Examining the Impacts of the COVID-19 Pandemic on Iraqi Refugees in Canada.

The COVID-19 pandemic has exacerbated health and social inequities among migrant groups more than others. Higher rates of poverty, unemployment, living in crowded households, and language barriers have placed resettled refugees at a higher risk of facing disparities during the COVID-19 pandemic. To understand how this most vulnerable population has been impacted by the ongoing pandemic, this study reports on the responses of 128 Iraqi refugees in the city of London, Ontario, to a survey on the economic, social, and health-related impacts that they have faced for almost two years since the beginning the pandemic. The analysis of the survey indicated that 90.4% of the study population reported having health concerns during the pandemic while 80.3% expressed facing financial distress. The results also show that 58.4% of respondents experienced some form of social isolation. These all suggest that refugees are faced with several barriers which can have a compounding effect on their resettlement experience. These findings provide resettlement and healthcare providers with some information that may assist in reducing the impact of COVID-19 and other possible health security emergencies on resettled refugees and their communities.

Phosphate is associated with frailty in older patients with chronic kidney disease not on dialysis.

PURPOSE: Frailty is common in older patients with chronic kidney disease (CKD) and has been considered an independent risk factor for adverse clinical outcomes in this population. CKD-associated mineral and bone metabolism (CKD-MBD) increases energy expenditure and causes malnutrition and inflammation leading to frailty. We investigated whether CKD-MBD markers and energy metabolism are associated with frailty in patients with advanced CKD on conservative management. METHODS: In this cross-sectional study, we investigated factors associated with frailty in a sample of 75 patients ≥ 65 years, with stage 4 or 5 CKD. Collected data included age, sex, body mass index, physical activity status, educational level, Charlson Comorbidity Index, and laboratory markers. Frailty was evaluated according to Fried's classification. RESULTS: Frailty was observed in 51.3% and pre-frailty in 47.3%. The frail population was significantly older, with a high proportion of females, more inactive, had lower educational levels, spent a long time sitting throughout the day, and had higher phosphate and fibroblast growth factor 21 (FGF-21). In the multivariate logistic analysis age (odds ratio 1.13, p = 0.026) and phosphate (odds ratio 3.38, p = 0.021) remained independently associated with frailty. CONCLUSION: Serum phosphate seems to be a toxin associated with the frailty phenotype in older patients with CKD. Whether strategies to decrease serum phosphate would reduce the risk of frailty in this population deserves further evaluation.

Operations Research to Solve Kidney Allocation Problems: A Systematic Review.

BACKGROUND: Operations research techniques enable health care administrators to optimize resource allocation and to find solutions to staff and patient scheduling problems. We aimed to conduct the first systematic review of the international literature on the use of operations research for allocating deceased-donor kidneys. METHODS: We searched the MEDLINE, EMBASE, and PubMed databases from inception to February 2023. Two reviewers independently screened the title/abstract and subsequently the full text of potentially eligible articles and abstracted the data. Quality assessment of the final set of studies was conducted using Subben's checklist. RESULTS: Of the 302 citations identified, 5 studies were included. These studies covered three themes, including (1) provider-facing decision aids to determine the timing of transplant for single or multiple patients; (2) system-level planning on kidney allocation based on blood type matching rules; and (3) patient-facilitated wait times estimation using incomplete information. Markov models, sequential stochastic assignment models, and queuing models were amongst the most used techniques. Although we found all included studies to meet Subben's criteria, we believe the checklist in its current form lacks items to assess the validity of model inferences. As such, we ended this review with a set of practical recommendations. CONCLUSIONS: Our review demonstrated the utility of operations research techniques in assisting the system, healthcare providers, and patients in the transplantation process. More research is needed to reach a consensus on a model that can be used to support the decision-making of different stakeholders for efficient kidney allocation, with the ultimate goal of reducing the gap between kidney supply and demand and enhancing the population's well-being.

Critical appraisal and comparison of recommendations of clinical practice guidelines for the treatment of schizophrenia in children and adolescents: a methodological survey.

