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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., Graphical Abstract Graphical Abstract

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.

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.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.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.Simultaneous measurements of invasive aortic BP and noninvasive BP.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.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).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.

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.

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

BACKGROUND In the ISCHEMIA-CKD trial, the primary analysis showed no significant difference in the risk of death or myocardial infarction with initial angiography and revascularization plus guideline-based medical therapy (invasive strategy) as compared with guideline-based medical therapy alone (conservative strategy) in participants with stable ischemic heart disease, moderate or severe ischemia, and advanced chronic kidney disease (an estimated glomerular filtration rate of

Key Points Question Is glomerular hyperfiltration associated with future cardiovascular events in healthy individuals? Findings In this cohort study of 9515 patients with health information accessed through the CARTaGENE research platform, glomerular hyperfiltration was shown to be associated with increased risk of cardiovascular events in middle-aged healthy individuals. Meaning This study found an increased cardiovascular disease risk associated with glomerular hyperfiltration in middle-aged healthy individuals, suggesting that glomerular hyperfiltration could be a useful cardiovascular biomarker in this population., This population-based cohort study examines whether glomerular hyperfiltration is associated with a higher risk of cardiovascular events in healthy middle-aged 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.

Background Missing preadmission serum creatinine (SCr) values are a common obstacle to assess acute kidney injury (AKI) diagnosis and outcomes. The Kidney Disease Improving Global Outcomes (KDIGO) guidelines suggest using a SCr computed from the Modification of Diet in Renal Disease (MDRD) with an estimated glomerular filtration rate of 75 ml/min/1.73 m2. We aimed to identify the best surrogate method for baseline SCr to assess AKI diagnosis and outcomes. Methods We compared the use of 1) first SCr at hospital admission 2) minimal SCr over 2 weeks after intensive care unit admission 3) MDRD computed SCr and 4) Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) computed SCr to assess AKI diagnosis and outcomes. We then performed multilinear regression models to predict preadmission SCr and imputation strategies to assess AKI diagnosis. Results Our one-year retrospective cohort study included 1001 critically ill adults; 498 of them had preadmission SCr values. In these patients, AKI incidence was 25.1% using preadmission SCr. First SCr had the best agreement for AKI diagnosis (22.5%; kappa = 0.90) and staging (kappa = 0.81). MDRD, CKD-EPI and minimal SCr overestimated AKI diagnosis (26.7%, 27.1% and 43.2%;kappa = 0.86, 0.86 and 0.60, respectively). However, MDRD and CKD-EPI computed SCr had a better sensitivity than first SCr for AKI (93% and 94% vs. 87%). Eighty-eight percent of patients experienced renal recovery at least 3 months after hospital discharge. All methods except the first SCr significantly underestimated the percentage of renal recovery. In a multivariate model, age, male gender, hypertension, heart failure, undergoing surgery and log first SCr best predicted preadmission SCr (adjusted R2 = 0.56). Imputation methods with first SCr increased AKI incidence to 23.9% (kappa = 0.92) but not with MDRD computed SCr (26.7%;kappa = 0.89). Conclusion In our cohort, first SCr performed better for AKI diagnosis and staging, as well as for renal recovery after hospital discharge than MDRD, CKD-EPI or minimal SCr. However, MDRD SCr and CKD-EPI SCr improved AKI diagnosis sensitivity. Imputation methods minimally increased agreement for AKI diagnosis. Electronic supplementary material The online version of this article (doi:10.1186/s12882-017-0552-3) contains supplementary material, which is available to authorized users.

Whether early chronic kidney disease (CKD) is associated with fracture in middle-aged adults is unclear. In a cross-sectional analysis of the CARTaGENE survey, we observed that early CKD was not associated with increased fracture, did not modify the association between calcaneal QUS and fracture, but modified the association between clinical, pharmacological parameters and fracture. The association between advanced CKD and increased fracture risk is well described. However, whether early CKD is associated with increased fractures, especially in middle-aged adults, is unclear. We aimed to assess if early CKD is associated with increased fracture status and whether early CKD status modifies the association between calcaneal quantitative ultrasound parameters, clinical, pharmacological parameters, and fractures. Cross-sectional analysis of CARTaGENE, a population-based survey of 40- to 69-year-old individuals. Individuals with CKD (stage 2, estimated glomerular filtration rate [eGFR] 60–89 ml/min/1.73 m2; stage 3, eGFR 30–59) were compared to non-CKD individuals (eGFR > 90). Fracture status (excluding face, toe, hand, and patella) was identified through a questionnaire at baseline. Calcaneal quantitative ultrasound (QUS) was measured in each participant. A total of 17,608 individuals (656 CKD stage 3; 8227 stage 2; 8725 non-CKD) were included. CKD stage 2 and 3 individuals (mean eGFR 78 and 53 ml/min/1.73 m2) were older and had more diabetes, cardiovascular disease, and hypertension. Fracture status prevalence was 14.9% in CKD stage 3, 10.8% in CKD stage 2, and 9.0% in non-CKD individuals. Fracture status prevalence was similar between CKD and non-CKD individuals when stratified by age or after adjustment for demographic and clinical parameters. QUS stiffness index was associated with fracture status in both CKD stage 3 (standardized odds ratio [sOR] = 1.525 [1.200 to 1.939] per 1 SD decrease), stage 2 (sOR = 1.415 [1.310 to 1.530]), and non-CKD individuals (sOR = 1.477 [1.361 to 1.602]). The associations between blood pressure, antihypertensive, and fracture status followed a U-shape throughout the progression of CKD. CKD stage 3 was not associated with an increase in fracture status. QUS parameters were similarly associated with fracture status in patients with and without CKD.

Cardiovascular disease is more common in patients with chronic kidney disease (CKD), and traditional risk factors do not adequately predict those at risk for cardiovascular (CV) events. Recent evidence suggests elevated trimethylamine N-oxide (TMAO), created by gut microflora from dietary L-carnitine and choline, is associated with CV events. We investigated the relationship of TMAO levels in patients with stages 3b and 4 CKD to ischemic CV events using the CanPREDDICT cohort, a Canada-wide observational study with prospective 3-year follow-up of adjudicated CV events. Baseline samples were obtained for 2529 CKD patients. TMAO, choline, and L-carnitine levels were measured using tandem mass spectrometry. Baseline median TMAO level was high for the whole cohort (20.41 μM; interquartile range [IQR]: 12.82–32.70 μM). TMAO was independently associated with CV events (hazard ratio 1.23; 95% confidence interval: 1.06–1.42 / 1 SD lnTMAO) after adjusting for all potential CV risk factors. Those in the highest TMAO quartile had significantly higher risk of CV events (adjusted hazard ratio 1.59; 95% confidence interval: 1.04–2.43; P = 0.0351) in the analysis of recurring ischemic events. Among those with stage 3b CKD (hazard ratio 1.45; 95% confidence interval: 1.12–1.87 / 1 SD lnTMAO), independent of kidney function, TMAO levels identified those at highest risk for events. Our results suggest that TMAO may represent a new potentially modifiable CV risk factor for CKD patients. Further studies are needed to determine sources of variability and if lowering of TMAO reduces CV risk in CKD.

