The Transplant Learning Center Indices

Published Date: 02 Nov 2017

Background. Nonadherence to immunosuppressive agents (ISA) in renal transplant recipients (RTRs) is a common problem that adversely impacts graft outcome. Methods. Aim of the study was to determine the prevalence of nonadherence in a cohort of RTRs (n=310) using specific questionnaires, and to evaluate prospectively (6 months follow-up) whether a greater clinical surveillance and the reduction in pill number, through the adoption of once-daily Tacrolimus (D-TAC), may enhance adherence to ISA. Results. The prevalence of nonadherence was 24.8% and was associated with previous rejection episodes (p<0.002), and inversely related with high life satisfaction index (p<0.006), anxiety (p<0.0001) and low GFR (p<0.028). Nonadherent patients were significantly less satisfied about the medical care they received and the relationships with the medical staff. A shift from bis-in-die-TAC to D-TAC was performed in 121 patients (Group SHIFT), whereas the remaining patients did not change their treatments (Group CON); the same questionnaires were repeated after 3 and 6 months. In Group SHIFT a significant reduction in pill number was observed (p<0.01), associated with an improved adherence to ISA after 3 and 6 months (+25% and + 36%, respectively, both p<0.05 vs basal), with no change in Group CON. The shift to D-TAC determined a decrease in TAC trough levels after 3 and 6 months (-9%, p<0.003 vs basal), despite a slight increase in its dosage (+6.5%, p<0.03), but no clinical side effect. Conclusions. The reduced pill burden improves patients’ compliance to ISA, but major efforts by the transplant team in preventing NA is requested.

Key words: adherence, calcineurin inhibitors, pill burden, renal transplant, tacrolimus

Short Summary:

We have carried out a cross-sectional study on a large cohort of renal transplant recipients (n=310) to assess, by specific questionnaires, their adherence to calcineurin inhibitors and some aspects of their life satisfaction and transplant care. We then performed a prospective study (6-months follow-up) to evaluate the same parameters after the shift from twice-daily to once-daily tacrolimus in 121 patients, using those on cyclosporine as controls. Last, we evaluated once-daily tacrolimus pharmacokinetics, since data reported in literature are conflicting.

Main results of the study are: (A) 24.8% of patients were nonadherent; (B) nonadherent patients evidenced peculiar psychological and clinical problems potentially affecting their compliance to CNI; (C) the reduced pill burden after the shift significantly improved patients’ adherence; (D) only marginal differences exist between once-daily tacrolimus and twice-daily tacrolimus, with no important side effect on patients and renal function.

We conclude that a reduced number of pills is associated with a better therapeutic adherence, but greater efforts by the transplant team are requested to further improve it.

INTRODUCTION

In 2003, the World Health Organization declared nonadherence to treatment as a major public health problem (1) that may result in disease progression, increased healthcare costs and even premature death (2); ten years later, the problem is even greater and the low compliance to the prescribed treatment is considered a significant negative predictor of outcome mostly in patients with chronic diseases like renal transplant recipients (RTRs), especially prone to therapeutic nonadherence because of the complexity and life-long character of their immunosuppressive therapeutic regimen (3).

In clinical controlled trials, nonadherence to treatment ranges between 43 to 78% (2), and similar results are described with immunosuppressive agents (ISA) in RTRs (18–68%), with such wide ranges reflecting the difficulty of correctly defining and quantifying the phenomenon (4-7).

A recent Consensus Conference concluded that nonadherence to ISA "is more prevalent than previously assumed, is difficult to measure accurately, confers worse outcomes, occurs for a variety of reasons, and is hard to change from a behavioral perspective" (8). Therefore, it is not surprising that nonadherence represents the third leading cause of graft loss after rejections and infections (9), is associated with reduced 5-year graft survival (10), a seven-fold higher odd of graft loss (11), and accounts for about half of the graft failures due to rejection (12).

Although nonadherence is a complex and challenging problem, a better knowledge of its basis and of its appropriate remedies could dramatically improve transplant outcomes, since understanding patient behaviors and the level of satisfaction in their daily experiences with graft problems should provide insights to the mechanisms leading to it.