INTRODUCTION: The production of clinical practice guidelines (CPGs) has grown in the past years. Notwithstanding, the quality of these documents and their recommendations for the treatment of schizophrenia in children and adolescents is still unknown. OBJECTIVE: To assess the quality of the guidelines and recommendations for the treatment of schizophrenia in this population. METHODS: CPGs from 2004 to December 2020 were identified through a systematic search on EMBASE, MEDLINE, PsycINFO, PubMed, Epistemonikos, VHL, Global Index Medicus and specific CPG databases. The CPGs' quality was independently assessed by three reviewers using AGREE II and they were considered of high quality if they scored ≥60% in domains 3 and 6. The evidence classification systems were described, the quality of recommendations was assessed in pairs using AGREE-REX and the recommendations were compared. RESULTS: The database search retrieved 3182 results; 2030 were screened and 29 were selected for full-text reading. Four guidelines were selected for extraction. Two CPGs were considered of high quality in the AGREE II assessment. We described the commonly agreed recommendations for each treatment phase. The pharmacological recommendations were described in all treatment phases. Scores of AGREE-REX were lower for psychosocial recommendations. CONCLUSION: There are still few clinical studies and CPGs regarding schizophrenia in children and adolescents. The quality of the documents was overall low, and the quality of the recommendations report has much to improve. There is also a lack of transparency about the quality of the evidence and the strength of the recommendations. PROTOCOL REGISTRATION NUMBER: CRD42020164899.

Prognostic value of blood pressure in ambulatory heart failure: a meta-analysis and systematic review. Ambulatory blood pressure predicts heart failure prognosis.

Previous primary studies have explored the association between blood pressure (BP) and mortality in ambulatory heart failure (HF) patients reporting varying and contrasting associations. The aim is to determine the pooled BP prognostic value and explore potential reasons for between-study inconsistency. We searched Medline, Cochrane, EMBASE and CINAHL from January 2005 to October 2018 for studies with ≥ 50 events (mortality and/or hospitalization) and included BP in a multivariable model in ambulatory HF patients. We pooled hazard ratios (random effects model) for systolic BP (SBP) or diastolic BP (DBP) effect on mortality and/or hospitalization risk. We used a priori defined sub-group analyses to explore heterogeneity and GRADE approach to assess the certainty of the evidence. Seventy-one eligible articles (239,467 screened) at low to moderate risk of bias included 235,752 participants. Higher SBP was associated with reduced all-cause mortality (HR 0.93, 95%CI 0.91-0.95, I2 = 87.13%, moderate certainty), all-cause hospitalization events (HR 0.91, 95%CI 0.88-0.93, I2 = 44.4%, high certainty) and their composite endpoint (HR 0.93 per 10 mmHg, 95%CI 0.91-0.94, I2 = 86.3%, high certainty). DBP did not demonstrate a statistically significant effect for all outcomes. The association strength was significantly weaker in studies following patients with either LVEF > 40%, higher average SBP (> 130 mmHg), increasing age and diabetes. All other a priori subgroup hypotheses did not explain between study differences. Higher ambulatory SBP is associated with reduced risk of all-cause mortality and hospitalization. Patients with lower BP and reduced LVEF are in a high-risk group of developing adverse events with moderate certainty of evidence.

GRADE concept paper 2: Concepts for judging certainty on the calibration of prognostic models in a body of validation studies.

BACKGROUND: Prognostic models combine several prognostic factors to provide an estimate of the likelihood (or risk) of future events in individual patients, conditional on their prognostic factor values. A fundamental part of evaluating prognostic models is undertaking studies to determine whether their predictive performance, such as calibration and discrimination, is reproduced across settings. Systematic reviews and meta-analyses of studies evaluating prognostic models' performance are a necessary step for selection of models for clinical practice and for testing the underlying assumption that their use will improve outcomes, including patient's reassurance and optimal future planning. METHODS: In this paper, we highlight key concepts in evaluating the certainty of evidence regarding the calibration of prognostic models. RESULTS AND CONCLUSION: Four concepts are key to evaluating the certainty of evidence on prognostic models' performance regarding calibration. The first concept is that the inference regarding calibration may take one of two forms: deciding whether one is rating certainty that a model's performance is satisfactory or, instead, unsatisfactory, in either case defining the threshold for satisfactory (or unsatisfactory) model performance. Second, inconsistency is the critical GRADE domain to deciding whether we are rating certainty in the model performance being satisfactory or unsatisfactory. Third, depending on whether one is rating certainty in satisfactory or unsatisfactory performance, different patterns of inconsistency of results across studies will inform ratings of certainty of evidence. Fourth, exploring the distribution of point estimates of observed to expected ratio across individual studies, and its determinants, will bear on the need for and direction of future research.

