Diazoxide in the Treatment of Asymptomatic Refractory Hypoglycemia in End Stage Renal Disease

Introduction: Diabetic patients with end-stage renal disease (ESRD) treated with insulin or any other diabetic agent show high variations in their glucose metabolism, lower insulin clearance level, and uncertain accuracy of glycemic control measurements. Therefore, these patients are at a greater risk of developing hypoglycemia. Diazoxide use in the treatment of spontaneous and refractory hypoglycemia in this population has not been well documented. We report a case of a young diabetic male that has been successfully treated with diazoxide for his asymptomatic refractory hypoglycemic episodes. Case Description: A young man with type 2 diabetes mellitus complicated by diabetic nephropathy, on hemodialysis for ESRD, presented with shortness of breath due to COVID pneumonia. After resolution of his infection, he was noted to have recurrent asymptomatic hypoglycemic episodes, although he has been off his diabetes medications for the past few years due to worsening of his kidney function. His oral intake was adequate and there was no concern for malnutrition, or any substance use. From the testing performed, we were able to exclude exogenous insulin or insulin secretagogues use and the presence of insulin antibodies. Insulin and noninsulin (insulin-like growth factor) mediated mechanisms were also ruled out. Since he was having recurrent and refractory asymptomatic hypoglycemic episodes and to minimize the need for supplemental dextrose containing fluids, he was started on diazoxide at 3 mg/kg/day. Knowing the risk of fluid retention with diazoxide, this patient on hemodialysis tolerated it well. Diazoxide helped reduce his episodes of hypoglycemia and he was then safely discharged on it. Discussion(s): In ESRD, hypoglycemia can be explained by the impaired contribution of the kidneys to gluconeogenesis and glucose release, as well as the higher insulin levels caused by insulin resistance and decrease in insulin clearance. When his hypoglycemia persisted even after the resolution of his infection, further testing and work-up was done and other causes of hypoglycemia were ruled out. Generally, diazoxide is used as a treatment to manage the symptoms of hypoglycemia in congenital hyperinsulinism, insulinomas and post bariatric surgery cases of hyperinsulinemic hypoglycemia. However, it has not been the optimal treatment when it comes to treating hypoglycemia in ESRD patients because of its side effects;specifically, fluid retention, and electrolyte imbalances. In our case, the patient was treated with diazoxide as a last resort, despite its known side effects and the limited documentation of its use in ESRD patients. Actually, a few other case reports, have also shown promising results with the use of diazoxide for that purpose with no or minimal side effects. However, there are not enough studies that have shown the benefits or risks of long-term treatment of diazoxide in ESRD patients, an area of growing interest.Copyright © 2023

Role of C-Reactive Protein in Kidney Diseases.

Background: C-reactive protein (CRP) is an acute-phase protein and has been found to be a risk factor for acute kidney injury (AKI) and chronic kidney diseases (CKD). However, the role and mechanisms of CRP in AKI and CKD remain largely unclear. Summary: Clinically, elevated serum CRP is a risk factor or biomarker for patients with AKI and CKD. Interestingly, in critically ill COVID-19 patients, increased serum CRP is also associated with the development of AKI. Functionally, studies using human CRP transgenic mouse models find that CRP is pathogenic and can function as a mediator for AKI and CKD as mice overexpressing human CRP promote AKI and CKD. Mechanistically, CRP can promote AKI and CKD via NF-κB and Smad3-dependent mechanisms. We found that CRP can activate Smad3 signaling directly and cause AKI via the Smad3-p27-dependent G1 cell cycle arrest mechanism. Thus, targeting CRP-Smad3 signaling with a neutralizing antibody or Smad3 inhibitor can inhibit AKI. Key Messages: CRP acts not only as a biomarker but also as a mediator for AKI and CKD. CRP can activate Smad3 to induce cell death and cause progressive renal fibrosis. Thus, targeting CRP-Smad3 signaling may represent a promising therapy for AKI and CKD.

De Ritis Ratio A Potential Biomarker in Covid- 19 Admitted Patient's Survivors and Non Survivors

Dysregulation of liver enzymes aspartate transaminase (AST) and alaninetransaminase (ALT) are common in CO VID-19 patients. De Ritis ratio (ASTIALT) ratio is a noninvasive, cost-effective test however usefulness of De Ritis ratio in COVID-19 is unclear. Intraindividual variation of AS T and ALT are large leading to misclassification as normal on repeat testing compared to De Ritis ratio which may not be relatively large as predicted by the product of the individual variances. This was a retrospective study which included subject's male and female adults aged 18-50 years. Dyslipidemic, obese, hypothyroid, nephrotic syndrome, diabetes mellitus, pregnant women were excluded from the study. The study aimed to determine the levels of AST, ALT and De Ritis ratio and investigate association of De Ritis ratio between COVID-19 admitted patient's survivors and inhospital mortality in 500patients admitted to ESIC Medical College and Hospital, Faridabad.The De Ritis ratio was significantly lower in survivors than nonsurvivors (median: 0.94;IQR: 0.71-1.2 vs 1.53;IQR: 1.11-2.46,P= .04)whereas no significant differences was seen in ALT and AST concentrations. In ROC Curve analysis, the AUC value of the De Ritis ratio was 0.80(95% CI 0.56 to 0.65, P < 0.0001) with sensitivity and specificity of 70.64% and 70.27%, respectively as compared toAST (0.60) and ALT (0.64).De Ritis ratio along with correlation with inflammatory markers can be used as a significant biomarker in prognosis and management of COVID-19 admitted patients without incurring any additional cost.

