Monoclonal antibodies to the interleukin-6 receptor in the treatment of COVID-19 in patients with chronic kidney disease

Interleukin-6 (IL-6) plays a key role in the pathogenesis of COVID-19, which determines the indications for the therapeutic use of its antagonists. However, data on their effectiveness and optimal timing of appointment are contradictory. The question of the possibility of their use in patients with impaired kidney function has not been studied. The aim of the study is to evaluate the efficacy and safety of the use of monoclonal antibodies to IL-6 receptors in COVID-19 in patients with chronic kidney disease (CKD) of stages 2-5 (predialysis) who do not need renal replacement therapy. Material and methods. A clinical retrospective uncontrolled single-center study included 45 patients (60% of men) with CKD stages 2-5 aged 22-95 years (median - 58 years) hospitalized with predominantly severe uncritical COVID-19 infection. Treatment of COVID-19 was carried out in accordance with the Interim guidelines for the prevention and treatment of new coronavirus infection of the Ministry of Health of Russian Federation. Results. The majority of patients (n=36;73.3%) had CKD stage 3b-5, CKD stage 2 was in 7 (15.5%) and stage 3a - in 5 (11.1%) patients. The median serum creatinine level (Cr) was 164 [131;292] mumol/l, glomerular filtration rate (GFR) was 30 [13;49] ml/min/1.73 m2, CRP 67.5 [37.2;106.75] mg/l. The introduction of monoclonal antibody to IL-6 receptors led to a decrease in the activity of the infectious process (CRP 1.55 [0.33;4.15] mg/l, p<0.001), regression of pneumonia, which did not require mechanical ventilation and hospitalization in the intensive care unit. According to the decision of the medical commission, patients were injected with monoclonal antibodies to IL-6 receptors: tocilizumab (n=36;80%), levilimab (n=2;4.4%), combined therapy with two drugs (n=7;15.5%). Therapy with IL-6 antagonists did not have a negative effect on kidney function. The levels of Cr decreased on average from 224.3+/-145.2 mmol/l at admission to 160+/-92.55 mmol/l at discharge (p<0.001), GFR increased from 32.6+/-20.9 ml/min/1.73 m2 at admission to 53+/-31.7 ml/min/1.73 m2 at discharge (p<0.001). In the majority of patients (n=36, 80%) GFR has risen, and only in 9 (20%) cases it remained approximately at the same low level. No serious adverse events have been reported with the use of IL-6 antagonists, as well as concomitant infectious complications. No deaths have been reported. The median length of stay in bed was 14 [10;19] days. Conclusion. The results of the study allow us to state that in patients with CKD, monoclonal antibodies to IL-6 receptors have a good safety profile and can be successfully used in moderate and severe forms of COVID-19, regardless of the state of kidney function.Copyright © 2022 by the authors.

COVID-19 in hemodialysis patients

Objective. Evaluation of clinical observation, the course, the risk factors, and treatment options for SARS-CoV-2 infection in hemodialysis patients with end-stage chronic kidney disease. Material and methods. The retrospective, single-center, uncontrolled study involved 231 patients (132 M/99 W) aged 61.7+/-14.7 years with COVID-19 diagnosed. The SPSS software package was used for statistical analysis. Results. 72 (31.2%) of patients died, 68 (94.4%) of them had ARDS as the main cause of death. Comparative analysis in groups with favorable and unfavorable outcomes of the disease showed that age (68.1+/- 13.2 years vs 58.7+/-14.5 years, p<0.0001) and the comorbidity index (8.8+/-2.2 vs 6.2+/-2.6, p<0.0001) were significantly higher in those who have died compared to survivors. According to CT data, they were more likely to have 3rd or 4th-degree lung damage (72.2 vs 36.5%, p<0.0001), and the minimum oxygen saturation index: 67.6+/-12.8 and 87.8+/-10.9%, respectively (p<0.0001). Somorbidity index and the need for invasive ventilation were independent predictors of the fatal outcome of COVID-19. Early administration of monoclonal antibodies to IL-6 (in the first 3 days after hospitalization) in patients with a low prevalence of the pulmonary process (CT stage 1-2) was associated with a significantly lower frequency of fatal outcome. Conclusions. SARS-CoV-2 infection in HD patients is characterized by a high rate of mortality. Predictors of severe disease in this population are comorbidity index and the need for invasive ventilation.Copyright © Infectious Diseases: News, Opinions, Training.

