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      Symptom burden and health-related quality of life in chronic kidney disease: A global systematic review and meta-analysis

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          Abstract

          Background

          The importance of patient-reported outcome measurement in chronic kidney disease (CKD) populations has been established. However, there remains a lack of research that has synthesised data around CKD-specific symptom and health-related quality of life (HRQOL) burden globally, to inform focused measurement of the most relevant patient-important information in a way that minimises patient burden. The aim of this review was to synthesise symptom prevalence/severity and HRQOL data across the following CKD clinical groups globally: (1) stage 1–5 and not on renal replacement therapy (RRT), (2) receiving dialysis, or (3) in receipt of a kidney transplant.

          Methods and findings

          MEDLINE, PsycINFO, and CINAHL were searched for English-language cross-sectional/longitudinal studies reporting prevalence and/or severity of symptoms and/or HRQOL in CKD, published between January 2000 and September 2021, including adult patients with CKD, and measuring symptom prevalence/severity and/or HRQOL using a patient-reported outcome measure (PROM). Random effects meta-analyses were used to pool data, stratified by CKD group: not on RRT, receiving dialysis, or in receipt of a kidney transplant. Methodological quality of included studies was assessed using the Joanna Briggs Institute Critical Appraisal Checklist for Studies Reporting Prevalence Data, and an exploration of publication bias performed. The search identified 1,529 studies, of which 449, with 199,147 participants from 62 countries, were included in the analysis. Studies used 67 different symptom and HRQOL outcome measures, which provided data on 68 reported symptoms. Random effects meta-analyses highlighted the considerable symptom and HRQOL burden associated with CKD, with fatigue particularly prevalent, both in patients not on RRT (14 studies, 4,139 participants: 70%, 95% CI 60%–79%) and those receiving dialysis (21 studies, 2,943 participants: 70%, 95% CI 64%–76%). A number of symptoms were significantly ( p < 0.05 after adjustment for multiple testing) less prevalent and/or less severe within the post-transplantation population, which may suggest attribution to CKD (fatigue, depression, itching, poor mobility, poor sleep, and dry mouth). Quality of life was commonly lower in patients on dialysis (36-Item Short Form Health Survey [SF-36] Mental Component Summary [MCS] 45.7 [95% CI 45.5–45.8]; SF-36 Physical Component Summary [PCS] 35.5 [95% CI 35.3–35.6]; 91 studies, 32,105 participants for MCS and PCS) than in other CKD populations (patients not on RRT: SF-36 MCS 66.6 [95% CI 66.5–66.6], p = 0.002; PCS 66.3 [95% CI 66.2–66.4], p = 0.002; 39 studies, 24,600 participants; transplant: MCS 50.0 [95% CI 49.9–50.1], p = 0.002; PCS 48.0 [95% CI 47.9–48.1], p = 0.002; 39 studies, 9,664 participants). Limitations of the analysis are the relatively few studies contributing to symptom severity estimates and inconsistent use of PROMs (different measures and time points) across the included literature, which hindered interpretation.

          Conclusions

          The main findings highlight the considerable symptom and HRQOL burden associated with CKD. The synthesis provides a detailed overview of the symptom/HRQOL profile across clinical groups, which may support healthcare professionals when discussing, measuring, and managing the potential treatment burden associated with CKD.

          Protocol registration

          PROSPERO CRD42020164737.

          Abstract

          In a systematic review and meta analysis, Benjamin R. Fletcher and colleagues study patient-reported symptom prevalence, severity, and health related quality of life among individuals with different stages of chronic kidney disease in 62 countries.

          Author summary

          Why was this study done?
          • Chronic kidney disease (CKD) is a common disease globally.

          • Patients with CKD have a reduced quality of life and a greater risk of hospitalisation, heart problems, and death.

          • Monitoring patient symptoms and quality of life can provide important information to help optimise CKD management.

          • There is a lack of clear evidence on differences in patient quality of life between CKD groups and which symptoms are experienced most often and/or are most severe.

          What did the researchers do and find?
          • We reviewed 449 studies that included 199,147 patients from 62 countries.

