Associations of Estradiol With Mortality and Health Outcomes in Patients Undergoing Hemodialysis: A Prospective Cohort Study.

Background: Both lower and higher estradiol (E2) levels have been associated with increased mortality among women with kidney failure. However, robust data are still lacking. Objective: We investigated the interaction of diabetes and age on linear and nonlinear associations between E2 levels, adverse outcomes, and health-related quality of life (HRQOL) in Canadian women undergoing hemodialysis (HD). Design: Population-based cohort study; data from Canadian Kidney Disease Cohort Study (CKDCS). Setting & patients: A total of 427 women undergoing HD enrolled in the CKDCS. Measurements: Baseline E2 (in pmol/L) and E2 tertiles (<38 pmol/L, 38-95 pmol/L, >95 pmol/L). Methods: Cox-proportional hazards used for all-cause and cardiovascular disease (CVD) mortality. Fine-Gray models used for incident CVD. Mixed models used for Health Utilities Index Mark 3 (HUI3), Kidney Disease Quality of Life Physical Component Scores (KDQOL12-PCS), and Mental Component Scores (KDQOL12-MCS). Results: Over a median follow-up of 3.6 (interquartile range [IQR]: 1.6-7.5) years, 250 (58.6%) participants died; 74 deaths (29.6%) were CV-related. Among 234 participants without prior CV events, 80 (34.2%) had an incident CVD event. There were no significant linear associations between E2 and all-cause mortality, CVD mortality, and incident CVD. However, E2 showed a significant concave association with all-cause mortality, but not with CVD mortality and incident CVD. Among patients aged ≥63 years, higher E2 levels were associated with lower HUI3 scores, mean difference (MD) = -0.062 per 1 - SD pmol/L, 95% confidence interval (CI) = -0.112 to -0.012, but the opposite was observed in younger patients (<63 years) in whom higher E2 levels were associated with higher HUI3 scores (MD = 0.032 per 1 - SD pmol/L, 95% CI = 0.008-0.055), Pinteraction = .045. No associations were observed among E2, KDQOL12-PCS (MD = -0.15 per 1 - SD pmol/L, 95% CI = -1.15 to 0.86), and KDQOL12-MCS (MD = -0.63 per 1 - SD pmol/L, 95% CI = -1.82 to 0.57). Limitations: Unmeasured confounding and small sample size. Conclusions: The association between E2 and all-cause mortality may be nonlinear, while no association was observed for CVD mortality, incident CVD, KDQOL12-PCS, and KDQOL12-MCS. Furthermore, the association between serum E2 and HUI3 was modified by age: Higher levels were associated with higher utility among women aged <63 years and the converse observed among older women.

Contexte: Les taux faibles comme les taux élevés d'estradiol (E2) ont été associés à une mortalité accrue chez les femmes souffrant d'insuffisance rénale. Les données fiables à ce sujet font cependant encore défaut. Objectif: Nous avons étudié l'incidence du diabète et de l'âge sur les associations linéaires et non linéaires entre les niveaux d'E2, les issues défavorables et la qualité de vie liée à la santé (QVLS) chez les Canadiennes suivant des traitements d'hémodialyse (HD). Conception: Étude de cohorte en population réalisée à partir des données de la Canadian Kidney Disease Cohort Study (CKDCS). Sujets et cadre de l'étude: 427 femmes sous HD inscrites à la CKDCS. Mesures: Le taux d'E2 initial (pmol/L) et les taux d'E2 tertiles (<38 pmol/L; 38-95 pmol/L; >95 pmol/L). Méthodologie: Des modèles à risques proportionnels de Cox ont été utilisés pour mesurer la mortalité toutes causes confondues et la mortalité liée aux maladies cardiovasculaires (MCV). Des modèles Fine-Gray ont été utilisés pour mesurer les MCV incidentes; et des modèles mixtes ont été utilisés pour calculer l'indice Health Utilities Index Mark 3 (HUI3) et les scores des composantes physique (KDQOL12-PCS [Physical Component Score]) et mentale (KDQOL12-MCS [Mental Component Score])) du questionnaire sur la qualité de vie (KDQOL). Résultats: Au cours d'un suivi médian de 3,6 ans (intervalle interquartile [IIQ]: 1,6 à 7,5 ans), 250 participantes (58,6 %) sont décédées; 74 décès (29,6 %) étaient liés à un événement CV. Parmi les 234 participantes sans événements cardiovasculaires antérieurs, 80 (34,2 %) ont vécu un événement incident de MCV. Aucune association linéaire significative n'a été observée entre le taux d'E2 et la mortalité toutes causes confondues, la mortalité par MCV ou les MCV incidentes. Le taux d'E2 a cependant montré une association concave significative avec la mortalité toutes causes confondues, mais pas avec la mortalité par MCV ni avec les MCV incidentes. Chez les patientes âgées de 63 ans et plus, des taux élevés d'E2 ont été associés à des scores HUI3 plus faibles (différence moyenne [DM] = -0,062 par 1-SD pmol/L; intervalle de confiance à 95 % [IC95]: -0,112 à 0,012); alors qu'on a observé le contraire chez les patientes plus jeunes (< 63 ans), où des taux élevés d'E2 étaient plutôt associés à des scores plus élevés d'HUI3 (DM = 0,032 par 1-SD pmol/L; IC95: 0,008 à 0,055; p=0,045). Aucune association n'a été observée entre le taux d'E2, le KDQOL12-PCS (DM = -0,15 par 1-SD pmol/L; IC 95: -1,15 à 0,86) et le KDQOL12-MCS (DM = -0,63 par 1-SD pmol/L; IC95: -1,82 à 0,57). Limites: Facteurs de confusion non mesurés; échantillon de petite taille. Conclusion: Il pourrait exister une association non linéaire entre le taux d'E2 et la mortalité toutes causes confondues. Aucune association n'a toutefois été observée entre le taux d'E2 et la mortalité par MCV, les MCV incidentes, le KDQOL12-PCS et le KDQOL12-MCS. En outre, l'association entre le taux sérique d'E2 et l'HUI3 a été modifiée par l'âge: des taux plus élevés d'E2 ont été associés à un indice de santé plus élevé (HUI) chez les femmes âgées de moins de 63 ans, alors que l'inverse a été observé chez les femmes plus âgées.

