Ethan M Balk

National Kidney Foundation Practice Guidelines for Chronic Kidney Disease: Evaluation, Classification, and Stratification

Chronic kidney disease is a worldwide public health problem. In the United States, the incidence and prevalence of kidney failure are rising, the outcomes are poor, and the costs are high. The number of persons with kidney failure who are treated with dialysis and transplantation is projected to increase from 340 000 in 1999 to 651 000 in 2010 (1). The major outcomes of chronic kidney disease, regardless of cause, include progression to kidney failure, complications of decreased kidney function, and cardiovascular disease (CVD). Increasing evidence indicates that some of these adverse outcomes can be prevented or delayed by early detection and treatment (2). Unfortunately, chronic kidney disease is underdiagnosed and undertreated, resulting in lost opportunities for prevention (3-5), in part because of a lack of agreement on a definition and classification of stages in the progression of chronic kidney disease (6) and a lack of uniform application of simple tests for detection and evaluation. In February 2002, the Kidney Disease Outcomes Quality Initiative (K/DOQI) of the National Kidney Foundation (NKF) published 15 clinical practice guidelines on chronic kidney disease [7]. The goals of the guidelines are to 1) define chronic kidney disease and classify its stages, regardless of underlying cause; 2) evaluate laboratory measurements for the clinical assessment of kidney disease; 3) associate the level of kidney function with complications of chronic kidney disease; and 4) stratify the risk for loss of kidney function and development of CVD. Our goal is to disseminate the simple definition and five-stage classification system of chronic kidney disease, to summarize the major recommendations on early detection of chronic kidney disease in adults (Table 1), and to consider some of the issues associated with these recommendations. Because of the high prevalence of early stages of chronic kidney disease in the general population, this information is particularly important for general internists and specialists. Table 1. Guidelines, Recommendations, Ratings, and Key References Methods The guidelines of the K/DOQI are based on a systematic review of the literature. The approach used for the review was outlined by the Agency for Healthcare Research and Quality (formerly the Agency for Health Care Policy and Research) (46), with modifications appropriate to the available evidence and the goals of the K/DOQI Work Group. The Work Group considered diverse topics, which would have been too large for a comprehensive review of the literature. Instead, a selective review of published evidence was used to focus on specific questions: a summary of reviews for established concepts and a review of original articles and data for new concepts. The strength of recommendations is graded according to a new classification (Table 2) recently adopted by the K/DOQI Advisory Board (see Appendix 1). Table 2. National Kidney Foundation Kidney Disease Outcomes Quality Initiative Rating of the Strength of Recommendations Framework The Work Group defined two principal outcomes of chronic kidney disease: the progressive loss of kidney function over time (Figure 1) and the development and progression of CVD. Figure 1, which defines stages of chronic kidney disease, as well as antecedent conditions, outcomes, risk factors for adverse outcomes, and actions to improve outcomes, is a model of the course of chronic kidney disease. This diagram provides a framework that has previously been lacking for the development of a public health approach to chronic kidney disease. Figure 1. Evidence model for stages in the initiation and progression of chronic kidney disease ( CKD ) and therapeutic interventions. black dark gray light gray white GFR Table 3. Risk Factors for Chronic Kidney Disease and Its Outcomes Risk factors for chronic kidney disease are defined as attributes associated with increased risk for adverse outcomes of chronic kidney disease (Table 3). The guidelines focus primarily on identifying susceptibility factors and initiation factors (to define persons at increased risk for developing chronic kidney disease) and progression factors (to define persons at high risk for worsening kidney damage and subsequent loss of kidney function). Because kidney disease usually begins late in life and progresses slowly, most persons in the stage of decreased glomerular filtration rate (GFR) die of CVD before they develop kidney failure. However, decreased GFR is associated with a wide range of complications, such as hypertension, anemia, malnutrition, bone disease, neuropathy, and decreased quality of life, which can be prevented or ameliorated by treatment at earlier stages. Treatment can also slow the progression to kidney failure. Thus, measures to prevent, detect, and treat chronic kidney disease in its earlier stages could reduce the adverse outcomes of chronic kidney disease. Cardiovascular