Cytomegalovirus reactivation with high viral load in a patient of coronavirus disease 2019 acute respiratory distress syndrome: a case report.

INTRODUCTION: Cytomegalovirus establishes life-long latency after primary infection in childhood. Cytomegalovirus reactivation has been well reported in immune-compromised patients; however, in the last few years it has been observed that cytomegalovirus reactivation also occurs in critically ill patients without exogenous immunosuppression, which increases length of intensive care unit stay and mortality rate. CASE REPORT: A 63-year-old Indian male, without any known comorbidity, developed severe coronavirus disease 2019 and was admitted to the intensive care unit. He received remdesivir, tocilizumab, steroids, anticoagulants, and empiric antibiotics over the next 3 weeks. However, his clinical condition did not improve much, and during the 9th week of illness his condition started deteriorating and routine bacterial cultures, fungal cultures, and cytomegalovirus real-time polymerase chain reaction on blood were negative. His clinical condition worsened rapidly, which led to the need for invasive mechanical ventilation. Tracheal aspirate bacterial and fungal culture showed no growth, but cytomegalovirus real-time polymerase chain reaction showed 21,86,000 copies/mL in tracheal aspirates. After 4 weeks of ganciclovir treatment, the patient improved clinically and was discharged. Currently he is doing well and able to do his routine activity without the need of oxygen. CONCLUSION: Timely management with ganciclovir is associated with favorable outcome in cytomegalovirus infection. Thus, it can be suggested that treatment should be initiated with ganciclovir if a patient with coronavirus disease 2019 has high cytomegalovirus load in tracheal aspirates, along with unexplained and prolonged clinical and/or radiological features.

Fenfluramine provides clinically meaningful reduction in frequency of drop seizures in patients with Lennox-Gastaut syndrome: Interim analysis of an open-label extension study.

OBJECTIVE: This study was undertaken to evaluate the long-term safety and effectiveness of fenfluramine in patients with Lennox-Gastaut syndrome (LGS). METHODS: Eligible patients with LGS who completed a 14-week phase 3 randomized clinical trial enrolled in an open-label extension (OLE; NCT03355209). All patients were initially started on .2 mg/kg/day fenfluramine and after 1 month were titrated by effectiveness and tolerability, which were assessed at 3-month intervals. The protocol-specified treatment duration was 12 months, but COVID-19-related delays resulted in 142 patients completing their final visit after 12 months. RESULTS: As of October 19, 2020, 247 patients were enrolled in the OLE. Mean age was 14.3 ± 7.6 years (79 [32%] adults) and median fenfluramine treatment duration was 364 days; 88.3% of patients received 2-4 concomitant antiseizure medications. Median percentage change in monthly drop seizure frequency was -28.6% over the entire OLE (n = 241) and -50.5% at Month 15 (n = 142, p < .0001); 75 of 241 patients (31.1%) experienced ≥50% reduction in drop seizure frequency. Median percentage change in nondrop seizure frequency was -45.9% (n = 192, p = .0038). Generalized tonic-clonic seizures (GTCS) and tonic seizures were most responsive to treatment, with median reductions over the entire OLE of 48.8% (p < .0001, n = 106) and 35.8% (p < .0001, n = 186), respectively. A total of 37.6% (95% confidence interval [CI] = 31.4%-44.1%, n = 237) of investigators and 35.2% of caregivers (95% CI = 29.1%-41.8%, n = 230) rated patients as Much Improved/Very Much Improved on the Clinical Global Impression of Improvement scale. The most frequent treatment-emergent adverse events were decreased appetite (16.2%) and fatigue (13.4%). No cases of valvular heart disease (VHD) or pulmonary arterial hypertension (PAH) were observed. SIGNIFICANCE: Patients with LGS experienced sustained reductions in drop seizure frequency on fenfluramine treatment, with a particularly robust reduction in frequency of GTCS, the key risk factor for sudden unexpected death in epilepsy. Fenfluramine was generally well tolerated; VHD or PAH was not observed long-term. Fenfluramine may provide an important long-term treatment option for LGS.