New Onset Renal Replacement Therapy Is a Predictor of Covid-19 Adverse Outcome in Patients with Advanced Chronic Kidney Disease Due to Type 2 Diabetes Mellitus

Introduction: The patients with diabetic kidney disease (DKD) due to type 2 diabetes mellitus (T2DM) are at a high risk of adverse outcomes of COVID-19. In some cases, rapidly progressive kidney injury requires urgent initiation of renal replacement therapy (RRT) - hemodialysis de novo (HD de novo). The objective of this study is to identify risks factors of adverse outcomes and predictive value of HD de novo in patients with DKD due to T2DM and COVID-19. Method(s): The patients with chronic kidney disease 4-5 stages (CKD 4-5) with laboratory-confirmed COVID-19 were included in the retrospective observational study. The observation period 04.01-10.30.2020. Data were collected from electronic medical database. The following independent variables were analyzed at hospital admission: age, gender, body mass index (BMI), general comorbidity (Charlson Index, CCI), the insulin demand (InsD), fasting blood glucose (FBG), glomerular filtration rate (GFR), Plasma creatinine (Pcr), serum albumin (SA), proteinuria, time from onset to admission, NEWS2-scale points, pulmonary involvement (Chest CT), Hb, WBC, lymphocytes, platelet count, LDH, CPR, ferritin, D-dimer, procalcitonin, Interleukin-6. The observation group was divided into subgroups: 1 - HD not required (HD n/r), 2 - HD de novo. Result(s): A total of 55 patients were included. Mediana age was 69 y (IQR 64;80), fe-males 59%. The overall mortality - 38.2%. In 18 patients (32.7%) HD de novo was initiated due to rapidly progressive renal failure. The results of comparative analyses of demographic, initial clinical and laboratory data are presented in Tables (*Mann-Whitney U-test;IQR, interquartile range;Me, mediana). [Formula presented] [Formula presented] The mortality in both subgroups was 21.6 % vs 72.2 % respectively (p <0,001). HD de novo was determined as an independent predictor of adverse outcome (OR 9.42;95% CI, 2.58-34.4, p = 0.001). The analysis showed that FBG >= 10 mmol/L at admission (OR, 3.38;95% CI, 1.04-10.98, p = 0.050), SA at admission <= 35 g/L (OR 3.41;95% CI, 1.00-11.55, p = 0.050), News2 >4 points (OR 5.60;95% CI, 1.67-19.47, p = 0.006), GFR <= 20 ml/min/1,73m2 at admission (OR 4.24;95%;CI 1.29-13.99, p = 0.020) were independent predictors of HD de novo. Cumulative survival in subgroup HD de novo was 10% (significantly less, than in patients HD n/r) (Fig.). [Formula presented] Conclusion(s): Approximately every third patient with advanced nondialysis DKD required new onset RRT.New onset RRT is an independent predictor of lethal outcome of COVID-19. High FBG, low SA, low GFR and high NEWS2 score at admission are the risk factors of HD initiation during hospitalization. No conflict of interestCopyright © 2023

An Early Detection Of NIPAH Infectious Disease Based On Integrated Medical Features For Human Using Ensemble RBM Techniques

Background: The importance of early diagnosis of a hazardous illness cannot be overstated. The transmission rate is extremely high, especially in the current pandemic condition. The ability to predict epidemics will aid public health in reducing mortality and morbidity. Machine Learning (ML) approaches are used in the construction of an effective disease prognosis model. Furthermore, only if the model learns good associated features from the data is it possible to generate a speedy outcome. As a result, selecting features is also necessary before beginning the forecasting process. Objective(s): However, because of the virus's dynamic structure, it's difficult to predict Nipah disease and/or zoonotic infection. Furthermore, there is no clinical treatment for Nipah. The major goal of this research is to develop a prognostic model for early diagnosis of Nipah disease using a combination of several clinical factors such as symptoms, disease incubation information, and routine blood test results confirmed by a lab technician.Proposed System: The healthcare application and data are more complex to handle than other ML applications since various clinical features are assessed throughout disease manifestation. As a result, selecting the most relevant variables is critical when designing a prognosis model for any viral disease. To deal with clinical features from a vast number of features, we proposed a Restricted Boltzmann Machine (RBM) method in this research. Additionally, we employed a hybrid ensemble learning method to predict if the patient was infected with NiV after choosing features using the RBM. Data Collection: The proposed system is being implemented using the NiV infection dataset that erupted in Kozhikode, Kerala in 2018 and 2019. Result(s): The developed stacking-based ensemble Meta classifier was successfully implemented using the python programming language, and its performance was evaluated using a variety of metrics includingaccuracy, precision, recall, f1-score, log loss, AUROC and MCC. Our proposed Stacking Ensemble Meta Classifier (SEMC) model achieved an accuracy rate of 88.3% with a log loss of 0.36. Model precision, recall, f1-score, AUROC, and MCC value were 92.5%, 89.2%, 90.9%, 92.1%, and 0.74 respectively. In addition, we calculated the gravitational pull of each feature using the SHAP approach and discovered that altered sensorium, fever, headache, and cough were the most critical clinical indicators that distinguished NiVD infection from our dataset. Therefore, this classification may assist the pathologist in diagnosing NiVD with symptoms before performing the RT-PCR medical test. Conclusion(s): Using our proposed SEMC technique, we developed a prognostic model for the diagnosis of Nipah in humans. The proposed technique's discriminatory efficiency exhibited good NiVD diagnosis efficacy. We anticipate that this model will aid medics in determining a prognosis more quickly during future epidemics. However, to achieve maximum accuracy, the model requires more unique samples.Copyright © 2022 Wolters Kluwer Medknow Publications. All rights reserved.

