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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

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 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.

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

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)-β1. 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., Graphical abstract

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.

Objective:Several studies have reported an association between hypertension and fracture incidence. Nevertheless, whether peripheral and central arterial parameters are associated with bone density and fracture incidence has not been studied. Furthermore, whether these associations are influenced by

Background: Central blood pressure (CBP) is a better predictor of cardiovascular burden than peripheral blood pressure (BP). While studies have suggested a reduction in peripheral BP with statins, it remains uncertain to what extent statins reduce CBP and whether this reduction is mediated through a decrease in LDL-cholesterol (LDL). Methods: Of the 20,004 CARTaGENE participants, 17,011 had CBP and LDL measurements (n = 13,439 without, n = 3,133 with statins). Linear and logistic regression analyses were used to evaluate the association between CBP, LDL and statin use (after stratification for treatment indication for the latter). The impact of LDL on the association between statin use and CBP was determined by mediation analyses. All analyses were adjusted for age, sex, diabetes, cardiovascular disease, smoking, eGFR, BMI, uric acid, heart rate, anti-hypertensive agents and aspirin. Results: Lower levels of LDL were associated with lower systolic and diastolic CBP in participants treated with (b = 0.098 and 0.125; p < 0.001) and without statins (b = 0.089 and 0.105; p < 0.001). Statin use as primary prevention (per ACC/AHA guidelines; n = 8,865) was also associated with lower systolic CBP, diastolic CBP and central pulse pressure (b = −0.091, −0.073 and −0.055; p < 0,001). Mediation analyses demonstrated that 15%, 46% and -22% of these effects were achieved through the concomitant changes in LDL (Table 1). In secondary prevention (n = 995), statins use was not associated with lower CBP, although the small sample size may lack power. Conclusion: In this populational cohort, statin use as primary prevention is associated with lower CBP. These changes are mediated directly by statins but also indirectly through effects on LDL.

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.

The initiation of continuous renal replacement therapy (CRRT) in acute kidney injury (AKI) with severe hypernatremia is challenging since sodium concentrations in commercial replacement fluid (RF) and dialysate solutions are usually fixed at 140 mEq/L. We present a case of AKI with severe hypernatremia successfully treated with CRRT using commercial RF solutions customized to prevent rapid correction of hypernatremia. None of the few case reports published on hypernatremia and AKI requiring CRRT have included formulas to help modulate the sodium content in the solutions. We present an equation to facilitate adjustment of the sodium concentration in this setting.

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

Contains fulltext : 174174.pdf (Publisher’s version ) (Open Access) Background: The aim of this study was to assess the impact of follow-up in renal protection clinics on the prescription of and adherence to cardioprotective drugs in patients with chronic kidney disease (CKD). Methods: We studied stage 4 and 5 CKD patients who initiated follow-up in three renal protection clinics. The prescription pattern of antihypertensive agents (AHA) and lipid-lowering agents (LLAs) was measured as the percentage of patients who are prescribed the agents of interest at a given time. Adherence to drug therapy was defined as the percentage of days, during a pre-defined observation period, in which patients have an on-hand supply of their prescribed medications. Results: A total of 259 CKD patients were enrolled and followed for up to 1 year after referral to renal protection clinics. There was a significant increase in the prescription of angiotensin-converting enzyme inhibitors (34-39%), angiotensin II receptor blockers (11-14%), beta-blockers (40-51%), calcium channel blockers (62-74%), diuretics (66-78%) and LLAs (39-47%) during follow-up in the renal protection clinic compared with baseline (P-values /= 80%) and poor (< 80%) adherence to AHA (P = 0.41) and LLAs (P = 0.11) were similar in the year preceding and the year following the first visit to the renal protection clinics. Conclusion: Our results suggest that referral and follow-up in a renal protection clinic may increase the prescription of cardioprotective agents in CKD patients, but does not appear to improve adherence to these medications.