Heart rate variability as a function of menopausal status, menstrual cycle phase, and estradiol level.

Low estradiol status is associated with increased cardiovascular risk. We sought to determine the association between heart rate variability (HRV), a marker of cardiovascular risk, at baseline and in response to stressor as a function of menopausal status, menstrual cycle phase and estradiol level. Forty-one healthy women (13 postmenopausal, 28 premenopausal) were studied. Eleven premenopausal women were additionally studied in the high and low estradiol phases of the menstrual cycle. HRV was calculated by spectral power analysis (low Frequency (LF), high frequency (HF) and LF:HF) at baseline and in response to graded Angiotensin II (AngII) infusion. The primary outcomes were differences in HRV at baseline and in response to AngII. Compared to premenopausal women in the low estradiol phase, postmenopausal women demonstrated lower baseline LF (p = 0.01) and HF (p < 0.001) measures, which were not significant after adjustment for age and BMI. In response to AngII, a decrease in cardioprotective HRV (ΔHF = -0.43 ± 0.46 ln ms2 , p = 0.005 vs. baseline) was observed in postmenopausal women versus premenopausal women. Baseline HRV parameters did not differ by menstrual phase in premenopausal women. During the low estradiol phase, no differences were observed in the HRV response to AngII challenge. In contrast, women in the high estradiol phase were unable to maintain HRV (ΔLF = -0.07 ± 0.46 ln ms2 , p = 0.048 response vs. baseline, ΔHF = -0.33 ± 0.74 ln ms2, p = 0.048 response vs. baseline). No association was observed between any measure of HRV and estradiol level. Menopausal status and the high estradiol phase in premenopausal women were associated with reduced HRV, a marker of cardiovascular risk. Understanding the role of estradiol in the modulation of cardiac autonomic tone may help guide risk reduction strategies in women.

Anti-Müllerian hormone and vascular dysfunction in women with chronic kidney disease.

Young women with chronic kidney disease (CKD) have disproportionately increased risk of cardiovascular mortality. Reduced anti-Müllerian hormone (AMH) is linked to poor cardiovascular outcomes in the general population, but whether AMH is associated with increased cardiovascular risk in the high-risk CKD population is unknown. This study examined the association between AMH and vascular function, validated markers of cardiovascular risk, in women with CKD. An exploratory cross-sectional study was performed in 47 young women with CKD. Laboratory measurements of AMH were collected. Using standardized protocols, endothelial function was measured with brachial artery flow-mediated dilation and hyperemic velocity time integral. Arterial stiffness was measured with aortic augmentation index and pulse wave velocity. Multivariate linear regression analyses were utilized to evaluate the association between AMH levels and each measure of vascular health. Forty women (36 ± 7 years) with non-dialysis-dependent CKD and 7 women (38 ± 6 years) with dialysis-dependent CKD participated. AMH levels were inversely associated with age (p = 0.01) but not associated with eGFR (p = 0.59) or dialysis status (p = 0.97). AMH was associated with brachial artery flow-mediated dilation (R2  = 0.21 [p = 0.03]) and aortic augmentation index (R2  = 0.20 [p = 0.04]) in the non-dialysis-dependent participants, and with aortic augmentation index in all participants (R2  = 0.18 [p = 0.03]). No association between AMH and any measure of vascular function was demonstrated in the dialysis-dependent participants. AMH levels are associated with impaired vascular function in young women with CKD and may be an important marker of future cardiovascular risk. Further investigation into this female-specific cardiovascular risk factor is warranted in this high-risk population.

