Low-protein diet for conservative management of chronic kidney disease: a systematic review and meta-analysis of controlled trials.

BACKGROUND: Recent data pose the question whether conservative management of chronic kidney disease (CKD) by means of a low-protein diet can be a safe and effective means to avoid or defer transition to dialysis therapy without causing protein-energy wasting or cachexia. We aimed to systematically review and meta-analyse the controlled clinical trials with adequate participants in each trial, providing rigorous contemporary evidence of the impact of a low-protein diet in the management of uraemia and its complications in patients with CKD. METHODS: We searched MEDLINE (PubMed) and other sources for controlled trials on CKD to compare clinical management of CKD patients under various levels of dietary protein intake or to compare restricted protein intake with other interventions. Studies with similar patients, interventions, and outcomes were included in the meta-analyses. RESULTS: We identified 16 controlled trials of low-protein diet in CKD that met the stringent qualification criteria including having 30 or more participants. Compared with diets with protein intake of >0.8 g/kg/day, diets with restricted protein intake (<0.8 g/kg/day) were associated with higher serum bicarbonate levels, lower phosphorus levels, lower azotemia, lower rates of progression to end-stage renal disease, and a trend towards lower rates of all-cause death. In addition, very-low-protein diets (protein intake <0.4 g/kg/day) were associated with greater preservation of kidney function and reduction in the rate of progression to end-stage renal disease. Safety and adherence to a low-protein diet was not inferior to a normal protein diet, and there was no difference in the rate of malnutrition or protein-energy wasting. CONCLUSIONS: In this pooled analysis of moderate-size controlled trials, a low-protein diet appears to enhance the conservative management of non-dialysis-dependent CKD and may be considered as a potential option for CKD patients who wish to avoid or defer dialysis initiation and to slow down the progression of CKD, while the risk of protein-energy wasting and cachexia remains minimal.

Association of serum vitamin B12 and folate with mortality in incident hemodialysis patients.

BACKGROUND: Vitamin B12 (B12) and folate are essential vitamins that play important roles in physiological processes. In the general population, many studies have evaluated the association of these vitamins with clinical outcomes, yet this association in hemodialysis (HD) patients remains unclear. METHODS: We examined the association of serum folate and B12 with mortality in a 5-year cohort of 9517 (folate) and 12 968 (B12) HD patients using Cox models with hierarchical adjustment for sociodemographics, comorbidities, and laboratory variables associated with the malnutrition and inflammation complex syndrome. The associations of baseline B12 and folate (separately) with all-cause mortality were evaluated across five categories of B12 [<400 (reference), 400-<550, 550-<650, 650-<750 and ≥750 pg/mL] and folate [<6.2, 6.2-<8.4, 8.4-<11 (reference), 11-<14.3 and ≥14.3 ng/mL]. RESULTS: The study cohort with B12 measurements had a mean ± standard deviation age of 63 ± 15 years, among whom 43% were female, 33% were African-American, and 57% were diabetic. Higher B12 concentrations ≥550 pg/mL were associated with a higher risk of mortality after adjusting for sociodemographic and laboratory variables. However, only lower serum folate concentrations <6.2 ng/mL were associated with a higher risk of all-cause mortality when adjusted for sociodemographic variables [adjusted hazard ratio (95% confidence-interval): 1.18 (1.03-1.35)]. CONCLUSIONS: Higher B12 concentrations are associated with higher all-cause mortality in HD patients independent of sociodemographics and laboratory variables, whereas lower folate concentrations were associated with higher all-cause mortality after accounting for sociodemographic variables. Further studies are warranted to determine the optimal B12 and folate level targets in this population.

Pain and Kidney Function Decline and Mortality: A Cohort Study of US Veterans.

