Recent randomized controlled trials (RCTs) have reported risks and benefits in the correction of anemia using erythropoietin-stimulating agents (ESAs) in patients with predialysis chronic kidney ...disease (CKD) or end-stage renal disease. The purpose of this review is to critically appraise the RCTs most relevant to clinical decision-making.
The Trial to Reduce cardiovascular Events with Aransep Therapy (TREAT) is the biggest and best designed RCT performed so far, enrolling 4038 diabetic patients with CKD in a double-blind, placebo-controlled trial. Comparing the high hemoglobin (Hb) darbopoietin group with placebo, it reported no difference in cardiac and renal outcomes, a significantly increased risk of stroke, and modest improvement in fatigue and transfusion rate. Meta-analysis demonstrated that correction of anemia with ESA was associated with a significantly increased risk of hypertension and vascular access clotting and an increased risk of death that approached statistical significance. Quality-of-life improvements appeared to maximize in the target Hb range of 10-12 g/dl.
Treatment of renal anemia using ESAs to target Hb higher than 13 g/dl is harmful. Treatment of Hb below 9 g/dl provides substantial transfusion and quality-of-life benefits, but safety is unknown. Target Hb levels of 10-12 g/dl seem reasonable, but increasing ESA doses in hyporesponsive patients to achieve a specific target is not.
Cilia and flagella are microtubule-based structures nucleated by modified centrioles termed basal bodies. These biochemically complex organelles have more than 250 and 150 polypeptides, respectively. ...To identify the proteins involved in ciliary and basal body biogenesis and function, we undertook a comparative genomics approach that subtracted the nonflagellated proteome of
Arabidopsis from the shared proteome of the ciliated/flagellated organisms
Chlamydomonas and human. We identified 688 genes that are present exclusively in organisms with flagella and basal bodies and validated these data through a series of in silico, in vitro, and in vivo studies. We then applied this resource to the study of human ciliation disorders and have identified
BBS5, a novel gene for Bardet-Biedl syndrome. We show that this novel protein localizes to basal bodies in mouse and
C. elegans, is under the regulatory control of
daf-19, and is necessary for the generation of both cilia and flagella.
Clinical epidemiology is the science of human disease investigation with a focus on diagnosis, prognosis, and treatment. The generation of a reasonable question requires definition of patients, ...interventions, controls, and outcomes. The goal of research design is to minimize error, to ensure adequate samples, to measure input and output variables appropriately, to consider external and internal validities, to limit bias, and to address clinical as well as statistical relevance. The hierarchy of evidence for clinical decision-making places randomized controlled trials (RCT) or systematic review of good quality RCTs at the top of the evidence pyramid. Prognostic and etiologic questions are best addressed with longitudinal cohort studies.
The rs2282679 A>C polymorphism in the vitamin D binding protein gene is associated with lower circulating levels of vitamin D. We investigated associations of this SNP with colorectal cancer (CRC) ...risk and survival and whether the associations vary by dietary vitamin D intake and tumor molecular phenotype.
A population-based case-control study identified 637 incident CRC cases (including 489 participants with follow-up data on mortality end-points) and 489 matched controls. Germline DNA samples were genotyped with the Illumina Omni-Quad 1 Million chip in cases and the Affymetrix Axiom® myDesign™ Array in controls. Logistic regression examined the association between the rs2282679 polymorphism and CRC risk with inclusion of potential confounders. Kaplan-Meier curves and multivariable Cox models assessed the polymorphism relative to overall survival (OS) and disease-free survival (DFS).
The rs2282679 polymorphism was not associated with overall CRC risk; there was evidence, however, of effect modification by total vitamin D intake (P
= 0.019). Survival analyses showed that the C allele was correlated with poor DFS (per-allele HR, 1.36; 95%CI, 1.05-1.77). The association of rs2282679 on DFS was limited to BRAF wild-type tumors (HR, 1.58; 95%CI, 1.12-2.23). For OS, the C allele was associated with higher all-cause mortality among patients with higher levels of dietary vitamin D (HR, 2.11; 95%CI, 1.29-3.74), calcium (HR, 1.93; 95%CI, 1.08-3.46), milk (HR, 2.36; 95%CI, 1.26-4.44), and total dairy product intakes (HR, 2.03; 95%CI, 1.11-3.72).
The rs2282679 SNP was not associated with overall CRC risk, but may be associated with survival after cancer diagnosis. The association of this SNP on survival among CRC patients may differ according to dietary vitamin D and calcium intakes and according to tumor BRAF mutation status.