Sex influences the effect of adiposity on arterial stiffness and renin-angiotensin aldosterone system activity in young adults.

INTRODUCTION: Sex influences the cardiovascular risk associated with body mass index (BMI) in older adults. Whether this risk differs by sex in younger adults is unknown. We aimed to evaluate the association between measures of adiposity and arterial stiffness and reninangiotensin-aldosterone system (RAAS) activity in younger adults, stratified by sex. METHODS: Body mass index (BMI), waist circumference (WC), hip circumference (HC), waist-to-hip ratio (WHR), waist-to-height ratio (WHtR) and fat mass% (FM%) were measured in healthy participants in a fasting, high-salt state. Arterial stiffness [pulse wave velocity (PWV) and aortic augmentation index (AIx)] were measured at baseline and in response to angiotensin II challenge, a validated marker of RAAS activity. Associations were evaluated using linear regression analysis and stratified by sex. RESULTS: Ninety-five healthy, normotensive, non-diabetic females (n = 67, 37 ± 2 y, BMI 25 ± 1 kg/m2 ) and males (n = 28, 39 ± 3 y, BMI 27 ± 1 kg/m2 ) participated in the study. No association was observed between any measure of adiposity and PWV, either at baseline or in response to angiotensin II challenge in premenopausal females. In contrast, all measures of adiposity except HC were associated with PWV at baseline (BMI r = 0.32; WC r = 0.18; WHtR r = 0.34; FM r = 0.21; all values p < .05) and in response to AngII (BMI r = -0.39; WC r = -0.42; WHR r = -0.39; and WHtR r = -0.55) in males. Most adiposity measures were positively associated with baseline AIx (BMI r = 0.33; WC r = 0.27; WHtR r = 0.35; FM% r = 0.25; p < .05) in females, while only WHtR was associated with baseline AIx (r = 0.39; p = .04) in males. All measures of adiposity were positively associated with a blunted Aix response to Ang II (all values p < .001) in females. BMI, WC, WHR and WHtR were associated with a blunted AIx response to Ang II (ΔAIx: BMI r = -0.37; WC r = -0.31; WHR r = -0.16; and WHtR r = -0.22; all values p < .05) in males. CONCLUSION: The associations between adiposity measures and cardiovascular risk differ by sex in a young population. These factors should be considered when managing cardiovascular risk.

Estradiol and mortality in women with end-stage kidney disease.

BACKGROUND: Young women with end-stage kidney disease (ESKD) have early menopause compared with women in the general population and the highest mortality among the dialysis population. We hypothesized that low estrogen status was associated with death in women with ESKD. METHODS: We measured estradiol and sex hormone levels in female ESKD patients initiating hemodialysis from 2005 to 2012 in four Canadian centers. We divided women into quintiles based on estradiol levels and tested for associations between the estradiol level and cardiovascular (CV), non-CV and all-cause mortality. Participants were further dichotomized by age. RESULTS: A total of 482 women (60 ± 15 years of age, 53% diabetic, estradiol 116 ± 161 pmol/L) were followed for a mean of 2.9 years, with 237 deaths (31% CV). Estradiol levels were as follows (mean ± standard deviation): Quintile 1: 19.3 ± 0.92 pmol/L; Quintile 2: 34.6 ± 6.6 pmol/L; Quintile 3: 63.8 ± 10.6 pmol/L; Quintile 4: 108.9 ± 19.3; Quintile 5: 355 ± 233 pmol/L. Compared with Quintile 1, women in Quintiles 4 and 5 had significantly higher adjusted all-cause mortality {hazard ratio [HR] 2.12 [95% confidence interval (CI) 1.38-3.25] and 1.92 [1.19-3.10], respectively}. Similarly, compared with Quintile 1, women in Quintile 5 had higher non-CV mortality [HR 2.16 (95% CI 1.18-3.96)]. No associations were observed between estradiol levels and CV mortality. When stratified by age, higher quintiles were associated with greater all-cause mortality (P for trend <0.001) and non-CV mortality (P for trend = 0.02), but not CV mortality in older women. CONCLUSIONS: In women with ESKD treated with hemodialysis, higher estradiol levels were associated with greater all-cause and non-CV mortality. Further studies are required to determine the mechanism for the observed increased risk.