BACKGROUND: Chronic pain is a common condition in the general population. However, large epidemiologic studies examining the role of pain in the deterioration of kidney function, development of chronic kidney disease, and risk for death are lacking. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: A nationally representative cohort of 2,360,056 US veterans with baseline estimated glomerular filtration rates (eGFRs) ≥ 60mL/min/1.73m(2), followed up from October 2004 to September 2006. PREDICTOR: 4 pain categories were compared: none (score, 0), mild (1-4), moderate (5-6), or severe (≥7). OUTCOMES: eGFR decline (determined by eGFR slope) and combined incident eGFR<60mL/min/1.73m(2) or all-cause death. MEASUREMENTS: We examined the pain management pattern and association of reported pain with (1) rapid eGFR decline and (2) a composite outcome of incident eGFR<60mL/min/1.73m(2) or all-cause death using logistic regression and Cox models adjusted for baseline eGFR, demographics, comorbid conditions, cardiovascular risk factors, and depression. RESULTS: ∼60% of veterans reported pain of any severity during the baseline period. The most commonly prescribed analgesics were opioids. In a dose-response relationship, veterans reporting moderate or severe pain had a higher risk for faster eGFR decline compared with those reporting none (ORs of 1.11 [95% CI, 1.09-1.14] and 1.17 [95% CI, 1.13-1.21] for moderate and severe pain, respectively). In combined analyses, veterans reporting moderate or severe pain both had 30% higher risk of the combined outcome (incident eGFR, 60 mL/min/1.73 m(2) or death) compared with those reporting none (HRs of 1.30 [95% CI, 1.28-1.31] and 1.30 [95% CI, 1.28-1.32] for moderate and severe pain, respectively). LIMITATIONS: Lack of granular data regarding type and location of pain. CONCLUSIONS: We observed a high prevalence of pain and analgesic prescription in the US veteran population with normal eGFRs. Pain was associated with a higher incidence of eGFRs<60mL/min/1.73m(2), faster kidney function decline, and higher mortality.

The dual roles of obesity in chronic kidney disease: a review of the current literature.

PURPOSE OF REVIEW: Obesity is a major risk factor for the development of de novo chronic kidney disease (CKD). However, once kidney disease is acquired, obesity is paradoxically linked with greater survival, especially in those with advanced CKD. This review examines current evidence for obesity as a risk factor for incident CKD, studies of obesity and mortality across various CKD populations, and potential mechanisms underlying the 'obesity paradox' in kidney disease. RECENT FINDINGS: Large cohort studies show that overweight body habitus, especially in the context of metabolic syndrome, is associated with higher risk of incident CKD. Emerging data also suggest weight-loss interventions retard or reverse early CKD progression, whereas in hemodialysis patients weight-loss paradoxically heralds poor outcomes. Although the pathogenesis of CKD in obesity remains unclear, studies indicate that excess body fat leads to kidney disease via indirect and direct mechanisms. Meta-analyses suggest that overweight and obese BMI ranges are counterintuitively associated with lower mortality in advanced predialysis and dialysis-dependent CKD patients, whereas a pooled analysis observed that higher pretransplantation BMI was associated with higher mortality in kidney transplantation recipients. SUMMARY: In addition to its role as a risk factor for de novo CKD, there appears to be a consistent association between obesity and lower mortality in those with established CKD, particularly among hemodialysis patients, suggesting that the reverse epidemiology of obesity is biologically plausible.

Association of Body Mass Index With Mortality in Peritoneal Dialysis Patients: A Systematic Review and Meta-Analysis.

UNLABELLED: ♦ BACKGROUND: Although higher body mass index (BMI) is associated with better outcomes in hemodialysis patients, the relationship in peritoneal dialysis (PD) patients is less clear. We aimed to synthesize the results from all large and high-quality studies to examine whether underweight, overweight, or obesity is associated with any significantly different risk of death in peritoneal dialysis patients. ♦ METHODS: We searched MEDLINE, EMBASE, Web of Science, CINAHL, and Cochrane CENTRAL, and screened 7,123 retrieved studies for inclusion. Two investigators independently selected the studies using predefined criteria and assessed each study's quality using the Newcastle-Ottawa Quality Assessment Scale. We meta-analyzed the results of the largest studies with no overlap in their data sources. ♦ RESULTS: We included 9 studies (n = 156,562) in the systematic review and 4 studies in the meta-analyses. When examined without stratifying studies by follow-up duration, the results of the studies were inconsistent. Hence, we pooled the study results stratified based upon their follow-up durations, as suggested by a large study, and observed that being underweight was associated with higher 1-year mortality but had no significant association with 2- and 3- to 5-year mortalities. In contrast, being overweight or obese was associated with lower 1-year mortality but it had no significant association with 2-, and 3- to 5-year mortalities. ♦ CONCLUSION: Over the short-term, being underweight was associated with higher mortality and being overweight or obese was associated with lower mortality. The associations of body mass with mortality were not significant over the long-term.

Reverse Epidemiology of Traditional Cardiovascular Risk Factors in the Geriatric Population.

