Efficacy of Psychoeducational Intervention on Allograft Function in Kidney Transplant Patients: 10-Year Results of a Prospective Randomized Study

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1 ARTICLe Efficacy of Psychoeducational Intervention on Allograft Function in Kidney Transplant Patients: 10-Year Results of a Prospective Randomized Study Nathalie Breu-Dejean, 1 Damien Driot, 2,3 Julie Dupouy, 2,3 Maryse Lapeyre-Mestre, 3 Lionel Rostaing 1,4,5 Abstract Objectives: Improving treatment adherence to immunosuppressive agents could have positive effects on the morbidity and mortality of kidney transplant recipients. Our objective was to determine whether psychoeducational intervention aimed at improving treatment adherence also could improve 10-year kidney allograft survival rates. Materials and Methods: A randomized open-label study compared a group who received psycho - educational intervention (n = 55) with a control group (n = 55), with all patients being kidney transplant recipients in the Department of Nephrology and Organ Transplantation (University Hospital, Toulouse, France). Psychoedu cational intervention comprised 8 weekly sessions provided by multidisciplinary teams. Patients were included between 2002 and The primary endpoint was allograft survival at 10 years (ie, by 2012). A failed allograft or death with a functioning allograft was considered an event. Results: Mean overall allograft survival rate at 10 years was 78.2% (95% confidence interval, ). In the control group, 48 patients (43.6%) still had a functioning graft at 10 years versus 38 patients (34.5%) in the psychoeducational intervention group (P =.02). However, a log-rank test did not find any significant difference in allograft survival between the From the 1 Département de Nephrology and Organ Transplantation, CHU Rangueil, Toulouse, France; the 2 Département Universitaire de Médecine Générale, Faculté de médecine, Toulouse, France; the 3 UMR 1027 Inserm-Université Toulouse III Paul Sabatier, Toulouse, France; the 4 INSERM U563, IFR-BMT, CHU Purpan, Toulouse, France; and the 5 Université Paul Sabatier, Toulouse, France Acknowledgements: The authors declare that they have no sources of funding for this study, and they have no conflicts of interest to declare. Corresponding author: Lionel Rostaing, Department of Nephrology and Organ Transplantation, CHU Rangueil, TSA 50032, Toulouse Cedex 9, France Phone: Fax: rostaing.l@chu-toulouse.fr Experimental and Clinical Transplantation (2016) 1: groups (P =.06). In multivariate analyses (Cox model), no factor was significantly associated with allograft survival at 10 years. Conclusions: After an initial 6-month observational adherence survey, there was no benefit to kidney allograft survival at 10 years after the psycho - educational intervention, which had aimed to improve patient adherence to treatment with immunosuppressive agents. This might be related to the fact that booster interventions are needed (eg, on a yearly basis). Key words: Kidney transplant, Graft survival, Education Introduction Kidney transplant is the first therapeutic choice for patients with end-stage renal disease. In a US study performed between 1991 and 1997 and that included patients, the long-term mortality rate was lower in patients who received kidney transplants (48%) than in those who were treated with dialysis and waiting for transplant (82%). 1 Moreover, survival of patients with a kidney transplant was improved whatever the type of donor 2 ; a transplant also can significantly improve the quality of life of kidney transplant recipients. 3 However, nonadherence to immunosuppressive therapies occurs in 22% to 28% of kidney transplant recipients. 4,5 This can cause acute rejection episodes 6 and kidney allograft failure, mainly related to chronic antibody (donor-specific)-mediated rejection. 6,7 The latter condition represents the cause of allograft failure in 16% to 36% of kidney transplant patients according to different studies. 6,7 In addition, non - adherence has important economic consequences. In 2007, sixty thousand nine hundred French patients with end-stage renal disease were treated with Copyright Başkent University 2016 Printed in Turkey. All Rights Reserved. DOI: /ect