Accommodating ''History Effects'' in Long Duration, Multisite Clinical Trials to Ensure Relevant and Compelling Evidence

Over the course of a clinical trial, changes in the practice environment have the potential to reduce internal and external validity and impact change in patient outcomes. Such ''history effects''1 can take the form of changes in standard of care, clinical guidelines and recommendations, new drug/device availability in the marketplace, testing and screening procedures, and, as recently experienced, a global pandemic. Clinical trials conducted over many years are particularly susceptible to history effects. Such effects can impact foundational ability to continue a trial, including clinician equipoise and ability to implement trial interventions, necessitating awareness and action planning. For example, Curtis et al.2 acknowledged challenges with clinical guideline history effects and issued recommendations for addressing them such as consideration of participant wellbeing, stakeholder engagement, safety monitoring, review of guideline and policy changes, and development of rules for protocol changes. This session will explore how four multisite clinical trials conducted with VA Cooperative Studies Program sponsorship and coordination have weathered history effects during prolonged periods of enrollment. Topics to be covered include the implementation of pragmatic designs, monitoring of clinical guidelines, assessing control group treatment conditions, modifying protocols, adjusting quality assurance procedures, refining recruitment pathways, and training site investigators. The speakers, Study Chairs, will describe best practices and provide recommendations for navigating history effects in prolonged multisite clinical trials that can ensure outcomes remain relevant and compelling to inform public health at trial commencement. The CSP 2008/PTXRx study is a pragmatic, randomized, double-blind, placebo-controlled, multicenter clinical trial of Veteran patients with diabetic kidney disease (DKD) examining whether pentoxifylline (PTX), when added to usual care, can delay time to end-stage renal disease or death. Enrollment for the study began in 2019, and it is anticipated that 9 years of follow-up will be required to observe the required number of primary events. Given the long duration of the study, changes in clinical guidelines were anticipated and have occurred, including the approval of new DKD therapies and introduction of a new formula for estimated glomerular filtration rate (eGFR) calculation. In anticipation of these changes, the study design allows for whatever standard of care is extant at any time during the course of the study. PTXR's pragmatic trial design and protocol leverage the VA's research infrastructure and remote platforms allowing the study to be responsive to external changes and to safely continue during a global pandemic. The CSP 596/OPTION study is a randomized, double- blind, multicenter trial of Veteran patients with a first or second recurrent Clostridium difficile infection (CDI) comparing (1) fidaxomicin and (2) vancomycin, followed by a taper and pulse to (3) a standard vancomycin regimen. Since enrollment began in 2016, significant changes in CDI epidemiology and clinical management have impacted the study. The COVID-19 pandemic also resulted in an administrative hold on all trial activity followed by staggered reopening of sites due to variable COVID-19 activity and clinical priorities. Many clinical laboratories switched to algorithms that included free toxin assays in addition to polymerase chain reaction (PCR) tests out of concern for overdiagnosis based on PCR testing alone, reducing the number of potentially enrollable cases. There has been increased empirical vancomycin treatment for recurrent CDI without confirmation by stool testing, a requirement for enrollment, and a recruitment strategy for identifying potential cases. Finally, conflicting clinical guidelines for recurrent CDI has created potential equipoise when considering enrollment. Ongoing educational efforts have been made to clarify the protocol and emphasize the validity of the research question as well as protoco changes to allow safe enrollment and follow-up of participants in the face of the ongoing COVID-19 pandemic. The CSP 2005/VALOR is a phase III randomized, open label, multicenter clinical trial of Veteran patients with operable stage I non-small cell lung cancer that compares stereotactic radiotherapy and anatomic pulmonary resection with a primary outcome measure of overall survival. The study was activated in 2017 and recruitment to the trial has been affected by ongoing changes in public and clinician perceptions about stereotactic radiotherapy and surgery that have interfered with equipoise and willingness of participants to enroll. The study team perpetually addresses this challenge through group conversations with local site investigators, study coordinators, and other research personnel to preserve group equipoise across the study. Since the study's activation, new safety information about stereotactic radiotherapy has emerged necessitating protocol modifications while aiming to preserve internal and external validity. The includes modifying standard operating procedures for the study's centralized quality assurance program that has had to adapt its process to remain contemporary. STARPORT, funded by VA CSRD with CSP collaboration, is a randomized, open label, multicenter clinical trial of Veteran patients with oligorecurrent prostate cancer comparing the effects of standard systemic therapy (SST) alone or with PET-directed local therapy using surgery or radiation. Although enrollment was initiated in 2021, changes are already evident in clinical practice guidelines regarding the use of imaging in workup in this patient population. Shortly before the start of accrual, 18F-DCFPyL PSMA PET/CT received FDA-approval. Consequently, it is being rapidly adopted at the STARPORT VA medical centers and the use of conventional imaging using CT or bone scan prior to PET/CT imaging-part of the original eligibility criteria-quickly is falling out of favor. Furthermore, shortly after the start of enrollment, NCCN guidelines adopted the stance that conventional imaging was no longer required in the setting of PSMA PET/CT imaging, solidifying the transition away from conventional imaging. Thus, the protocol is being amended to remove the requirement for conventional imaging as part of workup for oligorecurrence. In addition, to be generalizable, the study is designed to integrate future PSMA radiotracers that are incorporated into practice as well as changes in SST regimens over the time of the study.

Impact of the Covid-19 Pandemic in Patients Attending Renal Clinic at Kingston Public Hospital, Jamaica