Traditional risk factors of cardiovascular death in the general population, including body mass index (BMI), serum cholesterol, and blood pressure (BP), are also found to relate to outcomes in the geriatric population, but in an opposite direction. Some degrees of elevated BMI, serum cholesterols, and BP are reportedly associated with lower, instead of higher, risk of death among the elderly. This phenomenon is termed "reverse epidemiology" or "risk factor paradox" (such as obesity paradox) and is also observed in a variety of chronic disease states such as end-stage renal disease requiring dialysis, chronic heart failure, rheumatoid arthritis, and AIDS. Several possible causes are hypothesized to explain this risk factor reversal: competing short-term and long-term killers, improved hemodynamic stability in the obese, adipokine protection against tumor necrosis factor-α, lipoprotein protection against endotoxins, and lipophilic toxin sequestration by the adipose tissue. It is possible that the current thresholds for intervention and goal levels for such traditional risk factors as BMI, serum cholesterol, and BP derived based on younger populations do not apply to the elderly, and that new levels for such risk factors should be developed for the elderly population. Reverse epidemiology of conventional cardiovascular risk factors may have a bearing on the management of the geriatric population, thus it deserves further attention.

Effectiveness of teaching evidence-based medicine to undergraduate medical students: a BEME systematic review.

BACKGROUND: Despite the widespread teaching of evidence-based medicine (EBM) to medical students, the relevant literature has not been synthesized appropriately as to its value and effectiveness. AIM: To systematically review the literature regarding the impact of teaching EBM to medical students on their EBM knowledge, attitudes, skills and behaviors. METHODS: MEDLINE, SCOPUS, Web of science, ERIC, CINAHL and Current Controlled Trials up to May 2011 were searched; backward and forward reference checking of included and relevant studies was also carried out. Two investigators independently extracted data and assessed the quality of the studies. RESULTS: 10,111 potential studies were initially found, of which 27 were included in the review. Six studies examined the effect of clinically integrated methods, of which five had a low quality and the other one used no validated assessment tool. Twelve studies evaluated the effects of seminars, workshops and short courses, of which 11 had a low quality and the other one lacked a validated assessment tool. Six studies examined e-learning, of which five having a high or acceptable quality reported e-learning to be as effective as traditional teaching in improving knowledge, attitudes and skills. One robust study found problem-based learning less effective compared to usual teaching. Two studies with high or moderate quality linked multicomponent interventions to improved knowledge and attitudes. No included study assessed the long-term effects of the teaching of EBM. CONCLUSIONS: Our findings indicated that some EBM teaching strategies have the potential to improve knowledge, attitudes and skills in undergraduate medical students, but the evidenced base does not demonstrate superiority of one method. There is no evidence demonstrating transfer to clinical practice.

Association of Body Mass Index with Clinical Outcomes in Non-Dialysis-Dependent Chronic Kidney Disease: A Systematic Review and Meta-Analysis.

BACKGROUND: Previous studies have not shown a consistent link between body mass index (BMI) and outcomes such as mortality and kidney disease progression in non-dialysis-dependent chronic kidney disease (CKD) patients. Therefore, we aimed to complete a systematic review and meta-analysis study on this subject. METHODS: We searched MEDLINE, EMBASE, Web of Science, Cumulative Index to Nursing and Allied Health Literature (CINAHL), and Cochrane Central Register of Controlled Trials (CENTRAL), and screened 7,123 retrieved studies for inclusion. Two investigators independently selected the studies using predefined criteria and assessed each study's quality using the Newcastle-Ottawa quality assessment scale. We meta-analyzed the results based on the BMI classification system by the WHO. RESULTS: We included 10 studies (with a total sample size of 484,906) in the systematic review and 4 studies in the meta-analyses. The study results were generally heterogeneous. However, following reanalysis of the largest reported study and our meta-analyses, we observed that in stage 3-5 CKD, being underweight was associated with a higher risk of death while being overweight or obese class I was associated with a lower risk of death; however, obesity classes II and III were not associated with risk of death. In addition, reanalysis of the largest available study showed that a higher BMI was associated with an incrementally higher risk of kidney disease progression; however, this association was attenuated in our pooled results. For earlier stages of CKD, we could not complete meta-analyses as the studies were sparse and had heterogeneous BMI classifications and/or referent BMI groups. CONCLUSION: Among the group of patients with stage 3-5 CKD, we found a differential association between obesity classes I-III and mortality compared to the general population, indicating an obesity paradox in the CKD population.

Body mass index and mortality in kidney transplant recipients: a systematic review and meta-analysis.

