Are in-hospital COVID-19-related mortality and morbidity in pregnancy associated with gestational age?

OBJECTIVE: Pregnancy involves dynamic changes in the maternal immune system, thus potentially affecting women's response to infection. The aim of this study was to investigate whether gestational age at the time of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is associated with mortality and morbidity related to coronavirus disease 2019 (COVID-19) in hospitalized pregnant women. METHODS: This was a cohort study of pregnant women with confirmed SARS-CoV-2 infection at any gestational age (categorized into trimesters) who were hospitalized in Brazil from February 2020 to November 2021. Sociodemographic and epidemiological characteristics, signs and symptoms, comorbidities, interventions, vaccination status and type of healthcare establishment were obtained from a nationwide database. Multivariate logistic and Cox regression analyses were used to identify independent risk factors for in-hospital COVID-19-related mortality and morbidity (defined as time from hospital admission to recovery). RESULTS: A total of 7461 SARS-CoV-2-infected pregnant women were included in the study (9.3%, 28.4% and 62.3% in the first, second and third trimesters, respectively). After adjustment for sociodemographic, epidemiological and clinical characteristics, and intervention-related variables, gestational age at infection was found not to be associated with COVID-19-related mortality and morbidity. Women admitted to establishments with an obstetric center, compared to hospitals without, were 38% less likely to die from SARS-CoV-2 infection (adjusted odds ratio, 0.62; 95% CI, 0.48-0.80), while patients who received private not-for-profit healthcare had a 13% shorter time to recovery (adjusted hazard ratio, 1.13; 95% CI, 1.07-1.20) compared to those who received public healthcare. CONCLUSIONS: Despite a higher percentage of women being admitted in the third trimester, we found no association between gestational age and COVID-19 mortality and morbidity. The previously reported increase in morbidity and mortality in the third trimester in pregnant women with COVID-19 may be attributable to other gestational-age-affected variables for which adjustment was made in our study. © 2022 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Posterior urethral valves: comparison of clinical outcomes between postnatal and antenatal cohorts.

BACKGROUND: Posterior urethral valves (PUVs) constitute the most common infravesical urinary obstruction in boys and are often accompanied by severe consequences to the lower and upper urinary tract. Currently, about two-thirds of diagnosis of PUVs has been suspected by prenatal ultrasonography findings. The aim of this study was to compare long-term clinical outcomes in two groups of patients with PUVs, with antenatal vs. postnatal diagnosis. STUDY DESIGN: This was a retrospective cohort study of 173 patients with PUVs systematically followed up in a tertiary center. Median follow-up time was 66.5 months (interquartile range [IQ], 11.4-147.9 months) for those patients who survived neonatal period. Seventy-nine (45.6%) patients were followed up for more than 5 years and 55 (32%) for more than 10 years. For analysis, the cohort was stratified into two groups according to the clinical presentation (prenatal vs. postnatal). The events of interest were urinary tract infection (UTI), surgical interventions, proteinuria, hypertension, chronic kidney disease (CKD), and death. Survival analyses were performed to evaluate time until occurrence of the events. RESULTS: Sixty-two patients (35.8%) were diagnosed by fetal sonography. Patients of postnatal group presented a higher incidence rate of UTI episodes (6.5, 95% confidence interval [CI], 4.9-8.3) than antenatal group (1.2, 95% CI, 0.4-2.7) (P < 0.001). Thirty-six patients (21%) presented hypertension, and 77 (44.5%) had persistent mild proteinuria. There was no significant difference in the estimated incidence of hypertension (P = 0.28) and proteinuria (P = 0.78) between antenatal and postnatal groups. The cumulative incidence of CKD stage ≥3 was estimated to be about 37% at 10 years of age, and 56% at 18 years of age. By survival analysis, there was no significant difference in the estimated incidence of CKD stage ≥3 (log-rank = 0.32, P = 0.57) and CKD stage 5 (log-rank = 1.08, P = 0.28, Figure) between antenatal and postnatal groups. Of 173 patients included in the analysis, 13 (7.5%) died during follow-up with a median age of 2.6 months (IQ, 15 days-62 months). Survival analyses have not shown any significant difference in the estimated incidence of death between antenatal and postnatal groups (log-rank = 1.38, P = 0.24). CONCLUSION: The study findings did not corroborate the initial hypothesis that the rates of renal function declining in patients with PUVs would be attenuated by an early diagnosis and intervention after antenatal diagnosis.

