Hormonal Contraception and Risk of Cardiometabolic Disease in Women with HIV.

Objective: We sought to determine the association of hormonal contraception (HC) and cardiometabolic outcomes among women with human immunodeficiency virus (HIV). Methods: We included women with HIV aged 18-45 years in clinical care in the Southeastern United States between 1998 and 2018. Oral and injectable HC use was captured from medication records. Our outcomes included incident cardiovascular/thrombotic disease (CVD) (atherosclerosis, hypertension, cerebrovascular disease, thrombosis, and heart failure) and incident metabolic disorders (diabetes, dyslipidemia, obesity, and non-alcoholic steatohepatitis). We excluded women with prevalent conditions. We used multivariable marginal structural models to examine time-varying current and cumulative HC use and cardiometabolic outcomes in separate analyses, adjusting for age, race, smoking, time-varying comorbidities, CD4 cell count, HIV RNA, and antiretroviral use. Women with HC exposure were compared with women without HC exposure. Results: Among the 710 women included, 201 women (28%) used HC. CVD analyses included 603 women without prevalent CVD and 93 incident events; metabolic analyses included 365 women without prevalent metabolic disease and 150 incident events. Current and cumulative oral HC use was associated with increased odds of CVD, though this was not statistically significant (adjusted odds ratio [aOR] = 2.08, [95% confidence interval (CI): 0.80-5.43] and aOR = 1.24 [95% CI: 0.96-1.60] per year of use, respectively). Oral HC was not associated with risk of incident metabolic disorders. Depot medroxyprogesterone acetate (DMPA) was not associated with risk of incident CVD. Current and cumulative DMPA use was significantly associated with decreased odds of incident metabolic disorders (aOR = 0.48 [95% CI: 0.23, 1.00] and aOR = 0.65 [95% CI: 0.42-1.00] per year of use, respectively). Conclusion: Our results suggest that cardiovascular risk should be considered when selecting contraception for women with HIV.

Relationships Between Patient Race and Residential Race Context With Missed Human Immunodeficiency Virus Care Visits in the United States, 2010-2015.

BACKGROUND: Racial inequities exist in retention in human immunodeficiency virus (HIV) care and multilevel analyses are needed to contextualize and address these differences. Leveraging data from a multisite clinical cohort of people with HIV (PWH), we assessed the relationships between patient race and residential characteristics with missed HIV care visits. METHODS: Medical record and patient-reported outcome (PRO; including mental health and substance-use measures) data were drawn from 7 participating Center for AIDS Research Network of Integrated Clinical Systems (CNICS) sites including N = 20 807 PWH from January 2010 through December 2015. Generalized estimating equations were used to account for nesting within individuals and within census tracts in multivariable models assessing the relationship between race and missed HIV care visits, controlling for individual demographic and health characteristics and census tract characteristics. RESULTS: Black PWH resided in more disadvantaged census tracts, on average. Black PWH residing in census tracts with higher proportion of Black residents were more likely to miss an HIV care visit. Non-Black PWH were less likely to miss a visit regardless of where they lived. These relationships were attenuated when PRO data were included. CONCLUSIONS: Residential racial segregation and disadvantage may create inequities between Black PWH and non-Black PWH in retention in HIV care. Multilevel approaches are needed to retain PWH in HIV care, accounting for community, healthcare setting, and individual needs and resources.

Low Rates of Contraception Use in Women With Human Immunodeficiency Virus.

Background: Women with human immunodeficiency virus (WWH) have low rates of hormonal or long-acting contraceptive use. Few studies have described contraception use among WWH over time. Methods: We examined contraception (including all forms of hormonal contraception, intrauterine devices, and bilateral tubal ligations) use among cisgender women aged 18-45 years in care at Vanderbilt's human immunodeficiency virus (HIV) clinic in Nashville, Tennessee, from 1998 through 2018. Weighted annual prevalence estimates of contraception use were described. Cox proportional hazards models examined factors associated with incident contraception use and pregnancy. Results: Of the 737 women included, median age at clinic entry was 31 years; average follow-up was 4.1 years. At clinic entry, 47 (6%) women were on contraception and 164 (22%) were pregnant. The median annual percentage of time on any contraception use among nonpregnant women was 31.7% and remained stable throughout the study period. Younger age was associated with increased risk of pregnancy and contraceptive use. Psychiatric comorbidity decreased likelihood of contraception (adjusted hazard ratio [aHR], 0.52 [95% CI {confidence interval}, .29-.93]) and increased likelihood of pregnancy (aHR, 1.77 [95% CI, .97-3.25]). While not associated with contraceptive use, more recent year of clinic entry was associated with higher pregnancy risk. Race, substance use, CD4 cell count, HIV RNA, smoking, and antiretroviral therapy were not associated with contraception use nor pregnancy. Conclusions: Most WWH did not use contraception at baseline nor during follow-up. Likelihood of pregnancy increased with recent clinic entry while contraception use remained stable over time. Continued efforts to ensure access to effective contraception options are needed in HIV clinics.