BACKGROUND: A higher body mass index (BMI) seems to be linked to survival advantage in maintenance hemodialysis patients. However, it is uncertain if this 'obesity survival paradox' is also observed in kidney transplant recipients. Hence, we systematically reviewed the literature on the impact of pre-transplantation BMI on all-cause mortality in this population. METHODS: We searched MEDLINE, EMBASE, Web of Science, CINAHL, and Cochrane CENTRAL for relevant studies up to July 2013. Two investigators independently selected the studies using predefined criteria, abstracted the data from the included studies, and independently assessed each study's quality using the Newcastle-Ottawa Quality Assessment Scale. In addition to the qualitative synthesis, we quantitatively pooled the results of the studies with clinical, methodological, and statistical homogeneity. RESULTS: We screened 7,123 records, from which we included 11 studies (with a total of 305,392 participants) in this systematic review and 4 studies in the meta-analyses. In the only study that included children, obesity was linked to higher mortality in children of 6-12 years old. For adults, our meta-analyses indicated that compared to normal BMI, underweight [Hazard Ratio (HR): 1.09; 95% Confidence Interval (CI): 1.02-1.20], overweight (HR: 1.07; 95% CI: 1.04-1.12), and obese (HR: 1.20; 95% CI: 1.14-1.23) levels of BMI were associated with higher mortality. CONCLUSION: The presence of the obesity survival paradox is unlikely in kidney transplant recipients since both extremes of pre-transplantation BMI are linked to higher mortality in this population.

Obesity paradox in end-stage kidney disease patients.

In the general population, obesity is associated with increased cardiovascular risk and decreased survival. In patients with end-stage renal disease (ESRD), however, an "obesity paradox" or "reverse epidemiology" (to include lipid and hypertension paradoxes) has been consistently reported, i.e. a higher body mass index (BMI) is paradoxically associated with better survival. This survival advantage of large body size is relatively consistent for hemodialysis patients across racial and regional differences, although published results are mixed for peritoneal dialysis patients. Recent data indicate that both higher skeletal muscle mass and increased total body fat are protective, although there are mixed data on visceral (intra-abdominal) fat. The obesity paradox in ESRD is unlikely to be due to residual confounding alone and has biologic plausibility. Possible causes of the obesity paradox include protein-energy wasting and inflammation, time discrepancy among competitive risk factors (undernutrition versus overnutrition), hemodynamic stability, alteration of circulatory cytokines, sequestration of uremic toxin in adipose tissue, and endotoxin-lipoprotein interaction. The obesity paradox may have significant clinical implications in the management of ESRD patients especially if obese dialysis patients are forced to lose weight upon transplant wait-listing. Well-designed studies exploring the causes and consequences of the reverse epidemiology of cardiovascular risk factors, including the obesity paradox, among ESRD patients could provide more information on mechanisms. These could include controlled trials of nutritional and pharmacologic interventions to examine whether gain in lean body mass or even body fat can improve survival and quality of life in these patients.

Challenging script concordance test reference standard by evidence: do judgments by emergency medicine consultants agree with likelihood ratios?

BACKGROUND: We aimed to compare the clinical judgments of a reference panel of emergency medicine academic physicians against evidence-based likelihood ratios (LRs) regarding the diagnostic value of selected clinical and paraclinical findings in the context of a script concordance test (SCT). FINDINGS: A SCT with six scenarios and five questions per scenario was developed. Subsequently, 15 emergency medicine attending physicians (reference panel) took the test and their judgments regarding the diagnostic value of those findings for given diseases were recorded. The LRs of the same findings for the same diseases were extracted from a series of published systematic reviews. Then, the reference panel judgments were compared to evidence-based LRs. To investigate the test-retest reliability, five participants took the test one month later, and the correlation of their first and second judgments were quantified using Spearman rank-order coefficient. In 22 out of 30 (73.3%) findings, the expert judgments were significantly different from the LRs. The differences included overestimation (30%), underestimation (30%), and judging the diagnostic value in an opposite direction (13.3%). Moreover, the score of a hypothetical test-taker was calculated to be 21.73 out of 30 if his/her answers were based on evidence-based LRs. The test showed an acceptable test-retest reliability coefficient (Spearman coefficient: 0.83). CONCLUSIONS: Although SCT is an interesting test to evaluate clinical decision-making in emergency medicine, our results raise concerns regarding whether the judgments of an expert panel are sufficiently valid as the reference standard for this test.

A comparison of answer retrieval through four evidence-based textbooks (ACP PIER, Essential Evidence Plus, First Consult, and UpToDate): a randomized controlled trial.