disease deserves special consideration as a complication of chronic kidney disease because 1) CVD events are more common than kidney failure in patients with chronic kidney disease, 2) chronic kidney disease seems to be a risk factor for CVD, and 3) CVD in patients with chronic kidney disease is treatable and potentially preventable (48-50). The 1998 Report of the NKF Task Force on Cardiovascular Disease in Chronic Renal Disease recommended that patients with chronic kidney disease be considered in the highest risk group for subsequent CVD events and that most interventions that are effective in the general population should also be applied to patients with chronic kidney disease (49). Definition and Classification of Stages of Chronic Kidney Disease Guideline 1. Definition and Stages of Chronic Kidney Disease Adverse outcomes can often be prevented or delayed through early detection and treatment of chronic kidney disease. Earlier stages of chronic kidney disease can be detected through routine laboratory measurements. Chronic kidney disease is defined as either kidney damage or decreased kidney function (decreased GFR) for 3 or more months (level A recommendation). Kidney disease can be diagnosed without knowledge of its cause. Kidney damage is usually ascertained by markers rather than by kidney biopsy. According to the Work Group, persistent proteinuria is the principal marker of kidney damage (8, 9). An albumincreatinine ratio greater than 30 mg/g in untimed (spot) urine samples is usually considered abnormal; proposed sex-specific cut points are greater than 17 mg/g in men and greater than 25 mg/g in women (10, 11). Other markers of damage include abnormalities in urine sediment, abnormalities in blood and urine chemistry measurements, and abnormal findings on imaging studies. Persons with normal GFR but with markers of kidney damage are at increased risk for adverse outcomes of chronic kidney disease. Glomerular filtration rate is the best measure of overall kidney function in health and disease (12). The normal level of GFR varies according to age, sex, and body size. Normal GFR in young adults is approximately 120 to 130 mL/min per 1.73 m2 and declines with age (12-15). A GFR level less than 60 mL/min per 1.73 m2 represents loss of half or more of the adult level of normal kidney function. Below this level, the prevalence of complications of chronic kidney disease increases. Although the age-related decline in GFR has been considered part of normal aging, decreased GFR in the elderly is an independent predictor of adverse outcomes, such as death and CVD (51-53). In addition, decreased GFR in the elderly requires adjustment in drug dosages, as in other patients with chronic kidney disease (54). Therefore, the definition of chronic kidney disease is the same, regardless of age. Because GFR declines with age, the prevalence of chronic kidney disease increases with age; approximately 17% of persons older than 60 years of age have an estimated GFR less than 60 mL/min per 1.73 m2 (16). The guidelines define kidney failure as either 1) GFR less than 15 mL/min per 1.73 m2, which is accompanied in most cases by signs and symptoms of uremia, or 2) a need to start kidney replacement therapy (dialysis or transplantation). Approximately 98% of patients with kidney failure in the United States begin dialysis when their GFR is less than 15 mL/min per 1.73 m2 (17). Kidney failure is not synonymous with end-stage renal disease (ESRD). End-stage renal disease is an administrative term in the United States. It indicates that a patient is treated with dialysis or transplantation, which is the condition for payment for health care by the Medicare ESRD Program. The classification of ESRD does not include patients with kidney failure who are not treated with dialysis and transplantation. Thus, although the term ESRD provides a simple operational classification of patients according to treatment, it does not precisely define a specific level of kidney function. The level of kidney function, regardless of diagnosis, determines the stage of chronic kidney disease according to the K/DOQI chronic kidney disease classification (level A recommendation). Data from the Third National Health and Nutrition Examination Survey (NHANES III) show the increasing prevalence of complications of chronic kidney disease at lower levels of GFR (7). These data and other studies provide a strong basis for using GFR to classify the stage of severity of chronic kidney disease. Table 4 shows the classification of stages of chronic kidney disease and the prevalence of each stage, estimated by using data from NHANES III (16). Approximately 11% of the U.S. adult population (20 million persons from 1988 to 1994) have chronic kidney disease. The prevalence of early stages of disease (stages 1 to 4; 10.8%) is more than 100 times greater than the prevalence of kidney failure (stage 5; 0.1%). The burden of illness associated with earlier stages of chronic kidney disease has not been systematically studied (55,

