Lifestyle intervention to improve quality of life and prevent weight gain after renal transplantation: Design of the Active Care after Transplantation (ACT) randomized controlled trial

The target population for the study are adult RTR, recruited during routine post-transplantation care shortly, but at least within the first year after transplantation. Inclusion criteria are: written informed consent; age > 18 years; < 1 year after transplantation; approval for participation based on a general medical evaluation by their nephrologist. Exclusion criteria included the following: multiple organ transplantation; psychopathology or serious cognitive impairment; physical or clinical limitations that make participation impossible; pregnancy, negative screening verdict by the nephrologist or cardiologist. Participants receive a small financial reimbursement (10 Euro) for participation in the final follow-up measurement at 15 months. Participation in the exercise training sessions and dietary care are financed by research funds, and participants’ travel expenses are reimbursed. Pre-defined reasons to discontinue participation in the study included pregnancy and conversion to dialysis. Furthermore, reasons to discontinue participation are: changes in ECG during maximal aerobic capacity testing, systolic blood pressure > 250 mmHg, diastolic blood pressure > 120 mmHg or blood pressure decline of > 20 mmHg during maximal aerobic capacity testing, and severe cardio-pulmonary complaints during the exercise trainings sessions.

All RTR patients are screened for eligibility during the post-transplantation recovery period, so within 7–10 days after surgery, by the nephrologist. Eligible RTR are invited to participate, informed about the study protocol and if agreed are asked to participate and sign written informed consent. In case of non-Dutch or non-English speaking patients, interpreters are used.

In total, 219 participants (73 per group) will be recruited. The sample size is based on the expected improvement on the physical functioning scale of quality of life of 13.8 points in the intervention group and 8.8 points in usual care (α=0.05, β= 0.80, SD = 11.0) [26]. A difference of 5.0 points between the standard effect is considered a relevant effect. This results in a required number of 57 RTR per group. Taking into account a potential dropout rate of 15% and a correction for heterogeneity between centers of 10%, this results in a total required number of 73 RTR per group (N = 219 in total). Randomization to one of the three arms is computerized using the ‘PROC SURVEYSELECT’ function in the software program SAS (Cary, North Carolina, USA). It is performed by an independent data management company hosting the data entry facility, who are not involved in conducting the study itself (Nefrovisie foundation, Utrecht, the Netherlands). Participants are randomized by block randomization in groups of 6–9 for rehabilitation centers and in groups of 3 for physiotherapy practices.

Recruitment takes place in three Dutch hospitals with good geographical coverage, in the north (University Medical Center Groningen), west (Amsterdam Medical Center) and south (Maastricht University Medical Center) of The Netherlands. The exercise training is offered in rehabilitation centers or in local physiotherapy practices if there is no rehabilitation center within reasonable travel distance of the residence of the participant.

Delivery of the exercise training is standardised by providing protocols and the same exercise training protocol for all interventionists.

The interventionists of the participating centers all received personal instructions of exercise scientists on the protocols, the basic medicine of renal disease, and adverse effects of the immunosuppressive- and other medication. Furthermore, all interventionists participated in a mandatory kickoff meeting where the lifestyle counseling part of the intervention was explained and practiced, including the theoretical background (stages of change model and motivational interviewing). All participating rehabilitation centers and physiotherapy practices meet the following criteria: expertise in rehabilitation of cardiovascular or oncology patients; adequate training facilities; all the necessary fitness equipment for submaximal cycle ergometry and strength tests; and, for physiotherapy practices only, provide opportunities for participants to continue their fitness activities during the active follow-up.

Concerning the diet intervention, dieticians are required to meet the following selection criteria: experience in counseling renal patients or other patients with a serious chronic metabolic condition; educated and experienced in motivational interviewing; educated and experienced in Subjective Global Assessment of malnutrition. Lifestyle coaches had to fulfill the following selection criteria: experience in lifestyle counseling of renal patients or other patients with a serious chronic metabolic condition; educated and experienced in motivational interviewing. In most cases the lifestyle counseling is done by the physiotherapist who supervises the training.