Expression of ACE2 in the Intact and Acutely Injured Kidney.

Background: The actions of angiotensin-converting enzyme 2 (ACE2) oppose those of the renin-angiotensin-aldosterone system. ACE2 may be a cytoprotectant in some tissues. This study examined ACE2 expression in models of AKI. Methods: ACE2 mRNA and protein expression and ACE2 activity were assessed in murine ischemic AKI. Renal ACE2 mRNA expression was evaluated in LPS-induced AKI in wild-type (C57BL/6J) mice, in heme oxygenase-1+/+ and heme oxygenase-1-/- mice, and after unilateral ureteral obstruction (UUO) in wild-type mice. The effect of sex and age on renal ACE2 protein expression was also assessed. Results: In ischemic AKI, ACE2 mRNA and protein expression and ACE2 activity were reduced as compared with such indices in the intact kidney. In ischemic AKI, ACE2, which, in health, is prominently expressed in the tubular epithelium, especially proximal tubules, is decreased in expression in these segments. Decreased ACE2 expression in AKI did not reflect reduced GFR, because ACE2 mRNA expression was unaltered after UUO. LPS induced renal ACE2 mRNA expression in wild-type mice, but this effect did not occur in heme oxygenase-1-deficient mice. In ischemic and LPS-induced AKI, renal expression of the Mas receptor was increased. In the intact kidney, renal ACE2 protein expression decreased in female mice as compared with male mice, but was unaltered with age. Conclusion: We conclude that renal ACE2 expression is decreased in ischemic AKI, characterized by decreased GFR and abundant cell death, but is upregulated in LPS-induced AKI, an effect requiring heme oxygenase-1. Determining the significance of ACE2 expression in experimental AKI merits further study. We suggest that understanding the mechanism underlying ACE2 downregulation in AKI may offer insights relevant to COVID-19: ACE2 expression is downregulated after ACE2 mediates SARS-CoV-2 cellular entry; such downregulation is proinflammatory; and AKI commonly occurs and determines outcomes in COVID-19.

Single-Cell RNA Sequencing of Urinary Cells Reveals Distinct Cellular Diversity in COVID-19-Associated AKI.

Background: AKI is a common sequela of infection with SARS-CoV-2 and contributes to the severity and mortality from COVID-19. Here, we tested the hypothesis that kidney alterations induced by COVID-19-associated AKI could be detected in cells collected from urine. Methods: We performed single-cell RNA sequencing (scRNAseq) on cells recovered from the urine of eight hospitalized patients with COVID-19 with (n=5) or without AKI (n=3) as well as four patients with non-COVID-19 AKI (n=4) to assess differences in cellular composition and gene expression during AKI. Results: Analysis of 30,076 cells revealed a diverse array of cell types, most of which were kidney, urothelial, and immune cells. Pathway analysis of tubular cells from patients with AKI showed enrichment of transcripts associated with damage-related pathways compared with those without AKI. ACE2 and TMPRSS2 expression was highest in urothelial cells among cell types recovered. Notably, in one patient, we detected SARS-CoV-2 viral RNA in urothelial cells. These same cells were enriched for transcripts associated with antiviral and anti-inflammatory pathways. Conclusions: We successfully performed scRNAseq on urinary sediment from hospitalized patients with COVID-19 to noninvasively study cellular alterations associated with AKI and established a dataset that includes both injured and uninjured kidney cells. Additionally, we provide preliminary evidence of direct infection of urinary bladder cells by SARS-CoV-2. The urinary sediment contains a wealth of information and is a useful resource for studying the pathophysiology and cellular alterations that occur in kidney diseases.

The spike protein of SARS-CoV-2 induces heme oxygenase-1: Pathophysiologic implications.