CD4/CD8 Ratio and Cancer Risk Among Adults With HIV.

BACKGROUND: Independent of CD4 cell count, a low CD4/CD8 ratio in people with HIV (PWH) is associated with deleterious immune senescence, activation, and inflammation, which may contribute to carcinogenesis and excess cancer risk. We examined whether low CD4/CD8 ratios predicted cancer among PWH in the United States and Canada. METHODS: We examined all cancer-free PWH with 1 or more CD4/CD8 values from North American AIDS Cohort Collaboration on Research and Design observational cohorts with validated cancer diagnoses between 1998 and 2016. We evaluated the association between time-lagged CD4/CD8 ratio and risk of specific cancers in multivariable, time-updated Cox proportional hazard models using restricted cubic spines. Models were adjusted for age, sex, race and ethnicity, hepatitis C virus, and time-updated CD4 cell count, HIV RNA, and history of AIDS-defining illness. RESULTS: Among 83 893 PWH, there were 5628 incident cancers, including lung cancer (n = 755), Kaposi sarcoma (n = 501), non-Hodgkin lymphoma (n = 497), and anal cancer (n = 439). The median age at cohort entry was 43 years. The overall median 6-month lagged CD4/CD8 ratio was 0.52 (interquartile range = 0.30-0.82). Compared with a 6-month lagged CD4/CD8 of 0.80, a CD4/CD8 of 0.30 was associated with increased risk of any incident cancer (adjusted hazard ratio = 1.24 [95% confidence interval = 1.14 to 1.35]). The CD4/CD8 ratio was also inversely associated with non-Hodgkin lymphoma, Kaposi sarcoma, lung cancer, anal cancer, and colorectal cancer in adjusted analyses (all 2-sided P < .05). Results were similar using 12-, 18-, and 24-month lagged CD4/CD8 values. CONCLUSIONS: A low CD4/CD8 ratio up to 24 months before cancer diagnosis was independently associated with increased cancer risk in PWH and may serve as a clinical biomarker.

Risk of Incident Diabetes Mellitus, Weight Gain, and Their Relationships With Integrase Inhibitor-Based Initial Antiretroviral Therapy Among Persons With Human Immunodeficiency Virus in the United States and Canada.

BACKGROUND: Integrase strand transfer inhibitor (INSTI)-based combination antiretroviral therapy (cART) is associated with greater weight gain among persons with human immunodeficiency virus (HIV), though metabolic consequences, such as diabetes mellitus (DM), are unclear. We examined the impact of initial cART regimen and weight on incident DM in a large North American HIV cohort (NA-ACCORD). METHODS: cART-naive adults (≥18 years) initiating INSTI-, protease inhibitor (PI)-, or nonnucleoside reverse transcriptase inhibitor (NNRTI)-based regimens from January 2007 through December 2017 who had weight measured 12 (±6) months after treatment initiation contributed time until clinical DM, virologic failure, cART regimen switch, administrative close, death, or loss to follow-up. Multivariable Cox regression yielded adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for incident DM by cART class. Mediation analyses, with 12-month weight as mediator, similarly adjusted for all covariates. RESULTS: Among 22 884 eligible individuals, 47% started NNRTI-, 30% PI-, and 23% INSTI-based cART with median follow-up of 3.0, 2.3, and 1.6 years, respectively. Overall, 722 (3%) developed DM. Persons starting INSTIs vs NNRTIs had incident DM risk (HR, 1.17 [95% CI, .92-1.48]), similar to PI vs NNRTI initiators (HR, 1.27 [95% CI, 1.07-1.51]). This effect was most pronounced for raltegravir (HR, 1.42 [95% CI, 1.06-1.91]) vs NNRTI initiators. The INSTI-DM association was attenuated (HR, 1.03 [95% CI, .71-1.49] vs NNRTIs) when accounting for 12-month weight. CONCLUSIONS: Initiating first cART regimens with INSTIs or PIs vs NNRTIs may confer greater risk of DM, likely mediated through weight gain.