Introduction: Early in the pandemic various lockdown measures were implemented to decrease spreading of Covid-19. This resulted in many clinics and hospitals observing a decrease in the usual numbers of patients accessing care. Patients have also expressed fears and challenges with accessing care at health clinics and hospitals during this time. Since May 2020, there has been a gradual decrease in the restrictions and stay at home orders for Covid-19 by the government in Jamaica and more persons have begun to access care again at health facilities. The impact of the Covid-19 pandemic in patients with chronic kidney disease especially those who were not admitted with Covid-19 is limited. This study seeks to determine why patients were not accessing care early in the pandemic and the possible longer-term impact of the Covid-19 pandemic on the care and prognosis of patients with chronic kidney disease. Method(s): All patients who attended Renal clinic, Kingston Public Hospital (KPH) from April 20th to July 14th 2021 were eligible for inclusion in the study. Those who consented to participate in the study had an interview with the researcher at the Renal clinic where a questionnaire was administered. Demographic data was collected as well as whether they were a new or follow-up patient and number of appointments missed was noted. Their renal diagnosis and labs were obtained from their dockets by the researchers. The data was analysed using Microsoft excel and Epi info software Results: There were 185 participants. 45.7% of the participants were 51 to 70 years old. 61.1% were females and 38.9% were males. Follow-up patients accounted for 76.2% of the participants whilst 23.8% were new patients. 92.2% of the follow-up patients reported attending clinic in the past year. 15.1% of the participants reported missing at least one appointment in the past year. Most common reasons given for missing appointments were forgot date of appointment, afraid of coming to hospital, was sick at home or admitted to hospital. 2.7% of the participants reported having had Covid-19. Only 7.0% of the study participants were on dialysis. 76.9% of those receiving dialysis were started on haemodialysis since March 2020. 93.0% reported receiving all or most of their medications through the free public health care system during the pandemic. 44.3% of the participants reported working in the past year. Most common reasons given for not working in the past year were medical condition, receiving family support or retired. Only 3.6% reported being sent home by an employer due to the pandemic. The most common renal diagnoses were diabetic nephropathy and hypertensive nephrosclerosis followed by lupus nephritis and sickle cell nephropathy. 49.2% were CKD stage 3b to Stage 5. 14.6% of those who were CKD stage 3 near to March 2020 progressed to CKD stage 4 or 5 by a year later. Conclusion(s): During the pandemic, attendance of patients at Renal clinic, Kingston Public Hospital and their access to medications remained high. Approximately 15% of those with CKD stage 3 near the onset of the pandemic progressed to CKD stage 4 or 5 by a year later. This warrants further study. No conflict of interestCopyright © 2023

Appraising SARS-CoV-2 infections after full mRNA COVID-19 vaccination in patients with systemic lupus erythematosus (SLE)

The 2019 Coronavirus disease (COVID-19) vaccine is a major weapon in the fight against the severe acute respiratory syndrome brought about by coronavirus 2 (SARS-CoV-2). The vaccine significantly reduces the risk and severity of infection by SARS-CoV-2. Patients with systemic lupus erythematosus (SLE) need protection from vaccine-preventable diseases including COVID-19. SLE patients have higher rates of severe infections due to immunosuppressive therapies and multiple immunologic defects - both of which are capable of blunting the immune responses after vaccination. In the management of COVID-19, recommendations have been developed to guide adjustments and/or continuation of immunosuppressive therapies for an effective immune response following vaccination with mRNA-based or viral vector-delivered vaccines. Monoclonal antibodies have also become available since December 2021. Here we present three cases of SLE patients who contracted COVID-19 after vaccination. One was managed in ambulatory settings and two required inpatient hospital admission.Copyright © 2022

Covid-19 Infection in Peritoneal Dialysis Patients: Epidemiological and Clinical Profile, Risk Factors and Mortality

Introduction: Since the beginning of the coronavirus infection 2019 (COVID-19) pandemic, the population of dialysis patients has been recognized as a population at high risk of infection due to immune background and comorbidities. This study aims to describe the epidemiological characteristics, mortality and risk factors for COVID-19 infection in this population. Study design: Retrospective cohort study Methods: Patients on peritoneal dialysis in a university hospital center tested positive for coronavirus-19 by PCR method by nasopharyngeal swab from January 2020 to June 2022. Epidemiological and medical data collected from computerized medical records and from the Registry of French language peritoneal dialysis. Analytical approach: Logistic regression analyzes conducted to identify epidemiological and clinical characteristics associated with COVID-19 and risk factors associated with COVID-19 infection Results: 21 (31.8%) patients on peritoneal dialysis developed COVID-19. The male sex was slightly predominant with 11 men (52.4%). The average age of the patients was 67.48 years +/- 16.48, the average body mass index of the patients affected was 24.26, the average length of seniority in dialysis of the patients was 2.54 years +/- 1.3 years. The predominant initial nephropathy was diabetic nephropathy, glomerulosclerosis, IgA nephropathy and interstitial nephropathy with rates of 38.1%, 19%, 9.5% and 9.5% respectively. The risk factors for covid infection found were: an antecedent of ischemic cardiopathy, the diabetic nephropathy Conclusion(s): While it is true that Sars-cov 2 infection and its complications have increased the mortality rate in most dialysis centres, it should be noted that other factors have contributed to the increase in mortality such as socioeconomic circumstances related to financial financial difficulties, missed consultation appointments secondary to the apprehension of contracting the disease while traveling to the centers as well as the difficult due to confinement. No conflict of interestCopyright © 2023

EFFECTS OF RAS INHIBITORS ON TISSUE ACE2 EXPRESSION IN ANIMAL MODELS

Angiotensin-converting enzyme 2 (ACE2) protects against organ damages by overactivated renin-angiotensin system (RAS). Also, ACE2 exerts a role as the receptors for SARS-CoV-2 to enter host target cells. Based on limited number of articles reporting that RAS inhibitors induced upregulation of cardiac or renal ACE2 in animal models, concern have arisen that RAS inhibitors may aggravate SARS-CoV-2 infection and COVID-19 severity. Therefore, we performed a comprehensive review by applying the standard searching strategy for systematic reviews to investigate the effects of RAS inhibitors on cardiac, vascular, renal and pulmonary mRNA/protein ACE2 expression in healthy animals and disease animal models. We identified 88 eligible articles including 167 experiments. In RAS inhibitors-treated healthy animals, only 3 (heart 2, kidneys 1) of 37 experiments showed ACE2 expression greater than twice of the control (overexpression) whereas others showed no/marginal change in the heart, arteries, kidneys, lungs, and other organs. Among 102 disease models (130 experiments), baseline ACE2 was overexpressed in 16 models (18 experiments), less than half the control level (repression) in 28 models (40 experiments) and remained no/marginal change in 51 models (74 experiments). RAS inhibitors induced ACE2 overexpression from no/marginal change levels in only 7 experiments, 4 (myocardial infarction 2, heart failure 1, diabetic nephropathy 1) of which were not supported by other experiments under similar conditions. In 36 experiments, RAS inhibitors reversed or prevented disease-induced repression, yielding no/marginal change. Thus, ACE2 overexpression is a rare consequence of RAS inhibitors treatment in healthy animals and disease models. Future studies should clarify the pathophysiological significance of reversal or prevention of ACE2 repression induced by RAS inhibitors in disease models.