BACKGROUND: Acute kidney injury (AKI) is both a consequence and determinant of outcomes in COVID-19. The kidney is one of the major organs infected by the causative virus, SARS-CoV-2. Viral entry into cells requires the viral spike protein, and both the virus and its spike protein appear in the urine of COVID-19 patients with AKI. We examined the effects of transfecting the viral spike protein of SARS-CoV-2 in kidney cell lines. METHODS: HEK293, HEK293-ACE2+ (stably overexpressing ACE2), and Vero E6 cells having endogenous ACE2 were transfected with SARS-CoV-2 spike or control plasmid. Assessment of gene and protein expression, and syncytia formation was performed, and the effects of quercetin on syncytia formation examined. FINDINGS: Spike transfection in HEK293-ACE2+ cells caused syncytia formation, cellular sloughing, and focal denudation of the cell monolayer; transfection in Vero E6 cells also caused syncytia formation. Spike expression upregulated potentially nephrotoxic genes (TNF-α, MCP-1, and ICAM1). Spike upregulated the cytoprotective gene HO-1 and relevant signaling pathways (p-Akt, p-STAT3, and p-p38). Quercetin, an HO-1 inducer, reduced syncytia formation and spike protein expression. INTERPRETATION: The major conclusions of the study are: 1) Spike protein expression in kidney cells provides a relevant model for the study of maladaptive and adaptive responses germane to AKI in COVID-19; 2) such spike protein expression upregulates HO-1; and 3) quercetin, an HO-1 inducer, may provide a clinically relevant/feasible protective strategy in AKI occurring in the setting of COVID-19. FUNDING: R01-DK119167 (KAN), R01-AI100911 (JPG), P30-DK079337; R01-DK059600 (AA).

Nicotinamide Adenine Dinucleotide Biosynthetic Impairment and Urinary Metabolomic Alterations Observed in Hospitalized Adults With COVID-19-Related Acute Kidney Injury.

INTRODUCTION: Acute kidney injury (AKI) is common in COVID-19 and associated with increased morbidity and mortality. We investigated alterations in the urine metabolome to test the hypothesis that impaired nicotinamide adenine dinucleotide (NAD+) biosynthesis and other deficiencies in energy metabolism in the kidney, previously characterized in ischemic, toxic, and inflammatory etiologies of AKI, will be present in COVID-19-associated AKI. METHODS: This is a case-control study among the following 2 independent populations of adults hospitalized with COVID-19: a critically ill population in Boston, Massachusetts, and a general population in Birmingham, Alabama. The cases had AKI stages 2 or 3 by Kidney Disease Improving Global Outcomes (KDIGO) criteria; the controls had no AKI. Metabolites were measured by liquid chromatography-mass spectrometry. RESULTS: A total of 14 cases and 14 controls were included from Boston and 8 cases and 10 controls from Birmingham. Increased urinary quinolinate-to-tryptophan ratio (Q/T), found with impaired NAD+ biosynthesis, was present in the cases at each location and pooled across locations (median [interquartile range]: 1.34 [0.59-2.96] in cases, 0.31 [0.13-1.63] in controls, P = 0.0013). Altered energy metabolism and purine metabolism contributed to a distinct urinary metabolomic signature that differentiated patients with and without AKI (supervised random forest class error: 2 of 28 in Boston, 0 of 18 in Birmingham). CONCLUSION: Urinary metabolites spanning multiple biochemical pathways differentiate AKI versus non-AKI in patients hospitalized with COVID-19 and suggest a conserved impairment in NAD+ biosynthesis, which may present a novel therapeutic target to mitigate COVID-19-associated AKI.

Recovery after Critical Illness and Acute Kidney Injury.