A website dedicated to the study (in Dutch language) provides all protocols, explanations and hosts a data entry system (www.​act-studie.​nl).

Participants randomized to the usual care group receive standard post-transplant care as usual in the hospitals. Current standard nutrition care after kidney transplantation consists of 1–4 inpatient consultations by a renal dietitian during the inpatient stay (7–10 days), followed by 1 outpatient consultation. During inpatient consultations attention is paid to optimal nutritional intake, maintaining a stable body weight and muscle mass, or increasing body weight when needed. After a few months, during the outpatient follow-up, attention is paid to maintaining a stable body weight, or increasing or decreasing body weight when needed. When a participant has increased cholesterol, (un)saturated fat intake is discussed, and mono/disaccharides are discussed when a participant has increased HbA1c. Likewise, salt consumption is discussed in case of increased 24-h sodium excretion. Exercise or lifestyle counseling are not included in the standard post-transplant care in either of the participating hospitals. Participants randomized to the usual care group receive general advice to meet the standard Dutch exercise guidelines (30 min of moderate physical activity per day) and follow the Dutch Dietary guidelines.

The exercise intervention consists of two phases. The first phase is a 3-month exercise training program, followed by the second phase; a 12-month active follow-up with lifestyle counseling (Figure 2). Exercise training sessions are done in groups of 4–10 participants in the rehabilitation centers and with 1–6 participants in the physiotherapy centers.

The training program encompasses two exercise training sessions per week (21 exercise training sessions and 3 test sessions in total) and is focused on improving maximal muscle strength, local muscle endurance, and aerobic capacity. Each exercise training session consists of 30-min dynamic resistance training of all the major muscle groups (Additional file 1: Table S1) using resistance training machines, 30 min of aerobic training (cycle-ergometry and treadmill walking), and is concluded with a 30-min supervised sports activity or swimming, depending on the available facilities.

The dynamic resistance training includes both maximal strength training (relatively high load, fewer repetitions), and muscle endurance training (relatively low load, large number of repetitions).

Optimal resistance training load is determined using one-repetition maximum testing (1RM) for each participant. The content of the training program is in line with the American College of Sports Medicine guidelines exercise in healthy adults [27], and was previously shown to be effective in improving muscle strength and aerobic capacity in RTR [22]. The full resistance- and aerobic training program is shown in Additional files 1 and 2: Tables S1 and S2.

Maximal muscle strength (1RM) for all exercise machines (Additional file 1: Table S1) is assessed at baseline. For maximal muscle strength training, moderate loading is used (50–60% 1RM), for 2–3 sets of 8–10 repetitions. Higher loads are known to be more appropriate for maximal muscle strength, however 50–60% 1RM is used in our protocol as most participants are untrained, and RTR have increased risk of tendon ruptures. For local muscle endurance training a light-to-moderate load is used (25–35% 1RM), for 1–3 sets of 30 repetitions. All resistance exercise involved exercise machines, no free weights are used for safety reasons.

The load for the aerobic cycle training is determined based on the baseline symptom-limited graded maximal cycle ergometry test. Treadmill walking is performed at the load at which heart rate is similar to the heart rate during aerobic cycle-training. If the physiotherapists notice that a subject is training below or above the optimal intensity (e.g. in case a baseline exercise test is performed sub optimally), they are allowed to make slight adjustments to the participants’ exercise intensity.

The exercise training program in the exercise + diet intervention group is identical to that of the exercise intervention group, and additionally, participants receive dietary counseling. The dietary counseling runs throughout the entire 15 months of the study period and consists of a total of 12 counseling sessions with a renal dietician. The dietary counseling takes place in the hospital face-to-face. If this is not feasible some counseling sessions are done by phone. The dieticians are trained to use motivational interviewing techniques which they apply during the dietary counseling sessions.