It is well documented that the lack of knowledge regarding ISA and their side effects as well as the frequency of drug doses are two of the main factors leading to nonadherence (7,13), and that the reduction of pill burden and the patient education should be considered as priorities for action to improve therapeutic adherence, as being the easiest to modify (14). The recent introduction in the market of a once-daily Tacrolimus formulation offered the opportunity to evaluate whether the shift from a double (BID-TAC) to a single daily (D-TAC) administration of the drug may improve patients’ adherence by reducing the number of pills.

Therefore, aims of the present study were: [a] to evaluate the prevalence of nonadherence to calcineurin inhibitors (CNI) in a cohort of stable RTRs through specific questionnaires; [b] to ascertain whether the reduction in pills number of CNI and an "educational plan" (written and oral information associated with more intensive clinical surveillance) may prospectively influence non-adherence. As secondary endpoint, we have also examined the pharmacokinetics of D-TAC, to verify its efficacy compared to BID-TAC, since data reported in current literature are not univocal (15) .

PATIENTS AND METHODS

Study design

The study was proposed to 370 RTRs regularly visiting our Clinic as outpatient, all first transplant from deceased donors. Inclusion criteria were: age>18 years, a transplant vintage >1 year, and absence of cognitive impairment and ability to read and understand the meaning of questionnaires. Three questionnaires were proposed to all the eligible patients, visited during a 8-month timeframe, to evaluate the prevalence of nonadherence (Cross-sectional Study). Subsequently, all the patients treated with BID-TAC were invited to take D-TAC to reduce the cumulative daily number of pills (Group SHIFT), whereas the patients under Cyclosporine and/or mTOR-Inhibitors and those under BID-TAC refusing the shift constituted the Group Control (CON); these patients were followed-up for 6 months to evaluate again their therapeutic adherence after 3 and 6 months (Prospective study). Since, as a prerequisite, the patients had to maintain the same daily number of pills throughout the follow-up period, 37 patients were excluded from the study due to clinical necessities to modify their therapy, including 10 subjects that preferred to return to BID-TAC for either clinical (GI upset, diarrhea, tremors) or bureaucratic reasons; twenty-three additional patients refused to answer the questionnaires, so the reported data refer to 310 patients, 160 under BID-TAC and 150 under cyclosporine and/or mTOR inhibitors.

Cross sectional study (Time 0)

To analyze the prevalence of nonadherence, three short questionnaires were proposed to the patients during their medical visit (T0). The first two questionnaires have been elaborated for the Transplant Learning Center Program (16), aimed to improve and to preserve graft function through a better knowledge of the factors affecting the life of RTRs. The sum of the single item scores, based on a 5-point Likert scale (0-4), leads to the formulation of two indices: (a) the Life Satisfaction Index (LSI), based on 8 questions (score: 0-32, with higher values denoting better quality of life); (b) the Transplant Care Index (TCI), based on 6 questions (score: 0-24, with higher values denoting easier care). Both questionnaires were designed to serve as single composite measures to track transplant-specific quality of life and several issues related to caring for the graft (see Appendix A and B).

The third questionnaire was represented by the ITAS (Immunosuppressant Therapy Adherence Scale), based on a four-item scale developed to indicate how often transplant recipients were non-adherent to ISA (17). The items of ITAS are addressed to explore how often in the last 3 months the patients: (a) forgot to take their CNI; (b) were careless about taking their CNI; (c) stopped taking their CNI because they felt worse; and (d) missed taking their CNI for any reason. For each item, the scores were: 3 = perfect compliance, i.e. 0% of nonadherence; 2 = 1–20% of nonadherence to ISA; 1 = 21–50%, and 0 = nonadherence greater than 50% of the time. Item responses are summed (range 0-12), with the highest score indicating perfect adherence to ISA. Cukor et al. (18) have recently categorized 3 possibilities based on the level of patients’ compliance: perfect adherence (score 12/12), nearly perfect adherence (score 10-11/12) and less than perfect adherence (score ≤9/12); for the purpose of our study, only adherence to CNI was evaluated by ITAS, and all the patients with a score ≤10 were considered nonadherent. A specific question was also made to evaluate the presence of anxiety, as previously reported (19).