Economic Consequences of Adult Living Kidney Donation: A Systematic Review.

OBJECTIVES: Current guidelines mandate organ donation to be financially neutral such that it neither rewards nor exploits donors. This systematic review was conducted to assess the magnitude and type of costs incurred by adult living kidney donors and to identify those at risk of financial hardship. METHODS: We searched English-language journal articles and working papers assessing direct and indirect costs incurred by donors on PubMed, MEDLINE, Scopus, the National Institute for Health Research Economic Evaluation Database, Research Papers in Economics, and EconLit in 2005 and thereafter. Estimates of total costs, types of costs, and characteristics of donors who incurred the financial burden were extracted. RESULTS: Sixteen studies were identified involving 6158 donors. Average donor-borne costs ranged from US$900 to US$19 900 (2019 values) over the period from predonation evaluation to the end of the first postoperative year. Less than half of donors sought financial assistance and 80% had financial loss. Out-of-pocket payments for travel and health services were the most reported items where lost income accounted for the largest proportion (23.2%-83.7%) of total costs. New indirect cost items were identified to be insurance difficulty, exercise impairment, and caregiver income loss. Donors from lower-income households and those who traveled long distances reported the greatest financial hardship. CONCLUSIONS: Most kidney donors are undercompensated. Our findings highlight gaps in donor compensation for predonation evaluation, long-distance donations, and lifetime insurance protection. Additional studies outside of North America are needed to gain a global prospective on how to provide for financial neutrality for kidney donors.

Dialysis Initiation and All-Cause Mortality Among Incident Adult Patients With Advanced CKD: A Meta-analysis With Bias Analysis.

RATIONALE & OBJECTIVES: Due to unmeasured confounding, observational studies have limitations when assessing whether dialysis initiation reduces mortality compared with conservative therapy among adults with advanced chronic kidney disease (CKD). We addressed this issue in this meta-analysis. STUDY DESIGN: Meta-analysis with bias analysis for unmeasured confounding. SETTING & STUDY POPULATION: Adults with stage 4 or 5 CKD who had initiated dialysis or conservative treatment. SELECTION CRITERIA FOR STUDIES: Prospective or retrospective cohort studies comparing survival of dialysis versus conservatively managed patients were searched on MEDLINE and Embase from January 2009 to March 20, 2019. DATA EXTRACTION: HRs of all-cause mortality associated with dialysis initiation compared with conservative treatment. ANALYTICAL APPROACH: We pooled HRs using a random-effects model. We estimated the percentage of effect sizes more protective than HRs of 0.80 and severity of unmeasured confounding that could reduce this percentage to only 10%. Subgroup analysis was performed for studies with only older patients (aged ≥ 65 years). RESULTS: 12 studies were included that involved 16,609 dialysis patients and 3,691 conservatively managed patients. A random-effects model suggested that dialysis initiation was associated with a mean mortality HR of 0.47 (95% CI, 0.34-0.64), in which 92% (95% CI, 50%-100%) of the true effects were more protective than HRs of 0.80. To reduce the percentage of HRs < 0.80 to 10%, unmeasured confounder(s) would need to be associated with both dialysis initiation and mortality by relative risks of 4.05 (95% CI, 2.39-4.15), which is equivalent to shifting each study's estimated HR by 2.31-fold (95% CI, 1.51-2.36). Restricting studies to include only older patients did not modify the results. LIMITATIONS: Limited number of studies and evidence on the absence of publication bias. CONCLUSIONS: Our findings suggest that dialysis initiation considerably reduces mortality among adults with advanced CKD. Future bias-adjusted meta-analyses need to assess outcomes beyond mortality.

