Faculty Bibliography

IMPORTANCE:Hypertension is a leading cause of cardiovascular disease in adults; preclinical associations between hypertension and cardiovascular disease are seen in childhood. Nicotine is a known toxin, but its association with pediatric hypertension is unclear. OBJECTIVE:To test the hypothesis that tobacco exposure is associated with the presence of elevated blood pressure in US children and adolescents and that this association is dose dependent. DESIGN, SETTING, AND PARTICIPANTS:This cross-sectional study used data from the 2007 to 2016 National Health and Nutrition Examination Survey (NHANES), a population-based nationally representative sample of US children and adolescents. Children were eligible if they were aged 8 to 19 years at the time of participation in the main NHANES study. Exclusion criteria included those of the main NHANES study, inability to complete testing, or missing questionnaires. Of the 10 143 participants in NHANES aged 8 to 19 during the study years, 8520 were included in the analysis. Analysis was conducted from October 12, 2019, to July 9, 2020. EXPOSURES:Tobacco exposure, defined as serum cotinine levels greater than 0.05 µg/L, or reporting living with a smoker or smoking themselves. MAIN OUTCOMES AND MEASURES:Elevated blood pressure, classified as greater than 90% for a child's age, sex, and height according to the 2017 American Academy of Pediatrics Clinical Practice Guidelines. The a priori hypothesis that there is a positive association between tobacco exposure and elevated blood pressure in the study population was tested. Analysis included logistic regression with adjustment for possible confounders. Subgroup and sensitivity analyses were conducted. RESULTS:A total of 8520 children were included in the analysis, representing 41 million US children. The mean (SD) age of the participants was 13.1 (0.05) years, 51% (95% CI, 49%-52%) were male, and 58% (95% CI, 54%-62%) were non-Hispanic White individuals. Participants with any tobacco smoke exposure were more likely than those without exposure to be older (mean [SD] age, 13.3 [0.07] years vs 12.8 [0.06] years), male (53% [95% CI, 51%-55%] vs 49% [95% CI, 47%-50%]), and non-Hispanic Black individuals (19% [95% CI, 16%-22%] vs 10% [95% CI, 8%-12%]). The odds of having elevated blood pressure was 1.31 (95% CI, 1.06-1.61) for any tobacco exposure after adjustment; odds were similar across subgroups and remained significant in multiple sensitivity analyses. CONCLUSIONS AND RELEVANCE:This study suggests that tobacco exposure is associated with elevated blood pressure in US children and adolescents. This modifiable risk factor represents a target for further research into reducing hypertension in children and adolescents.

AIMS/HYPOTHESIS:and/or n-3 fatty acid supplementation vs placebo on 5 year changes in serum inflammatory and cardiac biomarkers in adults with type 2 diabetes. METHODS:(2000 IU/day) vs placebo and n-3 fatty acids (eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA]; 1 g/day) vs placebo in a 2 × 2 factorial design. Participants, examiners, and researchers assessing outcomes were blinded to intervention assignment. We measured serum IL-6, high-sensitivity C-reactive protein (hsCRP) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) at baseline and after 2 and 5 years. RESULTS:had a 1.24-fold greater increase in NT-proBNP over 5 years (95% CI 1.09, 1.41; p = 0.003), while IL-6 and hsCRP did not have a significant difference in change. Comparing n-3 fatty acids with placebo, there was no significant difference in change in IL-6, hsCRP or NT-proBNP. No heterogeneity was observed in subgroup analyses accounting for baseline eGFR, urine albumin to creatinine ratio, initial biomarker concentration, 25-hydroxyvitamin D level or EPA+DHA index. CONCLUSIONS/INTERPRETATION:or n-3 fatty acids did not reduce IL-6, hsCRP or NT-proBNP over 5 years. TRIAL REGISTRATION:ClinicalTrials.gov NCT01684722 FUNDING: The study was funded by grant R01DK088762 from the National Institute of Diabetes and Digestive and Kidney Diseases. Graphical abstract.

