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Effects of Social Deprivation on the Proportion of Preemptive Kidney Transplantation: A Mediation Analysis

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Effects of Social Deprivation on the Proportion of Preemptive Kidney Transplantation: A Mediation Analysis
Eve Calvar, MBBS, 1,2,3 Ludivine Launay, MS, 4 Annabel Boyer, MD, 1,2,3 Guy Launoy, MD, PhD, 4 Thierry Lobbedez, MD, 1,2,3,5,4 and Valérie Châtelet, MD, PhD 1,2,3,4 I t is widely accepted that, compared with dialysis, renal transplantation is associated with a lower risk of mortality and a greater quality of life. 1 Large-scale studies have demonstrated that patients transplanted before beginning dialysis had a lower risk of death than subjects who were transplanted while on dialysis. 2,3 Furthermore, it has been shown that the time spent on dialysis before transplantation affects patient survival. 3 The beneficial effect of preemptive transplantation on renal allograft survival is more controversial. 4 Nevertheless, longer transplant survival was found when transplantation was performed from a living donor [5][6][7] and when living-donor transplantation was performed preemptively rather than after the initiation of dialysis. 7 Recent recommendations encourage preemptive living-donor kidney transplantation (LDKT). 8 On the other hand, it has been demonstrated that there are social inequalities in access to preemptive renal transplantation. [9][10][11] In France, it has been suggested that social deprivation could influence access to preemptive registration. 12 There is a lack of data regarding the underlying mechanism by which social deprivation affects preemptive renal transplantation. Decreased access to living-donor transplantation of the most deprived population may partially explain this social inequity. 9,10,13 The European Deprivation Index (EDI) is a composite index that measures social deprivation. It contains variables common, on the one hand, to the European Union Statistics on Income and Living survey that studied objective poverty and the concept of individual perception of needs called "subjective poverty" in 26 European countries 14 and, on the other hand, Background. Social inequalities in health lead to an increased risk of chronic kidney disease and less access to renal transplantation. The objective of this study was to assess the association between social deprivation estimated by the fifth quintile of the European Deprivation Index (EDI) and preemptive kidney transplantation (PKT) and to explore the potential mediators of this association. Methods. This retrospective observational multicenter study included 8701 patients who received their first renal transplant in France between 2010 and 2014. Mediation analyses were performed to assess the direct and indirect effects of the EDI on PKT. Results. Among the 8701 transplant recipients, 32.4% belonged to the most deprived quintile of the EDI (quintile 5) and 16% received a PKT (performed either with a deceased-or living-donor). There was a significant association between quintile 5 of the EDI and PKT (total effect: odds ratio [ to the census-based data of the National Institute for Statistics and Economic Studies. The 10 individual items that constitute the EDI are: foreign nationality, low level of education, unemployment, unskilled worker, no access to a car, no access to central or electric heating, single-parent family, household ≥ 6 people, overcrowded housing, and nonowner. As these variables are applied to the smallest French geographical area (Ilôts Regroupés pour l'Information Statistique [IRIS]), the EDI constitutes an ecological index of social deprivation. It allows comparisons between European countries where it has been validated. 14,15 Two studies from our team demonstrated that the EDI was associated with the outcomes of renal transplantation and with the proportion of living-donor transplantation. 16,17 To our knowledge, there are no data about the effects of social disparities in health, estimated by a European transnational indicator, and preemptive transplantation. Moreover, although 3 studies have evaluated the role of social disparities on access to transplantation using mediation analyses, [18][19][20] none have examined the mediators that could explain the association between social deprivation and preemptive renal transplantation.
The objective of our study was to assess the association between social deprivation, estimated by the most deprived quintile of the EDI, and preemptive renal transplantation. The objective was also to estimate the direct and indirect effects of social deprivation on the outcome. [21][22][23]

Study Population and Data Sources
This was a retrospective study, using the CRISTAL database of the French Biomedicine Agency (Agence de la Biomédecine, Saint-Denis, France) where the data of transplanted patients of 32 French transplantation centers were registered. The patients older than 18 y receiving a first deceased-or living-donor kidney ransplantation between January 1, 2010, and December 31, 2014, and for whom a precise home address in France was provided at registration for the waiting list (required for EDI calculation) were included in the study. Patients who had already been transplanted (renal, cardiac, or liver transplant) or who had received a multiorgan transplantation were excluded. Of the 9205 transplanted patients from the original dataset, home address was missing for 504 of them. There was no statistical difference regarding the patients' characteristics between individuals excluded because of missing address and the other patients. Ultimately, 8701 patients were included.