          • Patients with CKD reported a range of common and/or severe symptoms; the exact symptom burden depended on the stage of the disease and how it was being treated. Fatigue, however, was a very common and severe symptom in all patient groups.

          • Quality of life for patients with CKD was significantly lower than for individuals without the disease, and was worst in patients receiving dialysis.

          • In general, patients who had received a kidney transplant experienced fewer and less severe symptoms and had an improved quality of life, but this was still worse than that of people without CKD.

          What do these findings mean?
          • Symptom burden and negative impact on quality of life are considerable for people with CKD, especially for those receiving dialysis treatment.

          • The findings of this study will support healthcare professionals when discussing, measuring, and managing the potential treatment burden associated with CKD.

          • This global review of symptoms in patients with CKD will help in the selection of symptoms for inclusion in remote monitoring to identify patients in need of intervention.

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          Most cited references34

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          Measuring inconsistency in meta-analyses.

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            Global, regional, and national burden of chronic kidney disease, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017

            Summary Background Health system planning requires careful assessment of chronic kidney disease (CKD) epidemiology, but data for morbidity and mortality of this disease are scarce or non-existent in many countries. We estimated the global, regional, and national burden of CKD, as well as the burden of cardiovascular disease and gout attributable to impaired kidney function, for the Global Burden of Diseases, Injuries, and Risk Factors Study 2017. We use the term CKD to refer to the morbidity and mortality that can be directly attributed to all stages of CKD, and we use the term impaired kidney function to refer to the additional risk of CKD from cardiovascular disease and gout. Methods The main data sources we used were published literature, vital registration systems, end-stage kidney disease registries, and household surveys. Estimates of CKD burden were produced using a Cause of Death Ensemble model and a Bayesian meta-regression analytical tool, and included incidence, prevalence, years lived with disability, mortality, years of life lost, and disability-adjusted life-years (DALYs). A comparative risk assessment approach was used to estimate the proportion of cardiovascular diseases and gout burden attributable to impaired kidney function. Findings Globally, in 2017, 1·2 million (95% uncertainty interval [UI] 1·2 to 1·3) people died from CKD. The global all-age mortality rate from CKD increased 41·5% (95% UI 35·2 to 46·5) between 1990 and 2017, although there was no significant change in the age-standardised mortality rate (2·8%, −1·5 to 6·3). In 2017, 697·5 million (95% UI 649·2 to 752·0) cases of all-stage CKD were recorded, for a global prevalence of 9·1% (8·5 to 9·8). The global all-age prevalence of CKD increased 29·3% (95% UI 26·4 to 32·6) since 1990, whereas the age-standardised prevalence remained stable (1·2%, −1·1 to 3·5). CKD resulted in 35·8 million (95% UI 33·7 to 38·0) DALYs in 2017, with diabetic nephropathy accounting for almost a third of DALYs. Most of the burden of CKD was concentrated in the three lowest quintiles of Socio-demographic Index (SDI). In several regions, particularly Oceania, sub-Saharan Africa, and Latin America, the burden of CKD was much higher than expected for the level of development, whereas the disease burden in western, eastern, and central sub-Saharan Africa, east Asia, south Asia, central and eastern Europe, Australasia, and western Europe was lower than expected. 1·4 million (95% UI 1·2 to 1·6) cardiovascular disease-related deaths and 25·3 million (22·2 to 28·9) cardiovascular disease DALYs were attributable to impaired kidney function. Interpretation Kidney disease has a major effect on global health, both as a direct cause of global morbidity and mortality and as an important risk factor for cardiovascular disease. CKD is largely preventable and treatable and deserves greater attention in global health policy decision making, particularly in locations with low and middle SDI. Funding Bill & Melinda Gates Foundation.
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              Bias in meta-analysis detected by a simple, graphical test.

