Natasha Wiebe

Chronic Kidney Disease and Mortality Risk: A Systematic Review

Current guidelines identify people with chronic kidney disease (CKD) as being at high risk for cardiovascular and all-cause mortality. Because as many as 19 million Americans may have CKD, a comprehensive summary of this risk would be potentially useful for planning public health policy. A systematic review of the association between non-dialysis-dependent CKD and the risk for all-cause and cardiovascular mortality was conducted. Patient- and study-related characteristics that influenced the magnitude of these associations also were investigated. MEDLINE and EMBASE databases were searched, and reference lists through December 2004 were consulted. Authors of 10 primary studies provided additional data. Cohort studies or cohort analyses of randomized, controlled trials that compared mortality between those with and without chronically reduced kidney function were included. Studies were excluded from review when participants were followed for < 1 yr or had ESRD. Two reviewers independently extracted data on study setting, quality, participant and renal function characteristics, and outcomes. Thirty-nine studies that followed a total of 1,371,990 participants were reviewed. The unadjusted relative risk for mortality in participants with reduced kidney function compared with those without ranged from 0.94 to 5.0 and was significantly more than 1.0 in 93% of cohorts. Among the 16 studies that provided suitable data, the absolute risk for death increased exponentially with decreasing renal function. Fourteen cohorts described the risk for mortality from reduced kidney function, after adjustment for other established risk factors. Although adjusted relative hazards were consistently lower than unadjusted relative risks (median reduction 17%), they remained significantly more than 1.0 in 71% of cohorts. This review supports current guidelines that identify individuals with CKD as being at high risk for cardiovascular mortality. Determining which interventions best offset this risk remains a health priority.

Relation Between Kidney Function, Proteinuria, and Adverse Outcomes

CONTEXT The current staging system for chronic kidney disease is based primarily on estimated glomerular filtration rate (eGFR) with lower eGFR associated with higher risk of adverse outcomes. Although proteinuria is also associated with adverse outcomes, it is not used to refine risk estimates of adverse events in this current system. OBJECTIVE To determine the association between reduced GFR, proteinuria, and adverse clinical outcomes. DESIGN, SETTING, AND PARTICIPANTS Community-based cohort study with participants identified from a province-wide laboratory registry that includes eGFR and proteinuria measurements from Alberta, Canada, between 2002 and 2007. There were 920 985 adults who had at least 1 outpatient serum creatinine measurement and who did not require renal replacement treatment at baseline. Proteinuria was assessed by urine dipstick or albumin-creatinine ratio (ACR). MAIN OUTCOME MEASURES All-cause mortality, myocardial infarction, and progression to kidney failure. RESULTS The majority of individuals (89.1%) had an eGFR of 60 mL/min/1.73 m(2) or greater. Over median follow-up of 35 months (range, 0-59 months), 27 959 participants (3.0%) died. The fully adjusted rate of all-cause mortality was higher in study participants with lower eGFRs or heavier proteinuria. Adjusted mortality rates were more than 2-fold higher among individuals with heavy proteinuria measured by urine dipstick and eGFR of 60 mL/min/1.73 m(2) or greater, as compared with those with eGFR of 45 to 59.9 mL/min/1.73 m(2) and normal protein excretion (rate, 7.2 [95% CI, 6.6-7.8] vs 2.9 [95% CI, 2.7-3.0] per 1000 person-years, respectively; rate ratio, 2.5 [95% CI, 2.3-2.7]). Similar results were observed when proteinuria was measured by ACR (15.9 [95% CI, 14.0-18.1] and 7.0 [95% CI, 6.4-7.6] per 1000 person-years for heavy and absent proteinuria, respectively; rate ratio, 2.3 [95% CI, 2.0-2.6]) and for the outcomes of hospitalization with acute myocardial infarction, end-stage renal disease, and doubling of serum creatinine level. CONCLUSION The risks of mortality, myocardial infarction, and progression to kidney failure associated with a given level of eGFR are independently increased in patients with higher levels of proteinuria.

Systematic review and meta-analysis: renal safety of tenofovir disoproxil fumarate in HIV-infected patients.