Event of Interest
The event of interest was preemptive renal transplantation, with either a deceased-or living-kidney donor, among the study population. Preemptive kidney transplantation (PKT) was defined as transplantation with no previous history of dialysis.

Social Deprivation
The explanatory variable was the EDI. The EDI is a validated European ecological index, for which there is a French version, 14 calculated for the smallest geographical scale available in France (IRIS) corresponding to about 2000 inhabitants. Each patient's home address corresponds to an IRIS for which the EDI has been measured and has been interpreted as a proxy of the individual social deprivation. The induced ecological bias of this proxy is considered to be limited because the accuracy of socioeconomic measures decreases with the size of the geographical unit used.
The EDI was categorized into 5 quintiles to describe the general population (quintile 5 being the most deprived), as recommended by Pornet et al 14 after studying its distribution. Subsequently, as was necessary for the mediation analyses, the EDI was dichotomized and used as a binary variable (quintile 5 versus other quintiles).
Of note, ethnicity could not be studied in our work since the collection of this variable is not authorized by the French law.

Patient Characteristics
Patient information provided at registration for the renal transplant waiting list is collected in the CRISTAL database of the Agence de la Biomédecine. The following variables were extracted: age, sex, body mass index (BMI), underlying nephropathy, diabetes, cardiovascular disease (coronaropathy, myocardial infarction, chronic heart failure, angiopathy, and stroke), tobacco use, hypertension, hepatitis C virus (HCV) serology, cytomegalovirus (CMV) serology, Epstein-Barr virus serology, positive HLA antibodies, blood group, preemptive registration, and preemptive transplantation.

Potential Confounders and Mediators
Our assumptions for potential confounders and mediators were defined based on the literature data (SDC, http://links. lww.com/TXD/A357) and their hypothetical relations with quintile 5 of the EDI and PKT are graphically represented in a directed acyclic graph (DAG) (Figure 1). 24 This study was conducted in the French regulation context regarding living donor transplantation. Patients awaiting renal transplantation, whatever the modality, must be registered on the waiting list for deceased-donor transplantation. That means that even patients due for living donor are registered on the waiting list pending the end of the transplantation work up of their living donor. Consequently, of the patients who have a living donor, there are individuals that accept a proposal for a deceased-donor transplant before the completion of the living-donor transplantation. "Registration with a living donor," which is on the pathway to preemptive transplantation, could have been considered as a marker of the access to LDKT, unfortunately this information is not collected in the registry. We hypothesized that the most deprived patients had a lower likelihood of preemptive transplantation that could be partly explained by a lower access to living donor. As the variable "registration with a living donor" was not available in the database, "LDKT" was used as a proxy and considered as a mediator of the effect of social deprivation on the rate of preemptive transplantation.

Statistical Analyses
For the univariate analysis, characteristics of the complete cohort were described according to the 5 quintiles of the EDI. Categorical data were described by frequencies and percentages.
Using a logistic regression model, 2 bivariate analyses were performed to estimate the association of each covariate with quintile 5 of the EDI and with PKT. Regression splines were used to explore the functional form of the continuous variables "age" and "BMI." As there was no linear relationship between these covariates and the logit event of interest, they were transformed into categorical variables.
Mediation analyses explore the underlying mechanism by which one exposure variable influences an outcome variable through a mediator variable. The relationship between the exposure variable, the outcome variable, potential confounders, and potential mediators are graphically represented by rows in a DAG ( Figure 1). In traditional regression modeling, when controlling for the mediator, the association between the exposure and outcome is reduced.
Based on the DAG, mediation analyses using a counterfactual approach were performed to assess the extent to which the effect of social deprivation on PKT was direct or mediated by other variables. [21][22][23] Confidence intervals (CIs) of the estimates were obtained using a nonparametric bootstrap procedure.
As there were 5 potential mediators, a mediation analysis with 1 mediator at a time was first performed. Subsequently, a sequential mediation analysis was conducted (model 1: single mediator "living-donor transplantation," model 2: model 1 + "positive CMV serology," model 3: model 2 + "HLA immunization," model 4: model 3 + "positive HCV serology," model 5: model 4 + "blood group B"). Mediators were entered based on the strength of their association with the outcome in the bivariate analysis.
All mediation analyses were adjusted for age, gender, diabetes, and underlying nephropathy. The "total effect" of the exposure on the outcome was decomposed into a "natural direct effect" (the effect of the exposure on the outcome) and into a "natural indirect effect" (the effect of the exposure on the outcome through a mediator). There were no exposuremediator or mediator-mediator interactions.
This study using data from the CRISTAL database was conducted with the approval of the French National Ethics Committee (Commission Nationale de l'Informatique et des Libertés).