Frequency of SARS-CoV-2 infection in hemodialysis patients

Patients with end-stage chronic kidney disease treated with hemodialysis are at risk of infection and severe course of the new coronavirus infection. This opinion was based on the data obtained as a result of PCR testing during the active phase of the disease with detailed clinical symptoms. However, this diagnostic method does not allow one to fully assess the prevalence of infection in the population. The aim - studying of the frequency of SARS-CoV-2 infection in patients receiving hemodialysis treatment and the spectrum of antiviral antibodies, depending on the nature of the course of COVID-19. Material and methods. 100 patients with chronic kidney disease (stage 5D) treated at the outpatient Dialysis Center (MCVTP) were included in the study by a simple random sample. The assessment of SARS-CoV-2 infection was carried out by analyzing the material of smears obtained from the naso-oropharynx by PCR and blood serum samples by ELISA. The study excluded 14 patients with dubious results for the determination of serological markers SARS-CoV-2 and 1 patient with active infection, who was isolated from the RNA of the virus. Results. IgM and IgG antibodies were detected in 49 (57.6%) of the 85 examined patients. 24 of them (group 1) were diagnosed with COVID-19 infection with typical clinical symptoms 3-9 months ago, and 25 (group 2) had no clinical manifestations of the acute respiratory infection at the appropriate time suggesting an asymptomatic course of the disease. IgM class antibodies were detected with equal frequency in group 1 and in group 2 (33.3 vs 24.0%, respectively, p<0.6). IgG antibodies exclusively to the nucleocapsid N-protein (IgGn) were detected only in the latent form of the disease (32%), while antibodies against the S-protein (spike protein) of the virus (IgGs and IgGn+s) were detected more often in the manifest form compared to the asymptomatic one (100 vs 60%, respectively, p<0.05). Conclusion. In a random cohort of patient receiving hemodialysis treatment, more than half were asymptomatic.Despite a wide range of prevention measures, SARS-CoV-2 infection among patients treated with hemodialysis is more than 2 times higher than in the general population.Copyright © 2021 Geotar Media Publishing Group. All rights reserved.

Monoclonal antibodies to the interleukin-6 receptor in the treatment of COVID-19 in patients with chronic kidney disease

Interleukin-6 (IL-6) plays a key role in the pathogenesis of COVID-19, which determines the indications for the therapeutic use of its antagonists. However, data on their effectiveness and optimal timing of appointment are contradictory. The question of the possibility of their use in patients with impaired kidney function has not been studied. The aim of the study is to evaluate the efficacy and safety of the use of monoclonal antibodies to IL-6 receptors in COVID-19 in patients with chronic kidney disease (CKD) of stages 2-5 (predialysis) who do not need renal replacement therapy. Material and methods. A clinical retrospective uncontrolled single-center study included 45 patients (60% of men) with CKD stages 2-5 aged 22-95 years (median - 58 years) hospitalized with predominantly severe uncritical COVID-19 infection. Treatment of COVID-19 was carried out in accordance with the Interim guidelines for the prevention and treatment of new coronavirus infection of the Ministry of Health of Russian Federation. Results. The majority of patients (n=36;73.3%) had CKD stage 3b-5, CKD stage 2 was in 7 (15.5%) and stage 3a - in 5 (11.1%) patients. The median serum creatinine level (Cr) was 164 [131;292] μmol/l, glomerular filtration rate (GFR) was 30 [13;49] ml/min/1.73 m2, CRP 67.5 [37.2;106.75] mg/l. The introduction of monoclonal antibody to IL-6 receptors led to a decrease in the activity of the infectious process (CRP 1.55 [0.33;4.15] mg/l, p<0.001), regression of pneumonia, which did not require mechanical ventilation and hospitalization in the intensive care unit. According to the decision of the medical commission, patients were injected with monoclonal antibodies to IL-6 receptors: tocilizumab (n=36;80%), levilimab (n=2;4.4%), combined therapy with two drugs (n=7;15.5%). Therapy with IL-6 antagonists did not have a negative effect on kidney function. The levels of Cr decreased on average from 224.3±145.2 mmol/l at admission to 160±92.55 mmol/l at discharge (p<0.001), GFR increased from 32.6±20.9 ml/min/1.73 m2 at admission to 53±31.7 ml/min/1.73 m2 at discharge (p<0.001). In the majority of patients (n=36, 80%) GFR has risen, and only in 9 (20%) cases it remained approximately at the same low level. No serious adverse events have been reported with the use of IL-6 antagonists, as well as concomitant infectious complications. No deaths have been reported. The median length of stay in bed was 14 [10;19] days. Conclusion. The results of the study allow us to state that in patients with CKD, monoclonal antibodies to IL-6 receptors have a good safety profile and can be successfully used in moderate and severe forms of COVID-19, regardless of the state of kidney function. © 2022 by the authors.