Machine learning for predicting long-term kidney allograft survival: a scoping review.

Supervised machine learning (ML) is a class of algorithms that "learn" from existing input-output pairs, which is gaining popularity in pattern recognition for classification and prediction problems. In this scoping review, we examined the use of supervised ML algorithms for the prediction of long-term allograft survival in kidney transplant recipients. Data sources included PubMed, the Cumulative Index to Nursing and Allied Health Literature, and the Institute for Electrical and Electronics Engineers (IEEE) Xplore libraries from inception to November 2019. We screened titles and abstracts and potentially eligible full-text reports to select studies and subsequently abstracted the data. Eleven studies were identified. Decision trees were the most commonly used method (n = 8), followed by artificial neural networks (ANN) (n = 4) and Bayesian belief networks (n = 2). The area under receiver operating curve (AUC) was the most common measure of discrimination (n = 7), followed by sensitivity (n = 5) and specificity (n = 4). Model calibration examining the reliability in risk prediction was performed using either the Pearson r or the Hosmer-Lemeshow test in four studies. One study showed that logistic regression had comparable performance to ANN, while another study demonstrated that ANN performed better in terms of sensitivity, specificity, and accuracy, as compared with a Cox proportional hazards model. We synthesized the evidence related to the comparison of ML techniques with traditional statistical approaches for prediction of long-term allograft survival in patients with a kidney transplant. The methodological and reporting quality of included studies was poor. Our study also demonstrated mixed results in terms of the predictive potential of the models.

Resting Heart Rate as an Important Predictor of Mortality and Morbidity in Ambulatory Patients With Heart Failure: A Systematic Review and Meta-Analysis.

BACKGROUND: Resting heart rate is a risk factor of adverse heart failure outcomes; however, studies have shown controversial results. This meta-analysis evaluates the association of resting heart rate with mortality and hospitalization and identifies factors influencing its effect. METHODS AND RESULTS: We systematically searched electronic databases in February 2019 for studies published in 2005 or before that evaluated the resting heart rate as a primary predictor or covariate of multivariable models of mortality and/or hospitalization in adult ambulatory patients with heart failure. Random effects inverse variance meta-analyses were performed to calculate pooled hazard ratios. The Grading of Recommendations, Assessment, Development and Evaluation approach was used to assess evidence quality. Sixty-two studies on 163,445 patients proved eligible. Median population heart rate was 74 bpm (interquartile range 72-76 bpm). A 10-bpm increase was significantly associated with increased risk of all-cause mortality (hazard ratio 1.10, 95% confidence interval 1.08-1.13, high quality). Overall, subgroup analyses related to patient characteristics showed no changes to the effect estimate; however, there was a strongly positive interaction with age showing increasing risk of all-cause mortality per 10 bpm increase in heart rate. CONCLUSIONS: High-quality evidence demonstrates increasing resting heart rate is a significant predictor of all-cause mortality in ambulatory patients with heart failure on optimal medical therapy, with consistent effect across most patient factors and an increased risk trending with older age.

Developing trustworthy recommendations as part of an urgent response (1-2 weeks): a GRADE concept paper.

OBJECTIVES: The aim of this study is to propose an approach for developing trustworthy recommendations as part of urgent responses (1-2 week) in the clinical, public health, and health systems fields. STUDY DESIGN AND SETTING: We conducted a review of the literature, outlined a draft approach, refined the concept through iterative discussions, a workshop by the Grading of Recommendations Assessment, Development and Evaluation Rapid Guidelines project group, and obtained feedback from the larger Grading of Recommendations Assessment, Development and Evaluation working group. RESULTS: A request for developing recommendations within 2 week is the usual trigger for an urgent response. Although the approach builds on the general principles of trustworthy guideline development, we highlight the following steps: (1) assess the level of urgency; (2) assess feasibility; (3) set up the organizational logistics; (4) specify the question(s); (5) collect the information needed; (6) assess the adequacy of identified information; (7) develop the recommendations using one of the 4 potential approaches: adopt existing recommendations, adapt existing recommendations, develop new recommendations using existing adequate systematic review, or develop new recommendations using expert panel input; and (8) consider an updating plan. CONCLUSION: An urgent response for developing recommendations requires building a cohesive, skilled, and highly motivated multidisciplinary team with the necessary clinical, scientific, and methodological expertise; adapting to shifting needs; complying with the principles of transparency; and properly managing conflicts of interest.