Bivariate Analyses
Patient characteristics of age older than 60 y, female gender, diabetes, positive HCV serology, positive CMV serology, HLA immunization, blood group B, and the underlying nephropathy were associated with quintile 5 of the EDI ( Factors associated with preemptive transplantation were age older than 30 y, female gender, diabetes, cardiovascular disease, tobacco use, positive HCV serology, positive CMV serology, HLA immunization, blood group B, and underlying nephropathy ( Tables S2 and S3 (SDC. http://links.lww.com/TXD/A357), respectively, represent the comparison of factors between each quintile of the EDI and factors associated with preemptive registration.

Mediation Analyses
After adjustment for potential confounders, the mediation analysis showed a significant total effect (OR: 0.  The results of the sequential mediation analysis are provided in Table 5.

Additional Analyses
Additional mediation analyses focusing on preemptive registration as the outcome are presented in Tables S4 and S5 (SDC, http://links.lww.com/TXD/A357).
The results of the multivariable analysis stratified by donor type are presented in Table S6 (SDC, http://links.lww.com/ TXD/A357). In this analysis, quintile 5 of the EDI was associated with preemptive registration and preemptive transplantation in the deceased-donor kidney transplanted group but not in the living-donor kidney transplanted group. This could be explained by the fact that patients belonging to quintile 5 who received a living-donor transplant may have particular characteristics not measured in our study or may have a different treatment modality. However, the interaction term between EDI (exposure) and donor type (mediator) had no effect on PKT (outcome), which allowed us to conduct the mediation analysis reflecting the natural effect models.

