Cardiac Effects of Renin-Angiotensin System Inhibitors in Nonproteinuric CKD.

BACKGROUND: In contrast to proteinuric chronic kidney disease (CKD), the relative cardioprotective benefits of antihypertensive medications in nonproteinuric CKD are unknown. We examined long-term cardiovascular outcomes and mortality in patients with nonproteinuric CKD treated with renin-angiotensin system inhibitors (RASIs) versus other antihypertensive medications. METHODS: Among participants of the CRIC study (Chronic Renal Insufficiency Cohort) without proteinuria, we used intention-to-treat analyses with inverse probability of treatment weighting and Cox proportional hazards modeling to determine the association of RASIs versus other antihypertensive medications with a composite cardiovascular outcome (myocardial infarction, stroke, heart failure hospitalization, and death) and mortality. Secondary analyses included per-protocol analyses accounting for continuous adherence and time-updated analyses accounting for the proportion of time using RASIs during follow-up. RESULTS: A total of 2806 participants met the inclusion criteria. In the intention-to-treat analyses, RASIs versus other antihypertensive medications were not associated with an appreciable difference in cardiovascular events (adjusted hazard ratio [aHR], 0.94 [95% CI, 0.80-1.11]) or mortality (aHR, 1.06 [95% CI, 0.88-1.28]). In the per-protocol analyses, RASIs were associated with a lower risk of adverse cardiovascular events (aHR, 0.78 [95% CI, 0.63-0.97]) and mortality (aHR, 0.64 [95% CI, 0.48-0.85]). Similarly, in the time-updated analyses, a higher proportion of RASI use over time was associated with a lower mortality risk (aHR, 0.33 [95% CI, 0.14-0.86]). CONCLUSIONS: Among individuals with nonproteinuric CKD, after accounting for time-updated use, RASIs are associated with fewer cardiovascular events and a lower mortality risk compared with other antihypertensive medications. Patients with nonproteinuric CKD may benefit from prioritizing RASIs for hypertension management.

Cardiovascular and Kidney Outcomes of Non-Diabetic CKD by Albuminuria Severity: Findings From the CRIC Study.

RATIONALE & OBJECTIVE: The clinical trajectory of normoalbuminuric chronic kidney disease (CKD), particularly in the absence of diabetes, has not yet been well-studied. This study evaluated the association of kidney and cardiovascular outcomes with levels of albuminuria in a cohort of patients with non-diabetic CKD. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: 1,463 adults with non-diabetic CKD without known glomerulonephritis and diagnosed with hypertensive nephrosclerosis or unknown cause of CKD participating in the Chronic Renal Insufficiency Cohort (CRIC) Study. EXPOSURE: Albuminuria stage at study entry. OUTCOME: Primary outcome: Composite kidney (halving of eGFR, kidney transplantation, or dialysis), Secondary outcomes: (1) eGFR slope, (2) composite cardiovascular disease events (hospitalization for heart failure, myocardial infarction, stroke, or all-cause death), (3) all-cause death. ANALYTICAL APPROACH: Linear mixed effects and Cox proportional hazards regression analyses. RESULTS: Lower levels of albuminuria were associated with female sex and older age. For the primary outcome, compared with normoalbuminuria, those with moderate and severe albuminuria had higher rates of kidney outcomes (adjusted hazard ratio [aHR] 3.3, 95% CI 2.4-4.6; aHR 8.6, 95% CI 6.0-12.0) and cardiovascular outcomes (aHR 1.5, 95% CI 1.2-1.9; aHR 1.5, 95% CI 1.1-2.0). Those with normoalbuminuria (<30 mcg/mg; N=863) had a slower decline in eGFR (-0.46 mL/min/1.73m2/year), compared to those with moderate (30-300 mcg/mg, N=372; 1.41 mL/min/1.73m2/ year), or severe albuminuria (>300 mcg/mg, N=274; 2.63 mL/min/1.73m2/year). Kidney outcomes, in adjusted analyses, occurred, on average, sooner among those with moderate (8.6 years) and severe (7.3 years) albuminuria compared to those with normoalbuminuria (9.3 years), whereas the average times to cardiovascular outcomes were similar across albuminuria groups (8.2, 8.1, and 8.6 years, respectively). LIMITATIONS: Self-report of CKD etiology without confirmatory kidney biopsies. Residual confounding. CONCLUSIONS: Participants with normoalbuminuric non-diabetic CKD experienced substantially slower CKD progression but only modestly lower cardiovascular risk than those with high levels of albuminuria. These findings inform the design of future studies investigating interventions among individuals with lower levels of albuminuria.

