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

Effects of Lysophosphatidic Acid, a Novel Lipid Mediator, on Cytosolic Ca 2+

Abstract Lysophosphatidic acid (LPA), the smallest and structurally simplest phospholipid, has the potential to modulate cellular signaling in diverse tissues and cell types, including fibroblasts. In the present study, we assessed the effects of LPA on cultured rat glomerular mesangial cells. Quantitative changes of [Ca 2+ ] i in response to LPA were measured in monolayers of mesangial cells loaded with the fluorescent Ca 2+ indicator fura 2. LPA (10 nmol/L to 100 μmol/L) increased [Ca 2+ ] i in a dose-dependent manner and evoked inositol trisphosphate formation. LPA (1 μmol/L to 30 μmol/L) also elicited a marked, albeit transient, contractile response in mesangial cells cultured on collagen gel, as assessed by a decrease in cell surface area (CSA). The contraction persisted for 5 minutes (CSA decreased by 31%), whereupon the mesangial cells gradually relaxed with a consequent increase in CSA. Pretreatment of mesangial cells with isradipine (1 μmol/L), a dihydropyridine-sensitive Ca 2+ channel blocker, completely blocked LPA-induced contraction. Isradipine also decreased resting [Ca 2+ ] i levels as well as the peak and the subsequently sustained [Ca 2+ ] i levels induced by LPA, suggesting that the contractile effects of LPA are dependent on Ca 2+ entry through voltage-gated Ca 2+ channels. Finally, LPA stimulated an increase in both prostaglandin E 2 synthesis and cAMP accumulation, indicating that these mediators may modulate the contractile effects of LPA. Our study is the first demonstration that exogenous LPA induces mesangial cell contraction and suggests that the contraction is mediated by mobilization of intracellular Ca 2+ by activation of the phosphoinositide cascade as well as by promotion of Ca 2+ entry across the plasma membrane

A Quantitative Assessment of Renal Blood Flow Autoregulation in Experimental Diabetes

Several approaches have been utilized to describe renal blood flow (RBF) autoregulation in normal and pathological conditions. When describing the relation between RBF and stepwise decrements in renal perfusion pressure (RPP), these methods have several limitations, including: the necessity for predetermining a pressure ‘break-point’, and establishing constraints on changes in flow. To circumvent these limitations, we successfully utilized a third order polynomial, the cubical parabola, to characterize the autoregulatory responses in untreated streptozotocin (STZ) diabetic and control rats. The nonlinear relationship occurring between RBF and RPP was estimated from individual observations using the equation RBF=a + b× 10-6 (RPP-c)3. Variables a and c represent RBF and RPP at the inflection point of the curve, respectively; variable b represents the rate of fall of RBF as RPP decreases (shape factor). Variable c was significantly lower in the diabetic group than in the control group whereas variable b was greater in the diabetic group. RBF (a) did not differ between the two groups. In conclusion, we determined that the range of RBF autoregulation in untreated diabetic rats is reset to a lower RPP Furthermore, the curve below the inflection point declines more rapidly in diabetic rats than in controls. We propose that the equation described herein constitutes a promising and reproducible method for describing RBF autoregulation in vivo

Impairment of Afferent Arteriolar Myogenic Responsiveness in the Galactose-Fed Rat

Abstract Previous studies from our laboratory have demonstrated impaired afferent arteriolar responsiveness to pressure in rats 4-6 weeks after the induction of diabetes mellitus. Although the responsible mechanisms mediating this renal autoregulatory defect have not been fully defined, increased polyol metabolism has been implicated as a possible factor involved in the pathogenesis of diabetic complications. We therefore investigated the possible role of this metabolic disturbance in renal autoregulation using the galactose-fed rat, a model characterized by increased polyol pathway activity independent of hyperglycemia or insulin deficiency. Hydronephrosis was induced to permit direct visualization of renal microvessels. Pressure-induced vasoconstriction of afferent arterioles was assessed by quantitating vessel diameter following stepwise increments of renal perfusion pressure (RAP; from 80 to 180 mm Hg) in the hydronephrotic kidneys from control rats and rats fed a 50% galactose diet for 2 or 4 weeks. Vessel diameters were measured from video images by computer-assisted image processing. Control rats exhibited progressive afferent arteriolar vasoconstriction when RAP was increased from 80 to 180 mm Hg (-17.3% ± 1.0%; P < 0.001). In contrast, myogenic responses to increases in pressure were absent in the afferent arterioles of rats fed a 50% galactose diet for either 2 (-4.1% ± 1.9%; not significant) or 4 weeks (-2.9 ± 3.4%; not significant). Our demonstration that the impairment of afferent arteriolar responsiveness to increasing RAP in the normoglycemic galactose-fed rat was identical to that observed in the STZ-diabetic rat suggests that increased polyol accumulation may contribute to the impairment of renal auto-regulation in the diabetic rat