The present review assesses recent publications, from 2001 until the present, which address the relationship between cardiovascular disease (CVD) and anaemia in patients with chronic kidney disease.
Insights from the recently published basic science literature have helped to place findings from clinical studies into a new context, and thereby assist us to understand and further explore the complex relationship between haemoglobin level and survival in chronic kidney disease. The effects of erythropoietin molecules and the presence of receptors in vascular endothelium, myocardium and other tissues are described. Both observational and interventional clinical studies are examined, and limitations in the methodology and statistical analysis of clinical studies are emphasized, but are given context within the body of literature preceding the past year's publications.
Data suggest that development of CVD in patients with kidney disease is multifactorial. Several factors associated with CVD are also associated with anaemia, thereby making causal arguments for the role of anaemia in CVD and survival difficult. Arguments are made for the importance of prevention of anaemia and of individualizing therapeutic goals for its treatment. Well designed prospective studies with both CVD events and mortality as outcomes, and with enrollment beginning before the start of dialysis, are essential if we are to determine the optimal therapeutic strategies.
Glomerulonephritis (GN) is a group of rare kidney diseases with a substantial health burden and high risk of progression to end-stage renal disease. Research in GN has been limited by poor availability of large comprehensive registries. Substantial variations in access to and administration of treatment and outcomes in GN have been described. Leveraging provincial resources and existing infrastructure, the British Columbia (BC) GN Network is an initiative which serves to combine research and clinical care objectives. The goal of the BC GN Network is to coordinate and improve health care, including robust data capture, on all patients with GN in BC, a Canadian province of over 4.6 million people. This provincial initiative will serve as a model for Canadian or other national and international endeavours.
The BC Provincial Renal Agency (BCPRA) is the provincial governmental agency responsible for health delivery for all kidney patients in BC. The BC GN Network has been created by the BCPRA to ensure high quality and equitable access to care for all patients with GN and is a platform for evidence based clinical care programs and associated health policy. All patients with biopsy-proven GN are registered at the time of kidney biopsy into the BCPRA provincial database of kidney disease patients, forming the BC GN Registry. Thereafter, all laboratory results and renal related outcomes are captured automatically. Histology data and core clinical variables are entered into the database. Additional linkages between the GN Registry and administrative databases ensure robust capture of medications, hospital admissions, health care utilization, comorbidities, cancer and cardiac outcomes, and vital statistics.
The BC GN Network and Registry is a unique model in that it combines robust data capture, data linkages, and health care delivery and evaluation into one integrated system. This model utilizes existing health infrastructure to prospectively capture population level data on patients with GN, producing a rich dataset capable of real-time identification and evaluation of GN health policy initiatives, of supporting observational cohort studies and health services research in GN, and of facilitating patient recruitment into GN clinical trials.
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Cardiovascular events are 10 to 100 times more frequent in chronic kidney disease (CKD). We tested the hypothesis that the rate of atherosclerotic plaque growth is faster in severe versus moderate CKD.
We performed a prospective cohort study in 318 prevalent CKD patients with initial creatinine clearance (CCr) between 20 and 50 ml/min/1.73 m(2). Baseline clinical and laboratory data were obtained on all patients. Plaque area was determined every 6 mo using bilateral carotid ultrasonography. Plaque area distribution was normalized using a cube root transformation. Unadjusted and adjusted associations between CCr quintiles and rate of change in the transformed plaque area were assessed using multiple linear regression.
The rate of plaque progression appeared lower in patients with the lowest CCr. Median rate of plaque growth was 0.4 mm(2)/yr in the lowest quintile of CCr ( 43 ml/min/1.73 m(2)). This association remained significant after adjustment for potential confounders. A secondary analysis using quintiles of Modification of Diet in Renal Disease (MDRD) GFR confirmed the absence of increased plaque growth at low GFR, although a reduced rate of growth in the lowest quintile of MDRD GFR was not observed.
We did not observe accelerated plaque growth at low levels of renal function. We suggest that mechanisms other than plaque growth are responsible for the observed excess of cardiovascular disease in CKD patients.
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Although evidence supporting the advantages of multidisciplinary team-based chronic kidney disease (CKD) care is not well developed, many groups are advocating increased availability of this model.
The research design is a mailed survey sent to 523 members of the Canadian and Quebec Societies of Nephrology.