The Partnership to Improve Diabetes Education Trial: a Cluster Randomized Trial Addressing Health Communication in Diabetes Care.

BACKGROUND: Effective type 2 diabetes care remains a challenge for patients including those receiving primary care in safety net settings. OBJECTIVE: The Partnership to Improve Diabetes Education (PRIDE) trial team and leaders from a regional department of health evaluated approaches to improve care for vulnerable patients. DESIGN: Cluster randomized controlled trial. PATIENTS: Adults with uncontrolled type 2 diabetes seeking care across 10 unblinded, randomly assigned safety net clinics in Middle TN. INTERVENTIONS: A literacy-sensitive, provider-focused, health communication intervention (PRIDE; 5 clinics) vs. standard diabetes education (5 clinics). MAIN MEASURES: Participant-level primary outcome was glycemic control [A1c] at 12 months. Secondary outcomes included select health behaviors and psychosocial aspects of care at 12 and 24 months. Adjusted mixed effects regression models were used to examine the comparative effectiveness of each approach to care. KEY RESULTS: Of 410 patients enrolled, 364 (89%) were included in analyses. Median age was 51 years; Black and Hispanic patients represented 18% and 25%; 96% were uninsured, and 82% had low annual income level (< $20,000); adequate health literacy was seen in 83%, but numeracy deficits were common. At 12 months, significant within-group treatment effects occurred from baseline for both PRIDE and control sites: adjusted A1c (- 0.76 [95% CI, - 1.08 to - 0.44]; P < .001 vs - 0.54 [95% CI, - 0.86 to - 0.21]; P = .001), odds of poor eating (0.53 [95% CI, 0.33-0.83]; P = .01 vs 0.42 [95% CI, 0.26-0.68]; P < .001), treatment satisfaction (3.93 [95% CI, 2.48-6.21]; P < .001 vs 3.04 [95% CI, 1.93-4.77]; P < .001), and self-efficacy (2.97 [95% CI, 1.89-4.67]; P < .001 vs 1.81 [95% CI, 1.1-2.84]; P = .01). No significant difference was observed between study arms in adjusted analyses. CONCLUSIONS: Both interventions improved the participant's A1c and behavioral outcomes. PRIDE was not more effective than standard education. Further research may elucidate the added value of a focused health communication program in this setting.

Insulin resistance is a significant determinant of sarcopenia in advanced kidney disease.

Maintenance hemodialysis (MHD) patients display significant nutritional abnormalities. Insulin is an anabolic hormone with direct effects on skeletal muscle (SM). We examined the anabolic actions of insulin, whole-body (WB), and SM protein turnover in 33 MHD patients and 17 participants without kidney disease using hyperinsulinemic-euglycemic-euaminoacidemic (dual) clamp. Gluteal muscle biopsies were obtained before and after the dual clamp. At baseline, WB protein synthesis and breakdown rates were similar in MHD patients. During dual clamp, controls had a higher increase in WB protein synthesis and a higher suppression of WB protein breakdown compared with MHD patients, resulting in statistically significantly more positive WB protein net balance [2.02 (interquartile range [IQR]: 1.79 and 2.36) vs. 1.68 (IQR: 1.46 and 1.91) mg·kg fat-free mass-1·min-1 for controls vs. for MHD patients, respectively, P < 0.001]. At baseline, SM protein synthesis and breakdown rates were higher in MHD patients versus controls, but SM net protein balance was similar between groups. During dual clamp, SM protein synthesis increased statistically significantly more in controls compared with MHD patients ( P = 0.03), whereas SM protein breakdown decreased comparably between groups. SM net protein balance was statistically significantly more positive in controls compared with MHD patients [67.3 (IQR: 46.4 and 97.1) vs. 15.4 (IQR: -83.7 and 64.7) µg·100 ml-1·min-1 for controls and MHD patients, respectively, P = 0.03]. Human SM biopsy showed a positive correlation between glucose and leucine disposal rates, phosphorylated AKT to AKT ratio, and muscle mitochondrial markers in controls but not in MHD patients. Diminished response to anabolic actions of insulin in the stimulated setting could lead to muscle wasting in MHD patients.

Chronic kidney disease alters lipid trafficking and inflammatory responses in macrophages: effects of liver X receptor agonism.

