Quality of life of patients with kidney failure in sub-Saharan Africa: protocol for a systematic review of quantitative studies

pop-ABSTRACT Introduction: The burden of chronic kidney disease (CKD) is rising in sub-Saharan Africa. Access to kidney replacement therapy (KRT) remains limited and modelling suggests a significant hidden burden of kidney failure managed without KRT. Kidney failure is contributing to serious health-related suffering (SHS) at a global level. Despite this, access to palliative care remains extremely disparate. There is an urgent need for greater palliative care provision for patients with kidney failure in sub-Saharan Africa. To inform this, it is important to understand their current quality of life. This article outlines our review protocol, ensuring transparency of our planned methods and reporting. Methods and analysis: A comprehensive search will be conducted of MEDLINE (Ovid), EMBASE, CINAHL, African Index Medicus and Africa Journals Online. ProQuest Dissertations & Theses Global will be searched for grey literature. Eligible sources will be quantitative observational studies, conducted in sub-Saharan Africa, and published in English or French. The primary outcome measure will be quality of life of those with kidney failure, measured using a validated quality of life tool. Abstract screening, data extraction and risk of bias assessments will be conducted independently by two reviewers. Meta-analysis will be performed on study subgroups, if appropriate, based on heterogeneity of included studies; otherwise results will be summarised narratively. This protocol is structured according to the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P) guidance. Ethics and dissemination: Ethical approval is not required because this review will synthesise published data. Findings will be disseminated in a peer-reviewed journal.


INTRODUCTION
Non-communicable diseases (NCDs), including chronic kidney disease (CKD), are a growing public health problem worldwide, particularly in low-and middle-income countries (LMICs) [1].Although more high-quality data are needed, the burden of CKD and kidney failure in sub-Saharan Africa is thought to be at least as great as in other LMICs and is expected to rise significantly [2][3][4][5][6], in line with the growing prevalence of other NCDs including hypertension and diabetes [7][8][9][10].
ulations, including those with hypertension, diabetes and HIV [6].Precise estimates are hampered by significant heterogeneity among studies, including differences in reporting and methods of calculating estimated glomerular filtration rate (eGFR) [3,5,6].
Patients living with advanced CKD are at risk of developing kidney failure during their lifetime, yet data on the prevalence of kidney failure in sub-Saharan Africa are particularly scarce, largely owing to a lack of renal registries in most African countries [11,12].Estimates generated from modelling suggest a significant hidden burden of kidney failure in Africa, with only 9-16% of patients in need of kidney replacement therapy (KRT) able to access it [12][13][14].For this reason, hundreds of thousands of people with kidney failure in Africa die every year without access to KRT [13].Even for those who do start KRT, resource limitations affect the ability to provide optimal KRT on a long-term basis and discontinuation rates are high, with only 10% of adult incident dialysis patients continuing treatment beyond 3 months [14].
Patients with kidney failure in sub-Saharan Africa are therefore suffering even in settings where facilities for diagnosis and KRT are available.Indeed, kidney failure has been recognised as one of 21 conditions contributing to serious health-related suffering (SHS) at a global level [15][16][17].However, global access to basic palliative care remains extremely disparate with 80% of the patients who experience SHS each year residing in LMICs [17].Across sub-Saharan Africa, there have been significant and welcome advances in palliative care provision since 2004 [18], particularly in the context of HIV and cancer care, but distribution of palliative care services remains uneven, limited to relatively few countries, and big challenges remain in key areas including availability of essential medications [18].There is therefore a continuing urgent need for greater provision of palliative care for patients suffering from kidney failure in sub-Saharan Africa [17].
In order to inform the development of these services, it is important to understand more about the quality of life (QoL) of patients currently living with kidney failure in sub-Saharan Africa, including those both with and without access to KRT.The term "quality of life" is a broad one used variably in the literature [19], but is defined by the World Health Organisation as "an individual's perception of their position in life in the context of the culture and value systems in which they live and in relation to their goals, expectations, standards and concerns" [20].The term "health-related quality of life" (HRQoL) is also loosely defined, but can broadly be thought of as an individual's subjective experience of physical and mental health over time in relation to their overall functional and socioeconomic status [21].
A wide array of tools exists for measuring quality of life in population-based studies; these can generally be divided into generic and disease-specific assessment tools.The most commonly used generic quality of life assessment tool is the Medical Outcomes Study 36-Item Short Form (SF-36) [22,23].Other frequently employed generic tools include the 12-Item Short Form Health Survey (SF-12) and the EuroQol (EQ-5D) [24,25].
Recommended disease-specific quality of life tools for patients with kidney failure include, though are not limited to, the KDQOL, the KDQOL-Short Form (KDQOL-SF), the Kidney Disease Quality of Life-36 (KDQOL-36) and the End Stage Renal Disease-Symptom Checklist Transplantation Module (ESRD-SCLTM) [27][28][29][30].The KDQOL-SF was designed and validated for use in dialysis patients [26,27].KDQOL-36 was originally validated in dialysis patients but subsequent evidence has emerged to support its use in pre-dialysis CKD patients [26,28].The ESRD-SCLTM is recommended for assessment of quality of life in kidney transplant recipients [26,29].
A large number of systematic reviews have been conducted that explore the quality of life of patients living with kidney failure globally; 21 of these have been published since 2010 and are summarised in Supplementary Table S1 .Almost all of the studies included in these systematic reviews were conducted in high-and upper-middle-income countries.Among these 21 reviews, the only primary studies conducted in sub-Saharan Africa included two from South Africa.One of these (Okpechi IG et al., 2013) [52] features in four systematic reviews [39,41,47,50] and the other, more recent study (Tannor EK et al., 2017) [53] features in only one [50].It is therefore unclear how applicable the findings of these reviews are to patients suffering with kidney failure in sub-Saharan Africa.Studies from other sub-Saharan African countries may have been missed in these systematic reviews due to limitations introduced by inclusion criteria, including specific search terms, language and range of publication dates.To date, no systematic review has been conducted that specifically explores the quality of life of patients living with kidney failure in sub-Saharan Africa.

