Humanistic burden and economic impact of chronic kidney

Chronic kidney disease (CKD) is increasing in prevalence Background: worldwide. Progression of CKD to end-stage renal disease (ESRD) can result in the requirement for renal replacement therapy, which incurs considerable healthcare costs and imposes restrictions on patients’ daily living. This systematic review was conducted to inform understanding of the humanistic and economic burden of CKD by collecting quality of life (QoL), symptom burden, and cost and resource use data, with a focus on the impact of disease progression. Embase, MEDLINE, the Cochrane Library, and conference Methods: proceedings were searched in May 2017 according to predefined inclusion criteria. Data were extracted for full publications reporting either QoL or symptom burden (published 2007–2017; reporting data from ≥ 100 patients) or costs and resource use (published 2012–2017). Relevant QoL studies were those that used the 6-dimension or 8-, 12-, or 36-item Short-Form Health Surveys, 5-dimension EuroQol questionnaire, Healthy Days/Health-Related Quality of Life questionnaire, or Kidney Disease Quality of Life Questionnaire. Data were extracted from 95 studies reporting QoL data, 47 Results: studies reporting cost and resource use data, and eight studies reporting descriptions of symptoms; 12 studies (seven QoL; five costs/resource use) reported data for patients with and without CKD, and 15 studies (seven QoL; eight costs/resource use) reported data by disease stage. Patients with CKD, including those with ESRD, had worse QoL than those with normal kidney function, and incurred higher healthcare costs. Disease progression was associated with cost increases, particularly for later stages and in patients receiving dialysis. Increasing CKD severity was also associated with reductions in QoL, although not all studies identified showed a consistent decrease with increasing disease stage. The presence of CKD and CKD progression are associated Conclusions: with reductions in patients’ QoL and increased economic impact. This may be mitigated by interventions that slow progression.


Introduction
Chronic kidney disease (CKD) is characterized by a gradual loss of kidney function over time. With an estimated global prevalence of 11-13%, CKD is a common condition that is associated with a significant economic burden across the world 1 . The prevalence of the disease is rising, owing in part to an increase in the median age of populations worldwide, and the growing number of individuals with diabetes mellitus (DM) or hypertension 1 . These conditions are the two main causes of CKD and are commonly present in patients with diminished renal function 2 . In the USA, for example, approximately 40% of people with CKD also have DM, and 32% of people with CKD have hypertension 3 .
When CKD progresses, patients may experience complications such as anaemia, cardiovascular disease (CVD), peripheral arterial disease, pruritus, and increased risk of infection. Both disease progression and its associated complications require medical treatment, which further impacts patients' quality of life (QoL) and contributes to the humanistic and economic burden of CKD 4,5 . Moreover, progression to end-stage renal disease (ESRD) has a significant effect on patients' daily lives and is often associated with considerable costs due to the common requirement for renal replacement therapy (RRT) via dialysis or kidney transplantation 1 . Therefore, slowing the rate of progression of CKD to advanced stages, in particular to ESRD, is an important medical objective 4 .
Many studies have investigated the humanistic and economic burden of CKD, although quantification of this remains challenging owing to differences between methodologies and patient populations across studies. To gain a better understanding of the current evidence, and evidence gaps, we conducted systematic reviews (SRs) to identify relevant evidence on the humanistic burden of CKD, defined here as the effect of CKD on patients' QoL, and the economic burden, comprising resource use and healthcare costs associated with CKD. In particular, we reviewed data on QoL and costs for patients with CKD compared with the general population, and across disease stages.