[COVID-19 in haemodialysis patients: result analysis of the first year of the pandemic].

BACKGROUND: Present concepts of the novel coronavirus infection prognosis in haemodialysis (HD) patients are rather controversial. There is little information on therapy efficiency and safety in such patients. We studied COVID-19 course specifics, prognostic factors associated with fatal outcomes, therapy efficiency and its transformation at different stages of the pandemic first year. MATERIALS AND METHODS: Single-centre retrospective uncontrolled study included 653 COVID-19 HD-patients treated at Moscow City Nephrology Centre from April 1 to December 31, 2020. RESULTS: This period mortality rate was 21.0%. Independent predictors of COVID-19 unfavourable outcome in HD patients were pulmonary lesion extension (CT grades 34), high comorbidity index, and mechanical ventilation. Approaches to COVID-19 treatment modified significantly at different periods. Immunomodulatory drugs (monoclonal antibodies to IL-6, corticosteroids) were used largely at later stages. With tocilizumab administration, mortality was 15.1%, tocilizumab together with dexamethasone 13.3%; without them 37.8% (р0,001). Tocilizumab administration in the first 3 days after hospitalization of patients with CT grades 12 was associated with more favourable outcomes: 1 out of 29 died vs 6 out of 20 (tocilizumab administered at later periods); p0.04. There was no significant difference in death frequency in patients with CT grades 34 depending on tocilizumab administration time. CONCLUSION: COVID-19 in HD patients can manifest in a severe course with unfavourable outcome. It is urgent to identify reliable disease outcome predictors and develop efficient treatment in this population.

Frequency of SARS-CoV-2 infection in hemodialysis patients

Patients with end-stage chronic kidney disease treated with hemodialysis are at risk of infection and severe course of the new coronavirus infection. This opinion was based on the data obtained as a result of PCR testing during the active phase of the disease with detailed clinical symptoms. However, this diagnostic method does not allow one to fully assess the prevalence of infection in the population. The aim – studying of the frequency of SARS-CoV-2 infection in patients receiving hemodialysis treatment and the spectrum of antiviral antibodies, depending on the nature of the course of COVID-19. Material and methods. 100 patients with chronic kidney disease (stage 5D) treated at the outpatient Dialysis Center (MCVTP) were included in the study by a simple random sample. The assessment of SARS-CoV-2 infection was carried out by analyzing the material of smears obtained from the naso-oropharynx by PCR and blood serum samples by ELISA. The study excluded 14 patients with dubious results for the determination of serological markers SARS-CoV-2 and 1 patient with active infection, who was isolated from the RNA of the virus. Results. IgM and IgG antibodies were detected in 49 (57.6%) of the 85 examined patients. 24 of them (group 1) were diagnosed with COVID-19 infection with typical clinical symptoms 3–9 months ago, and 25 (group 2) had no clinical manifestations of the acute respiratory infection at the appropriate time suggesting an asymptomatic course of the disease. IgM class antibodies were detected with equal frequency in group 1 and in group 2 (33.3 vs 24.0%, respectively, p<0.6). IgG antibodies exclusively to the nucleocapsid N-protein (IgGn) were detected only in the latent form of the disease (32%), while antibodies against the S-protein (spike protein) of the virus (IgGs and IgGn+s) were detected more often in the manifest form compared to the asymptomatic one (100 vs 60%, respectively, p<0.05). Conclusion. In a random cohort of patient receiving hemodialysis treatment, more than half were asymptomatic.Despite a wide range of prevention measures, SARS-CoV-2 infection among patients treated with hemodialysis is more than 2 times higher than in the general population. © 2021 Geotar Media Publishing Group. All rights reserved.