DISCUSSION
Our study showed that in France, social deprivation estimated by the EDI was highly prevalent among transplanted patients and that it was associated with a lower proportion of preemptive renal transplantation directly but also indirectly through living-donor transplantation, which appeared to be the main mediator. Our findings were consistent with the results of previous studies, which highlighted social disparities  in access to preemptive transplantation [9][10][11][12] and confirmed that the EDI can be used in the nephrology field of social deprivation. 12,[16][17][18]25,26 The factors that may explain this association could depend on the healthcare system, the recipient, and the donor, as well as the physician. Disparities in access to primary care, necessary for referral to a nephrologist, may partially explain the lower proportion of preemptive transplantation in the most deprived patients compared with the other transplanted patients. It has been shown that individuals with a greater income received more prescription medication and more often visited medical specialists and underwent advanced imaging procedures. 27 In one study from the United States, routine healthcare visits were a mediator between socioeconomic status and chronic kidney disease (CKD). 28 In France, inequities in access to primary care have been recently described in the general population. 29 A faster decline in renal function in the most deprived population could also affect the timing of the nephrology referral. It has been demonstrated that low socioeconomic status was associated with a higher risk of chronic diseases 30 and with risk factors for CKD progression. 28 Lower socioeconomic status was associated with albuminuria, estimated glomerular filtration rate decline, and end-stage renal disease in previous reports. 31,32 In Europe, low education levels were associated with CKD progression. 33 In a report from the United Kingdom, socially deprived populations had a higher risk of severe CKD at presentation to a renal service. 34 Moreover, a French study showed that the most deprived patients had a higher risk of requiring emergency dialysis than the other patients, 26 whereas the emergency start was associated with a lower chance of being waitlisted in a recent study. 35 Lower socioeconomic and educational status resulted in delayed nephrology referral, 36 even though late referral is known to reduced transplantation access. 37 An association among health literacy, socioeconomic status, and CKD has been demonstrated. 38 Thus, the lack of understanding of what CKD is and what it involves is influenced by socioeconomic status and could also affect access to healthcare and referral to nephrology.
Moreover, there is a potential association between social deprivation and geographic isolation, which would suggest that distance to the transplantation center might delay registration on the waiting list; however, previous studies among dialysis patients have reported controversial results. 39,40 To the best of our knowledge, there are no data about the effect of the distance from patient home to transplantation center and preemptive registration. Socioeconomic status could impact the whole process of kidney transplantation from the potential recipient to the potential donor because of difficulty in navigating the health system. Navigator programs may help the most deprived subjects move through the complex pathway that leads to transplantation. 41 The cost associated with the transplantation workup may as well decrease access to preemptive registration on the waiting list. Disparities between private centers or for-profit ownership of dialysis facilities were described regarding access to the exams required for registration. 42 In a recent US study, disparities in patients' access to PKT were associated with the type of health insurance. 11 However, in Sweden, despite a universal healthcare coverage, low income was also associated with lower registration on the waiting list for renal transplantation. 43 The sequential mediation analysis we conducted has identified LDKT as being the main and above all modifiable   20 socioeconomic status was a mediator between ethnicity and access to registration and renal transplantation. To our knowledge, there is no mediation analysis that has evaluated LDKT as an outcome. Large-scale studies conducted in Australia, the United Kingdom, and the United States showed that socially deprived patients had lower access to LDKT. [9][10][11] Since socially deprived relatives are exposed to the same risk factors as deprived recipients, 28 the prevalence of chronic diseases among potential donors could reduce the possibility of organ donation in the most disadvantaged populations. Data about living donors in the United States showed that living donors were more frequently employed than the general population. 44 Gill et al 13 reported that the rate of LDKT was greater in the highest income population and that the least deprived living donors had greater access to medical specialists who performed the transplantation workup. It can also be speculated that difference in health literacy related to socioeconomic status, cultural, and religious factors may influence the willingness toward living organ donation. [45][46][47] To decrease ethnic disparities in access to living-donor transplantation, web programs for education on LDKT have been developed. 48 Finally, the socioeconomic status of patients may influence physicians' perception and practice. In support of this, a qualitative study conducted in Australia and New Zealand highlighted that nephrologists tended to consider that the most socially disadvantaged patients were less likely to receive a living-donor kidney. 49 In our mediation analyses, positive CMV serology, known to be associated with an increased risk of cardiovascular disease 50 ; hepatitis C, which is more prevalent in disadvantaged populations 51 ; and blood group B had an indirect effect on preemptive transplantation, but the magnitude of the effect was marginal compared with living-donor.
Our study has limitations. Residual confounders not collected in the database may affect the association between the EDI and preemptive transplantation. As an example, ethnicity has not been studied because the collection of this data is not authorized in France. The EDI potentially contains mediators of the relationship between social deprivation and PKT, such as foreign nationality, no access to a car, low level of education, unemployment, single-parent family, or household ≥6 people. 14 Last, the association between the EDI and preemptive transplantation was estimated among transplanted patients, whereas a study of patients registered for renal transplantation would have provided a more accurate estimation.
Our work demonstrated that social deprivation estimated by the EDI was associated with PKT. Our study emphasized that the effect of social deprivation on preemptive transplantation was mainly mediated by living-donor transplantation. This result is interesting since, unlike the other mediators highlighted in our study, living-donor transplantation is a modifiable factor. Further studies are needed to explore the role of social deprivation on LDKT. To increase preemptive renal transplantation in the most deprived populations, measures should be implemented to promote living-donor transplantation, targeting both practitioners and patients. Physicians should be able to promote health literacy and to provide information about living-donor transplantation tailored to the patients' health literacy. 52 Widespread use of web or mobile programs for shared decision aid in the treatment of CKD should be encouraged 48,53 to help inform socially deprived patients.