Analysis of Survival in Patients with End-End Chronic Kidney Disease Switching from Peritoneal Dialysis to Hemodialysis Due to Refractory Peritonitis

Introduction: Peritonitis associated with peritoneal dialysis (PD) has complications such as transfer from PD to HD and increased morbidity and mortality. In our environment, there is little information regarding survival in this population. Method(s): Retrospective cohort, 147 PD patients, 18 years, with PD catheter removal between 2018-2021. Clinical, biochemical and technique-related variables were measured. Patients who died of cancer and other unrelated causes were excluded. Descriptive statistics, Kaplan-Mayer analysis and Cox regression analysis were used Results: Age 42 +- 17 years, 65% men, 65% unknown cause of CKD. The time between peritonitis diagnosis and catheter removal was 37 (25-61) days. Nine patients (6%) returned to PD, the rest (94%) remained on HD due to unfit abdomen (55%), patient decision (9%), unknown (17%), others (19%). Mortality was 31% and the causes of death were: sepsis (33%), COVID-19 (29%), pneumonia (19%), pulmonary edema (5%), hyperkalemia (5%), CVD (5%), others (4%). Survival after the refractory peritonitis event was 25 (95% CI 22-28) months. Survival at 3, 12, 24, and 36 months was 87%, 71%, 61%, and 35%. In the bivariate analysis, age, DM, time on dialysis, and serum albumin were associated with a higher risk of death. However, in the multivariate analysis, only time on dialysis was significant (OR 1.014, 95% CI 1.002-1.027). [Formula presented] Conclusion(s): Mortality was 31% and the most frequent cause of death was sepsis. Patient survival was 25 (95% CI 22-28) months. Time on dialysis was associated with a higher probability of death. It is necessary to compare these results with a group of patients who do not present failure of the technique. No conflict of interestCopyright © 2023

ENDOTHELIAL INFLAMMATION AND DYSFUNCTION INDUCED BY SARS-COV-2 SPIKE PROTEIN 1 INVOLVE ADAM17 AND INTERFERON ACTIVATION PATHWAYS

Objective: COVID19 is associated with vascular inflammation. IFN-alpha (IFNa) and IFN-lambda3 (IFNl3) are potent cytokines produced in viral infections. Their effects involve interferon-stimulated genes (ISGs) and may influence expression of angiotensin-converting enzyme 2 (ACE2), the receptor for S-protein (S1P) of SARS-CoV-2. We hypothesized that S1P-induced immune/inflammatory responses in endothelial cells (EC) are mediated via IFN-activated pathways Design and methods: Human ECs were stimulated with S1P (1 mg/mL), IFNa (100ng/mL) or IFNl3 (100IU/mL). Because ACE2, ADAM17 and TMPRSS2 are important for SARS-CoV-2 infection, we used inhibitors of ADAM17 (marimastat, 3.8 nM), ACE2 (MLN4760, 440pM), and TMPRSS2 (camostat, 50 mM). Gene and protein expression was investigated by real-time PCR and immunoblotting, respectively. Vascular function was assessed in mesenteric arteries from wild-type (WT) normotensive and hypertensive (LinA3) mice and in ISG15-deficient (ISG15KO) mice. Results: S1P increased expression of IFNa (3-fold), IFNl3 (4-fold) and ISGs (2-fold) in EC (p < 0.05). EC responses to IFNa (ISG15: 16-fold) were greater than to IFNl3 (ISG15: 1.7-fold) (p < 0.05). S1P increased gene expression of IL-6 (1.3-fold), TNFa (6.2-fold) and IL-1b (3.3-fold), effects that were amplified by IFNs. Only the ADAM17 inhibitor marimastat inhibited S1P effects. IFNa and IFNl3 increase protein expression of ADAM17 (27%) and TMPRSS2 (38%). No changes were observed on ACE2 expression. This was associated with increased phosphorylation of Stat1 (134%), Stat2 (102%), ERK1/2 (42%). EC production of IL-6 was increased by IFNa (1,230pg/mL) and IFNl3 (1,124pg/mL) vs control (591pg/mL). Nitric oxide generation and eNOS phosphorylation (Ser1177) were reduced by IFNa (40%) and IFNl3 (40%). Vascular functional responses demonstrated that endothelium-dependent vasorelaxation (% Emax) in vessels from WT-mice stimulated with IFNa (67%) and IFNl3 (71%) were reduced vs control (82%) (p < 0.05). Responses were not altered in vessels from ISG15KO mice. Increased contraction was observed only in vessels from hypertensive mice treated with IFNa (9.1 ± 0.5mN vs control: 7.3 ± 0.3mN) (p < 0.05). Conclusions: In ECs, S1P, IFNa and IFNl3 increased ISG15 and IL-6 by mechanisms dependent on ADAM17. IFNs amplifies endothelial cell inflammatory responses and induced vascular dysfunction through ISG15-dependent mechanisms, with augmented effects in hypertension. Our findings demonstrate that S1P induces immune/inflammatory responses that may be important in endotheliitis associated with COVID-19. This may be especially important in the presence of cardiovascular risk factors, including hypertension.