BACKGROUND The efficacy of tenofovir disoproxil fumarate (TDF) as part of combination antiretroviral treatment (ART) has been demonstrated in several randomized, controlled trials. However, an increasing number of case reports suggest that TDF use may be associated with significant nephrotoxicity. Our objective was to determine the renal safety of TDF-containing ART regimens for HIV-infected individuals. METHODS MEDLINE, EMBASE, Global Health, Scopus, Biosis Previews, Cochrane Library, Web of Science, and existing systematic reviews were searched. Prospective studies comparing TDF-containing with non-TDF containing ART regimens were selected for inclusion. We extracted data on study characteristics, participant characteristics, therapeutic interventions, renal function, bone density, and fracture rates. RESULTS A total of 17 studies (including 9 randomized, controlled trials) met the selection criteria. Median sample size was 517 participants. Constituent ART regimens were diverse. There was a significantly greater loss of kidney function among the TDF recipients, compared with control subjects (mean difference in calculated creatinine clearance, 3.92 mL/min; 95% confidence interval [CI], 2.13-5.70 mL/min), as well as a greater risk of acute renal failure (risk difference, 0.7%; 95% CI, 0.2-1.2). There was no evidence that TDF use led to increased risk of severe proteinuria, hypophosphatemia, or fractures. CONCLUSIONS Although TDF use was associated with a statistically significant loss of renal function, the clinical magnitude of this effect was modest. Our findings do not support the need to restrict TDF use in jurisdictions where regular monitoring of renal function and serum phosphate levels is impractical.

Systematic Review: Kidney Transplantation Compared With Dialysis in Clinically Relevant Outcomes

Individual studies indicate that kidney transplantation is associated with lower mortality and improved quality of life compared with chronic dialysis treatment. We did a systematic review to summarize the benefits of transplantation, aiming to identify characteristics associated with especially large or small relative benefit. Results were not pooled because of expected diversity inherent to observational studies. Risk of bias was assessed using the Downs and Black checklist and items related to time‐to‐event analysis techniques. MEDLINE and EMBASE were searched up to February 2010. Cohort studies comparing adult chronic dialysis patients with kidney transplantation recipients for clinical outcomes were selected. We identified 110 eligible studies with a total of 1 922 300 participants. Most studies found significantly lower mortality associated with transplantation, and the relative magnitude of the benefit seemed to increase over time (p < 0.001). Most studies also found that the risk of cardiovascular events was significantly reduced among transplant recipients. Quality of life was significantly and substantially better among transplant recipients. Despite increases in the age and comorbidity of contemporary transplant recipients, the relative benefits of transplantation seem to be increasing over time. These findings validate current attempts to increase the number of people worldwide that benefit from kidney transplantation.

Meta-analysis: beta-blocker dose, heart rate reduction, and death in patients with heart failure.

