Regional Variation in Hemoglobin Distribution Among Individuals With CKD: the ISN International Network of CKD Cohorts.

Introduction: Despite recognized geographic and sex-based differences in hemoglobin in the general population, these factors are typically ignored in patients with chronic kidney disease (CKD) in whom a single therapeutic range for hemoglobin is recommended. We sought to compare the distribution of hemoglobin across international nondialysis CKD populations and evaluate predictors of hemoglobin. Methods: In this cross-sectional study, hemoglobin distribution was evaluated in each cohort overall and stratified by sex and estimated glomerular filtration rate (eGFR). Relationships between candidate predictors and hemoglobin were assessed from linear regression models in each cohort. Estimates were subsequently pooled in a random effects model. Results: A total of 58,613 participants from 21 adult cohorts (median eGFR range of 17-49 ml/min) and 3 pediatric cohorts (median eGFR range of 26-45 ml/min) were included with broad geographic representation. Hemoglobin values varied substantially among the cohorts, overall and within eGFR categories, with particularly low mean hemoglobin observed in women from Asian and African cohorts. Across the eGFR range, women had a lower hemoglobin compared to men, even at an eGFR of 15 ml/min (mean difference 5.3 g/l, 95% confidence interval [CI] 3.7-6.9). Lower eGFR, female sex, older age, lower body mass index, and diabetic kidney disease were all independent predictors of a lower hemoglobin value; however, this only explained a minority of variance (R2 7%-44% across cohorts). Conclusion: There are substantial regional differences in hemoglobin distribution among individuals with CKD, and the majority of variance is unexplained by demographics, eGFR, or comorbidities. These findings call for a renewed interest in improving our understanding of hemoglobin determinants in specific CKD populations.

Association of Clonal Hematopoiesis of Indeterminate Potential with Worse Kidney Function and Anemia in Two Cohorts of Patients with Advanced Chronic Kidney Disease.

BACKGROUND: Clonal hematopoiesis of indeterminate potential (CHIP) is an inflammatory premalignant disorder resulting from acquired genetic mutations in hematopoietic stem cells. This condition is common in aging populations and associated with cardiovascular morbidity and overall mortality, but its role in CKD is unknown. METHODS: We performed targeted sequencing to detect CHIP mutations in two independent cohorts of 87 and 85 adults with an eGFR<60 ml/min per 1.73m2. We also assessed kidney function, hematologic, and mineral bone disease parameters cross-sectionally at baseline, and collected creatinine measurements over the following 5-year period. RESULTS: At baseline, CHIP was detected in 18 of 87 (21%) and 25 of 85 (29%) cohort participants. Participants with CHIP were at higher risk of kidney failure, as predicted by the Kidney Failure Risk Equation (KFRE), compared with those without CHIP. Individuals with CHIP manifested a 2.2-fold increased risk of a 50% decline in eGFR or ESKD over 5 years of follow-up (hazard ratio 2.2; 95% confidence interval, 1.2 to 3.8) in a Cox proportional hazard model adjusted for age, sex, and baseline eGFR. The addition of CHIP to 2-year and 5-year calibrated KFRE risk models improved ESKD predictions. Those with CHIP also had lower hemoglobin, higher ferritin, and higher red blood cell mean corpuscular volume versus those without CHIP. CONCLUSIONS: In this exploratory analysis of individuals with preexisting CKD, CHIP was associated with higher baseline KFRE scores, greater progression of CKD, and anemia. Further research is needed to define the nature of the relationship between CHIP and kidney disease progression.

Defining the Scope of Knowledge Translation Within a National, Patient-Oriented Kidney Research Network.

PURPOSE OF PROGRAM: Integrated knowledge translation (IKT) is a collaborative approach whereby knowledge created through health research is utilized in ways that are relevant to the needs of all stakeholders. However, research teams have limited capacity and know-how for achieving IKT, resulting in a disconnect between the generation and application of knowledge. The goal of this report is to describe how IKT research was achieved across a large-scale, patient-oriented research network, Canadians Seeking Solutions and Innovations to Overcome Chronic Kidney Disease (Can-SOLVE CKD). SOURCES OF INFORMATION: Resources to facilitate knowledge translation (KT) planning across the network were developed by the Can-SOLVE CKD Knowledge User/Knowledge Translation Committee with reference to established Canadian KT and patient engagement tools and frameworks, review of the published and gray literature, and expertise of committee members. METHODS: The Can-SOLVE CKD Knowledge User/Knowledge Translation Committee consisting of patient partners, health care providers, policymakers, and researchers provided oversight of the development and implementation of the network's IKT initiatives. Guided by its strategic framework, the committee developed KT planning templates and review checklists to assist network projects with preparing for dissemination, implementation, and scale and spread of their interventions. The committee has acted in a consultative capacity to facilitate IKT across network initiatives and has supported capacity building through KT activities aimed at network membership and knowledge users more broadly. KEY FINDINGS: The Can-SOLVE CKD Knowledge User/Knowledge Translation Committee established a nation-wide strategy for KT infrastructure and capacity building. Acting as a knowledge intermediary, the committee has connected research teams with knowledge users across Canada to support practices and policies informed by evidence generated by the network. The committee has developed KT initiatives, including a Community of Practice, whereby participants across different regions and disciplines convene regularly to share health research knowledge and communications strategies relevant to the network. Critically, patients are engaged and contribute throughout the research process. Examples of IKT activities from select projects are provided, as well as ways for sustaining the network's KT platform. LIMITATIONS: The KT resources developed by the committee were adapted from other established resources to meet the needs of the network and have not undergone formal evaluation in this context. Given the broad scope of the network, resources to facilitate implementation and knowledge user engagement may not meet the needs of all initiatives and must be tailored accordingly. Knowledge barriers, including a lack of information and skills related to conceptual and practical aspects of KT, among network members provided a rationale for various KT capacity-building initiatives. IMPLICATIONS: The approach described here offers a practical method for achieving IKT, including how to plan, implement, and sustain initiatives across large-scale health research networks. Within the context of Can-SOLVE CKD, these efforts will shorten knowledge-practice gaps through producing and applying relevant research to improve the lives of people living with kidney disease.