INTRODUCTION/BACKGROUND:Black men are over-represented in the end stage kidney disease population and are at disproportionate risk of unfavorable outcomes. There is a paucity of investigation to elucidate the mediators of this risk. This study attempts to identify residential community attributes as a possible contributor. METHODS:A post-hoc analysis of prospectively collected data from a cohort of Black men enrolled in the US Dialysis Outcomes and Practice Patterns Study (DOPPS), 2010--2015, linked to the American Community Survey, by dialysis facility zip codes was undertaken. The exposure variable was the dialysis facility community composition as defined by percent Black residents. Negative binomial regression was used to estimate incidence rate ratio (IRR) of hospitalization (first outcome) for Black men in crude and adjusted models. Similarly, Cox proportional hazards modeling was used to estimate mortality (second outcome) for Black men by type of community. RESULTS:A total of 702 Black men receiving chronic hemodialysis were included in the study. Black men receiving hemodialysis in communities with greater proportions of Black residents had lower Charlson scores and fewer comorbidities, but a higher rate of hypertension. They had equivalent adherence to dialysis treatments, but a lower rate of arteriovenous fistula use and fewer dialysis minutes prescribed. Black men receiving dialysis in communities with a greater proportion of Black residents (per 10% increase) had higher adjusted hospitalization rates (IRR 1.09, 95% confidence interval [CI] 1.00-1.19) and mortality (hazard ratio [HR] 1.29, 95% CI 1.05-1.59). CONCLUSIONS:This study supports the unique role of residential community as a risk factor for Black men with end stage kidney disease, showing higher hospitalization and mortality in those treating in Black versus non-Black communities, despite equivalent adherence and fewer comorbidities.

RATIONALE & OBJECTIVE:Underlying kidney disease is an emerging risk factor for more severe coronavirus disease 2019 (COVID-19) illness. We examined the clinical courses of critically ill COVID-19 patients with and without pre-existing chronic kidney disease (CKD) and investigated the association between the degree of underlying kidney disease and in-hospital outcomes. STUDY DESIGN:Retrospective cohort study. SETTINGS & PARTICIPANTS:4,264 critically ill patients with COVID-19 (143 patients with pre-existing kidney failure receiving maintenance dialysis; 521 patients with pre-existing non-dialysis-dependent CKD; and 3,600 patients without pre-existing CKD) admitted to intensive care units (ICUs) at 68 hospitals across the United States. PREDICTOR(S):Presence (vs absence) of pre-existing kidney disease. OUTCOME(S):In-hospital mortality (primary); respiratory failure, shock, ventricular arrhythmia/cardiac arrest, thromboembolic events, major bleeds, and acute liver injury (secondary). ANALYTICAL APPROACH:We used standardized differences to compare patient characteristics (values>0.10 indicate a meaningful difference between groups) and multivariable-adjusted Fine and Gray survival models to examine outcome associations. RESULTS:Dialysis patients had a shorter time from symptom onset to ICU admission compared to other groups (median of 4 [IQR, 2-9] days for maintenance dialysis patients; 7 [IQR, 3-10] days for non-dialysis-dependent CKD patients; and 7 [IQR, 4-10] days for patients without pre-existing CKD). More dialysis patients (25%) reported altered mental status than those with non-dialysis-dependent CKD (20%; standardized difference=0.12) and those without pre-existing CKD (12%; standardized difference=0.36). Half of dialysis and non-dialysis-dependent CKD patients died within 28 days of ICU admission versus 35% of patients without pre-existing CKD. Compared to patients without pre-existing CKD, dialysis patients had higher risk for 28-day in-hospital death (adjusted HR, 1.41 [95% CI, 1.09-1.81]), while patients with non-dialysis-dependent CKD had an intermediate risk (adjusted HR, 1.25 [95% CI, 1.08-1.44]). LIMITATIONS:Potential residual confounding. CONCLUSIONS:Findings highlight the high mortality of individuals with underlying kidney disease and severe COVID-19, underscoring the importance of identifying safe and effective COVID-19 therapies in this vulnerable population.