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

Background and objectives The urinary excretion of uromodulin is influenced by common variants in the UMOD gene, and it may be related to NaCl retention and hypertension. Levels of uromodulin are also dependent of the renal function, but other determinants remain unknown. Design, setting, participants, & measurements We tested associations between the urinary excretion of uromodulin; medical history and medication; serum and urinary levels of electrolytes, glucose, and uric acid; and the genotype at the UMOD/Protein Disulfide Isomerase–Like, Testis Expressed locus (rs4293393 and rs12446492); 943 participants from the CARTaGENE Cohort, a random sample from the Canadian population of 20,004 individuals, were analyzed. Participants with available genotyping were obtained from a substudy addressing associations between common variants and cardiovascular disease in paired participants with high and low Framingham risk scores and vascular rigidity indexes. Results The population studied was 54±9 years old, with 51% women and eGFR of 9±14 ml/min per 1.73 m 2 . Uromodulin excretion was 25 (11–42) mg/g creatinine. Using linear regression, it was independently higher among patients with higher eGFR, the TT genotype of rs4293393, and the TT genotype of rs12446492. The fractional excretions of urate and sodium showed a strong positive correlation with uromodulin, likely linked to the extracellular volume status. The presence of glycosuria and the use of uricosuric drugs, which both increased the fraction excretion of urate, were independently associated with a lower uromodulin excretion, suggesting novel interactions between uric acid and uromodulin excretion. Conclusions In this large cohort, the excretion of uromodulin correlates with clinical, genetic, and urinary factors. The strongest associations were between uric acid, sodium, and uromodulin excretions and are likely linked to the extracellular volume status.

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.