Goals are set to improve nutrition status to preserve renal function, to prevent weight gain, type 2 diabetes, and hypercholesterolemia. These goals are set together with the participant to facilitate an autonomy supportive counseling climate [33]. A three-day food diary is used as input during the dietary consultations and for personal goal setting. Participants also receive a food logbook which contains information and exercises to help the participant set diet goals. During the dietary counseling sessions, special attention is given to salt intake, whole-wheat grains and fruit and vegetable intake, intake of saturated and unsaturated fat, and the use of sugar-rich products, sugar-sweetened beverages (soft drinks, sweetened dairy drinks and fruit juices) and preventing overeating. In addition, participants are reminded of their physical activity goals, and the importance of protein intake for maintaining and increasing muscle mass. In case of disease after transplantation, for example infections, the dietician assists the patient in maintaining an energy- and protein-rich diet to prevent further deterioration or decline in muscle mass.

Dietary counseling session 9 (of total 12) is a group meeting for which the participants are encouraged to bring significant others such as their partner or other supportive family members. The dietary counseling is in line with the 2006 Guidelines for a Healthy Diet by the Dutch Food and Nutrition Council [34], supplemented with diet guidelines for RTR [35] and diet guidelines for the prevention of type 2 diabetes [36] and cardiovascular risk [37].

All participants receive standard immunosuppressive treatment. In the UMCG this consists of induction therapy with methylprednisolone (40 mg) and basiliximab (20 mg) on day 1 and at day 4 post-operation. This is followed by a maintenance immunosuppressive regimen of tacrolimus, mycophenolate mofetil and prednisolone, tapered to a maintenance dose of 5-10 mg per day. Standard immunosuppressive treatment in the MUMC consists of no induction therapy, methylprednisolone 125 mg per day intravenous during the first 48 h, starting perioperative, followed by a maintenance immunosuppressive regimen of mycofenolate mofetil 2dd 1000 mg, after two weeks 2dd 500 mg and tacrolimus .

Standard immunosuppressive treatment in the AMC consisted of induction therapy CD25 mAB intravenous prior to transplantation, and at day 4 post-operation. Methyl prednisolone 2 × 50 mg intravenous during the first 48 h, starting perioperative. This is followed by a maintenance immunosuppressive regimen of tacrolimus, mycophenolate mofetil and prednisolone tapered to a dose of 5–10 mg per day.

The primary outcome is the subdomain physical functioning of quality of life of the SF-36. Secondary outcomes include other evaluations of quality of life (SF-36, KDQOL-SF, EQ-5D), muscle strength (Additional file 1: Table S1), aerobic capacity, physical activity, gain in adiposity (body fat percentage by bio-electrical impedance assessment, BMI, waist circumference), and cardiometabolic risk factors (blood pressure, lipids, glucose metabolism). Furthermore, data on renal function, medical history, medication, psychosocial factors (motivation, kinesiophobia, coping style), nutrition knowledge, nutrition intake, nutrition status, fatigue, work participation, process evaluation and cost-effectiveness are collected. Effectiveness of the diet intervention will be determined at 15 months. To study barriers and success factors regarding lifestyle counseling in RTR, data are gathered on psychological factors including motivation, kinesiophobia, and coping style. A comprehensive overview of the measurements in the ACT trial is shown in Table 1.

The physical functioning subscale of the short form 36 (SF-36), version 2 is used as a measure of physical functioning in the present study. Besides subjective measures of physical functioning, objective assessments are also included in the study as described below.

Furthermore, Quality of life is measured by the SF-36, the Kidney Disease Quality of Life Instrument - Short Form (KDQOL-SF) and the EuroQol (EQ-5D). SF-36 consists of 36 items which measure self-reported physical functioning, social functioning, role limitations due to physical and emotional problems, mental health, vitality, pain and general health on a scale of 0–100. The scores are added up into two summary scores, the physical component summary (PCS) and the mental component summary (MCS). The KDQOL-SF contains 13 items targeted at quality of life related to matters of special relevance for renal patients, such as disease burden and social interaction [38]. The KDQOL-SF has been translated into Dutch and validated in Dutch patient population [39]. The EQ-5D is a general questionnaire and contains questions on mobility, self-care, usual activities, pain/discomfort and anxiety/depression and a VAS scale for self-rated health.