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 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.

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 (β=0.077 and 0.106; P P P P

Context Hemoperfusion (HP) or dialysis is occasionally used following carbamazepine (CBZ) toxicity but it remains unclear which is the most efficient modality. We describe a case of severe CBZ intoxication treated with different extracorporeal modalities during which CBZ toxicokinetics were compared. Case details A 58-year-old man was transferred to our facility 24 hours after ingesting over 14 g of sustained-release CBZ. Because of worsening neurological condition requiring mechanical ventilation and CBZ levels reaching 47.6 μg/mL, he underwent three intermittent hemodialysis (IHD), two continuous veno-venous hemofiltration (CVVH), and one IHD with HP (IHD-HP). IHD and CVVH removed 1.73 g of carbamazepine over 43 hours. Mean apparent half-life was 8.8 hours during IHD 49.1 hours during CVVH, and 5.1 hours during IHD-HP, while measured endogenous half-life after extracorporeal therapies was 81.4 hours. Mean CBZ clearances were 106.2 mL/min during IHD and 21.2 mL/ min during CVVH. His neurological status improved during extracorporeal elimination, and he was discharged without sequela after 16 days. Treatments were well tolerated aside from thrombocytopenia during IHDHP. Discussion All extracorporeal treatments facilitated CBZ elimination, although CVVH was significantly less efficient than IHD and IHD-HP. IHD-HP may be better than IHD alone but must be weighed against its risks. IHD appears sufficient to eliminate CBZ and may need to be repeated or prolonged according to the clinical context if CBZ absorption is delayed.

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

Background— Anemia is a highly prevalent and strong independent prognostic marker in heart failure (HF), yet this association is not completely understood. Whether anemia is simply a marker of disease severity and concomitant chronic kidney disease or represents the activation of other detrimental pathways remains uncertain. We sought to determine which pathophysiological pathways are exacerbated in patients with HF, reduced ejection fraction (HFrEF) and anemia in comparison with those without anemia. Methods and Results— In a prospective study involving 151 patients, selected biomarkers were analyzed, each representing proposed contributive mechanisms in the pathophysiology of anemia in HF. We compared clinical, echocardiographic, and circulating biomarkers profiles among patients with HFrEF and anemia (group 1), HFrEF without anemia (group 2), and chronic kidney disease with preserved EF, without established HF (chronic kidney disease control group 3). We demonstrate here that many processes other than those related to chronic kidney disease are involved in the anemia–HF relationship. These are linked to the pathophysiological mechanisms pertaining to left ventricular systolic dysfunction and remodeling, systemic inflammation and volume overload. We found that levels of interleukin-6 and interleukin-10, specific markers of cardiac remodeling (procollagen type III N-terminal peptide, matrix metalloproteinase-2, tissue inhibitor of matrix metalloproteinase 1, left atrial volume), myocardial stretch (NT-proBNP [N-terminal probrain natriuretic peptide]), and myocyte death (troponin T) are related to anemia in HFrEF. Conclusions— Anemia is strongly associated not only with markers of more advanced and active heart disease but also with the level of renal dysfunction in HFrEF. Increased myocardial remodeling, inflammation, and volume overload are the hallmarks of patients with anemia and HF. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00834691.

Item does not contain fulltext Little is known about the risk of venous thrombosis following kidney transplant. To determine this we estimated the risk of thromboembolic events (TEs) in a cohort of consecutive patients who underwent kidney transplantation at a single tertiary care center over an 11-year period and calculated standardized incidence ratios (SIRs) for a first TE in kidney transplant recipients compared with the general population. We then performed a nested case-control study and compared patients with and without TEs to identify risk factors for thrombosis. Among 913 kidney transplant recipients (KTRs), 68 patients developed these events. The SIR for TEs in KTRs compared with the general population was 7.9 over the duration of follow-up. The risk was particularly higher in the first post-transplant year (SIR 26.1) but remained elevated afterward (SIR 5.2). Hospitalization, use of sirolimus, low hemoglobin level, and use of renin-angiotensin system inhibitors were independently associated with these events. When cases of TEs that occurred during hospitalization were excluded, the risk of these events remained elevated. The risk of TEs in KTRs was eightfold higher than in the general population but not fully explained by the increased risk associated with hospitalization. Our results underscore the important risk of thrombosis in patients who received a kidney transplant, making vigilance mandatory especially during hospitalization.

Background The osmolal gap has been used for decades to screen for exposure to toxic alcohols. However, several issues may affect its reliability. We aimed to develop equations to calculate osmolarity with improved performance when used to screen for intoxication to toxic alcohols. Study Design Retrospective cohort study. Setting & Participants 7,525 patients undergoing simultaneous measurements of osmolality, sodium, potassium, urea, glucose, and ethanol or undergoing similar measurements performed within 30 minutes of a measurement of toxic alcohol levels at a single tertiary-care center from April 2001 to June 2016. Patients with detectable toxic alcohols were excluded. Index Test Equations to calculate osmolarity using multiple linear regression. Outcomes The performance of new equations compared with published equations developed to calculate osmolarity, and to diagnose toxic alcohol intoxications more accurately. Results We obtained 7,525 measurements, including 100 with undetectable toxic alcohols. Among them, 3,875 had undetectable and 3,650 had detectable ethanol levels. In the entire cohort, the best equation to calculate osmolarity was 2.006×Na + 1.228×Urea + 1.387×Glucose + 1.207×Ethanol (values in mmol/L, R2=0.96). A simplified equation, 2.0×Na + 1.2×Urea + 1.4×Glucose + 1.2×Ethanol, had a similar R2 with 95% of osmolal gap values between −10.9 and 13.8. In patients with undetectable ethanol concentrations, the range of 95% of osmolal gap values was narrower than previous published formulas, and in patients with detectable ethanol concentrations, the range was narrower or similar. We performed a subanalysis of 138 cases for which both the toxic alcohol concentration could be measured and the osmolal gap could be calculated. Our simplified equation had superior diagnostic accuracy for toxic alcohol exposure. Limitations Single center, no external validation, limited number of cases with detectable toxic alcohols. Conclusions In a large cohort, coefficients from regression analyses estimating the contribution of glucose, urea, and ethanol were higher than 1.0. Our simplified formula to precisely calculate osmolarity yielded improved diagnostic accuracy for suspected toxic alcohol exposures than previously published formulas.