Cost-effectiveness of Deceased-donor Renal Transplant Versus Dialysis to Treat End-stage Renal Disease: A Systematic Review.

Deceased-donor renal transplant (DDRT) is an expensive and potentially risky health intervention with the prospect of improved life and lower long-term costs compared with dialysis. Due to the increasing shortage of kidneys and the associated rise of transplantation costs, certain patient groups may not benefit from transplantation in a cost-effective manner compared with dialysis. The objective of this systematic review was to provide a comprehensive synthesis of evidence on the cost-effectiveness of DDRT relative to dialysis to treat adults with end-stage renal disease and patient-, donor-, and system-level factors that may modify the conclusion. A systematic search of articles was conducted on major databases including MEDLINE, Embase, Scopus, EconLit, and the Health Economic Evaluations Database. Eligible articles were restricted to those published in 2001 or thereafter. Two reviewers independently assessed the suitability of studies and excluded studies that focused on recipients with age <18 years old and those of a living-donor or multiorgan transplant. We show that while DDRT is generally a cost-effective treatment relative to dialysis at conventional willingness-to-pay thresholds, a range of drivers including older patient age, comorbidity, and long wait times significantly reduce the benefit of DDRT while escalating healthcare costs. These findings suggest that the performance of DDRT on older patients with comorbidities should be carefully evaluated to avoid adverse results as evidence suggests that it is not cost-effective. Delayed transplantation may reduce the economic benefits of transplant which necessitates targeted policies that aim to shorten wait times. More recent findings have demonstrated that transplantation using high-risk donors may be a cost-effective and promising alternative to dialysis in the face of a lack of organ availability and fiscal constraints. This review highlights key concepts of health economic evaluations and the relevance of cost-effectiveness to inform care and decision-making in renal programs.

Defining ranges for certainty ratings of diagnostic accuracy: a GRADE concept paper.

OBJECTIVE: The objective of the study was to clarify how the Grading of Recommendations Assessment, Development and Evaluation (GRADE) concept of certainty of evidence applies to certainty ratings of test accuracy. STUDY DESIGN AND SETTING: After initial brainstorming with GRADE Working Group members, we iteratively refined and clarified the approaches for defining ranges when assessing the certainty of evidence for test accuracy within a systematic review, health technology assessment, or guideline. RESULTS: Ranges can be defined both for single test accuracy and for comparative accuracy of multiple tests. For systematic reviews and health technology assessments, approaches for defining ranges include some that do not require value judgments regarding downstream health outcomes. Key challenges arise in the context of a guideline that requires ranges for sensitivity and specificity that are set considering possible effects on all critical outcomes. We illustrate possible approaches and provide an example from a systematic review of a direct comparison between two test strategies. CONCLUSIONS: This GRADE concept paper provides a framework for assessing, presenting, and making decisions based on the certainty of evidence for test accuracy. More empirical research is needed to support future GRADE guidance on how to best operationalize the candidate approaches.

Risk factors for diabetic kidney disease in adults with longstanding type 1 diabetes: results from the Canadian Study of Longevity in Diabetes.