Systematic literature review
Two systematic searches, one on humanistic burden/QoL and one on economic burden, were performed in MEDLINE and MEDLINE In-Process, Embase, and the Cochrane Library via Ovid. Cutoff dates were January 2002 and May 2017 for the humanistic burden SR and January 2007 and May 2017 for the economic burden SR; the shorter review window for the economic burden SR was specified because economic data are considered to decrease in relevance more quickly than QoL data. As supplementary searches, congress abstracts published between 2015 and 2017 (or the most recent 2 years available) from relevant health economics and outcomes research and nephrology meetings were reviewed. The search strings used to identify evidence are listed in Extended data: Supplementary content 1 6 .
Citation screening and full text review Abstracts and titles identified were screened by an independent reviewer to determine whether they met the PICOS (patient, interventions, comparisons, outcomes, and study design) eligibility criteria (Table 1), in accordance with 2009 Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines 7 . All publications that met entry criteria for review were obtained as full articles and reassessed against the predefined inclusion criteria. Owing to the large number of citations meeting these criteria, a decision was taken to restrict the extraction of data from eligible studies. For both SRs, data were extracted only from full publications. This meant that, although congress abstract screening was performed, no data from congress abstracts were extracted. For the humanistic burden SR, study publication dates for data extraction were restricted to 2007-2017; for the economic burden SR, the relevant time period was restricted to 2012-2017. Furthermore, for the humanistic burden SR, data were not extracted if the study population included fewer than 100 patients with CKD or if the study did not use any of the following instruments: Focus of this review These SRs were conducted to collect information on the overall impact of CKD development and progression on patients' QoL or their healthcare costs. Therefore, we chose to focus this review on studies that compared QoL or costs for patients with CKD and individuals without CKD, or that compared by CKD severity, defined by either disease stage or estimated glomerular filtration rate (eGFR) category. Other studies identified in the SRs are grouped into key themes and listed separately to indicate the scope of the evidence identified in our searches.

Search results
In total, 5219 papers were identified in the initial searches, of which 1114 papers were removed as duplicates, and 4105 were included for screening by abstract and title. This screening identified 3539 papers that did not meet the inclusion criteria. In total, 444 papers were included for full paper review. Following full paper review, 284 references were identified for inclusion, plus 79 abstracts identified in supplementary searches. In total, data were extracted from 95 references reporting QoL data, 47 references reporting cost and resource use data, and eight references reporting descriptions of symptoms. A PRISMA flow diagram is shown in Figure 1. Details of the patient populations in the studies discussed in this review are given in Table 2. Figure 2 shows all studies identified in these SRs, grouped into key themes according to the data reported.  QoL by severity of CKD Several studies reporting QoL data stratified by CKD stage were identified, in addition to studies that examined the impact of demographic factors and comorbidities on the relationship between disease severity and QoL.
Overall, later stages of CKD were associated with worse QoL, but the trends for physical QoL were slightly different from those for mental QoL.  In several studies, the presence of comorbidities affected whether worsening CKD severity was linked to reductions in QoL. reported QoL in patients with pre-dialysis CKD (stage 3-4) or receiving dialysis, with or without anaemia 21 . Lower SF-12 and EQ-5D scores were reported by patients with CKD stage 4 than those with CKD stage 3, and the lowest scores were reported by patients receiving dialysis; however, no statistical analysis of the difference between stages was reported. This trend was present both in patients with anaemia and in those without anaemia (Figure 4)  A total of eight studies were identified on symptom burden in patients with CKD, of which two studies 105,106 discussed the symptoms experienced by patients with CKD stage 5 who were not receiving dialysis, and six studies 24,34,67,107-109 discussed symptom burden in patients receiving dialysis (Extended data: Supplementary content 3 104 ).