OBJECTIVES
The objective of this systematic review is to evaluate available quantitative evidence regarding the quality of life of patients living with kidney failure in sub-Saharan Africa.
HrQOL and kidney failure in sub-Saharan Africa: review protocol In this review, kidney failure will be defined as follows: • CKD G5 * treated without KRT, including treatment with or without conservative care.
• Receipt of a kidney transplant.
These definitions are adapted for pragmatic purposes from the clinical trial definitions that were agreed at the recent International Society of Nephrology (ISN) consensus meeting, and from the KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease [54,55].

ELIGIBILITY CRITERIA
Studies will be eligible for inclusion in the review if they meet the following criteria.

Study design
Eligible study designs will include cross-sectional studies, case-control studies, retrospective and prospective cohort studies, other observational studies and mixed-methods studies.For mixed-methods studies, only quantitative data will be extracted and analysed.Systematic reviews and meta-analyses will be included during screening in order to scan the reference lists for any eligible primary studies of the previously specified designs that may have been missed by the search strategy.However, data will not be extracted from systematic reviews or meta-analyses as this could lead to duplication of data from primary studies.Qualitative studies, interventional studies, case series and case reports will be excluded.
Studies included must evaluate quality of life using a generic or disease-specific quality of life tool validated in at least one language and healthcare setting.Studies will be excluded if they do not specify the quality of life assessment tool used.

Participants
Eligible studies will include adults and/or children with kidney failure, as defined by any of the following: • CKD G5, not on KRT (either "pre-dialysis" or kidney failure being managed without KRT).
• Receipt of a kidney transplant.
Studies involving patients with acute kidney injury (AKI) will be excluded, unless they include patients with both CKD G5 and AKI and report quality of life separately for each group.
* For the purposes of this review, a single session of dialysis will be adequate to meet these definitions.

Intervention/Comparison
This systematic review will not include interventional studies.Patients with kidney failure in the studies referenced may be receiving no KRT, or KRT in the form of haemodialysis, peritoneal dialysis or transplant.Studies may include participants in one or more of these treatment modality groups, but will be included only if they report quality of life outcomes separately for each group.We will aim to determine the quality of life separately for patients with kidney failure in each treatment modality group.

