Sharanya Ramesh

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.

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

BackgroundAlthough 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.MethodsWe 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.ResultsForty 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 (I2 = 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.ConclusionCurrent 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.

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.

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

BackgroundChronic 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/designStudies 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.DiscussionGiven 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 registrationThe final protocol was registered with PROSPERO (CRD42014014566).

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

BackgroundThe 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.MethodsWe 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.DiscussionBy 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 registrationPROSPERO CRD42016050651

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.

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.