Prospective study

For clinical and ethical reasons the shift was proposed to all the patients previously treated with BID-TAC. After basal evaluation, 121 out of 160 patients accepted the conversion to D-TAC (same milligram-for-milligram total daily dose), and constituted the Group SHIFT; patients on cyclosporine and/or m-TOR inhibitors and the remaining 39 patients on BID-TAC defined the Group CON (n=189). After the basal questionnaires, the patients of both Groups received a printed booklet ("Welcome in the world of Transplantation!", written by M.S., Nexthealth Publisher, Milan, Italy) in which the most common problems of transplant care are easily and extensively reported; the aim and the content of the booklet was explained to the patients, that were strongly encouraged to read it.

Blood samples were withdrawn 7 and 14 days after the beginning of follow-up, to ensure that similar pre-shift TAC trough levels were reached in patients of Group SHIFT, modifying the dose of D-TAC when necessary, or to confirm the stability of CNI trough levels in patients of Group CON. No further modification in D-TAC dose was made in the following months. Three and 6 months after the basal interview (T3 and T6, respectively), the patients were administered the same questionnaires during scheduled visits. All the patients of Group CON had the same number of visits and of blood withdrawals as the patients of Group SHIFT.

TAC-D pharmacokinetics

In Group SHIFT, the average value of the last 3 determinations of BID-TAC trough levels was considered as basal value of the pre-conversion period. After the shift to D-TAC, blood concentrations of the drug were measured after 7 and 15 days and then after 3 and 6 months (T3 and T6, respectively).

Blood drug concentrations were measured by the ARCHITECT tacrolimus immunoassay (Abbott), with a lower limit of detection of 1.5 ng/mL, and a standard curve range of 0–30 ng/mL (20).

Statistical Analysis

Data were analyzed using STATA version 12.0. (STATA Inc., Texas, USA). Continuous variables are reported as either mean ± SD. Comparisons of continuous variables with normal distribution were performed by unpaired Student’s t test. For variables with non-normal distribution we used unpaired Wilcoxon non-parametric test. Categorical variables are expressed as percent and analyzed by chi-squared test.

Multivariable logistic regression analysis was used to identify baseline factors associated with a risk of nonadherence (ITAS<10) at baseline. The model was built by identifying a priori the main potential determinants of nonadherence; the model accounted for demographic (age, gender, job activity, years of school, marital status), clinical characteristics (diabetes, body mass index, dialysis and transplantation vintage, rejection episodes, anxiety, glomerular filtration rate) and questionnaires scores (LSI, TSI).

Doses and trough levels obtained during D-TAC treatment were compared to mean values of BID-TAC treatment by ANOVA for repeated measures. A p value <0.05 was considered statistically significant.

RESULTS

Cross-sectional study

Table 1 shows the main characteristics at baseline (T0) of the cohort of patients under study and of the same patients divided into "adherent" and "nonadherent" subjects, according to our classification.

Overall data denote a well preserved renal function and satisfactory values of the main laboratory data and of blood pressure despite a quite long transplant vintage; 76 patients resulted nonadherent (24.5%): 54 of these (71%) showed a ITAS score of 10 and 22 had a score ≤9. All these patients acknowledged that forgetfulness was the primary reason for their lower compliance, with some of them feeling worse after CNI administration (3.5%) or careless about taking their medications (2.9%).

The scores of both LSI and TCI of the whole cohort averaged 84.0% and 77.5% of their respective maximal scores, denoting a satisfactory quality of life and only minor "barriers" to an adequate graft care.

When the patients were divided into adherent and nonadherent, some differences were noted in marital status, presence of anxiety, higher in adherent patients, whereas number of previous rejection episodes resulted significantly higher in nonadherent patients.

Moreover, compared to compliant patients, nonadherent patients showed a reduction in both LSI (p<0.0005) and TCI (p<0.006), with interesting differences in the single items of both indices. Concerning LSI, in fact, nonadherent patients were less satisfied about their life (Item 8, p<0.0002 vs adherent) and about the medical care they received (Item 3, p<0.04), and had a worse relationship with both the medical staff (Item 2, p<0.0007) and their partners (Item 4, p<0.0004). The examination of the single items of TCI evidenced some difficulties in keeping the scheduled visits in nonadherent patients (Item 1, p<0.0006 vs adherent), in taking their medicines (Item 5, p<0.0001) and in following the prescribed diet (Item 3, p<0.002).