Objectives: Diabetic kidney disease (DKD) is an independent predictor of cardiovascular morbidity and mortality in type 1 diabetes (T1D). We aimed to explore clinical and biochemical factors, including the achievement of American Diabetes Association (ADA) recommended targets associated with DKD in people living with T1D for ≥50 years. Methods: This was a post hoc analysis of a cross-sectional study of 75 participants enrolled in the Canadian Study of Longevity in T1D. We explored diabetes-related complications, including neuropathy, retinopathy, cardiovascular disease, and DKD. Study participants were dichotomized based on the achievement of ADA recommended targets as the low-target group (achieving ≤4 targets, n = 31) and high-target group (achieving >4 targets, n = 44). The outcome of interest was DKD defined by estimated glomerular filtration rate (eGFR) values <60/mL/min/1.73 m2 and/or 24-h albumin excretion >30 mg. Multivariable logistic regression models were employed to estimate odds ratios (ORs) for DKD with 95% confidence intervals (CIs). Results: Of the 75 participants with prolonged T1D duration (45% male, mean age 66 years), 25 participants had DKD and 50 did not. There was no statistical difference between the high- and low-target groups in terms of age and body mass index. eGFR was significantly higher and the prevalence of diabetic retinopathy was significantly lower in the high-target group. Older age at diagnosis of T1D and lower frequency component to high-frequency component ratio increased the odds of having DKD. Conclusions: In adults with prolonged T1D duration, older age at diagnosis and lower heart rate variability may be associated with DKD.

Assessment of health systems guidance using the Appraisal of Guidelines for Research and Evaluation - Health Systems (AGREE-HS) instrument.

Health systems guidance (HSG) documents contain systematically developed statements or recommendations intended to address a health system challenge. The concept of HSG is fairly new and considerable effort has been undertaken to build tools to support the contextualization of recommendations. One example is the Appraisal of Guidelines for REsearch and Evaluation - Health Systems (AGREE-HS), created by international stakeholders and researchers, to assist in the development, reporting and evaluation of HSG. Here, we present the quality appraisal of 85 HSG documents published from 2012 to 2017 using the AGREE-HS. The AGREE-HS consists of five items (Topic, Participants, Methods, Recommendations, and Implementability), which are scored on a 7-point response scale (1=lowest quality; 7=highest quality). Overall, AGREE-HS item scores were highest for the 'Topic' and 'Recommendations' items (means above the mid-point of 4), while the 'Participants', 'Methods', and 'Implementability' items received lower scores. Documents without a specific health focus and those authored by the National Institute for Health and Care Excellence group, achieved higher AGREE-HS overall scores than their comparators. No statistically significant changes in overall scores were observed over time. This is the first time that the AGREE-HS has been applied, providing a current quality status report of HSG and identifying where improvements in HSG development and reporting can be made.

Estimates of health utility scores in chronic kidney disease.

INTRODUCTION: Coverage decisions in publicly funded healthcare systems require a formal, systematic and transparent assessment process for policies related to distribution of resources. The process is complex and employs multiple types of information, such as clinical effectiveness, costs and health utility scores which are used to produce quality-adjusted life years. The purpose of this study was to create health utility scores for CKD patients within the Canadian population. METHODS: This is a cross-sectional study of CKD patients. We administered the Short-Form 36 Quality of Life Questions to all participants and employed the Short-Form 6 Dimension index to create health utility scores which were created using a set of parametric preference weights, nonparametric preference weights and ordinal health state valuation techniques obtained from a sample of the general population. RESULTS: Utility values in the dialysis group were lower than in the non-dialysis group. There was a significant relationship between age and health utility scores: As age increases, health utility scores decrease. Diabetes was associated with lower health utility scores in dialysis patients, whereas other covariates did not reach levels of statistical significance in our stepwise regression models. The parametric Bayesian model and standard gamble approach yielded the same results, while the correlation between the nonparametric and parametric methods was above 0.9. CONCLUSION: Health utility scores were low relative to the general population norm in our study cohort. Longitudinal assessment of CKD patients to capture possible fluctuations in health utility scores may add useful information.

Effects of different phosphate lowering strategies in patients with CKD on laboratory outcomes: A systematic review and NMA.