The Calgary student run clinic in context: a mixed-methods case study.

BACKGROUND: Student Run Clinics (SRCs) provide students with clinical education while caring for underserved populations. While much of the research on SRCs comes from the USA, SRCs in other contexts need to be appraised in the context of the systems they interact with. This study explored how stakeholders in the University of Calgary's SRC perceived its purpose and beneficiaries with respect to patients, students, undergraduate medical education, and its intersections within the healthcare system in Calgary. METHODS: Data came from the SRC's EMR and stakeholder interviews at the Inn from the Cold (IFTC) shelter. Qualitative data were analyzed using standard grounded theory techniques. RESULTS: There were 13 interviews - seven with student clinicians and six with preceptors and other stakeholders. Interviews highlighted the uncertainty of the SRCs role. Majority of participants saw the SRC as facilitating further access to other healthcare services, while some commented on its primarily education-focused role. Major limitations in the SRC's scope of care and its integration with other services were identified. CONCLUSION: SRCs need to consider their accountabilities, both educational and healthcare-focused at individual and organization levels, in order to function as responsible healthcare providers in Calgary.

Sex Hormone Status in Women With Chronic Kidney Disease: Survey of Nephrologists' and Renal Allied Health Care Providers' Perceptions.

BACKGROUND: Chronic kidney disease (CKD) in reproductive-age women is accompanied by menstrual and fertility disorders and premature menopause. OBJECTIVE: We sought to determine nephrologists' and allied health care providers' perceptions on management of sex hormone status in women with CKD. METHODS: An anonymous, Internet-based survey was sent to nephrology society members from Canada, Australia, New Zealand, and the United Kingdom, and the Canadian Association of Nephrology Nurses and Technologists (February-November 2015). We assessed reported perceptions and management of sex hormone status in women with CKD. RESULTS: One hundred seventy-five nephrologists (21% response rate) and 121 allied health care providers (30%; 116 nurses, 5 pharmacists) responded. Sixty-eight percent of nephrologists and 46% of allied providers were between the ages of 30 and 50 years, and 38% of nephrologists and 89% of allied workers were female. Ninety-five percent of nephrologists agreed that kidney function impacts sex hormone status, although only a minority of nephrologists reported often discussing fertility (35%, female vs male nephrologists, P = .06) and menstrual irregularities with their patients (15%, female vs male nephrologists,P = .02). Transplant nephrologists reported discussing fertility more often than did nontransplant nephrologists (53% vs 30%, P = .03). Physicians were more likely to report discussing fertility (33% vs 7.5%, P < .001) and menstrual irregularities (15% vs 9%, P = .04) with patients than allied health care providers. Forty-three percent of physicians reported uncertainty about the role for postmenopausal hormone therapy in women with CKD. CONCLUSION: Nephrologists and allied health care providers recognize an impact of CKD on sex hormones in women but report not frequently discussing sex hormone-related issues with patients. Our international survey highlights an important knowledge gap in nephrology.