Over the past decade, several randomized clinical trials have established that -blockers are beneficial in patients with heart failure (1, 2). Although resting heart rate is known to be a prognostic factor in patients with heart failure (3, 4), it remains unclear whether the benefits of -blockade in patients with heart failure are related to the degree of reduction in heart rate or the dosage of -blocker administered. This question is important because the adverse effects of -blockers are dose-related (5). Although heart failure guidelines recommend up-titration of -blockers to the target doses used in -blocker trials, outcome studies reveal that only some patients achieve these doses outside of specialized heart failure clinics (68). Secondary analyses of the CIBIS (Cardiac Insufficiency Bisoprolol Study) (9), COMET (Carvedilol Or Metoprolol European Trial) (10), and CIBIS II (11) data suggested that the magnitude of heart rate reduction with -blockers was an important mediator of -blocker effect. In addition, a small clinical trial of 49 pacemaker-dependent patients with left ventricular systolic dysfunction demonstrated that patients who were paced at a lower rate (60 beats/min) had improvements in left ventricular function and left ventricular dimensions compared with those paced at a higher rate (80 beats/min) (12). However, other studies have not confirmed a relationship between the magnitude of heart rate reduction and the efficacy of -blockers (1315). We designed this meta-analysis to investigate the between-study heterogeneity in heart failure -blocker trials. Specifically, we examined whether -blocker dose or magnitude of heart rate reduction could account for the differences in treatment effects among heart failure -blocker trials. Methods Identifying Relevant Studies We searched for randomized trials in MEDLINE (1966 to 2008), EMBASE (1980 to 2008), CINAHL (1982 to 2008), SIGLE (1980 to 2008), Web of Science, and the Cochrane Central Register of Controlled Trials. We did not apply language restrictions, but we restricted our searches to human studies and clinical trial or randomized, controlled trial publications. We used the keywords and Medical Subject Headings adrenergic -antagonists, heart failure, and congestive (exp). We also hand-searched bibliographies of identified studies, recent meta-analyses of -blockers in heart failure (1, 2), and heart failure guidelines. Study Selection and Data Abstraction Two authors independently reviewed the results of the search strategy and selected all studies that reported the effect of -blockers on all-cause mortality in patients with heart failure. The authors excluded studies if they were published in abstract form only, did not report death, used -blockers for 1 month or less, or enrolled fewer than 50 patients. Two authors extracted all outcome data independently, with subsequent discussion of any discrepancies. Outcomes from each study were extracted in intention-to-treat categories rather than per-protocol categories (that is, all outcomes were analyzed by randomization group to avoid bias from excluding patients who dropped out, were withdrawn, or did not adhere to treatment). We calculated the magnitude of heart rate reduction in each trial by comparing the heart rate at the end of the dose titration phase of each trial with the baseline values and subtracted the change in the placebo group from the change in the -blocker group. Statistical Analysis Because of the expected differences in patient samples and length of follow-up in these studies, we did our primary analyses by using the DerSimonianLaird random-effects model. We did analyses by using Review Manager, version 4.2 (The Cochrane Collaboration, Copenhagen, Denmark), and Stata SE, version 10 (StataCorp, College Station, Texas). Because the outcome of interest was relatively common, we calculated risk ratios (RRs) and 95% CIs. We assessed and quantified statistical heterogeneity for each outcome of interest by using the Cochran Q test and the I 2 statistic, respectively (16). The I 2 statistic quantifies the percentage of statistical heterogeneity due to between-study variability. By convention, values less than 25%, 25% to 50%, and greater than 50% are considered low, moderate, and high amounts of heterogeneity, respectively (17). To explore potential explanations for the between-trial heterogeneity, we did meta-regression analyses by using the weighted least-squares method (16). The logarithm of relative risk for death, weighted by the inverse variance of each study, was regressed against the following variables 1 at a time: sex, age, ischemic cause, left ventricular ejection fraction (LVEF), New York Heart Association (NYHA) class, atrial fibrillation, use of digoxin, heart rate at baseline, magnitude of heart rate reduction achieved with treatment, dose of -blocker reached, systolic blood pressure (SBP) at baseline, magnitude of treatment-related SBP reduction, and specific -blocking