After excluding 113 respondents who declared themselves to be ineligible, the response rate was 54%. Ninety-one percent of nephrologists reported that they usually or always use a CKD clinic. Decisions about when to perform CKD-related tasks were based mainly on an estimate of glomerular filtration rate, rather than time remaining before end-stage renal disease (ESRD). The ideal creatinine clearance for referral to a CKD clinic was 30 to 59 mL/min (0.50 to 0.98 mL/s), but the usual level was 20 to 29 mL/min (0.33 to 0.44 mL/s). The ideal time for referral was more than 12 months before ESRD. Renal replacement therapy discussions were initiated at a creatinine clearance of 20 to 29 mL/min (57%). Nephrologists supported promotion of home dialysis for suitable patients, but not mandating this. Nephrologists did not provide a blunt prognosis to patients who did not specifically ask. Late referral based on adequate time for ESRD preparation was reported to be 4 to 6 months (27%), 7 to 9 months (26%), or 10 to 12 months (30%). Thirty-eight percent said that optimal preparation takes 13 months or longer.
The literature's common definition of less than 3 months as a cutoff value between late and early referral is not endorsed. Given that multidisciplinary team-based care is widely available in Canada, this study might inform other jurisdictions about the merits and problems associated with multidisciplinary team-based care and might shape the agenda for future empirical research.
Current recommendations for the management of chronic renal insufficiency (CRI) include the use of angiotensin-converting enzyme inhibitors (ACEI) and achieving target blood pressure control. We designed this study to describe the use of these therapeutic strategies, and to investigate barriers to their implementation.
This was a prospective study of 304 consecutive CRI patients, seen at follow-up in four nephrology clinics across Canada. The use of blood pressure control and antihypertensive medication (AHM) in each of these clinics was recorded, and a questionnaire was administered to nephrologists to determine the basis for decisions concerning AHM regimens and ACEI use/non-use.
Mean age was 60.8+/-15.7 years, mean creatinine clearance was 30.3+/-18 ml/min, and underlying renal diseases were similar to registry data. Mean arterial pressure (MAP) achieved was 99.4+/-14.4 and 98.9+/-11.9 mmHg in individuals with >1 and
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.
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.
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%.
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.
The British Columbia Nephrologists' Access Study (BCNAS) - a prospective, health services interventional study to develop waiting time benchmarks and reduce wait times for out-patient nephrology consultations.
Early referral and management of high-risk chronic kidney disease may prevent or delay the need for dialysis. Automatic eGFR reporting has increased demand for out-patient nephrology consultations and in some cases, prolonged queues. In Canada, a national task force suggested the development of waiting time targets, which has not been done for nephrology.
We sought to describe waiting time for outpatient nephrology consultations in British Columbia (BC). Data collection occurred in 2 phases: 1) Baseline Description (Jan 18-28, 2010) and 2) Post Waiting Time Benchmark-Introduction (Jan 16-27, 2012). Waiting time was defined as the interval from receipt of referral letters to assessment. Using a modified Delphi process, Nephrologists and Family Physicians (FP) developed waiting time targets for commonly referred conditions through meetings and surveys. Rules were developed to weigh-in nephrologists', FPs', and patients' perspectives in order to generate waiting time benchmarks. Targets consider comorbidities, eGFR, BP and albuminuria. Referred conditions were assigned a priority score between 1-4. BC nephrologists were encouraged to centrally triage referrals to see the first available nephrologist. Waiting time benchmarks were simultaneously introduced to guide patient scheduling. A post-intervention waiting time evaluation was then repeated.
In 2010 and 2012, 43/52 (83%) and 46/57 (81%) of BC nephrologists participated. Waiting time decreased from 98(IQR44,157) to 64(IQR21,120) days from 2010 to 2012 (p =
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This randomized clinical trial is designed to assess whether the prevention and/or correction of anemia, by immediate versus delayed treatment with erythropoietin alfa in patients with chronic kidney disease, would delay left ventricular (LV) growth. Study design and sample size calculations were based on previously published Canadian data.
One hundred seventy-two patients were randomly assigned. The treatment group received therapy with erythropoietin alfa subcutaneously to maintain or achieve hemoglobin (Hgb) level targets of 12.0 to 14.0 g/dL (120 to 140 g/L). The control/delayed treatment group had Hgb levels of 9.0 +/- 0.5 g/dL (90 +/- 5 g/L) before therapy was started: target level was 9.0 to 10.5 g/dL (90 to 105 g/L). Optimal blood pressure and parathyroid hormone, calcium, and phosphate level targets were prescribed; all patients were iron replete. The primary end point is LV growth at 24 months.
