Subclinical Primary Aldosteronism and Cardiovascular Health: A Population-Based Cohort Study.

BACKGROUND: Primary aldosteronism, characterized by overt renin-independent aldosterone production, is a common but underrecognized form of hypertension and cardiovascular disease. Growing evidence suggests that milder and subclinical forms of primary aldosteronism are highly prevalent, yet their contribution to cardiovascular disease is not well characterized. METHODS: This prospective study included 1284 participants between the ages of 40 and 69 years from the randomly sampled population-based CARTaGENE cohort (Québec, Canada). Regression models were used to analyze associations of aldosterone, renin, and the aldosterone-to-renin ratio with the following measures of cardiovascular health: arterial stiffness, assessed by central blood pressure (BP) and pulse wave velocity; adverse cardiac remodeling, captured by cardiac magnetic resonance imaging, including indexed maximum left atrial volume, left ventricular mass index, left ventricular remodeling index, and left ventricular hypertrophy; and incident hypertension. RESULTS: The mean (SD) age of participants was 54 (8) years and 51% were men. The mean (SD) systolic and diastolic BP were 123 (15) and 72 (10) mm Hg, respectively. At baseline, 736 participants (57%) had normal BP and 548 (43%) had hypertension. Higher aldosterone-to-renin ratio, indicative of renin-independent aldosteronism (ie, subclinical primary aldosteronism), was associated with increased arterial stiffness, including increased central BP and pulse wave velocity, along with adverse cardiac remodeling, including increased indexed maximum left atrial volume, left ventricular mass index, and left ventricular remodeling index (all P<0.05). Higher aldosterone-to-renin ratio was also associated with higher odds of left ventricular hypertrophy (odds ratio, 1.32 [95% CI, 1.002-1.73]) and higher odds of developing incident hypertension (odds ratio, 1.29 [95% CI, 1.03-1.62]). All the associations were consistent when assessing participants with normal BP in isolation and were independent of brachial BP. CONCLUSIONS: Independent of brachial BP, a biochemical phenotype of subclinical primary aldosteronism is negatively associated with cardiovascular health, including greater arterial stiffness, adverse cardiac remodeling, and incident hypertension.

Impact of Successive Office Blood Pressure Measurements During a Single Visit on Cardiovascular Risk Prediction: Analysis of CARTaGENE.

BACKGROUND: Multiple office blood pressure (BP) readings correlate more closely with ambulatory BP than single readings. Whether they are associated with long-term outcomes and improve cardiovascular risk prediction is unknown. Our objective was to assess the long-term impact of multiple office BP readings. METHODS: We used data from CARTaGENE, a population-based survey comprising individuals aged 40 to 70 years. Three BP readings (BP1, BP2, and BP3) at 2-minute intervals were obtained using a semiautomated device. They were averaged to generate BP1-2, BP2-3, and BP1-2-3 for systolic BP (SBP) and diastolic BP. Cardiovascular events (major adverse cardiovascular event [MACE]: cardiovascular death, stroke, and myocardial infarction) during a 10-year follow-up were recorded. Associations with MACE were obtained using adjusted Cox models. Predictive performance was assessed with 10-year atherosclerotic cardiovascular disease scores and their associated C statistics. RESULTS: In the 17 966 eligible individuals, 2378 experienced a MACE during follow-up. Crude SBP values ranged from 122.5 to 126.5 mm Hg. SBP3 had the strongest association with MACE incidence (hazard ratio, 1.10 [1.05-1.15] per SD) and SBP1 the weakest (hazard ratio, 1.06 [1.01-1.10]). All models including SBP1 (SBP1, SBP1-2, and SBP1-2-3) were underperformed. At a given SBP value, the excess MACE risk conferred by SBP3 was 2× greater than SBP1. In atherosclerotic cardiovascular disease scores, SBP3 yielded the highest C statistic, significantly higher than most other SBP measures. In contrast to SBP, all diastolic BP readings yielded similar results. CONCLUSIONS: Cardiovascular risk prediction is improved by successive office SBP values, especially when the first reading is discarded. These findings reinforce the necessity of using multiple office BP readings.

Screening for Primary Aldosteronism Among Hypertensive Adults with Obstructive Sleep Apnea: A Retrospective Population-Based Study.

BACKGROUND: Hypertension plus obstructive sleep apnea (OSA) is recommended in some guidelines as an indication to screen for primary aldosteronism (PA), yet prior data has brought the validity of this recommendation into question. Given this context, it remains unknown whether this screening recommendation is being implemented into clinical practice. METHODS: We conducted a population-based retrospective cohort study of all adult Ontario (Canada) residents with hypertension plus OSA from 2009 to 2020 with follow-up through 2021 utilizing provincial health administrative data. We measured the proportion of individuals who underwent PA screening via the aldosterone-to-renin ratio by year. We further examined screening rates among patients with hypertension plus OSA by the presence of concurrent hypokalemia and resistant hypertension. Clinical predictors associated with screening were assessed via Cox regression modeling. RESULTS: The study cohort included 53,130 adults with both hypertension and OSA, of which only 634 (1.2%) underwent PA screening. Among patients with hypertension, OSA, and hypokalemia, the proportion of eligible patients screened increased to 2.8%. Among patients ≥65 years with hypertension, OSA, and prescription of ≥4 antihypertensive medications, the proportion of eligible patients screened was 1.8%. Older age was associated with a decreased likelihood of screening while hypokalemia and subspecialty care with internal medicine, cardiology, endocrinology, or nephrology were associated with an increased likelihood of screening. No associations with screening were identified with sex, rural residence, cardiovascular disease, diabetes, or respirology subspecialty care. CONCLUSIONS: The population-level uptake of the guideline recommendation to screen all patients with hypertension plus OSA for PA is exceedingly low.