Aims The evolution of diabetic nephropathy is incompletely accounted by current clinical tools. New biomarkers may refine patient assessment and help monitor therapy. We compared the added predictive value of 7 candidate inflammatory urinary biomarkers to known risk factors of progression. Methods We prospectively followed 83 patients with overt diabetic nephropathy for a median 2.1 years and obtained repeated measurements of proteinuria, IL-1β, IL-6, IL-8, MCP-1, TNF-α, TGF-β1, and PAI-1. Results Patients had an initial estimated glomerular filtration rate of 25 ± 9 mL/min/1.73 m 2 , blood pressure of 142/69 mmHg and used a median of 4 anti-hypertensive medications over the course of the study. The observed rate of renal function decline was 2.9 ± 3.0 mL/min/1.73 m 2 /year. All urinary biomarkers levels were collinear and for each one except IL-1β, elevated levels predicted a more rapid progression. MCP-1 was the only biomarker increasing during follow-up, which also correlated with a worst outcome. Using multivariate linear regression adjusting for clinical risk factors of progression, urinary MCP-1 and TGF-β1 predicted progression independently and additively to the degree of proteinuria. We dichotomized these 3 biomarkers and observed a renal function decline with 0, 1, 2 or 3 elevated biomarkers of −0.8 ± 1.4, −2.1 ± 2.1, −4.2 ± 2.8 and −6.0 ± 2.8 mL/min/1.73 m 2 /year, respectively ( p Conclusions Multiple urinary biomarkers predict outcome in overt diabetic nephropathy. However, urinary MCP-1 and TGF-β1 are also independent and additive to proteinuria in predicting the rate of renal function decline and could serve as useful clinical tools in patient risk stratification.

Renal failure in multiple myeloma is frequent, and portends a dismal prognosis. Precipitation of free light chains in tubules contributes to development of cast nephropathy and renal failure. Treatment with plasmapheresis is reported as an adjunct to chemotherapy in these patients, but evidence regarding its efficacy in the literature is conflicting. In this article, we report the case of a 63-year-old man who presented with severe acute renal failure due to myeloma cast nephropathy and whose kidney function improved significantly following treatment with dexamethasone and a course of 8 plasma exchanges. We then provide a review of the technical aspects of plasmapheresis, followed by an analysis of the randomized trials that have been published to date on the efficacy of plasmapheresis for myeloma cast nephropathy.

OBJECTIVES Central hemodynamic parameters are better predictors of the cardiovascular burden than peripheral blood pressure (BP). Beta-blockers are known to reduce central BP to a lesser extent than peripheral BP, a hypothesized mechanistic consequence of heart rate (HR) reduction. METHODS The association between beta-blocker use, HR and central hemodynamics indices was studied in treated hypertensive participants of the CARTaGENE study using propensity score analyses and multivariate linear regressions. RESULTS Of the 20 004 participants, 2575 were treated hypertensive patients with valid pulse wave analysis. Using propensity score analyses, beta-blocker users (n = 605) were matched to nonusers having similar clinical characteristics with (Model 1) and without (Model 2) adjustment for HR. This resulted in 457 and 510 pairs with adequate balance, except for a HR difference in Model 2 (62.5 ± 10.5 vs. 70.4 ± 11.5 bpm, p

SummaryBleeding and thrombotic disorders are major complications affecting patients with chronic kidney disease (CKD). Exposure of circulating platelets to uraemic toxins and contact with artificial surfaces during dialysis induce platelet abnormalities and alter the platelet proteome. We hypothesised that these changes may be subsequent to changes in the composition and/or regulation of the platelet transcriptome. In this study, we investigated the circulating platelets of 10 CKD patients (i.e. five chronic haemodialysis patients and five stage 4 CKD uraemic patients) and five age- and sex-matched healthy subjects. We observed an alteration of the platelet messenger RNA (mRNA) and microRNA transcriptome in CKD patients. Impaired in uraemic platelets, the levels of some mRNAs and of most microRNAs appeared to be corrected by dialysis, which is consistent with a beneficial effect of dialysis and a mRNA regulatory role of platelet microRNAs. Reduced in platelets of uraemic patients, phosphatidylcholine transfer protein (PCTP) and WD repeat-containing protein 1 (WDR1) were found to be regulated by microRNAs, the latter of which involving hsa-miR-19b, a microRNA increased in platelets of uraemic patients and involved in platelet reactivity. These results suggest that an alteration of microRNA-based mRNA regulatory mechanisms may underlie the platelet response to uremia and entail the development of platelet-related complications in CKD.

BACKGROUND In patients with chronic kidney disease (CKD), anemia is associated with left ventricular hypertrophy and adverse cardiovascular and clinical outcomes. Moreover, anemia is associated with a reduction in quality of life, particularly when the hemoglobin level drops below 100 g/l. 1 Thus, the goal of treating anemia in iron-replete patients with erythropoietic-stimulating agents (ESAs) is to reduce the likelihood of cardiovascular events, improve patients’ survival, and improve patients’ quality of life while minimizing any deleterious effects of the drug. Given that ESAs increase blood pressure and have other potential side effects, it is also important to assess whether the quantity of the ESA used might contribute to adverse events such as more rapid deterioration of kidney function, earlier requirement for dialysis, and vascular access failure. It is acknowledged that, if left untreated, patients with severe anemia may require blood transfusions, which have associated risks and costs, and possible implications for patients awaiting a kidney transplant. In light of this, in most developed countries, the question for CKD patients with significant anemia has often not been whether to use ESAs, but when to use them and what target hemoglobin level to aim for. 2 The earliest anemia correction studies in nondialysischronic kidney disease (ND-CKD) and hemodialysis-chronic kidney disease (HD-CKD) patients compared the use of erythropoietin a with placebo. 3–5 Most early studies were not designed and powered to examine clinical outcomes other than quality of life, and no differences were apparent in such other outcomes. Several of the studies showed improvements in quality of life compared with placebo. 3–5 Subsequent randomized control trials (RCTs) have tended to examine the impact of using ESAs to achieve different target hemoglobin level ranges on surrogate endpoints, such as left ventricular (LV) mass, where patients with the lower hemoglobin target would be less likely to require the use of an ESA or would require lower doses to maintain the prespecified lower target hemoglobin. Two RCTs 6,7 in HDCKD patients compared with the use of ESAs to achieve intermediate hemoglobin and high hemoglobin targets. Although both studies showed no difference in progression of LV mass, the higher target hemoglobin led to improved quality of life in some of the domains, but the size of this

Supplemental therapies are treatment strategies to enhancethe responsiveness of erythropoietic-stimulating.agents(ESAs) in the management of anemia in chronic kidneydisease (CKD) patients, including those who exhibitresistance to ESAs. The desired outcome is an improvementin hemoglobin levels, reduction in ESA dose, or both.Although the outcomes of these studies (hemoglobin level,ESA dose) are arguably the relevant outcomes of interest, asthe outcome is not a ‘clinical outcome,’ each of the studies isassigned either a Grade C or D level of evidence.