Predicting the clinical trajectories of chronic kidney disease (CKD) to discern personalized care remains a complex challenge in nephrology. Understanding the appropriate risk thresholds and time frame associated with predicting risks of key outcomes (kidney failure, cardiovascular (CV) events, and death) is critical in facilitating decision-making. As part of an exploratory research and practice support needs assessment, we aimed to determine the importance of the time frames for predicting key outcomes, and to assess the perceived demand for risk prediction tools among Canadian nephrologists.A web-based survey was developed by a pan-Canadian expert panel of practitioners. Upon pre-test for clarity and ease of completion, the final survey was nationally deployed to Canadian nephrologists. Anonymous responses were gathered over a 4-month period. The results were analyzed using descriptive statistics.One hundred eleven nephrologists responded to our survey. The majority of the respondents described prediction of events over time frames of 1-5 years as being "extremely important" or "very important" to decision-making on a 5-point Likert scale. To plan for arteriovenous fistula referral, the respondents deemed thresholds which would predict probability of kidney failure between30 and50 % at 1 year, as useful, while many commented that the rate of progression should be included for decision-making. Over 80 % of the respondents were not satisfied with their current ability to predict the progression to kidney failure, CV events, and death. Most of them indicated that they would value and use validated risk scores for decision-making.Our national survey of nephrologists shows that the risk prediction for major adverse clinical outcomes is valuable in CKD at multiple time frames and risk thresholds. Further research is required in developing relevant and meaningful risk prediction models for clinical decision-making in patient-centered CKD care.Un défi de taille subsiste dans le domaine de la néphrologie. En effet, il demeure difficile de prévoir l’évolution de la néphropathie chronique et donc, d’établir un programme de soin personnalisé pour les patients. Pour ce faire, il serait essentiel de comprendre les seuils de risque ainsi que les marges de temps qui pourraient aider à prévoir l’évolution de la maladie vers les complications inhérentes (l’insuffisance rénale chronique, des événements cardiovasculaires ou la mort). La connaissance de ces paramètres pourrait s’avérer un outil indispensable pour aider les néphrologues à prendre des décisions plus rapidement et plus efficacement quant à la suite du traitement à offrir à leurs patients. Dans le but d’offrir du support à la pratique et de faciliter la prise de décisions cliniques, cette étude exploratoire faite auprès des néphrologues canadiens visait à évaluer l’importance d’établir des cadres temporels et des seuils de risque permettant de prévoir l’évolution défavorable de la néphropathie chronique vers ses principales complications.Un groupe d’experts provenant de tous les coins du pays a mis au point un sondage sur le web pour questionner directement les néphrologues. Une version pilote du test a d’abord été distribuée à un groupe restreint pour en vérifier la clarté et faire en sorte de le rendre le plus convivial possible pour les répondants. La version définitive été envoyée par courriel à des néphrologues pratiquant à travers le Canada. Les réponses au questionnaire ont été compilées en préservant l’anonymat des répondants, sur une période de quatre mois, et ont été analysées par statistique descriptive.Un total de cent-onze néphrologues ont répondu au sondage, et sur une échelle de Likert en cinq points, la majorité d’entre eux a qualifié d’« extrêmement importante » ou de « très importante » pour faciliter la prise de décision, la possibilité de prévoir les événements défavorables sur une période de un à cinq ans. Dans le cas précis de la pose d’une fistule artérioveineuse, une bonne proportion de répondants a mentionné qu’ils la recommanderaient à leurs patients s’ils pouvaient estimer le risque de développer une insuffisance rénale chronique à plus de 50 % à l’intérieur d’une période d’un an, alors que d’autres ont mentionné qu’ils le feraient si ce risque se situait à plus de 30 % pour la même période. Tous ont mentionné qu’ils trouveraient utile d’avoir la capacité de prévoir une telle issue, et plusieurs ont ajouté que le rythme de progression de la maladie devrait être considéré dans la prise de décision. En tout, plus de 80 % des répondants se sont dits insatisfaits de leur capacité actuelle à prévoir la progression de la maladie vers l’insuffisance rénale chronique, des complications d’ordre cardiovasculaires ou la mort. Enfin, la plupart d’entre eux ont indiqué qu’ils jugeraient utile la création d’une charte validée de seuils de risques permettant de prédire l’évolution défavorable de la maladie et qu’ils seraient enclins à l’utiliser dans leurs prises de décisions.Les résultats de ce sondage national effectué auprès de néphrologues-praticiens montrent que la capacité de prévoir, dans une gamme de périodes de référence donnée, les risques de résultats cliniques défavorables chez les patients atteints de néphropathie chronique serait grandement utile pour la prise de décisions quant au choix du traitement. Des recherches plus approfondies sont requises en vue de développer des modèles pertinents et concrets de prévision des risques d’évolution défavorable de la maladie, dans le but de faciliter la prise de décisions cliniques et d’offrir aux patients des soins axés sur leurs besoins particuliers.