KDIGO clinical practice guideline for the care of kidney transplant recipients: a summary

The 2009 Kidney Disease: Improving Global Outcomes (KDIGO) clinical practice guideline on the monitoring, management, and treatment of kidney transplant recipients is intended to assist the practitioner caring for adults and children after kidney transplantation. The guideline development process followed an evidence-based approach, and management recommendations are based on systematic reviews of relevant treatment trials. Critical appraisal of the quality of the evidence and the strength of recommendations followed the Grades of Recommendation Assessment, Development, and Evaluation (GRADE) approach. The guideline makes recommendations for immunosuppression and graft monitoring, as well as prevention and treatment of infection, cardiovascular disease, malignancy, and other complications that are common in kidney transplant recipients, including hematological and bone disorders. Limitations of the evidence, especially the lack of definitive clinical outcome trials, are discussed and suggestions are provided for future research. This summary includes a brief description of methodology and the complete guideline recommendations but does not include the rationale and references for each recommendation, which are published elsewhere.

Systematic Review: Vitamin D and Cardiometabolic Outcomes

BACKGROUND Vitamin D may modify risk for cardiometabolic outcomes (type 2 diabetes, hypertension, or cardiovascular disease). PURPOSE To examine the association between vitamin D status, including the effect of vitamin D supplementation, and cardiometabolic outcomes in generally healthy adults. DATA SOURCES English-language studies in MEDLINE (inception to 4 November 2009) and the Cochrane Central Register of Controlled Trials (fourth quarter of 2009). STUDY SELECTION 11 reviewers screened citations to identify longitudinal cohort studies that reported associations between vitamin D status and cardiometabolic outcomes, including randomized trials of vitamin D supplementation. DATA EXTRACTION 5 independent reviewers extracted data about study conduct, participant characteristics, outcomes, and quality. Differences were resolved by consensus. DATA SYNTHESIS 13 observational studies (14 cohorts) and 18 trials were eligible. Three of 6 analyses (from 4 different cohorts) reported a lower incident diabetes risk in the highest versus the lowest vitamin D status groups. Eight trials found no effect of vitamin D supplementation on glycemia or incident diabetes. In meta-analysis of 3 cohorts, lower 25-hydroxyvitamin D concentration was associated with incident hypertension (relative risk, 1.8 [95% CI, 1.3 to 2.4]). In meta-analyses of 10 trials, supplementation nonsignificantly reduced systolic blood pressure (weighted mean difference, -1.9 mm Hg [CI, -4.2 to 0.4 mm Hg]) and did not affect diastolic blood pressure (weighted mean difference, -0.1 mm Hg [CI, -0.7 to 0.5 mm Hg]). Lower 25-hydroxyvitamin D concentration was associated with incident cardiovascular disease in 5 of 7 analyses (6 cohorts). Four trials found no effect of supplementation on cardiovascular outcomes. LIMITATIONS Studies included primarily white participants. Observational studies were heterogeneous. Several trials reported post hoc analyses. CONCLUSION The association between vitamin D status and cardiometabolic outcomes is uncertain. Trials showed no clinically significant effect of vitamin D supplementation at the dosages given. PRIMARY FUNDING SOURCE National Institute of Diabetes and Digestive and Kidney Disease, the National Institutes of Health Office of Dietary Supplements, U.S. Food and Drug Administration, Agency for Healthcare Research and Quality, and Public Health Agency of Canada.