The logistic regression analysis (Table 2) showed that nonadherence to CNI was significantly predicted by previous rejection episodes (p<0.002), whereas the presence of high values of LSI, anxiety, and GFR values below 60 ml/min represented "protective factors", favoring patients compliance. It is noteworthy that age, gender, living with a partner, level of school education, and number of pills were not associated with nonadherence to CNI.

Prospective study

In the prospective study, the patients were divided into 2 Groups: Group SHIFT, that included patients accepting the shift to D-TAC (n=121), and Group CON, consisting of patients under Cyclosporin and/or mTOR inhibitors and of patients under BID-TAC refusing the shift (n=189).

At T0 (Table 3), the prevalence of nonadherent patients and the cumulative daily number of pills were similar in the two Groups under study. The conversion to TAC-D in Group SHIFT determined a significant and stable reduction in the daily number of pills (10.7±4.1 vs 13.3+4.7, p<0.01), which, conversely, did not vary throughout the study in Group CON.

Beyond the obvious differences in CNI use, significant differences between the Groups were noted in school years, transplant vintage, and plasma albumin concentration, although of scarce clinical value. Patients of Group CON showed a higher prevalence of previous rejection episodes, and a slightly lower score of LSI.

Data of ITAS at T3 showed that the reduced number of pills and the educational plan were able to significantly increase patients’ compliance in Group SHIFT, since 7 patients reached an ITAS score >10 (p<0.05 vs T0), and 3 further patients became adherent at T6 (p<0.05 vs T0); the sole "educational plan", conversely, sorted no change in CNI compliance in Group CON (Fig. 1).

There was a modest, although significant, reduction in LSI observed at T0 in Group CON compared to Group SHIFT (Table 3), that persisted throughout the study and was due to the lower LSI observed in in nonadherent patients of such Group (-12% vs. adherent, p<0.003), whereas no difference was detected between nonadherent and compliant patients of Group SHIFT during the follow-up period.

TCI score at T0 , conversely, was similar between the two Groups and did not vary at T3 and T6, also when the patients of both Groups were divided into adherent and nonadherent.

No significant modification was observed in eGFR and in the main laboratory data in both Groups, nor rejection episodes or infectious diseases were recorded throughout the follow-up period. Twelve additional patients complained of minor side effects (pruritus, tremors, GI upset) that, however, did not require treatment interruption.

D-TAC pharmacokinetics

The data of the pharmacokinetic study are represented in Figure 2. After the shift to D-TAC, small, although significant, modifications of D-TAC doses were performed at day 7 and 15 (+1.7% and +6.5% vs T0, respectively, p<0.03) in the attempt to maintain tacrolimus trough levels similar as at T0; no further change was made thereafter. Trough levels decreased by 5% after 7 days, returned to normal values after 15 days, but tended to decrease again after 3 and 6 months of follow-up when the dose of D-TAC was fixed (-8.7% and -9.2% vs T0, respectively, both p<0.03); those concentrations, however, always remained in the recommended therapeutic range.

DISCUSSION

The results of the present study confirm the high prevalence of nonadherence to CNI in our RTRs, and demonstrate that the pill burden represents an obstacle to patients’ compliance to CNI. However, even if a significant improvement in patients compliance was demonstrated after the shift to D-TAC, these data evidence that 64% of nonadherent patients did not change their behavior despite the reduced number of pills, a more careful education and the closer clinical surveillance.

Since nonadherence to ISA is the leading preventable cause of graft loss, to identify non-compliant patients should represent a priority for the transplant team. There are many factors associated with nonadherence: lack of appropriate instructions from healthcare providers, elevated number of pills, forgetfulness, intentional failure to consume the medication, drugs adverse effects (21); it seems clear that a greater effort of medical team in offering appropriate education and the widest reduction of the "barriers" that may favor nonadherence should be combined to modify wrong patients’ habits.