CONTEXTE: Chez les femmes en âge de procréer, l'insuffisance rénale chronique (IRC) peut être associée à des irrégularités du cycle menstruel, des problèmes de fertilité et à la survenue d'une ménopause précoce. OBJECTIFS DE L'ÉTUDE: Cette étude visait deux objectifs. D'abord, on a voulu connaître la manière dont les néphrologues et les autres professionnels de la santé perçoivent les troubles hormonaux associés à l'IRC chez les femmes en âge de procréer. Ensuite, nous souhaitions établir comment ces perceptions influencent la prise en charge des patientes. MÉTHODOLOGIE: Entre février et novembre 2015, nous avons fait parvenir un sondage Web anonyme aux membres de la Société de néphrologie du Canada, de l'Australie, de la Nouvelle-Zélande et du Royaume-Uni, de même qu'aux membres de l'Association canadienne des infirmières et infirmiers et des technologues de néphrologie (ACITN/CANNT). Nous avons compilé et analysé les réponses obtenues au sujet des perceptions et de la prise en charge de l'activité hormonale dans le suivi des femmes atteintes d'IRC. RÉSULTATS: Un total de 175 néphrologues (taux de réponse de 21 %) et de 123 autres professionnels de la santé, soit 116 infirmières et 5 pharmaciens (taux de réponse de 30 %) ont répondu au sondage. Les répondants étaient majoritairement âgés de 30 à 50 ans (68 % des néphrologues et 46 % des autres professionnels de la santé). Un peu plus du tiers des néphrologues étaient des femmes (38 %) alors que ces dernières représentaient la très grande majorité (89 %) des autres professionnels de la santé ayant répondu au sondage. La plupart des néphrologues (95 %) ont admis que la fonction rénale perturbe l'activité des hormones sexuelles chez leurs patientes, bien qu'une minorité reconnaissait discuter des enjeux liés à la fertilité (35 %) et des irrégularités du cycle menstruel (15 %) avec elles. Dans les deux cas, bien que les différences ne soient pas statistiquement significatives, les néphrologues féminines étaient plus nombreuses que leurs collègues masculins à aborder ces sujets de façon régulière avec leurs patientes (ratio homme-femme p=0,06 pour l'infertilité, et p=0,02 pour les irrégularités du cycle menstruel). De plus, le sondage indique que les néphrologues transplantologues abordent plus souvent les questions de fertilité avec leurs patientes que les néphrologues qui ne pratiquent pas de greffes (53 % contre 30 %, p=0,03). De manière générale, les médecins se montraient plus enclins à discuter des problèmes de fertilité (33 % contre 7,5 %, p<0,001) et des irrégularités du cycle menstruel (15 % contre 9 %, p=0.04) avec les patientes atteintes d'IRC que les autres professionnels de la santé. Enfin, en ce qui concerne le suivi des cas de ménopause précoce, 43 % des médecins se sont dits incertains quant au rôle que pourrait jouer l'hormonothérapie post-ménopausique pour les femmes atteintes d'IRC. CONCLUSION: De manière générale, les néphrologues et les autres professionnels de la santé admettent que l'activité des hormones sexuelles est influencée par la fonction rénale chez les femmes atteintes d'IRC. Néanmoins, ils reconnaissent ne pas aborder d'emblée les enjeux de fertilité et les irrégularités du cycle menstruel associés à l'IRC avec leurs patientes. Ainsi, ce sondage mené à l'international témoigne d'un écart important entre les connaissances et les pratiques dans le domaine de la néphrologie.

The effect and safety of postmenopausal hormone therapy and selective estrogen receptor modulators on kidney outcomes in women: a protocol for systematic review and meta-analysis.

BACKGROUND: The prevalence of menopause in women with or at risk of chronic kidney disease is increasing globally. Although international guidelines on menopause recommend the use of postmenopausal hormone therapy with or without selective estrogen receptor modulators for control of vasomotor symptoms, the effects of these treatments on kidney function and albuminuria are unclear. Furthermore, women with chronic kidney disease are at significantly increased risk of venous thromboembolism and malignancy, well-documented adverse effects of postmenopausal hormone therapy. Our study aims to establish the effect of these treatments on kidney function and albuminuria in women, as well as determine the safety of these treatments in the chronic kidney disease population. METHODS: We will conduct a systematic review and meta-analysis addressing the effect and safety of postmenopausal hormone therapy and selective estrogen receptor modulators on kidney outcomes in women. We plan to search for published (MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), tables of contents of relevant journals) and unpublished (ongoing studies, conference proceedings) studies in all languages examining the effect of postmenopausal hormone therapy, including selective estrogen receptor modulators, on kidney function and albuminuria, as well as the risk of adverse outcomes of these treatments in women with chronic kidney disease. Two independent investigators will screen identified abstracts and select studies that examine the effect of postmenopausal hormone therapy and selective estrogen receptor modulators on kidney outcomes in the general population or adverse outcomes in the chronic kidney disease population. Data on study population, intervention, outcomes, as well as study quality and risk of bias will be independently extracted from each eligible study. Along with descriptive presentation of data, outcome measures will be presented as meta-analyses using a random effects model. Planned subgroup analyses will be completed, and meta-regression will be performed if significant heterogeneity is noted. DISCUSSION: By examining the effects of postmenopausal hormone therapy and selective estrogen receptor modulators on kidney function and albuminuria, the results of this systematic review and meta-analysis will inform management of postmenopausal women in the general population. Furthermore, it will evaluate the safety, including the risks of known adverse outcomes of postmenopausal hormone therapy and selective estrogen receptor modulators, in the already vulnerable chronic kidney disease population. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42016050651.

Sex differences in associations between insulin resistance, heart rate variability, and arterial stiffness in healthy women and men: a physiology study.