ACE2, angiotensin-(1-7) and Mas receptor axis in inflammation and fibrosis.

Recent advances have improved our understanding of the renin-angiotensin system (RAS). These have included the recognition that angiotensin (Ang)-(1-7) is a biologically active product of the RAS cascade. The identification of the ACE homologue ACE2, which forms Ang-(1-7) from Ang II, and the GPCR Mas as an Ang-(1-7) receptor have provided the necessary biochemical and molecular background and tools to study the biological significance of Ang-(1-7). Most available evidence supports a counter-regulatory role for Ang-(1-7) by opposing many actions of Ang II on AT1 receptors, especially vasoconstriction and proliferation. Many studies have now shown that Ang-(1-7) by acting via Mas receptor exerts inhibitory effects on inflammation and on vascular and cellular growth mechanisms. Ang-(1-7) has also been shown to reduce key signalling pathways and molecules thought to be relevant for fibrogenesis. Here, we review recent findings related to the function of the ACE2/Ang-(1-7)/Mas axis and focus on the role of this axis in modifying processes associated with acute and chronic inflammation, including leukocyte influx, fibrogenesis and proliferation of certain cell types. More attention will be given to the involvement of the ACE2/Ang-(1-7)/Mas axis in the context of renal disease because of the known relevance of the RAS for the function of this organ and for the regulation of kidney inflammation and fibrosis. Taken together, this knowledge may help in paving the way for the development of novel treatments for chronic inflammatory and renal diseases.

Fisiopatología da síndrome nefrótica em crianças e adolescentes / Pathophysiology of nephrotic syndrome in children and adolescents

A Síndrome nefrótica (SN), caracterizada por proteinúria, hipoalbuminemia e edema, é a glomerulopatia mais comum em crianças. Apesar dos avanços, sua fisiopatologia permanece desconhecina. Considera-se que a SN é um distúrbio complexo e multifatorial, envolvendo agentes desencadeadores, alteraçôes genéticas e do sistema imune. Alteraçôes genéticas podem aumentar a susceptibilidade à SN ou provocar distúrbios de permeabilidade que se manifestam logo após o nascimento. Várias evidências sugerem também um papel significativo do sistema imne na fisiopatologia dessa doença, com uma aparente resposta anormal dos linfócitos T, Participaçâo de citocinas e quimiocinas, com destaque para o TGFß. Outros echaos sugerem a existência de algum fator circulante de permeabilidade, provavelmente derivado do sistema imune, relacionado às recidivas pós-transplante. O estudo mais aprofundado da fisiopatología da SN poderia proporiconar o desemvolvimiento de fármacos com maior respecificidade e menos efectos adversos

Interactions between angiotensin-(1-7), kinins, and angiotensin II in kidney and blood vessels.

The heptapeptide angiotensin (Ang)-(1-7) is currently considered one of the biologically active end products of the renin-angiotensin system. The formation of Ang-(1-7) by pathways independent of Ang II generation, the selectivity of its actions, and its peculiar property of exhibiting effects that are partially opposite of those of the parent compound, Ang II, confer a unique biochemical and functional profile to this peptide. In this article, we will review novel aspects of the biological actions of Ang-(1-7), dealing with its interaction with Ang II and kinins, especially in the kidney and blood vessels.

Effect of selective angiotensin antagonists on the antidiuresis produced by angiotensin-(1-7) in water-loaded rats

In the present study we evaluated the nature of angiotensin receptors involved in the antidiuretic effect of angiotensin-(1-7) (Ang-(1-7)) in water-loaded rats. Water diuresis was induced in male Wistar rats weighing 280 to 320 g by water load (5 ml/100 g body weight by gavage). Immediately after water load the rats were treated subcutaneously with (doses are per 100 g body weight): 1) vehicle (0.05 ml 0.9 percenr NaCl); 2) graded doses of 20, 40 or 80 pmol Ang-(1-7); 3) 200 nmol Losartan; 4) 200 nmol Losartan combined with 40 pmol Ang-(1-7); 5) 1.1 or 4.4 nmol A-779; 6) 1.1 nmol A-779 combined with graded doses of 20, 40 or 80 pmol Ang-(1-7); 7) 4.4 nmol A-779 combined with graded doses of 20, 40 or 80 pmol Ang-(1-7); 8) 95 nmol CGP 42112A, or 9) 95 nmol CGP 42112A combined with 40 pmol Ang-(1-7). The antidiuretic effect of Ang-(1-7) was associated with an increase in urinary Na+ concentration, an increase in urinary osmolality and a reduction in creatinine clearance (CCr: 0.65 ñ 0.04 ml/min vs 1.45 ñ 0.18 ml/min in vehicle-treated rats, P<0.05). A-779 and Losartan completely blocked the effect of Ang-(1-7) on water diuresis (2.93 ñ 0.34 ml/60 min and 3.39 ñ 0.58 ml/60 min, respectively). CGP 42112A, at the dose used, did not modify the antidiuretic effect of Ang-(1-7). The blockade produced by Losartan was associated with an increase in CCr and with an increase in sodium and water excretion as compared with Ang-(1-7)-treated rats. When Ang-(1-7) was combined with A-779 there was an increase in CCr and natriuresis and a reduction in urine osmolality compared with rats treated with Ang-(1-7) alone. The observation that both A-779, which does not bind to AT1 receptors, and Losartan blocked the effect of Ang-(1-7) suggests that the kidney effects of Ang-(1-7) are mediated by a non-AT1 angiotensin receptor that is recognized by Losartan.