University of Montreal's Clinician-Investigator Program: A 10-Year Descriptive Evaluation.

PURPOSE: Clinician-investigators have an important role in the development and implantation of new therapies and treatment modalities; however, there have been several reports highlighting a pending shortage in the clinician-investigators' workforce. In Canada, the Royal College has promoted the development of clinician-investigators programs (CIP) to facilitate the training of these individuals. There is currently a paucity of data regarding the outcomes of such programs. This study aims to identify the strengths and areas of improvement of the Montreal University CIP.  Methods: An internet-based 51-question survey was distributed to all the alumni from the University of Montreal CIP. Participation was voluntary and no incentives were provided. The response rate was 64%.  Results: Among respondents, 50% (n=16) had completed their clinical residency and all CIP requirements. The majority of these individuals (63%) had become independent investigators and had secured provincial and national funding. Satisfaction of the respondents was high regarding the overall program (85%), the research skills developed during the CIP (84%) and the financial support obtained during the program (72%). The satisfaction rate regarding career planning was lower (63%).  Conclusion: This survey demonstrates that, while indicators are favorable, some areas still require improvement. Several steps to improve the CIP have been identified; notably, the transition from the CIP to early independent career has been identified as critical in the development of clinician-investigators and steps have been taken to improve this progression.

Prediction of Cardiovascular Events by Pulse Waveform Parameters: Analysis of CARTaGENE.

Background Waveform parameters provide approximate data about aortic wave reflection. However, their association with cardiovascular events remains controversial and their role in cardiovascular prediction is unknown. Methods and Results We analyzed participants aged between 40 and 69 from the population-based CARTaGENE cohort. Baseline pulse wave analysis (central pulse pressure, augmentation index) and wave separation analysis (forward pressure, backward pressure, reflection magnitude) parameters were derived from radial artery tonometry. Associations between each parameter and major adverse atherosclerotic events (MACE; cardiovascular death, stroke, myocardial infarction) were obtained using adjusted Cox models. The incremental predictive value of each parameter compared with the 10-year atherosclerotic cardiovascular disease score alone was assessed using hazard ratios, c-index differences, continuous net reclassification indexes, and integrated discrimination indexes. From 17 561 eligible patients, 2315 patients had a MACE during a median follow-up of 10.1 years. Central pulse pressure, forward pressure, and backward pressure, but not augmentation index and reflection magnitude, were significantly associated with MACE after full adjustment. All parameters except forward pressure statistically improved MACE prediction compared with the atherosclerotic cardiovascular disease score alone. The greatest prediction improvement was seen with augmentation index and reflection magnitude but remained small in magnitude. These 2 parameters enhanced predictive performance more strongly in patients with low baseline atherosclerotic cardiovascular disease scores. Up to 5.7% of individuals were reclassified into a different risk stratum by adding waveform parameters to atherosclerotic cardiovascular disease scores. Conclusions Some waveform parameters are independently associated with MACEs in a population-based cohort. Augmentation index and reflection magnitude slightly improve risk prediction, especially in patients at low cardiovascular risk.

Accuracy Difference of Noninvasive Blood Pressure Measurements by Sex and Height.