Costs for CKD or ESRD, compared with normal kidney function
The SR identified several studies that compared costs and resource use between individuals with CKD and those with normal kidney function. Some of the studies differentiated between patients with pre-dialysis CKD and those who required RRT, and the patients in several of the studies had additional comorbidities.
Across all studies, pre-dialysis CKD and ESRD requiring RRT were associated with significant increases in cost and resource use. Kim et al. found that patients with pre-dialysis CKD were significantly more likely to experience hip fracture-related hospitalization than patients with normal kidney function, and those receiving RRT were at higher risk than patients with predialysis CKD. Median hospital costs were significantly greater in patients with CKD than for the general population and were highest for patients requiring RRT. This trend was also observed in the length of hospital stay, although the absolute differences between groups were small ( Figure 5)   very similar results in a study examining hospitalization rates and length of stay for pulmonary embolism in patient populations with normal kidney function, with pre-dialysis CKD or receiving dialysis ( Figure 5) 112 . In a study of patients with hepatitis C, total healthcare costs were 2.9 times higher for those who had CKD, compared with those who had hepatitis C without CKD (USD 548 vs USD 1922; P < 0.001) 112 . Some patients with CKD in this study were defined as having ESRD; however, patients' dialysis or transplant status was not specified. In a fourth study, patients with bone metastases and impaired kidney function incurred 60% higher total healthcare costs than a control group of patients with bone metastases and normal kidney function (USD 142,267 vs USD 88,839; P < 0.001). These increased costs were driven by hospital admission, emergency department and outpatient visits, longer length of stay in hospital, and higher pharmacy costs 113 . An Australian study by Wyld et al. also showed that patients with any stage of pre-dialysis CKD incurred significantly higher costs than individuals with no CKD (Figure 6a

Costs by severity of CKD
In total, six studies reported costs for patient populations stratified by CKD stage. Across the evidence base, later-stage disease was associated with comparatively higher costs, both in studies including only patients with pre-dialysis CKD and in those in which some patients were receiving RRT.
Wyld et al. showed that costs increased significantly across predialysis CKD stages (Figure 6a) 114 . Patients with CKD stage 3 incurred approximately 28% higher direct annual healthcare costs than those with CKD stage 1-2; however, there was a much larger cost increase for CKD stage 4-5, with patients in this group incurring more than fourfold higher costs than patients with CKD stage 3. This cost increase was apparent in subgroups of patients both with and without DM, suggesting that the high costs associated with CKD stage 4 and 5 were not attributable solely to the presence of DM. However, only 18 patients in this study had CKD stage 4-5, meaning that the results may have been skewed by a small number of individuals who incurred exceptionally high healthcare expenditure.
Two studies examined the costs of CKD across stages 4-5 or 3-5. An Italian study by Turchetti et al. of patients with predialysis CKD showed a 31% increase in the direct annual medical costs associated with CKD stage 5, compared with CKD stage 4 (P < 0.01; Figure 6b) 115 . DM and CVD were shown to have an impact on costs incurred by patients at either CKD stage. Smith et al., who conducted a study in the USA, found that patients with CKD stage 3a who had comorbidities and patients with CKD stage 3b incurred similar monthly costs associated with health insurance claims (Figure 6c) 116 . Those with CKD stage 4-5, however, incurred more than double these costs (P < 0.05). Patients' dialysis status was not specified in the study publication, but a breakdown of costs was reported. Later-stage CKD was associated with higher inpatient, outpatient, and professional services costs than CKD stage 3a or 3b, whereas the highest prescription costs were incurred by patients with CKD stage 3b.
Several studies examining costs by CKD stage included patients who had progressed to RRT and therefore incurred additional costs 117,118 . Two studies were conducted in patient populations  with CKD and DM in the USA. McQueen et al. found an increase in annual costs for each successive CKD stage, with the exception of CKD stage 2, which was associated with slightly lower costs than CKD stage 1. As in other studies, the largest increase was between the later disease stages, with a 71% increase in costs for stage 5 compared with stage 4 (Figure 7a) 117 . A similar cost increase was reported by Vupputuri et al. who compared costs between patients whose disease progressed and those who remained stable. Individuals who progressed to RRT incurred 77% higher annual medical costs than patients who remained at CKD stage 4 (Figure 7b) 118 . In a third study, Ariyaratne et al. examined the impact of CKD stage on patients undergoing percutaneous coronary intervention (PCI) in Australia. Direct cardiovascular costs, assessed 1 year after PCI, did not increase significantly for CKD stage 3 from stage 1-2 (AUD 4851 vs AUD 4442; 9% increase; P = 0.052), whereas patients with CKD stage 4-5, some of whom were receiving dialysis, incurred significantly higher costs than those at stage 1-2 (AUD 6958; 57% increase; P < 0.001) 119 .
Costs for pre-dialysis CKD compared with RRT Two studies were identified that compared costs for patients with pre-dialysis CKD with those for patients receiving dialysis (Extended data: Supplementary content 4) 120-122 . 4% of patients at CKD stage 4 had a procedure code for dialysis during the baseline period. b 70.3% of patients at CKD stage 5 had a procedure code for dialysis during the baseline period. c ESRD was defined as a requirement for dialysis or renal transplant, and was considered to be equivalent to CKD stage 5 in this study. CKD, chronic kidney disease. ESRD, end-stage renal disease. NS, nonsignificant. T2DM, type 2 diabetes mellitus. USD, US dollars.
Eriksson et al. compared costs and resource use in Sweden between four treatment groups: patients with pre-dialysis CKD (stage 4-5), those receiving haemodialysis, those receiving peritoneal dialysis, and patients with renal transplant. Patients with pre-dialysis CKD incurred the lowest total costs and had the lowest rate of outpatient visits of any treatment group, but had a slightly higher hospitalization rate and a greater mean number of hospital days annually than those who had received a renal transplant 121 . Both types of dialysis incurred higher inpatient and outpatient costs than pre-dialysis CKD or renal transplant, with more than 70% of the costs associated with haemodialysis contributed by outpatient care. All types of RRT were associated with additional expenditure on drugs, compared with pre-dialysis CKD. In addition, a study by Escudero-Vilaplana et al. showed that among patients receiving erythropoietin-stimulating agents (ESAs), the monthly cost of ESA therapy was significantly higher for patients receiving peritoneal dialysis than for those with pre-dialysis CKD (stage 2-5) 122 .