ACE2 IS INVOLVED IN SARS-COV-2 INDUCED ENDOTHELIAL CELL INFLAMMATION INDEPENDENT OF VIRAL REPLICATION

Objective: COVID-19 association with cardiovascular disease is thought to be due to endothelial cell inflammation. ACE2 interactions with SARS-CoV-2 spike protein S1 subunit is important to viral infection. Here we questioned whether SARS-CoV-2 induces vascular inflammation via ACE2 and whether this is related to viral infection. Design and Methods: Human microvascular endothelial cells (EC) were exposed to recombinant S1p (rS1p) 0.66 ug/mL for 10 min, 5 h and 24 h. Gene expression was assessed by RT-PCR and levels of IL6 and MCP1, as well as ACE2 activity, were assessed by ELISA. Expression of ICAM1 and PAI1 was assessed by immunoblotting. ACE2 activity was blocked by MLN4760 (ACE2 inhibitor) and siRNA. Viral infection was assessed by exposing Vero E6 (kidney epithelial cells;pos ctl) and EC to 105 pfu of SARS-CoV-2 where virus titre was measured by plaque assay. Results: rS1p increased IL6 mRNA (14.2 ± 2.1 vs. C:0.61 ± 0.03 2-ddCT) and levels (1221.2 ± 18.3 vs. C:22.77 ± 3.2 pg/mL);MCP1 mRNA (5.55 ± 0.62 vs. C:0.65 ± 0.04 2-ddCT) and levels (1110 ± 13.33 vs. C:876.9 ± 33.4 pg/mL);ICAM1 (17.7 ± 3.1 vs. C:3.9 ± 0.4 AU) and PAI1 (5.6 ± 0.7 vs. C: 2.9 ± 0.2), p < 0.05. MLN4760, but not rS1p, decreased ACE2 activity (367.4 ± 18 vs. C: 1011 ± 268 RFU, p < 0.05) and blocked rS1p effects on ICAM1 and PAI1. ACE2 siRNA blocked rS1p-induced IL6 release, ICAM1, and PAI1 responses as well as rS1p-induced NFkB activation. EC were not susceptible to SARS-CoV-2 infection, while the virus replicated well in Vero E6. Conclusion: rS1p induces an inflammatory response through ACE2 in endothelial cells;an effect that was independent of viral infection.