A recent Consensus Conference (14) established 3 priorities of action to reduce the incidence of nonadherence to ISA: a lower pill burden, a better patient education and an adequate peer support to patients, as the easiest factors to modify. This justifies the attempt to address our attention to these priorities, evaluating, with LSI and TCI, also psychological or practical barriers that may condition patients’ adherence. Despite the positive answers to both questionnaires, the prevalence of nonadherence was substantially high. We used a "strict" definition of nonadherence in the present study (ITAS score ≤10), despite some studies claim as the minimum threshold an adherence <80% (22,23), which corresponds to a score <10 in ITAS; our choice takes into account that questionnaires underestimate the prevalence of nonadherence, due to the reluctance of patients to admit their mistakes or the limits of their memory (24).

Indeed, despite several strategies are available to quantify nonadherence, like the use of electronic device, pharmacy records, drug level monitoring or questionnaires, these latter probably represent the easiest methodology to evaluate the phenomenon in large cohorts of patients, despite their inherent limitations. We selected ITAS because it has been validated by correlating composite item scores with refill record adherence rate, serum ISA concentrations, and episodes of graft rejection or increased serum creatinine (17). Moreover, it is practical for recipients and may be completed in a short time period; therefore it results feasible, convenient and cost-effective.

In the present study, the main predictor of nonadherence was the previous presence of rejection episodes, an obvious consequence of low compliance to immnosuppressors; positive factors in preventing a low compliance, conversely, were a better quality of life, that certainly predisposes to a better care of the graft, and the presence of anxiety or lower levels of GFR, a consequence of the greater attention to medical prescriptions by patients who fear to lose their graft. At difference with other studies, no relationship was observed with gender, marital status or level of education, quite low in our cohort of patients (9,11, 25).

It is interesting to note that nonadherent patients of the cross-sectional study showed some significant differences in specific items of both LSI and TCI that witness difficult relationships with the transplant team, lower satisfaction in the health care they receive or difficulties in attending the scheduled visits: this demonstrates that these patients need a greater attention by medical personnel and underlines the crucial role in enhancing therapeutic compliance by the transplant team.

Recently, a randomized trial by Kuypers et al. in 219 patients has demonstrated, using electronic monitoring, that the switch to D-TAC significantly improved patients’ adherence to the therapeutic regimen as compared to patients continuing BID-TAC during a 6-months follow-up period (26). Our prospective data confirmed these findings, previously suggested also in different solid organs grafts (27,28), but offered additional information about the effects of the educational plan and of the closer clinical surveillance on adherence, and the potential role of psychological, practical and clinical problems in contributing to nonadherence. Indeed, the absolute lack of changes in patients’ compliance in Group CON during the prospective study, despite comparable "educational plan" and greater clinical surveillance as in Group SHIFT, seems to suggest no role for them in improving adherence; indeed, our negative result is probably conditioned by the high transplant and dialysis vintage and the low degree of education of these patients that probably induce a particular refractoriness to modify wrong but consolidated behaviors.

As recently shown by Urstad and coworkers, in fact, any educational plan should start immediately after the transplantation, should be tailored for each patient and intensively maintained thereafter by dedicated personnel (29), and further supported by adequate social and peer support, a valid opportunity to inform the patients about the need of a perfect adherence to ISA.

Our data suggest that D-TAC may represent an option to increase patients’ compliance since its pharmacokinetic profile is almost comparable to BID-TAC, despite minor dose-adjustments and fluctuations of its plasma levels, and did not expose the patients to rejection episodes or undesirable side effects. Indeed, the modifications in blood TAC concentrations in this study were modest, averaging -9.2% after 6 months of follow-up, a value quite different from that reported in a recent retrospective study on 55 patients shifted to D-TAC, in whom a reduction in TAC plasma levels of 21.7% was observed despite the concomitant rise in D-TAC doses up to 17.2% vs basal, during a 6-months follow-up (31). The discrepancy between these data is not clear, but could due to differences in patients’ demographics, in their therapeutic compliance or in pharmacogenomics; on the other hand, in a large cohort of patients observed for 12 months, Guirado et al (32) found lower decreases in TAC through levels (-9.2%) with only minor increases in its doses (+1.24%). Taken together, however, these data clearly suggest that a closer monitoring of trough levels must be provided to all the patients on D-TAC, mostly in first months after conversion.