OBJECTIF DU PROGRAMME: L'application intégrée des connaissances (AIC) est une approche collaborative à répondre aux besoins de tous les intervenants. Les équipes de recherche ont cependant une capacité et un savoir-faire limités pour réaliser l'AIC, ce qui entraîne un décalage entre la production et l'application des connaissances. L'objectif de cet article est de décrire comment la recherche sur l'AIC a été réalisée dans le cadre d'un vaste réseau de recherche axée sur le patient, le réseau CAN-SOLVE CKD (Canadians Seeking Solutions and Innovations to Overcome Chronic Kidney Disease). SOURCES: Les ressources visant à faciliter la planification de l'application des connaissances (AC) dans l'ensemble du réseau ont été élaborées par le Comité des utilisateurs/de l'application des connaissances (Knowledge User/Knowledge Translation Committee) de Can-SOLVE CKD en se référant à des outils et des cadres d'AC et de participation des patients établis au Canada, à l'examen de la documentation publiée et de la littérature grise et à l'expertise des membres du comité. MÉTHODOLOGIE: Le Comité des utilisateurs/de l'application des connaissances de CAN-SOLVE, constitué de partenaires patients, de fournisseurs de soins, de décideurs et de chercheurs, a supervisé le développement et la mise en œuvre des initiatives d'AIC du réseau. Guidé par son cadre stratégique, le comité a élaboré des modèles de planification pour l'AC et des listes de vérification pour aider les projets du réseau à se préparer à la diffusion et à la mise en œuvre de leurs interventions, de même qu'à leur élargissement et leur diffusion. Le comité a agi à titre consultatif pour faciliter l'AIC dans l'ensemble des initiatives du réseau, et a appuyé le renforcement des capacités par le biais d'activités d'AC destinées aux membres du réseau et, plus largement, aux utilisateurs des connaissances. PRINCIPAUX RÉSULTATS: Le Comité des utilisateurs/de l'application des connaissances de CAN-SOLVE a établi une stratégie nationale pour l'infrastructure et le renforcement des capacités en matière d'AC. En tant qu'intermédiaire, le comité a mis en relation des équipes de recherche et des utilisateurs des connaissances partout au Canada afin d'appuyer les pratiques et les politiques fondées sur les données probantes produites par le réseau. Le comité a élaboré des initiatives d'AC, notamment une communauté de pratique où les participants des différentes régions et disciplines se réunissent sur une base régulière pour partager les connaissances générées en recherche et les stratégies de communication pertinentes pour le réseau. Il est essentiel que les patients s'engagent et contribuent tout au long du processus de recherche. Des exemples d'activités d'AIC tirés de projets sélectionnés sont fournis, de même que des moyens de maintenir la plateforme d'AC du réseau. LIMITES: Les ressources d'AC développées par le comité ont été adaptées à partir de ressources établies pour répondre aux besoins du réseau et, dans ce contexte, n'ont pas fait l'objet d'une évaluation officielle. Compte tenu de la vaste portée du réseau, les ressources destinées à faciliter la mise en œuvre et la participation des utilisateurs des connaissances pourraient ne pas répondre aux besoins de toutes les initiatives et devraient être adaptées en conséquence. Les freins à la connaissance parmi les membres du réseau, notamment le manque d'information et de compétences liées aux aspects conceptuels et pratiques de l'AC, ont servi de justification à diverses initiatives de renforcement des capacités en matière d'AC. CONCLUSION: L'approche décrite offre une méthode pratique pour parvenir à l'AIC, notamment dans la façon de planifier, de mettre en œuvre et d'appuyer des initiatives dans les réseaux de recherche d'envergure. Dans le contexte de CAN-SOLVE CKD, ces efforts permettront de réduire les écarts entre les connaissances et les pratiques, en produisant et en appliquant des recherches visant l'amélioration de la vie des personnes atteintes de néphropathies.

A Framework to Ensure Patient Partners Have Equal and Contributing Voices Throughout the Research Program Evaluation Process.

PURPOSE OF PROGRAM: Traditionally, peer review was a closed process conducted only by individuals working in the research field. To establish a more integrated and patient-centered approach, one of Canada's largest kidney research networks (Can-SOLVE CKD) has created a Research Operations Committee (ROC) that includes patients as key members. The ROC represents one way for achieving meaningful patient-oriented research (POR). SOURCE OF INFORMATION: Can-SOLVE CKD, a network created as part of the Canadian Institutes of Health Research (CIHR) Strategy for Patient-Oriented Research (SPOR). METHODS: The ROC consists of patients, physicians, scientists, Indigenous partners, experts in research methodology, and a member of Can-SOLVE CKD's operational team. On an annual basis, Can-SOLVE CKD's research teams provide the ROC with a review package, which incorporates information from patient engagement check-in calls and surveys, the project's knowledge translation plan and products, and a progress report written by the project team. The ROC evaluates the review package and provides feedback and recommendations accordingly. KEY FINDINGS: The transparent nature of the process, regular feedback and review, along with an overt accountability and scoring system, has been embraced by both patients and researchers. As a result of the ROC process, the number of patient leads for each project has grown over a 3-year period and more researchers have received POR and cultural sensitivity training. LIMITATIONS: While anecdotal evidence suggests this approach is beneficial for achieving POR, formal mechanisms of evaluation are currently lacking. IMPLICATIONS: This ROC framework ensures patients are active contributors throughout the research process and could be adopted by other organizations to achieve a more patient-centered approach to research.

OBJECTIF DU PROGRAM: L'évaluation par les pairs consiste habituellement en un processus fermé et mené uniquement par des personnes travaillant dans le domaine de la recherche. Pour développer une approche plus intégrée et davantage axée sur les patients, un des plus importants réseaux canadiens de recherche sur les maladies rénales (Can-SOLVE CKD) a créé un comité de gestion de la recherche (CGR) où les patients sont des membres à part entière. Une approche qui vise la conduite d'activités de recherches significatives et davantage orientées vers le patient. SOURCE: Can-SOLVE CKD, un réseau créé dans le cadre de la Stratégie de recherche axée sur le patient (SRAP) des Instituts de recherche en santé du Canada (IRSC). MÉTHODOLOGIE: Le CGR rassemble des patients, des médecins, des chercheurs, des partenaires autochtones, des experts en méthodologie de recherche et un membre de l'équipe d'intervention de Can-SOLVE CKD. Une fois par année, l'équipe de recherche de Can-SOLVE CKD fournit au CGR un dossier d'examen. Ce dossier contient les informations recueillies lors d'appels ou de sondages vérifiant l'engagement des patients, le plan d'application des connaissances du projet et ses résultats, de même qu'un rapport périodique rédigé par l'équipe responsable du projet. Le CGR évalue ce dossier et émet ses commentaires et recommandations. PRINCIPAUX RÉSULTATS: La transparence du processus, la rétroaction et la révision sur une base régulière, de même que les systèmes de responsabilité et de notation ouverts ont été adoptés tant par les patients que par les chercheurs. Grâce à ce processus, le nombre de patients candidats pour chaque projet a augmenté sur une période de trois ans, et davantage de chercheurs ont reçu une formation sur les réalités culturelles et la pratique d'activités de recherche axées sur le patient. LIMITES: Bien que des preuves anecdotiques suggèrent que cette approche soit bénéfique à la conduite de recherches axées sur le patient, des mécanismes formels pour son évaluation manquent toujours. CONCLUSION: Le cadre proposé par le CGR assure une contribution active des patients tout au long du processus de recherche. Ce program pourrait être adopté par d'autres organizations et permettre la réalisation d'activités de recherche davantage axées sur le patient.