COVID-19 humoral and T-cell mediated vaccination responses in people with multiple sclerosis

Background: For people living with MS (pwMS) the impact of disease modifying treatments (DMT) on vaccine efficacy has been a growing concern. Method(s): We used remote sampling to assess humoral response using dried blood spot (DBS) and ELISA for anti-SARS-CoV-2 IgG and performed T-cell analysis on a selection of participants. Compliance rates were maintained at ~70% post each vaccination time-point and DBS quality rates improved across the time frame of the study. Result(s): The cohort consisted of 184 participants who could be grouped by DMT into;anti-CD20 (40%), fingolimod (8%) and all other DMT/no DMT (52%).The primary vaccination course was Oxford/AstraZeneca for 61% and Pfizer-BioNTech for the remainder. Post-v2 76/110 (69%) of participants had seroconverted, increasing to 131/173 (76%) post v3. Vaccine response was influenced by DMT. After v2 13/38 (34%) of participants on anti-CD20 and 1/9 (11%) on fingolimod seroconverted compared to 63/63 (100%) of those on other/no DMT. Lower vaccine responses were seen post-v2 in those on anti- CD20;6.6 BAU/ml (IQR 63) and fingolimod;9.9 BAU/ml (IQR 9) compared to all other/no DMT;326.7 BAU/ml (IQR 535), p<0.001. In v2 responders successive vaccinations further increased response. A median of 313 BAU/ml (IQR 440) was found post v2, increasing to 936 BAU/ml (IQR 1362) at v3 and 1559 BAU/ml (IQR 1374) at v4, p<0.001. Amongst v2 non-responders third vaccinations increased seroconversion. 9/32 (28%) of v2 non-responders seroconverted after v3;3/23 (13%) of these were on anti-CD20 and 5/9 (56%) were on fingolimod. T-cell responses were found in the majority of individuals regardless of seroconversion status. All 14 anti-CD20 participants tested had a positive T-cell response at v3. Preliminary evidence suggests that T-cell response is sustained for at least 6 months post vaccination. Conclusion(s): DMT influences both seroconversion and antibody titre in response to vaccination. Additional vaccination courses post-v2 result in increased titre, and even in those who failed to seroconvert after v2, increase chance of seroconversion. Amongst those who fail to show a humoral response, a T-cell response is evident in the majority.

Humoral and T- cell response to multiple COVID-19 booster vaccinations in people with MS

Introduction: People with multiple sclerosis (PwMS) treated with anti-CD20 therapies and fingolimod are less likely to successfully produce a humoral response to COVID-19 vaccines 1 and 2. Objective(s): To measure the humoral and/or cellular response to COVID-19 booster vaccinations in a cohort of PwMS who were previously seronegative after their initial COVID vaccine course. Aim(s): To determine whether there is a benefit of COVID-19 booster vaccinations for people with MS who are known to have had an attenuated response to initial vaccines. Method(s): We studied a cohort of PwMS all of whom were seronegative for anti-SARS-CoV-2 spike protein IgG after the 1st and 2nd COVID-19 vaccines, including PwMS treated with ocrelizumab (n=53), fingolimod (n=15), other DMTs (n=9) and no DMT (n=2). Dried blood spot +/- whole blood samples were obtained from participants at 2-8 weeks after their 3rd (n=79) and 4th (n=40) COVID-19 vaccines. Samples were used to measure anti-SARS-CoV-2 spike protein IgG (ELISA) and T-cell response (IFN-g release assay measured on whole blood). Result(s): Overall 27/79 (34%) who were seronegative after COVID vaccine 2 seroconverted after vaccine 3. Seroconversion rates were 17% for PwMS treated with ocrelizumab, 47% for fingolimod and 100% for other DMTs. A further 2/30 (7%) of those who remained seronegative after vaccine 3 seroconverted after vaccine 4. Anti-SARS-CoV-2 T-cell responses were measurable in 26/40 (65%) after vaccine 3 and 13/19 (68%) after vaccine 4 but were conspicuously absent in people treated with fingolimod. Overall, 75% of participants showed either humoral or cellular response after receiving 4 COVID vaccinations. PwMS with laboratory evidence of prior COVID-19 infection had higher measurable T-cell responses. Conclusion(s): Booster vaccinations for COVID-19 are associated with incremental benefits in measurable immunity in those with attenuated responses to the initial vaccine course. Overall, three quarters of those who were seronegative after COVID vaccines 1 & 2 had a measurable immune response after COVID vaccine 4. This data supports the use of booster vaccinations in pwMS at risk of attenuated vaccine response.

