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Short Term Induction of Ketosis in PKD (RESET-PKD)

Primary Purpose

ADPKD

Status
Completed
Phase
Not Applicable
Locations
Germany
Study Type
Interventional
Intervention
Fasting
Ketogenic diet
Sponsored by
University of Cologne
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional other trial for ADPKD focused on measuring ADPKD, dietary intervention, ketosis, fasting, ketogenic diet

Eligibility Criteria

18 Years - 60 Years (Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Male and female ADPKD-patients (diagnosed by genetics / typical MRI / ultrasound)
  • With evidence of fast progression, at least one of the following criteria

    1. Mayo Class 1C-1E
    2. Truncating PKD1-mutation
    3. Hypertension < 35 years
    4. Urological complications < 35 years
    5. ≥ 1 first class or second class family member with need of renal replacement therapy < 60 years
    6. eGFR loss > 2,5 ml/min/1,73m2 per year
    7. PROPKD-Score > 6
  • Age ≥ 18 and ≤ 60 years
  • CKD stage 1-3a according to eGFR
  • Signed written informed consent

Exclusion Criteria:

  • Currently under tolvaptan
  • BMI < 18 or > 35
  • Diabetes mellitus (Type I, Type II, MODY, LADA)
  • Active alcoholism
  • Vegan or vegetarian lifestyle
  • Inability to sign or understand written informed consent
  • Anamnestically known circumstances which forbid the induction of a ketonic state by ketogenic diet or acute fasting (Liver damage (AST/ALT > 3x upper limit of normal, alkaline phosphatase > 6x upper limit of normal , Bilirubin ≥ 3 mg/dl), Diabetes mellitus, Pyruvate carboxylase deficiency, defects of gluconeogenesis, defects of ketolysis / ketogenesis, hyperinsulinism, defects of fatty acid oxidation )
  • Allergies or food intolerance against components of a ketogenic diet
  • Eating disorders (Anorexia nervosa / Bulimia)
  • Participation in a weight loss program (e.g. Optifast) or intake of medication to promote weight loss within the last six months
  • Ketogenic Diet > 1 month within the last 12 months
  • Chronic renal replacement therapy
  • Previous history of kidney transplantation
  • Uncontrolled local or systemic infection (according to clinical assessment)
  • Simultaneous participation in other interventional studies
  • Pregnant or breastfeeding women
  • Persons who are dependent of or employed by the study investigators
  • Contraindications against MRI examinations (stents, pacemakers or other metal inserts, claustrophobia)
  • Persons living in an establishment by court order or official instructions

Sites / Locations

  • Department II of Internal Medicine, University Hospital Cologne

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

Fasting arm

Diet arm

Arm Description

Participants will be fasting during 72 hours

Participants will be using ketogenic diet for 14 days

Outcomes

Primary Outcome Measures

Relative difference of TKV immediately before and after the ketonic state
MRI-based kidney volumetry at study visit 2 and study visit 3

Secondary Outcome Measures

Absolute and relative difference of TKV
assessed by MRI-based volumetry at all study visits
Absolute and relative difference of height-adjusted total kidney volume (htTKV)
assessed by MRI-based volumetry at all study visits
Absolute and relative difference of total liver volume (TLV)
assessed by MRI-based volumetry at all study visits
Absolute and relative difference of cystic burden of kidneys and liver
assessed by MRI at all study visits
Absolute and relative change of Renal Function Panel
Measurement of creatinine, urea and uric acid in blood and urine samples (measurement unit mg/dl)
Absolute and relative change of electrolytes and minerals
Measurement of electrolyte and minerals (sodium, natrium, potassium, magnesium, chloride, phosphate) in blood (measurement unit mmol/L) and urine samples (measurement unit mmol/24h)
Absolute and relative change of albumin
Measurement in blood and urine samples
Absolute and relative change of glucose
Measurement in blood and urine samples
Absolute and relative change of Hepatic Function Panel
Measurement of Alanine aminotransferase(ALT), Aspartate Aminotransferase (ASP), Alkaline Phosphatase (ALP), gamma-glutamyl transferase (GGT) and Lactate Dehydrogenase (LD) in blood samples (measurement unit U/L)
Absolute and relative change of bilirubin
Measurement in blood samples
Absolute and relative change of lipid panel
Measurement of high density lipoprotein (HDL), low density lipoprotein (LDL), total cholesterol, triglycerides and lipoprotein(a) in blood samples
Absolute and relative change of inflammatory parameters
Measurement of c-reactive protein (CRP) and high sensitivity c-reactive protein (hsCRP) in blood samples ( measurement unit mg/L)
Absolute and relative change in blood count
Measurement of white blood cells, red blood cells, platelets in blood samples (measurement unit 10^9/L )
Absolute and relative change of hemoglobin
Measurement in blood samples
Absolute and relative change of hematokrit
Measurement in blood samples
Absolute and relative change of betahydroxybutyrate level
Measurement of betahydroxybutyrate level in blood samples for determination of ketosis
Absolute and relative change in blood gas analysis
Measurement with blood gas analyzer for determination of ketosis
Analysis of the ketonic state with betahydroxybutyrate level
Betahydroxybutyrate measurement from blood samples of the fingertip by patients at home
Analysis of the ketonic state with ketonuria
Ketonuria measured with urine stix by patients at home
Analysis of the ketonic state with acetoacetate in breath
determination of acetoacetate in breath by patients at home
Absolute and relative change of height
Determination of height
Absolute and relative change of weight
Determination of weight
Absolute and relative change of waist circumference
Determination of waist circumference
Relative change of calorimetry
Could be determined instead of anthropometric parameters
Changes in Bioimpedance
Bioimpedance measurements on each visit
Feeling of hunger, discomforts and problems
measured and documented at home in a study dietary in between study visits
Acetoacetate-concentrations
measured and documented at home in a study dietary in between study visits