Conversion of Urine Protein-Creatinine Ratio or Urine Dipstick Protein to Urine Albumin-Creatinine Ratio for Use in Chronic Kidney Disease Screening and Prognosis : An Individual Participant-Based Meta-analysis.

BACKGROUND: Although measuring albuminuria is the preferred method for defining and staging chronic kidney disease (CKD), total urine protein or dipstick protein is often measured instead. OBJECTIVE: To develop equations for converting urine protein-creatinine ratio (PCR) and dipstick protein to urine albumin-creatinine ratio (ACR) and to test their diagnostic accuracy in CKD screening and staging. DESIGN: Individual participant-based meta-analysis. SETTING: 12 research and 21 clinical cohorts. PARTICIPANTS: 919 383 adults with same-day measures of ACR and PCR or dipstick protein. MEASUREMENTS: Equations to convert urine PCR and dipstick protein to ACR were developed and tested for purposes of CKD screening (ACR ≥30 mg/g) and staging (stage A2: ACR of 30 to 299 mg/g; stage A3: ACR ≥300 mg/g). RESULTS: Median ACR was 14 mg/g (25th to 75th percentile of cohorts, 5 to 25 mg/g). The association between PCR and ACR was inconsistent for PCR values less than 50 mg/g. For higher PCR values, the PCR conversion equations demonstrated moderate sensitivity (91%, 75%, and 87%) and specificity (87%, 89%, and 98%) for screening (ACR >30 mg/g) and classification into stages A2 and A3, respectively. Urine dipstick categories of trace or greater, trace to +, and ++ for screening for ACR values greater than 30 mg/g and classification into stages A2 and A3, respectively, had moderate sensitivity (62%, 36%, and 78%) and high specificity (88%, 88%, and 98%). For individual risk prediction, the estimated 2-year 4-variable kidney failure risk equation using predicted ACR from PCR had discrimination similar to that of using observed ACR. LIMITATION: Diverse methods of ACR and PCR quantification were used; measurements were not always performed in the same urine sample. CONCLUSION: Urine ACR is the preferred measure of albuminuria; however, if ACR is not available, predicted ACR from PCR or urine dipstick protein may help in CKD screening, staging, and prognosis. PRIMARY FUNDING SOURCE: National Institute of Diabetes and Digestive and Kidney Diseases and National Kidney Foundation.

Glomerular Filtration Rate-Specific Cutoffs Can Refine the Prognostic Value of Circulating Cardiac Biomarkers in Advanced Chronic Kidney Disease.

BACKGROUND: Using standard cutoffs derived from healthy adults, high-sensitivity cardiac troponin T (hs-cTnT) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) are frequently elevated in patients with reduced glomerular filtration rate (GFR), with unclear implications. We sought to compare GFR-specific cutoffs of each biomarker with standard cutoffs for discrimination of cardiovascular risk in asymptomatic patients with chronic kidney disease. METHODS: We investigated a prospective cohort of 1956 participants with median GFR of 27 mL/min/1.73 m2. Cox proportional hazards models were used to examine the association between each biomarker and first adjudicated cardiovascular event (unstable angina, myocardial infarction, heart failure, stroke, cardiovascular death). We used an outcome-based approach to identify optimal risk-based cutoffs for each biomarker within GFR strata (< 20, 20-29, 30-44 mL/min/1.73 m2). We evaluated the added prognostic value of each biomarker to a multivariable base model, comparing GFR-specific with standard cutoffs. RESULTS: Hs-cTnT and NT-proBNP were elevated in 76% and 82% of participants, respectively. A total of 401 events were recorded during 6772 person-years at risk. Both biomarkers were independent predictors of cardiovascular events. Optimal cutoffs for each biomarker were higher than standard thresholds, being highest at GFR values < 20 mL/min/1.73 m2. Addition of hs-cTnT to the base model using GFR-specific cutoffs significantly improved reclassification for events (52%) and nonevents (21%). Similar findings were observed for NT-proBNP. In contrast, use of standard cutoffs failed to reclassify patients who had no event as lower risk. CONCLUSIONS: Among asymptomatic patients with advanced chronic kidney disease, optimal cutoffs for hs-cTnT and NT-proBNP differed according to GFR level and outperformed standard cutoffs for discrimination of cardiovascular risk.

GFR-Specific versus GFR-Agnostic Cutoffs for Parathyroid Hormone and Fibroblast Growth Factor-23 in Advanced Chronic Kidney Disease.

BACKGROUND: In the majority of patients with advanced chronic kidney disease (CKD), values of parathyroid hormone (PTH1-84) and fibroblast growth factor 23 (FGF-23) exceed the normal reference range, potentially as an appropriate adaptation to reduced glomerular filtration rate (GFR). We tested whether GFR-specific cutoffs for PTH1-84 and FGF-23 could better identify patients with inappropriately high PTH1-84 and FGF-23 for their degree of CKD and thereby improve prognostication of clinical outcomes compared to a uniform threshold. METHODS: Prospective pan-Canadian cohort of 1,812 patients with mean estimated GFR (eGFR) 28.9 mL/min/1.73 m2 followed for a median of 52 months. Repeated log-rank tests were used to identify optimal cutoffs for PTH1-84 and FGF-23 within eGFR strata (<20, 20-29 and ≥30 mL/min/1.73 m2) that maximally differentiated high- and low-risk populations for (1) cardiovascular (CV) events (fatal or nonfatal myocardial infarction, coronary revascularization, stroke, heart failure) and (2) renal events (initiation of chronic renal replacement therapy). In multivariable models, we examined the association between -GFR-specific cutoffs and outcomes and compared their added prognostic value to existing uniform thresholds. RESULTS: Risk-based cutoffs for PTH1-84 and FGF-23 increased in a graded fashion with decreasing eGFR. Among patients with eGFR <20 mL/min/1.73 m2, CV risk-based cutoffs for PTH1-84 and FGF-23 were 3.4 and 5.5 times the upper limit of normal, respectively, and reclassified 31.9 and 35.1% of patients when added to a multivariable base model for CV events. In contrast, the addition of PTH1-84 and FGF-23 to the base model using uniform cutoffs failed to reclassify such patients. Similar findings were demonstrated for renal outcomes. CONCLUSION: GFR-specific risk-based cutoffs for PTH1-84 and FGF-23 may facilitate more meaningful risk stratification in advanced CKD than current GFR-agnostic reference ranges derived from healthy adults. This may be most applicable in those with severely reduced GFR.