BACKGROUND: Our aim was to evaluate lipid trafficking and inflammatory response of macrophages exposed to lipoproteins from subjects with moderate to severe chronic kidney disease (CKD), and to investigate the potential benefits of activating cellular cholesterol transporters via liver X receptor (LXR) agonism. METHODS: LDL and HDL were isolated by sequential density gradient ultracentrifugation of plasma from patients with stage 3-4 CKD and individuals without kidney disease (HDLCKD and HDLCont, respectively). Uptake of LDL, cholesterol efflux to HDL, and cellular inflammatory responses were assessed in human THP-1 cells. HDL effects on inflammatory markers (MCP-1, TNF-α, IL-1ß), Toll-like receptors-2 (TLR-2) and - 4 (TLR-4), ATP-binding cassette class A transporter (ABCA1), NF-κB, extracellular signal regulated protein kinases 1/2 (ERK1/2) were assessed by RT-PCR and western blot before and after in vitro treatment with an LXR agonist. RESULTS: There was no difference in macrophage uptake of LDL isolated from CKD versus controls. By contrast, HDCKD was significantly less effective than HDLCont in accepting cholesterol from cholesterol-enriched macrophages (median 20.8% [IQR 16.1-23.7] vs control (26.5% [IQR 19.6-28.5]; p = 0.008). LXR agonist upregulated ABCA1 expression and increased cholesterol efflux to HDL of both normal and CKD subjects, although the latter continued to show lower efflux capacity. HDLCKD increased macrophage cytokine response (TNF-α, MCP-1, IL-1ß, and NF-κB) versus HDLCont. The heightened cytokine response to HDLCKD was further amplified in cells treated with LXR agonist. The LXR-augmentation of inflammation was associated with increased TLR-2 and TLR-4 and ERK1/2. CONCLUSIONS: Moderate to severe impairment in kidney function promotes foam cell formation that reflects impairment in cholesterol acceptor function of HDLCKD. Activation of cellular cholesterol transporters by LXR agonism improves but does not normalize efflux to HDLCKD. However, LXR agonism actually increases the pro-inflammatory effects of HDLCKD through activation of TLRs and ERK1/2 pathways.

Metabolic Effects of Diet and Exercise in Patients with Moderate to Severe CKD: A Randomized Clinical Trial.

CKD is steadily increasing along with obesity worldwide. Furthermore, obesity is a proinflammatory risk factor for progression of CKD and cardiovascular disease. We tested the hypothesis that implementation of caloric restriction and aerobic exercise is feasible and can improve the proinflammatory metabolic milieu in patients with moderate to severe CKD through a pilot, randomized, 2×2 factorial design trial. Of 122 participants consented, 111 were randomized to receive caloric restriction and aerobic exercise, caloric restriction alone, aerobic exercise alone, or usual care. Of those randomized, 42% were women, 25% were diabetic, and 91% were hypertensive; 104 started intervention, and 92 completed the 4-month study. Primary outcomes were a change from baseline in absolute fat mass, body weight, plasma F2-isoprostane concentrations, and peak oxygen uptake (VO2 peak). Compared with usual care, the combined intervention led to statistically significant decreases in body weight and body fat percentage. Caloric restriction alone also led to significant decreases in these measures, but aerobic exercise alone did not. The combined intervention and each independent intervention also led to significant decreases in F2-isoprostane and IL-6 concentrations. No intervention produced significant changes in VO2 peak, kidney function, or urine albumin-to-creatinine ratio. In conclusion, 4-month dietary calorie restriction and aerobic exercise had significant, albeit clinically modest, benefits on body weight, fat mass, and markers of oxidative stress and inflammatory response in patients with moderate to severe CKD. These results suggest healthy lifestyle interventions as a nonpharmacologic strategy to improve markers of metabolic health in these patients.

Evaluation of a Prediction Model for the Development of Atrial Fibrillation in a Repository of Electronic Medical Records.