Diabetes confers greater cardiovascular risk to women than to men. Whether insulin-resistance-mediated risk extends to the healthy population is unknown. Measures of insulin resistance (fasting insulin, homeostatic model assessment, hemoglobin A1c, quantitative insulin sensitivity check index, glucose) were determined in 48 (56% female) healthy subjects. Heart rate variability (HRV) was calculated by spectral power analysis and arterial stiffness was determined using noninvasive applanation tonometry. Both were measured at baseline and in response to angiotensin II infusion. In women, there was a non-statistically significant trend towards increasing insulin resistance being associated with an overall unfavourable HRV response and increased arterial stiffness to the stressor, while men demonstrated the opposite response. Significant differences in the associations between insulin resistance and cardiovascular physiological profile exist between healthy women and men. Further studies investigating the sex differences in the pathophysiology of insulin resistance in cardiovascular disease are warranted.

The VITAH Trial-Vitamin D Supplementation and Cardiac Autonomic Tone in Patients with End-Stage Kidney Disease on Hemodialysis: A Blinded, Randomized Controlled Trial.

End-stage kidney disease (ESKD) patients are at increased cardiovascular risk. Vitamin D deficiency is associated with depressed heart rate variability (HRV), a risk factor depicting poor cardiac autonomic tone and risk of cardiovascular death. Vitamin D deficiency and depressed HRV are highly prevalent in the ESKD population. We aimed to determine the effects of oral vitamin D supplementation on HRV ((low frequency (LF) to high frequency (HF) spectral ratio (LF:HF)) in ESKD patients on hemodialysis. Fifty-six subjects with ESKD requiring hemodialysis were recruited from January 2013-March 2015 and randomized 1:1 to either conventional (0.25 mcg alfacalcidol plus placebo 3×/week) or intensive (0.25 mcg alfacalcidol 3×/week plus 50,000 international units (IU) ergocalciferol 1×/week) vitamin D for six weeks. The primary outcome was the change in LF:HF. There was no difference in LF:HF from baseline to six weeks for either vitamin D treatment (conventional: p = 0.9 vs. baseline; intensive: p = 0.07 vs. baseline). However, participants who remained vitamin D-deficient (25-hydroxyvitamin D < 20 ng/mL) after treatment demonstrated an increase in LF:HF (conventional: n = 13, ∆LF:HF: 0.20 ± 0.06, p < 0.001 vs. insufficient and sufficient vitamin D groups; intensive: n = 8: ∆LF:HF: 0.15 ± 0.06, p < 0.001 vs. sufficient vitamin D group). Overall, six weeks of conventional or intensive vitamin D only augmented LF:HF in ESKD subjects who remained vitamin D-deficient after treatment. Our findings potentially suggest that while activated vitamin D, with or without additional nutritional vitamin D, does not appear to improve cardiac autonomic tone in hemodialysis patients with insufficient or sufficient baseline vitamin D levels, supplementation in patients with severe vitamin D deficiency may improve cardiac autonomic tone in this higher risk sub-population of ESKD. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01774812.

Hormone therapy and clinical and surrogate cardiovascular endpoints in women with chronic kidney disease: a systematic review and meta-analysis.

OBJECTIVE: Women with chronic kidney disease (CKD) experience kidney dysfunction-mediated premature menopause. The role of postmenopausal hormone therapy (HT) in this population is unclear. We sought to summarize current knowledge regarding use of postmenopausal HT and cardiovascular (CV) outcomes, and established surrogate measures of CV risk in women with CKD. METHODS: This is a systematic review and meta-analysis of adult women with CKD. We searched electronic bibliographic databases (MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials) (inception to 2014 December), relevant conference proceedings, tables of contents of journals, and review articles. Randomized controlled trials and observational studies examining postmenopausal HT compared with either placebo or untreated control groups were included. The intervention of interest was postmenopausal HT, and the outcome measures were all-cause and CV mortality, nonfatal CV event (myocardial infarction, stroke), and surrogate measures of CV risk (serum lipids, blood pressure). RESULTS: Of 12,482 references retrieved, four randomized controlled trials and two cohort studies (N = 1,666 participants) were identified. No studies reported on CV outcomes or mortality. Compared with placebo, postmenopausal HT was associated with decreased low-density lipoprotein cholesterol (-13.2 mg/dL [95% CI, -23.32 to -3.00 mg/dL]), and increased high-density lipoprotein (8.73 mg/dL [95% CI, 4.72-12.73 mg/dL]) and total cholesterol (7.96 mg/dL [95% CI, 0.07-15.84 mg/dL]). No associations were observed between postmenopausal HT triglyceride levels and blood pressure. CONCLUSIONS: Studies examining the effect of postmenopausal HT on CV outcomes in women with CKD are lacking. Further prospective study of the role of postmenopausal HT in this high-risk group is required.

