Effects of Exogenous Ketosis on Proteinuria and Renal Function (KETO-CKD)

Effects of Exogenous Ketosis on Proteinuria and Renal Function in Patients with Chronic Kidney Disease and Patients with Polycystic Kidney Disease

A randomized, placebo-controlled, double-blinded crossover study will be conducted. Fourteen patients with polycystic kidney disease (PKD) and 29 patients with proteinuric kidney disease will receive ketone bodies (Ketone-IQ) and placebo in a randomized order. Each treatment period is four weeks. There will be a wash-out period of two weeks in between treatment periods. Effect variables will be measured in the last day of each treatment period.

Study Overview

• Status: Recruiting
• Conditions: Renal Insufficiency, Chronic; Proteinuria; Ketosis; Polycystic Kidney Diseases
• Intervention / Treatment: Dietary supplement: Ketone Diol, R-1,3-butanediol (Ketone-IQ); Other: Placebo drink

Detailed Description

Background: Until recently, the only treatment shown to slow progression of chronic kidney disease (CKD) has been angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs).

The use of sodium glucose transporter 2 (SGLT2)-inhibitors, which work by blocking the activity of sodium-glucose-cotransporter 2 channels in the proximal kidney tubule, has completely transformed the treatment of proteinuric kidney disease, with a 28% decrease in the risk for cardiorenal outcomes. Despite these new treatment options, a significant proportion of patients still succumb to kidney failure, require hospitalization for heart failure and die prematurely. Thus, additional preventive measures are essential.

Renewed interest in the physiological role of ketone bodies (KB) has emerged. It has become increasingly clear that ketosis has several beneficial effects including anti-epileptic effects, improved exercise capacity, lipid profile, cardiac function and cognition.

However, only few clinical studies have studied renal effects of exogenous ketosis, and to our knowledge there are no clinical studies examining the effects long term effects of renal ketosis in patients with CKD.

Hypothesis: Ketosis decreases urine albumin to creatinine ratio (ACR) and glomerular filtration rate (GFR) in patients with CKD/PKD.

Methods: A randomized, placebo-controlled, double-blinded crossover study will be conducted. Twenty-nine patients with proteinuric kidney disease (study a) and 14 patients with PKD (study b) will receive ketone bodies (Ketone-IQ) and placebo in a randomized order. Each treatment period is four weeks. There will be a wash-out period of two weeks in between treatment periods. Effect variables will be measured in the last day of each treatment period.

Perspectives: The study has the potential to provide information regarding the therapeutic potential of ketone bodies in patients with CKD/PKD.

• Study Type: Interventional
• Enrollment (Estimated): 43
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Trine Z Lyksholm, MD; Phone Number: 0045 78432534; Email: trizur@rm.dk

Study Locations

• Denmark
  • Jutland
    • Herning, Jutland, Denmark, 7400
      • Recruiting
      • University Clinic in Nephrology and Hypertension, Gødstrup Region Hospital
      • Contact: Trine Z Lyksholm, MD; Phone Number: +4578432534; Email: trizur@rm.dk

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria

Study A (patients with CKD):

• ACR > 200 mg/g <3000 mg/g
• eGFR >30 ml/min/1,73m2
• Treatment with Renin-Angiotension System (RAS) blockers and SGLT-2 inhibitors for a minimum of 4 weeks prior to inclusion
• Safe contraception if women in childbearing age

Study B (patients with PKD):

• Prior diagnose with PKD
• eGFR >30 ml/min/1,73m2
• Treatment with Renin-Angiotension System (RAS) blockers for a minimum of 4 weeks prior to inclusion
• Safe contraception if women in childbearing age

Exclusion Criteria (Study A+B)

• Diabetes Mellitus type 1
• Heart Failure
• Liver Disease
• Kidney transplant
• Malignant diseases (except skin cancer)
• Recent acute myocardial infarction (AMI), apoplexia/transient ischemic attack (TIA) (within 3 months of inclusion)
• Pregnancy or breast feeding
• Alcohol or drug abuse
• Periodic fasting within four weeks of inclusion
• Routinely intake of ketogenic diet within four weeks of inclusion
• Treatment with nitrate