Meta-analysis: The Effect of Dietary Counseling for Weight Loss

Key Summary Points This systematic review suggests that, on average, dietary counseling interventions for weight loss have resulted in a net loss of approximately 2 BMI units (6%) at 12 months compared with usual care. This weight difference narrows considerably over the subsequent 4 years. Long-term trials that evaluate the time course of weight changes are needed to confirm these conclusions. Factors that may alter the effectiveness of dietary counseling interventions require additional investigation. Future studies must improve their analyses, reporting of study design and findings, and follow-up of study participants. Obesity-related medical problems are among the most serious health problems facing U.S. adults. Approximately 65% of U.S. adults are overweight (body mass index [BMI] >25 kg/m2), and approximately half of overweight adults are obese (BMI >30 kg/m2) (1). Coronary heart disease is twice as common in obese people as in normal-weight people, and obesity substantially exacerbates all metabolic cardiac risk factors (2, 3). Obesity is associated with decreased longevity (47) and quality of life (8). Dietary and lifestyle modification efforts are the primary methods for treating and preventing obesity. Several important systematic reviews show that dietary-based lifestyle modification efforts can statistically significantly improve body weight and decrease related medical problems (917). The average weight change due to dietary counseling compared with usual care is unclear, particularly over the long term. We systematically reviewed and quantitatively synthesized published data on the net effect of dietary-based counseling compared with usual care over time. We also evaluated various sources of heterogeneity on the effectiveness of weight loss strategies. Methods Data Sources and Searches The starting point for the literature search was an extensive systematic review published in 1998, on which current clinical guidelines regarding identification, evaluation, and treatment of overweight and obesity in adults are based (9). For that report, a 24-member panel of experts methodically and critically examined all relevant scientific literature published between January 1980 and September 1997. After identifying all relevant studies from that report, we conducted a systematic literature search in all languages in MEDLINE and in the Cochrane Central Register of Controlled Trials databases from January 1997 through July 2006 to identify the effect on BMI of dietary-based weight-loss counseling interventions. We found additional studies from reference lists of other systematic reviews and included studies. Terms used in the searches of recent studies were weight loss, body mass index, obesity, diet, behavior therapy, and lifestyle. The search was limited to randomized, controlled trials. Study Selection We included randomized trials that reported original data on the effect of dietary counseling (advice to change dietary patterns) on body weight or BMI compared with the effect of control interventions (usual care or a minimal intervention, such as general verbal or written advice given at baseline, which was designed to approximate usual care). We excluded studies in which patients were younger than 18 years, the goal of the intervention was not weight loss, exercise was the only intervention, mean baseline BMI was less than 25 kg/m2, or SEs could not be determined. In keeping with the eligibility criteria of the 1998 evidence report (9), we also excluded studies with interventions that lasted fewer than 12 weeks and those that did not report effects at a minimum of 16 weeks. Figure 1 shows the number of studies that did not meet the eligibility criteria and the reasons for their exclusion. Figure 1. Study flow diagram. Cochrane = Cochrane Central Register of Controlled Trials; NHLBI/NIDDK = National Heart, Lung, and Blood Institute/National Institute of Diabetes and Digestive and Kidney Diseases. *Not randomized or quasi-randomized; no usual care control; weight loss not goal of intervention; exercise-only intervention; intervention duration less than 12 weeks or follow-up duration less than 16 weeks; baseline body mass index less than 25 kg/m2; no weight change data; insufficient data to calculate standard error; duplicate publication of study; abstract or letter. Data Extraction and Quality Assessment One of 3 reviewers used standardized forms to extract all studies that met the eligibility criteria. A second reviewer reviewed all extracted data. When necessary, disagreements were resolved by consensus of 2 or more authors. For all included studies, we extracted or estimated the net change in BMI and the SE of the net change from the reported data. Net change was defined as the change from baseline in the treatment group minus the change from baseline in the control group. We did not analyze change from baseline in the treatment groups alone (without subtracting changes in the control groups). When necessary, we calculated the change in BMI by using the ratio of baseline BMI to kilograms as the conversion factor. For the 9 studies that did not report such data, we assumed a ratio of 2.7 (equal to a height of 1.64 m), which corresponded well to ratios from other studies. Within studies, we preferentially chose data from intention-to-treat analyses; however, we retained data from all studies regardless of whether their analyses omitted missing data, used last observations carried forward, or replaced missing data with baseline data. For each study that reported change in BMI at multiple time points, we calculated the slopes of the net change in BMI across the different time points. When necessary, the SE of the net change was estimated from the SEs of the changes in BMI in the intervention and control groups, assuming that these values were independent of each other. Similarly, when necessary, the SEs of the intervention and control group changes in BMI were calculated from the SEs of the baseline and final values by using the following equation: where SE1, SE2 and SE12 are the SEs for baseline values, final values, and change in values, respectively, and is the correlation between SE1 and SE2 (18). We arbitrarily chose to be 0.50, the midpoint value. In secondary analyses, we used correlations of 0.25 and 0.75 (18). For the meta-analysis, we calculated the SE of the net BMI slopes by using the same methods. We also extracted data that described the counseling and usual care interventions, participants, study design, and adverse events. Active and maintenance phases of weight loss were defined according to the designations provided by the authors of each study. All studies were assessed for methodological quality according to the design, conduct, and reporting of the clinical study. We used a 3-level classification of study quality (19). Studies rated as good mostly adhered to the commonly held concepts of good quality, including clear description of the sample, setting, intervention, and comparison groups; blinding of outcome assessors; appropriate statistical and analytic methods and reporting of these methods, including randomization technique and intention-to-treat analysis; no obvious reporting errors; participant withdrawal less than 20%; clear reporting of those who withdrew; and no obvious bias. Fair-quality studies had some deficiencies (but none that were likely to cause major bias) or may have had missing information that made it difficult to assess limitations and potential problems. Poor-quality studies had serious errors in design, analysis, or reporting or may have had a large amount of missing information, discrepancies in reporting, or high rates of withdrawal. Data Synthesis and Analysis To summarize the net changes in BMI over time, we used different methods to analyze the data. All analyses were performed separately for data from the active and the maintenance phases of the behavioral weight loss programs. We graphed the net change in BMI for each study against time from the start of the intervention. Separate random-effects model meta-analyses assign a weight to each study on the basis of individual study variance and between-study heterogeneity (20) at each time point for which data were available from at least 3 cohorts of patients. For studies that reported data at multiple time points, not including baseline, we calculated slopes for each available period (for example, if data were reported at 3, 6, and 12 months, we calculated slopes for 3 to 6, 3 to 12, and 6 to 12 months). For periods where we had data from at least 3 cohorts of patients, we meta-analyzed the slopes by using a random-effects model. The calculated SEs of the slopes were used only for weighting the studies in the meta-analysis, not for estimating the statistical significance of the slopes. These SEs capture the relative variances of the net weight changes from baseline at the multiple time points but do not accurately estimate the SEs of the slopes themselves. For each period, we compared the effect of diabetes (inclusion vs. exclusion of patients with diabetes) and intervention (diet and exercise vs. diet alone) by using 2-sample t tests. In addition, all data were analyzed in a random-effects model meta-regressiona meta-analytic technique of multivariable linear regression across studiesaccording to the method of Morris (21) as described by Berkey and colleagues (22). This model is similar to the DerSimonian and Laird (20) random-effects model meta-analysis. We regressed net change BMI against time in months. We also conducted analyses with study-level variables that were potentially associated with the magnitude of the treatment effect, based on known associations within individual studies or on what we considered to be clinically or methodologically relevant from previous studies. These variables included intervention type (diet vs. diet and exercise) (23), frequency of support meetings (prorated for the first