Incidence of sudden cardiac death in adults with end-stage renal disease: a systematic review and meta-analysis.

BACKGROUND: Although sudden cardiac death (SCD) is recognized as a distinct cause of death in patients with end stage renal disease (ESRD), its incidence has not been well summarized. METHODS: We performed a systematic review and meta-analysis of the literature based on a protocol developed a priori. We searched MEDLINE and EMBASE (inception to March 2015) for randomized controlled trials and cohort studies reporting the incidence of SCD in adult patients with ESRD on hemodialysis or peritoneal dialysis. We collected data on number of SCD as well as the definition of SCD for each individual study. A random-effects model was used to summarize the incidence of SCD. We conducted subgroup analyses to explore sources of heterogeneity. RESULTS: Forty two studies (n = 80,382 patients) were included in the meta-analysis. The incidence of SCD among adults with ESRD ranged from 0.4 to 10.04 deaths per 100 person-years. The definitions and assessment of SCD varied across the included studies. There was evidence of significant heterogeneity (I(2) = 98; p < 0.001), which was not explained by subgroup analyses stratified by mean age, proportion of hypertensive or diabetic patients, follow-up time, study size, or type of cohort studied. CONCLUSION: Current estimates of the incidence of SCD among adults with ESRD vary widely. There is a need for further studies to more accurately estimate the incidence of SCD in patients with ESRD.

Sex hormones in women with kidney disease.

Menstrual disorders, infertility and premature menopause are common but often underrecognized phenomena among women with chronic kidney disease. Hypothalamic, rather than ovarian dysfunction, may be the cause of the abnormal reproductive milieu, which can be at least partially reversed by kidney transplantation and increased intensity of hemodialysis. Endogenous sex hormones, and specifically estradiol, appear to be renoprotective in women, although the effects of exogenous estradiol (as an oral contraceptive and postmenopausal hormone therapy) on kidney function are more controversial. Treatment with postmenopausal hormone therapy in women with end-stage kidney disease (ESKD) has been associated with improved quality of life, bone health and markers of cardiovascular risk, as well as an increased risk of arteriovenous access thrombosis. The selective estrogen receptor modulator raloxifene has been associated with both a decreased fracture risk as well as renoprotection in women with kidney disease. Young women with ESKD are more likely to die from infection or develop malignancy, suggesting an immunomodulatory role of estrogen. Whether the premature menopause commonly observed in female patients with kidney disease results in increased cardiovascular morbidity and mortality is unknown, although preliminary studies have suggested a possible therapeutic role for manipulation of the sex hormone milieu to mitigate risk in this population. Large, prospective, randomized studies examining the role of sex hormones in women with kidney disease are required to address the question.

The effect of hormone therapy on all-cause and cardiovascular mortality in women with chronic kidney disease: protocol for a systematic review and meta-analysis.

BACKGROUND: Chronic kidney disease affects approximately one in ten North Americans and is associated with a high risk of cardiovascular disease. Chronic kidney disease in women is characterized by an abnormal sex hormone profile and low estradiol levels. Since low estradiol levels are associated with an increased cardiovascular risk in healthy women, our objective is to determine the effect of hormone therapy on all-cause mortality, cardiovascular mortality, and cardiovascular morbidity in women with chronic kidney disease. METHODS/DESIGN: Studies examining hormone therapy for adult women with chronic kidney disease will be included. The primary outcome is all-cause or cardiovascular mortality and morbidity. We will search electronic bibliographic databases (MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials (CENTRAL)) along with relevant conference proceedings, table of contents of journals, and review articles. Two investigators will independently screen identified abstracts and select observational cohort studies, case-control studies, and randomized controlled trials examining hormone therapy in women with chronic kidney disease. These investigators will also independently abstract data from relevant full-text journal articles and assess risk of bias. Where possible, these data will be summarized using pooled or combined estimates for the risk ratio or hazard ratio of all-cause mortality, cardiovascular mortality, and cardiovascular morbidity in women with chronic kidney disease with and without hormone therapy. A random effects model will be used, and meta-regression and subgroup analyses will be used to explore potential source of heterogeneity. DISCUSSION: Given the high burden of cardiovascular disease in women with chronic kidney disease, this study will help guide clinical practice by summarizing current evidence on the use of hormone therapy for prevention of all-cause mortality, cardiovascular mortality, and cardiovascular morbidity in this population. SYSTEMATIC REVIEW REGISTRATION: The final protocol was registered with PROSPERO ( CRD42014014566) .

Testosterone is associated with the cardiovascular autonomic response to a stressor in healthy men.