Importance: Women are at higher risk of cardiovascular events than men with similar blood pressure (BP). Whether this discrepancy in risk is associated with the accuracy of brachial cuff BP measurements is unknown. Objectives: To examine the difference in brachial cuff BP accuracy in men and women compared with invasively measured aortic BP and to evaluate whether noninvasive central BP estimation varies with sex. Design, Setting, and Participants: This cross-sectional study enrolled 500 participants without severe aortic stenosis or atrial fibrillation from January 1 to December 31, 2019, who were undergoing nonurgent coronary angiography at a tertiary care academic hospital. Exposures: Simultaneous measurements of invasive aortic BP and noninvasive BP. Main Outcomes and Measures: Sex differences in accuracy were determined by calculating the mean difference between the noninvasive measurements (brachial and noninvasive central BP) and the invasive aortic BP (reference). Linear regression and mediation analyses were performed to identify mediators between sex and brachial cuff accuracy. Results: This study included 500 participants (145 female [29%] and 355 male [71%]; 471 [94%] White; mean [SD] age, 66 [10] years). Baseline characteristics were similar for both sexes apart from body habitus. Despite similar brachial cuff systolic BP (SBP) (mean [SD], 124.5 [17.7] mm Hg in women vs 124.4 [16.4] in men; P = .97), invasive aortic SBP was higher in women (mean [SD], 130.9 [21.7] in women vs 124.7 [20.1] mm Hg in men; P < .001). The brachial cuff was relatively accurate compared with invasive aortic SBP estimation in men (mean [SD] difference, -0.3 [11.7] mm Hg) but not in women (mean [SD] difference, -6.5 [12.1] mm Hg). Noninvasive central SBP (calibrated for mean and diastolic BP) was more accurate in women (mean [SD] difference, 0.6 [15.3] mm Hg) than in men (mean [SD] difference, 8.3 [14.2] mm Hg). This association of sex with accuracy was mostly mediated by height (3.4 mm Hg; 95% CI, 1.1-5.6 mm Hg; 55% mediation). Conclusions and Relevance: In this cross-sectional study, women had higher true aortic SBP than men with similar brachial cuff SBP, an association that was mostly mediated by a shorter stature. This difference in BP measurement may lead to unrecognized undertreatment of women and could partly explain why women are at greater risk for cardiovascular diseases for a given brachial cuff BP than men. These findings may justify the need to study sex-specific BP targets or integration of sex-specific parameters in BP estimation algorithms.

Can Peer Review Be Kinder? Supportive Peer Review: A Re-Commitment to Kindness and a Call to Action.

Peer review aims to select articles for publication and to improve articles before publication. We believe that this process can be infused by kindness without losing rigor. In 2014, the founding editorial team of the Canadian Journal of Kidney Health and Disease (CJKHD) made an explicit commitment to treat authors as we would wish to be treated ourselves. This broader group of authors reaffirms this principle, for which we suggest the terminology "supportive review."

L'évaluation par les pairs vise à sélectionner les articles à publier et à en améliorer le contenu avant publication. Nous sommes d'avis que ce processus peut être fait avec bienveillance sans perdre en rigueur. En 2014, l'équipe de rédaction fondatrice du Canadian Journal of Kidney Health and Disease (CJKHD) a pris l'engagement ferme de traiter les auteurs comme ses membres souhaiteraient eux-mêmes être traités. Aujourd'hui, notre groupe élargi d'auteur(e)s réaffirme ce principe pour lequel nous proposons la terminologie « évaluation constructive ¼.

Meta-GWAS Reveals Novel Genetic Variants Associated with Urinary Excretion of Uromodulin.

BACKGROUND: Uromodulin, the most abundant protein excreted in normal urine, plays major roles in kidney physiology and disease. The mechanisms regulating the urinary excretion of uromodulin remain essentially unknown. METHODS: We conducted a meta-analysis of genome-wide association studies for raw (uUMOD) and indexed to creatinine (uUCR) urinary levels of uromodulin in 29,315 individuals of European ancestry from 13 cohorts. We tested the distribution of candidate genes in kidney segments and investigated the effects of keratin-40 (KRT40) on uromodulin processing. RESULTS: Two genome-wide significant signals were identified for uUMOD: a novel locus (P 1.24E-08) over the KRT40 gene coding for KRT40, a type 1 keratin expressed in the kidney, and the UMOD-PDILT locus (P 2.17E-88), with two independent sets of single nucleotide polymorphisms spread over UMOD and PDILT. Two genome-wide significant signals for uUCR were identified at the UMOD-PDILT locus and at the novel WDR72 locus previously associated with kidney function. The effect sizes for rs8067385, the index single nucleotide polymorphism in the KRT40 locus, were similar for both uUMOD and uUCR. KRT40 colocalized with uromodulin and modulating its expression in thick ascending limb (TAL) cells affected uromodulin processing and excretion. CONCLUSIONS: Common variants in KRT40, WDR72, UMOD, and PDILT associate with the levels of uromodulin in urine. The expression of KRT40 affects uromodulin processing in TAL cells. These results, although limited by lack of replication, provide insights into the biology of uromodulin, the role of keratins in the kidney, and the influence of the UMOD-PDILT locus on kidney function.

Screening Rates for Primary Aldosteronism Among Individuals With Hypertension Plus Hypokalemia: A Population-Based Retrospective Cohort Study.