The Risk of Adverse Events in Patients With Polycystic Kidney Disease With Advanced Chronic Kidney Disease.

BACKGROUND: Polycystic kidney disease (PKD) leads to progressive chronic kidney disease (CKD) with a subsequent risk of adverse events such as cardiac disease, infections, end-stage kidney disease (ESKD), and mortality. OBJECTIVES: To determine the risks of CKD-related adverse outcomes in patients with PKD compared with patients without PKD. SETTING: Canadian study of prediction of death, dialysis and interim cardiovascular events (CanPREDDICT) was a prospective pan-Canadian cohort study from 2008-2013 involving 28 facilities with adjudicated outcomes. PATIENTS: Adult CKD patients (estimated glomerular filtration rate [eGFR] = 15-45 mL/min/1.73 m2) under the care of a nephrologist. MEASUREMENTS: Polycystic kidney disease as identified by the treating physician. METHODS: Patients with PKD (PKD) and non-PKD were propensity score (PS) matched (1:4) using demographics, comorbidities, and laboratory values. We used conditional Cox proportional hazards models to examine the risk of cardiac disease (defined as coronary artery disease or congestive heart failure), infection, ESKD, or all-cause mortality in patients with PKD compared with no PKD. RESULTS: Among a total of 2370 patients, 105 with PKD were matched with 416 without PKD with a baseline mean age and eGFR of 62.6 years and 27.8 mL/min, respectively. During 1680 person-years of follow time (median follow-up: 3.8 years), there were a total of 43 cardiac, 83 ESKD, 117 infectious, and 39 all-cause mortality events. PKD was associated with a higher risk of cardiac events (9.5% vs 7.9%, hazard ratio [HR] = 1.46, 95% confidence interval [CI] = 1.04-2.04) and ESKD (25.7% vs 13.5%, HR = 2.00, 95% CI = 1.33-3.01), and with similar risks for infection (21.9% vs 22.6%, HR = 1.16, 95% CI = 0.75-1.82) or all-cause mortality (6.7% vs 7.7%, HR = 0.87, 95% CI = 0.40-1.91) compared with non-PKD. There were no differences in the types of infections (urinary, respiratory, hematologic, or other) between the 2 groups (P = .585). CONCLUSIONS: Patients with PKD with advanced CKD are at a potentially higher risk of ESKD and cardiac events compared with patients without PKD. These findings, if confirmed in larger cohorts, suggest that monitoring and treatment for adverse outcomes in patients with PKD, especially related to cardiac disease, may be beneficial.

CONTEXTE: La maladie polykystique des reins (MPR) mène à l'insuffisance rénale chronique (IRC) progressive, laquelle augmente à son tour la probabilité d'apparition de pathologies subséquentes, notamment cardiopathie, infections et insuffisance rénale terminale (IRT), ainsi que le risque de décès du patient. OBJECTIFS DE L'ÉTUDE: L'étude visait à évaluer le risque de survenue d'une pathologie associée à l'IRC chez les patients atteints d'une MPR en comparaison avec les patients non atteints d'une MPR. CADRE ET TYPE D'ÉTUDE: Il s'agit d'une étude de cohorte prospective pancanadienne, la CanPREDDICT (Canadian Study of Prediction of Death, Dialysis and Interim Cardiovascular Events). L'étude s'est tenue entre 2008 et 2013 au sein de 28 établissements, et les issues étaient rigoureusement définies et jugées par un comité. PARTICIPANTS: Des patients adultes atteints d'IRC (DFGe = 15-45 mL/min/1,73 m2) suivis par un néphrologue. MESURE: La maladie polykystique des reins (MPR) telle que diagnostiquée par le médecin traitant. MÉTHODOLOGIE: Le jumelage des patients atteints de la maladie polykystique rénale autosomique dominante (MPRAD) avec les sujets contrôles s'est fait sur la base du score de propension dans un rapport d'un pour quatre (1:4). Les autres critères employés pour le jumelage étaient le profil démographique des patients, leurs comorbidités et leurs résultats de laboratoire. Des modèles conditionnels des risques proportionnels de Cox ont été utilisés pour évaluer le risquei) de développer une cardiopathie (coronopathie ou insuffisance cardiaque congestive) ouii) une infection ouiii) une évolution vers l'IRT, de même queiv) le risque de mortalité (toutes causes confondues), dans les deux groupes de patients. RÉSULTATS: Parmi les 2 370 participants, 105 atteints de MPR ont été jumelés à 416 patients non atteints. L'âge initial moyen des participants était de 62,6 ans et leur DFGe moyen se situait à 27,8 mL/min/1,73 m2. Au cours des 1 680 années-personnes de suivi (suivi moyen de 3,8 ans par patient), on a répertorié 43 cas de cardiopathie et 117 cas d'infection; 83 patients ont développé une IRT et 39 sont décédés (toutes causes confondues). La MPR a été associée à un risque plus élevé de cardiopathie (9,5 % [MPR] c. 7,9 % [non MPR]; RR : 1,46; IC à 95 % : 1,04-2,04) et d'évolution vers l'IRT (25,7 % [MPR] c. 13,5 % [non MPR]; RR : 2,00; IC à 95 % : 1,33-3,01) par rapport aux patients non atteints. Les risques d'infection (21,9 % [MPR] c. 22,6 % [non MPR]; RR : 1,16; IC à 95 % : 0,75-1,82) et de mortalité toutes causes confondues (6,7 % [MPR] c. 7,7 % [non MPR]; RR : 0,87; IC à 95 %; 0,40-1,91) se sont toutefois avérés similaires dans les deux groupes. De plus, aucune différence n'a été observée selon le type d'infection (urinaire, respiratoire, hématologique ou autre) entre les deux groupes (P = 0,585). CONCLUSION: Les patients atteints d'un stade avancé d'IRC et d'une MPR sont plus à risque d'évoluer vers l'IRT ou de développer une cardiopathie que les patients non atteints d'une MPR. Ces résultats, s'ils sont confirmés par des études sur cohortes plus nombreuses, suggèrent que le suivi et le traitement des pathologies associés à la MPR sur la santé des patients, particulièrement la cardiopathie, pourraient s'avérer bénéfiques.

Canadians Seeking Solutions and Innovations to Overcome Chronic Kidney Disease (Can-SOLVE CKD): Form and Function.