There are some limits in this paper deriving from the observational nature of the study and the unavoidable selection bias of patients in the two Groups of the prospective study. In this specific topic, however, the observational nature of the study may rather represent a strength, since the awareness of patients to participate in a prospective clinical trial may spuriously improve therapeutic compliance. Beyond the ethical and clinical problems, however, also obvious "commercial" problems induced us to shift to D-TAC only patients on BID-TAC; this probably accounts for some differences between the Groups, like the higher number of rejection episodes in Group CON, mostly on cyclosporine, but does not affect the final results of the study, based on the impact of a lower pill number on therapeutic compliance. A strength of the paper, conversely, resides in the extraordinary effort to maintain the same pill burden and in providing the identical clinical surveillance to all the patients throughout the follow-up period, at difference with Kuipers’ study in which the number of visits and pills did vary during the study between the Groups. It is well known, in fact, that the frequency of visits and blood withdrawals may positively affect therapeutic adherence (30).

In conclusion, this study demonstrates that a reduced pill burden significantly affects patients’ adherence to ISA and, therefore, it is strongly advisable that we consider the total number of pills, when providing the optimal therapy to any patient; a further interesting finding is that nonadherent patients may have conflictive relationships with the medical team that might predispose them to wrong behaviors. A greater effort should be made to ascertain patients’ compliance to treatment, keeping in mind that adherence requires a lifelong dedication from both patients and clinicians and that we tend to overestimate patients’ understanding and consciousness; this, in association with the reduced pill burden, a careful and early "educational plan", and an increased number of visits when nonadherence is even suspected, might lead to an improved compliance to ISA and a better outcome of the graft.

"Transparency declaration" Section

Conflicts of interest: none to declare by any of the Authors.

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Table 1. Main data of the whole cohort of patients (All), and of Adherent and Nonadherent patients according to the ITAS score (≤10) at baseline.

All

Adherent

Nonadherent

p

(n=310)

(n=234)

(n=76)

Demographic

Age (yrs)

49.3±12.1

49.3±11.8

49.3±12.6

0.993

Female gender (%)

60.9

61.1

60.6

0.928

Diabetes (%)

23.8

23.5

25.0

0.790

CVDs (%)

16.1

17.5

11.8

0.242

School years

9.3±3.1

9.4±3.1

9.2±3.0

0.575

Active workers (%)

63.5

62.0

65.8%

0.594

Living with a partner (%)

77.0

80.8

65.8

<0.007

Clinic

Blood Pressure (mmHg)

129±15/80±8

130±15/80±7

126±15/80±9

0.142/0.988

BMI (Kg/m2)

26.8±4.5

26.7±4.3

26.8±4.5

0.846

Time since TX (yrs)

7.9±5.0

8.2±5.1

7.2±4.7

0.136

Time on Dyalisis (mo)

36.9±24.3

38.2±25.3

32.9±25.3

0.104

Rejection episodes (%)

11.6

8.5

21

<0.003

Anxiety (%)

43,5

48

29,8

0.007

Laboratory

GFR (mL/min/1.73m2)

61.5±31.6

61.1±23.9

62.9±23.3

0.564

Urea (mg/dl)

62.0±27.3

66.3±33.8

64.9±27.9

0.744

Hemoglobin (g/dL)

12.8±1.7

12.7±1.7

12.9±1.7

0.513

Albumin (g/dL)

4.5±0.3

4.5±0.4

4.5±0.3

0.903

Proteinuria (g/day)

0.44±0.84

0.45±0.80

0.41±0.97

0.737

Immunosuppression

Tacrolimus (%)

57.1

57.7

55.3

0.726

Cyclosporin ± mTOR-I (%)

42.9

42.3

44.7

0.711

Steroids (%)

77.7

78.2

76.3

0.731

Mycophenolic acid (%)

49.6

51.7

43.4

0.209

Questionnaires scales

LSI

26.9±3.9

27.3±3.9

25.5±3.7

<0.0005

TCI

18.6±2.9

18.9±2.9

17.7±2.5

<0.006

ITAS ≤10* (%)

24.5 (n=76)

Data are expressed as means±SD; for statistics, see Methods.