BACKGROUND:AKI is a common sequela of coronavirus disease 2019 (COVID-19). However, few studies have focused on AKI treated with RRT (AKI-RRT). METHODS:We conducted a multicenter cohort study of 3099 critically ill adults with COVID-19 admitted to intensive care units (ICUs) at 67 hospitals across the United States. We used multivariable logistic regression to identify patient-and hospital-level risk factors for AKI-RRT and to examine risk factors for 28-day mortality among such patients. RESULTS:A total of 637 of 3099 patients (20.6%) developed AKI-RRT within 14 days of ICU admission, 350 of whom (54.9%) died within 28 days of ICU admission. Patient-level risk factors for AKI-RRT included CKD, men, non-White race, hypertension, diabetes mellitus, higher body mass index, higher d-dimer, and greater severity of hypoxemia on ICU admission. Predictors of 28-day mortality in patients with AKI-RRT were older age, severe oliguria, and admission to a hospital with fewer ICU beds or one with greater regional density of COVID-19. At the end of a median follow-up of 17 days (range, 1-123 days), 403 of the 637 patients (63.3%) with AKI-RRT had died, 216 (33.9%) were discharged, and 18 (2.8%) remained hospitalized. Of the 216 patients discharged, 73 (33.8%) remained RRT dependent at discharge, and 39 (18.1%) remained RRT dependent 60 days after ICU admission. CONCLUSIONS:AKI-RRT is common among critically ill patients with COVID-19 and is associated with a hospital mortality rate of >60%. Among those who survive to discharge, one in three still depends on RRT at discharge, and one in six remains RRT dependent 60 days after ICU admission.

Metabolic acidosis is fairly common in patients with chronic kidney disease (CKD). The prevalence of metabolic acidosis increases with worsening kidney function and is observed in ∼40% of those with stage 4 CKD. For the past 2 decades, clinical practice guidelines have suggested treatment of metabolic acidosis to counterbalance adverse effects of metabolic acidosis on bone and muscle. Studies in animal models of CKD also demonstrated that metabolic acidosis causes kidney fibrosis. During the past decade, results from observational studies identified associations between metabolic acidosis and adverse kidney outcomes, and results from interventional studies support the hypothesis that treating metabolic acidosis with sodium bicarbonate preserves kidney function. However, convincing data from large-scale, double-blinded, placebo-controlled, randomized trials have been lacking. This review discusses findings from recent interventional trials of alkali therapy in CKD and new findings linking metabolic acidosis with cardiovascular disease in adults and CKD progression in children. Finally, a novel agent that treats metabolic acidosis in patients with CKD by binding hydrochloric acid in the gastrointestinal tract is discussed.

RATIONALE & OBJECTIVE:Community racial composition has been shown to be associated with mortality in patients receiving maintenenance dialysis. It is unclear whether living in communities with predominantly Black residents is also associated with risk for hospitalization among patients receiving hemodialysis. STUDY DESIGN:Retrospective analysis of prospectively collected data from a cohort of patients receiving hemodialysis. SETTING & PARTICIPANTS:4,567 patients treated in 154 dialysis facilities located in 127 unique zip codes and enrolled in US Dialysis Outcomes and Practice Patterns Study (DOPPS) phases 4 to 5 (2010-2015). EXPOSURE:Tertile of percentage of Black residents within zip code of patients' dialysis facility, defined through a link to the American Community Survey. OUTCOME:Rate of hospitalizations during the study period. ANALYTIC APPROACH:/Fisher exact tests. Negative binomial regression was used to estimate the incidence rate ratio for hospitalizations between these communities, with and without adjustment for potential confounding variables. RESULTS:Mean age of study patients was 62.7 years. 53% were White, 27% were Black, and 45% were women. Median and threshold percentages of Black residents in zip codes in which dialysis facilities were located were 34.2% and≥14.4% for tertile 3 and 1.0% and≤1.8% for tertile 1, respectively. Compared with those in tertile 1 facilities, patients in tertile 3 facilities were more likely to be younger, be Black, live in urban communities with lower socioeconomic status, have a catheter as vascular access, and have fewer comorbid conditions. Patients dialyzing in communities with the highest tertile of Black residents experienced a higher adjusted rate of hospitalization (adjusted incidence rate ratio, 1.32; 95% CI, 1.12-1.56) compared with those treated in communities within the lowest tertile. LIMITATIONS:Potential residual confounding. CONCLUSIONS:The risk for hospitalization for patients receiving maintenance dialysis is higher among those treated in communities with a higher percentage of Black residents after adjustment for dialysis care, patient demographics, and comorbid conditions. Understanding the cause of this association should be a priority of future investigation.

