Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Longitudinal analysis of estimated glomerular filtration rate in a cohort of health service users

Abstract of a Mini Oral Presentation at the 15th Asian Pacific Congress of Nephrology (APCN) and 52nd ANZSN ASM, 17-21 September 2016, Perth Convention and Exhibition Centre, Western Australia

The effects of acute waterborne exposure to sublethal concentrations of molybdenum on the stress response in rainbow trout, Oncorhynchus mykiss.

To determine if molybdenum (Mo) is a chemical stressor, fingerling and juvenile rainbow trout (Oncorhynchus mykiss) were exposed to waterborne sodium molybdate (0, 2, 20, or 1,000 mg l-1 of Mo) and components of the physiological (plasma cortisol, blood glucose, and hematocrit) and cellular (heat shock protein [hsp] 72, hsp73, and hsp90 in the liver, gills, heart, and erythrocytes and metallothionein [MT] in the liver and gills) stress responses were measured prior to initiation of exposure and at 8, 24, and 96 h. During the acute exposure, plasma cortisol, blood glucose, and hematocrit levels remained unchanged in all treatments. Heat shock protein 72 was not induced as a result of exposure and there were no detectable changes in total hsp70 (72 and 73), hsp90, and MT levels in any of the tissues relative to controls. Both fingerling and juvenile fish responded with similar lack of apparent sensitivity to Mo exposure. These experiments demonstrate that exposure to waterborne Mo of up to 1,000 mg l(-1) did not activate a physiological or cellular stress response in fish. Information from this study suggests that Mo water quality guidelines for the protection of aquatic life are highly protective of freshwater fish, namely rainbow trout

Liver (A) and gill (B) total hsp70 levels in fingerling rainbow trout after a 96 h molybdenum exposure to 0, 2, 20 or 1,000 mg l^-1.

<p>Fish were sampled prior to exposure (PE = pre-exposure) and at 8, 24 and 96 h during exposure. Data plotted as means ± 1 SEM (n = 6). No significant differences (p > 0.05) were found.</p

Liver (A), gill (B), heart (C), and erythrocyte (D) hsp90 levels (relative to positive control) of juvenile rainbow trout exposed for 96 h to waterborne Mo at concentrations of 0, 2, or 20 mg l^-1.

<p>Data plotted as means ± 1 SEM (n = 6). There were no significant differences (p > 0.05) between groups. Representative Western blots for total hsp70 in the each tissues are shown above their respective bar graphs with the location of location of the MagicMark XP Western Protein Standard indicated on the left side of each blot (in kDa).</p

Liver and gill MT levels (relative to positive control) of juvenile rainbow trout exposed for 96 h to waterborne Mo at concentrations of 0, 2, or 20 mg l^-1.

<p>Data were plotted as means ± 1 SEM (n = 6). There were no significant differences (p > 0.05) between groups.</p

Liver MT levels (relative to positive control) in fingerling rainbow trout after a 96 h exposure to 0, 2, 20, or 1,000 mg l^-1 of molybdenum.

<p>Fish were sampled prior to (PE = pre-exposure) and after 8, 24, and 96 h of exposure. Data plotted as means ± 1 SEM (n = 6). No significant differences (p > 0.05) were found.</p

Tissue total protein concentration (mg g^-1 tissue wet weight) in rainbow trout after 96 h molybdenum exposure.

<p>Tissue total protein is shown for liver, gill, heart and erythrocyte total protein in juvenile trout exposed to 0, 2 or 20 mg l^-1 (A) and liver (B) and gill (C) in fingerling trout exposed to 0, 2, 20 or 1,000 mg l^-1molybdenum. Fingerlings were sampled prior to (PE = pre-exposure) and at 8, 24, and 96 h of exposure. Data plotted as means ± 1 SEM (n = 6). No significant differences (p>0.05) were found.</p

Erythrocyte hsp72 levels in from juvenile rainbow trout exposed to molybdenum (0, 2, or 20 mg l^-1) for 96 h.

<p>(A) Representative Western blot of hsp72 expression in juvenile rainbow trout erythrocytes. (B) Erythrocyte hsp72 levels (relative to positive control). Data plotted means ± 1 SEM (n = 6). There were no significant differences (p > 0.05) between groups.</p

Liver hsp90 levels (relative to positive control) in fingerling rainbow trout exposed to 0, 20, or 1,000 mg l^-1 of molybdenum prior to exposure (PE = pre-exposure) and during exposure (8, 24 and 96 h).

<p>Data presented as means ± 1 SEM (n = 6). No significant differences (p > 0.05) were found.</p