Primary aldosteronism is a common, yet highly underdiagnosed, cause of hypertension that leads to disproportionately high rates of cardiovascular disease. Hypertension plus hypokalemia is a guideline-recommended indication to screen for primary aldosteronism, yet the uptake of this recommendation at the population level remains unknown. We performed a population-based retrospective cohort study of adults ≥18 years old in Ontario, Canada, with hypertension plus hypokalemia (potassium <3.5 mEq/L) from 2009 to 2015 with follow-up through 2017. We measured the proportion of individuals who underwent primary aldosteronism screening via the aldosterone-to-renin ratio based upon hypokalemia frequency and severity along with concurrent antihypertensive medication use. We assessed clinical predictors associated with screening via Cox regression. The cohort included 26 533 adults of which only 422 (1.6%) underwent primary aldosteronism screening. When assessed by number of instances of hypokalemia over a 2-year time window, the proportion of eligible patients who were screened increased only modestly from 1.0% (158/15 983) with one instance to 4.8% (71/1494) with ≥5 instances. Among individuals with severe hypokalemia (potassium <3.0 mEq/L), only 3.9% (58/1422) were screened. Among older adults prescribed ≥4 antihypertensive medications, only 1.0% were screened. Subspecialty care with endocrinology (hazard ratio [HR], 1.52 [95% CI, 1.10-2.09]), nephrology (HR, 1.43 [95% CI, 1.07-1.91]), and cardiology (HR, 1.39 [95% CI, 1.14-1.70]) were associated with an increased likelihood of screening, whereas age (HR, 0.95 [95% CI, 0.94-0.96]) and diabetes (HR, 0.66 [95% CI, 0.50-0.89]) were inversely associated with screening. In conclusion, population-level uptake of guideline recommendations for primary aldosteronism screening is exceedingly low. Increased education and awareness are critical to bridge this gap.

Increased Excess Pressure After Creation of an Arteriovenous Fistula in End-Stage Renal Disease.

BACKGROUND: Reservoir-wave analysis (RWA) separates the arterial waveform into reservoir and excess pressure (XSP) components, where XSP is analogous to flow and related to left ventricular workload. RWA provides more detailed information about the arterial tree than traditional blood pressure (BP) parameters. In end-stage renal disease (ESRD), we have previously shown that XSP is associated with increased mortality and is higher in patients with arteriovenous fistula (AVF). In this study, we examined whether XSP increases after creation of an AVF in ESRD. METHODS: Before and after a mean of 3.9 ± 1.2 months following creation of AVF, carotid pressure waves were recorded using arterial tonometry. XSP and its integral (XSPI) were derived using RWA through pressure wave analysis alone. Aortic stiffness was assessed by carotid-femoral pulse wave velocity (CF-PWV). RESURLTS: In 38 patients (63% male, age 59 ± 15 years), after AVF creation, brachial diastolic BP decreased (79 ± 10 vs. 72 ± 12 mm Hg, P = 0.002), but the reduction in systolic BP, was not statistically significant (133 ± 20 vs. 127 ± 26 mm Hg, P = 0.137). However, carotid XSP (14 [12-19] to 17 [12-22] mm Hg, P = 0.031) and XSPI increased significantly (275 [212-335] to 334 [241-439] kPa∙s, P = 0.015), despite a reduction in CF-PWV (13 ± 3.6 vs. 12 ± 3.5 m/s, P = 0.025). CONCLUSIONS: Creation of an AVF resulted in increased XSP in this population, despite improvement in diastolic BP and aortic stiffness. These findings underline the complex hemodynamic impact of AVF on the cardiovascular system.

Prediction of Cardiovascular Events by Type I Central Systolic Blood Pressure: A Prospective Study.

Compared with brachial blood pressure (BP), central systolic BP (SBP) can provide a better indication of the hemodynamic strain inflicted on target organs, but it is unclear whether this translates into improved cardiovascular risk stratification. We aimed to assess which of central or brachial BP best predicts cardiovascular risk and to identify the central SBP threshold associated with increased risk of future cardiovascular events. This study included 13 461 participants of CARTaGENE with available central BP and follow-up data from administrative databases but without cardiovascular disease or antihypertensive medication. Central BP was estimated by radial artery tonometry, calibrated for brachial SBP and diastolic BP (type I), and a generalized transfer function (SphygmoCor). The outcome was major adverse cardiovascular events. Cox proportional-hazards models, differences in areas under the curves, net reclassification indices, and integrated discrimination indices were calculated. Youden index was used to identify SBP thresholds. Over a median follow-up of 8.75 years, 1327 major adverse cardiovascular events occurred. The differences in areas under the curves, net reclassification indices, and integrated discrimination indices were of 0.2% ([95% CI, 0.1-0.3] P<0.01), 0.11 ([95% CI, 0.03-0.20] P=0.01), and 0.0004 ([95% CI, -0.0001 to 0.0014] P=0.3), all likely not clinically significant. Central and brachial SBPs of 112 mm Hg (95% CI, 111.2-114.1) and 121 mm Hg (95% CI, 120.2-121.9) were identified as optimal BP thresholds. In conclusion, central BP measured with a type I device is statistically but likely not clinically superior to brachial BP in a general population without prior cardiovascular disease. Based on the risk of major adverse cardiovascular events, the optimal type I central SBP appears to be 112 mm Hg.

Association of Glomerular Hyperfiltration and Cardiovascular Risk in Middle-Aged Healthy Individuals.