How we completed major maintenance and new installations at Las Cumbres Observatory during the COVID-19 Pandemic

Las Cumbres Observatory (LCOGT) operates a network of more than 25 telescopes that are globally distributed over seven sites. Despite the COVID-19 pandemic restricting travel to most of those sites since March 2020, LCOGT achieved several significant operational milestones: (i) We deployed a new multi-channel imager (MuS-CAT3) at Haleakala Observatory. (ii) We installed two new 1-meter telescopes at Teide Observatory. (iii) We performed essential maintenance with local staff at the sites. The latter included opening two of the NRES spectrograph's thermal and pressure enclosures - a task traditionally executed by trained LCOGT personnel only. We discuss the evolution of LCOGT's paradigm for maintenance. Sustaining observatory operations increasingly relied on local observatory staff, of various skill levels and capabilities, to execute the highest priority work with remote support. We made this possible with extensive planning, being sensitive to local conditions, and bringing in expertise to support and guide in real-time via extended Zoom sessions.

IMMUNE DYSREGULATION INDUCED BY SPIKE PROTEIN 1 OF SARS-COV-2 INCREASES ENDOTHELIAL CELL DYSFUNCTION VIA TYPE I AND TYPE III INTERFERON ACTIVATION PATHWAYS

Objective: COVID19-associated immunopathology is associated with increased production of interferon (IFN)-alpha (IFNα) and lambda3 (IFNL3). Effects of IFNs are mediated by interferon-stimulated genes (ISGs) and influence expression of angiotensin-converting enzyme 2 (ACE2), the receptor for S-protein (S1P) of SARS-CoV-2. Increasing evidence indicates vascular inflammation in cardiovascular sequelae of COVID19. We hypothesized that S1P-induced immune/inflammatory responses in endothelial cells (EC) are mediated via IFNα and IFNL3. Design and method: Human ECs were stimulated with S1P (1 μg/mL), IFNα (100ng/mL) or IFNL3 (100IU/mL). Because ACE2, metalloproteinase domain-17 (ADAM17) and type-II transmembrane serine protease (TMPRSS2) are important for SARS-CoV-2 infection, cells were treated with inhibitors of ADAM17 (marimastat, 3.8 nM), ACE2 (MLN4760, 440pM), and TMPRSS2 (camostat, 50 μM). Gene and protein expression was investigated by real-time PCR immunoblotting, respectively. Vascular function was assessed in mesenteric arteries from wild-type (WT) normotensive and hypertensive mice and in ISG15-deficient (ISG15KO) mice. Results: EC stimulated with S1P increased expression of IFNα (3-fold), IFNL3 (4-fold) and ISG (2-fold)(p < 0.05). EC exhibited higher responses to IFNα (ISG15: 16-fold) than to IFNL3 (ISG15: 1.7-fold)(p < 0.05). S1P increased gene expression of IL-6 (1.3-fold), TNFα (6.2-fold) and IL-1β (3.3-fold), effects that were maximized by IFNs. Only marimastat inhibited S1P effects. IL-6 was increased by IFNα (1,230pg/mL) and IFNL3 (1,124pg/mL) vs control (591pg/ mL). This was associated with increased phosphorylation of Stat1 (134%), Stat2 (102%), ERK1/2 (42%). Nitric oxide production and eNOS phosphorylation (Ser1177) were reduced by IFNα and (40%) and IFNL3 (40%). Reduced endothelium relaxation maximal response (%Emax) was observed in vessels from WTmice stimulated with IFNα (67%) and IFNL3 (71%) vs control (82%)(p < 0.05) but not in vessels from ISG15KO mice. Increased contraction was observed only in vessels from hypertensive mice treated with IFNα (9.1 ± 0.5mN vs control: 7.3 ± 0.3mN, p < 0.05). Conclusions: In ECs, S1P, IFNα and IFNL3 increased ISG15 and IL-6, processes that involve ADAM17. Inflammation induced by S1P was amplified by IFNs. IFNs induce vascular dysfunction through ISG15-dependent mechanisms, with augmented effects in hypertension. Our findings demonstrate that S1P induces immune/inflammatory responses that may be important in endotheliitis associated with COVID-19. This is especially important in the presence of cardiovascular risk factors, including hypertension.

