Modification of Diet in Renal Transplantation (MDRT)

Study Overview
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Brief Summary
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Abnormalities in lipid metabolism are present in 50-80% of patients with a kidney transplant and together with concurrent comorbidities and other associated cardiovascular risk factors put kidney transplant recipients at a high-risk for cardiovascular disease. First line lipid-lowering therapy in this population is pharmacological with 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins), however there is a paucity of data on the efficacy of therapeutic lifestyle modification for cardiovascular risk management in kidney transplant recipients. The aim of the present study is to assess efficacy, safety and feasibility of a nutritional intervention for lowering cardiovascular risk factors in kidney transplant recipients. Investigators will conduct a randomized controlled trial on the effects of a low-fat, unrefined, plant-based diet compared to the currently recommended diet according to nutrition guidelines and based on the Mediterranean diet pattern to lower the primary end-point LDL-cholesterol and other secondary end-points validated as risk factors for cardiovascular events. Length of the intervention will be 6 weeks, with a late follow-up after additional 3 months. Stabile kidney transplant recipients with LDL-cholesterol >2.6 mmol/l and/or receiving lipid lowering treatment will be randomized in a 1:1 ratio to either interventional low-fat, unrefined, plant-based diet or to a control diet based on the Mediterranean dietary pattern. Both diets will be prescribed in the form of a weekly menu, both will be allowed to be eaten ad libitum (without prespecified calorie restriction) and in both groups study participants will be supported by tutor classes and counseling to maximise their adherence to prescribed dietary pattern.

Detailed Description
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BACKGROUND. Abnormalities in lipid metabolism are present in 50-80% of patients with a kidney transplant, as a consequence of both the primary cause of end-stage renal disease, its complications and immunosuppressive therapy. Concurrent comorbidities and cardiovascular risk factors put kidney transplant recipients at high-risk for cardiovascular disease, therefore the target LDL-cholesterol was set to below 2.6 mmol/l (< 100 mg/dl) by the guidelines. First line lipid-lowering therapy in this population is pharmacological, namely with HMG-CoA reductase inhibitors (statins), which have potential interactions with immunosuppressive drugs and increased risk of adverse effects. There is a paucity of data on the efficacy of therapeutic lifestyle modification for cardiovascular risk management in the kidney transplant recipient. Studies in the general population showed a significant effect of mostly plant-based nutrition on lowering lipid levels, achieving approximately 10-15% reduction in both total and LDL-cholesterol, while the effect on cardiovascular protection of such nutritional intervention remains hypothetical. The aim of the present study is to confirm efficacy, safety and feasibility of nutritional intervention for lowering cardiovascular risk factors in kidney transplant recipients. METHODS. Investigators will conduct a randomized controlled trial on the effects of a low-fat, unrefined, plant-based diet compared to the currently recommended diet based on the Mediterranean dietary pattern and complying with current nutrition guidelines for general population to lower LDL-cholesterol. Duration of dietary intervention will be 6 weeks with further extension of intervention and assessment of end-points after additional 3 months. Final follow-up is scheduled after 12 months regardless of continuation of the intervention as decided by subjects themselves. Subjects in the experimental group will receive a meal plan based on low-fat, unrefined, plant based foods with the goal macronutrient intake of approximately 15% protein, <15 % fats and 70-75% of carbohydrates, and will additionally receive polyunsaturated fatty acid (PUFA n-3) supplement (daily dose 840 mg) to ensure daily recommended intake. Subjects in the control group will receive a meal plan in accordance with recommendations by the Task Force for the Management of Dyslipidaemias of the European Society of Cardiology and European Atherosclerosis Society incorporating foods according to the Mediterranean dietary pattern including the usage of (but not limited to) olive oil, fatty-fish and low-fat dairy products. To promote adherence to the meal plan, subjects will receive dietary counselling and will be invited to attend weekly peer-group meetings together with a next of kin. Both diets will be allowed to be eaten at libitum and no calorie counts will be made. A random 24-hour recall, announced prospective 3-day food diary analysis and analysis of a 24-hour urine collection to determine adherence to the prescribed meal plan will be performed. To ensure safety, periodically monitoring of basic serum electrolyte concentrations, body weight and composition, and adjustment of antihypertensive and antihyperglycemic medications will be allowed. No change of lipid lowering agents will be allowed for the first 6-week study period. Feasibility of the intervention will be assessed by adherence monitoring as described above and with the Kidney Disease Quality of Life Short Form questionnaire. Analysis of covariance with baseline parameter value used as a covariate will be used for primary statistical analysis. Based on expected effect of nutritional intervention on lowering LDL-cholesterol by 0.6 mmol/l (23 mg/dl) in the study population by the end of intervention period, standard deviation of LDL-cholesterol of 0.6 mmol/l (23 mg/dl) in the study population with the expected drop-out rate of 15 %, the required sample size of 43 participants in each group to achieve a statistical significance p < 0.05 and statistical power of 80% is defined.