Importance: Glomerular hyperfiltration is associated with increased risk of cardiovascular disease in high-risk conditions, but its significance in low-risk individuals is uncertain. Objective: To determine whether glomerular hyperfiltration is associated with increased cardiovascular risk in healthy individuals. Design, Setting, and Participants: This was a prospective population-based cohort study, for which enrollment took place from August 2009 to October 2010, with follow-up available through March 31, 2016. Analysis of the data took place in October 2019. The cohort was composed of 9515 healthy individuals, defined as individuals without hypertension, diabetes, cardiovascular disease, estimated glomerular filtration rate (eGFR) less than 60 mL/min/1.73 m2, or statin and/or aspirin use, identified among 20 004 patients aged 40 to 69 years with health information accessed through the CARTaGENE research platform. Exposures: Individuals with glomerular hyperfiltration (eGFR >95th percentile after stratification for sex and age) were compared with individuals with normal filtration rate (eGFR 25th-75th percentiles). Main Outcomes and Measures: Adverse cardiovascular events were defined as a composite of cardiovascular mortality, myocardial infarction, unstable angina, heart failure, stroke, and transient ischemic attack. Risk of adverse cardiovascular events was assessed using Cox and fractional polynomial regressions and propensity score matching. Results: From the 20 004 CARTaGENE participants, 9515 healthy participants (4050 [42.6%] male; median [interquartile range] age, 50.4 [45.9-55.6] years) were identified. Among these, 473 had glomerular hyperfiltration (median [interquartile range] eGFR, 112 [107-115] mL/min/1.73 m2) and 4761 had a normal filtration rate (median [interquartile range] eGFR, 92 [87-97] mL/min/1.73 m2). Compared with the normal filtration rate, glomerular hyperfiltration was associated with an increased cardiovascular risk (hazard ratio, 1.88; 95% CI, 1.30-2.74; P = .001). Findings were similar with propensity score matching. The fractional polynomial regression showed that only the highest eGFR percentiles were associated with increased cardiovascular risk. The cardiovascular risk of individuals with glomerular hyperfiltration was similar to that of the 597 participants with an eGFR between 45 and 60 mL/min/1.73 m2 (hazard ratio, 0.90; 95% CI, 0.56-1.42; P = .64). Conclusions and Relevance: These findings suggest that glomerular hyperfiltration is independently associated with increased cardiovascular risk in middle-aged healthy individuals. This risk profile appears to be similar to stage 3a chronic kidney disease.

Impact of updated recommendations on acetylsalicylic acid use for primary prevention of cardiovascular disease in Canada: a population-based survey.

BACKGROUND: The debate over acetylsalicylic acid (ASA) therapy for primary prevention of cardiovascular disease (CVD) has recently resurfaced, but scarce data are available on prophylactic ASA use in Canada for this purpose. This study aimed to evaluate the prevalence and factors associated with ASA use, and the potential impact of implementing the most recent (2016) US Preventive Services Task Force recommendations for primary CVD prevention in a Canadian setting. METHODS: We performed a cross-sectional analysis using data from the CARTaGENE study, which included a representative sample (n = 20 004) of the 2018 general population of the province of Quebec. We assessed eligibility for ASA treatment using US Preventive Services Task Force criteria (age 50-69 yr, no past history of myocardial infarction or stroke, and 10-year risk of CVD of at least 10%). We extrapolated to the entire 2018 Quebec population the number of people who would need to start ASA treatment. RESULTS: A total of 6231 respondents in the CARTaGENE study (54.2% of those aged 50-69 yr with no prior history of CVD) were found to be potentially eligible for ASA use for primary CVD prevention. Of the 6231, 1379 (22.1%) were receiving prophylactic ASA treatment. Factors found to be related to ASA use included age, male sex, regular medical visits, lower education level, obesity, hypertension, diabetes and dyslipidemia. Income and smoking status were not found to be significantly associated with ASA use. Our results indicate that 885 261 people would potentially have started ASA treatment if the US Preventive Services Task Force recommendations had been implemented in Quebec in 2018. INTERPRETATION: Prevalent ASA use for primary CVD prevention was low. Implementation of the 2016 US Preventive Services Task Force recommendations would require initiating ASA treatment in a substantial proportion of people, with undetermined potential benefits.

Incidence of fractures in middle-aged individuals with early chronic kidney disease: a population-based analysis of CARTaGENE.

BACKGROUND: Previous studies evaluating fractures in chronic kidney disease (CKD) have mostly focused on hip or major fractures in aged populations with moderate to advanced CKD. We aimed at evaluating the association between early CKD and fracture incidence at all sites across age and sex in middle-aged individuals. METHODS: We analyzed CARTaGENE, a prospective population-based survey of 40- to 69-year-old individuals from Quebec (Canada). Estimated glomerular filtration rate (eGFR) at baseline was evaluated categorically or continuously using restricted cubic splines. Fractures at any site (except toes, hand and craniofacial) for up to 7 years of follow-up were identified through administrative databases using a validated algorithm. Adjusted Cox models were used to evaluate the association of CKD with fracture. Interaction terms for age and sex were also added. RESULTS: A total of 19 391 individuals (756 CKD Stage 3; 9114 Stage 2; 9521 non-CKD) were included and 829 fractures occurred during a median follow-up of 70 months. Compared with the median eGFR of 90 mL/min/1.73 m2, eGFRs of ≤60 mL/min/1.73 m2 were associated with increased fracture incidence in unadjusted and adjusted models [adjusted hazard ratio (HR) = 1.25 (95% confidence interval 1.05-1.49) for 60 mL/min/1.73 m2; 1.65 (1.14-2.37) for 45 mL/min/1.73 m2]. The eGFR was linearly associated with fracture incidence <75 mL/min/1.73 m2 [HR = 1.18 (1.04-1.34) per 10 mL/min/1.73 m2 decrease] but not above [HR = 0.98 (0.91-1.06) per 10 mL/min/1.73 m2 decrease). The effect of decreased eGFR on fracture incidence was more pronounced in younger individuals [HR = 2.45 (1.28-4.67) at 45 years; 1.11 (0.73-1.67) at 65 years] and in men. CONCLUSIONS: Even early CKD increases fracture incidence, especially in younger individuals and in men.

