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Tocilizumab in COVID-19: some clarity amid controversy
[...]one of the concerns surrounding tocilizumab use in patients with COVID-19 is the risk of secondary infection, and although tocilizumab did not result in any deaths from secondary infection, the investigators did not collect data on non-fatal infections or other adverse events. [...]important physiological data regarding hypoxaemia, such as longitudinal assessment of the partial pressure of arterial oxygen to the fraction of inspired oxygen, were not collected. [...]given that patients with COVID-19 often have a prolonged hospital course, it is unclear whether a reduction in 28-day mortality will translate into longer-term mortality benefit, and we look forward to the preplanned analyses at 6 months.
Journal Article
Another Win for SGLT2 Inhibitors in Chronic Kidney Disease
Chronic kidney disease affects 14% of the U.S. population
1
and is associated with an extraordinarily high risk of poor outcomes, including progression to end-stage kidney disease, cardiovascular events, and death.
2
Finally, after decades of therapeutic stagnation, a recent explosion of new therapies has revolutionized treatment options in this vulnerable patient population. Prominent among these therapies are the sodium–glucose cotransporter 2 (SGLT2) inhibitors, as described in landmark trials, including the EMPA-KIDNEY trial of empagliflozin in 2023.
3
In this issue of the
Journal
,
4
Herrington et al. report the long-term results of the EMPA-KIDNEY follow-up trial involving patients with chronic kidney disease who . . .
Journal Article
Hispanic ethnicity and mortality among critically ill patients with COVID-19
Hispanic persons living in the United States (U.S.) are at higher risk of infection and death from coronavirus disease 2019 (COVID-19) compared with non-Hispanic persons. Whether this disparity exists among critically ill patients with COVID-19 is unknown.
To evaluate ethnic disparities in mortality among critically ill adults with COVID-19 enrolled in the Study of the Treatment and Outcomes in Critically Ill Patients with COVID-19 (STOP-COVID).
Multicenter cohort study of adults with laboratory-confirmed COVID-19 admitted to intensive care units (ICU) at 67 U.S. hospitals from March 4 to May 9, 2020. Multilevel logistic regression was used to evaluate 28-day mortality across racial/ethnic groups.
A total of 2153 patients were included (994 [46.2%] Hispanic and 1159 [53.8%] non-Hispanic White). The median (IQR) age was 62 (51-71) years (non-Hispanic White, 66 [57-74] years; Hispanic, 56 [46-67] years), and 1462 (67.9%) were men. Compared with non-Hispanic White patients, Hispanic patients were younger; were less likely to have hypertension, chronic obstructive pulmonary disease, coronary artery disease, or heart failure; and had longer duration of symptoms prior to ICU admission. During median (IQR) follow-up of 14 (7-24) days, 785 patients (36.5%) died. In analyses adjusted for age, sex, clinical characteristics, and hospital size, Hispanic patients had higher odds of death compared with non-Hispanic White patients (OR, 1.44; 95% CI, 1.12-1.84).
Among critically ill adults with COVID-19, Hispanic patients were more likely to die than non-Hispanic White patients, even though they were younger and had lower comorbidity burden. This finding highlights the need to provide earlier access to care to Hispanic individuals with COVID-19, especially given our finding of longer duration of symptoms prior to ICU admission among Hispanic patients. In addition, there is a critical need to address ongoing disparities in post hospital discharge care for patients with COVID-19.
Journal Article
We need more data to help guide the care of patients with cancer who develop kidney related problems
Healthcare staff caring for patients with cancer must have access to high quality and generalizable data regarding the toxicities and repercussions of cancer treatments
Journal Article
Iron as an emerging therapeutic target in critically ill patients
The multiple roles of iron in the body have been known for decades, particularly its involvement in iron overload diseases such as hemochromatosis. More recently, compelling evidence has emerged regarding the critical role of non-transferrin bound iron (NTBI), also known as catalytic iron, in the care of critically ill patients in intensive care units (ICUs). These trace amounts of iron constitute a small percentage of the serum iron, yet they are heavily implicated in the exacerbation of diseases, primarily by catalyzing the formation of reactive oxygen species, which promote oxidative stress. Additionally, catalytic iron activates macrophages and facilitates the growth of pathogens. This review aims to shed light on this underappreciated phenomenon and explore the various common sources of NTBI in ICU patients, which lead to transient iron dysregulation during acute phases of disease. Iron serves as the linchpin of a vicious cycle in many ICU pathologies that are often multifactorial. The clinical evidence showing its detrimental impact on patient outcomes will be outlined in the major ICU pathologies. Finally, different therapeutic strategies will be reviewed, including the targeting of proteins involved in iron metabolism, conventional chelation therapy, and the combination of renal replacement therapy with chelation therapy.