PURPOSE OF REVIEW: This article serves to describe the Can-SOLVE CKD network, a program of research projects and infrastructure that has excited patients and given them hope that we can truly transform the care they receive. ISSUE: Chronic kidney disease (CKD) is a complex disorder that affects more than 4 million Canadians and costs the Canadian health care system more than $40 billion per year. The evidence base for guiding care in CKD is small, and even in areas where evidence exists, uptake of evidence into clinical practice has been slow. Compounding these complexities are the variations in outcomes for patients with CKD and difficulties predicting who is most likely to develop complications over time. Clearly these gaps in our knowledge and understanding of CKD need to be filled, but the current state of CKD research is not where it needs to be. A culture of clinical trials and inquiry into the disease is lacking, and much of the existing evidence base addresses the concerns of the researchers but not necessarily those of the patients. PROGRAM OVERVIEW: The Canadian Institutes of Health Research (CIHR) has launched the national Strategy for Patient-Oriented Research (SPOR), a coalition of federal, provincial, and territorial partners dedicated to integrating research into care. Canadians Seeking Solutions and Innovations to Overcome Chronic Kidney Disease (Can-SOLVE CKD) is one of five pan-Canadian chronic kidney disease networks supported through the SPOR. The vision of Can-SOLVE CKD is that by 2020 every Canadian with or at high risk for CKD will receive the best recommended care, experience optimal outcomes, and have the opportunity to participate in studies with novel therapies, regardless of age, sex, gender, location, or ethnicity. PROGRAM OBJECTIVE: The overarching objective of Can-SOLVE CKD is to accelerate the translation of knowledge about CKD into clinical research and practice. By focusing on the patient's voice and implementing relevant findings in real time, Can-SOLVE CKD will transform the care that CKD patients receive, and will improve kidney health for future generations.

OBJECTIF DE LA REVUE: Le présent article décrit le réseau Can-SOLVE CKD, un réseau basé sur un programme de projets et d'infrastructures de recherche qui ont soulevé l'enthousiasme des patients et qui nourrissent leur espoir de voir une réelle réforme des soins qu'ils reçoivent. CONTEXTE: L'insuffisance rénale chronique (IRC) est un trouble complexe qui affecte plus de quatre millions de Canadiens et qui engendre au système de santé canadien des coûts annuels de l'ordre de 40 milliards de dollars. Les données probantes sous-tendant les soins en IRC sont rares, et dans les branches où ces données existent, leur intégration à la pratique clinique se montre insuffisante. Ces problèmes sont aggravés d'abord par la grande variabilité du pronostic de la maladie, puis par la difficulté de prévoir quels patients seront les plus susceptibles de développer des complications. Ces lacunes de connaissances et de compréhension de l'IRC doivent manifestement être comblées; cependant, force est de constater que la recherche actuelle sur l'IRC est inadéquate. Outre l'absence d'une culture médicale qui encourage les essais cliniques, les données recueillies rejoignent les préoccupations des chercheurs sans nécessairement refléter celles des patients. PRÉSENTATION DU PROGRAMME: Lancée par l'Institut de recherche en santé du Canada (IRSC), la Stratégie de recherche axée sur le patient (SRAP) consiste en une coalition de partenaires fédéraux, provinciaux et territoriaux visant l'intégration des résultats de la recherche dans les soins prodigués aux patients. Le réseau Can-SOLVE CKD (Canadians Seeking Solutions and Innovations to Overcome Chronic Kidney Disease) est l'un des cinq réseaux de recherche pancanadiens sur les maladies chroniques soutenus par la SRAP. L'objectif du réseau Can-SOLVE CKD est tripartite : on souhaite que, d'ici 2020, tous les Canadiens atteints d'IRC (ou à haut risque de développer la maladie) 1- reçoivent les meilleurs soins; 2- obtiennent des résultats de santé optimaux; 3- aient l'occasion de participer à des études cliniques pertinentes (et ce, sans égard à leur âge, leur sexe, leur ethnicité ou leur lieu de résidence). OBJECTIF DU PROGRAMME: L'objectif principal du réseau Can-SOLVE CKD est d'accélérer l'application des connaissances sur l'IRC, tant en recherche qu'en pratique clinique. En s'intéressant aux préoccupations des patients et en appliquant en temps réel les résultats pertinents de la recherche, Can-SOLVE CKD transformera la façon dont seront soignés les patients atteints d'IRC et améliorera la santé rénale globale des générations futures.

Randomized Controlled Trial for the Effect of Vitamin D Supplementation on Vascular Stiffness in CKD.

BACKGROUND AND OBJECTIVES: Vitamin D is implicated in vascular health in CKD. This study compared placebo, calcifediol, and calcitriol treatment with changes in vascular stiffness, BP, proteinuria, mineral metabolism parameters, C-reactive protein, and fibroblast growth factor 23 in patients with stable CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We conducted a double-blind, randomized controlled trial in out-patient CKD clinics in Vancouver, Canada, from February of 2011 to August of 2014, enrolling 119 patients with an eGFR of 15-45 ml/min per 1.73 m2. Change in pulse wave velocity (PWV) was measured after 6 months of treatment with a fixed dose of oral calcifediol (5000 IU 25-hydroxyvitamin D3), calcitriol (0.5 µg 1,25-dihydroxyvitamin D3), or placebo, thrice weekly. RESULTS: Eighty-seven participants were evaluated. Mean age was 66 years, 71% were men, 40% were diabetic, and mean baseline PWV was 11.5 m/s (SD=3.9 m/s). After 6 months, the PWV decreased in the calcifediol group (mean change, -1.1; 95% confidence interval [95% CI], -2.2 to 0.1 m/s), remained unchanged in the calcitriol group (mean change, 0.2; 95% CI, -0.9 to 1.4 m/s), and increased in the placebo group (mean change, 1.1; 95% CI, -0.1 to 2.2 m/s). The overall P value for between-arm changes was 0.03. Absolute PWV change was significantly different between groups (P=0.04): the combined vitamin D treatment group saw decreased PWV (mean change, -0.4; 95% CI, -1.2 to 0.4 m/s) whereas the placebo group saw increased PWV (mean change, +1.1; 95% CI, -0.1 to 2.2 m/s). The treatment group demonstrated significantly decreased serum parathyroid hormone (mean difference, -0.5; 95% CI, -0.7 to -0.3 ln[pg/ml]; P<0.001) and increased calcium (mean difference, 0.4; 95% CI, -0.1 to 0.7 mg/dl; P=0.02). In observational analysis, participants in the highest 25-hydroxyvitamin D tertile at trial end had significant decreases in PWV (mean change, -1.0; 95% CI, -2.0 to 0.0 m/s) compared with the middle and lowest tertiles (P<0.01). Side effects were minor and rare. CONCLUSIONS: Six months of supplemental vitamin D analogs at fixed doses may achieve a reduction of PWV in patients with advanced CKD. Because the treatment effect was attenuated when baseline PWV was included as a covariate, these findings should be replicated in larger populations and further studied.