              Funnel plots (plots of effect estimates against sample size) may be useful to detect bias in meta-analyses that were later contradicted by large trials. We examined whether a simple test of asymmetry of funnel plots predicts discordance of results when meta-analyses are compared to large trials, and we assessed the prevalence of bias in published meta-analyses. Medline search to identify pairs consisting of a meta-analysis and a single large trial (concordance of results was assumed if effects were in the same direction and the meta-analytic estimate was within 30% of the trial); analysis of funnel plots from 37 meta-analyses identified from a hand search of four leading general medicine journals 1993-6 and 38 meta-analyses from the second 1996 issue of the Cochrane Database of Systematic Reviews. Degree of funnel plot asymmetry as measured by the intercept from regression of standard normal deviates against precision. In the eight pairs of meta-analysis and large trial that were identified (five from cardiovascular medicine, one from diabetic medicine, one from geriatric medicine, one from perinatal medicine) there were four concordant and four discordant pairs. In all cases discordance was due to meta-analyses showing larger effects. Funnel plot asymmetry was present in three out of four discordant pairs but in none of concordant pairs. In 14 (38%) journal meta-analyses and 5 (13%) Cochrane reviews, funnel plot asymmetry indicated that there was bias. A simple analysis of funnel plots provides a useful test for the likely presence of bias in meta-analyses, but as the capacity to detect bias will be limited when meta-analyses are based on a limited number of small trials the results from such analyses should be treated with considerable caution.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: Writing – original draftRole: Writing – review & editing
                Role: ConceptualizationRole: Funding acquisitionRole: Writing – original draftRole: Writing – review & editing
                Role: ConceptualizationRole: Data curationRole: MethodologyRole: Writing – original draftRole: Writing – review & editing
                Role: ConceptualizationRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: SupervisionRole: Writing – original draftRole: Writing – review & editing
                Role: ConceptualizationRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: Writing – original draftRole: Writing – review & editing
                Role: ConceptualizationRole: Funding acquisitionRole: Writing – original draftRole: Writing – review & editing
                Role: ConceptualizationRole: Formal analysisRole: Funding acquisitionRole: MethodologyRole: Writing – original draftRole: Writing – review & editing
                Role: ConceptualizationRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: Writing – original draftRole: Writing – review & editing
                Role: ConceptualizationRole: Funding acquisitionRole: Writing – original draftRole: Writing – review & editing
                Role: ConceptualizationRole: Formal analysisRole: MethodologyRole: Writing – original draftRole: Writing – review & editing
                Role: ConceptualizationRole: Funding acquisitionRole: Writing – original draftRole: Writing – review & editing
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: Project administrationRole: SupervisionRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Role: Academic Editor
                Journal
                PLoS Med
                PLoS Med
                plos
                PLoS Medicine
                Public Library of Science (San Francisco, CA USA )
                1549-1277
                1549-1676
                6 April 2022
                April 2022
                : 19
                : 4
                : e1003954
                Affiliations
                [1 ] Centre for Patient Reported Outcomes Research, Institute of Applied Health Research, University of Birmingham, Birmingham, United Kingdom
                [2 ] National Institute for Health Research Applied Research Collaboration West Midlands, Institute of Applied Health Research, University of Birmingham, Birmingham, United Kingdom
                [3 ] National Institute for Health Research Birmingham Biomedical Research Centre, University of Birmingham, Birmingham, United Kingdom
                [4 ] Department of Renal Medicine, Queen Elizabeth Hospital Birmingham, University Hospitals Birmingham, Birmingham, United Kingdom
                [5 ] National Institute for Health Research Surgical Reconstruction and Microbiology Research Centre, University of Birmingham, Birmingham, United Kingdom
                [6 ] Institute of Inflammation and Ageing, University of Birmingham, Birmingham, United Kingdom
                [7 ] Psychometric Laboratory for Health Sciences, University of Leeds, Leeds, United Kingdom
                [8 ] Department of Child and Family Welfare, Faculty of Behavioural and Social Sciences, University of Groningen, Groningen, The Netherlands
                [9 ] MD Anderson Center for INSPiRED Cancer Care, University of Texas, Houston, Texas, United States of America
                [10 ] Centre for Inflammation Research, University of Edinburgh, Edinburgh, United Kingdom
                [11 ] School of Allied Health and Community, University of Worcester, Worcester, United Kingdom
                Harvard Medical School, UNITED STATES
                Author notes