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Ketone diol (Ketone-IQ), then Placebo drink; For four weeks each subject will receive Ketone Diol, R-1,3-butanediol, administered as a drink (Ketone-IQ) twice a day, then crossed over to receive a taste and volume matched placebo drink for four weeks. Each individual will receive 400mg/kg before bedtime in addition to 200mg/kg with a minimum of 6 hours in between throughout the treatment period.	Dietary supplement: Ketone Diol, R-1,3-butanediol (Ketone-IQ); Effect variables will be measured on the last day of treatment with Ketone-IQ; Other: Placebo drink; Effect variables will be measured on the last day of treatment with Placebo
Other: Placebo drink, then Ketone diol (Ketone-IQ); For four weeks each subject will receive a placebo drink twice a day, then crossed over to receive Ketone Diol, R-1,3-butanediol, administered as a drink (Ketone-IQ) twice a day for four weeks. Each individual will receive 400mg/kg before bedtime in addition to 200mg/kg with a minimum of 6 hours in between throughout the treatment period.	Dietary supplement: Ketone Diol, R-1,3-butanediol (Ketone-IQ); Effect variables will be measured on the last day of treatment with Ketone-IQ; Other: Placebo drink; Effect variables will be measured on the last day of treatment with Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proteinuria	Mean difference between Log UACR after 4 weeks treatment with ketone bodies and placebo (primary outcome study a)	Measured on 24 hour urine collection on the last day in each treatment period (each treatment period is 4 weeks)
GFR	Mean difference between GFR measured by Technetium99 (Tc99m) - Diethylene Triamine Pentaacetic Acid (DTPA) clearance after 4 weeks treatment with ketone bodies and placebo (primary outcome study b, secondary outcome in study a)	Measured on the last day in each treatment period (each treatment period is 4 weeks)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Aldosterone	Mean difference in plasma levels of aldosterone (pmol/L) after 4 weeks treatment with ketone bodies and placebo	Measured on the last day in each treatment period (each treatment period is 4 weeks)
P-Beta-hydroxybutyrate	Change ind p-beta-hydroxybutyrate concentration	Measured on the last day in each treatment period (each treatment period is 4 weeks)
Excretion rate of renal tubular transport proteins	Mean difference between urine excretion rate of aquaporin 2 (AQP2) (pq/min), thiazide-sensitive sodium-chloride cotransporter (NCC)(pg/min), and distal epithelial sodium channel (ENaC)(pg/min) after 4 weeks treatment with ketone bodies and placebo	Measured on the last day in each treatment period (each treatment period is 4 weeks)
24-hour Ambulatory Blood Pressure	Mean difference between systolic and diastolic 24-hour ambulatory blood pressure (mmHg) after treatment with ketone bodies and placebo.	Measured using a Mobil-o-graph on the last day in each treatment period (each treatment period is 4 weeks)
Sodium and potassium excretion	Diffeence between mean fractional and absolute excretion af sodium and postassium after 4 weeks treatment with ketone bodies and placebo	Measured on 24 hour urine collection on the last day in each treatment period (each treatment period is 4 weeks)
Peripherial Vascular Resistance	Mean difference between peripherial vascular resistance (dyn*s/cm5) during treatment with ketone bodies compared to placebo	Measured using a Mobil-o-graph on the last day in each treatment period (each treatment period is 4 weeks)
Heart rate	Mean difference between heart rate after 4 weeks treatment with ketone bodies and placebo	Measured using a Mobil-o-graph on the last day in each treatment period (each treatment period is 4 weeks)
Pulse Wave Velocity	Mean difference between pulse wave velocity (m/s) after 4 weeks treatment with ketone bodies and placebo	Measured using a Mobil-o-graph on the last day in each treatment period (each treatment period is 4 weeks)
Renin	Mean difference in plasma concentration of renin(pmol/L) after 4 weeks treatment with ketone bodies and placebo	Measured on the last day in each treatment period (each treatment period is 4 weeks)

Collaborators and Investigators

• Sponsor: Gødstrup Hospital
• Investigators: Principal Investigator: Trine Z Lyksholm, MD, University Clinic in Nephrology and Hypertenion, Godstrup Region Hospital

Study record dates

Study Major Dates

• Study Start (Actual): September 11, 2024
• Primary Completion (Estimated): December 1, 2025
• Study Completion (Estimated): December 1, 2025

Study Registration Dates

• First Submitted: November 20, 2024
• First Submitted That Met QC Criteria: March 6, 2025
• First Posted (Actual): March 25, 2025

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: March 6, 2025
• Last Verified: March 1, 2025

More Information

Terms related to this study

• Keywords: Proteinuria; Natriuresis; Chronic Kidney disease; Ketosis; Glomerular Filtration Rate; Kidney physiology
• Additional Relevant MeSH Terms: Ciliopathies; Urogenital Diseases; Pathologic Processes; Male Urogenital Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Chronic Disease; Disease Attributes; Genetic Diseases, Inborn; Metabolic Diseases; Urination Disorders; Urological Manifestations; Congenital Abnormalities; Abnormalities, Multiple; Acid-Base Imbalance; Kidney Diseases, Cystic; Acidosis; Renal Insufficiency; Kidney Diseases; Renal Insufficiency, Chronic; Proteinuria; Polycystic Kidney Diseases; Ketosis
• Other Study ID Numbers: TZL-2-2024

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No