Discussion
The studies identified in these SRs clearly illustrate the humanistic and economic impact of CKD. Patients with pre-dialysis CKD as well as patients who require RRT are likely to have worse QoL than the general population, and also incur higher healthcare costs. Several studies indicated that increasing CKD severity is associated with a gradual reduction in physical QoL; however, evidence for the impact of CKD on mental QoL was inconsistent. The economic burden SR identified strong evidence that costs and resource use are higher for patients with CKD than for the general population. Costs are especially high for patients at the most severe stage of CKD, for whom dialysis is often required. In patients with pre-dialysis CKD, costs increase incrementally with disease severity, particularly when comparing CKD stages 4-5 with stages 2-3. These findings underline the importance of early intervention in CKD to prevent patients from progressing to late-stage CKD and dialysis.
Several studies identified in these SRs report data concerning the impact of comorbidities on QoL or costs. It is likely that some of the humanistic and economic burden associated with CKD, particularly later-stage disease, is linked to comorbidities. Patients with CKD may be more likely to have comorbidities than the general population; furthermore, CKD is itself a risk factor for several complications and comorbidities, which contribute to the effect that the disease has on long-term outcomes. By examining subgroups of patients with particular comorbidities, as in the study by Wyld et al., it is possible to gain an understanding of the relative contribution of various comorbidities to overall disease burden. However, in order to study the burden of CKD specifically, analyses should be adjusted only for comorbidities that are unrelated to or are risk factors for CKD, but not comorbidities that are usually consequences of CKD. Exact differentiation between these types of comorbidities is not always possible, which can confound attempts to determine the true burden of CKD as distinct from co-existing conditions.
In this review, the impact of disease severity has been inferred almost exclusively from cross-sectional data; only one longitudinal study was identified. The economic study by Vupputuri et al. examined the impact and long-term consequences of increasing CKD severity in a patient cohort over time by comparing patients who remained at the same CKD stage and those whose disease progressed; however, the remaining economic studies and all QoL studies were cross-sectional. A longitudinal cohort study of patients with early-stage CKD could provide additional insights into the within-patient effects of CKD progression, the development of comorbidities and complications, and the competing risk of death, helping to quantify the extent to which this results in over-representation of relatively young patients or patients with few comorbidities in the later CKD stages, due to their better overall survival.
Moreover, definitions of CKD stage and grouping of patients into categories were not consistent across the evidence base, and in some cases eGFR category was used as a measure for disease severity but did not correspond exactly to the CKD stages used in other studies. Patients' dialysis status differed between studies, as did the definition of ESRD, which was defined as the requirement for dialysis only in some studies and was expanded to include renal transplant in others. Similarly, CKD stage 5 was considered a pre-dialysis disease stage in some studies, but in others was analogous to RRT. For QoL, the use of different instruments across studies also contributed to the difficulty in drawing comparisons between different data sets. Therefore, it was not possible to strengthen our findings by performing a meta-analysis using the data identified.
These SRs identified a broad range of studies reporting QoL or cost and resource use data for patients with CKD, including the impact of treatment modality and the effect of comorbidities. In the majority of studies, however, the scope of the data reported was relatively limited or comparisons were made between two groups of patients with CKD, differentiated by other factors, such as sociodemographic characteristics or treatment; these studies were outside the scope of this review. Owing to the design of the SRs, in which restrictions were applied to publication type, population size, and QoL instrument, it is also possible that some studies of interest may not have been examined in detail. Furthermore, no assessment of risk of bias was performed.