Renal failure is a frequent complication of multiple myeloma and portends a poor prognosis. Plasmapheresis has been suggested as an adjunct to chemotherapy to halt or reverse renal injury associated with multiple myeloma. The purpose of this article is to review the rationale for using plasmapheresis for this indication and then provide a discussion of the evidence regarding its use.The outcome of patients with multiple myeloma has improved considerably in recent years, mostly owing to the introduction of new highly effective chemotherapeutic agents. However, patients with renal failure who do not recover independent renal function continue to have very poor prognosis. Recent evidence now indicates that an early and sustained reduction in circulating free light chains (FLCs) is associated with improved renal recovery in patients with myeloma kidney. Extracorporeal removal of FLCs with plasmapheresis, or other techniques, can achieve rapid and sustained reduction in serum FLC concentration in patients with acute myeloma kidney. Unfortunately, there is currently no convincing evidence in the literature that the addition of mechanical removal of FLC to standard chemotherapy translates into clinical benefits for patients.Plasmapheresis is theoretically attractive as a means of rapidly lowering serum FLC burden in the hope of reducing nephrotoxicity in patients with multiple myeloma. However, the role of plasmapheresis in improving renal prognosis and patient survival remains to be demonstrated.

Background: Recommendations for the management of left ventricular (LV) systolic dysfunction in the general population and patients with end-stage renal disease (ESRD) include the use of angiotensin-converting enzyme (ACE) inhibitors and β-blockers. Limited data from the literature suggest that these pharmacological agents may be underused in patients with ESRD. The goal of this study is to describe the use of these medications and investigate barriers to their use in dialysis patients. Methods: We prospectively studied 420 hemodialysis patients. Diagnosis of systolic dysfunction was based on echocardiogram results. Use of cardiac medication was recorded for all patients with systolic dysfunction, and a questionnaire was administered to nephrologists to determine the basis for decisions concerning ACE-inhibitors and β-blockers use/nonuse. Results: Forty-seven patients (11%) were found to have an LV ejection fraction of 40% or less. Of those, 72% were administered a β-blocker and 36% were administered an ACE inhibitor. Only 12 patients (25.5%) were administered a combination of β-blocker and ACE inhibitor. Reasons indicated by nephrologists for not prescribing these medications were "concern about adverse reactions (eg, hypotension, hyperkalemia)" in 88% of cases, "adequate control of symptoms with ultrafiltration" in 38%, "unproven benefit" in 25%, and "unfavorable risk-benefit ratio" in 17%. Medication costs and concern about patient compliance were not identified as significant concerns by physicians. Conclusion: Only 25.5% of patients with ESRD with LV systolic dysfunction receive appropriate treatment. Concern regarding adverse reactions was the most frequent reason indicated by nephrologists for not prescribing ACE inhibitors and β-blockers.

BACKGROUND Uraemia is associated with endothelial dysfunction, but the effect of uraemic plasma on the gene expression pattern of human coronary arterial endothelial cells (HCAEC) has never been defined. METHODS HCAECs were exposed for 48 h to a culture medium supplemented with 20% uraemic vs normal plasma. We extracted mRNA and hybridized it onto Affymetrix HG-U133 Plus2 microarrays. We validated our findings for five genes of interest by real-time PCR and performed evaluations of cell proliferation and apoptosis in HCAECs exposed to uraemic vs normal plasma. RESULTS Six genes involved in the regulation of cell-cycle progression (CDK-1, topoisomerase II, PDZ-binding kinase, CDCA1, protein SDP35, E2F transcription factor 8) and two genes of the cholesterol efflux system (ABCA1 and ABCG1) were down-regulated in HCAECs exposed to uraemic plasma (>1.75-fold change vs normal). Real-time PCR confirmed the down-regulation observed in the microarray experiment. Cell proliferation was significantly decreased in HCAECs exposed to uraemic vs normal plasma for 48 h (86 vs 95% of serum-starved control, P = 0.006). Exposure to uraemic plasma for 48 h was associated with increased apoptosis of HCAEC as compared with normal plasma (7.7 vs 2.8%, P < 0.001), a phenomenon that was further enhanced when oxidized LDLs (150 microg protein/ml) were added to the medium containing uraemic plasma (16.9 vs 7.7%, P < 0.001). CONCLUSIONS The down-regulation of genes involved in cell-cycle progression and cholesterol efflux from HCAECs exposed to uraemic conditions could contribute to enhancing endothelial dysfunction and atherosclerosis in patients with chronic renal failure.

We congratulate the KDIGO (Kidney Disease: Improving Global Outcomes) work group on their comprehensive work in a broad subject area and agreed with many of the recommendations in their clinical practice guideline on the evaluation and management of chronic kidney disease. We concur with the KDIGO definitions and classification of kidney disease and welcome the addition of albuminuria categories at all levels of glomerular filtration rate (GFR), the terminology of G categories rather than stages to describe level of GFR, the division of former stage 3 into new G categories 3a and 3b, and the addition of the underlying diagnosis. We agree with the use of the heat map to illustrate the relative contributions of low GFR and albuminuria to cardiovascular and renal risk, though we thought that the highest risk category was too broad, including as it does people at disparate levels of risk. We add an albuminuria category A4 for nephrotic-range proteinuria and D and T categories for patients on dialysis or with a functioning renal transplant. We recommend target blood pressure of 140/90mm Hg regardless of diabetes or proteinuria, and against the combination of angiotensin receptor blockers with angiotensin-converting enzyme inhibitors. We recommend against routine protein restriction. We concur on individualization of hemoglobin A1c targets. We do not agree with routine restriction of sodium intake to 3.3g/d). We suggest screening for anemia only when GFR is 60mg/mmol or proteinuria with protein excretion > 1g/d as the referral threshold for proteinuria.

A single-center cohort study of kidney and kidney-pancreas recipients was conducted to evaluate the association between new immunosuppressive regimens and risk of thrombotic microangiopathy (TMA). From January 1st,1996 to December 31, 2002, 368 patients received a kidney or kidney-pancreas transplant at our center. Four immunosuppressive regimens were evaluated as potential risk factors of TMA: cyclosporin + mycophenolate mofetil (CsA + MMF), cyclosporin + sirolimus (CsA + SRL), tacrolimus + myophenolate mofetil (FK + MMF), and tacrolimus + sirolimus (FK + SRL). Thirteen patients developed biopsy-proven TMA in the absence of vascular rejection. The incidence of TMA was significantly different in the four immunosuppressive regimens studied (p < 0.001). The incidence of TMA was highest in the CsA + SRL group (20.7%). The relative risk of TMA was 16.1 [95% confidence interval (CI): 4.3-60.8] for patients in the CsA + SRL group as compared with those in the FK + MMF group. We also investigated in vitro the pathophysiological basis of this association. The CsA-SRL combination was found to be the only regimen that concomitantly displayed pro-necrotic and anti-angiogenic activities on arterial endothelial cells. We propose that this combination concurs to development of TMA through dual activities on endothelial cell death and repair.