Journal Article
Therapeutic advances in COVID-19
Over 2 years have passed since the start of the COVID-19 pandemic, which has claimed millions of lives. Unlike the early days of the pandemic, when management decisions were based on extrapolations from in vitro data, case reports and case series, clinicians are now equipped with an armamentarium of therapies based on high-quality evidence. These treatments are spread across seven main therapeutic categories: anti-inflammatory agents, antivirals, antithrombotics, therapies for acute hypoxaemic respiratory failure, anti-SARS-CoV-2 (neutralizing) antibody therapies, modulators of the renin–angiotensin–aldosterone system and vitamins. For each of these treatments, the patient population characteristics and clinical settings in which they were studied are important considerations. Although few direct comparisons have been performed, the evidence base and magnitude of benefit for anti-inflammatory and antiviral agents clearly outweigh those of other therapeutic approaches such as vitamins. The emergence of novel variants has further complicated the interpretation of much of the available evidence, particularly for antibody therapies. Importantly, patients with acute and chronic kidney disease were under-represented in many of the COVID-19 clinical trials, and outcomes in this population might differ from those reported in the general population. Here, we examine the clinical evidence for these therapies through a kidney medicine lens.The COVID-19 pandemic was met with large-scale efforts to assess novel and repurposed therapeutic interventions that could reduce patient morbidity and mortality. Here, the authors discuss the different types of therapies available to treat COVID-19, including their relevance to patients with kidney failure and kidney transplant recipients.
Journal Article
De novo NAD+ biosynthetic impairment in acute kidney injury in humans
Nicotinamide adenine dinucleotide (NAD
+
) extends longevity in experimental organisms, raising interest in its impact on human health. De novo NAD
+
biosynthesis from tryptophan is evolutionarily conserved yet considered supplanted among higher species by biosynthesis from nicotinamide (NAM). Here we show that a bottleneck enzyme in de novo biosynthesis, quinolinate phosphoribosyltransferase (QPRT), defends renal NAD
+
and mediates resistance to acute kidney injury (AKI). Following murine AKI, renal NAD
+
fell, quinolinate rose, and QPRT declined. QPRT
+/−
mice exhibited higher quinolinate, lower NAD
+
, and higher AKI susceptibility. Metabolomics suggested an elevated urinary quinolinate/tryptophan ratio (uQ/T) as an indicator of reduced QPRT. Elevated uQ/T predicted AKI and other adverse outcomes in critically ill patients. A phase 1 placebo-controlled study of oral NAM demonstrated a dose-related increase in circulating NAD
+
metabolites. NAM was well tolerated and was associated with less AKI. Therefore, impaired NAD
+
biosynthesis may be a feature of high-risk hospitalizations for which NAD
+
augmentation could be beneficial.
Impaired NAD
+
biosynthesis may be a common feature of high-risk hospitalizations for which NAD
+
augmentation could improve therapeutic outcome.
Journal Article
Randomized Controlled Trial of Calcitriol in Severe Sepsis
Vitamin D and its metabolites have potent immunomodulatory effects in vitro, including up-regulation of cathelicidin, a critical antimicrobial protein.
We investigated whether administration of 1,25-dihydroxyvitamin D (calcitriol) to critically ill patients with sepsis would have beneficial effects on markers of innate immunity, inflammation, and kidney injury.
We performed a double-blind, randomized, placebo-controlled, physiologic study among 67 critically ill patients with severe sepsis or septic shock. Patients were randomized to receive a single dose of calcitriol (2 μg intravenously) versus placebo. The primary outcome was plasma cathelicidin protein levels assessed 24 hours after study drug administration. Secondary outcomes included leukocyte cathelicidin mRNA expression, plasma cytokine levels (IL-10, IL-6, tumor necrosis factor-α, IL-1β, and IL-2), and urinary kidney injury markers.
Patients randomized to calcitriol (n = 36) versus placebo (n = 31) had similar plasma cathelicidin protein levels at 24 hours (P = 0.16). Calcitriol-treated patients had higher cathelicidin (P = 0.04) and IL-10 (P = 0.03) mRNA expression than placebo-treated patients 24 hours after study drug administration. Plasma cytokine levels (IL-10, IL-6, tumor necrosis factor-α, IL-1β, and IL-2) and urinary kidney injury markers were similar in calcitriol- versus placebo-treated patients (P > 0.05 for all comparisons). Calcitriol had no effect on clinical outcomes nor were any adverse effects observed.
Calcitriol administration did not increase plasma cathelicidin protein levels in critically ill patients with sepsis and had mixed effects on other immunomodulatory markers. Additional phase II trials investigating the dose and timing of calcitriol as a therapeutic agent in specific sepsis phenotypes may be warranted. Clinical trial registered with www.clinicaltrials.gov (NCT 01689441).
Journal Article