BACKGROUND: Chronic kidney disease-mineral and bone disorder (CKD-MBD), a complication of chronic kidney disease, has been linked to reduced quality and length of life. High serum phosphate levels that result from CKD-MBD require phosphate-lowering agents, also known as phosphate binders. The objective of this systematic review is to compare the effects of available phosphate binders on laboratory outcomes in patients with CKD-MBD. METHODS: Data sources included MEDLINE and EMBASE from January 1996 to April 2016, and the Cochrane Register of Controlled Trials up to April 2016. Teams of two reviewers, independently and in duplicate, screened titles and abstracts and potentially eligible full text reports to determine eligibility, and subsequently abstracted data and assessed risk of bias in eligible randomized controlled trials (RCTs). Eligible trials enrolled patients with CKD-MBD and randomized them to receive calcium-based phosphate binders (delivered as calcium acetate, calcium citrate or calcium carbonate), non-calcium-based phosphate binders (NCBPB) (sevelamer hydrochloride, sevelamer carbonate, lanthanum carbonate, sucroferric oxyhydroxide and ferric citrate), phosphorus restricted diet (diet), placebo or no treatment and reported effects on serum levels of phosphate, calcium and parathyroid hormone. We performed Bayesian network meta-analyses (NMA) to calculate the effect estimates (mean differences) and 95% credible intervals for serum levels of phosphate, calcium and parathyroid hormone. We calculated direct, indirect and network meta-analysis estimates using random-effects models. We applied the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach to rate the quality of evidence for each pairwise comparison. RESULTS: Our search yielded 1108 citations; 71 RCTs were retrieved for full review and 16 proved eligible. Including an additional 13 studies from a previous review, 29 studies that enrolled 8335 participants proved eligible; 26 trials provided data for quantitative synthesis. Sevelamer, lanthanum, calcium, iron, diet and combinations of active treatments (calcium or sevelamer or lanthanum and combination of calcium and sevelamer) resulted in significantly lower serum phosphate as compared to placebo (moderate to very low quality of evidence). We found no statistically significant differences between active treatment categories in lowering serum phosphate. Sevelamer, lanthanum and diet resulted in lower serum calcium compared to calcium (moderate quality evidence for lanthanum and diet; low quality evidence for Sevelamer). Iron, sevelamer and calcium yielded lower parathyroid hormone levels as compared to lanthanum. Meta-regression analyses did not yield a statistically significant association between treatment effect and trial duration. DISCUSSION/CONCLUSIONS: We found few differences between treatments in impact on phosphate and differences in parathyroid hormone. Relative to calcium, sevelamer, lanthanum and diet showed significant reduction in serum calcium from baseline. Treatment recommendations should be based on impact on patient-important outcomes rather than on surrogate outcomes. Systematic review registration: PROSPERO CRD-42016032945.

A critical appraisal of chronic kidney disease mineral and bone disorders clinical practice guidelines using the AGREE II instrument.

BACKGROUND: Patients with chronic kidney disease mineral and bone disorders (CKD-MBD) suffer high rates of morbidity and mortality, in particular related to bone and cardiovascular outcomes. The management of CKD-MBD remains challenging. The objective of this systematic survey is to critically appraise clinical practice guidelines (CPGs) addressing CKD-MBD. METHODS/DESIGN: Data sources included MEDLINE, EMBASE, the National Guideline Clearinghouse, Guideline International Network and Turning Research into Practice up to May 2016. Teams of two reviewers, independently and in duplicate, screened titles and abstracts and potentially eligible full text reports to determine eligibility and subsequently appraised the guidelines using the Advancing Guideline Development, Reporting and Evaluation in Health Care instrument II (AGREE). RESULTS: Sixteen CPGs published from 2003 to 2015 addressing the diagnosis and management of CKD-MBD in adult patients (11 English, two Spanish, one Italian, one Portuguese and one Slovak) proved eligible. The National Institute for Health and Care Excellence guideline performed best with respect to AGREE II criteria; only three other CPGs warranted high scores on all domains. All other guidelines received scores of under 60% on one or more domains. Major discrepancies in recommendations were not, however, present, and we found no association between quality of CPGs which was not associated with resulting recommendations. CONCLUSIONS: Most guidelines assessing CKD-MBD suffer from serious shortcomings using AGREE criteria although limitations with respect to AGREE criteria do not necessarily lead to inappropriate recommendations.

Limited responsiveness related to the minimal important difference of patient-reported outcomes in rare diseases.