2 Nathalie Breu-Dejean et al/experimental and Clinical Transplantation (2016) 1: supportive therapy. Of these, were treated with hemodialysis (51%), 2600 (4%) with peritoneal dialysis, and (45%) were kidney transplant recipients. 8 The subsequent health cost of these patients is estimated at 4 billion per year; of this amount, hemodialysis patients account for 77% of this cost. 8 Kidney transplant is a major economic alternative to hemodialysis; it has an estimated mean annual cost of per patient ( in the first year) versus per year for patients treated with hemodialysis. 8 Improving treatment adherence in kidney transplant patients could have positive effects on morbidity and mortality rates. Some interventional studies have evaluated the benefit of psycho - educational interventions to improve treatment adherence. These studies have evaluated treatment adherence and other parameters, such as quality of life, the patient s knowledge regarding renal problems, and survival of the kidney allograft, within short-term periods (5-12 mo). However, very few studies have investigated whether psycho - educational programs are associated with increased treatment adherence, although it has been shown that a combination of multidisciplinary interventions could be efficient in the longer term A recent interventional study showed that treatment adherence could be increased within the short term; however, follow-up was only 6 months and the study was underpowered. 13 To the best of our knowledge, no study has yet assessed the efficacy of a psychoeducational program on long-term kidney allograft survival. The primary objective of our study was to determine whether psychoeducational intervention, when implemented early at post - tansplant, could improve 10-year allograft survival rates and The inclusion criteria were as follows: stable kidney transplant patients, > 18 years old, received transplant within the previous 5 years, and without any cognitive or psychiatric disorders that were incompatible with the psychoeducational intervention. Informed consent was obtained from every patient. The study was approved by the hospital s ethics committee. The patients were randomized into 2 groups: a control group of patients who received standard care and a second group who received psychoeducational intervention. Randomization was performed with the use of sealed envelopes and a list of random numbers. The psychoeducational intervention group was divided into subgroups of 10 patients, with each subgroup undergoing psychoeducational intervention every week for 8 weeks. Each session lasted for 2 hours and was conducted by a multidisciplinary team that included 1 physician, 1 psychologist, 2 nurses, 1 kinesiotherapist, 1 dietician, and 1 social worker. The main objectives of the psychoeducational intervention were to provide patients with information about their disease and to translate this information into a form that enabled them to gain increased competence during normal daily life. The study s goal was to increase treatment adherence, which would thus Figure 1. Study Flowchart Materials and Methods This was a randomized, open-label, two-armed study, in which psychoeducational intervention was analyzed versus standard care (control) in stable kidney transplant patients. 14,15 Figure 1 shows a flow chart of the study. Participating patients were stable kidney transplant patients seen in the outpatient clinic at Toulouse University Hospital (Toulouse, France) by a single physician (LR), who included them in the study after checking that they met the inclusion criteria. Patients were included between Abbreviations: HD, hemodialysis

3 40 Nathalie Breu-Dejean et al/experimental and Clinical Transplantation (2016) 1: Exp Clin Transplant reduce long-term complications and long-term health care costs. Study outline Three evaluations were made during the study. The first was a global meeting of all patients within the study; during this meeting, 1 team member (NBD) explained the overall objective of the study. This meeting was followed by patients in the psycho - educational intervention group having their first psychoeducational intervention session. Patients from both groups completed 4 questionnaires at the first evaluation: a self-questionnaire on treatment adherence, a questionnaire on depression (the Beck Depression Inventory), a questionnaire on quality of life through the World Health Organization Quality of Life 26-item inventory, 13 and a representation and knowledge questionnaire. The second evaluation was performed 8 weeks later. Patients