SARS-CoV-2 infection in kidney transplant recipients

The study aimed to assess the clinical course and risk factors for adverse outcomes, as well as the treatment options for COVID-19 in renal transplant recipient (RTR). Patients and methods: a retrospective study included 279 RTRs (M 60.9%, age 49.9±10.9 years), infected with SARS-CoV-2 from 01.04.2020 to 30.11.2020. After confirmation of COVID-19 by PCR and chest CT, MMF/Aza were canceled. In severe cases, the CNI dose was minimized while that of CS was increased. Observation endpoints: hospital discharge/recovery or death. Results: SARS-CoV-2 was identified in 84.2% of RTRs. In almost 90% of patients, the COVID-19 was confirmed by CT data. Duration after transplantation at the time of infection was 54.0 (14.0;108.0) months, in 17.6% of cases it was 6 months or less. 223/79.9% RTRs were treated in the hospital. The period from the onset of the disease to the hospitalization was 6.8±4.5 days. Severe lung damage (>50%) occurred in 43.1% RTRs;45.3% of patients required respiratory support. Hospital mortality was 13.9%, overall mortality was 11.1%. The most common cause of death (93.5%) was acute respiratory distress syndrome (ARDS). The risk factors associated with an unfavorable outcome were a high comorbidity index, the severity of the pulmonary lesion, the degree of graft dysfunction at the onset of the disease, decreased SpO2 and the use of mechanical ventilation, as well as anemia, leukocytosis, lymphocytopenia, and hypoalbuminemia, increased levels of creatinine, AST, CRP, LDH, and D-dimer, interleukin-6 and procalcitonin. Scr during the course of the disease increased from 171.6±78.0 μM to 221.5±121.3 μM (p<0.01) with no signs of acute rejection. In 2 recipients with severe graft failure at the time of infection with SARS-CoV-2, HD was resumed from the moment of hospitalization. We were unable to identify the effect of hydroxychloroquine on the outcome of COVID-19. At the same time, mortality in patients with hydroxychloroquine use was higher than in recipients treated with immunobiological drugs: 25.6% and 11.4%, respectively, p<0.02. When immunomodulators were combined with dexamethasone, mortality decreased to 4.8%. The independent factors of adverse outcome were high levels of procalcitonin (p<0.019) and mechanical ventilation (p<0.001). Conclusion: COVID-19 in RTRs is characterized by a severe course and high mortality, which necessitates hospitalization of the majority of infected patients. An increase in procalcitonin levels and the need for mechanical ventilation were independent predictors of an unfavorable outcome of COVID-19. © 2021 JSC Vidal Rus. All rights reserved.

Covid-19: Relationship with kidney diseases: Literature review

COVID-19 is a severe acute respiratory disease caused by the SARS-CoV-2 virus. Although COVID-19 is characterized mainly by diffuse alveolar damage and acute respiratory failure, in some cases COVID-19 may acquire extra-respiratory features, including renal dysfunction that has existed earlier or developed de novo. The reasons for the extra-respiratory manifestations are biological properties of SARS-CoV-2 based on its multiple organ tropism. It has been shown that at least 50% of patients hospitalized for COVID-19 have proteinuria, hematuria, and signs of renal dysfunction, which in some cases reaches the degree of acute kidney injury (AKI). Here we present a review that discusses the clinical aspects and possible pathophysiological mechanisms of kidney damage in COVID-19. It is believed that renal damage observed in this disease is the result of a complex mechanism induced directly or indirectly by SARS-CoV-2 with the development of acute kidney injury. Two main pathophysiological mechanisms of kidney damage in COVID-19 are discussed. The first of them is the direct cytopathic effect of SARS-CoV-2 on the renal epithelium with the development of acute tubulonecrosis. The second mechanism is the cytokine storm syndrome that results from hyperactivation of the immune system with the development of acute renal and multiorgan infl ammatory damage accompanied by hypoxia, persistent hypotension, rhabdomyolysis, hyperactivation of the coagulation cascade, and microcirculation disorders. From a clinical point of view, it should be noted that signs of kidney damage are associated with an increase in the severity of COVID-19 and a poor outcome of the disease, and the prognosis becomes the worst with the development of AKI (the risk of death may increase by 5.3 times). The incidence of COVID-19 in patients with ESRD is higher than in the general population. The most typical for these patients is a severe course of the disease, which determines the increased mortality in comparison with the general population, caused by a respiratory failure with hyperactive infl ammation, cytokine storm, hemodynamic, and multiple organ failures. © 2021 JSC Vidal Rus. All rights reserved.