OBJECTIVES: To explore the responsiveness of patient-reported outcomes (PROs) in interventional studies involving patients with rare lysosomal storage diseases (LSDs). STUDY DESIGN AND SETTING: We searched eight databases for experimental and nonexperimental studies. Pairs of trained reviewers independently screened articles and subsequently extracted data from the eligible studies. Among studies with 10 or more patients using a valid PRO, we assessed the responsiveness of PROs based on a reanalysis of the data using minimal important difference estimates. Our analyses focused on statistically significant within-group differences in PROs for observational studies or the statistically significant between-group differences in PRO scores for controlled studies. RESULTS: Of 2,679 unique records, 62 interventional studies addressing patients with Fabry (55%), Gaucher (19%), Pompe (16%), and mucopolysaccharidoses (11%) proved eligible. The most frequently used PROs were the Short-Form-36 (25 studies), Brief Pain Inventory (20 studies), EuroQoL-5D (9 studies), and the Fatigue Severity Scale (6 studies). Observational studies suggest that PROs sometimes detect significant within-group changes when present. Randomized trials raise questions regarding the responsiveness of PROs to small differences between groups. CONCLUSIONS: Most studies have relied on generic PROs to evaluate quality of life and symptoms in patients with rare LSDs. PROs appear more responsive in observational studies than randomized trials.

Comparative Effectiveness of Phosphate Binders in Patients with Chronic Kidney Disease: A Systematic Review and Network Meta-Analysis.

BACKGROUND: Chronic kidney disease-mineral and bone disorder (CKD-MBD) has been linked to poor health outcomes, including diminished quality and length of life. This condition is characterized by high phosphate levels and requires phosphate-lowering agents-phosphate binders. The objective of this systematic review is to compare the effects of available phosphate binders on patient-important outcomes in patients with CKD-MBD. METHODS: Data sources included MEDLINE and EMBASE Trials from 1996 to February 2016. We also searched the Cochrane Register of Controlled Trials up to April 2016. Teams of two reviewers, independently and in duplicate, screened titles and abstracts and potentially eligible full text reports to determine eligibility, and subsequently abstracted data and assessed risk of bias in eligible randomized controlled trials (RCTs). Eligible trials enrolled patients with CKD-MBD, randomized them to receive calcium (delivered as calcium acetate, calcium citrate or calcium carbonate), non-calcium-based phosphate binders (NCBPB) (sevelamer hydrochloride, sevelamer carbonate, lanthanum carbonate, sucroferric oxyhydroxide and ferric citrate), phosphorus restricted diet, placebo or no treatment, and reported effects on all-cause mortality, cardiovascular mortality or hospitalization at ≥4 weeks follow-up. We performed network meta-analyses (NMA) for all cause-mortality for individual agents (seven-node analysis) and conventional meta-analysis of calcium vs. NCBPBs for all-cause mortality, cardiovascular mortality and hospitalization. In the NMAs, we calculated the effect estimates for direct, indirect and network meta-analysis estimates; for both NMA and conventional meta-analysis, we pooled treatment effects as risk ratios (RR) and calculated 95% confidence intervals (CIs) using random effect models. We used the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach to rate the quality of evidence for each paired comparison. RESULTS: Our search yielded 1190 citations, of which 71 RCTs were retrieved for full review and 15 proved eligible. With 13 eligible studies from a prior review, we included 28 studies with 8335 participants; 25 trials provided data for our quantitative synthesis. Results suggest higher mortality with calcium than either sevelamer (NMA RR, 1.89 [95% CI, 1.02 to 3.50], moderate quality evidence) or NCBPBs (conventional meta-analysis RR, 1.76 [95% CI, 1.21 to 2.56, moderate quality evidence). Conventional meta-analysis suggested no difference in cardiovascular mortality between calcium and NCBPBs (RR, 2.54 [95% CI, 0.67 to 9.62 low quality evidence). Our results suggest higher hospitalization, although non-significant, with calcium than NCBPBs (RR, 1.293 [95% CI, 0.94 to 1.74, moderate quality evidence). DISCUSSION/CONCLUSIONS: Use of calcium results in higher mortality than either sevelamer in particular and NCBPBs in general (moderate quality evidence). Our results raise questions about whether administration of calcium as an intervention for CKD- MBD remains ethical. Further research is needed to explore the effects of different types of phosphate binders, including novel agents such as iron, on quality and quantity of life. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD-42016032945.