BACKGROUND: The efficacy of bedside information products has not been properly evaluated, particularly in developing countries. AIM: To compare four evidence-based textbooks by comparing efficacy of their use by clinical residents, as measured by the proportion of questions for which relevant answers could be obtained within 20 min, the time to reach the answer and user satisfaction. METHODS: One hundred and twelve residents were taught information mastery basics and were randomly allocated to four groups to use: (1) ACP PIER, (2) Essential Evidence Plus (formerly InfoRetriever), (3) First Consult, and (4) UpToDate. Participants received 3 of 24 questions randomly to retrieve the answers from the assigned textbook. Retrieved answers and time-to-answers were recorded by special designed software, and the researchers determined if each recorded answer was relevant. RESULTS: The rate of answer retrieval was 86% in UpToDate, 69% in First Consult, 49% in ACP PIER, and 45% in Essential Evidence Plus (p < 0.001). The mean time-to-answer was 14.6 min using UpToDate, 15.9 min using First Consult, 16.3 min using Essential Evidence Plus, and 17.3 min using ACP PIER (p < 0.001). CONCLUSION: UpToDate seems more comprehensive in content and also faster than the other three evidence-based textbooks. Thus, it may be considered as one of the best sources for answering clinicians' questions at the point of care.

To compare PubMed Clinical Queries and UpToDate in teaching information mastery to clinical residents: a crossover randomized controlled trial.

PURPOSE: To compare PubMed Clinical Queries and UpToDate regarding the amount and speed of information retrieval and users' satisfaction. METHOD: A cross-over randomized trial was conducted in February 2009 in Tehran University of Medical Sciences that included 44 year-one or two residents who participated in an information mastery workshop. A one-hour lecture on the principles of information mastery was organized followed by self learning slide shows before using each database. Subsequently, participants were randomly assigned to answer 2 clinical scenarios using either UpToDate or PubMed Clinical Queries then crossed to use the other database to answer 2 different clinical scenarios. The proportion of relevantly answered clinical scenarios, time to answer retrieval, and users' satisfaction were measured in each database. RESULTS: Based on intention-to-treat analysis, participants retrieved the answer of 67 (76%) questions using UpToDate and 38 (43%) questions using PubMed Clinical Queries (P<0.001). The median time to answer retrieval was 17 min (95% CI: 16 to 18) using UpToDate compared to 29 min (95% CI: 26 to 32) using PubMed Clinical Queries (P<0.001). The satisfaction with the accuracy of retrieved answers, interaction with UpToDate and also overall satisfaction were higher among UpToDate users compared to PubMed Clinical Queries users (P<0.001). CONCLUSIONS: For first time users, using UpToDate compared to Pubmed Clinical Queries can lead to not only a higher proportion of relevant answer retrieval within a shorter time, but also a higher users' satisfaction. So, addition of tutoring pre-appraised sources such as UpToDate to the information mastery curricula seems to be highly efficient.

Efficacy and safety of naloxone in the management of postseizure complaints of tramadol intoxicated patients: a self-controlled study.

BACKGROUND AND AIMS: Tramadol has become a major cause of drug-induced seizure recently. Naloxone is reported to attenuate the seizurogenic activity of tramadol. Thus, the authors aimed to study the efficacy and safety of naloxone in the management of postseizure complaints. METHODS: This self-controlled study was conducted from August 2006 to August 2008. 59 tramadol intoxicated patients who did have postseizure complaints entered the study. After initial resuscitation and work-up, they received intravenous naloxone 0.05 mg every 3-5 min, and the presence of symptoms, presence of abnormal waves in cerebral state monitor (CSM), cerebral state index (CSI) and optical density (OD) were assessed. RESULTS: 47 participants completed the study, of whom 43 (91%) had symptom resolution after the intervention, and the presence of symptoms was significantly different before and after the intervention (p<0.001). 47 patients had abnormal waves in the CSM before the intervention, while 15 had abnormal waves in the CSM after intervention (p<0.001). The baseline mean of CSI was 81 (SD: 5.17), which was significantly increased to 92 (SD: 2.35) after naloxone injection (p<0.001). The baseline mean of OD was 7.1 (SD: 0.23), which was significantly increased to 7.7 (SD: 0.29) after naloxone injection (p<0.001). CONCLUSION: Naloxone can be considered in the management of postseizure complaints of tramadol toxicity, but further rigorous studies are needed to provide sufficient evidence to support its routine use.