Protective associations of fruits, vegetables, and fiber intake with colorectal cancer risk have been shown in many, but not all epidemiologic studies. One possible reason for study heterogeneity is ...that dietary factors may have distinct effects by colorectal cancer molecular subtypes. Here, we investigate the association of fruit, vegetables, and fiber intake with four well-established colorectal cancer molecular subtypes separately and in combination. Nine observational studies including 9,592 cases with molecular subtypes for microsatellite instability (MSI), CpG island methylator phenotype (CIMP), and somatic mutations in
and
genes, and 7,869 controls were analyzed. Both case-only logistic regression analyses and polytomous logistic regression analyses (with one control set and multiple case groups) were used. Higher fruit intake was associated with a trend toward decreased risk of
-mutated tumors OR 4th vs. 1st quartile = 0.82 (95% confidence interval, 0.65-1.04) but not
-wildtype tumors 1.09 (0.97-1.22);
difference as shown in case-only analysis = 0.02. This difference was observed in case-control studies and not in cohort studies. Compared with controls, higher fiber intake showed negative association with colorectal cancer risk for cases with microsatellite stable/MSI-low, CIMP-negative,
-wildtype, and
-wildtype tumors (
range from 0.03 to 3.4e-03), which is consistent with the traditional adenoma-colorectal cancer pathway. These negative associations were stronger compared with MSI-high, CIMP-positive,
-mutated, or
-mutated tumors, but the differences were not statistically significant. These inverse associations for fruit and fiber intake may explain, in part, inconsistent findings between fruit or fiber intake and colorectal cancer risk that have previously been reported. SIGNIFICANCE: These analyses by colorectal cancer molecular subtypes potentially explain the inconsistent findings between dietary fruit or fiber intake and overall colorectal cancer risk that have previously been reported.
Background The incidence of end-stage renal disease (ESRD) has been consistently shown to be higher among blacks and Hispanics compared to whites with unmeasured risk factors and access to care as ...suggested explanations. In a high-risk cohort with frequent protocol-directed follow-up, we evaluated the influence of race on cardiovascular (CV) outcomes and incidence of ESRD. Methods TREAT was a randomized, double-blind, placebo-controlled study. This secondary analysis focused on role of race on outcomes. TREAT enrolled 4,038 patients with type 2 diabetes, chronic kidney disease (estimated glomerular filtration rate 20-60 mL/min per 1.73 m2 ), and anemia (hemoglobin level ≤11 g/dL) treated with either darbepoetin alfa or placebo. We compared self-described black and Hispanic patients to white patients with regard to baseline characteristics and outcomes, including mortality, CV outcomes (myocardial infarction, stroke, heart failure, resuscitated sudden death, and coronary revascularization), and incident ESRD. Multivariate adjusted Cox models were developed for these outcomes. Results Black and Hispanic patients were younger, more likely women, had less prior CV disease, and higher blood pressure. During a mean follow-up of 2.4 years with comparable access to care, blacks and Hispanics had a greater risk of ESRD but a significant lower risk of myocardial infarction and coronary revascularization than whites. After adjusting for confounders, blacks remained at significantly greater risk of ESRD than whites (hazard ratio 1.53, 95% CI 1.26-1.85, P < .001), whereas this ESRD risk did not persist among Hispanics. Conclusion Despite similar access to care and lower CV event rates, the risk of ESRD was higher among blacks and Hispanics than whites. For blacks, but not Hispanics, this increase was independent of known attributable risk factors.
Abstract Background Unlike conventional time-to-event analysis of composite endpoints in clinical trials, the “win ratio” method allows for flexibility in prioritizing their components. Here, we ...compare the EVOLVE trial findings using the win ratio with those from time-to-event analysis. Methods Exposure : Randomization to cinacalcet or placebo. Outcome : The primary composite endpoint combining all-cause mortality and non-fatal myocardial infarction, hospitalization for unstable angina, heart failure, and peripheral vascular events. Analysis : In an unadjusted analysis, we paired each participant from the cinacalcet arm with every participant from the placebo arm within randomization strata. Pairs were classified as “winners” or “losers,” according to which participant died first during the shared follow-up time, or experienced the next ranked event first. We ranked non-fatal events in two ways: 1) all ranked evenly; and 2) prioritized by their effect on health-related quality of life. The win ratio equaled the total winners divided by total losers. Further analyses were conducted where the win ratio was stratified by, or adjusted for, age. Results The unadjusted win ratio for the primary composite endpoint was 1.09 (95% CI 0.97 to 1.21), a statistically non-significant result which supports the primary trial result — unadjusted hazard ratio 0.93 (95% CI 0.85 to 1.02). Age-stratified analyses showed a nominally significant benefit of cinacalcet (win ratio 1.14, 95% CI 1.04 to 1.26). Ranking of non-fatal outcomes by their relative effects on quality of life did not materially alter the results. Conclusion The win ratio method corroborated the findings of EVOLVE based on conventional time-to-event analysis. EVOLVE ClinicalTrials.gov number: NCT00345839.