Validation of a novel citrate anticoagulation regimen for continuous venovenous hemodiafiltration (CVVHDF).Prospective cohort trial in medicosurgical intensive care units of two university-affiliated teaching institutions.Participants were patients at high risk for bleeding, with renal failure requiring CVVHDF without heparin. Fourteen patients completed the study.A convection-based citrate anticoagulation CVVHDF regimen using an isotonic replacement fluid containing citrate administered in predilution. A neutralizing solution of calcium chloride and magnesium sulfate was infused at the end of the circuit. Blood flow rate was set and kept at 125 ml/min, and the flow rate of the replacement fluid was initiated at 1250 ml/h and adjusted thereafter according to the monitoring of blood activated coagulation time (ACT), with a target between 180 to 220 s.The average filter time-life was 44 h. Thrombosis of the proximal portion of the circuit (which was not anticoagulated) was the main reason for technique failure. A mean urea clearance of 21 ml/min was obtained. Electrolytes and acid-base balance were both well maintained. Six percent (16/287) of Ca(i) readings less than 0.3 mmol/l were associated with very high ACT levels (300 s).This regimen is shown to be safe, efficacious, and convenient. Citrate anticoagulation should be monitored using postfilter ACT and/or ionized calcium with respective targets of 200-250 s or 0.3-0.4 mmol/l.

Intradialytic hypotension remains a frequent complication of dialysis, occurring in up to 33% of patients. We tested a fully integrated biofeedback system (the Hemocontrol system) that monitors and regulates blood volume contraction during hemodialysis. Seven hypotension prone patients were selected for the study. We conducted a prospective crossover study alternating dialysis sessions using the blood volume regulation system and standard dialysis sessions. Event free sessions were defined as dialysis sessions not requiring any therapeutic intervention for hypotension related signs or symptoms. There was a significant improvement in the number of event free sessions with blood volume regulation compared with standard dialysis (50.8% of sessions vs. 29.2%; p < 0.01). Percentages of event free sessions and mean postdialysis systolic blood pressure improved progressively over the course of the study, indicating improved hemodynamic stability over the study period. Therefore, the use of a biofeedback system to monitor and regulate blood volume during dialysis was helpful in restoring cardiovascular stability in a population of hypotension prone hemodialysis patients. Further studies are needed to confirm these preliminary results and to establish the role of blood volume regulation systems in reducing the incidence of hypotension during hemodialysis.

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Item does not contain fulltext BACKGROUND AND OBJECTIVES: It is uncertain how many patients with CKD and cardiovascular risk factors in publicly funded universal health care systems are aware of their disease and how to achieve their treatment targets. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The CARTaGENE study evaluated BP, lipid, and diabetes profiles as well as corresponding treatments in 20,004 random individuals between 40 and 69 years of age. Participants had free access to health care and were recruited from four regions within the province of Quebec, Canada in 2009 and 2010. RESULTS: CKD (Chronic Kidney Disease Epidemiology Collaboration equation

Background Newer biomarkers, reflective of biological processes, such as inflammation and fibrosis, cardiac stretch or damage and vascular health may be useful in understanding clinical events in chronic kidney disease (CKD). We assessed whether these newer biomarkers, alone or as a panel, improve risk prediction for renal replacement therapy or death, over and above conventional clinical, demographic and laboratory variables. Methods We conducted a prospective observational Canadian cohort study in 2544 CKD patients with estimated glomerular filtration rate (eGFR) of 15-45 mL/min/1.73 m(2), under nephrology care, in urban and rural centers. We measured traditional clinical and laboratory risk factors, as well as newer biomarkers: cystatin C, high sensitivity c-reactive protein (hsCRP), interleukin 6 (IL6), transforming growth factor β1 (TGFβ1), fibroblast growth factor 23 (FGF23), N-terminal probrain natriuretic peptide (NT-proBNP), troponin I and asymmetric dimethylarginine (ADMA). Key outcomes were renal replacement therapy (RRT, dialysis or transplantation) and death, during the first year follow-up after enrollment: a time point important for clinical decision-making for patients and providers. Results Newer biomarkers do not improve the prediction of RRT, when added to conventional risk factors such as eGFR, urine albumin to creatinine ratio, hemoglobin, phosphate and albumin. However, in predicting death within 1 year, cystatin C, NT-proBNP, hsCRP and FGF23 values significantly improved model discrimination and reclassification: c statistic increased by absolute 4.3% and Net Reclassification Improvement for categories of low, intermediate and high risk at 11.2%. Conclusions Our findings suggest that the addition of newer biomarkers may be useful in predicting death in patients with established CKD within a 1-year timeframe. This information may be useful in informing prognosis and redirect resources to serve patients at higher risk to improve outcomes and sustainability of the nephrology care system.

Anemia management of adult hemodialysis patients in the U.S.: Results from the 1997 ESRD Core Indicators Project.BackgroundThe Health Care Financing Administration's End-Stage Renal Disease (ESRD) Core Indicators Project collects clinical information on prevalent adult patients receiving in-center hemodialysis (HD) care in the United States to assess the quality of care delivered. Although hematocrit values, transferrin saturations, and iron prescription practices have improved over the last five years, we sought to determine whether continued opportunities for improvement of this domain of care exist.MethodsA random sample of 7292 adult in-center HD patients was selected. Dialysis facility staff provided clinical information for the period of October through December 1996 for 6858 (94%) patients; complete laboratory information was available from 4991 (73%) returned forms. Hematocrit values, transferrin saturations, serum ferritin concentrations, epoetin alfa dosing, and iron prescriptions were abstracted from patient medical records to assess anemia management practices.ResultsThe mean hematocrit for this cohort was 32.6 ± 3.5%. Seventy-two percent of patients had hematocrit values> 30%. Forty-two percent had hematocrit values of 33 to 36%, and 10% were severely anemic (hematocrit 100 and> 800 ng/mL, respectively. Nine percent of the sample (N = 434) had a transferrin saturation

the hemoglobin levels used todefine a chronic kidney disease (CKD) patient as anemic arebased on gender-specific values under the 5th percentile foran age of more than 18 years. The data are taken from thethird National Health and Nutrition Examination Survey(NHANES III) data set of the US population, 1988–1994