Body composition is estimated using a multi-frequency bio-electrical impedance device (BIA, Biostat Quadscan 4000, Douglas, Isle of Man) at 5, 50, 100 and 200 Hz, which allows for distinction between body fat mass and lean body mass taking into account differences in volume status. BIA is used to estimated fat mass, fat free mass and body fat percentage. Muscle mass is estimated as fat free mass from BIA and from 24-h urinary creatinine excretion. The 24-h creatinine excretion is considered a reliable measure of muscle mass even in patients with advanced renal failure, in elderly people, and in patients with wasting conditions [3, 44]. Anthropometry measures include bodyweight, height, waist- and hip circumference. All anthropometry measures are done twice. Bodyweight is measured in lightweight clothing without shoes, preferably in the morning, on a calibrated scale (Seca 877, Seca GMBH, Hamburg, Germany), to the nearest 0.1 kg. Height is measured using a wall-secured stadiometer (Seca 222, Seca GMBH, Hamburg, Germany). Waist circumference is measured with the subject in standing position at the level midway between the lowest rib and iliac crest at the end of an expiration to the nearest 0.1 cm. Waist circumference is also measured in participants with polycystic kidney disease which may create noise in the data, although in case a participant had polycystic kidney disease this is clearly defined in our dataset. Hip circumference is measured as the maximum circumference over the trochanter major to the nearest 0.1 cm. A tape with standardized retraction mechanism (Seca 201, Seca GMBH, Hamburg, Germany) is used. Nutrition status is assessed by subjective global assessment (SGA) [45]. The SGA consists of an anamnesis (questions about change in bodyweight, food intake and gastrointestinal symptoms) and a physical examination (subcutaneous fat, muscular atrophy of the upper and lower body) resulting in an SGA-classification (seriously malnourished, moderately malnourished or normally nourished).

Blood samples are collected after an overnight fast and assayed for triglycerides, total cholesterol, HDL- and LDL cholesterol for lipid profile and for glucose and insulin to calculate insulin resistance (HOMA2-index) [46]. Impaired glucose metabolism is measured using 7-timepoint Oral Glucose Tolerance Test [47]. After fasting blood sampling, the participant consumes a 300 ml glucose solution which contains 75 g of glucose (82.5 g glucose monohydrate). After glucose ingestion, blood is drawn at 10, 20, 30, 40, 60, 90 and 120 min. During the test participants are not allowed to eat or drink, except for a limited amount of water. Blood samples are stored until further analysis. Oral Glucose Tolerance Testing was performed in a subsample (participants from University Medical Center Groningen).

Serum creatinine concentrations are determined using the Jaffé method. Creatinine clearance is calculated from 24-h urinary creatinine excretion and serum creatinine. Medical information is collected from the participants’ medical files, including renal parameters (underlying cause of the renal disease, dialysis duration and type, transplantation type, time since transplantation), medication use, hospital admissions, complications after transplantation, co-morbidities and mortality. Medication is derived from the participants’ medical records.

A quite extensive set of questionnaires to address potential psychological aspects, mostly aspects of motivation, is included in the questionnaires for participants. Details about moment of assessment is given in Table 1. The following questionnaires are included: Basic Needs Satisfaction in General Scale [48, 49]Basic Psychological Needs in Exercise Scale [50], Behavioral Regulation in Exercise Questionnaire version 2 [51], Treatment Self-regulation Questionnaire [52], Intrinsic Motivation Inventory [53], Exercise Motivations Inventory version 2 [54], Perceived Competence Scale [55, 56] and the Health Care Climate Questionnaire [55, 57]. Furthermore, fear of movement is determined using the 17-item Tampa Score for Kinesiophobia [58]. Questions are answered on a 4-point likert-type scale ranging from 0 (not true for me) to 4 (very true for me). Coping style is measured using the Utrecht Coping List, a Dutch 47-item questionnaire [59]. Coping style refers to a persons’ specific efforts to master, tolerate, or reduce stress in stressful conditions. Nutrition knowledge is estimated using items from a national survey, developed by the Netherlands Nutrition Center to assess knowledge of the Dutch dietary guidelines on dietary fibre, fruits, vegetables, calories, fats, and extended with items about potassium and sodium. Chronic fatigue is measured using the Dutch Checklist Individual Resilience (CIS-20) [60‐62] consisting of 20 items covering the subjective experience of fatigue, reduction in motivation, reduction in concentration and reduction in physical activity. CIS-20 is tested thoroughly in the clinical setting among patients with chronic fatigue syndrome and other chronic diseases and healthy controls [63‐65]. Work-induced fatigue is assessed by the Need for Recovery scale [66]. This 11-item questionnaire measures fatigue as a result of exposure to physical and mental demands imposed by work [66, 67]. Work participation is assessed using a previously developed questionnaire for patients with renal disease [68]. Furthermore, the ACT questionnaire contains questions about demographics, smoking, and alcohol consumption.