Determinants of Increased Central Excess Pressure in Dialysis: Role of Dialysis Modality and Arteriovenous Fistula.

BACKGROUND: Arterial reservoir-wave analysis (RWA)-a new model of arterial hemodynamics-separates arterial wave into reservoir pressure (RP) and excess pressure (XSP). The XSP integral (XSPI) has been associated with increased risk of clinical outcomes. The objectives of the present study were to examine the determinants of XSPI in a mixed cohort of hemodialysis (HD) and peritoneal dialysis (PD) patients, to examine whether dialysis modality and the presence of an arteriovenous fistula (AVF) are associated with increased XSPI. METHOD: In a cross-sectional study, 290 subjects (232 HD and 130 with AVF) underwent carotid artery tonometry (calibrated with brachial diastolic and mean blood pressure). The XSPI was calculated through RWA using pressure-only algorithms. Logistic regression was used for determinants of XSPI above median. Through forward conditional linear regression, we examined whether treatment by HD or the presence of AVF is associated with higher XSPI. RESULTS: Patients with XSPI above median were older, had a higher prevalence of diabetes and cardiovascular disease, had a higher body mass index, and were more likely to be on HD. After adjustment for confounders, HD was associated with a higher risk of higher XSPI (odds ratio = 2.39, 95% confidence interval: 1.16-4.98). In a forward conditional linear regression analysis, HD was associated with higher XSPI (standardized coefficient: 0.126, P = 0.012), but on incorporation of AVF into the model, AVF was associated with higher XSPI (standardized coefficient: 0.130, P = 0.008) and HD was excluded as a predictor. CONCLUSION: This study suggests that higher XSPI in HD patients is related to the presence of AVF.

Clinical Value of Complement Activation Biomarkers in Overt Diabetic Nephropathy.

BACKGROUND: Experimental studies support a role of complement activation in diabetic nephropathy (DN), yet few clinical correlates exist. We evaluated urinary levels of sC5b-9 membrane attack complex (MAC) in patients with overt DN, and examined its association with the glomerular filtration rate (GFR) decline, proteinuria, and inflammatory biomarkers. We explored different complement pathways and compared our findings to autoimmune glomerulonephritis. METHODS: We prospectively followed 83 patients with DN and obtained repeated measurements of proteinuria, complement fragments (sC5b-9, C4a, C1q, mannose-binding lectin-associated serine protease [MASP]-1, and factor Bb), monocyte chemoattractant protein-1 (MCP-1), and transforming growth factor (TGF)-ß1. We assessed independence and interactions using general linear models and repeated measures analyses and compared levels with subjects with active focal and segmental glomerulosclerosis, ANCA-associated vasculitis, and membranous and IgA nephropathies (n = 63). RESULTS: The diabetic cohort had an initial GFR of 25 ± 9 ml/min per 1.73 m2 and a renal function decline of 2.9 ± 3.0 ml/min per 1.73 m2 per year. All complement biomarkers were strongly intercorrelated and associated with biomarker inflammation and fibrosis, proteinuria, and the rate of renal function decline. There was a significant interaction (P = 0.03) between the level of proteinuria and urinary sC5b-9: in individuals with higher levels of urinary MAC, the relationship between proteinuria and the rate of renal function decline was more pronounced than in those with low urinary MAC. Finally, patients with DN had levels of urinary sC5b-9 comparable to autoimmune glomerulonephritis, when stratified by the level of proteinuria. CONCLUSION: Urinary MAC is present in patients with overt DN at levels comparable to autoimmune glomerulonephritis and correlates with the GFR decline, supporting that complement activation and its measurement are clinically relevant in DN.

Uromodulin in a Pathway Between Decreased Renal Urate Excretion and Albuminuria.