IMPORTANCE: Atrial fibrillation (AF) contributes to substantial morbidity, mortality, and health care expenditures. Accurate prediction of incident AF would enhance AF management and potentially improve patient outcomes. OBJECTIVE: To validate the AF risk prediction model originally developed by the Cohorts for Heart and Aging Research in Genomic Epidemiology-Atrial Fibrillation (CHARGE-AF) investigators using a large repository of electronic medical records (EMRs). DESIGN, SETTING, AND PARTICIPANTS: In this prediction model study, deidentified EMRs of 33 494 individuals 40 years or older who were white or African American and had no history of AF were reviewed and analyzed. The participants were followed up in the internal medicine outpatient clinics at Vanderbilt University Medical Center for incident AF from December 31, 2005, until December 31, 2010. Adjusting for differences in baseline hazard, the CHARGE-AF Cox proportional hazards model regression coefficients were applied to the EMR cohort. A simple version of the model with no echocardiographic variables was also evaluated. Data were analyzed from October 31, 2013, to January 31, 2014. MAIN OUTCOMES AND MEASURES: Incident AF. Predictors in the model included age, race, height, weight, systolic and diastolic blood pressure, treatment for hypertension, smoking status, type 2 diabetes, heart failure, history of myocardial infarction, left ventricular hypertrophy, and PR interval. RESULTS: Among the 33 494 participants, the median age was 57 (interquartile range, 49-67) years; 57% of patients were women, 43% were men, 85.7% were white, and 14.3% were African American. During the mean (SD) follow-up of 4.8 (0.9) years, 2455 individuals (7.3%) developed AF. Both models had poor calibration in the EMR cohort, with underprediction of AF among low-risk individuals and overprediction of AF among high-risk individuals (10th and 90th percentiles for predicted probability of incident AF, 0.005 and 0.179, respectively). The full CHARGE-AF model had a C index of 0.708 (95% CI, 0.699-0.718) in our cohort. The simple model had similar discrimination (C index, 0.709; 95% CI, 0.699-0.718; P = .70 for difference between models). CONCLUSIONS AND RELEVANCE: Despite reasonable discrimination, the CHARGE-AF models showed poor calibration in this EMR cohort. This study highlights the difficulties of applying a risk model derived from prospective cohort studies to an EMR cohort and suggests that these AF risk prediction models be used with caution in the EMR setting. Future risk models may need to be developed and validated within EMR cohorts.

The Kidney Transplant Evaluation Process in the Elderly: Reasons for Being Turned down and Opportunities to Improve Cost-Effectiveness in a Single Center.

Background. The kidney transplant evaluation process for older candidates is complex due to the presence of multiple comorbid conditions. Methods. We retrospectively reviewed patients ≥60 years referred to our center for kidney transplantation over a 3-year period. Variables were collected to identify reasons for patients being turned down and to determine the number of unnecessary tests performed. Statistical analysis was performed to estimate the association between clinical predictors and listing status. Results. 345 patients were included in the statistical analysis. 31.6% of patients were turned down: 44% due to coronary artery disease (CAD), peripheral vascular disease (PVD), or both. After adjustment for patient demographics and comorbid conditions, history of CAD, PVD, or both (OR = 1.75, 95% CI (1.20, 2.56), p = 0.004), chronic obstructive pulmonary disease (OR = 8.75, 95% CI (2.81, 27.20), p = 0.0002), and cancer (OR 2.59, 95% CI (1.18, 5.67), p = 0.02) were associated with a higher risk of being turned down. 14.8% of patients underwent unnecessary basic testing and 9.6% underwent unnecessary supplementary testing with the charges over a 3-year period estimated at $304,337. Conclusion. A significant number of older candidates are deemed unacceptable for kidney transplantation with primary reasons cited as CAD and PVD. The overall burden of unnecessary testing is substantial and potentially avoidable.

Fibroblast growth factor 23 levels are elevated and associated with severe acute kidney injury and death following cardiac surgery.

Fibroblast growth factor 23 (FGF23) is elevated in chronic kidney disease and associated with increased mortality, but data on FGF23 in humans with acute kidney injury (AKI) are limited. Here we tested whether FGF23 levels rise early in the course of AKI following cardiac surgery and if higher postoperative FGF23 levels are independently associated with severe AKI and adverse outcomes. Plasma C-terminal FGF23 (cFGF23) levels were measured preoperatively, at the end of cardiopulmonary bypass, and on postoperative days 1 and 3 in 250 patients undergoing cardiac surgery. We also measured intact FGF23, parathyroid hormone, phosphate, and vitamin D metabolites in a subgroup of 18 patients with severe AKI and 18 matched non-AKI controls. Beginning at the end of cardiopulmonary bypass, cFGF23 levels were significantly and consistently higher in patients who developed AKI compared with those who did not. The early increase in cFGF23 predated changes in other mineral metabolites. The levels of intact FGF23 also increased in patients who developed severe AKI, but the magnitude was lower than cFGF23. In analyses adjusted for age, preoperative eGFR, and cardiopulmonary bypass time, higher cFGF23 levels at the end of cardiopulmonary bypass were significantly associated with greater risk of severe AKI and the need for renal replacement therapy or death. Thus, cFGF23 levels rise early in AKI following cardiac surgery and are independently associated with adverse postoperative outcomes.

Assessment of arterial stiffness using pulse wave velocity in tacrolimus users the first year post kidney transplantation: a prospective cohort study.