AKI is a common complication in hospitalized and critically ill patients. Its incidence has steadily increased over the past decade. Whether transient or prolonged, AKI is an independent risk factor associated with poor short- and long-term outcomes, even if patients do not require KRT. Most patients with early AKI improve with conservative management; however, some will require dialysis for a few days, a few weeks, or even months. Approximately 10%-30% of AKI survivors may still need dialysis after hospital discharge. These patients have a higher associated risk of death, rehospitalization, recurrent AKI, and CKD, and a lower quality of life. Survivors of critical illness may also suffer from cognitive dysfunction, muscle weakness, prolonged ventilator dependence, malnutrition, infections, chronic pain, and poor wound healing. Collaboration and communication among nephrologists, primary care physicians, rehabilitation providers, physical therapists, nutritionists, nurses, pharmacists, and other members of the health care team are essential to create a holistic and patient-centric care plan for overall recovery. Integration of the patient and family members in health care decisions, and ongoing education throughout the process, are vital to improve patient well-being. From the nephrologist standpoint, assessing and promoting recovery of kidney function, and providing appropriate short- and long-term follow-up, are crucial to prevent rehospitalizations and to reduce complications. Return to baseline functional status is the ultimate goal for most patients, and dialysis independence is an important part of that goal. In this review, we seek to highlight the varying aspects and stages of recovery from AKI complicating critical illness, and propose viable strategies to promote recovery of kidney function and dialysis independence. We also emphasize the need for ongoing research and multidisciplinary collaboration to improve outcomes in this vulnerable population.

Ensuring optimal care for people with kidney disease during the COVID-19 pandemic

Пандемия COVID-19 создает серьезные проблемы для систем здравоохранения во всем мире. Различные меры, направленные на предотвращение распространения вируса, могут повлиять на оказание медицинской помощи пациентам с различными хроническими заболеваниями, особенно в странах с ограниченными ресурсами. Большинство пациентов с почечной недостаточностью нуждаются в лечении в центрах диализа каждые 2-3 дня, и лишь немногие получают диализ на дому. Жесткие карантинные меры затрудняют работу общественного транспорта и ограничивают возможности индивидуального транспорта, которым пользуются многие пациенты, проживающие на значительном удалении от центров, где проводится лечение. Кроме того, перебои в поставках и в то же время повышение потребности, ведет к дефициту средств индивидуальной защиты для персонала диализных центров, что создает повышенный риск для здоровья этой категории работников здравоохранения. Недостаток лекарств и расходных материалов для диализа также создает препятствия для оказания медицинской помощи пациентам с почечной недостаточностью. Карантинизация персонала в случае контакта с инфицированными пациентами или другими сотрудниками может привести к ограничению возможности проведения диализа в центрах. Многие диализные отделения прилагают усилия к тому, чтобы обеспечить достаточное количество рабочей силы, однако это не всегда успешно, и поиск альтернативного диализного центра нередко оказывается неразрешимой задачей для пациентов. Предварительные данные показывают, что у 20-30% пациентов, госпитализированных с COVID-19, развивается почечная недостаточность, что ведет к повышению потребности в диализе. Обеспечение программным диализом в ряде случаев уже оказалось нарушенным из-за необходимости перепрофилирования больниц под оказание помощи пациентам с COVID-19 patients. "Больницы должны быть подготовлены к наращиванию мощности диализной службы чтобы обеспечить эффективную помощь пациентам с COVID-19, и необходимо принять решительные меры дабы защитить диализную популяцию от инфицирования COVID-19," - сказал профессор Кармин Зоккали, президент Европейской почечной ассоциации. "Перерыв в жизнеобеспечивающем лечении буквально является смертным приговором для пациентов на поддерживающем диализе. Это будет настоящей трагедией, если такие больные станут косвенными жертвами пандемии" - отметил профессор Анупам Агравал, президент Американского общества нефрологов. "Пандемия COVID-19 создает дефицит медицинской помощи, особенно в странах с плохо развитой системой здравоохранения. Работники и организаторы здравоохранения всего мира должны работать на опережение и откликаться на особые потребности различных групп пациентов - таких как больные с почечной недостаточностью" - сказал профессор Вивекананд Джа, президент Международного общества нефрологов. От имени трех наших обществ мы обращаемся к правительственным структурам, осуществляющим контроль над диализными центрами в развивающихся странах, обеспечить максимальную поддержку персоналу, нефрологам и другим работникам здравоохранения, предоставляющим жизнеобеспечивающие методы лечения этим в высшей степени уязвимым пациентам. В то же время, несомненным приоритетом для правительственных структур должно быть осуществление ускоренного тестирования и обеспечение персонала индивидуальными средствами защиты.