from both groups completed the same questionnaires as those completed at the first evaluation. In addition, patients in the psycho - educational intervention group completed a satisfaction questionnaire regarding the psycho - educational intervention that they had received. At 3 months after the week 8 evaluation, patients from both groups completed the same questionnaires as at week 8. For both groups, at the week 8 and the evaluation 3 months later, the questionnaires were sent to all patients and returned via postal mail (with 100% returned). Questionnaire on adherence evaluation Our questionnaire was in French and was adapted from a French questionnaire that had been elaborated and validated (in French) to assess adherence in human immunodeficiency virus patients. We chose this because human immunodeficiency viruspositive patients have a chronic disease and need to take many medications on a daily basis, of which many have several and frequent adverse effects. We thought that human immunodeficiency viruspositive patients who are receiving treatment would be similar to our kidney transplant population regarding adherence issues. Nineteen questions were retrieved from this questionnaire, and we added others. Our adherence questionnaire was validated for the kidney transplant patients by NBD at 6 months after transplant. 15 The adherence cutoff rate was defined as the median score of both groups at the week 8 evaluation. Ten-year follow-up The primary endpoint at 10 years was allograft survival. A failed allograft or patient death with a nonfunctioning allograft was considered an event. During this 10-year period, patients were seen in the outpatient clinic every 4 months. At every visit, serum creatinine and immunosuppressant trough levels were assessed. Biologic analyses were performed either in the hospital or in private laboratories. The targeted values for immuno - suppressant trough levels in these maintenance kidney transplant patients were as follow: 5 to 15 ng/ml for tacrolimus, 100 to 300 ng/ml for cyclosporine, 6 to 15 ng/ml for sirolimus, and 4 to 8 ng/ml for everolimus. At the 10-year follow-up, a questionnaire was sent to all living patients. Statistical analyses Qualitative variables are shown as their numbers and percentages. Quantitative variables are expressed as means and standard deviations when the distribution was Gaussian or as their median and interquartile range if distribution was not Gaussian. Qualitative variables were compared between the 2 groups with chi-square test or with Fisher exact test when the chisquare test was not applicable. Quantitative variables were compared with t test or with Wilcoxon nonparametric test when the t test was not applicable. A P value of.05 was considered statistically significant. The time until allograft loss (primary outcome) was investigated through survival analysis and was represented by a Kaplan-Meier curve; a log-rank test was used to compare the groups according to graft survival at 10 years. Factors associated with allograft survival were investigated using Cox regression models. Age, sex, treatment, and other variables associated with the endpoint and with a P of.20 in the univariate Cox models or factors known to affect allograft survival as reported in the literature (eg, hypertension, diabetes, obesity) were included in the multivariate analyses. A backward, stepwise Cox proportional hazards model was used to select variables with a P value <.05 to be included in the final model. All of the analyses were done with SAS 9.3 statistical software (2011, SAS Institute Inc, Cary, NC, USA).

4 Nathalie Breu-Dejean et al/experimental and Clinical Transplantation (2016) 1: Results Our study included 55 patients who received the psychoeducational intervention and 55 patients who received the standard intervention (control group). Tables 1 and 2 show the clinical and sociodemographic data of the 2 groups. Results were similar except for profession (P =.0475) and the type of major immunosuppressive drug; that is, 20% of control patients and 7.3% of patients from the psycho - educational intervention group received sirolimus (P =.05). At the first evaluation, overall adherence to immunosuppressive therapy in both groups, based on immunosuppressant trough levels, was 85.4% (n = 94 patients). Regarding adherence score, overall adherence was only shown in 65 patients (59.1%). A weak correlation