Conclusions
Our findings indicate that the development and progression of CKD are associated with both a reduction in patients' QoL and an increase in healthcare costs. Interventions and initiatives to prevent CKD progression, especially to later stages of disease and the requirement for dialysis, could improve patients' wellbeing and may limit the growing economic burden of CKD. We have also identified the need for further research, particularly longitudinal studies, as well as studies that collect full information on patients' disease history, treatment status, and comorbidities, and adjust for these factors when necessary. Such studies will be vital to quantify the impact of slowing CKD progression on the disease's humanistic and economic burden.

Data availability
Underlying data All data underlying the results are available as part of the article and no additional source data are required. Freeman started an ambitious project by reporting meta-analyses on both the quality of life (QoL) et al. and the cost of treatment of patients with chronic kidney disease (CKD) The overall conclusion confirms existing knowledge that progressing CKD is associated with a reduction in QoL and increasing costs.

I have several concerns:
To describe and analyse the QoL over all stages of kidney disease is a major undertaking. So is meta-analyzing the costs. The authors do not clearly describe why they decided to perform two meta-analyses and report it in one manuscript. In their manuscript, the authors in essence describe two meta-analyses. In clinical practice, and in governing healthcare, it is important to know the effects of a disease and its treatment on both QoL and costs. I miss a clear rationale for why both topics are presented combined in this manuscript. The manuscript reads like a manuscript on QoL and a second on costs. The authors do not make a clear connection between the two. I would invite the authors to better connect the two topics or consider writing two separate manuscripts, one focusing on QoL and one focusing on costs.
The cut off date used for both analyses was May 2017. Both QoL of kidney patients and costs of kidney care are topics of major interest in recent years. Many studies have been published since. For a manuscript to be published in 2020, an update of the search is essential The literature was screened by a single independent reviewer. Reviewing by two reviewers is the accepted norm in meta-analyses.
The authors do not provide a table stating the risks of bias in the studies analyzed (Prisma checklist item 12) In table 2 the authors provide an overview of the literature reported in both meta-analyses. In the first column the text is rotated 90 degrees, making this column illegible (on my laptop). In the current lay-out I can not read which studies are reviewed! 1 2 5. 6. 1.
current lay-out I can not read which studies are reviewed! It is difficult to summarize studies with different ways of staging CKD, using different measurement tools. The authors mainly describe the results of individual studies, both in the figures and in the text of the manuscript. Prisma guidelines suggest providing a summary and a synthesis of results (Prisma items 13,14). Not all studies selected use the standard KDIGO staging of CKD and not all use the same measures of QoL and costs. I would suggest a synthesis of results from those studies that do use the standard KDIGO classification of CKD and do use the same measures of QoL and costs.