Steroids and mortality in non-critically ill COVID-19 patients: a propensity score-weighted study in a Chilean cohort.

OBJECTIVES: The aim of this study was to evaluate the impact on 30-day mortality of early use of corticosteroids in COVID-19 patients with supplementary oxygen requirements and without invasive mechanical ventilation at the initiation of therapy. METHODS: All patients hospitalized with COVID-19 between April 15 and July 15, 2020, and requiring supplementary oxygen, were prospectively included in a database. Patients who died or required intubation within the first 48 hours were excluded. Patients who received corticosteroids within the first 5 days of hospitalization and at least 24 hours prior to intubation were allocated to the 'early corticosteroids' group. To compare both populations and adjust for non-random treatment assignment bias, a weight-adjusted propensity score model was used. RESULTS: In total, 571 patients met the inclusion criteria, 520 had sufficient information for the analysis. Of these, 233 received early corticosteroids and 287 did not. Analysis showed a reduction of 8.5% (p = 0.038) in 30-day mortality in the early corticosteroid group. The reduction in mortality was not significant when patients with corticosteroid initiation between day 5 and day 8 of hospitalization were included. CONCLUSION: Early corticosteroid use reduced mortality in patients with pneumonia due to COVID-19, who required supplementary oxygen but not initial invasive mechanical ventilation.

[Structural capacity, technological human resources and mechanical ventilation requirements in 58 intensive care units in Argentina during the SARS-CoV-2 pandemic. A SATICOVID-19 Study]

During the SARS-CoV-2 pandemic, there was a marked requirement for critical care beds, supplies and trained professionals to assist patients with severe respiratory failure. The Argentine Society of Intensive Care (SATI) designed a study to characterize these aspects in intensive care units (ICUs). Multicenter, prospective cohort study;the participating ICUs completed a form at the end of the study (31/10/2020) on hospital characteristics, number of beds in pre- and intra-pandemic critical areas, incorporation of professionals, technological resources, and workload. Fifty-eight ICUs participated;28(48%) were located in Buenos Aires Province, 22(38%) in Buenos Aires Autonomous City and 10 (17%) in other provinces;31 (53%) of UCIs belonged to the public sector;23 (47%) to the private-social security. In 35/58 (60%) of the hospitals critical care beds increased from 902 to 1575 (75%), 37% in ICU and 63% mainly in Coronary Care Unit and Emergency-shock room. In 41/55 (75%) UCIs, staff were incorporated: 27(49%) physicians (70% intensivists), 36 (65%) nurses, 28 (51%) respiratory therapists, 20(36%) cleaning staff, and 1(2%) others. A 96% of the ICUS reported having sufficient ventilators and 95% enough supplies and PPE. Of all patients on invasive mechanical ventilation, 55% [43-64] had COVID-19. Oxygen therapy was required as noninvasive support in 14% [8-24] of COVID-19 admissions. There was a significant expansion of critical operational areas, secondary to the increase in beds, staff, and adequate availability of ventilators and essential supplies. The burden of critical illness from COVID-19 was intense, with more than half of patients on mechanical ventilation.