Knowledge generation through randomized controlled trials (RCTs) is critical to advance the medical evidence base, inform decision-making, and improve care and outcomes. Unfortunately, nephrology has typically lagged behind other medical specialties in this regard. The establishment of formal clinical trial networks can facilitate the successful conduct of RCTs and has significantly increased the number of RCTs performed worldwide in other medical specialties. No such formal network of nephrology trialists exists in Canada. On April 24, 2014, the Canadian Kidney Knowledge Translation and Generation Network (CANN-NET) Clinical Trials Committee held a stakeholder engagement meeting to address this gap and improve the nephrology clinical trial landscape in Canada. The meeting was held in Vancouver in association with the 2014 Canadian Society of Nephrology Annual General Meeting and was co-sponsored by the Kidney Foundation of Canada and CANN-NET. Attendees included nephrologists from university- and non-university-affiliated nephrology practices, administrators, and representatives from the Kidney Foundation of Canada. Through structured presentations and facilitated group discussions, the group explored the extent to which nephrology trials are currently happening in Canada, barriers to leading or participating in larger investigator-initiated trials, and strategies to improve clinical trial output in nephrology in Canada. The themes and action items arising from this meeting are discussed.La création d’un bagage de connaissances commun par la conduite d’essais cliniques est essentielle pour assurer l’avancement des notions de base en médecine, étayer la prise de décisions, améliorer les soins aux patients et assurer de meilleurs résultats cliniques. L’établissement d’un réseau officiel et reconnu de partage des connaissances issues d’essais cliniques peut en faciliter la conduite et assurer leur bon déroulement. La preuve en est faite par l’augmentation du nombre d’essais cliniques probants ayant été menés à travers le monde, dans d’autres disciplines médicales. Malheureusement, la néphrologie tire de l’arrière à cet égard par rapport aux autres spécialités, un tel réseau de partage n’existe pas dans le domaine au Canada. C’est dans ce contexte que le 24 avril 2014, le comité des essais cliniques de la « Canadian Kidney Knowledge Translation and Generation Network » (CANN-NET) a tenu une assemblée générale afin de mobiliser les parties intéressées. On a voulu leur exposer cette lacune, tenter d’apporter des solutions et ultimement, faire progresser le bilan de la néphrologie en cette matière. La conférence, en collaboration avec l’assemblée générale annuelle de la Société canadienne de néphrologie, s’est tenue à Vancouver et était subventionnée conjointement par la Fondation canadienne du Rein et le CANN-NET. Parmi les participants, on comptait des néphrologues pratiquants associés ou non à un établissement universitaire ainsi que des administrateurs et des représentants de la Fondation canadienne du Rein. À l’aide de présentations structurées et de discussions de groupe, les participants ont pu observer l’état actuel des essais cliniques au pays, identifier les barrières entravant la participation à plus grande échelle à des essais entrepris sous l’initiative d’un chercheur, et discuter de stratégies pour améliorer les résultats d’essais cliniques en néphrologie au Canada. Le présent article fait état des thèmes abordés lors de cette assemblée et des mesures à prendre pour atteindre les objectifs fixés.

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.

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.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.A 7-week, open-label, multicenter study with a single treatment arm, conducted between October 2013 and March 2016.Ten sites in Canada.A total of 152 patients with end-stage renal disease requiring 3 to 4 HD sessions per week.The primary outcome was the proportion of HD sessions completed without premature termination due to inadequate anticoagulation.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.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 time10 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.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 aspirin100 mg/d.Overall, an adjustable dalteparin sodium dose regimen allowed safe completion of HD, with clinical benefits over fixed dosing.ClinicalTrials.gov NCT01879618, registered June 13, 2013.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.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.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.L’étude a eu lieu dans dix centres de dialyse au Canada.L’étude a inclus 152 patients atteints d’IRT et nécessitant trois à quatre séances d’HD par semaine.Le résultat principal était la proportion de séances d’HD complétées, non interrompues de manière prématurée en raison d’une anticoagulation inadéquate.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.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.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.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.

Anticoagulation is required during continuous renal replacement therapy to prevent filter clotting and optimize filter performance. However, anticoagulation may also be associated with serious bleeding complications. Patients with liver failure often suffer from underlying coagulopathy and are especially prone to anticoagulation complications. The aim of this review is to present the unique features of patients with hepatic injury in terms of anticoagulation disorders and to analyze data on safety and efficacy of the different anticoagulation methods for liver failure patients undergoing continuous renal replacement therapy.

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.

Congestive heart failure (CHF) is highly prevalent in patients on renal replacement therapy and is a leading cause of death in such patients. Several studies suggest that therapeutic agents for the treatment of CHF, particularly angiotensin converting enzyme inhibitors and beta-blockers, are underused in end-stage renal disease patients with CHF. Although limited data are available, growing evidence suggests that therapeutic agents for CHF improve survival and are safe to use, assuming close monitoring of adverse events. The reluctance of physicians in prescribing these therapeutic agents and the reasons underlying the inconsistent use of these agents in the dialysis population need to be addressed.

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.