Cytoprotective action of renalase in diabetic kidney disease: an update on its association with cardiovascular disease and COVID -19

Renalase is a mono amine oxidase enzyme that can metabolise the active catecholamines in the body. Renalase is typically expressed in the cardiovascular system, skeletal muscle, and renal system. Renalase gene is important in human diseases and is known to break down catecholamines in the blood. Gene for renalase as extreme frequency of congestive heart failure disease in people with long term renal disease and other disorders was shown to be explained by a protein that is released by the kidney. Recent advances have increased our understanding of its structure, enzymatic activity, mechanisms of action, relationships with human disease states, and potential therapeutic value. An enzyme description of renalase is provided in this review, along with COVID-19 infection. Copyright © 2022, Indian Association of Biomedical Scientists. All rights reserved.

Medication adherence evaluated through electronic monitors during the COVID19 pandemic lockdown in Switzerland

Introduction: During the lockdown enforced from March to June 2020 by authorities due to the COVID19 pandemic in Switzerland, patients included in the Interprofessional Medication Adherence Programme (IMAP) in Lausanne and Bern continued to use electronic monitors (EM), which register daily doses intake. Objective(s): The aim of this study is to use EM data to understand to what extent patients' medication implementation, described as the extent to which the patient takes the daily prescribed regimen, was impacted by the lockdown. The authors hypothesised that medication implementation might be lower during and after the lockdown compared to before. Method(s): Included participants attending the IMAP were diagnosed with diabetic kidney disease (DKD), solid cancer, HIV and miscellaneous long-term diseases. Patients' implementation was defined through a proxy: if all EM of each patient were at least opened once daily, implementation was considered optimal (= 1);and suboptimal (= 0) otherwise. 1) Implementation before (from December 2019 to March 2020), during (March to June 2020) and after (June to September 2020) the lockdown was compared. Subanalyses were also performed according to sub-groups of patients. 2) As comparison, implementation of included patients using at least one EM the year before, in 2019, during the same time frame, defined as winter, spring and summer periods, was analysed. A logistic regression model was used to estimate medication implementation according to the period, using 'before the lockdown' or 'winter' as the reference. The model was fitted using generalized estimating equation. Result(s): 1) In 2020, implementation of the 118 patients did not differ statistically before and during (OR = 0.97, CI: 0.84 - 1.15, p = 0.789), and before and after (OR = 0.91, CI: 0.79 - 1.06, p = 0.217) the lockdown. These findings remain stable even when analysing separately the implementation of patients with HIV (n = 61), DKD (n = 25) or miscellaneous long-term diseases (n = 22). Too few patients with cancer (n = 10) were included in the analysis to interpret their results. 2) In 2019, implementation of the 61/118 (51.7%) patients was statistically significantly lower during summertime compared to winter (OR = 0.73, CI: 0.59 - 0.89, p = 0.002). Conclusion(s): The authors results infirm their hypothesis as the implementation remained steady during and after the lockdown in 2020 in comparison to the period before. Still, adherence in 2020 was different compared to 2019 as the decreased implementation during summertime 2019 was not observed after the lockdown in summer 2020. Because of the COVID-19 pandemic, many patients slowed down their activities, travelled less, and may have been more cautious in managing their treatment due to the fear of developing a complication of their disease in a difficult sanitary context. Moreover, during the pandemic, continuity of care was ensured by medical teleconsultation between patients and their health care providers, mailing medications to patients' home by the pharmacy and leading interviews by phone calls for patients included in IMAP. The IMAP before, during and after the lockdown may have supported the adherence of complex patients across the pandemic in 2020. Interprofessional adherence programmes should support patients during routine-disturbance periods, such as a lockdown in a pandemic context or during summertime.

A systematic review approach in understanding the COVID-19 mechanism in diabetes and its progression to diabetic microvascular complications

Introduction: In uncontrolled hyperglycemia, lungs, tongue, oropharyngeal and nasopharyngeal airways having increased glycosylated angiotensin-converting enzyme 2 (ACE2) can serve as good viral binding sites for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) leading to a greater tendency and considerable risk of prolonged life-threatening disease. This review was written with the objective to extract the recent advances, updates, and discoveries about the effects of coronavirus disease-2019 (COVID-19) on patients with diabetes and its microvascular complications. It was further written with the aim to discuss the current state of knowledge that has not yet been confirmed or unconfirmed, leading to various debatable issues about COVID-19-associated with microvascular complications in diabetes mellitus. Materials and Methods: We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and searched scientific sites related to our review article such as Web of Science, Embase, PubMed, Scopus, Google Scholar, and MEDLINE of last nearly two and half years. Results: The individuals who are suffering from type 2 diabetes mellitus experience more organ damage by SARS-Cov-2 due to cytokine storm. The pro-inflammatory state, lower primary immune system response, and increased ACE2 level with dysregulation of vascular function and the prothrombic state in patients with diabetes may increase the vulnerability for COVID-19 and worsened prognosis. The patients have reduced prognosis leading to microvascular complications such as diabetic nephropathy, neuropathy and retinopathy. In diabetes retinopathy, it induces the changes in the vasculature of the retinal veins. These viruses can directly affect the nervous tissue and/or can indirectly via activating the immune system-mediated mechanisms leading to diabetic neuropathy as well. Conclusions and Implications: During the cytokine storm the amount of D-dimer in the serum gets significantly increased, due to increased activating plasmin at the early stage of inflammation. Uncontrolled hyperglycemia leads to diabetic complications leading to increased mortality rate in patients with COVID-19. Thus, diabetes and its associated microvascular complications may lead to the severity and mortality in the patients with COVID-19. More of clinical practice and further studies should be implicated through this review article. Laboratory findings and clinical records are of much help in patients with diabetes and COVID-19. Worldwide studies from different countries apart from China should be considered to reach a conclusion about the conditions of patients with diabetes and microvasculature complications around the world.