Outcomes
The primary outcomes of interest will be the quality of life indicators described in the studies included using their specified, validated quality of life instruments.Studies referenced may use any validated generic or disease-specific quality of life tool.
For example, the 8 dimensions of the SF-36 are as follows [23]: • Limitation of physical activity due to health problems.
• Limitation of social activity due to either physical or emotional health problems.
• Limitation of usual activities due to physical health problems.
• Limitation of usual role activities due to emotional problems.
• General mental health and psychological well-being.
• General health perceptions.
Scores from these dimensions are grouped to form two summary scales, the physical component summary (PCS) and the mental component summary (MCS) [23].
The disease-specific tool KDQOL-SF combines these 8 generic quality of life dimensions from the SF-36 with 11 disease-specific dimensions [27]: • Symptoms/problems • Impact of kidney disease on everyday life Studies will be excluded if they do not use a tool validated in at least one language in one health setting, or if they do not specifiy the tool used.
No secondary outcomes will be assessed.

Setting
Only studies carried out in sub-Saharan Africa will be included.To maximise inclusivity, for the purposes of this review, countries of sub-Saharan Africa will be defined as broadly as possible according to the MEDLINE MeSH term "sub-Saharan Africa" -which includes both Mauritania and Sudan -with additional inclusion of the island states of Comoros, Mauritius and Seychelles (which are included in classifications outlined by the United Nations and by the African Union) [57,58].
Patients may be receiving their treatment in primary, secondary or tertiary care.

Timeframe and publication status
Both published studies and grey literature will be included, dating from 1995 (after adoption of validated QoL tools) to the present day.

Language
Included studies will be limited to those written in English or French.

INFORMATION SOURCES
The following databases will be searched to identify eligible studies from 1 January 1995 to the present: MEDLINE (Ovid), EMBASE, CINAHL, African Index Medicus and Africa Journals Online.ProQuest Dissertations & Theses Global will be searched to identify eligible grey literature.Grey literature to be considered will include unpublished studies, dissertations, theses and conference abstracts.We will also manually scan the reference lists of included studies to identify any additional studies meeting the inclusion criteria.

SEARCH STRATEGY
The specific literature search strategy was developed using a combination of medical subject headings (MeSH -for MEDLINE), Emtree terms (for EMBASE) and text words with the assistance of an experienced health sciences librarian.
The search strategy for Ovid MEDLINE and Emtree is included as Supplementary Table S2.
The search strategy framework includes search terms relating to kidney failure, geographical location and quality of life.
The search will be re-run if more than 24 months have elapsed between the initial search and submission for publication.

Data management
Citations and abstracts for the studies identified via the literature search will be uploaded to Rayyan [59], an online systematic review software management program.Articles written in French will be translated by seeking voluntary assistance through the Cochrane TaskExchange platform [60], or if this is unsuccessful, via Google Translate [61].
Duplicate reports of the same study will be removed.Full texts will be uploaded for studies that meet the inclusion criteria following abstract screening and for those for which there is uncertainty regarding eligibility.

Selection process
Two authors (CMS and CCS) will independently screen titles and abstracts identified by the search against the prespecified inclusion and exclusion criteria using the abstract screening tool (see Supplementary Table S3).
Articles will be included if they: a) Involve adults and/or children with kidney failure.b) Are conducted in sub-Saharan Africa as defined for this review.c) Are written in English or French.d) Evaluate quality of life using a specified quality of life tool validated in at least one language/healthcare setting.e) Report quality of life separately for patients in receipt of different treatment modalities, that is, CKD G5 not in receipt of KRT, or in receipt of haemodialysis, peritoneal dialysis or kidney transplant.f) Are conducted using one of the pre-specified study methodologies.
The abstract screening tool will first be piloted on 10 abstracts as a training and calibration exercise [60].Amendments to the screening tool will be avoided where possible but if necessary these will be documented and the study protocol amended.
Abstracts that clearly fail to meet the inclusion criteria using the screening tool will be removed, as will duplicate reports.
Full texts will be obtained for all studies that clearly meet the inclusion criteria using the screening tool or for which there is uncertainty regarding inclusion.In the event that there are multiple (but not identical) reports of the same study, these will be linked together.Two authors (CMS and CCS) will then independently screen the full text reports to determine if they meet the inclusion criteria.Any uncertainty or disagreement will be resolved via discussion, and if still unresolved, through involvement of a third author (EE).
Reasons will be recorded for all excluded studies.
Reference lists from the included full texts will also be screened to identify additional studies meeting the inclusion criteria that may not have been identified through the literature search.
Studies that are ongoing, incomplete or unobtainable will be tagged and listed separately.