Risk factors for AKI and mortality in COVID-19 in Western Mexico

Background: Acute kidney injury (AKI) in COVID-19 is associated with disease severity. The aim of this study was to identify risk factors associated with the development of AKI and its clinical impact, such as need for RRT and mortality. Methods: Retrospective cohort study of hospitalized adult patients COVID-19, with normal kidney function, from April to December 2020 in Western Mexico. Results: 882 patients (60.8% men) with a mean age of 58.9y were included. 342 (38.8%) had a prior diagnosis DM, 412 (46.7%) HTN, 161 (18.3%) obesity, 59 (6.7%) heart diseases, 25 (2.8%) neurological disease, 47 (5.3%) lung disease. 216 (24.5%) smoking history. 270 patients (30.6%) developed AKI, 95 (10.77%) KDIGO stage 1, 44 (4.98%) stage 2, and 84 (9.52%) stage 3. 59 patients required RRT (6.23%), and 111 patients (12.6%) mechanical ventilation. Overall mortality was 30.6% (270 patients). Risk factors for mortality were: DM, HTN, neurological disease, age > 65 y, need for MV, and MAP < 65 mmHg, hyperNa, increased D-dimer or decreased HCO3 at admission. Risk factors for AKI were: DM, HTN, heart disease, age > 65 y, need for MV, and MAP < 65 mmHg, hyperNa, increased D-dimer or decreased HCO3 at admission. Image shows risk factors, ORs with CI. Conclusions: A high incidence of AKI in the Mexican population compared to reports from other countries, with a significantly high risk for death.

Mortality in COVID-19 patients with CKD with and without kidney replacement therapy in Western Mexico

Background: COVID-19 is a new disease of pandemic proportions. Currently, there are no reports on clinical outcomes in patients with CKD with and without KRT in the Mexican population. Our aim was to describe the clinical outcomes in patients with CKD. Methods: Retrospective cohort study of hospitalized adult patients COVID-19 confirmed with RT-PCR, from April to December 2020 in a second-level hospital in Western Mexico. Information was obtained from medical records. Results: 1012 patients were included, of which 130 patients (12.8%) had CKD (65.3% men), with a mean age of 53.8 years, 43.8% with Diabetes Mellitus and 82.3% with Hypertension. 84 patients (64.6%) were on KRT, within which 47 patients were on hemodialysis, 31 on peritoneal dialysis and 6 with a kidney transplant. 46 patients had no KRT, in stages ranging from KDIGO 3b to 5. 78.4%. 14 patients (10.7%) required mechanical ventilation. In our study, mortality among patients with normal kidney function was 30.6%. Regarding patients with CKD, patients on hemodialysis had a mortality of 25.5% (OR 0.74, 95% CI 0.39-1.5), patients on peritoneal dialysis had a mortality of 54.8% (OR 2.75, 95% CI 1.33-5.66), patients with CKD and no KRT had a mortality of 43.5% (OR 1.74, 95% CI 1.15-3.17). Conclusions: In our population, an increased mortality was found in patients with CKD with and without KRT, highlighting the mortality of patients on PD.

Severe pneumonia due to COVID-19 cured with conscious proning and tocilizumab. A report of a case and review of the pharmacological therapeutic evidence

BACKGROUND: At the end of December 2019 it was described the first outbreak of atypical pneumonias in Wuhan, China, with the following detection of the agent of the genus coronavirus, today denominated SARS-CoV-2 and its disease COVID-19. CLINICAL CASE: A 41-year-old male patient affected by COVID-19 in the form of severe pneumonia (CORADS-6), who had no response to conventional drugs that only added comorbidity (QT prolongation), deserving non-invasive ventilatory strategy in the prone and conscious mode, combined with the administration of tocilizumab, presenting adequate clinical, blood gas, and tomographic evolution, currently without pulmonary sequelae. CONCLUSIONS: Many controlled clinical studies are still lacking in order to demonstrate the concrete utility of a specific drug and the current evidence leads to abandoning initially proposed schemes;however, some drugs may still have some utility in mild to moderate cases. © 2020 Comunicaciones Cientificas Mexicanas S.A. de C.V.. All rights reserved.