Adverse Renal Events After BNT162b2 Pfizer/BioNTech COVID-19 Vaccine in Kidney Transplant Recipients

Purpose: Adverse events of a novel mRNA vaccine are not well described in Kidney Transplant Recipients(KTR), especially the risk of immune activation or recurrent glomerulonephritis(GN), which has been described in native GN after COVID-19 vaccines. Method(s): In this single-center prospective study, 147 KTR were enrolled after informed consent and administered 2 doses of Pfizer/BioNTech vaccine 21 days apart. Follow-up was 3 weeks after Dose2. Result(s): Mean age of KTR was 51 years;55.1% male;65.3% Chinese, 19% Malay, 11.6% Indian;69.5% Living donor, 29.9% Deceased donor, 0.7% Pancreas-kidney transplants;71.5% had biopsy-proven or presumptive chronic GN(CGN), 12.9% diabetic nephropathy, 15.6% other causes. 11(7.5%) KTR had delayed Dose2 administered at median 29 days(range 24-93) after Dose1. 7(4.8%)were delayed due to renal events: rise in creatinine(n=3), or proteinuria(n=2), or both creatinine and proteinuria with allograft biopsy showing acute T-cell and antibody-mediated rejection(n=1), new BK viraemia(n=1). Other reasons were possible anaphylaxis(n=1), intercurrent infection(n=2), and inability to attend due to quarantine(n=1). 27 KTR had new microhaematuria(MH) after Dose1;9 persisted after Dose2. Additional 18 had new MH after Dose2. Of 45 KTR with new MH, 7 had underlying IgAN, 5 had other biopsy-proven-CGN and 22 had presumed CGN, suggesting 34/45 with possible immune activation. 12 KTR had new onset proteinuria (rise in urine protein:creatinine ratio (UPCR) <=30 to >30mg/mmol);5/7 who developed a rise after Dose1 remained elevated;additional 5 had a rise after Dose2. 7 KTR had rise in proteinuria from UPCR <=100 to >100mg/mmol. Conclusion(s): Subclinical changes in allograft monitoring parameters are frequent after COVID-19 mRNA vaccines with up to 40.1% of KTRs showing rises in creatinine, proteinuria or new MH. Although overt recurrent GN and acute rejection are infrequent, high vigilance and monitoring for these occurrences should be undertaken in KTRs receiving mRNA vaccines.

CLINICAL PROFILE AND UTILITY OF INFLAMMATORY MARKERS IN PREDICTING COVID-19 OUTCOMES AMONG PATIENTS ON MAINTENANCE HEMODIALYSIS–AN EXPERIENCE FROM A TERTIARY CARE CENTER IN SOUTH INDIA

Introduction: Patients on maintenance hemodialysis are at higher risk for severe COVID-19. Various inflammatory markers have been used to assess the severity of COVID 19 in general population. However, whether the same markers are useful among hemodialysis patients is yet to be ascertained. Hence this study was conducted. Methods: This is an observational, retrospective and prospective study. All patients who were on maintenance hemodialysis, affected with COVID-19 infection and requiring hospitalization, between March 2020 to June 2021 were included. Clinical profile, biochemical parameters and inflammatory markers at admission, during the hospital stay and at the time of final outcome were noted. Patient’s clinical condition was scored as per WHO clinical progression scale (WHOCPS), and were classified as “non-severe” (0-5), and “severe” (6-10). The medications received by them in the hospital was noted. Patient’s discharge status was categorized into stable discharge, discharged with home oxygen therapy or death. Results: 140 patients were included in the study. Diabetic nephropathy was the major cause for ESRD (fig1). Most patients had co-morbidities as shown in fig2. 17% of the patients had a previous kidney transplant. 25.7 % required supplemental oxygen at presentation. 15% required ICU care and 12.9% required mechanical ventilation eventually. The % of lymphocytes, IL6, Albumin and LDH correlated with severity of the disease. These values were observed during the hospital stay, and were higher in patients who required ICU care and mechanical ventilation (table 1). % of lymphocytes, CRP, IL6, albumin and LDH were found to be higher at the time of admission in patients who required ICU care and Mechanical ventilation. Between Days 2-5, total WBC counts, %lymphocytes correlated with complications and mortality (Table 2). Rising CRP, LDH, Ferritin and total WBC counts were associated with longer ICU stay. CRP, LDH and Ferritin levels were higher in those who had higher WHOCP score, thus correlating poor outcomes (table 3). Ferritin and albumin showed a significant difference between severe and non-severe cases at discharge. ROC curve at admission (fig 5) showed that LDH had better AUC than IL 6. During days 2-5, the % of lymphocytes had better AUC than Total counts (Fig 6). At discharge, serum albumin was found to be the best predictor of the outcome (fig 7) 90% of the patients who required oxygen support/ ICU care/ mechanical ventilation received corticosteroids and remdesvir. Prophylactic anticoagulants were used in 101 patients. Tocilizumab(n=3) and Tofacitinib (n=1)were used in those patients who had severe COVID-19 illness, with very high inflammatory markers. 80% recovered, 17.1% expired and 2.9% required home oxygen therapy at discharge. 27 % of patients developed complications (secondary bacterial infections, mucormycosis, deep vein thrombosis, stroke, and myocardial infarction). Conclusions: LDH on day of admission, % of lymphocytes on days 2-5, and serum albumin on day of discharge were the best predictors of outcomes among CKD patients on hemodialysis having COVID-19. Use of these biomarkers will definitely be more helpful for optimum usage of drugs, and will help us risk stratification of hemodialysis patients. No conflict of interest

