Could Ketoanalogue-supplemented Low Protein Diet Defer Dialysis in Advanced Diabetic Kidney Disease? (K-DDD)

Study Overview
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Brief Summary
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This is a prospective single center open label randomized controlled trial aiming to assess the effectiveness and safety of a low protein diet (0.6 g/kg-day, mainly vegetarian) supplemented with ketoanalogues of essential amino-acids (sLPD) as compared to a mild protein restriction (0.8 g/kg-day, MPD) in reducing Chronic Kidney Disease (CKD) progression, with a planned total duration is of 18 months. Adult diabetic patients with CKD stage 4+ [estimated glomerular filtration rate (eGFR) using the Modification of Diet in Renal Disease 4-variable (MDRD4) formula <30 mL/min per year], with stable renal function (historical reduction of eGFR of < 10 ml/min-year) , proteinuria > 3g/g creatininuria and good nutritional status (SGA A) will be enrolled.

Detailed Description
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Adult diabetic patients with Chronic Kidney Disease (CKD) stage 4+ (estimated GFR using the Modification of Diet in Renal Disease 4-variable, MDRD4, formula <30 mL/min per year), with stable renal function (historical reduction of eGFR of < 10 ml/min-year), proteinuria > 3g/g creatininuria and good nutritional status (SGA A) will be enrolled. Patients with evidence of active kidney disease (except proteinuria), with indication of etiological or pathogenic treatment, those with poor control of diabetes (HbA1c >8%), those with uncontrolled high blood pressure (≥155/85 mmHg), those with significant co-morbidities (heart failure, active liver disease, malabsorption, active infections, inflammatory diseases requiring corticosteroids), those with uremic symptoms (pericarditis, digestive disorders ) or malnutrition (SGA B or C, serum albumin < 3.5 g/dl) will be excluded. Eligible patients will enter a run-in phase (3 mo), when mild protein restriction (0.8g/kg dry ideal bw) will be initiated and compliance will be evaluated twice monthly. Those who will prove compliant during the run-in phase and still fulfill the selection criteria will be randomized 1:1 (computer-generated numbers) to receive the low protein diet (0.6 g/kg-day, mainly vegetarian) supplemented with ketoanalogues of essential amino-acids (Ketosteril 1 tb/10 kg dry bw) or to continue the mild protein restriction (0.8 g/kg-day). The total recommended energy intake is of 30 kcal/kg of ideal dry body weight per day in all patients. The primary composite endpoint is the need for RRT initiation or a more than 50% reduction in the initial eGFR any time during the assessment phase. The decision to initiate RRT will be made by the Ethical Committee of the Hospital, based on the clinical and laboratory data. The need for RRT initiation, the quality of life [assessed by the Short Form-36 (SF-36) Questionnaire], the decline in GFR and the correction of metabolic complications of CKD [serum levels of urea, calcium, phosphates, serum parathyroid hormone levels, bicarbonate, potassium] will be secondary efficacy parameters. Parameters of nutritional status (SGA, anthropometric and biochemical parameters), compliance to the diet, occurrence of any adverse event and the number of withdrawals will be safety variables. All the parameters will be assessed at baseline, throughout the intervention phase and at end of the study.

Official Title
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Ketoanalogue-supplemented Low Protein Diet and Deferring Dialysis in Patients With Severe Proteinuria and Advanced Diabetic Kidney Disease

Conditions
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CKD Stage 4

Intervention / Treatment
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* Behavioral: Protein restriction