was found between adherence scores and when adherence was assessed by immunosuppressant trough levels (Cohen-Kappa coefficients of at the first evaluation, 0.03 at the second evaluation, and at the third evaluation). Regarding adherence as evaluated by the questionnaires, at the third evaluation, there was a significant difference between the 2 groups, with patients who received psychoeducational intervention having adherence of 74.5% and patients in the control group having adherence of 47.3%. For questionnaires to evaluate treatment adherence and quality of life sent at 10 years after the intervention, very few were returned, which prevented statistical conclusions. At 2 years and 5 years after patients were randomized, overall allograft survival was 98.2% and 94.6%, with very similar results at these time points for both groups. Figure 2 shows the 10-year allograft survival rate. Table 3 presents the 10-year results Table 1. Clinical Data at Baseline for Both Groups Mean ± SD or Number (%) All Patients Control Group Psychoeducational P Value (n = 110) (n = 55) Intervention Group (n = 55) Age (y) 48.8 ± 12.3 (MD = 2) 47.9 ± ± 11.6 (MD = 2).45 Age at transplant (y) 47 ± 12.3 (MD = 2) 46.0 ± ± 11.6 (MD = 2).36 Time since transplant (mo) ± ± ± Time on dialysis (y) 5 ± 5.1 (MD = 1) 5.0 ± 5.0 (MD = 1) 5 ± Adherence score at first evaluation 30.9 ± ± ± Number of immunosuppressants 2.77 ± ± ± Serum creatinine level at 1 y after transplant (µmol/l) ± 38.9 (MD = 1) ± 35.7 (MD = 1) ± Sex.44 Men 58 (57.2%) 27 (49.1%) 31 (56.4%) Women 52 (42.8%) 28 (50.9%) 24 (43.6%) Number of kidney transplants received (89.1%) 50 (90.9%) 48 (87.3%) 2 7 (6.4%) 3 (5.4%) 4 (7.3%) 3 5 (4.55%) 2 (3.6%) 3 (5.4%) Number of acute rejection episodes (72.7%) 41 (74.5%) 39 (70.9%) 1 27 (24.6%) 13 (23.6%) 14 (25.4%) 2 3 (2.7%) 1 (1.8%) 2 (3.6%) Original kidney disease.75 Glomerulonephritis 39 (35.4%) (MD = 2) 19 (34.5%) (MD = 1) 20 (36.4%) (MD = 1) Vascular nephropathy 18 (16.4%) 12 (21.8%) 6 (10.9%) Hereditary nephropathy 28 (25.4%) 13 (23.6%) 15 (27.3%) Interstitial nephropathy 17 (15.4%) 7 (12.7%) 10 (18.2%) Indeterminate nephropathy 6 (5.45%) 3 (5.4%) 3 (5.4%) Chronic rejection 19 (17.3%) (MD = 63) 8 (14.5%) (MD = 38) 11 (20%) (MD = 25).48 Related living-donor kidney transplant 4 (3.6%) 3 (5.4%) 1 (1.8%).61 Immunosuppressive treatment Cyclosporine 53 (48.2%) 0 26 (47.3%).84 Sirolimus 15 (13.6%) 11 (20%) 4 (7.3%).05 Tacrolimus 42 (38.2%) 18 (32.7%) 24 (43.6%).23 Mycophenolate mofetil 78 (70.9%) 40 (72.7%) 38 (69.1%).67 Enteric-coated mycophenolate sodium 1 (0.9%) 0 1 (1.8%) 1 Prednisone 99 (90%) 48 (87.3%) 51 (92.7%).34 Azathioprine 10 (9.1%) 4 (7.3%) 6 (10.9%).5 Everolimus 4 (3.6%) 0 4 (7.3%).06 Diabetic nephropathy 6 (5.5%) 2 (1.8%) 4 (3.6%).67 Pretransplant anti-hla antibodies 19 (17.3%) (MD = 1) 8 (7.3%) (MD = 1) 11 (10.1%).48 Anti-HLA antibodies at 1 y posttransplant 20 (18.2%) (MD = 1) 8 (7.3%) (MD = 1) 12 (11.0%).34 Antihypertensive treatment at 6 mo posttransplant 86 (78.2%) (MD = 11) 44 (44.4%) (MD = 6) 42 (42.4%) (MD = 5).39 Antihypertensive treatment at 1 y posttransplant 86 (78.2%) (MD = 11) 42 (42.4%) (MD = 6) 44 (44.4%) (MD = 5).73 Abbreviations: HLA, human leukocyte antigen; MD, missing data

5 42 Nathalie Breu-Dejean et al/experimental and Clinical Transplantation (2016) 1: Exp Clin Transplant Table 2. Sociodemographic Data at Baseline for Both Groups Mean ± SD or Number (%) All Patients Control Group Psychoeducational P Value (n = 110) (n = 55) Intervention Group (n = 55) Have had child/children 70 (63.6 %) (MD = 11) 35 (63.6 %) (MD = 1) 35 (63.6%).89 Relationship.41 A couple 76 (69.1%) 36 (65.5%) 40 (72.7%) Single 34 (30.9%) 19 (34.5%) 15 (27.3%) Education.78 None (certificate of elementary school) 77 (70%) 38 (69.1%) 14 (70.9%) High school or university 30 (27.3%) (MD = 3) 16 (29.1%) (MD =1) 39 (25.5%) (MD =2) Profession.0475 Farmer 15 (13.9%) 9 (16.7%) 6 (11.1%) Artisan 13 (12%) 9 (16.7%) 4 (7.4%) Manager 14 (13%) 7 (13%) 7 (13%) Intermediate profession 34 (31.5%) 16 (29.6%) 18 (33.3%) Employee 23 (21.3%) 8 (14.8%) 15 (27.8%) Worker 4 (3.7%) 0 4 (7.4%) Retiree 1 (0.9%) 1 (1.8%) 0 Not working 4 (3.7%) 4 (7.4%) 0 Adherent patient According to score at 1st evaluation 65 (59.1%) 27 (49.1%) 38 (69.1%).052 According to IS trough level 94 (85.4%) (MD = 9) 48 (87.3%) (MD = 3) 46 (87.6%) (MD =6).71 Abbreviations: IS, immunosuppressive agent; MD, missing data regarding the