Effect of Chromium Supplementation on Glucose Metabolism and Lipids

OBJECTIVE—A systematic review of the effect of chromium supplementation on glucose metabolism and lipid levels. RESEARCH DESIGN AND METHODS—A literature search was conducted in MEDLINE and the Commonwealth Agricultural Bureau. Eligible studies were English language randomized controlled trials of chromium supplement intake ≥3 weeks, with ≥10 participants receiving chromium. All trials with glucose metabolism outcomes and trials of individuals with diabetes or glucose intolerance for lipid outcomes were included. Meta-analyses were performed as appropriate. RESULTS—Forty-one studies met criteria, almost half of which were of poor quality. Among participants with type 2 diabetes, chromium supplementation improved glycosylated hemoglobin levels by −0.6% (95% CI −0.9 to −0.2) and fasting glucose by −1.0 mmol/l (−1.4 to −0.5) but not lipids. There was no benefit in individuals without diabetes. There were some indications of dose effect and differences among chromium formulations. Larger effects were more commonly observed in poor-quality studies. The evidence was limited by poor study quality, heterogeneity in methodology and results, and a lack of consensus on assessment of chromium status. CONCLUSIONS—No significant effect of chromium on lipid or glucose metabolism was found in people without diabetes. Chromium supplementation significantly improved glycemia among patients with diabetes. However, future studies that address the limitations in the current evidence are needed before definitive claims can be made about the effect of chromium supplementation.

Incidence and management of graft erosion, wound granulation, and dyspareunia following vaginal prolapse repair with graft materials: a systematic review

Introduction and hypothesisThis study describes the incidence, risk factors, and treatments of graft erosion, wound granulation, and dyspareunia as adverse events following vaginal repair of pelvic organ prolapse with non-absorbable synthetic and biologic graft materials.MethodsA systematic review in Medline of reports published between 1950 and November 2010 on adverse events after vaginal prolapse repairs using graft materials was carried out.ResultsOne hundred ten studies reported on erosions with an overall rate, by meta-analysis, of 10.3%, (95% CI, 9.7 – 10.9%; range, 0 – 29.7%; synthetic, 10.3%; biological, 10.1%). Sixteen studies reported on wound granulation for a rate of 7.8%, (95% CI, 6.4 – 9.5%; range, 0 – 19.1%; synthetic, 6.8%; biological, 9.1%). Dyspareunia was described in 70 studies for a rate of 9.1%, (95% CI, 8.2 – 10.0%; range, 0 – 66.7%; synthetic, 8.9%; biological, 9.6%).ConclusionsErosions, wound granulation, and dyspareunia may occur after vaginal prolapse repair with graft materials, though rates vary widely across studies.