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: diabetic patients CKD stage 4+ (estimated GFR using the Modification of Diet in Renal Disease 4-variable, MDRD4, formula <30 mL/min per year) stable renal function (historical reduction of eGFR of < 10 ml/min-year) proteinuria > 3g/g creatininuria good nutritional status (SGA A) Exclusion Criteria: evidence of active kidney disease (except proteinuria) indication for etiological or pathogenic treatment poor control of diabetes (HbA1c >8%) uncontrolled high blood pressure (≥155/85 mmHg) significant co-morbidities (heart failure, active liver disease, malabsorption, active infections, inflammatory diseases requiring corticosteroids) uremic symptoms (pericarditis, digestive disorders or malnutrition (SGA B or C, serum albumin < 3.5 g/dl)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 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: Eligible patients will enter a run-in phase (3 mo), when mild protein diet (0.8g/kg dry ideal bw) will be initiated and compliance will be evaluated twice monthly. Those who will prove compliant during the run-in phase and still fulfill the selection criteria will be randomized 1:1 (computer-generated numbers) to receive the low protein diet (0.6 g/kg-day, mainly vegetarian) supplemented with ketoanalogues of essential amino-acids (Ketosteril 1 tb/10 kg dry bw) or to continue the mild protein restriction (0.8 g/kg-day).
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Supplemented low protein diet (sLPD)<br>Protein restriction to a low level (0.6 g/kg-day, mainly vegetarian) + ketoanalogues of essential amino-acids supplementation (Ketosteril 1 tb/10 kg dry bw) | Behavioral: Protein restriction<br>* In both arms the dietary protein intake will be reduced. In the sLPD arm, the protein restriction is more severe and ketoanalogues of the essential aminoacids are offered.<br>|
| Active Comparator: Mild protein restriction diet (MPD)<br>Mild restriction in dietary protein intake (0.8 g/kg-day) | Behavioral: Protein restriction<br>* In both arms the dietary protein intake will be reduced. In the sLPD arm, the protein restriction is more severe and ketoanalogues of the essential aminoacids are offered.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| CKD progression | Percentage of patients requiring RRT initiation or a more than 50% reduction in the initial eGFR at anytime during the study | 15 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Need for renal replacement therapy (RRT) | Percentage of patients requiring RRT during the study | 15 months | 
| Patients' Quality of life | Patients' Quality of life, assessed by the SF-36 Questionnaire | at baseline and than every 3 months up to 15 months | 
| Decline in eGFR | Difference between eGFR at any timepoint and the initial eGFR | monthly up to 15 months | 
| Correction of nitrogen balance | Serum urea | monthly up to 15 months | 
| Correction of metabolic acidosis | Serum bicarbonate | monthly up to 15 months | 
| Correction of calcium metabolism abnormalities | Serum calcium | monthly up to 15 months | 
| Correction of mineral metabolism abnormalities | Serum phosphates | monthly up to 15 months | 
| Serum level of intact Parathyroid Hormone (iPTH) | iPTH | monthly up to 15 months | 
| Nutritional status - Subjective Global Assessment (SGA) | SGA | monthly up to 15 months | 
| Body Mass Index (BMI) | BMI | monthly up to 15 months | 
| Tricipital Skin Fold (TSF) | TSF | monthly up to 15 months | 
| Middle arm muscular circumference (MAMC) | MAMC | monthly up to 15 months | 
| Serum albumin | Serum albumin | monthly up to 15 months | 
| Serum cholesterol | Serum cholesterol | monthly up to 15 months | 
| Inflammatory status | Serum C-Reactive Protein (CRP) | monthly up to 15 months | 
| Compliance to the protein intake | Achieved protein intake (urinary urea excretion, Mitch-Maroni's formula) | twice-a-month during the run-in phase, weekly for the first month after randomization, every 4 weeks during the next 6 months, and then every 3 months up to 15 months | 
| Compliance to the energy intake | Achieved energy intake (3-days food dairy) | twice-a-month during the run-in phase, weekly for the first month after randomization, every 4 weeks during the next 6 months, and then every 3 months up to 15 months | 
| Occurence of the adverse events | Occurence of any adverse event | twice-a-month during the run-in phase, weekly for the first month after randomization, every 4 weeks during the next 6 months, and every 3 months up to 15 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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low protein diet, Diabetic Kidney Disease