Background: The Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events (EVOLVE) clinical trial evaluated the effects of cinacalcet on clinical events in patients with secondary ...hyperparathyroidism (sHPT) who were on hemodialysis. Health-related quality of life (HRQoL) was assessed by a generic, preference-based health outcome measure (EQ-5D) at scheduled visits and after a study event. Here, we report the HRQoL analysis from EVOLVE. Methods: We assessed changes in HRQoL from baseline to scheduled visits, and estimated the acute (3 mo) and chronic (beyond 3 mo) effects of sHPT-related events on HRQoL using generalized estimating equation analysis controlling for baseline HRQoL and randomized assignment. Results: Data on HRQoL were available for 3547 of 3883 subjects, with 1650 events in the placebo and 1502 in the cinacalcet arm. At the study end, no difference in change from baseline HRQoL was observed in the direct comparison of EQ-5D by treatment arms. The regression analysis showed significant effects of events on HRQoL and a modest positive effect of cinacalcet. Estimated quality-adjusted life-year gains were of similar magnitude based on the observed data or the predictions from the model, with only a small gain in precision from the predicted analysis. Conclusions: By contrast with a conventional comparison, a regression analysis demonstrated large decrements in HRQoL after events and a modest improvement in HRQoL with cinacalcet. As randomized controlled trials are rarely powered to detect differences in HRQoL, a prespecified regression analysis may be acceptable to improve precision of the effects and understand their origin.
Current clinical practice guidelines for anemia management in non–dialysis-dependent chronic kidney disease (NDD-CKD) recommend the use of erythropoiesis-stimulating agents (ESAs) as standard of ...care. Vadadustat, an investigational oral hypoxia-inducible factor prolyl-hydroxylase inhibitor, stimulates endogenous erythropoietin production. The PRO2TECT program comprises 2 global, Phase 3, randomized, open-label, active-controlled, sponsor-blind clinical trials to evaluate safety and efficacy of vadadustat vs darbepoetin alfa in adult patients with anemia associated with NDD-CKD. Patients recruited into the ESA-untreated NDD-CKD trial (N = 1751) had hemoglobin <10 g/dL and had not received an ESA within 8 weeks prior to inclusion in the study. Patients recruited into the ESA-treated NDD-CKD trial (N = 1725) had hemoglobin between 8 and 11 g/dL (US) or 9 and 12 g/dL (non-US) and were actively treated with an ESA for anemia associated with CKD. Trial periods in both trials include (1) correction/conversion (weeks 0-23); (2) maintenance (weeks 24-52); (3) long-term treatment (week 53 to end of treatment); and (4) safety follow-up (end-of-treatment to 4 weeks later). The primary safety endpoint is time to first adjudicated major adverse cardiovascular event, defined as all-cause mortality, nonfatal myocardial infarction, or nonfatal stroke, pooled across both trials. The primary efficacy endpoint in each trial is change in hemoglobin from baseline to primary evaluation period (weeks 24-36), comparing vadadustat vs darbepoetin alfa treatment groups. Demographics and baseline characteristics are similar among patients in both trials and broadly representative of the NDD-CKD population. These trials will help to evaluate the safety and efficacy of vadadustat for management of anemia associated with NDD-CKD.
•Blood urea is not routinely necessary with serum creatinine.•Removing urea from a laboratory requisition was associated with a halving of urea orders.•A process of audit and feedback to family ...doctors on urea test ordering further reduced urea ordering.•Academic detailing with family doctors following the above measures did not further reduce urea orders significantly.
Measuring blood urea at the same time as serum creatinine in stable ambulatory patients in family practice is largely unnecessary. The objective was to assess the relative impact of changing the laboratory requisition versus audit and feedback and academic detailing on the volume of orders for blood urea.
A natural experiment was observed over the period April 2015 to March 2018 in the Canadian province of Newfoundland where three health regions had different approaches to trying to reduce such urea testing. The Eastern and Western regions removed urea from the standard laboratory requisition but the test could still be ordered by writing it on the requisition. Central region requisitions continued to list urea. Audit and feedback was undertaken with family doctors in Eastern region after the requisition change and that was followed by academic detailing. A nephrologist gave presentations to groups of family doctors on one occasion in Central region.
The volume of serum creatinine testing was largely unchanged over time in each region. The volume of urea testing reduced by 73%, 48% and 28% in Eastern, Western and central regions. Interrupted time series analysis showed significant changes in test volume after requisition change in Eastern and Western regions as well as after audit and feedback in Eastern and the presentations in Central region. The incremental impact of academic detailing was not statistically significant.
We conclude that removing urea from standard test order menus was the most effective in reducing test volumes, but combination with audit and feedback augmented the impact.
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