                I have read the journal’s policy and the authors of this manuscript have the following competing interests: MC is Director of the Birmingham Health Partners Centre for Regulatory Science and Innovation, Director of the Centre for the Centre for Patient Reported Outcomes Research and is a National Institute for Health Research (NIHR) Senior Investigator. MC receives funding from the National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre, the NIHR Surgical Reconstruction and Microbiology Research Centre and NIHR ARC West Midlands at the at the University of Birmingham and University Hospitals Birmingham NHS Foundation Trust NIHR/UKRI., Health Data Research UK, Innovate UK (part of UK Research and Innovation), Macmillan Cancer Support, UCB Pharma, Janssen, GSK and Gilead. MC has received personal fees from Astellas Aparito Ltd, CIS Oncology, Takeda, Merck, Daiichi Sankyo, Glaukos, GSK and the Patient-Centered Outcomes Research Institute (PCORI) outside the submitted work. OLA is supported by the NIHR Birmingham BRC, West Midlands, Birmingham; UKRI, Janssen, Gilead and GSK. He declares personal fees from Gilead Sciences Ltd, Merck and GSK outside the submitted work. DK reports grants from Macmillan Cancer Support, Innovate UK, the NIHR, NIHR Birmingham Biomedical Research Centre, and NIHR SRMRC at the University of Birmingham and University Hospitals Birmingham NHS Foundation Trust, and personal fees from Merck outside the submitted work.

                Author information
                https://orcid.org/0000-0003-3633-7716
                https://orcid.org/0000-0003-3681-8608
                https://orcid.org/0000-0001-9122-8251
                https://orcid.org/0000-0002-0614-3198
                https://orcid.org/0000-0002-1856-837X
                https://orcid.org/0000-0002-2529-0409
                https://orcid.org/0000-0002-4732-7305
                https://orcid.org/0000-0003-2827-7741
                https://orcid.org/0000-0003-4547-873X
                https://orcid.org/0000-0002-7679-6741
                Article
                PMEDICINE-D-21-01326
                10.1371/journal.pmed.1003954
                8985967
                35385471
                2df9ea08-5ed8-4eb0-9cb7-dc4b810b8f97
                © 2022 Fletcher et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 19 March 2021
                : 23 February 2022
                Page count
                Figures: 11, Tables: 3, Pages: 25
                Funding
                Funded by: Kidney Research UK
                Award ID: Stoneygate Research Award (KS_RP_20180914)
                Award Recipient :
                This review was funded as part of a study funded by Kidney Research UK (Stoneygate Research Award KS_RP_013_20180914; www.kidneyresearchuk.org). The grant was awarded to DK, and funded BF full time. The funders did not play any role in study design, data collection/analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Medicine and Health Sciences
                Nephrology
                Renal Diseases
                Chronic Kidney Disease
                Medicine and Health Sciences
                Nephrology
                Medical Dialysis
                Medicine and Health Sciences
                Surgical and Invasive Medical Procedures
                Transplantation
                Organ Transplantation
                Renal Transplantation
                Medicine and Health Sciences
                Surgical and Invasive Medical Procedures
                Urinary System Procedures
                Renal Transplantation
                Medicine and Health Sciences
                Health Care
                Quality of Life
                Medicine and Health Sciences
                Clinical Medicine
                Signs and Symptoms
                Fatigue
                Biology and Life Sciences
                Anatomy
                Renal System
                Kidneys
                Medicine and Health Sciences
                Anatomy
                Renal System
                Kidneys
                Medicine and Health Sciences
                Clinical Medicine
                Signs and Symptoms
                Pain
                Myalgia
                Research and Analysis Methods
                Mathematical and Statistical Techniques
                Statistical Methods
                Metaanalysis
                Physical Sciences
                Mathematics
                Statistics
                Statistical Methods
                Metaanalysis
                Custom metadata
                All relevant data are within the manuscript and its Supporting information files.

                Medicine
                Medicine

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