agent. We explored continuous variables in these meta-regressions both linearly and categorically by using tertiles. We reported the P values from Wald tests. In a sensitivity analysis, we investigated the stability of our meta-regression result by using a Monte Carlo simulation to explore the effect of sampling variability around the point estimates of heart rate reduction in each trial (18). We sampled 5000 data sets, and the mean heart rate reduction was varied along a normal distribution (by using the mean and SE reported by each trial); trial selection remained fixed in each Monte Carlo iteration. In addition, we ran meta-regressions incorporating various combinations of 2 or 3 of these variables to investigate the robustness of our findings (the number of trials was insufficient to run meta-regressions with more than 3 variables). Role of the Funding Source There was no specific funding for this project. Results Study Selection and Evaluation Of the 548 citations that we identified in our search, 108 were potentially eligible for inclusion, but we excluded 85 after detailed review (Figure 1). Of note, the 34 trials that we excluded because they did not report death but instead evaluated levels of biomarkers or neurohormonal measurements, hemodynamic changes, or echocardiographic measurements, were generally small (mean sample size, 43 patients). The 12 trials that reported death, but were excluded because they included fewer than 50 patients (mean sample size, 28 patients), had a total of only 15 deaths (compared with 2720 deaths in the 23 randomized trials included in our meta-analysis). Disagreement between 2 reviewers about eligibility of the studies occurred on 3 occasions, for a value of 0.92. All disagreements were resolved by consensus. Figure 1. Study flow diagram. Studies Included in the Systematic Review Table 1 shows the baseline data from 23 randomized trials (1942). Three trials [23, 28, 38] reported outcome data in -blocker dosage subgroups (each of these subgroups is reported as a separate row in Table 1) (1942). The Appendix Table outlines -blocker titration schedules, dosing, duration, and effect on SBP and heart rate. Four trials (21, 24, 26, 40) could not be included in the analyses comparing death with physiologic variables because they did not report heart rate data for trial participants. Table 1. Baseline Data for Included Trials Appendix Table. Changes in Clinical Variables During Trials Qualitative Synthesis All but 2 (32, 41) trials were restricted to patients with systolic dysfunction, and only 4% of trial participants had preserved systolic function. Two trials enrolled only patients with nonischemic heart failure; 2 trials were restricted to patients with ischemic cardiomyopathy; and in the other trials, the frequency of ischemic heart disease ranged from 27% to 90%, with a median of 59% (Table 1). In addition to standard antiheart failure therapy except -blockers, the control groups received placebo in all but 2 trials (in which the control group received an angiotensin-converting enzyme inhibitor but no -blocker) (33, 36). Use of angiotensin-converting enzyme inhibitors (median, 93% [interquartile range {IQR}, 87% to 96%]) and digoxin (median, 75% [IQR, 57% to 91%]) was high in these trials (Table 1). Mean LVEF in these trials ranged from 0.17 to 0.36 (median, 0.24), with all but 1 trial reporting mean LVEF less than 0.30 (Table 1). Few trials reported comorbid conditions, but in those that did, 12% to 35% of participants had atrial fibrillation (Table 1) and 12% to 36% had diabetes mellitus. Most patients in these trials had NYHA class III or IV symptoms at baseline (median, 54% [IQR, 50% to 66%]). Most of these trials were of relatively short durationonly 6 trials (19, 3335, 39, 40) followed patients longer than 12 months (Appendix Table). Fifteen trials did not report subgroup analyses, whereas 8 trials did: patients with ischemic versus nonischemic heart failure (22, 31, 34, 35, 39, 41, 43); results by NYHA class (22, 3436, 39), age (22, 31, 36, 41, 43), sex (22, 31, 39, 41, 43), or race (39); and results for patients with comorbid conditions, such as diabetes (22, 36, 41), hypertension (22, 36), smoking (22), or chronic kidney disease (36). Although 6 trials reported that -blocker efficacy did not statistically differ between any of the subgroups examined, most of these subgroup analyses were presented as forest plots or KaplanMeier curves with no explicit reporting of raw numbers, such that we could not pool subgroup data to examine the consistency across trials with formal interaction tests. One trial (BEST [Beta-Blocker Evaluation of Survival Trial]) reported that -blockers demonstrated a survival benefit in nonblack patients but not in black patients (P for interaction= 0.02) (39). Because no other trials reported outcomes separately for black and nonblack patients, we could not evaluate the consistency of this subgroup finding across trials. The BEST trial enrol