BACKGROUND: The leading cause of death in end stage renal disease is cardiovascular disease (CVD). Kidney transplantation is associated with improved survival over dialysis. We hypothesized that arterial stiffness, a marker of CVD, would improve in patients post kidney transplant, potentially explaining one mechanism of survival benefit from transplant. METHODS: After obtaining Institutional Review Board approval and informed consent, we performed a longitudinal prospective cohort study of 66 newly transplanted adult kidney transplant recipients, using aortic pulse wave velocity (PWV) to assess arterial stiffness over a 12 month period. All patients were assessed within one month of transplant (baseline) and 12 months post transplant. The primary outcome was change in PWV score at 12 months which we assessed using Wilcoxon Signed Rank test. Secondary analyses included correlation of predictors with PWV score at both time points. RESULTS: The median age of the cohort was 49.7 years at transplant, with 27 % Black and 27 % female. At baseline, 43 % had tobacco use, 30 % had a history of CVD, and 42 % had diabetes. Median baseline calcium was 9.1 mg/dL and median phosphorus was 5.1 mg/dL. Median PWV score was 9.25 and 8.97 m/s at baseline versus month 12, respectively, showing no significant change (median change of -0.07, p = 0.7). In multivariable regression, subjects with increased age at transplant (p = 0.008), diabetes (p = 0.002), and a higher baseline PWV score (p < 0.001) were at increased risk of having a high PWV score 12 months post transplant. CONCLUSION: Aortic arterial stiffness does not progress in the first year post kidney transplant. Increasing age, diabetes, and higher baseline PWV score identify patients at risk for increased arterial stiffness. Further research that assesses patients for greater than one year and includes a control dialysis group would be helpful in further understanding the change in arterial stiffness post transplantation.

Association of cardiovascular and biochemical risk factors with tibial artery calcification.

The cardiovascular risk factors that contribute to coronary calcification have been extensively studied while those related to tibial artery calcium are less well defined. We sought to determine the associations between cardiovascular risk factors and tibial artery calcification in a cohort of patients with and without significant peripheral atherosclerosis. A total of 222 patients without end-stage renal disease were identified in a prospectively maintained database containing tibial artery calcification (TAC) scores, and demographic, cardiovascular, and biochemical risk factor information. Patients with prevalent tibial artery calcification were more likely to be older, male, and have a history positive for hypertension, hyperlipidemia, diabetes, and tobacco use. Patients with an abnormal ankle-brachial index (ABI) or symptoms of peripheral artery disease (PAD) were also more likely to have higher calcium values. In analyses using multivariable logistic regression, age, gender, diabetes, and tobacco use maintained their association with prevalent tibial calcification while hypertension, hyperlipidemia and body mass index did not. These associations remained when PAD was added to the model. After adjusting for relevant cardiovascular risk factors, we found that only abnormal ABI, current PAD symptoms, and lower serum calcium values were associated with the presence of tibial artery calcification. In conclusion, in patients without end-stage renal disease, tibial artery calcification has risk factors that are similar but not identical to those for coronary artery calcification and peripheral atherosclerosis.

Dysfunctional high-density lipoproteins in children with chronic kidney disease.

OBJECTIVES: Our aim was to determine if chronic kidney disease (CKD) occurring in childhood impairs the normally vasoprotective functions of high-density lipoproteins (HDLs). MATERIALS AND METHODS: HDLs were isolated from children with end-stage renal disease on dialysis (ESRD), children with moderate CKD and controls with normal kidney function. Macrophage response to HDLs was studied as expression of inflammatory markers (MCP-1, TNF-α, IL-1ß) and chemotaxis. Human umbilical vein endothelial cells were used for expression of adhesion molecules (ICAM-1, VCAM-1, E-selectin) and adhesion. Cellular proliferation, apoptosis, and necrosis of endothelial cells were measured by MTS/PMS reagent-based assay, flow cytometry, and ELISA. Cholesterol efflux was assessed by gas chromatographic measurements of cholesterol in macrophages exposed to HDLs. RESULTS: Compared with HDL(Control), HDL(CKD) and HDL(ESRD) heightened the cytokine response and disrupted macrophage chemotaxis. HDL(Control) reduced endothelial expression of ICAM-1, VCAM-1, E-selectin, whereas HDL(CKD) and HDL(ESRD) were less effective and showed reduced capacity to protect endothelial cells against monocyte adhesion. Compared with a dramatically enhanced endothelial proliferation following injurious stimulus by HDL(Control), neither HDL(CKD) nor HDL(ESRD) caused proliferative effects. HDLs of all three groups were equally protective against apoptosis assessed by flow cytometry and cleaved caspase-3 activity. Compared to HDL(Control), HDL(CKD) and HDL(ESRD) trended toward reduced capacity as cholesterol acceptors. CONCLUSION: CKD in children impairs HDL function. Even in the absence of long-standing and concomitant risk factors, CKD alters specific HDL functions linked to control of inflammation and endothelial responses.

