Agarwal, Anupam

AbstractObjectiveThis study was undertaken to evaluate the long‐term safety and effectiveness of fenfluramine in patients with Lennox–Gastaut syndrome (LGS).MethodsEligible 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.ResultsAs 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.SignificancePatients 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.

Abstract Key Points The healthy kidney prominently expresses angiotensin-converting enzyme 2 (ACE2) mRNA, protein, and activity, with ACE2 protein abundantly displayed in proximal tubules. Renal ACE2 expression decreases after ischemic AKI but is induced by LPS in a heme oxygenase-1-dependent manner. ACE2 induction/angiotensin (1–7) and angiotensin (1–7) may offer therapeutic approaches for AKI without or with coronavirus disease 2019, respectively. 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.

The American Society of Nephrology has established a new initiative, AKI!Now , with the goal of promoting excellence in the prevention and treatment of AKI by building a foundational program that transforms education and delivery of AKI care, aiming to reduce morbidity and associated mortality and to improve long-term outcomes. In this article, we describe our current efforts to improve early recognition and management involving inclusive interdisciplinary collaboration between providers, patients, and their families; discuss the ongoing need to change some of our current AKI paradigms and diagnostic methods; and provide specific recommendations to improve AKI recognition and care. In the hospital and the community, AKI is a common and increasingly frequent condition that generates risks of adverse events and high costs. Unfortunately, patients with AKI may frequently have received less than optimal quality of care. New classifications have facilitated understanding of AKI incidence and its impact on outcomes, but they are not always well aligned with AKI pathophysiology. Despite ongoing research efforts, treatments to promote or hasten kidney recovery remain ineffective. To avoid progression, the current approach to AKI emphasizes the promotion of early recognition and timely response. However, a lack of awareness of the importance of early recognition and treatment among health care team members and the heterogeneity of approaches within the health care teams assessing the patient remains a major challenge. Early identification is further complicated by differences in settings where AKI occurs (the community or the hospital), and by differences in patient populations and cultures between the intensive care unit and ward environments. To address these obstacles, we discuss the need to improve education at all levels of care and to generate specific guidance on AKI evaluation and management, including the development of a widely applicable education and an AKI management toolkit, engaging hospital administrators to incorporate AKI as a quality initiative, and raising awareness of AKI as a complication of other disease processes.