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 (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 < 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 TGFβ1 values were lower at lower GFR. These distributions of each of the newer biomarkers by eGFR and uACR categories were variable

Predicting kidney failure risk after acute kidney injury among people receiving nephrology clinic care

ACKNOWLEDGEMENTS We are grateful to Dr Nadia Zalunardo for her comments on this study. FUNDING Dr Sawhney received funding from a research training fellowship from the Wellcome Trust to conduct this study (102729/ Z/13/Z).Peer reviewedPublisher PD

Population-based analysis of the effect of a comprehensive, systematic change in an emergency medical service resource allocation plan on 24 hour mortality

Introduction The British Columbia Emergency Health Services developed a new resource allocation plan (RAP) using an evidenced informed methodology and with further clinical input from EMS physicians, paramedics and allied EMS providers. Population-based analysis was used to determine the effect by comparing 24-hour mortality before and after province-wide implementation of the revised RAP. Objectives and Approach The primary outcome, 24-hour mortality, was obtained through linked provincial health administrative data. All adult cases with evaluable outcome data were included in the analysis. A pre and post methodology was used to evaluate the effect of post-RAP revision (post-RAP-revision) on 24-hour mortality compared to pre-RAP revision (pre-RAP-revision). Multivariable logistic regression was used to adjust for variations in other significant factors associated with 24-hour mortality. The interrupted time series (ITS) estimated any immediate changes in the level or trend of outcome after the start of the revised RAP implementation (fall of 2013), while simultaneously controlling for pre-existing trends. Results The linked data set included some 1500–2000 children per school census classified as having a CP, representing a prevalence of some 0.3%. Provisionally, results show: prevalence of CP is higher amongst children living in relatively deprived areas; around 60% of CP children have a statement of SEN; the SEN type most commonly recorded for CP children with SEN is ‘Physical and medical difficulties’ and relatively high proportions have profound, multiple or severe learning difficulties; around 30% of CP children are educated in special schools; CP children in main stream (primary, middle and secondary) schools tended to miss more school sessions (~50% more) than other children and lower percentages achieved the expected levels at key stages 2 and 3 and the Level 2 GCSE threshold. Conclusion/Implications Our results demonstrate that a comprehensive, evidence informed reconstruction of a provincial EMS RAP is feasible. Despite considerable change in crew level response and resource allocation, there was significant decrease in 24 hour mortality in a large pan-provincial population based patient cohort

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

Disease-specific risk of venous thromboembolic events is increased in idiopathic glomerulonephritis

The risk of venous thromboembolic events is thought to be highest in patients with membranous nephropathy. This association has been recently questioned, and it is not known whether this simply reflects the severity of proteinuria. To better understand the relationship between histologic diagnosis and the risk of venous thromboembolic events we evaluated patients in the Toronto Glomerulonephritis Registry. Of 1313 patients with idiopathic glomerulonephritis, 395 were diagnosed with membranous nephropathy, 370 with focal segmental glomerulosclerosis (FSGS), and 548 with immunoglobulin-A nephropathy (IgAN). Risk factors were evaluated by Cox proportional hazards for 53 image-confirmed venous thromboembolic events in 44 patients during a median follow-up of 63 months. The risk was highest in patients with membranous nephropathy and FSGS (hazard ratios of 22 and 7.8, respectively) referenced to patients with IgAN. Following adjustment for gender, cancer history, proteinuria, and serum albumin by multivariable analysis, the histologic subtype remained an independent risk for venous thromboembolic events. This risk was still highest in patients with membranous nephropathy followed by FSGS with adjusted hazard ratios of 10.8 and 5.9, respectively. Thus, in this large cohort, histologic diagnosis was an independent risk factor for venous thromboembolic events. Further studies are needed to discover mechanisms responsible for this high risk in patients with membranous nephropathy

Linkage of Chronic Disease Data from Provincial Sources for Strategic Decision Support and Population Health Surveillance in British Columbia (BC)

Introduction BC Ministry of Health (MoH)’s health administrative data holdings for a variety of general health care data are not readily linked with various data registries maintained by specialized care agencies of the Provincial Health Services Authority (PHSA). These provincial data sources have rich chronic disease information for BC residents. Objectives and Approach The objective of this project is to develop a system for cross-agency linkage of provincial level chronic disease data to improve chronic disease information that would support the BC’s health system, MoH and PHSA agencies in particular, in healthcare delivery and chronic disease prevention planning. We aim to achieve linkage of data from various provincial chronic disease data sources of the MoH and PHSA, with further potential to link with variety of other external databases such as Census data for socio-economic determinants of health. We are reporting here the outcome of the first phase of this project. Results The outcomes from the project to date were as follows: Data linkage between the MoH’s administrative databases, Chronic Disease Registries (CDRs) in particular and Census based socio-economic status (SES) data was achieved, providing the population level evidence of health outcomes such as health inequity, comorbidities and multimorbidities (sub-project # 1). Preliminary results on data quality and health outcomes by SES will be presented. This was followed by completion of securing approval to ensure data security compliance for data linkages of CDRs with the Provincial Renal Agency’s Registry called “PROMIS” (sub-project # 2), Cardiac Services BC’s Registry called “HEARTis” ((sub-project # 3), and BC Cancer Agency’s Registry and BC Generations Project data (sub-project # 4), for implementation to answer agency specific research questions. Conclusion/Implications This data linkage project to consolidate information from chronic disease and socio-economic databases for providing answers to various analytic questions posed will improve decision support and enhanced population health surveillance. The lessons learned from this multi-agency collaboration and their implications for other jurisdictions will be addressed

The BC SUPPORT Unit Data Platform: Offering Data-Related Services To Researchers In British Columbia

Introduction The Canadian Institutes of Health Research (CIHR) and provinces co-fund local Units to increase the quality and quantity of patient-oriented research. These SUPPORT (Support for People and Patient-Oriented Research and Trials) Units include a prominent Data Plan component. The BC Plan is the result of collaboration between many organizational partners. Objectives and Approach A Data Advisory Committee comprised of eight organizational partners worked together for several months in 2016-2017 to develop BC’s provincial Data Plan. The Data Plan includes seven objectives; in general, the plan seeks to make additional data available for research, increase the speed and transparency of data access, and offer services to enable more efficient data use. The services resulting from the Data Plan are intended to improve support for the entire continuum of a research project, from developing a research question to analyzing the results. Several projects are part of Ministry of Health-led work developing a Health Data Platform. Results The projects initiated so far as part of the Data Plan include: • BC Data Scout\textsuperscript{TM}: an online tool that provides aggregate cohort information to inform research question development; • REDCap: software to support privacy-sensitive data collection and management; • INFORM: software to support data collection for complex clinical research studies and trials; • Direct Access: enables Population Data BC to access BC Ministry of Health databases so researchers have access to up-to-date data; • Streamlining: making the data request process more efficient; • New datasets: several projects that will provide new data sources, including patient experience and outcome measures and secondary use data drawn from electronic medical records; and • Inventory: an online catalog for all high-value and linkable data sets available to researchers. Conclusion/Implications The services and tools included in BC’s Data Plan will help researchers develop and deliver world-class research and inform important health care decisions. The patient-oriented focus of these services help to ensure that research is done in partnership with patients and centered on research questions that matter to them

Decline in Estimated Glomerular Filtration Rate and Subsequent Risk of End-Stage Renal Disease and Mortality

Peer reviewedPostprin

Regional variation in hemoglobin distribution among individuals with chronic kidney disease: the ISN International Network of Chronic Kidney Disease (iNET-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.</p