Renal replacement therapy in patients with acute renal failure: a systematic review

CONTEXT Acute renal failure requiring dialytic support is associated with a high risk of mortality and substantial morbidity. OBJECTIVES To summarize current evidence guiding provision of dialysis for patients with acute renal failure, to make recommendations for management, and to identify areas in which additional research is needed. DATA SOURCES Systematic searches of peer-reviewed publications in MEDLINE, EMBASE, and All EBM Reviews through October 2007. STUDY SELECTION Randomized controlled trials (RCTs) and prospective cohort studies studying dialytic support in adults with acute renal failure that reported the incidence of clinical outcomes such as mortality, length of stay, need for chronic dialysis, or development of hypotension. DATA EXTRACTION Quality was independently assessed by 2 reviewers using the Jadad score (RCTs) and the Downs and Black checklist (cohort studies). A single reviewer extracted data, which were independently verified by a second reviewer. Results of RCTs were pooled using a random-effects model. DATA SYNTHESIS From 173 retrieved articles, 30 RCTs and 8 prospective cohort studies were eligible. No conclusions could be drawn about optimal indications for or timing of renal replacement. Available data comparing continuous renal replacement therapy (CRRT) with intermittent hemodialysis demonstrated no clinically relevant difference between modalities, including for all-cause mortality (relative risk [RR], 1.10; 95% confidence interval [CI], 0.99-1.23; I2 = 0%) or for the requirement for chronic dialysis treatment in survivors (RR, 0.91; 95% CI, 0.56-1.49; I2 = 0%). For patients treated with CRRT, limited data suggest that bicarbonate may be preferable to other forms of dialysate alkali and that citrate infusion may be an alternative to systemic anticoagulation in patients at high risk of bleeding. Among patients treated with continuous venovenous hemofiltration (CVVHF), the risk of death was lower at doses of 35 mL/kg per hour (RR of death compared with doses of 20 mL/kg per hour, 0.74; 95% CI, 0.63-0.88). The use of unsubstituted cellulosic membranes should be avoided in intermittent hemodialysis (RR of death compared with biocompatible membranes, 1.23; 95% CI, 1.01-1.50). CONCLUSIONS Based on current data, intermittent hemodialysis and CRRT appear to lead to similar clinical outcomes for patients with ARF. If CVVHF is used, a dose of 35 mL/kg per hour should be provided. Given the paucity of good-quality evidence in this important area, additional large randomized trials are needed to evaluate clinically important outcomes.

Glomerular filtration rate, proteinuria, and the incidence and consequences of acute kidney injury: a cohort study

BACKGROUND Low values of estimated glomerular filtration rate (eGFR) predispose to acute kidney injury, and proteinuria is a marker of kidney disease. We aimed to investigate how eGFR and proteinuria jointly modified the risks of acute kidney injury and subsequent adverse clinical outcomes. METHODS We did a cohort study of 920,985 adults residing in Alberta, Canada, between 2002 and 2007. Participants not needing chronic dialysis at baseline and with at least one outpatient measurement of both serum creatinine concentration and proteinuria (urine dipstick or albumin-creatinine ratio) were included. We assessed hospital admission with acute kidney injury with validated administrative codes; other outcomes were all-cause mortality and a composite renal outcome of end-stage renal disease or doubling of serum creatinine concentration. FINDINGS During median follow-up of 35 months (range 0-59 months), 6520 (0·7%) participants were admitted with acute kidney injury. In those with eGFR 60 mL/min per 1·73 m(2) or greater, the adjusted risk of admission with this disorder was about 4 times higher in those with heavy proteinuria measured by dipstick (rate ratio 4·4 vs no proteinuria, 95% CI 3·7-5·2). The adjusted rates of admission with acute kidney injury and kidney injury needing dialysis remained high in participants with heavy dipstick proteinuria for all values of eGFR. The adjusted rates of death and the composite renal outcome were also high in participants admitted with acute kidney injury, although the rise associated with this injury was attenuated in those with low baseline eGFR and heavy proteinuria. INTERPRETATION These findings suggest that information on proteinuria and eGFR should be used together when identifying people at risk of acute kidney injury, and that an episode of acute kidney injury provides further long-term prognostic information in addition to eGFR and proteinuria. FUNDING The study was funded by an interdisciplinary team grant from Alberta Heritage Foundation for Medical Research.

Epinephrine and Dexamethasone in Children with Bronchiolitis

BACKGROUND Although numerous studies have explored the benefit of using nebulized epinephrine or corticosteroids alone to treat infants with bronchiolitis, the effectiveness of combining these medications is not well established. METHODS We conducted a multicenter, double-blind, placebo-controlled trial in which 800 infants (6 weeks to 12 months of age) with bronchiolitis who were seen in the pediatric emergency department were randomly assigned to one of four study groups. One group received two treatments of nebulized epinephrine (3 ml of epinephrine in a 1:1000 solution per treatment) and a total of six oral doses of dexamethasone (1.0 mg per kilogram of body weight in the emergency department and 0.6 mg per kilogram for an additional 5 days) (the epinephrine-dexamethasone group), the second group received nebulized epinephrine and oral placebo (the epinephrine group), the third received nebulized placebo and oral dexamethasone (the dexamethasone group), and the fourth received nebulized placebo and oral placebo (the placebo group). The primary outcome was hospital admission within 7 days after the day of enrollment (the initial visit to the emergency department). RESULTS Baseline clinical characteristics were similar among the four groups. By the seventh day, 34 infants (17.1%) in the epinephrine-dexamethasone group, 47 (23.7%) in the epinephrine group, 51 (25.6%) in the dexamethasone group, and 53 (26.4%) in the placebo group had been admitted to the hospital. In the unadjusted analysis, only the infants in the epinephrine-dexamethasone group were significantly less likely than those in the placebo group to be admitted by day 7 (relative risk, 0.65; 95% confidence interval, 0.45 to 0.95, P=0.02). However, with adjustment for multiple comparisons, this result was rendered insignificant (P=0.07). There were no serious adverse events. CONCLUSIONS Among infants with bronchiolitis treated in the emergency department, combined therapy with dexamethasone and epinephrine may significantly reduce hospital admissions. (Current Controlled Trials number, ISRCTN56745572.)