* = Indicates the percentage of non adherent patients (see Methods)

Abbreviations: CVDs: cardiovascular diseases; BMI: body mass index; TX: transplantation; GFR: glomerular filtration rate; LSI: Life Satisfaction Index; TCI: Transplant Care Index; ITAS: Immunosuppressant Therapy Adherence Scale.

Table 2. Predictive factors of nonadherence at baseline in the whole cohort of patients (n=310).

Odds Ratio (C.I. 95%)

p

Age

1.00 (0.97-1.03)

0.993

Female gender

1.12 (0.54-1.84)

0.984

School years

0.97 (0.88-1.07)

0.587

Active workers (yes vs no)

1.03 (0.56-1.91)

0.920

Living with a partner

0.88 (0.38-2.04)

0.770

Time on Dialysis

0.99 (0.98-1.00)

0.126

Time since TX

0.94 (0.89-1.01)

0.070

Rejection episodes

4.08 (1.67-9.98)

0.002

Life Satisfaction Index

0.29 (0.12-0.70)

0.006

Transplant Care Index

0.67 (0.33-1.35)

0.265

Anxiety (%)

0.24 (0.12-0.47)

<0.0001

Number of pills

1.01 (0.95-1.07)

0.816

GFR<60ml/min/1.73m2

0.49 (0.26-0.93)

0.028

Table 3. Basal data (T0) of the patients of Group SHIFT and Group CON.

Group SHIFT

(n=121)

Group CON

(n=189)

p

Demographic

Age (yrs)

47.9±12.2

49.7±12.0

0.209

Female gender (%)

61.7

53.7

0.176

Diabetes (%)

21.5

27.5

0.241

School years

9.8±3.4

9.0±2.8

0.025

Active workers (%)

67.0

61.1

0.307

Living with a partner (%)

84.3

73.7

0.031

Clinic

BMI (Kg/m2)

26.6±4.4

27.0±4.5

0.496

Time since Transplant (yrs)

6.3 (3.6-8.5)

7.5 (4.1-11.0)

0.010

Time on Dyalisis (mo)

33 (18-50)

36 (18-49)

0.415

Rejection episodes (%)

8.0

14.8

0.028

Laboratory

GFR (mL/min/1.73m2)

65±23

63±23

0.355

Urea (mg/dl)

60.1±27.7

63.7±27.3

0.261

Hemoglobin (g/dL)

13.0±1.7

12.7±1.7

0.119

Albumin (g/dL)

4.5±0.3

4.4±0.4

0.011

Immunosuppressive therapy

Tacrolimus (%)

100

20.6

Cyclosporin ± mTOR inhibitors (%)

0

79,4

Steroids (%)

80.2

78.4

0.722

Mycophenolic acid der. (%)

43.8

51.5

0.197

Daily number of pills (n)

13.3±4.5

13.9±4.7

0.266

Daily number of pills after shift

10.7±4.1°

Questionnaires Scales

LSI

27.8±3.2

26.4±4.1

0.002

TCI

18.6±2.6

18.6±3.1

0.768

ITAS ≤10* (%)

23.1 (n=28)

26.9 (n=45)

0.652

Data are expressed as means±SD

* = Indicates the percentage of non adherent patients (see Methods)

° = p<0.01 vs daily number of pills of Group SHIFT

Legends to Figures (can be reproduced as black and white images in the printed journal)

Figure 1. Prevalence of nonadherence in the two Groups under study throughout the observation period (T0 = basal; T3 and T6 = after three and six months of follow-up, respectively).

Group SHIFT: yellow bars; Group CON: blue bars;

* = p<0.05 vs T0; ° = p<0.05 vs Group CON (T6).

Figure 2. Doses (blue line) and trough levels (red line) of D-TAC throughout the observation period in patients of Group SHIFT. T0 represents the mean value of the last 3 BID-TAC trough levels and doses before the shift; 1W and 2W represent the determinations of trough levels one week and 15 days after the shift and the consequent changes in D-TAC doses; T3 and T6 represent the modifications in D-TAC trough levels after 3 and 6 months of follow-up, when the doses of D-TAC were unchanged.

* = p<0.003 vs T0; ° = p<0.003; 2WK, T3 and T6 vs T0.

Figure 1

Figure 2