primary endpoint. In the control group, 48 patients (87.3%) still had a functioning graft versus 38 patients (69.3%) in the psycho - education intervention group (P =.02). In the control group, 10 patients (9.1%) had died within 10 years, whereas 14 had died in the intervention group (12.7%; P =.35). Among those in the control Figure 2. Ten-year Allograft Survival Rates Percentage of Failed Allograft P =.06 Time (d) Until Failed Allograft* Group I (control) Group II *Patients who died with a functioning allograft or who had a failed allograft. Table 3. Ten-Year Results Regarding Primary Endpoint Mean ± SD or Number (%) All Patients Control Psychoeducational P (n = 110) Group Intervention Value (n = 55) Group (n = 55) Death 24 (22.0%) 10 (9.1%) 14 (12.7%).35 Death with a functioning graft 13 (11.8%) 4 (3.6%) 9 (8.2%).13 Failed allograft 13 (11.8%) 5 (4.5%) 8 (7.30%).37 Functioning allograft (including those who died with a functioning allograft) 86 (78.2%) 48 (87.3%) 38 (69.1%).02 Duration with a functioning graft (d) 3561 ± ± ± Primary endpoint was allograft survival at 10 years (ie, by 2012), with a failed allograft or death with a functioning allograft considered to be an event. group who died, 4 patients (3.6%) died with a nonfunctional graft, with 9 patients (8.2%) in the Table 4. Univariate Analyses of Factors Associated With Allograft Function at Ten Years Hazard 95% Confidence P Ratio Interval Value Sex Psychoeducational intervention (yes) Age < 40 y y y > 60 y Diploma (education) (yes) Living as a couple (yes) Related living-donor transplant (yes) Malignancy/child (yes) Profession Farmer Artisan Manager Intermediate profession 1 Employee Worker 0 Retiree 0 Not working 0 No. of kidney transplants 1 2 or No. of treatments Original kidney disease Glomerulonephritis 1.76 Renal vascular disease Hereditary nephropathy Interstitial nephropathy Indeterminate nephropathy Diabetic nephropathy Pretransplant anti-hla antibodies Anti-HLA antibody at 1 y after kidney transplant Posttransplant antihypertension medications y serum creatinine level (below median values)

6 Nathalie Breu-Dejean et al/experimental and Clinical Transplantation (2016) 1: psychoeducational intervention group who also died with a nonfunctional graft (P =.13). Five patients (4.5%) from the control group and 8 patients (5.5%) from the psychoeducational intervention group experienced allograft failure within 10 years transplant. In our univariate analyses (Table 4), only diabetes, as the cause of original end-stage renal disease, was associated with allograft loss at 10 years (hazard ratio = 3.89; 95% confidence interval, ; P =.01). In our multivariate analyses, we did not find any predictors for allograft loss at 10 years posttransplant (Table 5). As a result of interaction with time, diabetic nephropathy could not be included in the Cox regression model. Table 5. Multivariate Analyses of Factors Associated with Kidney Function at Ten Years After Transplant Adjusted 95% P Value Relative Risk Confidence Interval Sex, male vs female Age < 40 y y y > 60 y Psychoeducational intervention (yes) Discussion To the best of our knowledge, this is the first prospective, randomized, controlled study to evaluate the long-term effects of psychoeducational inter - vention in de novo kidney transplant recipients. This intervention was implemented to see whether this approach could increase patient adherence to immunosuppressive regimens. We were unable to demonstrate a long-term clinical benefit; that is, this intervention had no significant effect on kidney allograft survival at 2, 5, and 10 years. However, in the group of patients who received psychoeducational intervention, the psychoeducational therapy was associated with improved treatment adherence after 6 months when it was evaluated according to the clinical scores. 