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

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

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.

Study Overview

• Status: Recruiting
• Conditions: CKD Stage 4
• Intervention / Treatment: Behavioral: Protein restriction

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Anticipated): 120
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Liliana Garneata, Assoc Prof; Phone Number: +40722619358; Email: lilianagarna@yahoo.com
• Study Contact Backup: Name: Gabriel Stefan, MD; Phone Number: +40724906188; Email: gabriel_stefan@rocketmail.com

Study Locations

• Romania
  • Bucharest, Romania, 010731
    • Recruiting
    • "Dr Carol Davila" Teaching Hospital of Nephrology
    • Contact: Liliana Garneata, Assoc Prof; Phone Number: +40722619358; Email: lilianagarna@yahoo.com
    • Contact: Carmen Antonia Mocanu, MD; Phone Number: +40723673275; Email: carmen_a9@yahoo.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 85 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Supplemented low protein diet (sLPD); 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; 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.
Active Comparator: Mild protein restriction diet (MPD); Mild restriction in dietary protein intake (0.8 g/kg-day)	Behavioral: Protein restriction; 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.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Anemia Working Group Romania

Publications and helpful links

General Publications

• Mihalache A, Garneata L, Mocanu CA, Simionescu TP, Mircescu G. Low-salt low-protein diet and blood pressure control in patients with advanced diabetic kidney disease and heavy proteinuria. Int Urol Nephrol. 2021 Jun;53(6):1197-1207. doi: 10.1007/s11255-020-02717-2. Epub 2021 Jan 2.

Study record dates

Study Major Dates

• Study Start (Actual): October 1, 2019
• Primary Completion (Anticipated): September 30, 2022
• Study Completion (Anticipated): March 31, 2023

Study Registration Dates

• First Submitted: December 30, 2017
• First Submitted That Met QC Criteria: January 23, 2018
• First Posted (Actual): January 30, 2018

Study Record Updates

• Last Update Posted (Actual): February 24, 2020
• Last Update Submitted That Met QC Criteria: February 21, 2020
• Last Verified: February 1, 2020

More Information

Terms related to this study

• Keywords: Diabetic Kidney Disease; low protein diet
• Additional Relevant MeSH Terms: Urologic Diseases; Endocrine System Diseases; Diabetes Complications; Diabetes Mellitus; Kidney Diseases; Diabetic Nephropathies
• Other Study ID Numbers: AnemiaWGRomania

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: Unique patient number in the study, biological data; no data to enable patient identification will be provided
• IPD Sharing Time Frame: March 2022
• IPD Sharing Supporting Information Type: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF); Clinical Study Report (CSR); Analytic Code

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No