Full Information

First Posted
June 9, 2020
Last Updated
September 13, 2021
Sponsor
University of Cologne
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1. Study Identification

Unique Protocol Identification Number
NCT04472624
Brief Title
Short Term Induction of Ketosis in PKD
Acronym
RESET-PKD
Official Title
Short Term Induction of Ketosis in PKD
Study Type
Interventional

2. Study Status

Record Verification Date
September 2021
Overall Recruitment Status
Completed
Study Start Date
July 1, 2020 (Actual)
Primary Completion Date
July 1, 2021 (Actual)
Study Completion Date
July 1, 2021 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University of Cologne

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
Recently, it has been shown that ketose-inducing dietary interventions slow disease progression in animal models of polycystic kidney disease (PKD), even when the state of ketosis is only induced for a short period of time. The present study aims to investigate the effects of short term ketosis on total kidney volume (TKV) (and other parameters) in 10 ADPKD-patients with rapidly progressive disease.
Detailed Description
Recently, dietary models inducing ketosis have been shown to inhibit disease progression in animal models of PKD. Those beneficial dietary models included time-restricted feeding (TRF) without caloric reduction, ad libitum administered ketogenic diet (KD) and acute short-term fasting in mouse, rat and feline models of PKD. In a PKD rat model, TRF without caloric reduction resulted in a strong inhibition of mTOR signaling, proliferation and fibrosis in the affected kidneys. The adminstration of an ad libitum fed KD led to similar results. In rat, mouse and feline models of PKD, acute fasting led to a significant reduction of cyst volume. Therefore, cystic cells seem to be metabolically inflexible and exhibit an altered metabolism characterized by increased glycolysis and, amongst others, defective fatty acid oxidation, similar to the Warburg effect in cancer. (Torres, Kruger et al. 2019) While those beneficial observations were made in mouse, rat and feline models of PKD, the effects of a ketogenic diet in human ADPKD patients have not been investigated yet, even though the adminstration of ketogenic diets is used as a treatment for epilepsy in children since the 1920s and fasting is one of the oldest medical procedures. Therefore, the aim of the present study is to investigate the effects of a short-period ketonic state in 10 ADPKD patients with fast progressive disease. 10 ADPKD-patients (aged 18-60 years, CKD G 1-3a) will be enrolled after giving informed consent. These 10 subjects will go through four trial-related visits. During these visits, physical examinations will be performed, blood will be drawn, urine will be collected and ketone body measurements in breath, blood and urine will be carried out. Each study visit includes an abdominal MRI-scan. Between visit 1 and visit 2, patients will eat their regular carbohydrate-rich diet. After visit 2, a ketonic state will be induced in those patients. Patients can choose whether the ketonic state will be induced by acute fasting for 72 hours (under sufficient water consumption and salt substitution) or by eating a KD for 14 days. Study visit 3 will take place within 72 hours after finishing the dietary intervention. After study visit 3, patients will restart eating their regular diet. Study visit 4 will provide follow-up data 3-6 weeks after the dietary intervention. After study completion, the relative difference of TKV measured by MRI-based volumetry of the kidneys immediately before and immediately after the ketonic state, will be compared to TKV growth/decline while eating a regular carbohydrate-rich diet. In general, patients are counselled in our outpatient department as part of "The German AD(H)PKD Registry" (more than 700 patients enrolled). As from those patients, clinical data, laboratory data and imaging studies are present, identification and recruitment of patients with fast rapidly progressing disease will be facilitated. Also, the investigators are closely liaised with the German self-help group PKDCure (PKD Familiaere Zystennieren e.V.), which is dedicated to ADPKD-linked research. This will facilitate recruitment of patients even more. Data obtained from the study visits will be collected. The parameters listed below constitute the core data set, additional parameters can be included if considered essential. Registered patients will be provided with diaries for the documentation of feeling of hunger, problems and discomforts as well as acetoacetate concentrations in breath. Patients are also provided with a portable breath-analyzer to measure acetoacetate concentrations in breath in between study visits. Study diaries are collected on Visit 4. Data capture will be performed at each study visit after enrollment.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
ADPKD
Keywords
ADPKD, dietary intervention, ketosis, fasting, ketogenic diet