Effectiveness of Management Strategies for Renal Artery Stenosis: A Systematic Review

Context Is medical therapy as effective as revascularization for atherosclerotic renal artery stenosis? Contribution This systematic review found no trials that compared aggressive medical therapy and angioplasty with stent in adults with atherosclerotic renal artery stenosis. Some evidence suggested similar kidney outcomes but better blood pressure outcomes with angioplasty, particularly in patients with bilateral renal disease. Weak evidence suggested no large differences in mortality or cardiovascular events between medical and revascularization treatments. No evidence directly compared adverse event rates between treatments. Implications Available evidence comparing benefits and harms of modern treatments for atherosclerotic renal artery stenosis is sparse and inconclusive. The Editors Renal artery stenosis is defined as narrowing of the renal artery lumen. Atherosclerosis, which usually involves the ostium and proximal third of the main renal artery and the perirenal aorta, accounts for 90% of cases of renal artery stenosis (1). Atherosclerotic renal artery stenosis is increasingly common in aging populations, particularly elderly people with diabetes, hyperlipidemia, aortoiliac occlusive disease, coronary artery disease, or hypertension. Atherosclerotic renal artery stenosis is a progressive disease that may occur alone or in combination with hypertension and ischemic kidney disease (1). Although the prevalence of atherosclerotic renal artery stenosis is poorly defined, it may vary from 30% among patients with coronary artery disease identified by angiography (2) to 50% among elderly people or those with diffuse atherosclerotic vascular diseases (3). In the United States, 12% to 14% of patients in whom dialysis is initiated have been found to have atherosclerotic renal artery stenosis (4). Most authorities consider blood pressure control, preservation or salvage of kidney function, and prevention of flash pulmonary edema to be important treatment goals for patients with atherosclerotic renal stenosis. Treatment options include medication alone or revascularization of the stenosed artery or arteries. Combination therapy with multiple antihypertensive agents, often including angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers, calcium-channel blockers, and -blockers, is frequently prescribed. Some clinicians also use statins to decrease low-density lipoprotein cholesterol levels and antiplatelet agents, such as aspirin or clopidogrel, to reduce the risk for thrombosis. The current standard for revascularization in most patients is percutaneous transluminal angioplasty with stent placement across the stenosis. Angioplasty without stent placement is less commonly used. Revascularization by surgical reconstruction is generally done only in patients with complicated renal artery anatomy or in those who require pararenal aortic reconstructions for aortic aneurysms or severe aortoiliac occlusive disease. The American College of Cardiology and the American Heart Association recently published guidelines for management of patients with peripheral arterial disease, including renal artery stenosis (5, 6). Although these guidelines provide recommendations about which patients should be considered for revascularization, considerable uncertainty remains about which intervention provides the best clinical outcomes. Among patients treated with medical therapy alone, experts are concerned about the risk for deterioration of kidney function and worsening cardiovascular morbidity and mortality. Revascularization procedures may provide immediate improvement in kidney function and blood pressure, but they are invasive interventions that could result in substantial morbidity or death, and because of the risk for restenosis the durability of their benefits is questioned. Although evidence regarding the optimal management of atherosclerotic renal artery stenosis appears uncertain, a Medicare claims analysis found that the rate of percutaneous renal artery revascularization has rapidly increased between 1996 and 2000, with the number of interventions increasing from 7660 to 18520 (7). To determine which patients, if any, with atherosclerotic renal artery stenosis would most benefit from angioplasty with stent placement, as opposed to continued aggressive medical treatment, the National Institutes of Health has sponsored the large, multicenter Cardiovascular Outcomes in Renal Atherosclerotic Lesions (CORAL) trial. Participants are currently being enrolled in the trial, and results should be reported in 2010. Meanwhile, the Agency for Healthcare Research and Quality, under Section 1013 of the Medicare Modernization Act, commissioned a review asking key questions related to the effectiveness of aggressive medical therapy compared with renal artery angioplasty with stent placement. However, because no published evidence directly compared angioplasty with stent placement and aggressive medical treatment with currently available drugs, the review covered direct comparisons of revascularization, including angioplasty with or without stent placement and surgery, and various medical regimens and indirect comparisons of angioplasty (with stent placement) and surgical interventions, various medical therapies, and natural history (8). Methods Data Sources and Selection To identify articles relevant to several key questions, we searched the MEDLINE database from inception to 6 September 2005 for studies involving adults with atherosclerotic renal artery stenosis. The Figure shows the search and selection process. The full technical report (available at www.effectivehealthcare.ahrq.gov/reports/final.cfm) provides a more detailed description of the study methods. We also reviewed reference lists of related systematic reviews, selected narrative reviews, and primary articles, and we invited domain experts to provide additional citations. We combined search terms for renal artery stenosis, renal hypertension, and renal vascular disease, and we limited the search to English-language articles of studies in adult humans that had relevant research designs. We included peer-reviewed primary studies of adult patients treated for atherosclerotic renal artery stenosis and excluded studies that evaluated patients with renal artery stenosis in the setting of a transplanted kidney, renal artery aneurysm requiring repair, aortic disease requiring invasive intervention, or concurrent cancer or patients who had had previous surgical or angioplasty interventions for renal artery stenosis. We included only studies that reported outcomes of interest (mortality rate, kidney function, blood pressure, and cardiovascular events) at 6 months or more after the initial intervention. We excluded studies in which more than 20% of patients had renal artery stenosis due to other causes. We categorized studies according to whether they evaluated medical treatment, angioplasty, or surgical revascularization or were natural history studies, and by whether they directly compared interventions. Figure. Search and selection of studies for review. *Prospective study; enrolled 10 or more patients; study duration at least 6 months. Prospective study; angioplasty included stent placement; enrolled 30 or more patients; study duration at least 6 months; patients recruited in 1993 or later; patients did not have previous angioplasty. One study has data both for direct comparison of medical treatment to angioplasty and for natural history. Any study design; enrolled 10 or more patients; study duration at least 6 months. Studies with surgical intervention must have recruited patients in 1993 or later. Any study design; enrolled 10 or more patients; study duration at least 6 months; patients recruited in 1993 or later. Any study design; enrolled 100 or more patients (10 or more if the study was prospective); study duration at least 6 months; patients recruited in 1993 or later. We used different eligibility criteria for studies of different interventions, based on the varying number of studies available for each intervention and the relevance of the intervention to current practice. We included all direct comparisons of medical treatment with angioplasty and all uncontrolled (cohort) studies of medical treatment that had at least 10 patients in each group, regardless of study design. For angioplasty, surgical, or natural history studies, we included only those in which at least some patients were recruited in 1993 or later, after the publication of the Fifth Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure. These guidelines marked a substantial change from previous guidelines in treatment recommendations for hypertension, including more aggressive blood pressure targets (9). In addition, at this time point, angiotensin-converting enzyme inhibitors began to be used more routinely in the treatment of patients with severe hypertension. We included only angioplasty studies that used stent placement, were prospective, and had at least 30 patients and retrospective surgery studies that included at least 100 patients. Any prospective surgery study that otherwise met criteria was eligible. Data Extraction and Quality and Applicability Assessments Data from each study were extracted by one of the authors and confirmed by another. The extracted data included information about patient samples, interventions, outcomes, adverse events, study design, quality, and applicability. We used predefined criteria to grade study quality as good, fair, or poor; study applicability as high, moderate, or low; and the strength of the overall body of evidence as robust, acceptable, or weak (Appendix Table). Each included study was graded by at least 2 of the authors. Appendix Table. Study Quality, Applicability, and Strength of Evidence Ratings Data Synthesis Because the study designs, participants, interventions, and reported outcome measures varied marke