Urinary L-FABP predicts poor outcomes in critically ill patients with early acute kidney injury.

Biomarker studies for early detection of acute kidney injury (AKI) have been limited by nonselective testing and uncertainties in using small changes in serum creatinine as a reference standard. Here we examine the ability of urine L-type fatty acid-binding protein (L-FABP), neutrophil gelatinase-associated lipocalin (NGAL), interleukin-18 (IL-18), and kidney injury molecule-1 (KIM-1) to predict injury progression, dialysis, or death within 7 days in critically ill adults with early AKI. Of 152 patients with known baseline creatinine examined, 36 experienced the composite outcome. Urine L-FABP demonstrated an area under the receiver-operating characteristic curve (AUC-ROC) of 0.79 (95% confidence interval 0.70-0.86), which improved to 0.82 (95% confidence interval 0.75-0.90) when added to the clinical model (AUC-ROC of 0.74). Urine NGAL, IL-18, and KIM-1 had AUC-ROCs of 0.65, 0.64, and 0.62, respectively, but did not significantly improve discrimination of the clinical model. The category-free net reclassification index improved with urine L-FABP (total net reclassification index for nonevents 31.0%) and urine NGAL (total net reclassification index for events 33.3%). However, only urine L-FABP significantly improved the integrated discrimination index. Thus, modest early changes in serum creatinine can help target biomarker measurement for determining prognosis with urine L-FABP, providing independent and additive prognostic information when combined with clinical predictors.

Higher serum iron is associated with increased oxidant stress in HIV-infected men.

BACKGROUND: F2-isoprostanes (F2-IsoP) are oxidant stress biomarkers that are higher in HIV-infected women than men. We explored whether the effect of hemoglobin (Hgb), serum iron, or anemia on F2-IsoP is different between HIV-infected women and men. METHODS: Plasma F2-IsoP were quantified by gas chromatography/mass spectrometry; clinical and laboratory data were collected at enrollment or from the medical record. Multivariable linear regression was used to assess associations between F2-IsoP and Hgb, anemia as a dichotomous variable, and serum iron with adjustment for age, sex, race, body mass index, CD4 lymphocyte count, self-reported current smoking status, and antiretroviral therapy. RESULTS: Compared with men, women had lower Hgb [median: 12.7 (interquartile range: 11.8-13.9) vs. 14.9 (13.7-15.8) g/dL, P < 0.001], lower iron levels [75 (47-97) vs. 90 (69-121) µg/dL, P = 0.004], more anemia (29% vs. 10%, P < 0.001), and higher levels of F2-IsoP [42 (32-62) vs. 36 (25-46) pg/mL, P < 0.001]. The relationship between iron and F2-IsoP differed significantly between men and women (interaction P = 0.02). Men had a 21% (95% confidence interval: 8 to 36) increase in F2-IsoP per interquartile increase in iron (P = 0.001), whereas no relationship was seen among women [-4% (-17 to 13, P = 0.65]. CONCLUSIONS: Although women have overall higher F2-IsoP than men, a relationship between circulating F2-IsoP and iron levels was observed in men but not in women with HIV infection. The association between female sex and higher F2-IsoP is not explained by iron or Hgb levels because the association persists when controlling for these factors. The role of iron in oxidant stress and sex-specific differences among HIV-infected individuals require further study.

Inflammation and hypertension in rheumatoid arthritis.

