May Medium Cut-Off Dialysis Membranes Have Impact on Outcome of COVID-19 Hemodialysis Patients?

Purpose: Severe acute respiratory syndrome coronavirus 2 which is a novel type of coronavirus, may lead to high levels of expression of inammatory cytokines. Medium cut-off membranes may make greater clearances for large-middle molecules (including cytokines) than low ux membranes. In this study, we aimed to evaluate impact of type of hemodialysis membranes on outcome of COVID 19+ hemodialysis patients. Methods: Forty nine COVID 19 + hemodialysis patients were included into study. The patients were categorized into two groups regarding type of hemodialysis membranes. Clinical data, etiologies of kidney diseases, comorbidities, laboratory and radiologic ndings, antiviral, anti-cytokine treatments, and hemodialysis data were taken from medical records. Results: Medium cut-off membranes were used in 15 patients and low ux membranes were used in 34 patients. There were signicantly more patients with comorbidities in medium cut-off group compare to low ux group (p=0,014). CRP and ferritin which are each surragates of cytokine storm in COVID-19, were signicantly higher in medium cut-off membrane group compare to low ux group (p=0,00, 0,01, respectively). Conclusion: It may be an option to use medium cut-off membranes in hemodialysis patients with COVID 19 in order to reduce cytokine levels and prevent cytokine storm.


Introduction
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which is a novel type of coronavirus, rst emerged at December 2019 in Wuhan, China [1]. It has been reported that SARS-CoV may damage the respiratory system and causes serious outbreaks with high mortality rate [2,3]. The most common manifestation of infection is pneumonia which is characterized by bilateral in ltrates in the lung [4,5,6]. Positive reverse transcription-polymerase chain reaction (RT-PCR) assay for COVID-19 from upper respiratory system con rm the diagnosis [7]. Reports indicate that individuals with older age and/or with underlying illnesses, such as diabetes mellitus, hypertension, or cardiovascular diseases, indicate poor prognosis for COVID-19 [4,8,9]. These comorbidities are common in hemodialysis (HD) patients. Moreover, patients with chronic kidney failure have impaired immune function involving both innate and adaptive systems. These result in both immunodepression which increases vulnerability to infections [10].
HD is an extracorporeal process in which waste products that accumulate in patients with end-stage renal disease, is removed by a semipermeable membrane [17]. Three type of hemodialysis membranes are described: low ux (LF), high ux (HF) and medium cut-off (MCO) [18]. MCO membranes may make greater clearances and intradialytic reduction ratios for large-middle molecules (including cytokines) than LF and HF membranes [19].
In this study, we aimed to evaluate impact of type of hemodialysis membranes (MCO membrane versus LF membrane) on outcome of COVID 19+ HD patients.

Study setting
This study was performed in two tertiary care university hospitals which are serving in an area with approximately 16 million residents. The study was done in compliance to the Declaration of Helsinki. Institutional approval was taken from the local ethical review committee. The participants' identities were kept con dential.

Study population
All HD les of the COVID 19 + patients who had chronic HD treatment between the time period of 11 March 2020 and 15 May 2020 were examined. Hospital records were evaluated retrospectively. Forty nine COVID 19 + HD patients were included into study.
The patients were categorized into two groups regarding type of hemodialysis membranes: Group 1 patients underwent HD with MCO membranes and group 2 with LF membranes.

Data collection
The medical data of the patients were retrospectively obtained using standardized forms by a physician who did not know the outcome of the patients. Clinical data, etiologies of kidney diseases, comorbidities, laboratory and radiologic ndings, antiviral, anti-cytokine treatments, and HD data were taken from medical records.

Patient management
The positive RT-PCR and/or radiological ndings were used to con rm the diagnosis. Disease activity was described as follows: asymptomatic, mild disease (symptoms with or without mild dyspnea), moderate disease (dyspnea requiring oxygen therapy) and severe disease (dyspnea requiring intensive care treatment). All HD patients were hospitalized due to high mortality risk for COVID 19.