Bariatric surgery: a systematic review and network meta‐analysis of randomized trials

The clinical efficacy and safety of bariatric surgery trials were systematically reviewed. MEDLINE, EMBASE, CENTRAL were searched to February 2009. A basic PubCrawler alert was run until March 2010. Trial registries, HTA websites and systematic reviews were searched. Manufacturers were contacted. Randomized trials comparing bariatric surgeries and/or standard care were selected. Evidence‐based items potentially indicating risk of bias were assessed. Network meta‐analysis was performed using Bayesian techniques. Of 1838 citations, 31 RCTs involving 2619 patients (mean age 30–48 y; mean BMI levels 42–58 kg/m2) met eligibility criteria. As compared with standard care, differences in BMI levels from baseline at year 1 (15 trials; 1103 participants) were as follows: jejunoileal bypass [MD: −11.4 kg/m2], mini‐gastric bypass [−11.3 kg/m2], biliopancreatic diversion [−11.2 kg/m2], sleeve gastrectomy [−10.1 kg/m2], Roux‐en‐Y gastric bypass [−9.0 kg/m2], horizontal gastroplasty [−5.0 kg/m2], vertical banded gastroplasty [−6.4 kg/m2], and adjustable gastric banding [−2.4 kg/m2]. Bariatric surgery appears efficacious compared to standard care in reducing BMI. Weight losses are greatest with diversionary procedures, intermediate with diversionary/restrictive procedures, and lowest with those that are purely restrictive. Compared with Roux‐en‐Y gastric bypass, adjustable gastric banding has lower weight loss efficacy, but also leads to fewer serious adverse effects.

Benefits and harms of erythropoiesis-stimulating agents for anemia related to cancer: a meta-analysis

Background: Erythropoiesis-stimulating agents are used to treat anemia in patients with cancer. However, their safety and effectiveness is controversial. We did a systematic review of the clinical efficacy and harms of these agents in adults with anemia related to cancer or chemotherapy. Methods: We conducted a systematic review of published and unpublished randomized controlled trials (RCTs) using accepted methods for literature searches, article selection, data extraction and quality assessment. We included RCTs involving anemic adults with cancer. We compared the use of erythropoiesis-stimulating agents with nonuse and assessed clinical outcomes (all-cause mortality, cardiovascular events and hypertension, health-related quality of life, blood transfusions and tumour response) and harms (serious adverse events) between groups. Results: We identified 52 trials (n = 12 006) that met our selection criteria. The pooled all-cause mortality during treatment was significantly higher in the group receiving erythropoiesis-stimulating therapy than in the control group (relative risk [RR] 1.15, 95% confidence interval [CI] 1.03 to 1.29). Compared with no treatment, use of erythropoiesis-stimulating agents led to clinically detectable improvements in disease-specific measures of quality of life. It also reduced the use of blood transfusions (RR 0.64, 95% CI 0.56 to 0.73). However, it led to an increased risk of thrombotic events (RR 1.69, 95% CI 1.27 to 2.24) and serious adverse events (RR 1.16, 95% CI 1.08 to 1.25). Interpretation: Use of erythropoiesis-stimulating agents in patients with cancer-related anemia improved some disease-specific measures of quality of life and decreased the use of blood transfusions. However, it increased the risk of death and serious adverse events. Our findings suggest that such therapy not be used routinely as an alternative to blood transfusion in patients with anemia related to cancer.