Mesenchymal Stem/Stromal Cells: INTERIM REPORT FROM THE NEPHSTROM MULTI-CENTRE, RANDOMISED, DOUBLE-BLIND, PLACEBO-CONTROLLED PHASE-1B CLINICAL TRIAL OF A NOVEL MESENCHYMAL STROMAL CELL THERAPY IN PROGRESSIVE DIABETIC KIDNEY DISEASE

Background & Aim: Funded in 2015, the NEPHSTROM EU-H2020 consortium aimed to translate pre-clinical evidence of efficacy of “off-the-shelf” intravenous (i.v.) allogeneic mesenchymal stromal cells (allo-MSC) in diabetic nephropathy to early-phase clinical investigation in patients with progressive diabetic kidney disease (DKD). Methods, Results & Conclusion: Methods: The trial IMP, NEPHSTROM ORBCEL-M, consists of cryopreserved, CD362-selected bone marrow allo-MSCs or matching placebo (cryopreservation fluid). The protocol for a multi-site, randomised, placebo-controlled, double- blind, dose-escalation phase-1b clinical trial in adults with DKD due to type 2 diabetes was designed collaboratively by a group of academic nephrologists and cell therapy specialists from Italy, the UK, Ireland and the Netherlands. Inclusion criteria included age 40-85 yrs and type 2 diabetes with evidence of progressive DKD [eGFR 25- 55mL/min/1.73m2, urine albumin creatinine ratio >88mg/g and rapid eGFR decline or ≥15% risk of ESRD within 5 years]. Three dose cohorts were planned, each with n=12 NEPHSTROM ORBCEL-M recipients + n=4 Placebo recipients and 18 months follow-up. Results: Following regulatory approval of the trial dossier through the EMA’s Voluntary Harmonisation Procedure and ethical approvals at the Sponsor site (Bergamo, Italy) and three other sites (Galway, Ireland;Birmingham and Belfast, UK), the NEPHSTROM trial (NCT02585622) opened March 2018. To date, 27 patients have been treated and 14 have completed the trial protocol. We report here our (as-yet blinded) experiences with the first fixed-dose cohort (80x10e6 cells/placebo i.v.), consisting of 16 subjects enrolled at 3 sites and followed for 18 months. The trial intervention proved safe, with one quickly-resolved infusion reaction and no subsequent SAEs ascribed to the IMP. Two patients died of unrelated causes between 12 and 18 months. Serial serum assays for anti-HLA antibodies indicated no persistent allo-immune sensitisation. NEPHSTROM ORBCEL-M effects on trends in eGFR, true GFR (iohexol clearance), albuminuria, serum/plasma inflammatory biomarkers and immune cell profiles will be analysed after unblinding. Following DSMB approval and COVID-19-related trial pauses, 11 second dose cohort subjects (160x10e6 cells/placebo i.v.) have been treated and are undergoing follow-up with no IMP-related adverse events to date. Conclusion: A novel, off-the-shelf, i.v. allo-MSC IMP has thus far proven safe and feasible in adults with progressive DKD.

Corpus Callosum in COVID-19 Cytokinopathy

Objective: Report a COVID-19 related encephalopathy from selective white matter involvement of corpus callosum. Background: A 26-year-old African American female tested positive for SARS - COV 2 in April 2020. Her medical morbidities included uncontrolled type 1 DM (on insulin), obesity, and CKD stage III (diabetic nephropathy). She presented with fever, headache, dyspnea, myalgia, nausea, and loss of appetite. She was tachypneic, tachycardic, hypertensive, had a temperature of 39.2deg;C and saturating 98% at room air. Pertinent lab values included a glucose of 212 mg/dl, creatinine of 2.7 mg/dl, BUN of 34 mg/dl, and lipase 771 IU/L. CRP was 66.9 mg/L, with a normocytic anemia of 7.9 gm/dl, ferritin 1784 ng/ml, fibrinogen of 651 mg/dl and a peak D-dimer of 10,180 ng/ml. CXR was hypoinflated with mild bibasilar airspace opacities. A NCCT head obtained for a stroke alert, revealed a hypodense corpus collosum. She was admitted to the ICU with worsening hypoxia, kidney injury, metabolic acidosis, and alteration of consciousness. She received tocilizumab, steroids, remdesivir and convalescent plasma exchange for a severe COVID-19 infection. After extubation she developed a dysexecutive syndrome. Design/Methods: Case report Results: A contrast enhanced MR brain confirmed an expansile T2 hyperintense signal along the complete length of corpus callosum associated with restriction of diffusion, and T1 prolongation. There was no superimposed susceptibility or pathologic enhancement. No large vessel occlusions were identifiable from gradient echo (GRE), turbo spin echo (TSE), susceptibility weighted imaging (SWI) and post contrast MR sequences. A repeat MRI brain post discharge demonstrated an improving leukoencephalopathy by virtue of normalizing ADC values. Conclusions: Like prior coronaviridae, severe acute respiratory syndrome coronavirus 2 (SARSCoV-2) affects the brain over a spectrum of injury. Until we clarify direct neurotropism of SARS-CoV-2;this case is supportive of a cytokine mediated excitotoxic injury concomitant with the severity of disease.