Cross-sectional and prospective studies of men suggest a positive association between nephrolithiasis and hypertension. However, this association remains controversial in women. We conducted a prospective study of the relation between nephrolithiasis and the risk for hypertension in the Nurses' Health Study, a cohort of 89,376 women aged 34 to 59 years in 1980. Information on the history of nephrolithiasis, physician-diagnosed hypertension, and other relevant exposures was obtained by biennial mailed questionnaire. A history of nephrolithiasis before 1980 was reported by 2,558 women (2.9%), and a history of hypertension was reported by 11,883 women (13.3%). Among women without hypertension before 1980, 12,540 women reported a new diagnosis of hypertension between 1980 and 1992, during 711,039 person-years of follow-up. Compared with those without a history of nephrolithiasis, the age-adjusted relative risk (RR) for incident hypertension in women with such a history was 1.36 (95% confidence interval [CI], 1.20 to 1.43). After further adjustment for body mass index (BMI) and the intake of calcium, sodium, potassium, magnesium, caffeine, and alcohol, the RR was only slightly attenuated (RR=1.24; 95% CI, 1.13 to 1.37). In contrast, the occurrence of incident nephrolithiasis during follow-up was similar in women with hypertension at baseline compared with women without (adjusted odds ratio [OR]=1.01; 95% CI, 0.85 to 1.20). These data are consistent with the results obtained in men and support the hypothesis that a history of nephrolithiasis is associated with an increased risk for subsequent hypertension. Dietary factors, such as the intake of calcium, sodium, and potassium, do not explain this association. Unidentified pathogenic mechanisms common to nephrolithiasis and hypertension may be responsible for the development of both disorders.

Nitric oxide (NO) is a powerful vasoactive agent that contributes to the regulation of blood pressure (BP). However, the role of NO in uremic patients and during the course of hemodialysis is still debated. Blood L-arginine concentrations and exhaled NO concentrations were measured in 22 healthy controls and in 22 hemodialysis patients before and after dialysis. On the basis of their BP response during hemodialysis, the patients were divided into three groups: 6 of the 22 patients presented with a decrease in BP during dialysis (group 1), eight presented with a stable BP (group 2), and eight with an increase in BP (group 3). The exhaled NO concentration was higher in dialysis patients than in healthy controls (22.7 +/- 2.6 ppb in dialysis patients v 16.7 +/- 0.9 ppb in controls, mean +/- SEM, P = 0.044). The predialysis and postdialysis exhaled NO concentrations were inversely correlated with the change in BP during hemodialysis (r = -0.47, P = 0.013). Patients with a decrease in BP (group 1) had the highest NO concentrations; patients with an increase in BP (group 3) had the lowest values; and patients with a stable BP during the course of dialysis (group 2) had intermediary values (trend test, P = 0.0291). In addition, both the exhaled NO concentration and the blood L-arginine concentration decreased during dialysis in all patients (P = 0.005 and P = 0.001, respectively). These results provide several novel insights into NO metabolism and BP regulation during hemodialysis: (1) maintenance hemodialysis is associated with a chronic increase in NO concentrations; (2) changes in BP during hemodialysis are inversely correlated with exhaled NO concentrations, higher NO levels being associated with a decrease in BP and lower NO levels with an increase in BP during dialysis; (3) blood L-arginine levels decrease during hemodialysis, and this reduction may in turn influence NO production.

Background The Canadian Study of Prediction of Death, Dialysis and Interim Cardiovascular Events (CanPREDDICT) is a large, prospective, pan-Canadian, cohort study designed to improve our understanding of determinants of renal and cardiovascular (CV) disease progression in patients with chronic kidney disease (CKD). The primary objective is to clarify the associations between traditional and newer biomarkers in the prediction of specific renal and CV events, and of death in patients with CKD managed by nephrologists. This information could then be used to better understand biological variation in outcomes, to develop clinical prediction models and to inform enrolment into interventional studies which may lead to novel treatments. Methods/Designs Commenced in 2008, 2546 patients have been enrolled with eGFR between 15 and 45 ml/min 1.73m2 from a representative sample in 25 rural, urban, academic and non academic centres across Canada. Patients are to be followed for an initial 3 years at 6 monthly intervals, and subsequently annually. Traditional biomarkers include eGFR, urine albumin creatinine ratio (uACR), hemoglobin (Hgb), phosphate and albumin. Newer biomarkers of interest were selected on the basis of biological relevance to important processes, commercial availability and assay reproducibility. They include asymmetric dimethylarginine (ADMA), N-terminal pro-brain natriuretic peptide (NT-pro-BNP), troponin I, cystatin C, high sensitivity C-reactive protein (hsCRP), interleukin-6 (IL6) and transforming growth factor beta 1 (TGFβ1). Blood and urine samples are collected at baseline, and every 6 monthly, and stored at −80°C. Outcomes of interest include renal replacement therapy, CV events and death, the latter two of which are adjudicated by an independent panel. Discussion The baseline distribution of newer biomarkers does not appear to track to markers of kidney function and therefore may offer some discriminatory value in predicting future outcomes. The granularity of the data presented at baseline may foster additional questions. The value of the cohort as a unique resource to understand outcomes of patients under the care of nephrologists in a single payer healthcare system cannot be overstated. Systematic collection of demographic, laboratory and event data should lead to new insights. The mean age of the cohort was 68 years, 90% were Caucasian, 62% were male, and 48% had diabetes. Forty percent of the cohort had eGFR between 30–45 mL/min/1.73m2, 22% had eGFR values below 20 mL/min/1.73m2; 61% had uACR

Long-term survival with end-stage renal disease (ESRD) on dialysis is uncommon, mainly because of the high mortality associated with cardiovascular disease. To define the clinical characteristics of long-term ESRD survivors, especially their cardiovascular risk profile, patients were identified withor = 15 years of ESRD having at least 10 years on dialysis. Seventeen patients were identified with a duration of ESRD of 21.0 +/- 4.3 years (mean +/- SD). The age of the patients at the initiation of dialysis was 38.4 +/- 14.5 years. Eighty-eight percent of the survivors were white, and 12% were African-American. The primary causes of ESRD were glomerulonephritis, 65%; polycystic kidney disease, 18%; tubulointerstitial/obstructive disorders, 12%; and hypertension, 6%. At the initiation of dialysis, these long-term survivors presented with a low prevalence of cardiovascular risk factors (hypertension, 53%; diabetes mellitus, 0%; active smoking, 11.8%; family history, 25%) and cardiovascular disease (coronary heart disease, 5.9%; congestive heart failure, 5.9%; arrhythmias, 0%; peripheral vascular disease, 0%; and cerebrovascular disease, 5.9%). In addition, only 6.6% of the long-term ESRD survivors presented with systolic blood pressures110 mm Hg, a level suggestive of systolic dysfunction. Afteror = 15 years of dialysis, these long-term survivors remained with a low prevalence of cardiovascular risk factors and cardiovascular disease. These results suggest that the low cardiovascular risk profile and morbidity experienced by these patients may contribute to their prolonged survival on dialysis.

