40 In addition, it has been suggested that the ability to secrete aldosterone in response to elevated potassium is reduced in older adults. 41 NM is known to inhibit the activity of ENaC and aldosterone secretion, 15, 29, 30 so hyperkalaemia may be more likely to occur in the older adults treated with NM than in younger individuals. In addition, NM has been reported to inhibit ENaC activity from the day after administration, 15 and the gradual increase in K-releasing protein catabolism by steroids may lead to a situation where hyperkalaemia is more likely to occur as the duration of administration is prolonged.

We examined the use of NM for treating COVID-19 to clarify the risk factors for hyperkalaemia. We performed multivariable logistic regression analysis using the presence of hyperkalaemia as the dependent variable and the presence of fever and serum potassium level before NM administration, which have been shown to influence the increase in serum potassium level in previous studies, 21 and age and duration of NM administration, which were significantly 

This study revealed that the incidence of hyperkalaemia is high in COVID-19 patients treated with NM, and that the duration of NM administration is a key risk factor. SARS-CoV-2 infection and steroid treatment may have had a synergistic effect and exacerbated the development of hyperkalaemia. NM administration should be discontinued within 6 days in patients with COVID-19, in order to avoid the onset of hyperkalaemia.

No conflicts of interest have been declared.

The requirement for consent was waived because of the retrospective study design.

The data that support the findings of this study are available from the corresponding author upon reasonable request.

https://orcid.org/0000-0003-3617-8233

Toru Imai https://orcid.org/0000-0002-8648-7571

Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding

Presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with COVID-19 in the New York City area

World Health Organization. Coronavirus disease (COVID-19) n.d

World Health Organization. Novel Coronavirus (2019-nCoV) Situation Report -22 2020

Recent progress of antiviral therapy for coronavirus disease 2019

SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor

The anticoagulant nafamostat potently inhibits SARS-CoV-2 S protein-mediated fusion in a cell fusion assay system and viral infection in vitro in a celltype-dependent manner

Nafamostat Mesylate blocks activation of SARS-CoV-2: new treatment option for COVID-19

Comparative analysis of antiviral efficacy of FDA-approved drugs against SARS-CoV-2 in human lung cells

Nafamostat mesylate treatment in combination with favipiravir for patients critically ill with Covid-19: a case series

Three cases of treatment with nafamostat in elderly patients with COVID-19 pneumonia who need oxygen therapy

Pharmacological Studies of FUT-175, Nafamstat Mesilate I. Inhibition of protease activity in in vitro and in vivo experiments

Clinical efficacy of FUT-175 (nafamostat mesylate) in Disseminated Intravascular Coagulation (DIC): a Multicenter late-stage clinical phase II study

Clinical study of FUT-175 for pancreatitis

Inhibition of prostasin secretion by serine protease inhibitors in the kidney

SARS-CoV-2 strategically mimics proteolytic activation of human

Clinical characteristics of 113 deceased patients with coronavirus disease 2019: retrospective study

Assessment of hypokalemia and clinical characteristics in patients with coronavirus disease

Hypokalemia in patients with COVID-19

Hypokalemia as a sensitive biomarker of disease severity and the requirement for invasive mechanical ventilation requirement in COVID-19 pneumonia: a case series of 306 Mediterranean patients

Risk of hyperkalemia caused by nafamostat mesilate in geriatric patients

Nafamostat mesylate-induced hyperkalemia in critically ill patients with COVID-19: four case reports

Preventing thrombosis in a COVID-19 patient by combinatorial therapy with nafamostat and heparin during extracorporeal membrane oxygenation

Risk of respiratory failure among hospitalized patients with various admission serum potassium levels

Risk factors, clinical characteristics, and prognosis of acute kidney injury in hospitalized COVID-19 patients: aretrospective cohort study

Guidelines 2000 for cardiopulmonary resuscitation and emergency cardiovascular care. Part 8: advanced challenges in resuscitation: section 1: life-threatening electrolyte abnormalities. The American Heart Association in collaboration with the International Liaison Committee on Resuscitation

Epidemiology, prognosis and management of potassium disorders in Covid-19

Ltd The Drug Interview Form of Nafamostat (Futhan®)

Mechanisms of hyperkalemia caused by nafamostat mesilate

A serine protease inhibitor, nafamostat mesilate, suppresses aldosterone secretions in vivo

A Multibasic cleavage site in the spike protein of SARS-CoV-2 is essential for infection of human lung cells

International union of basic and clinical pharmacology. XCI. structure, function, and pharmacology of acidsensing ion channels and the epithelial Na+ channel

A practical guide to the monitoring and management of the complications of systemic corticosteroid therapy

The total electrolyte content of animals and its probable relation to the distribution of body water

The role of alanine and glutamine in steroid induced nitrogen wasting in man

Influence of concomitant prednisolone on trimethoprim-associated hyperkalaemia

Association between average plasma potassium levels and 30-day mortality during hospitalization in patients with COVID-19 in Wuhan. China

Nafamostat is hydrolysed by human liver cytosolic long-chain acyl-CoA hydrolase

Involvement of human blood arylesterases and liver microsomal carboxylesterases in nafamostat hydrolysis

Renal ENaC subunit, Na-K-2Cl and Na-Cl cotransporter abundances in aged, water-restricted F344 x Brown Norway rats

Aldosterone responses to hyperkalemia in healthy elderly humans

Dexamethasone in hospitalized patients with Covid-19

ACTT-1 study group members. Remdesivir for the treatment of Covid-19 -Final report

Incidence and risk factors for hyperkalaemia in patients treated for COVID-19 with nafamostat mesylate