PREDICTORS OF MORTALITY OF COVID-19 IN HAEMODIALYSIS PATIENTS

BACKGROUND AND AIMS: The COVID-19 pandemic has disproportionately affected patients with pre-existing comorbidities, particularly dialysis patients. These patients appear to be more susceptible to severe forms of the infection, due to underlying, coexisting pathologies and their immunocompromised status. The aim of this study was to determine predictors of mortality in this population. METHOD: We conducted an observational, retrospective, cohort study collecting data from the electronic medical records of a single dialysis centre at Hygeia Hospital Tirana, Albania. Baseline patient characteristics, including demographic, clinical and laboratory data were recorded. The receiver operating characteristic (ROC) analysis was used to determine predictors of mortality, their respective sensitivity, specificity and cut-off values. RESULTS: Of 170 haemodialysis patients, 52 were diagnosed with COVID-19. The prevalence of COVID-19 infection in haemodialysis patients in our study was 30.5%. The mean age was 61.5 ± 12.3 years and 65.4% were men. The mortality rate in our cohort was 19.2%. Mortality rates were higher in patients with Diabetic Nephropathy (P < 0.04) and Peripheral Vascular Disease (P < 0.01). High BMI (P < 0.024), high RDW (P < 0.03), elevated C-reactive protein (P < 0.018) and elevated serum ferritin (P < 0.021) levels, were found to be risk factors for severe COVID-19 disease. ROC analysis identified lymphopenia and eosinopenia as the strongest predictors of mortality. AUC for lymphopenia was 0.739. It showed a sensitivity of 80% and a specificity of 85.7%, at a cut-off value of 13.15%. AUC for eosinopenia was 0.814. At a cut-off value of 0.185%, it revealed a sensitivity and specificity of 72.7% and 75%, respectively. CONCLUSION: Our study revealed that risk factors for the development of severe COVID-19 infection were high BMI, high RDW, elevated levels of C-reactive protein (CRP) and serum ferritin. Lymphopenia and eosinopenia were determined as the most important predictors of mortality, in our cohort. Early recognition during the course of the infection, of a declining tendency of lymphocyte and eosinophil counts is paramount, in identifying high-risk patients for severe disease and poor outcomes among haemodialysis patients.

RELATIONSHIP BETWEEN VITAMIN D LEVELS AND SARS-COV-2 INFECTION IN DIALYSIS PATIENTS

BACKGROUND AND AIMS: Hypovitaminosis D is highly prevalent in patients with Chronic Kidney Disease (CKD). This is considered a consequence of a decreased renal mass and a reduction in the number of proximal tubular cells, which absorb the filtered native vitamin D and then be hydroxylated to its active form by 1α-hydroxylase. Hypovitaminosis D is defined as serum levels of 25-hydroxy-vitamin D3 lower than 30 ng/mL. The decrease in vitamin D causes bone and mineral abnormalities and can also play a role in various pathologies, such as cardiovascular disease, insulin resistance, diabetes, autoimmune diseases and infections. Clinical practice guidelines recommend treating hypovitaminosis D. The role of vitamin D in acute respiratory tract infections and other viral infections has been widely studied. It has an immunomodulatory role due to the expression of the enzyme 1α-hydroxylase by the epithelium of the respiratory tract, dendritic cells and lymphocytes, which is essential for the activation of vitamin D in the lungs. In this way, an influence is created on the lung capacity to fight infections and respond to allergic stimuli. Vitamin D has the potential to influence the severity and outcomes of COVID-19. In fact, several studies have established a consistent relationship between hypovitaminosis D and the severity of COVID-19. We have a population of dialysis patients with a tendency to hypovitaminosis D and, on the other hand, an influence of hypovitaminosis D in respiratory infections such as SARS-CoV-2 infection. Thus, we consider it interesting to study whether the incidence of hypovitaminosis D is higher in dialysis patients with SARS-CoV-2 infection than in those who do not. METHOD: An observational, analytical, ambispective, multicentre study was carried out under normal clinical practice conditions. The study subjects are patients on haemodialysis program of the province of Santa Cruz de Tenerife, in the period between January 2021 and January 2022. As variables we selected age, sex, personal history, haemodialysis time, serum levels of 25-hydroxy-vitD3, treatment with native vitamin D, presence of SARS-CoV-2 infection diagnosed by RT-PCR in nasopharyngeal swab, vaccination. The information collected is organized in a database of the SPSS Statistics v22 program. For quantitative variables, the comparison between groups is made by means of an analysis with the Student's t-test for independent samples. Qualitative variables are analyzed using the Chi-squared test or Fisher's exact test. All data were analyzed using the SPSS Statistics v22 program. The level of significance is established for a value of P < 0.05. RESULTS: A total of 60 haemodialysis patients were included, 36 men (60%) and 24 women (40%). The mean age was 64 years. The most common cause of kidney disease was diabetic nephropathy (35%). The median time on dialysis was 24.5 months. 73.3% of the patients presented hypovitaminosis D and 35% received treatment with vitamin D. 23 patients had SARS-CoV-2 infection (38.3%). 2 patients (3.3%) died of COVID-19. There were no significant differences between the two comparison groups (patients with and without SARS-CoV-2 infection) in relation to sex, age, cause of kidney disease, diabetes, time on dialysis, vitamin D intake. We also did not observe significant differences in relation to vitamin D levels or the presence of hypovitaminosis D. There are significant differences in relation to vaccination (p 0.00). 39.1% of the patients with SARS-CoV-2 infection were not vaccinated. 90% of all unvaccinated patients had SARS-CoV-2 infection. 97.3% of the uninfected patients were vaccinated. CONCLUSION: Hypovitaminosis D is very common in CKD patients on dialysis, however, despite its immunomodulatory role, we did not find a higher incidence of hypovitaminosis D in dialysis patients with SARS-CoV-2 infection. In our series, we have not found factors associated with SARS-CoV-2 infection in dialysis patients, with the exception of vaccination. Therefore, vaccination in our dialysis patients is being essential t prevent a higher number of cases of SARS-CoV-2 infection.