A stem cell roadmap of ribosome heterogeneity reveals a function for RPL10A in mesoderm production.

Recent findings suggest that the ribosome itself modulates gene expression. However, whether ribosomes change composition across cell types or control cell fate remains unknown. Here, employing quantitative mass spectrometry during human embryonic stem cell differentiation, we identify dozens of ribosome composition changes underlying cell fate specification. We observe upregulation of RPL10A/uL1-containing ribosomes in the primitive streak followed by progressive decreases during mesoderm differentiation. An Rpl10a loss-of-function allele in mice causes striking early mesodermal phenotypes, including posterior trunk truncations, and inhibits paraxial mesoderm production in culture. Ribosome profiling in Rpl10a loss-of-function mice reveals decreased translation of mesoderm regulators, including Wnt pathway mRNAs, which are also enriched on RPL10A/uL1-containing ribosomes. We further show that RPL10A/uL1 regulates canonical and non-canonical Wnt signaling during stem cell differentiation and in the developing embryo. These findings reveal unexpected ribosome composition modularity that controls differentiation and development through the specialized translation of key signaling networks.

Systemic and mucosal IgA responses are variably induced in response to SARS-CoV-2 mRNA vaccination and are associated with protection against subsequent infection.

Although SARS-CoV-2 infects the upper respiratory tract, we know little about the amount, type, and kinetics of antibodies (Ab) generated in the oral cavity in response to COVID-19 vaccination. We collected serum and saliva samples from participants receiving two doses of mRNA COVID-19 vaccines and measured the level of anti-SARS-CoV-2 Ab. We detected anti-Spike and anti-Receptor Binding Domain (RBD) IgG and IgA, as well as anti-Spike/RBD associated secretory component in the saliva of most participants after dose 1. Administration of a second dose of mRNA boosted the IgG but not the IgA response, with only 30% of participants remaining positive for IgA at this timepoint. At 6 months post-dose 2, these participants exhibited diminished anti-Spike/RBD IgG levels, although secretory component-associated anti-Spike Ab were more stable. Examining two prospective cohorts we found that participants who experienced breakthrough infections with SARS-CoV-2 variants had lower levels of vaccine-induced serum anti-Spike/RBD IgA at 2-4 weeks post-dose 2 compared to participants who did not experience an infection, whereas IgG levels were comparable between groups. These data suggest that COVID-19 vaccines that elicit a durable IgA response may have utility in preventing infection. Our study finds that a local secretory component-associated IgA response is induced by COVID-19 mRNA vaccination that persists in some, but not all participants. The serum and saliva IgA response modestly correlate at 2-4 weeks post-dose 2. Of note, levels of anti-Spike serum IgA (but not IgG) at this timepoint are lower in participants who subsequently become infected with SARS-CoV-2. As new surges of SARS-CoV-2 variants arise, developing COVID-19 booster shots that provoke high levels of IgA has the potential to reduce person-to-person transmission.

Early Onset Severe Hypertensive Disease in Pregnancy and Screening for Antiphospholipid Syndrome.