A three-day food diary is kept for two weekdays and one weekend day. Participants are instructed to fill out the food diary accurately using standard supply units or, in case of deviations, to weigh their food to improve estimate of consumption. Food diaries are analyzed by a dietitian, and the nutrition values are calculated using the software program EvryDietist, 6.4.2.1 (Evry, Alphen aan den Rijn, Netherlands), using the Dutch Food Composition Database 2016 to calculate macro- and micronutrient intake. As part of usual care all participants are instructed to collect a 24-h urine sample according to a strict protocol at the day before their visit to the outpatient clinic, from which dietary sodium intake is calculated. Twenty-four-hour urine collections are stored until further analysis.

Qualitative findings regarding organizing and carrying out the intervention is derived from focus groups with the participants, and separately with 1 focus group with professionals (physiotherapists, dieticians and lifestyle coaches). All participants that are randomized into the intervention groups are invited to take part in the focus group after they have finished the intervention. Each participant focus group lasts 90 min, during which they are asked a series of open questions to evaluate the exercise training phase, the follow-up phase, the lifestyle counseling sessions and dietary counseling sessions. The focus groups are recorded and the recordings are transcribed for analysis. A focus group with the professionals will be done at the end of the ACT study.

Costs en cost effectiveness of the interventions will be studied from a societal perspective over a 15 month time horizon. The effectiveness of the interventions will be assessed using information about the health-related quality of life of the participants, measured using the EQ-5D [69]. This instrument measures health-related quality of life and 60 translates responses into a utility score. The EQ-5D measures health in five dimensions of health-related quality of life (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression). Dutch-specific value sets will be used to translate responses into a utility score. Utility scores will be used to calculate quality-adjusted life-years (QALYs).

Healthcare consumption is measured using a standardized Dutch questionnaire. This questionnaire measures the amount of visits to a healthcare provider, and the means of travelling (i.e. walking/cycling, car, public transport, taxi or other). Unit costs from routinely available sources will be applied to the number of visits to calculate the total costs of these visits for each participant. The Dutch manual for cost-effectiveness analysis is used as a guideline for weighing the cost items [70, 71]. Additional cost calculations will be done for the interventions including personnel, materials, volume and overhead costs. The total costs and QALYs in the intervention groups will be compared to the total costs and QALYs in the control group. An incremental cost-effectiveness ratio (ICER) will be calculated to compare the exercise intervention, and the exercise + diet intervention with usual care. Furthermore, two cost-utility analyses will be done with EQ-5D as an outcome measure.

Short term differences between groups will be tested using students T-test or linear regression, and long term differences will be tested using General Linear Mixed models. Time will be analyzed for exercise intervention (phase 1) and maintenance period (phase 2). Centers will be taken into account as random factor. Intention to treat principle will be applied in primary analyses. Per protocol analysis will be based on completion of the exercise training sessions, and attendance of dietary counseling sessions. Stratified analysis are foreseen for time after transplantation, socio-economic status and immunosuppressive regime. Furthermore, potential preset determinants of intervention outcome will be evaluated in a GLM model: gender, age, coping style, fear of movement, work participation and clinical factors.