Data collection process
A specifically tailored data extraction tool will used to facilitate data extraction from the included studies (see Supplementary Table S4).Two reviewers (CMS and CCS) will independently extract data from each eligible study.
To ensure consistency, a calibration exercise will be carried out before starting the data extraction process.Extracted data will be compared and any discrepancies will be resolved by discussion.In the event of unresolved disagreement, a third reviewer (EE) will adjudicate.Where uncertainty remains, study authors will be contacted by email to provide clarification, up to a maximum of two attempts.

Data Items
Data extracted will include: • Data for each quality of life domain will be extracted separately for patients with CKD G5 not on KRT, those receiving HD, those receiving PD and those with a kidney transplant.In the event of missing information, the reviewers will attempt to contact the authors of the included studies by email to obtain this, up to a maximum of two attempts.

OUTCOMES AND PRIORITISATION
The primary outcomes will be the quality of life indicators assessed in the studies included.
Where studies use the same quality of life assessment tools, it may be possible to consider results from different studies together by grouping the results of assessments for the same quality of life domains.
All domains will be given equal consideration.Specific quality of life domains have been discussed previously.

RISK OF BIAS IN INDIVIDUAL STUDIES
Two reviewers (CMS and CCS) will independently appraise the quality of the included studies, including risk of bias, using the Joanna Briggs Institute (JBI) critical appraisal tools.These toolkits include separate checklists for prevalence studies, analytical cross-sectional studies, case-control studies and cohort studies [62][63][64].The AXIS tool for critical appraisal of cross-sectional studies will also be used [62,65,66] Using these appraisal tools, each reviewer will independently assess the risk of bias in each study and come to an overall judgement as to whether it is of sufficient methodological quality to merit inclusion, or whether further information is needed.The assessments of the two reviewers will be compared and any disagreement will be resolved via discussion and, if required, involvement of a third reviewer (EE).The results of the risk of bias assessment will be included in the "summary of findings" table.

DATA SYNTHESIS
Studies will be divided into subgroups according to patient treatment modality (HD, PD, transplant or CKD G5 without KRT).Clinical and methodological heterogeneity of the included studies in each subgroup will be assessed by considering the populations, treatment nature, range of quality of life instruments used, trial designs and risk of bias.Within each subgroup, if the studies are considered too dissimilar then meta-analysis will not be attempted.
Instead, a narrative synthesis will be performed.Summary tables and text will be used to describe the characteristics of the included studies and explain their findings.
In the event that studies appear homogeneous enough for meta-analysis -for example, a number of studies using the same quality of life instrument in patients receiving the same treatment modality -then suitable studies will be compared in a meta-analysis.This will be carried out using a random effects model to allow for residual heterogeneity.The I2 statistic will be used to assess statistical heterogeneity [67].If substantial statistical heterogeneity is demonstrated (I2 > 50%), then a sensitivity analysis will be performed.

META-BIAS(ES)
To assess for outcome reporting bias, outcomes reported in the results section of each publishe study of each published study will be compared to those described in the study protocol, if this is available [68,69].If a study protocol is not available, reported results will be compared to the intended outcomes described in the methods section [69].
In the event of partial or missing outcome data, study authors will be contacted with up to two attempts by email.The risk of bias associated with any persistent incomplete or missing results will be assessed using the Outcome Reporting Bias in Trials (ORBIT) classification system [70,71], the results of which will be recorded in the "summary of findings" table.If outcome reporting bias is suspected, this will be taken into account when considering the overall quality of evidence using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach.
In the event that a meta-analysis is carried out containing 10 or more studies, funnel plots with tests for funnel plot asymmetry will be used to assess for reporting bias including publication bias and small-study effects, amongst other causes of heterogenicity [72].

CONFIDENCE IN CUMULATIVE EVIDENCE
The quality of evidence will be assessed using the GRADE approach.This will allow evaluation of the quality of the body of evidence across five domains: risk of bias, consistency, precision, directness, and probability of publication bias [73].