Objective Although preterm delivery (PTD) before 34 weeks for severe hypertensive disease is a diagnostic criterion for antiphospholipid syndrome (APS), there is no consensus regarding testing for antiphospholipid antibodies (aPL) in this setting. We aim to describe the frequency of and the characteristics associated with inpatient aPL testing in this population. Study Design In this retrospective study of PTD before 34 weeks for severe hypertensive disease, charts were reviewed for aPL testing, gestational age at delivery, fetal complications, and severity of maternal disease. Wilcoxon rank-sum test, Fisher's exact, and chi-squared tests were used for analyses of continuous and categorical variables, and multivariate logistic regression for adjusted odds ratios. Results Among 133 cases, 14.3% had APS screening via aPL testing. Screened patients delivered earlier than unscreened patients (28.9 vs. 31.7 weeks, p <0.001). Each additional week of gestation was associated with a 39% decrease in the odds of screening (95% confidence interval: 0.43-0.85). There were no other differences between the groups. Conclusion APS screening after PTD for severe hypertensive disease is uncommon but more likely with earlier PTD. Despite conflicting recommendations from professional organizations, prior studies demonstrate contraceptive, obstetrical, and long-term risks associated with APS, suggesting that we should increase our screening efforts.

Obstructive Sleep Apnea, Hypertension, and Cardiovascular Risk: Epidemiology, Pathophysiology, and Management.

PURPOSE OF REVIEW: Given the rising prevalence of obstructive sleep apnea (OSA), we aimed to review the epidemiologic and pathophysiologic relationship of OSA, hypertension, and cardiovascular disease, and to summarize recent advances in the treatment of OSA. RECENT FINDINGS: OSA is associated with an elevated risk of hypertension and cardiovascular disease. Several pathophysiologic factors contribute to the relationship between OSA and vascular risk, including neurohormonal dysregulation, endothelial dysfunction, and inflammation. While CPAP reduces blood pressure, it has not been demonstrated to reduce cardiovascular risk. The combination of CPAP and weight loss has a synergistic effect on blood pressure and several metabolic parameters. Adherence to CPAP is poor across studies, potentially contributing to the attenuation of perceived cardiovascular benefit from CPAP therapy. A greater emphasis on adherence to CPAP and the combination of CPAP and weight loss are central to reducing cardiovascular risk among individuals with OSA.

Fetal Congenital Pulmonary Airway Malformation: The Role of an Objective Measurement of Cardiomediastinal Shift.

OBJECTIVE: To examine the relationship between cardiomediastinal shift angle (CMSA) and adverse perinatal outcomes and hydrops in cases of congenital pulmonary airway malformation (CPAM). STUDY DESIGN: This retrospective study evaluated CPAM cases referred to our institution from 2008 to 2015. The primary outcome was a composite score for adverse perinatal outcome. CMSA was measured for each case and evaluated for its association with the primary outcome. The prediction accuracy of CMSA for adverse perinatal outcome was assessed using receiver operator characteristic (ROC) curves. RESULTS: Eighteen (21.2%) of the 85 cases experienced an adverse perinatal outcome. Increases in CMSA were associated with adverse perinatal outcomes and hydrops in bivariate analyses. Adjusted analyses found each 10-degree increase in CMSA to be associated with increased odds of an adverse perinatal outcome (adjusted odds ratio [aOR] 2.2, 95% confidence interval [CI]: 1.4-3.3) and hydrops (aOR 3.0, 95% CI: 1.5-6.1). CMSA performed well and was comparable to CPAM volume ratio in predicting adverse perinatal outcomes (area under the curve 0.81 and 0.84, respectively). CONCLUSION: We describe a novel measurement of mediastinal shift in cases of CPAM and its relationship with adverse perinatal outcomes and hydrops. These findings may shape the evaluation and management of CPAMs, improve our understanding of their prognosis, and influence patient counseling.

Gender Differences in Academic Rank and NIH Funding among Academic Maternal-Fetal Medicine Physicians in the United States.