BACKGROUND: The mechanism explaining the inverse association between renal urate and albumin excretion remains unclear. First, we evaluated the impact of candidate variants in the main urate transporter genes (i.e., SLC2A9, SLC22A12, ABCG2) on the association between fractional excretion of uric acid (FEUA) and urinary albumin/creatinine ratio (uACR). Second, we examined uromodulin and sodium excretion as mediators of the association between FEUA and uACR. METHODS: We performed cross-sectional analysis of 737 French Canadians from the CARTaGENE cohort, a random sample of the Quebec population aged 40-69 years (a total of 20,004 individuals). Individuals with available genotyping and urinary data were obtained from a sub-study including gender-matched pairs with high and low Framingham Risk Score and vascular rigidity index. We further excluded individuals with an estimated glomerular filtration rate <60 ml/min/1.73 m2, glycosuria, and use of confounding medication. A spot urine sample was analyzed. Genotyping was performed using the Illumina Omni2.5-8 BeadChips. Genetic variants were analyzed using an additive model. RESULTS: Final analyses included 593 individuals (45.5% of men; mean age 54.3 ± 8.6). We observed an antagonistic interaction between rs13129697 variant of the SLC2A9 gene and FEUA tertiles on uACR (P = 0.002). Using the mediation analysis, uromodulin explained 32%, fractional excretion of sodium (FENa) 44%, and uromodulin together with FENa explained 70% of the inverse relationship between FEUA and uACR. Bootstrapping process confirmed the role of both mediators. CONCLUSIONS: Our data suggest that the association of albuminuria with decreased renal urate excretion may be modified by the transporter SLC2A9, and mediated by uromodulin and sodium handling.

An Adjustable Dalteparin Sodium Dose Regimen for the Prevention of Clotting in the Extracorporeal Circuit in Hemodialysis: A Clinical Trial of Safety and Efficacy (the PARROT Study).

BACKGROUND: Dalteparin sodium, a low-molecular-weight heparin, is indicated for prevention of clotting in the extracorporeal circuit during hemodialysis (HD). Product labeling recommends a fixed single-bolus dose of 5000 international units (IU) for HD sessions lasting up to 4 hours, but adjustable dosing may be beneficial in clinical practice. OBJECTIVE: The aim of the PARROT study was to investigate the safety and efficacy of an adjustable dose of dalteparin in patients with end-stage renal disease requiring 3 to 4 HD sessions per week. DESIGN: A 7-week, open-label, multicenter study with a single treatment arm, conducted between October 2013 and March 2016. SETTING: Ten sites in Canada. PATIENTS: A total of 152 patients with end-stage renal disease requiring 3 to 4 HD sessions per week. MEASUREMENTS: The primary outcome was the proportion of HD sessions completed without premature termination due to inadequate anticoagulation. METHODS: All participants initially received a dose of 5000 IU dalteparin, which could be adjusted at subsequent HD sessions when clinically indicated, by increment or decrement of 500 or 1000 IU, with no specified dose limits. RESULTS: Patients were followed for 256 patient-months. Nearly all (99.9%; 95% confidence interval [CI]: 99.7-100) evaluable HD sessions were completed without premature clotting. Dose was adjusted for more than half (52.3%) of participants, mostly owing to clotting or access compression time >10 minutes. Median dalteparin dose was 5000 IU (range: 500-13 000 IU). There were no major bleeds, and minor bleeding was reported in 2.3% of all HD sessions. There was no evidence of bioaccumulation. LIMITATIONS: This short-term study, with a single treatment arm, was designed to optimize dalteparin dose using a flexible dosing schedule; it was not designed to specifically evaluate dalteparin dose minimization, provide a direct comparison of dalteparin versus unfractionated heparin, or provide information on long-term safety for flexible dalteparin dosing. Patients were excluded if they were at high risk of bleeding, including those on anticoagulants and those on antiplatelet agents other than aspirin <100 mg/d. CONCLUSIONS: Overall, an adjustable dalteparin sodium dose regimen allowed safe completion of HD, with clinical benefits over fixed dosing. TRIAL REGISTRATION: ClinicalTrials.gov NCT01879618, registered June 13, 2013.