Omega-3 Fatty Acids and Cardiac Arrhythmias: Prior Studies and Recommendations for Future Research A Report from the National Heart, Lung, and Blood Institute and Office of Dietary Supplements Omega-3 Fatty Acids and Their Role in Cardiac Arrhythmogenesis Workshop

Compared with prehistoric times, the ratio of n-6 to n-3 fatty acids in the modern diet has increased ≈10-fold to 20:1.1,2 A substantial body of evidence suggests that n-3 polyunsaturated fatty acids (PUFAs) provide cardiovascular protection and prevent arrhythmias.3–5 This has led to the recommendation by the American Heart Association that all adults eat fatty fish at least 2 times per week and that patients with coronary heart disease (CHD) are advised to consume ≈1 g/d of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) combined.6,7 The evidence base is not entirely consistent, and a number of randomized trials have failed to show a protective effect of n-3 PUFAs against arrhythmias.8–10 This has led to some uncertainty regarding the appropriate recommendations for their use.11 The present review originates from the Omega-3 Fatty Acids and Their Role in Cardiac Arrhythmogenesis Workshop sponsored by the National Heart, Lung, and Blood Institute and the Office of Dietary Supplements on August 29–30, 2005, and includes the findings from the recently published trials. Data from epidemiological studies, randomized clinical trials, animal studies, and basic science mechanistic studies on the role of n-3 PUFAs in arrhythmia prevention are examined. Areas in which the data are conflicting or our current knowledge is lacking are emphasized. Fatty acids are classified by the length of the carbon chain (long chain, n=20 to 22; intermediate chain, n=18) and the number of double bonds (saturated, monounsaturated, polyunsaturated).1,2 For PUFAs, the location of the first double bond relative to the -CH3 or omega (n-) end is given. Long- and intermediate-chain fatty acids must be ingested as part of the diet because they cannot be synthesized by humans and are therefore referred to as essential. The most common dietary fatty acids include (1) the omega-6 linoleic acid …