COVID-19 in hemodialysis patients

Objective. Evaluation of clinical observation, the course, the risk factors, and treatment options for SARS-CoV-2 infection in hemodialysis patients with end-stage chronic kidney disease. Material and methods. The retrospective, single-center, uncontrolled study involved 231 patients (132 M/99 W) aged 61.7±14.7 years with COVID-19 diagnosed. The SPSS software package was used for statistical analysis. Results. 72 (31.2%) of patients died, 68 (94.4%) of them had ARDS as the main cause of death. Comparative analysis in groups with favorable and unfavorable outcomes of the disease showed that age (68.1± 13.2 years vs 58.7±14.5 years, p<0.0001) and the comorbidity index (8.8±2.2 vs 6.2±2.6, p<0.0001) were significantly higher in those who have died compared to survivors. According to CT data, they were more likely to have 3rd or 4th-degree lung damage (72.2 vs 36.5%, p<0.0001), and the minimum oxygen saturation index: 67.6±12.8 and 87.8±10.9%, respectively (p<0.0001). Сomorbidity index and the need for invasive ventilation were independent predictors of the fatal outcome of COVID-19. Early administration of monoclonal antibodies to IL-6 (in the first 3 days after hospitalization) in patients with a low prevalence of the pulmonary process (CT stage 1-2) was associated with a significantly lower frequency of fatal outcome. Conclusions. SARS-CoV-2 infection in HD patients is characterized by a high rate of mortality. Predictors of severe disease in this population are comorbidity index and the need for invasive ventilation. © Infectious Diseases: News, Opinions, Training.

Eculizumab in treatment of ANCA-associated vasculitis complicated with Covid-19 Clinical observations

Vasculitis associated with the antineutrophilic cytoplasmic antibodies (ANCA) is an autoimmune systemic severe, often life-threatening, disease characterized by necrotizing infl ammation of small vessels. In 75-90% of cases of ANCA-associated vasculitis (AAV), a rapidly progressive pauci-immune necrotizing crescentic glomerulonephritis develops. Despite current treatment with high-dose glucocorticoids and either cyclophosphamide or rituximab, patients have a nine-fold increased mortality risk during the fi rst year of disease compared with healthy subjects. This high mortality is attributed mainly to infections and vasculitis activity. Recent data suggest that the activation of the complement system, and in particular the alternative complement pathway, plays a signifi cant role in the pathogenesis of AAV. It has been suggested that neutrophils primed by infection or pro-infl ammatory cytokines release properdin, which activates an alternative complement cascade with cleavage of C5 into C5a and C5b. Anaphylatoxin C5a binds to receptors on the surface of neutrophils, enhancing their priming and activation and thus contributing to the infl ammation. The randomized clinical trial showed that the selective C5a-receptor inhibitor avakopan was effective in the treatment of AAV. However, avacopan is currently not available in the everyday clinical practice. On the other hand, reports showing successful usage of monoclonal antibody against C5 eculizumab in severe AAV had been published. Here we present four cases of AAV complicated by COVID-19, for which conventional therapy with cy?lophosphamide could not be applied due to the particularly high risk of serious infectious complications, and eculizumab was used off-label by decision of the medical council and special commission. Taking this decision, we took into account data demonstrating the role of complement activation and, in particular, C5a in the pathogenesis of acute lung disease, induced by pathogenic viruses. Moreover, the successful usage of eculizumab in severe COVID-19 was reported recently. Thus, we sought to apply an approach aimed simultaneously at the pathogenetic mechanisms of both AAV and viral lung damage. © 2020 JSC Vidal Rus. All rights reserved.