CONTEXTE: La daltéparine sodique, une héparine de faible poids moléculaire, est indiquée pour prévenir la formation de caillots dans le circuit extracorporel durant l'hémodialyse (HD). Pour une séance de dialyse d'une durée maximale de quatre heures, l'étiquette du produit recommande une dose fixe de 5 000 unités internationales (U.I.) administrée en bolus. Cependant, il est possible qu'il puisse être bénéfique d'ajuster la dose en pratique. OBJECTIF: Le but de l'étude PARROT était d'analyser l'innocuité et l'efficacité d'une dose ajustable de daltéparine chez des patients atteints d'insuffisance rénale terminale (IRT) et nécessitant trois à quatre séances d'HD par semaine. TYPE D'ÉTUDE: Il s'agit d'une étude ouverte et multicentrique à traitement unique d'une durée de sept semaines couvrant la période entre octobre 2013 et mars 2016. CADRE: L'étude a eu lieu dans dix centres de dialyse au Canada. SUJETS: L'étude a inclus 152 patients atteints d'IRT et nécessitant trois à quatre séances d'HD par semaine. MESURES: Le résultat principal était la proportion de séances d'HD complétées, non interrompues de manière prématurée en raison d'une anticoagulation inadéquate. MÉTHODOLOGIE: Tous les participants ont initialement reçu 5000 U.I. de daltéparine, dose qui a pu être ajustée lors des séances subséquentes, lorsqu'indiqué par le contexte clinique, à raison d'augmentation ou de réduction de 500 ou 1 000 U.I., sans spécification quant aux doses limites. RÉSULTATS: Les patients ont été suivis sur une période de 256 mois-patients. Pratiquement toutes les séances d'HD évaluables (99,9 %; IC 95 % : 99,7-100) ont été complétées sans coagulation prématurée. La dose de daltéparine a été ajustée pour plus de la moitié (52,3 %) des participants, essentiellement en raison de coagulation ou d'un besoin de procéder à une compression de l'accès vasculaire au-delà de 10 minutes. La dose médiane de daltéparine était de 5 000 U.I. (entre 500 et 13 000 U.I.). Aucune hémorragie majeure n'a été rapportée, mais une hémorragie mineure est survenue dans 2,3 % de toutes les séances d'HD analysées. Aucune bioaccumulation n'a été détectée. LIMITES: Cette étude de courte durée à traitement unique a été conçue pour optimiser le dosage de daltéparine à l'aide d'un schéma de posologie flexible. Elle ne visait pas à évaluer spécifiquement la minimisation de la dose ou à fournir des informations sur l'innocuité à long terme d'une posologie flexible pour la daltéparine. Également, les patients à haut risque d'hémorragie ont été exclus de l'étude, notamment ceux qui prenaient des anticoagulants ou des antiplaquettaires autres qu'une dose quotidienne de moins de 100 mg d'aspirine. CONCLUSION: Dans l'ensemble, un schéma posologique flexible pour la daltéparine sodique a permis de compléter les séances d'HD de façon sécuritaire, en plus de fournir des avantages cliniques par rapport à une dose fixe.

Central and Brachial Blood Pressures, Statins, and Low-Density Lipoprotein Cholesterol: A Mediation Analysis.

Central blood pressure may be a better predictor of cardiovascular disease than brachial pressure. Although statins reduce brachial pressure, their impact on central pressure remains unknown. Furthermore, whether this effect is mediated through a decrease in low-density lipoprotein cholesterol (LDL-c) is unknown. This study aims to characterize the association of statins and LDL-c with central and brachial blood pressures and to quantify their respective effects. Of the 20 004 CARTaGENE participants, 16 507 had available central blood pressure, LDL-c, and Framingham risk score. Multivariate analyses were used to evaluate the association between central pressure and LDL-c in subjects with or without statins. The impact of LDL-c on the association between statin and pressure parameters was determined through mediation analyses. LDL-c was positively associated with systolic and diastolic central pressure in nonusers (ß=0.077 and 0.106; P<0.001) and in participants with statins for primary (ß=0.086 and 0.114; P<0.001) and secondary prevention (ß=0.120 and 0.194; P<0.003). Statins as primary prevention were associated with lower central systolic, diastolic, and pulse pressures (-3.0, -1.6, and -1.3 mm Hg; P<0.001). Mediation analyses showed that LDL-c reduction contributed to 15% of central systolic and 44% of central diastolic pressure changes associated with statins and attenuated 22% of the effects on central pulse pressure. Similar results were found with brachial pressure components. In conclusion, reduction of LDL-c was associated with only a fraction of the lower blood pressures in statin user and seemed to be mostly associated with improvement of steady (diastolic) pressure, whereas non-LDL-c-mediated pathways were mostly associated with changes in pulsatile pressure components.

Uric acid association with pulsatile and steady components of central and peripheral blood pressures.

OBJECTIVE: Whether the cardiovascular risk attributed to elevated uric acid levels may be explained by changes in central and peripheral pulsatile and/or steady blood pressure (BP) components remains controversial. METHODS: In a cross-sectional analysis of normotensive and untreated hypertensive participants of the CARTaGENE populational cohort, we examined the relationship between uric acid, and both pulsatile and steady components of peripheral and central BP, using sex-stratified linear regressions. RESULTS: Of the 20 004 participants, 10 161 individuals without antihypertensive or uric acid-lowering drugs had valid pulse wave analysis and serum uric acid levels. In multivariate analysis, pulsatile components of BP were not associated with uric acid levels, whereas steady components [mean BP (MBP), peripheral and central DBP] were all associated with higher levels of uric acid levels in women and men (all P < 0.001). Furthermore, there was a gradual increase of central SBP (cSBP), DBP and MBP from the lowest to the highest quintiles of uric acid levels but not for MBP-adjusted cSBP. Peripheral and cSBP, which are aggregate measures of pulsatile and steady BP, were also associated with uric acid levels in women (ß = 0.063 and 0.072, respectively, both P < 0.001) and men (ß = 0.043 and 0.051, both P ≤ 0.003). After further adjustments for MBP to account for the concomitant increase in steady component of BP, SBPs were no longer associated with uric acid levels. CONCLUSION: Serum uric acid levels appear to be associated with both central and peripheral steady but not pulsatile BP, regardless of sex.