DISCUSSION
As far as we are aware, this will be the first systematic review to examine quality of life in people living with kidney failure in sub-Saharan Africa.Multiple systematic reviews exist that look at quality of life in the context of kidney failure in other, largely high-and upper-middle-income countries , but their findings are unlikely to be representative of patients living in sub-Saharan Africa due to the very small number of African studies included in these other reviews.Our systematic review will address an important issue because the prevalence of CKD and, by extrapolation, kidney failure, in Africa is growing, at a time when access to both KRT and palliative care on the continent remains limited [12][13][14][15][16][17][18].As a result, there is thought to be a significant burden of kidney failure managed without KRT in Africa, leading to excess SHS [17].In addition, in recent years there has been increasing recognition within the global nephrology community that in order to improve quality of kidney care a greater focus is needed on patientcentred outcomes including attention to symptom burden, quality of life and patient experience [74][75][76].
In order to guide development of palliative and supportive care services for patients with kidney failure in sub-Saharan Africa, it is important to understand more about the current need.This systematic review aims to contribute to this by synthesising available evidence on quality of life.
The anticipated strengths of this review include its broad search strategy and inclusive eligibility criteria, with inclusion of studies conducted in both English and French, and those involving both adults and children.The kidney failure definitions used have also been adapted to be as inclusive as possible.Potential limitations of this review may include the fact that it will be limited to observational quantitative studies, excluding qualitative and interventional studies, due to difficulty combining these different study types in a single systematic review.There may be scope for a later systematic review of qualitative studies focusing on this research question.
If the studies referenced demonstrate significantly heterogeneous populations, study designs and settings then this may also be a limitation, due to the challenge this would pose to undertaking a meta-analysis.
By publishing our results in a peer-reviewed journal the evidence generated will have an opportunity to influence patient care and health policy.2) Malaysia ( 2) Greece ( 2) Turkey ( 1) Chile ( 1) China ( 1)

•
Demographic data of included participants • Number of participants in each treatment modality group • Duration of treatment if receiving KRT • The type of quality of life assessment tool used • The results of quality of life assessments, by dimension and overall • The authors' conclusions

Table 1 .
Summary of systematic reviews of quantitative studies published since 2010 describing the quality of life of patients living with kidney failure.
Summary of systematic reviews of quantitative studies published since 2010 describing the quality of life of patients living with kidney failure.

Table 2 .
Supplementary Table 1 continued.Summary of systematic reviews of quantitative studies published since 2010 describing the quality of life of patients living with kidney failure.HrQOL and kidney failure in sub-Saharan Africa: review protocol Search strategy for Ovid MEDLINE and Emtree.OR 81 OR 82 OR 83 OR 84 OR 85 OR 86 OR 87 OR 88 OR 89 OR 90 OR 91 OR 92 OR 93 OR 94 OR 95 OR 96 OR 97 OR 98 OR 99 OR 100 OR 101 OR 102 OR 103 OR 104 OR 105 OR 106 OR 107 OR 108 OR 109 OR 110 OR 111 OR 112 OR 113 OR 114 OR 115 OR 116 OR 117 OR 118 OR 119 OR 120 OR 121 OR 122 OR 123 OR 124 OR 125 OR 126 OR 127 OR 128 OR 129 OR 130 OR 131 OR 132 OR 133 OR 134 OR 135 OR 136 OR 137 OR 138 OR 139 OR 140 OR 141 OR 142 OR 143 OR 144 OR 145 OR 146 OR 147 OR 148 OR 149 OR 150 OR 151 OR 152 OR 153 OR 154 OR 155 OR 156 OR 157 OR 158 OR 159 OR 160 OR 161 OR 162 OR 163 OR 164 OR 165 OR 166 OR 167 OR 168 OR 169 OR 170 OR 171 OR 172 OR 173 OR 174 OR 175 OR 176 OR 177 OR 178 OR 179 OR 180 OR 181 OR 182 OR 183 OR 184 OR 185 OR 186 OR 187 OR 188 OR 189 OR 190 OR 191 OR 192 OR 193 OR 194 OR 195 OR 196 OR 197 HrQOL and kidney failure in sub-Saharan Africa: review protocol Supplementary Table 2 continued.Search strategy for Ovid MEDLINE and Emtree.