Cardiovascular risk is similar in patients with glomerulonephritis compared to other types of chronic kidney disease: a matched cohort study.

BACKGROUND: Patients with chronic kidney disease (CKD) due to glomerulonephritis (GN) are thought to be at high risk for cardiovascular disease (CVD). However, no study has examined whether GN directly contributes to CV risk beyond the effects conferred by pre-existing traditional risk factors and level of renal function. METHODS: Matched cohort study using the previously described prospective CanPREDDICT study cohort. 2187 patients with CKD (eGFR 15-45 ml/min/m2) from 25 Canadian centres were divided into GN vs non-GN cause of CKD. Patients on immunotherapy for GN were not included in the study. Standardized measures of CV risk factors, biomarkers and CV outcomes were recorded over 3 years of follow-up, with the primary outcome measure being time to first all-cause CV event. RESULTS: In the overall cohort, CV events occurred in 25 (8.7%) of the GN group and 338 (17.8%) of the non-GN group (HR 0.45, 95% CI 0.30-0.67, p < 0.01). In a Cox regression multivariable model that included age, sex, prior diabetes and CVD, baseline eGFR and onset of renal replacement therapy, the risk of CV events was similar in the GN and non-GN groups (HR 0.71, 95% CI 0.47-1.08, p = 0.11). GN and non-GN patients were matched by age and using a propensity score including sex, prior diabetes and CVD and baseline eGFR. In the matched group, the risk of CV events was similar in GN vs non-GN patients (N = 25/271 (9.2%) in both groups, HR 1.01, 95% CI 0.05-1.77, p = 0.9). An interaction analysis showed that CRP, ACR and troponin conferred differing amounts of CV risk in the GN and non-GN groups. CONCLUSIONS: Patients with advanced CKD due to GN have a high 8.7% absolute 3-year risk of CVD, attributable to prior CV risk factors and level of kidney function rather than the GN disease itself.

The Association between Biomarker Profiles, Etiology of Chronic Kidney Disease, and Mortality.

BACKGROUND: Prognosis in chronic kidney disease (CKD) for adverse outcomes differs substantially based on the etiology of CKD. We examined whether the biomarker profile differed based on CKD etiology and whether they were associated with mortality. METHODS: Prospective observational study of 1,157 patients, 663 with diabetic kidney disease (DKD), 273 with glomerulonephritis (GN), and 221 with cystic/interstitial disease (polycystic kidney disease, pyelonephritis or chronic tubulointerstitial nephritis [PCK/TIN]) were identified in the Canadian Study of Prediction of Dialysis, Death and Interim Cardiovascular events over Time cohort. The outcome of interest was mortality before commencing dialysis. The biomarker profile consisted of N-terminal pro-brain natriuretic peptide (NT-proBNP), troponin I (TnI), asymmetric dimethylarginine (ADMA), interleukin (IL)-6, high sensitivity C-reactive protein, fibroblast growth factor-23 (FGF23), transforming growth factor-beta, 25-hydroxylvitamin D, and cystatin C (CysC). RESULTS: The mean estimated glomerular filtration rate was 27 mL/min/1.73 m2 and median follow-up time was 44 months. Mortality before dialysis commencement was the greatest in DKD (20%), followed by PCK/TIN (13%), and was least in those GN (8%). The majority of deaths were cardiovascular in nature, 17, 9, and 5.5% for DKD, PCK/TIN, GN, respectively. Those with DKD had higher hazard for mortality, unadjusted (hazard ratio [HR] 2.7, 95% CI 1.7-4.3) and adjusted (HR 1.7, 95% CI 1.1-2.8). The biomarker profiles associated with mortality differed significantly by CKD etiology as follows: DKD was associated with CysC (HR 1.3, 95% CI 1.0-1.6), ADMA (HR 1.3, 95% CI 1.1-1.6), and NT-proBNP (HR 1.7, 95% CI 1.4-2.1), GN was associated with FGF23 (HR 1.8, 95% CI 1.1-2.8), TnI (HR 3.6, 95% CI 1.3-9.5), and transforming growth factor-beta (HR 0.6, 95% CI 0.4-0.9) and PCK/TIN was associated with ADMA (HR 1.5, 95% CI 1.3-1.8) and IL-6 (HR 2.1, 95% CI 1.5-3.1). CONCLUSIONS: Biomarkers profiles differ according to the etiology of CKD and are associated with mortality.

Infection in advanced chronic kidney disease leads to increased risk of cardiovascular events, end-stage kidney disease and mortality.

The risk of infection in advanced chronic kidney disease (CKD) and its subsequent impact on adverse outcomes are not well established. Therefore, we determined the association of an infectious episode with the subsequent risk of cardiovascular ischemia, congestive heart failure, end-stage kidney disease or mortality in a Canadian prospective cohort (CanPREDDICT) of patients with advanced CKD (eGFR: 15-45 ml/min/1.73m(2)) followed by nephrologists for up to 5 years. Infectious episodes were classified by anatomic location and identified by positive culture, hospital admission, or use of antibiotics. Competing risk models were used to examine the time-varying risk of infection and the risk of cardiovascular ischemia, congestive heart failure, or end-stage kidney disease accounting for the competing risk of mortality. All outcomes were independently adjudicated. Of 2370 patients (mean age, 68 years; mean baseline eGFR, 28.2 mL/min/1.73m(2)), 575 patients (24.3%) had recorded infections; 378 had 1 infection episode, whereas 197 had 2 or more episodes, the most common being urinary and respiratory. An infectious episode was independently associated with an increased risk of cardiovascular ischemia (hazard ratio 1.80, 95% confidence interval 1.24-2.60), congestive heart failure (hazard ratio, 3.2; confidence interval, 2.25-4.61), end-stage kidney disease (hazard ratio, 1.58; confidence interval, 1.22-2.05) or mortality (hazard ratio, 3.39; confidence interval, 2.65-4.33). Thus, there is a high risk of infection in advanced CKD being associated with subsequent adverse outcomes.

Advanced chronic kidney disease populations have elevated trimethylamine N-oxide levels associated with increased cardiovascular events.

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.

N-Terminal Pro-B-Type Natriuretic Peptide (NT-proBNP) Immunoreactivity Is Reduced After 6 Years of Storage at -70 °C.