Diuresis and natriuresis produced by long term administration of a selective Angiotensin-(1-7) antagonist in normotensive and hypertensive rats.

In this study we evaluated the renal effects of chronic administration of the selective Angiotensin-(1-7)[Ang-(1-7)] antagonist, A-779, in normotensive and spontaneously hypertensive rats (SHR). Male adult SHR and Wistar rats were housed in metabolic cages with tap water and standard chow, for three-five days before starting infusion (Alzet osmotic mini-pumps) of A-779 (Wistar: 1 microg/h, n = 9; 2.5 microg/h, n = 6; SHR:2.5 microg/h, n = 6) or vehicle (0.9% NaCl - 1 microl/h, n = 7 and n = 10 for SHR and Wistar rats, respectively). Urine volume, water and food intake and urinary Na+ were measured daily. On the last day of infusions mean arterial pressure (MAP) was recorded and urine and blood samples were collected to determine renal function parameters. Chronic infusion of A-779 produced a sustained increase in diuresis in normotensive rats [seventh day values: 0.75+/-0.08 ml/h (1 microg/h) and 0.94+/-0.13 ml/h (2.5 microg/h) vs. 0.42 + 0.03 ml/h for the control group, P<0.05] associated to a dose-dependent increase in the creatinine clearance. In SHR, diuresis increased significantly after chronic infusion of A-779 (fifth day values: 0.44 + 0.06 ml/h vs. 0.25+/-0.04 ml/h for the control group, P<0.05), without changes in creatinine clearance. Infusion of A-779 in normotensive rats produced a decrease in water reabsorption. A-779 infusion also produced a dose-dependent increase in urinary Na+ excretion (1.49 + 0.14 mEq, 1 microg/h vs. 2.37+/-0.22 mEq, 2.5 microg/h, P<0.05), in Wistar rats, without modifying the fractional excretion of Na+. In SHR, urinary Na+ excretion was also increased by A-779 (2.21+/-0.46 mEq vs. 0.94+/-0.22 mEq for the control group, P<0.05). No significant changes in blood pressure were observed. These findings suggest that endogenous Ang-(l-7) participates in the control of hydroelectrolyte balance by modulating water excretion, acting at tubular and glomerular sites.

Effect of selective angiotensin antagonists on the antidiuresis produced by angiotensin-(1-7) in water-loaded rats.