Antiviral and cytokine-targeted therapy
Our managements were based on a national guide written by the scienti c board of our country and published by our health ministry. All of the hospitalized patients were initially medicated with hydroxychloroquine (400 mg BID for the rst day, and then 200 mg BID for four days; oral) and azithromycin (500 mg QD for the rst day, and then 250 mg QD for the four days; oral) and oseltamivir (75 mg BID for 5 days). Favipiravir (1600 mg BID for the rst day, and then 600 mg BID for the four days; oral) was given to refractory cases. Tocilizumab (400 mg QD for two days; intravenous) was used in the management of cytokine release syndrome which especially developed in severe cases.
Anticoagulation and oxygen treatment Standart heparin or low molecular weight heparin was used in hemodialysis sessions unless contraindicated. Half dose low molecular weight heparin was used in all patients at hemodialysis free days unless contraindicated. Oxygen treatment was givento the patients with oxygen saturation below 92%. If respiratory failure progressed, rstly non-invasive ventilation and then mechanical ventilation was performed in the intensive care unit .

Statistical analysis
Data were expressed as mean ± SD. Data of HD patients with LF membrane and MCO membrane were compared using Student's t test and chi-square test. All computations were made using the SPSS for Windows v.17.0 software (SPSS Inc., Chicago, IL, USA). P values of <.05 were considered signi cant.
MCO (Theranova 400, Baxter TM , U.S.A) membranes were used in 15 patients and LF membranes (Elisio-21 M, Nipro TM , Japan) were used in 34 patients. Initial demographics and clinical characteristics and labarotory ndings of two groups are shown in Table 1. Mean age of two groups was similar. There were signi cantly more patients with comorbidities in MCO group compare to LF group (p=0,014). Kt/V, serum creatinine and sodium levels and platelet count were signi cantly higher in MCO group compare to LF group (p=0,047, 0,001, 0,002, 0,005, respectively). CRP and ferritin which are each surragates of cytokine storm in COVID-19, were signi cantly higher in MCO group compare to LF group (p=0,00, 0,01, respectively).
Symptoms and physical ndings during onset of diagnosis are shown in Table 2. Majority of the patients had fever, cough, dyspnea and myalgia. All of the patients had radiological ndings for Covid-19. Whereas, 21(42,8%) patients had positive PCR test for COVID-19.
Disease activity of the patients during onset of diagnosis is shown in Table 3. Regarding LF group, majority of the patients had mild-moderate disease activity. Whereas, there were more severe patients in MCO group compare to LF group in terms of disease activity.
Regarding treatment types, two groups were treated by similar drugs according to severity of the disease (Table 4). In the MCO group, more patients needed to require favipravir and tocilizumab treatments compare to LF group.
The outcomes of two groups are shown in Table 5. Length of hospital stay was signi cantly longer in MCO group compare to LF group (p=0,012). However, there were no signi cant differences between two groups in terms of need for intensive care unit and death. There is no currently cure for COVID-19. Therefore, clinicians are nowadays trying treat COVID-19 patients who progressed to HLH-MAS by some agents such as anti-viral agents, glucocorticoids, IL-6 antagonists, IL-1 antagonists, intravenous immunoglobulin, convalescent plasma, janus kinase inhibitors [20]. Also it was speculated that blood puri cation technology can prevent COVID-19 patients from severe pneumonia via cytokine clearance [21,22].
MCO is a novel type membrane for HD. In a study performed by Kim et al., it was showed that HD with MCO membranes achieved signi cantly greater reduction ratio of large middle molecules (including cytokines such as IL-1 and IL-6), than HD with conventional membranes and online-hemodio ltration [19].
In this study, we divided HD patients into two groups (LF membrane versus MCO membrane) in order to evaluate impact of MCO membranes on survival of patients with COVID-19.
Regarding clinical symptoms and laboratory results (especially CRP and ferritin levels), there were more severe COVİD-19 patients in MCO group compare to LF group. In addition, MCO group patients stayed longer in the hospital due to possibly severity of disease. Despite these data, there were no differences between two groups in terms of need for intensive care unit and death. In the light of these results, we can assume that MCO membranes may protect patients from HLH-MAS via cytokine puri cation.
The limitations of our study are that we performed this study in a small population. In small groups, it may be di cult to interpret statististical analysis. In addition, we could not measure IL-6 levels before and after HD sessions in order to see reduction in IL-6 level which is a good marker for in ammation in COVID-19 disease.
In conclusion, it may be an option to use MCO membranes in HD patients with COVID 19 in order to reduce cytokine levels and prevent cytokine storm. Also we can speculate that COVID-19 patients with cytokine storm may bene t from standart HD with MCO membranes regardless renal failure.

Declarations
Funding: There is no funding Con icts of interest/Competing interests: There is no con ict of interest Ethics approval: Ethics approval was obtained from local committee Consent to participate: Consent of participation was obtained