BACKGROUND: Clinical trial samples may be stored frozen for prolonged periods before analysis, which can reduce the immunoreactivity of numerous analytes, particularly peptides. We sought to determine the effect of 6 years of frozen storage on serum N-terminal pro-B-type natriuretic peptide (NT-proBNP). METHODS: NT-proBNP was measured from serum samples taken from 99 different patients enrolled in the CanPREDDICT study after <1 year of storage at -70 °C using the Roche first-generation NT-proBNP assay on an e411 instrument. Separate aliquots of the same samples were analyzed after an additional 6 years of storage at -70 °C using the Roche second-generation assay on an e601 instrument. RESULTS: The median NT-proBNP immunoreactivity for the first measurement was 572 pg/mL (interquartile range [IQR] 205-1606, range 49-12820), while after an additional 6 years of storage at -70 °C, this value decreased to 526 pg/mL (IQR 181-1338, range 18-12880), resulting in a median percent difference of -7% (IQR -10.6% to -3.4%, P < 0.001). CONCLUSIONS: We report findings consistent with trends seen in previous work but have investigated the effect of a much longer storage period. Larger percent decreases in NT-proBNP reaching statistical significance are seen, although the median difference is still <10%.

The Variability of Estimated Glomerular Filtration Rate Decline in Alport Syndrome.

BACKGROUND: A progressive trajectory toward renal failure is common in patients with Alport syndrome. Genotype-phenotype correlations have been well described; however, the natural history of the trajectory toward renal failure is not well described. OBJECTIVE: The objective of this study is to describe the natural history of renal function decline in a cohort of Alport syndrome patients. DESIGN: Retrospective observational cohort study. SETTING: British Columbia, Canada, chronic renal disease registry 1995-2012. PATIENTS: 37 biopsy proven Alport syndrome or hematuria with family history of Alport syndrome. MEASUREMENTS: Serial estimated glomerular filtration rate (eGFR) Trajectory of renal decline described graphically by fitting a cubic smoothing spline to patient's eGFR measures. Various time points within a trajectory were indexed, randomly sampled, and followed for 2 years to estimate portion of progressors (>5 mL/min/1.73 m2 /y decline), stable state (0-2 mL/min/1.73 m2 /y decline), and regressors (>2 mL/min/1.73 m2 /y incline). METHODS: In this retrospective observational cohort study, participants were identified through a chronic renal disease registry in British Columbia, Canada, from 1995 to 2012. Inclusion criteria were biopsy proven or hematuria with a family history of Alport syndrome. Individual patients and family group members were studied. Trajectory of renal decline described graphically by fitting a cubic smoothing spline to patient's serial estimated glomerular filtration rate (eGFR) measures. Various time points within a trajectory were indexed, randomly sampled, and followed for 2 years to estimate portion of progressors (>5 mL/min/1.73 m2/y decline), stable state (0-2 mL/min/1.73 m2/y decline), and regressors (>2 mL/min/1.73 m2/y incline). LIMITATIONS: Histological or genetic evidence of Alport syndrome is not available in all patients. RESULTS: Median follow-up time was 48.2 months of 37 patients (78% male), with a median age of 36 (interquartile range [IQR], 18-47) and a median age of renal replacement therapy commencement (n = 23) of 38 (IQR = 20-52). Renal function changes were found to be heterogeneous overall, intra-individual and within families. Portion of progressors in eGFR 45-60 mL/min/1.73 m2 was 73.7% (SD, 10.3), whereas 23.6% (SD, 11.0) remained stable. Within eGFR 30-45 mL/min/1.73 m2, 45.6% (SD, 7.0) were progressors, whereas 53.4% (SD, 7.4) remained stable. A large portion of eGFR 15-30 mL/min/1.73 m2 patients were stable (54.8%; SD, 8.4), whereas 25.7% (SD, 7.1) progressed and 19.5% (SD, 5.6) regressed. CONCLUSIONS: The renal decline in Alport syndrome patients is heterogeneous which has implications for designing clinical trials of interventions.

MISE EN CONTEXTE: Les patients atteints du syndrome d'Alport voient souvent leur état de santé évoluer vers l'insuffisance rénale. La corrélation entre le génotype et le phénotype est bien établie. Par contre, l'histoire naturelle de la trajectoire menant à l'insuffisance rénale demeure mal connue. OBJECTIFS DE L'ÉTUDE: Le principal objectif de cette étude était de caractériser l'histoire naturelle du déclin de la fonction rénale chez une cohorte de patients atteints du syndrome d'Alport. CADRE ET TYPE D'ÉTUDE: Une étude de cohorte observationnelle rétrospective effectuée entre 1995 et 2012 à partir du registre provincial des maladies rénales chroniques de la Colombie-Britannique, au Canada. PATIENTS: Une cohorte de 37 patients dont le diagnostic avait été confirmé par biopsie ou qui présentaient une hématurie conjointement à un historique familial de syndrome d'Alport. MESURES: Le débit de filtration glomérulaire estimé (DFGe) a été mesuré à plusieurs reprises. La trajectoire du déclin de la fonction rénale a été représentée graphiquement en ajustant une méthode d'interpolation cubique par splines de lissage à la série de mesures du débit de filtration glomérulaire estimé (eGFR) du patient. Plusieurs périodes suivant une trajectoire déterminée ont été indexées, échantillonnées aléatoirement et suivies pendant deux ans afin d'évaluer la proportion de cas de progression de la maladie (>5 mL/min/173m2/année de déclin), de patients stationnaires (0 à 2 mL/min/1,73 m2/année de déclin) et de cas de régression (>2 mL/min/1,73 m2/année de remontée). MÉTHODOLOGIE: Les patients qui ont participé à cette étude de cohorte observationnelle et rétrospective ont été recrutés entre 1995 et 2012 au sein d'un registre des patients souffrant d'insuffisance rénale chronique de la Colombie-Britannique, au Canada. La sélection des participants s'est effectuée sur la base d'un diagnostic posé par biopsie OU d'une hématurie en présence d'un historique familial de syndrome d'Alport. Les patients eux-mêmes, ainsi que des membres de leurs familles respectives ont été observés. La trajectoire du déclin de la fonction rénale a été représentée graphiquement en ajustant une méthode d'interpolation cubique par splines de lissage à la série de mesures du débit de filtration glomérulaire estimé (eGFR) du patient. Plusieurs périodes suivant une trajectoire déterminée ont été indexées, échantillonnées aléatoirement et suivies pendant deux ans afin d'évaluer la proportion de cas de progression de la maladie (>5 mL/min/173m2/année de déclin), de patients stationnaires (0 à 2 mL/min/1,73m2/année de déclin) et de cas de régression (>2 mL/min/1,73m2/année de remontée). LIMITES DE L'ÉTUDE: Les données génétiques ou histologiques nécessaires pour la confirmation du syndrome d'Alport étaient absentes pour certains patients. RÉSULTATS: Le suivi s'est effectué auprès de 37 patients dont 78% étaient des hommes et s'est échelonné sur une période moyenne de 48,2 mois. L'âge médian des participants était de 36 ans (Ecart Interquartile [EI] 18, 47) et l'âge médian où ceux-ci avaient commencé une thérapie de remplacement de la fonction rénale était de 38 ans (EI 20, 52). Les changements dans la fonction rénale se sont avérés hétérogènes tant de façon globale pour l'étude que chez les individus ou au sein de leurs familles. La proportion de progression de la maladie pour les patients présentant des valeurs de eGFR entre 45 et 60 mL/min/1,73m2 était de 73,7% (Écart-type [ÉT]: 10,3) tandis que 23,6% (ÉT: 11,0) sont demeurés stables. Dans le groupe de patients dont les valeurs de eGFR se situaient entre 30 et 45 mL/min/1,73m2, une proportion de 45,6% (ÉT: 7,0) était en progression alors que 53,4% (ÉT: 7,4) sont demeurés stables. Une forte proportion des patients présentant des valeurs de eGFR entre 15 et 30 mL/min/1,73m2 soit 54,8% (ÉT: 8,4) sont demeurés stables, tandis que 25,7% (ÉT: 7,1) étaient en progression et 19,5% (ÉT: 5,6) étaient en régression. CONCLUSIONS: Le déclin de la fonction rénale chez les patients atteints du syndrome d'Alport est hétérogène ce qui entraîne des répercussions sur la façon de concevoir les essais d'intervention cliniques.