Background Recent trends in parathyroidectomy rates are not known. Our objective was to investigate the trend in parathyroidectomy rates between 2001 and 2010, and to evaluate if the availability and reimbursement of cinacalcet modified that trend. Methods Using a provincial administrative database, we included all adult patients receiving chronic dialysis treatments between 2001 and 2010 (incident and prevalent) in a time series analysis. The effect of cinacalcet availability on parathyroidectomy bimonthly rates was modeled using an ARIMA intervention model using different cut-off dates: September 2004 (Health Canada cinacalcet approval), January 2005, June 2005, January 2006, June 2006 (date of cinacalcet provincial reimbursement), and January 2007. Results A total of 12 795 chronic dialysis patients (mean age 64 years, 39% female, 82% hemodialysis) were followed for a mean follow-up of 3.3 years. During follow-up, 267 parathyroidectomies were identified, translating to an average rate of 7.0 per 1000 person-years. The average parathyroidectomy rate before cinacalcet availability was 11.4 /1000 person-years, and 3.6 /1000 person-years after cinacalcet public formulary listing. Only January 2006 as an intervention date in the ARIMA model was associated with a change in parathyroidectomy rates (estimate: -5.58, p = 0.03). Other intervention dates were not associated with lower parathyroidectomy rates. Conclusions A reduction in rates of parathyroidectomy was found after January 2006, corresponding to cinacalcet availability. However, decreased rates may be due to other factors occurring simultaneously with cinacalcet introduction and further studies are needed to confirm these findings.

International audience; Acute vascular rejection (AVR) is characterized by immune-mediated vascular injury and heightened endothelial cell (EC) apoptosis. We reported previously that apoptotic ECs release a bioactive C-terminal fragment of perlecan referred to as LG3. Here, we tested the possibility that LG3 behaves as a neoantigen, fuelling the production of anti-LG3 antibodies of potential importance in regulating allograft vascular injury. We performed a case-control study in which we compared anti-LG3 IgG titers in kidney transplant recipients with AVR (n=15) versus those with acute tubulo-interstitial rejection (ATIR) (n=15) or stable graft function (n=30). Patients who experienced AVR had elevated anti-LG3 titers pre and posttransplantation compared to subjects with ATIR or stable graft function (p

Rationale: Endothelial apoptosis is increased in association with acute and chronic vascular rejection (VR) of solid allografts. Apoptotic endothelial cells (EC) release LG3, a C-terminal fragment of perlecan of potential importance in vascular remodeling and neointima formation. Objective: Our 2 goals were to determine whether circulating levels of LG3 are increased in association with acute VR of renal allografts and to evaluate the impact of LG3 on vascular remodeling. Methods and Results: We conducted a case-control study to compare serum LG3 levels in human renal transplant patients with acute VR, tubulo-interstitial rejection (ATIR) and normal graft function. Aorta transplantation between fully MHC-mismatched mice in association with intravenous LG3 injection was used to characterize the impact of LG3 on vascular remodeling. Scratch assays evaluated the promigratory activity of LG3 on vascular smooth muscle cells (VSMC) in vitro. Serum LG3 levels were significantly elevated in human renal transplant patients with acute VR ( n =16) compared to ATIR ( n =16) and normal graft function ( n =32, P =0.004). In patients with acute VR, graft loss was associated with elevated LG3 levels. Increasing LG3 serum levels in aortic allograft recipients significantly increased neointima formation. LG3 injection fostered accumulation of α-smooth muscle actin–positive cells and decreased the number of CD31 positive EC. LG3 increased the migration of VSMC through extracellular signal-regulated kinases 1/2-dependent pathways. Conclusion: These results indicate that LG3 is a novel regulator of obliterative vascular remodeling during rejection.

Background Reliable biomarkers are needed to identify patients with glomerular disease at risk of progression. Transforming growth factor beta 1 (TGF-β1) and monocyte chemotactic protein 1 (MCP-1) play key roles in promoting renal tissue injury. Whether their urinary measurement adds value to current predictors of progression is uncertain. Methods We enrolled patients with diabetic (n=53) and nondiabetic (n=47) proteinuric renal disease and retrospectively studied their rate of renal function decline over a defined period of 2 years. We simultaneously measured urinary protein, MCP-1 and TGF-β1, standardized to urinary creatinine. Results The initial estimated glomerular filtration rate, proteinuria and rate of renal function decline (slope) were 36 ml/min per 1.73 m2, 1.1 g/day and -4.0 ± 7.2 ml/ min per 1.73 m2 year. Median urinary TGF-β1 and MCP- 1 levels were 0.3 (range 0.0-28.1) and 18 (range 3-370) ng/mmol of creatinine, respectively. Urinary protein and MCP-1 to creatinine ratios were associated with slope, and this applied to both diabetic and nondiabetic patients separately. Urinary TGF-β1 showed no relation to slope. However, the majority of its measurements were below the suggested reproducibility threshold. Using linear regression, both normalized urinary protein and MCP-1 were independently associated with the slope. Adding urinary MCP-1 to the model statistically raised the adjusted R2 from 0.35 to 0.40, refining patient risk stratification. Using cutoffs for urinary protein and MCP-1 obtained by receiver operating characteristic curves, the risk of progression was confidently determined in 80% of patients. Conclusion Urinary MCP-1 is a marker of renal function decline in diabetic and nondiabetic proteinuric renal disease, independent of and additive to proteinuria.

Background and objectives: Prior reports have suggested that patients with impaired renal function receive less aggressive care after an acute coronary syndrome (ACS). The aim of this study was to determine whether this held true in a contemporary cohort, after thorough adjustment for cotreatments/comorbidities. Design, setting, participants, & measurements: Patients who were admitted for an ACS in eight participating hospitals were stratified into three groups according to estimated creatinine clearance (CrC): less than 45 ml/min, 45 to 60 ml/min, and reference >60 ml/min. Results: During hospitalization, uses of reperfusion therapy in tertiary care centers [difference between CrC ≤45 ml/min and reference group (Δ): 4%, 95% confidence interval (CI): (−13%, 21%)] and systemic anticoagulation [Δ: 0%, CI (−5%, 5%)] were similar in the three groups. Coronary angiography was performed less often in patients with lower CrC [Δ: −16%, CI: (−31%, −1%)]. At discharge, nearly all patients received either an antiplatelet agent or warfarin regardless of CrC [Δ: −1%, CI: (−3%, 1%)]. Discharge use of angiotensin converting enzyme (ACE) inhibitors or angiotensin-receptor blockers was comparable [Δ: 7%, CI: (−1%, 15%)]. β-blockers [Δ: −9%, CI: (−17%, −1%)] and lipid-lowering drugs (LLDs) [Δ: −7%, CI: (−13%, −1%)] were used less frequently in patients with lower CrC. In multivariate analyses, decreased CrC predicted lower coronary angiography and LLD use, but not lower β-blocker use at discharge. Conclusions: These results suggest that in patients with ACS, the extent of undertreatment due to chronic kidney disease is less than reported previously, which is partially explained by more complete adjustment for cotreatments/comorbidities.