In the present study we evaluated the nature of angiotensin receptors involved in the antidiuretic effect of angiotensin-(1-7) (Ang-(1-7)) in water-loaded rats. Water diuresis was induced in male Wistar rats weighing 280 to 320 g by water load (5 ml/100 g body weight by gavage). Immediately after water load the rats were treated subcutaneously with (doses are per 100 g body weight): 1) vehicle (0.05 ml 0.9% NaCl); 2) graded doses of 20, 40 or 80 pmol Ang-(1-7); 3) 200 nmol Losartan; 4) 200 nmol Losartan combined with 40 pmol Ang-(1-7); 5) 1.1 or 4.4 nmol A-779; 6) 1.1 nmol A-779 combined with graded doses of 20, 40 or 80 pmol Ang-(1-7); 7) 4.4 nmol A-779 combined with graded doses of 20, 40 or 80 pmol Ang-(1-7); 8) 95 nmol CGP 42112A, or 9) 95 nmol CGP 42112A combined with 40 pmol Ang-(1-7). The antidiuretic effect of Ang-(1-7) was associated with an increase in urinary Na+ concentration, an increase in urinary osmolality and a reduction in creatinine clearance (CCr: 0.65 +/- 0.04 ml/min vs 1.45 +/- 0.18 ml/min in vehicle-treated rats, P < 0.05). A-779 and Losartan completely blocked the effect of Ang-(1-7) on water diuresis (2.93 +/- 0.34 ml/60 min and 3.39 +/- 0.58 ml/60 min, respectively). CGP 42112A, at the dose used, did not modify the antidiuretic effect of Ang-(1-7). The blockade produced by Losartan was associated with an increase in CCr and with an increase in sodium and water excretion as compared with Ang-(1-7)-treated rats. When Ang-(1-7) was combined with A-779 there was an increase in CCr and natriuresis and a reduction in urine osmolality compared with rats treated with Ang-(1-7) alone. The observation that both A-779, which does not bind to AT1 receptors, and Losartan blocked the effect of Ang-(1-7) suggests that the kidney effects of Ang-(1-7) are mediated by a non-AT1 angiotensin receptor that is recognized by Losartan.

Renal actions of angiotensin-(1-7).

The heptapeptide angiotensin-(1-7) is considered to be a biologically active endproduct of the renin-angiotensin system. This angiotensin, which is devoid of the most known actions of angiotensin II such as induction of drinking behavior and vasoconstriction, has several selective effects in the brain and periphery. In the present article we briefly review recent evidence for a physiological role of angiotensin-(1-7) in the control of hydroelectrolyte balance.

Renal actions of angiotensin-(1-7)

The heptapeptide angiotensin-(1-7) is considered to be a biologically active endproduct of the renin-angiotensin system. This angiotensin, which is devoid of the most known actions of angioatensin II such as induction of drinking behavior and vasoconstriction, has several selective effects in the brain and periphery. In the present article we briefly review recent evidence for a physiological role of angiotensin-(1-7) in the control of hydroelectrolyte balance.

Evidence for a physiological role of angiotensin-(1-7) in the control of hydroelectrolyte balance.

In this study we evaluated the possibility that angiotensin-(1-7) [Ang-(1-7)] acts as an endogenous osmoregulatory peptide by determining the effect of acute administration of its selective antagonist [D-Ala7]Ang-(1-7) (A-779) on renal function parameters in rats. In addition, we investigated the physiological mechanisms involved in the antidiuretic effect of Ang-(1-7). The antidiuretic effect of Ang-(1-7) (40 pmol/0.05 mL per 100 g BW) in water-loaded rats was completely blocked by A-779 (vehicle-treated, 3.34 +/- 0.43 mL/h; Ang-(1-7), 1.48 +/- 0.23; A-779, 2.72 +/- 0.35; Ang-(1-7) plus A-779, 3.26 +/- 0.49). In contrast, the antidiuretic effect of Ang-(1-7) was not significantly changed by a vasopressin V2 receptor antagonist in a dose that completely blocked the antidiuresis produced by an equipotent dose of vasopressin. In addition, Ang-(1-7) administration did not significantly change vasopressin plasma levels in water-loaded rats. The antidiuretic effect of Ang-(1-7) in water-loaded rats was associated with a reduction of creatinine clearance (0.68 +/- 0.04 versus 1.38 +/- 0.32 mL/min in vehicle-treated rats, P <.05) and an increase in urine osmolality (266.8 +/- 32.7 versus 182.8 +/- 14 mOsm/kg in vehicle-treated rats, P <.05). An effect of Ang-(1-7) in tubular water transport was demonstrated in vitro by a fourfold increase in the hydraulic conductivity of inner medullary collecting ducts in the presence of 1 nmol/L Ang-(1-7). Subcutaneous administration of A-779 (2.3 to 9.2 nmol/100 g) produced a significant increase in urine volume (4.6 nmol/100 g, 0.45 +/- 0.12 mL/h; vehicle-treated rats, 0.16 +/- 0.03 mL/h; P <.05) comparable to that of acute administration of a vasopressin V2 receptor antagonist. The diuretic effect of A-779 was associated with an increase in creatinine clearance and decrease in urine osmolality. In contrast, no significant effects on urine volume were observed after systemic administration of angiotensin subtype 1 or 2 receptor antagonists (DuP 753 and CGP 42112A, respectively). These findings suggest that endogenous Ang-(1-7), acting on specific receptors, participates in the control of hydroelectrolyte balance by influencing especially water excretion.