A randomized control trial to assess the impact of vitamin D supplementation compared to placebo on vascular stiffness in chronic kidney disease patients.

BACKGROUND: Vitamin D deficiency is associated with cardiovascular (CV) risk in multiple populations, including those with chronic kidney disease (CKD). The active form of the hormone (1,25 OH2D3) binds to receptors in multiple organs. CKD patients are deficient in both 25 Vitamin D and 1,25 OH2D3. Clinical trial data demonstrating the benefits of vitamin D formulations are limited, and fail to show significant benefits on CV outcomes, and have compared different compounds, in various populations, and focused on a variety of outcomes. A understanding of the mechanism by which different vitamin D compounds confer CV protection in CKD is important for the design of future studies. METHODS/DESIGN: This 3 arm randomized prospective double-blinded placebo-controlled study examining the impact of calcitriol (1,25 OH2D3) and 25-hydroxyvitamin D3 supplementation compared to placebo on vascular stiffness, as measured by pulse wave velocity (PWV). Patients are enrolled from 2 tertiary care institutions if they meet inclusion criteria (stable estimated glomerular filtration rate (eGFR) between 15-45ml/min, <±5ml/min change in previous 6 months), on stable doses of renin-angiotensin aldosterone system blockade. For those already receiving vitamin D therapies, a 3 month washout period before randomization is mandatory. Treatment duration is 6 months; medications are given thrice weekly in fixed doses. The primary outcome measure is Vascular stiffness, measured non-invasively by pulse wave velocity (PWV). Other measurements include BP, kidney function and serial blood levels of biomarkers. The primary analysis will compare any vitamin D therapy versus placebo for the primary outcome defined as the change of PWV from baseline to 6 months. Analysis of covariance will be used to detect differences between vitamin D preparations in the magnitude of reduction in PWV. DISCUSSION: This study is novel in that we are using a robust study design in CKD patients (not on dialysis) comparing placebo to different forms of vitamin D supplementation in fixed doses, irrespective of baseline values. We hope to demonstrate the biological mechanistic effect of vitamin D supplementation on vascular function in order for this information to be used in designing larger randomized controlled trials. TRIAL REGISTRATION: Current Controlled Trials NCT01247311. Date of Registration: November 12, 2010.

Biomarkers of inflammation, fibrosis, cardiac stretch and injury predict death but not renal replacement therapy at 1 year in a Canadian chronic kidney disease cohort.

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 ß1 (TGFß1), 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.

Cohort profile: Canadian study of prediction of death, dialysis and interim cardiovascular events (CanPREDDICT).

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 (TGFß1). 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 < 30. Serum albumin, hemoglobin, calcium and 25-hydroxyvitamin D (25(OH)D) levels were progressively lower in the lower eGFR strata, while parathyroid hormone (PTH) levels increased. Cystatin C, ADMA, NT-proBNP, hsCRP, troponin I and IL-6 were significantly higher in the lower GFR strata, whereas 25(OH)D and TGFß1 values were lower at lower GFR. These distributions of each of the newer biomarkers by eGFR and uACR categories were variable.

Responsiveness of FGF-23 and mineral metabolism to altered dietary phosphate intake in chronic kidney disease (CKD): results of a randomized trial.

BACKGROUND: High fibroblast growth factor-23 (FGF-23) levels are associated with adverse outcomes. We studied the responsiveness of FGF-23 and mineral metabolism to altered dietary phosphate intake in chronic kidney disease (CKD) and healthy control patients. METHODS: Thirty patients were enrolled: 18 normophosphatemic CKD subjects and 12 healthy controls. The study duration was 21 days with three 7-day dietary interventions; a high phosphate (HP, 2000 mg/day), low phosphate (750 mg/day) and low phosphate plus phosphate binder (aluminum hydroxide, 500 mg thrice daily with meals), with comparable macronutrient content, administered in random sequence. Baseline and weekly fasting morning measurements of FGF-23, serum phosphate (sPO(4)), 1,25-hydroxyvitamin D (1,25 D) and 24-h urinary calcium (uCa) and phosphate (uPO(4)) were collected. RESULTS: FGF-23 levels were higher in subjects versus controls (72 pg/mL versus 30 pg/mL) at baseline, while sPO(4) remained in the normal range throughout the study. The absolute changes of uPO(4) and uCa for CKD and controls vary according to diet. The absolute changes of FGF-23 and sPO(4) suggest that the effect of the diets might also depend on the CKD status (P-values interaction effect = 0.08 and 0.07, respectively); nonetheless, these changes are evident as a function of dietary interventions, irrespective of CKD status (P-values diet effect = 0.006 and <0.001, respectively). CONCLUSIONS: FGF-23 levels appear to be responsive to changes in diet in both CKD patients and controls. Further studies are required to determine whether lowering dietary phosphate and thus FGF-23 levels are of long-term benefit in CKD patients, irrespective of sPO(4) levels.