Although both inflammation and apoptosis occur in acute coronary syndromes (ACSs), previous studies have not tested the diagnostic and prognostic utility of an approach that measures circulating markers of these pathways. The aim of the present study was to assess whether measuring soluble Fas (sFas) and high-sensitivity C-reactive protein (hs-CRP), as markers of apoptosis and inflammation, improve ACS diagnostic and prognostic accuracy. In a prospective cohort of consecutive subjects admitted to the hospital for suspicion of ACS, we measured sFas, hs-CRP, and troponin T in those who had a final noncardiac chest pain diagnosis (n = 100), those who had an ACS diagnosis and experienced (n = 218) or did not experience (n = 170) recurrent cardiac events during 1 year of follow-up. sFas was strongly and independently associated with a discharge diagnosis of an ACS versus noncardiac chest pain during the index hospitalization (odds ratio 16.16 for the second vs first tertile, 95% confidence interval [CI] 7.07 to 36.91; and odds ratio 25.40 for the third vs first tertile, 95% CI 9.38 to 68.75). However, hs-CRP was not. sFas significantly improved the diagnostic accuracy for ACSs (C statistic increased from 0.85 to 0.93, difference +0.08, 95% CI for the difference 0.05 to 0.11). The sFas levels were high and did not vary with time in the subjects having early versus late measurements (beta 0.00 ln pg/ml/hour, 95% CI -0.01 to 0.01). In contrast, troponin increased with time since the beginning of the symptoms (beta 0.07 ln microg/L/hour, 95% CI 0.04 to 0.10). Baseline sFas and hs-CRP did not predict recurrent cardiac events. In conclusion, our results suggest that in suspected ACS cases, sFas, but not hs-CRP, helps to improve the diagnostic accuracy and timeliness over and above standard diagnostic criteria.

Background Accurate measurement of the international normalized ratio (INR) may be difficult in hemodialysis (HD) patients with heparin-locked central catheters. Blood contamination with locking solutions may interfere with INR measurement when samples are collected directly from the catheter. Methods The aim of our study was to evaluate a novel sampling method for the measurement of INR in HD patients with heparin-locked central catheters. This novel method consists of measuring the INR directly from the dialysis circuit (arterial bloodline sample port) after 1 hr of treatment regardless of heparin administration during dialysis. We compared this method to the gold standard (peripheral venipuncture prior to dialysis) using the paired t-test. We included 30 patients (23 with warfarin therapy and 7 without). Results INRs obtained using the novel sampling method were only minimally overestimated compared to venipuncture values (mean INR overestimation: 0.2 +/- 0.2). This overestimation was not clinically significant and did not lead to changes in warfarin prescription for any of the patients. Correlation tests confirmed the influence of heparin administration on INR overestimation (R=0.4; p=0.05). This influence was present mostly among patients receiving more than 100 Units/kg of heparin during their treatment. Conclusion This novel sampling technique provides a convenient and simple method of monitoring INR among HD patients.

Chronic kidney disease (CKD) is strongly associated with cardiovascular disease. After a myocardial infarction (MI), the risk of recurrent events is much higher in subjects suffering from CKD, even when traditional risk factors are taken into account. Some data suggest that thrombolysis and coronary revascularization are underused during acute MI episodes in subjects who suffer from CKD. We performed a systematic review of the medical literature to ascertain whether there is also a CKD-associated decrease in the use of cardioprotective medications (aspirin, beta-blockers, ACE inhibitors and lipid lowering drugs) after a MI. We did observe a CKD-associated underuse of these medications in this particular clinical context. The presence of co-morbidities and co-treatments, as well as the relative lack of evidence-based data on the efficacy of cardiopreventive drugs in patients with CKD probably explain much of the reported therapeutic differences. However, recent studies show that the differences in cardioprotective drug use across levels of kidney function tend to diminish over the years. This probably reflects a greater awareness of the high cardiovascular risk associated with CKD amongst clinicians caring for these patients.

UNLABELLED OBJECTIVE, DESIGN AND PATIENTS: The risk of acute kidney injury (AKI) associated with hydroxyethyl starch may be limited to higher molecular weight agents. We retrospectively evaluated the risk of AKI using pentastarch 10% (250 kDa, 0.45) in a random cohort of 563 patients operated for a cardiac surgery at a university hospital. MEASURES We assessed previously identified preoperative, perioperative, and postoperative risk factors, and the volume of pentastarch given until the end of the first postoperative day. We defined AKI by a 50% rise in serum creatinine within 4 days after surgery. Different propensity adjustment methods were used to further assess the selection bias. RESULTS Fifty-four (10%) patients developed AKI. Risk factors of AKI were age, female gender, preoperative creatinine clearance, hypertension, diuretic use, left ventricular ejection fraction, valvular surgery, duration of extracorporeal circulation, duration and dose of postoperative vasopressor support, and the number of red blood cells and fresh frozen plasma transfusions. Patients with AKI received 16 +/- 9 mL/kg of pentastarch as opposed to 10 +/- 7 mL/kg in controls (p < 0.001). Pentastarch remained independently predictive of AKI, with an adjusted odds ratio per mL/kg of 1.08 (95% confidence interval 1.04-1.12, p = 0.001). This risk was dose-dependent, and the optimal cutoff volume predicting AKI was 14 mL/kg. Different propensity adjustment methods were tested, and pentastarch as a risk factor of AKI was identified. CONCLUSIONS This study identified a dose-dependent risk of AKI with pentastarch following cardiac surgery, given until the end of the first postoperative day.

and management of iron deficiency Francois Madore, Colin T. White, Rob N. Foley, Brendan J. Barrett, Louise M. Moist, Scott W. Klarenbach, Bruce F. Culleton, Marcello Tonelli and Braden J. Manns Division of Nephrology, Department of Medicine, Hopital du Sacre-Cœur de Montreal, Universite de Montreal, Montreal, Quebec, Canada; Division of Nephrology, Department of Pediatrics, Faculty of Medicine, British Columbia Children’s Hospital, University of British Columbia, Vancouver, British Columbia, Canada; Minneapolis Medical Research Foundation, Minneapolis, Minnesota, USA; Department of Medicine, Memorial University, St John’s, Newfoundland and Labrador, Canada; Department of Medicine, University of Western Ontario, London, Ontario, Canada; Department of Medicine, University of Alberta, Edmonton, Alberta, Canada and Division of Nephrology, Department of Medicine, University of Calgary, Calgary, Alberta, Canada