OBJECTIVE: Men have high cardiovascular risk and unfavourable cardiac autonomic tone compared to premenopausal women. The role of sex hormones in control of autonomic tone is unclear. We sought to determine the association between sex hormones and cardiosympathovagal tone at baseline and in response to a physiological stressor. METHODS: Forty-eight healthy subjects (21 men, 27 premenopausal women) were studied in high-salt balance. Cardiac autonomic tone was assessed by heart rate variability, calculated by spectral power analysis (low frequency (LF, a measure of sympathetic modulation), high frequency (HF, a measure of vagal modulation) and LF:HF (a measure of cardiosympathovagal balance)) at baseline and in response to graded Angiotensin II (AngII) infusion (3 ng/kg/min × 30 min, 6 ng/kg/min × 30 min) were measured. The primary outcome was association between endogenous sex hormone levels and measures of cardiac autonomic tone. RESULTS: All subjects had sex hormone levels in the normal range. No associations were observed between sex hormones and baseline cardiac autonomic tone in men or women. Men with lower testosterone levels, however, were unable to maintain both cardiosympathetic (p = 0.045) and cardiovagal tone (p = 0.035) in response to AngII even after adjustments for covariates. No association was observed between estradiol and progesterone and cardiac autonomic response to AngII in either sex. CONCLUSION: An unfavourable shift in the cardiac autonomic tone in men with lower testosterone levels was observed in response to a stressor. Understanding the role of sex hormones in modulation of cardiac autonomic tone may help guide risk reduction strategies in men.

Serum uric acid level, blood pressure, and vascular angiotensin II responsiveness in healthy men and women.

Uric acid is associated with hypertension and increased renin-angiotensin system activity, although this relationship diminishes after chronic exposure to high levels. Uric acid is more strongly associated with poor outcomes in women compared to men, although whether this is due to a sex-specific uric acid-mediated pathophysiology or reflects sex differences in baseline uric acid levels remains unknown. We examined the association between uric acid and vascular measures at baseline and in response to angiotensin-II challenge in young healthy humans. Fifty-two subjects (17 men, 35 premenopausal women) were studied in high-salt balance. Serum uric acid levels were significantly higher in men compared to women (328 ± 14 µmol/L vs. 248 ± 10 µmol/L, P < 0.001), although all values were within normal sex-specific range. Men demonstrated no association between uric acid and blood pressure, either at baseline or in response to angiotensin-II. In stark contrast, a significant association was observed between uric acid and blood pressure at baseline (systolic blood pressure, P = 0.005; diastolic blood pressure, P = 0.02) and in response to angiotensin-II (systolic blood pressure, P = 0.035; diastolic blood pressure, P = 0.056) in women. However, this sex difference lost significance after adjustment for baseline uric acid. When all subjects were stratified according to high (>300 µmol/L) or low (≤300 µmol/L) uric acid levels, only the low uric acid group showed a positive association between uric acid and measures of vascular tone at baseline and in response to angiotensin-II. Differences in uric acid-mediated outcomes between men and women likely reflect differences in exposure to increased uric acid levels, rather than a sex-specific uric acid-mediated pathophysiology.

A peptide inhibitor of synuclein-γ reduces neovascularization of human endometriotic lesions.

Endometriosis is a chronic painful gynecological condition characterized by adherence and growth of endometrium outside of the uterine cavity. Neovascularization is essential to the developing endometriosis lesion to support its growth. Synuclein-γ (SNCG), a protein implicated in cellular proliferation, is associated with a broad range of malignancies as well as endometriosis. We hypothesized that SNCG plays an important role in the neovascularization and growth of endometriosis and blocking of SNCG will interfere with survival of endometriotic lesions in a mouse model. We developed SP012, a novel 12 amino acid peptide inhibitor of SNCG. SP012 inhibited three-dimensional endothelial cell tube formation in a dose-dependent manner. Using intravital microscopy, SP012 was shown to be successfully delivered to human endometriotic lesions in a xenograft mouse model in vivo. Alymphoid (BALB/c-Rag2-/-Il2rγ-/- lacking T, B and NK cells) mice were surgically induced with human endometriotic lesions and treated with SP012 or phosphate-buffered saline control. SP012 treated endometriotic lesions had decreased growth, development and vascularization at the time of necroscopy. Endometriotic lesions treated with SP012 also had fewer isolectin (+) microvessels. These results, using a mouse model, indicate that SNCG plays a role in the neovascularization and subsequent growth of human endometriotic lesions. Targeting SNCG function using peptide inhibitor might provide a potential therapeutic option for the treatment of endometriosis in the future.