OBJECTIVE: Hypertension (HTN), a common modifiable cardiovascular risk factor, is more common in patients with rheumatoid arthritis (RA), but the underlying mechanisms are unclear. We examined the hypothesis that mediators of inflammation and markers of cardiovascular risk are associated with HTN in RA. METHODS: We compared measures of inflammation [serum C-reactive protein (CRP), tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), homocysteine, and leptin concentrations] and insulin resistance [homeostasis model assessment index (HOMA)] in RA patients with (n = 90) and without HTN (n = 79). HTN was defined as blood pressure ≥ 140/90 mm Hg or treatment with antihypertensive therapy. The independent association of markers of interest with HTN was examined using multivariable logistic regression. RESULTS: Patients with HTN were significantly older and had longer disease duration than those without HTN (both p < 0.001). Concentrations of homocysteine [11.1 (8.5-13.5) µmol/l vs 9.3 (7.8-11.0) µmol/l] were significantly higher in patients with HTN (p < 0.001). After adjustment for age, sex, race, smoking, body mass index, and corticosteroid and nonsteroidal antiinflammatory drugs (NSAID) use, increased concentrations of homocysteine (OR 2.9, 95% CI: 1.5-5.5, p = 0.001), and leptin (OR 2.0, 95% CI: 1.0-3.8, p = 0.046) were significantly associated with HTN, but the 28-joint Disease Activity Score, IL-6, CRP, TNF-α, and HOMA index were not (all p > 0.05). CONCLUSION: HTN in patients with RA is not associated with generalized systemic inflammation or insulin resistance, but is associated with increasing concentrations of homocysteine and leptin. The pathogenesis of HTN in RA may involve pathways more regularly associated with fat and vascular homeostasis.

An association between adiposity and serum levels of macrophage inflammatory protein-1α and soluble CD14 in HIV-infected adults: results from a cross-sectional study.

BACKGROUND: Greater adipose tissue is associated with increased circulating high-sensitivity C-reactive protein (hsCRP) levels in HIV-infected adults on antiretroviral therapy (ART), but the relationship between adiposity and other inflammation biomarkers is not well-characterized. METHODS: We measured total and regional adipose tissue deposits using dual energy X-ray absorptiometry (DXA) and serum levels of interleukin-6 (IL-6), tumour necrosis factor-α (TNF-α) receptor 1 and 2, macrophage inflammatory protein-1α (MIP-1α), macrophage chemotactic protein-1 (MCP-1), soluble CD14 and hsCRP in a cohort of adults on long-term ART. Regression models were adjusted for age, sex, CD4(+) T-cell count, smoking status, protease-inhibitor-use and daily use of either non-steroidal anti-inflammatory drugs or aspirin. RESULTS: The majority (77%) of the 85 study participants were male, median CD4(+) T-cell count was 500 cells/µl (IQR 315-734) and median BMI was 25.1 kg/m(2) (IQR 22.7-28.1). DXA measurements of total fat mass were positively associated with serum hsCRP (ß=1.82, P<0.01) and MIP-1α (ß=1.36, P<0.01), but negatively associated with soluble CD14 (ß=0.90, P<0.01). Results were similar for trunk fat, limb fat and serum leptin level. The positive relationship between DXA measurements and TNF-α receptor 1 approached significance (P≤0.07 for all). There was no consistent relationship between adiposity and serum IL-6, TNF-α receptor 2 or MCP-1 levels. CONCLUSIONS: Total and regional adiposity was associated with serum hsCRP, but not other inflammatory cytokines shown to predict morbidity and mortality in treated HIV. Greater adiposity is associated with higher MIP-1α and lower soluble CD14 levels, possibly reflecting an important role for cells of the monocyte/macrophage lineage.

Distinct injury markers for the early detection and prognosis of incident acute kidney injury in critically ill adults with preserved kidney function.

The use of novel biomarkers to detect incident acute kidney injury (AKI) in the critically ill is hindered by heterogeneity of injury and the potentially confounding effects of prevalent AKI. Here we examined the ability of urine NGAL (NGAL), L-type fatty acid-binding protein (L-FABP), and cystatin C to predict AKI development, death, and dialysis in a nested case-control study of 380 critically ill adults with an eGFR over 60 ml/min per 1.73 m(2). One-hundred thirty AKI cases were identified following biomarker measurement and were compared with 250 controls without AKI. Areas under the receiver-operator characteristic curves (AUC-ROCs) for discriminating incident AKI from non-AKI were 0.58 (95% CI: 0.52-0.64), 0.59 (0.52-0.65), and 0.50 (0.48-0.57) for urine NGAL, L-FABP, and cystatin C, respectively. The combined AUC-ROC for NGAL and L-FABP was 0.59 (56-0.69). Both urine NGAL and L-FABP independently predicted AKI during multivariate regression; however, risk reclassification indices were mixed. Neither urine biomarker was independently associated with death or acute dialysis (NGAL hazard ratio 1.35 (95% CI: 0.93-1.96), L-FABP 1.15 (0.82-1.61)), although both independently predicted the need for acute dialysis alone (NGAL 3.44 (1.73-6.83), L-FABP 2.36 (1.30-4.25)). Thus, urine NGAL and L-FABP independently associated with the development of incident AKI and receipt of dialysis but exhibited poor discrimination for incident AKI using conventional definitions.