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Rationale & Objective: It is unclear whether the effect of canagliflozin on adverse kidney and cardiovascular events in those with diabetic kidney disease varies by age and sex. We assessed the effects of canagliflozin among age group categories and between sexes in the Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) study.Study Design: Secondary analysis of a randomized controlled trial.Setting & Participants: Participants in the CREDENCE trial.Intervention: Participants were randomly assigned to receive canagliflozin 100 mg/d or placebo.Outcomes: Primary composite outcome of kidney failure, doubling of serum creatinine concentration, or death due to kidney or cardiovascular disease. Prespecified secondary and safety outcomes were also analyzed. Outcomes were evaluated by age at baseline (Results: The mean age of the cohort was 63.0 ± 9.2 years, and 34% were female. Older age and female sex were independently associated with a lower risk of the composite of adverse kidney outcomes. There was no evidence that the effect of canagliflozin on the primary outcome (a composite of kidney failure, a doubling of serum creatinine concentration, or death from kidney or cardiovascular causes) differed between age groups (HRs, 0.67 [95% CI, 0.52-0.87], 0.63 [0.48-0.82], and 0.89 [0.61-1.29] for ages Limitations: This was a post hoc analysis with multiple comparisons.Conclusions: Canagliflozin consistently reduced the relative risk of kidney events in people with diabetic kidney disease in both sexes and across age subgroups. As a result of greater background risk, the absolute reduction in adverse kidney outcomes was greater in younger participants.Funding: This post hoc analysis of the CREDENCE trial was not funded. The CREDENCE study was sponsored by Janssen Research and Development and was conducted collaboratively by the sponsor, an academic-led steering committee, and an academic research organization, George Clinical.Trial Registration: The original CREDENCE trial was registered at ClinicalTrials.gov with study number NCT02065791.

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

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.

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.

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.

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.

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.

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.

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.

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.

Growing evidence has been gathered over the last 15 years regarding the role of nontraditional or uremia-related risk factors in the pathogenesis of atherosclerosis in subjects with renal failure. Among those factors, dyslipidemia, inflammation, hyperhomocysteinemia, and oxidant stress have been extensively studied. However, the clinical significance of many of these factors remains controversial in light of reported studies. In this article, the existing evidence regarding the role of uremia-related risk factors in the pathogenesis of atherosclerosis is reviewed, with special emphasis on prevalence, cardiac risk, and management in patients with chronic kidney disease (CKD). Consensus treatment recommendations are provided for risk factors for which there is evidence to support preventive or therapeutic interventions.

Patients with chronic kidney disease (CKD) do not always receive care consistent with guidelines, in part due to complexities in CKD management, lack of randomized trial data to inform care, and a failure to disseminate best practice. At a 2007 conference of key Canadian stakeholders in kidney disease, attendees noted that the impact of Canadian Society of Nephrology (CSN) guidelines was attenuated given limited formal linkages between the CSN Clinical Practice Guidelines Group, kidney researchers, decision makers and knowledge users, and that further knowledge was required to guide care in patients with kidney disease. The idea for the Canadian Kidney Knowledge Translation and Generation Network (CANN-NET) developed from this meeting. CANN-NET is a pan-Canadian network established in partnership with CSN, the Kidney Foundation of Canada and other professional societies to improve the care and outcomes of patients with and at risk for kidney disease. The initial priority areas for knowledge translation include improving optimal timing of dialysis initiation, and increasing the appropriate use of home dialysis. Given the urgent need for new knowledge, CANN-NET has also brought together a national group of experienced Canadian researchers to address knowledge gaps by encouraging and supporting multicentre randomized trials in priority areas, including management of cardiovascular disease in patients with kidney failure.Les patients atteints d’insuffisance rénale chronique (IRC) ne reçoivent pas toujours les soins recommandés dans les lignes directrices en raison de la complexité du traitement de l’IRC, de l’absence de données probantes sur différents aspects de l’IRC et d’un manque de diffusion des bonnes pratiques. Lors d’une conférence tenue en 2007 et réunissant différents acteurs clés impliqués en néphrologie, les participants ont attribué le peu d’impact des lignes directrices de la Société canadienne de néphrologie (SCN) à un manque de communication et d’arrimage entre le comité chargé des lignes directrices cliniques de la SCN et les chercheurs, les décideurs et les utilisateurs de connaissance. De plus, les participants ont aussi mentionné la nécessité d’acquérir plus de connaissances afin d’optimiser les soins de patients atteints d’IRC. L’idée du Canadian Kidney Knowledge Translation and Generation Network (CANN-NET) s’est développée suite à cette conférence. CANN-NET est un réseau pancanadien réunissant la SCN, la Fondation canadienne du rein et différentes sociétés savantes professionnelles et dont la visée est d’améliorer les soins et la survie des patients atteints ou à risque de maladie rénale. La détermination du moment optimal d’initiation de la dialyse ainsi que l’utilisation accrue des modalités de dialyse à domicile font partie des priorités initiales de transfert de connaissance identifiées par CANN-NET. De plus, compte tenu d’un besoin continu de nouvelles connaissances, CANN-NET a aussi créé un groupe national de chercheurs canadiens afin d’accroître les connaissances et l’acquisition de données en encourageant et en supportant des études cliniques randomisées et multicentriques sur des sujets jugés prioritaires tels que le traitement de la maladie cardiovasculaire chez les patients atteints de maladie rénale.

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

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

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.

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.