Official Title
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Nutritional Intervention for Management of Cardiovascular Risk Factors in Kidney Transplant Patients

Conditions
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Kidney Transplant; Complications

Intervention / Treatment
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* Behavioral: Plant-based diet
* Behavioral: Mediterranean diet


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: recipient of kidney transplant > 12 weeks after transplantation and evaluated as clinically stable age 18 years or more at inclusion estimated glomerular filtration rate (GFR) > 15 ml/min/1.73 diagnosed dyslipidemia (LDL-cholesterol > 2.6 mmol/l (> 100 mg/dl) at inclusion or receiving lipid-lowering therapy) ability to participate in a lifestyle modification study. Exclusion Criteria: acute illness, infection or surgical intervention requiring hospitalization in 6 weeks before inclusion, except procedures relating to arteriovenous fistula treatment of acute rejection or citomegalovirus infection in 6 weeks before inclusion chronic illness, associated with or increasing the risk of cachexia (including congestive heart failure New York Heart Association III or IV, AIDS, advanced chronic obstructive pulmonary disease, metastatic neoplastic disease or locally active neoplastic disease, chemotherapy treatment in 6 weeks before inclusion) clinically evident malnutrition (BMI < 18,5, reduction of body weight > 5% in 3 months before inclusion, reduction of dietary intake > 25 % from normal in 2 weeks before inclusion, serum albumin < 30 g/l (< 3 g/dl)) nephrotic syndrome pregnancy treatment with vitamin K antagonists change in lipid-lowering therapy in 3 weeks before inclusion

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Randomized controlled trial with two parallel groups.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Plant-based diet<br>Participants will receive a meal plan based on unrefined plant-based foods with the following macronutrient composition: approximately 15% of calories from vegetable protein, <15% from fat, and 70-75% from carbohydrates. Additionally, to ensure adequate intake of n-3 polyunsaturated fatty acids, they will receive a supplement in the form of one 840 mg n-3 acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) daily. Nutritional intervention includes dietary counselling and weekly peer-group meetings together with a next of kin. | Behavioral: Plant-based diet<br>* Prescription of a meal plan based on unrefined plant-based foods supported by peer group meetings and dietary counselling. Change from the standard western-type nutritional pattern to a low-fat, unrefined, plant-based nutritional pattern.<br>|
| Active Comparator: Mediterranean diet<br>Participants will receive a meal plan, based on the recommendations by the Task Force for the Management of Dyslipidaemias of the European Society of Cardiology and European Atherosclerosis Society, based on Mediterranean diet pattern with the following macronutrient composition: approximately 15% of calories from animal and vegetable protein, up to 30% of calories from fat, 50-65% from carbohydrates. Nutritional intervention includes dietary counselling and weekly peer-group meetings together with a next of kin. | Behavioral: Mediterranean diet<br>* Prescription of a meal plan based on Mediterranean diet pattern supported by peer group meetings and dietary counselling. Change from the standard western-type nutritional pattern to a Mediterranean nutritional pattern.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Serum low density lipoprotein (LDL)-cholesterol | Serum LDL-cholesterol concentration | 6 weeks and 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Apolipoprotein B | Apolipoprotein B serum concentration | 6 weeks and 3 months | 
| Reduction in insulin resistance | Change in insulin resistance, measured by Homeostatic Model Assessment (HOMA-IR) | 6 weeks and 3 months | 
| Serum cholesterol | Serum total cholesterol concentration | 6 weeks and 3 months | 
| Oxidized Low Density Lipoprotein (LDL)-cholesterol | Serum concentration of oxidized LDL-cholesterol | 6 weeks and 3 months | 
| Inflammatory marker high sensitive C-Reactive Protein (hs-CRP) | Serum concentration of inflammatory marker high sensitive C-reactive Protein | 6 weeks and 3 months | 
| Total fat tissue mass | Total body fat mass measured with bioimpedance analysis | 6 weeks and 3 months | 
| Lean tissue mass | Lean tissue mass measured by bioimpedance analysis | 6 weeks and 3 months | 
| Blood pressure | Office measured blood pressure | 6 weeks and 3 months | 
| Proteinuria | Spot urinary protein to creatinine-ratio of the second morning urine | 6 weeks and 3 months | 
| Serum potassium | Serum potassium concentration (safety outcome) | 6 weeks and 3 months | 
| Serum phosphate | Serum phosphate concentration | 6 weeks and 3 months | 
| Serum bicarbonate | Serum concentration of bicarbonate (safety outcome) | 6 weeks and 3 months | 
| Serum uric acid | Serum uric acid concentration (safety outcome) | 6 weeks and 3 months | 
| Micronutrient status of Selenium (safety outcome) | Plasma Selenium concentration | 6 weeks and 3 months | 
| n-3 Polyunsaturated Fatty Acid (PUFA) status | n-3 PUFA content of erythrocyte lipid fraction | 6 weeks and 3 months | 
| Urinary C-X-C motif chemokine 10 (CXCL10) | Urinary levels of C-X-C motif chemokine 10 (CXCL10) as an indicator of tubulointerstital and microvascular inflammation | 6 weeks and 3 months | 
| Gut produced uremic toxin p-cresyl sulphate | Serum level of total and free p-cresyl sulphate | 6 weeks and 3 months | 
| Urinary iodine concentration | Urinary level of iodine concentration in ug/L | 6 weeks and 3 months | 
| Plasma Zinc concentration (safety outcome) | Plasma zinc concentration | 6 weeks and 3 months | 
| Serum calcium concentration (safety outcome) | Serum concentration of total calcium in mmol/l | 6 weeks and 3 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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nutrition, dyslipidemia, insulin resistance, inflammation