OBJECTIVE: This article evaluates gender differences in academic rank and National Institutes of Health (NIH) funding among academic maternal-fetal medicine (MFM) physicians. STUDY DESIGN: This was a cross-sectional study of board-certified academic MFM physicians. Physicians were identified in July 2017 from the MFM fellowship Web sites. Academic rank and receipt of any NIH funding were compared by gender. Data on potential confounders were collected, including years since board certification, region of practice, additional degrees, number of publications, and h-index. RESULTS: We identified 659 MFM physicians at 72 institutions, 312 (47.3%) male and 347 (52.7%) female. There were 246 (37.3%) full, 163 (24.7%) associate, and 250 (37.9%) assistant professors. Among the 154 (23.4%) MFM physicians with NIH funding, 89 (57.8%) were male and 65 (42.2%) were female (p = 0.003). Adjusting for potential confounders, male MFM physicians were twice as likely to hold a higher academic rank than female MFM physicians (adjusted odds ratio [aOR], 2.04 [95% confidence interval, 1.39-2.94], p < 0.001). There was no difference in NIH funding between male and female MFM physicians (aOR, 1.23 [0.79-1.92], p = 0.36). CONCLUSION: Compared with female academic MFM physicians, male academic MFM physicians were twice as likely to hold a higher academic rank but were no more likely to receive NIH funding.

Sleep duration and 24-hour ambulatory blood pressure in adults not on antihypertensive medications.

Short sleep duration has been widely linked to increased cardiovascular morbidity and mortality. We performed a post hoc analysis of 24-hour ambulatory blood pressure monitoring (ABPM) in the Lifestyle Modification in Blood Pressure Lowering Study (LIMBS) and Penn Icelandic Sleep Apnea (PISA) Study. The 24-hour mean systolic blood pressure (BP) was 12.7 mm Hg higher in LIMBS (P < 0.001; n = 66) and 4.7 mm Hg higher in PISA (P = 0.005; n = 153) among participants with shorter sleep duration (less than 7 hours) compared to those with longer sleep duration (at least 7 hours). In multivariable adjusted models, shorter sleep duration was strongly associated with higher systolic BP on 24-hour ABPM, independent of nocturnal BP and in-office BP. There was no effect modification by obstructive sleep apnea. Adults with shorter sleep duration may benefit from screening with 24-hour ABPM to promote earlier detection of hypertension and potentially mitigate their increased risk for future cardiovascular disease.

Impact of maternal knowledge of recommended weight gain in pregnancy on gestational weight gain.

BACKGROUND: Obesity is prevalent among reproductive-aged women and is associated with increased obstetric complications. Weight gain recommendations exist; however, knowledge of these recommendations is low, and few women gain appropriate weight during their pregnancies. Excessive gestational weight gain is common and is associated with adverse outcomes. Little is known about the relationship between knowledge of gestational weight gain recommendations and actual weight gain. OBJECTIVES: Our objectives were to assess knowledge of weight gain recommendations in pregnancy and to determine its association with actual weight gain among women who seek care at an urban, regional perinatal center. We hypothesize that low levels of knowledge will predict inappropriate weight gain in this population. STUDY DESIGN: This is a cross-sectional study with linked chart review of 338 women who sought routine obstetric ultrasound scans at an urban, regional perinatal center that serves a largely low-income population of predominately black women. Descriptive statistics, chi-square test, and analysis of variance were performed. RESULTS: This population has low rates of accurate knowledge of weight gain recommendations in pregnancy (27%) and low rates of appropriate gestational weight gain (30%). Inappropriate gestational weight gain was highest among women who were obese before pregnancy. Accurate knowledge of gestational weight gain recommendations was associated with appropriate weight gain in pregnancy (P = .02), as was prepregnancy weight category (P = .004) and correct identification of prepregnancy weight category (P = .005). CONCLUSION: These findings support the need for improvements in educational efforts about weight gain in pregnancy for high-risk, low-income women in an urban setting, which may improve compliance with the recommendations.