IMPORTANCE:The US is currently an epicenter of the coronavirus disease 2019 (COVID-19) pandemic, yet few national data are available on patient characteristics, treatment, and outcomes of critical illness from COVID-19. OBJECTIVES:To assess factors associated with death and to examine interhospital variation in treatment and outcomes for patients with COVID-19. DESIGN, SETTING, AND PARTICIPANTS:This multicenter cohort study assessed 2215 adults with laboratory-confirmed COVID-19 who were admitted to intensive care units (ICUs) at 65 hospitals across the US from March 4 to April 4, 2020. EXPOSURES:Patient-level data, including demographics, comorbidities, and organ dysfunction, and hospital characteristics, including number of ICU beds. MAIN OUTCOMES AND MEASURES:The primary outcome was 28-day in-hospital mortality. Multilevel logistic regression was used to evaluate factors associated with death and to examine interhospital variation in treatment and outcomes. RESULTS:A total of 2215 patients (mean [SD] age, 60.5 [14.5] years; 1436 [64.8%] male; 1738 [78.5%] with at least 1 chronic comorbidity) were included in the study. At 28 days after ICU admission, 784 patients (35.4%) had died, 824 (37.2%) were discharged, and 607 (27.4%) remained hospitalized. At the end of study follow-up (median, 16 days; interquartile range, 8-28 days), 875 patients (39.5%) had died, 1203 (54.3%) were discharged, and 137 (6.2%) remained hospitalized. Factors independently associated with death included older age (≥80 vs <40 years of age: odds ratio [OR], 11.15; 95% CI, 6.19-20.06), male sex (OR, 1.50; 95% CI, 1.19-1.90), higher body mass index (≥40 vs <25: OR, 1.51; 95% CI, 1.01-2.25), coronary artery disease (OR, 1.47; 95% CI, 1.07-2.02), active cancer (OR, 2.15; 95% CI, 1.35-3.43), and the presence of hypoxemia (Pao2:Fio2<100 vs ≥300 mm Hg: OR, 2.94; 95% CI, 2.11-4.08), liver dysfunction (liver Sequential Organ Failure Assessment score of 2-4 vs 0: OR, 2.61; 95% CI, 1.30-5.25), and kidney dysfunction (renal Sequential Organ Failure Assessment score of 4 vs 0: OR, 2.43; 95% CI, 1.46-4.05) at ICU admission. Patients admitted to hospitals with fewer ICU beds had a higher risk of death (<50 vs ≥100 ICU beds: OR, 3.28; 95% CI, 2.16-4.99). Hospitals varied considerably in the risk-adjusted proportion of patients who died (range, 6.6%-80.8%) and in the percentage of patients who received hydroxychloroquine, tocilizumab, and other treatments and supportive therapies. CONCLUSIONS AND RELEVANCE:This study identified demographic, clinical, and hospital-level risk factors that may be associated with death in critically ill patients with COVID-19 and can facilitate the identification of medications and supportive therapies to improve outcomes.