Pneumothorax Following Thoracentesis: A Systematic Review and Meta-analysis

BACKGROUND Little is known about the factors related to the development of pneumothorax following thoracentesis. We aimed to determine the mean pneumothorax rate following thoracentesis and to identify risk factors for pneumothorax through a systematic review and meta-analysis. METHODS We reviewed MEDLINE-indexed studies from January 1, 1966, through April 1, 2009, and included studies of any design with at least 10 patients that reported the pneumothorax rate following thoracentesis. Two investigators independently extracted data on the pneumothorax rate, risk factors for pneumothorax, and study methodological quality. RESULTS Twenty-four studies reported pneumothorax rates following 6605 thoracenteses. The overall pneumothorax rate was 6.0% (95% confidence interval [CI], 4.6%-7.8%), and 34.1% of pneumothoraces required chest tube insertion. Ultrasonography use was associated with significantly lower risk of pneumothorax (odds ratio [OR], 0.3; 95% CI, 0.2-0.7). Lower pneumothorax rates were observed with experienced operators (3.9% vs 8.5%, P = .04), but this was nonsignificant within studies directly comparing this factor (OR, 0.7; 95% CI, 0.2-2.3). Pneumothorax was more likely following therapeutic thoracentesis (OR, 2.6; 95% CI, 1.8-3.8), in conjunction with periprocedural symptoms (OR, 26.6; 95% CI, 2.7-262.5), and in association with, although nonsignificantly, mechanical ventilation (OR, 4.0; 95% CI, 0.95-16.8). Two or more needle passes conferred a nonsignificant increased risk of pneumothorax (OR, 2.5; 95% CI, 0.3-20.1). CONCLUSIONS Iatrogenic pneumothorax is a common complication of thoracentesis and frequently requires chest tube insertion. Real-time ultrasonography use is a modifiable factor that reduces the pneumothorax rate. Performance of thoracentesis for therapeutic purposes and in patients undergoing mechanical ventilation confers a higher likelihood of pneumothorax. Experienced operators may have lower pneumothorax rates. Patient safety may be improved by changes in clinical practice in accord with these findings.

Self-Measured Blood Pressure Monitoring in the Management of Hypertension: A Systematic Review and Meta-analysis

BACKGROUND Clinical guidelines recommend that adults with hypertension self-monitor their blood pressure (BP). PURPOSE To summarize evidence about the effectiveness of self-measured blood pressure (SMBP) monitoring in adults with hypertension. DATA SOURCES MEDLINE (inception to 8 February 2013) and Cochrane Central Register of Controlled Trials and Cochrane Database of Systematic Reviews (fourth quarter 2012). STUDY SELECTION 52 prospective comparative studies of SMBP monitoring with or without additional support versus usual care or an alternative SMBP monitoring intervention in persons with hypertension. DATA EXTRACTION Data on population, interventions, BP, other outcomes, and study method were extracted. Random-effects model meta-analyses were done. DATA SYNTHESIS For SMBP monitoring alone versus usual care (26 comparisons), moderate-strength evidence supports a lower BP with SMBP monitoring at 6 months (summary net difference, -3.9 mm Hg and -2.4 mm Hg for systolic BP and diastolic BP) but not at 12 months. For SMBP monitoring plus additional support versus usual care (25 comparisons), high-strength evidence supports a lower BP with use of SMBP monitoring, ranging from -3.4 to -8.9 mm Hg for systolic BP and from -1.9 to -4.4 mm Hg for diastolic BP, at 12 months in good-quality studies. For SMBP monitoring plus additional support versus SMBP monitoring alone or with less intense additional support (13 comparisons), low-strength evidence fails to support a difference. Across all comparisons, evidence for clinical outcomes is insufficient. For other surrogate or intermediate outcomes, low-strength evidence fails to show differences. LIMITATION Clinical heterogeneity in protocols for SMBP monitoring, additional support, BP targets, and management; follow-up of 1 year or less in most studies, with sparse clinical outcome data. CONCLUSION Self-measured BP monitoring with or without additional support lowers BP compared with usual care, but the BP effect beyond 12 months and long-term benefits remain uncertain. Additional support enhances the BP-lowering effect. PRIMARY FUNDING SOURCE Agency for Healthcare Research and Quality.