One hundred fifty-two patients were eligible for the intention-to-treat analysis: mean age was 57 years, 30% were women, 38% had diabetes, and median glomerular filtration rate was 29 mL/min (0.48 mL/s; range, 12 to 55 mL/min [0.20 to 0.92 mL/s]). Blood pressure and angiotensin-converting enzyme inhibitor/angiotensin receptor blocker use were similar in the control/delayed treatment and treatment groups at baseline. Erythropoietin therapy was administered to 77 of 78 patients in the treatment group, with a median final dose of 2,000 IU/wk. Sixteen patients in the control/delayed treatment group were administered erythropoietin at a median final dose of 3,000 IU/wk. There was no statistically significant difference between groups for the primary outcome of mean change in LV mass index (LVMI) from baseline to 24 months, which was 5.21 +/- 30.3 g/m2 in the control/delayed treatment group versus 0.37 +/- 25.0 g/m2 in the treatment group. Absolute mean difference between groups was 4.85 g/m2 (95% confidence interval, -4.0 to 13.7; P = 0.28). Mean Hgb level was greater in the treatment group throughout the study and at study end was 12.75 g/dL (127.5 g/L in treatment group versus 11.46 g/dL [114.6 g/L] in control/delayed treatment group; P = 0.0001). LV growth occurred in 20.1% in the treatment group versus 31% in the control/delayed treatment group (P = 0.136). In patients with a stable Hgb level, mean LVMI did not change (-0.25 +/- 26.7 g/m2), but it increased in those with decreasing Hgb levels (19.3 +/- 28.2 g/m2; P = 0.002).
This trial describes disparity between observational and randomized controlled trial data: observed and randomly assigned Hgb level and LVMI are not linked; thus, there is strong evidence that the association between Hgb level and LVMI likely is not causal. Large randomized controlled trials with unselected patients, using morbidity and mortality as outcomes, are needed.
Comment In: Am J Kidney Dis. 2005 Nov;46(5):970-316253741
The optimal strategy for cardiovascular (CV) disease surveillance in kidney transplant candidates is uncertain. In this observational study of 604 wait-listed patients in British Columbia, the risk for CV event in diabetic and nondiabetic candidates was 12.7 and 4.5% per year, respectively. CV event rates were relatively constant during the first 3 yr of wait-listing (5.3 to 6.6 per 100 patient-years; 95% confidence interval [CI], 3.7 to 9.3) but rose dramatically during the peritransplantation period (39.6/100 patient-years; 95% CI, 20.6 to 76.1) and remained high throughout the first posttransplantation year (4.0 per 100 patient-years; 95% CI, 2.2 to 7.5). The results of noninvasive cardiac investigations before wait-listing were not predictive of the time to CV event after wait-listing. The practice of surveillance cardiac investigation in wait-listed patients on the basis of ongoing clinical assessment of cardiac risk resulted in fewer investigations (n = 171) than with the recommended practice of periodic screening on the basis of waiting time alone (n = 530) and was not associated with an increased frequency of CV events (CV event rate in patients with and without the recommended frequency of investigation was 9.9 [95% CI, 7.1 to 13.7] and 6.7 [95% CI, 5.2 to 8.7] per 100 patient-years). It is concluded that transplant candidates are at high risk for CV events particularly during the perioperative period. Initial cardiac investigations have limited value in guiding the timing of patient reevaluation after wait-listing. Periodic surveillance cardiac investigation after wait-listing may be unnecessary and requires further study.
Central vein stenosis (CVS) has been associated with subclavian (SCV) catheter insertions. The prevalence of CVS in the current era with minimal use of SCV catheters is unknown. Furthermore, the prevalence of CVS in patients with access problems has not been previously described to our knowledge. We evaluated 235 prevalent patients on hemodialysis (HD), and, of these, 133 underwent venography for access related concerns over a 14 month period. Of these 133 patients, 55 (41%) had evidence of significant CVS on venogram. Patients with CVS had a longer duration on HD (43 +/- 12 months vs. 34 +/- 15 months, p = 0.018) and a history of a previous HD catheter insertion (52/55 patients vs. 59/78 patients, p = 0.0039). There were only 18 patients with a subclavian catheter insertion. In those with any history of previous HD catheter insertion, multivariate analysis demonstrated that number of catheters remains a significant factor (OR 2.69, p = 0.0004) even after excluding those subclavian insertions. This study demonstrates that CVS occurs in almost half of the patients with access problems undergoing venography. We confirm the important contribution of central vein cannulation to CVS and show that, despite minimizing subclavian catheter insertion, CVS remains a relatively common occurrence. Thus further studies should attempt to determine the true incidence of this problem and ultimately address the optimal treatment strategies.