14 There are at least 2 reasons for this difference. First, the study was not initially planned for a long-term intervention and follow-up: after the initial psychoeducational therapy, there were no subsequent refresher sessions (eg, an annual refresher session). Therefore, the early benefit from our intervention may have been lost. Second, the initial number of randomized patients was not calculated to enable analyses of the significance of the long-term benefit of this intervention. We also sent questionnaires at 10 years after the initial intervention to evaluate treatment adherence and quality of life. However, very few were returned, preventing statistical conclusions to be made. This showed that, when there was no ongoing protocol, the patients motivation to answer the questionnaire was very low. We observed a very weak correlation between adherence, as assessed through the questionnaire, and adherence assessed in analyses of trough levels of immunosuppressive agents. This could question the validity of our adherence questionnaire. Some authors have evaluated intentional and nonintentional nonadherence. Investigators mostly found that (1) intentional nonadherence rate was low and (2) there was a strong divergence between adherence results found from patients questionnaires versus assessment using trough levels of immunosuppressive agents. When questioned, patients tend to overestimate their nonadherence (62.4%), whereas assessment of adherence using trough levels has shown a lower nonadherence rate (only 25.4%). 16 These results are similar to those that we observed: we found nonadherence in 40.9% of patients when we used the questionnaire versus 14.6% when we used trough levels. This discrepancy highlights that we still lack robust tools to assess nonadherence, and the assessment of trough levels only evaluates the last intake of the immunosuppressive agents and not the regular intake of medications over time. Moreover, when a patient knows that blood tests will be performed the next day or that a medical appointment is planned, the patient will be more adherent to treatment during the days leading up to the appointment. Most studies that have focused on patient adherence in the setting of kidney transplant have not examined the long-term effects (ie, they have not reported on long-term allograft survival). Although the factors associated with adherence have been well reported, those associated with allograft survival are less well documented. 21 A monocentric study that analyzed the factors associated with graft function at 34 years after transplant found that diabetes, a high level of serum creatinine at 1 year after transplant, and a history of acute rejection all had negative effects on allograft survival. In our study, which was

7 44 Nathalie Breu-Dejean et al/experimental and Clinical Transplantation (2016) 1: Exp Clin Transplant underpowered, the univariate analyses showed that only diabetes was significantly associated with allograft loss. However, in the multivariate analyses, we failed to find any predictive factors, despite taking many factors into account, including those reported as being the most important. This same monocentric study also found that 5-year allograft survival was 82% in de novo kidney transplant recipients who were < 17 years old, 80% in those who were 18 to 49 years old, and 61% in those who were > 49 years old. 21 In our study, the 10-year survival rate was 77.3%, which is similar to that from recent French registry data but was much better than data reported in a study initiated in 1967, a time when immunosuppressive agents were far less potent than today. Adherence to immunosuppressive agents is of major importance, and there are many ways to improve it ; however, our long-term results do not indicate that psychoeducational interventions are associated with better outcomes. In conclusion, this randomized controlled trial, which evaluated whether adherence was increased after psychoeducational intervention in de novo kidney transplant recipients, did not show a benefit in terms of allograft survival at 10 years, possibly due to (1) the range of factors that contribute to long-term attrition rate of the kidney allograft and (2) the need for iterative educational sessions to maintain patient awareness and interest. References 1. Wolfe RA, Ashby VB, Milford EL, et al. Comparison of mortality in all patients on dialysis, patients on dialysis awaiting transplantation, and recipients of a first cadaveric transplant. N Engl J Med. 1999;341(23): Sam R, Leehey DJ. 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Family strategies for achieving medication adherence in pediatric kidney transplantation. Nurs Res. 2011;60(3): Ruppar TM, Russell CL. Medication adherence in successful kidney transplant recipients. Prog Transplant. 2009;19(2): , Gordon EJ, Gallant M, Sehgal AR, Conti D, Siminoff LA. Medicationtaking among adult renal transplant recipients: barriers and strategies. Transpl Int. 2009;22(5):