7. Study Design

Primary Purpose
Other
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
10 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Fasting arm
Arm Type
Experimental
Arm Description
Participants will be fasting during 72 hours
Arm Title
Diet arm
Arm Type
Experimental
Arm Description
Participants will be using ketogenic diet for 14 days
Intervention Type
Other
Intervention Name(s)
Fasting
Intervention Description
Acute fasting for 72 hours
Intervention Type
Other
Intervention Name(s)
Ketogenic diet
Intervention Description
Intake of a ketogenic diet for 14 days
Primary Outcome Measure Information:
Title
Relative difference of TKV immediately before and after the ketonic state
Description
MRI-based kidney volumetry at study visit 2 and study visit 3
Time Frame
Visit 2: 2-4 Weeks after enrolment; Visit 3: 3 - 21 days after Visit 2
Secondary Outcome Measure Information:
Title
Absolute and relative difference of TKV
Description
assessed by MRI-based volumetry at all study visits
Time Frame
Baseline visit (V1) and final study visit (V4) after at maximum 95 days
Title
Absolute and relative difference of height-adjusted total kidney volume (htTKV)
Description
assessed by MRI-based volumetry at all study visits
Time Frame
Baseline visit (V1) and final study visit (V4) after at maximum 95 days
Title
Absolute and relative difference of total liver volume (TLV)
Description
assessed by MRI-based volumetry at all study visits
Time Frame
Baseline visit (V1) and final study visit (V4) after at maximum 95 days
Title
Absolute and relative difference of cystic burden of kidneys and liver
Description
assessed by MRI at all study visits
Time Frame
Baseline visit (V1) and final study visit (V4) after at maximum 95 days
Title
Absolute and relative change of Renal Function Panel
Description
Measurement of creatinine, urea and uric acid in blood and urine samples (measurement unit mg/dl)
Time Frame
Baseline visit (V1), study visit 2 (V2): 2-4 Weeks after enrolment; Visit 3: 3 - 21 days after Visit 2, and final study visit (V4) after at maximum 95 days
Title
Absolute and relative change of electrolytes and minerals
Description
Measurement of electrolyte and minerals (sodium, natrium, potassium, magnesium, chloride, phosphate) in blood (measurement unit mmol/L) and urine samples (measurement unit mmol/24h)
Time Frame
Baseline visit (V1), study visit 2 (V2): 2-4 Weeks after enrolment; Visit 3: 3 - 21 days after Visit 2, and final study visit (V4) after at maximum 95 days
Title
Absolute and relative change of albumin
Description
Measurement in blood and urine samples
Time Frame
Baseline visit (V1), study visit 2 (V2): 2-4 Weeks after enrolment; Visit 3: 3 - 21 days after Visit 2, and final study visit (V4) after at maximum 95 days
Title
Absolute and relative change of glucose
Description
Measurement in blood and urine samples
Time Frame
Baseline visit (V1), study visit 2 (V2): 2-4 Weeks after enrolment; Visit 3: 3 - 21 days after Visit 2, and final study visit (V4) after at maximum 95 days
Title
Absolute and relative change of Hepatic Function Panel
Description
Measurement of Alanine aminotransferase(ALT), Aspartate Aminotransferase (ASP), Alkaline Phosphatase (ALP), gamma-glutamyl transferase (GGT) and Lactate Dehydrogenase (LD) in blood samples (measurement unit U/L)
Time Frame
Baseline visit (V1), study visit 2 (V2): 2-4 Weeks after enrolment; Visit 3: 3 - 21 days after Visit 2, and final study visit (V4) after at maximum 95 days
Title
Absolute and relative change of bilirubin
Description
Measurement in blood samples
Time Frame
Baseline visit (V1), study visit 2 (V2): 2-4 Weeks after enrolment; Visit 3: 3 - 21 days after Visit 2, and final study visit (V4) after at maximum 95 days
Title
Absolute and relative change of lipid panel
Description
Measurement of high density lipoprotein (HDL), low density lipoprotein (LDL), total cholesterol, triglycerides and lipoprotein(a) in blood samples
Time Frame
Baseline visit (V1), study visit 2 (V2): 2-4 Weeks after enrolment; Visit 3: 3 - 21 days after Visit 2, and final study visit (V4) after at maximum 95 days
Title
Absolute and relative change of inflammatory parameters
Description
Measurement of c-reactive protein (CRP) and high sensitivity c-reactive protein (hsCRP) in blood samples ( measurement unit mg/L)
Time Frame
Baseline visit (V1), study visit 2 (V2): 2-4 Weeks after enrolment; Visit 3: 3 - 21 days after Visit 2, and final study visit (V4) after at maximum 95 days
Title
Absolute and relative change in blood count
Description
Measurement of white blood cells, red blood cells, platelets in blood samples (measurement unit 10^9/L )
Time Frame
Baseline visit (V1), study visit 2 (V2): 2-4 Weeks after enrolment; Visit 3: 3 - 21 days after Visit 2, and final study visit (V4) after at maximum 95 days
Title
Absolute and relative change of hemoglobin
Description
Measurement in blood samples
Time Frame
Baseline visit (V1), study visit 2 (V2): 2-4 Weeks after enrolment; Visit 3: 3 - 21 days after Visit 2, and final study visit (V4) after at maximum 95 days
Title
Absolute and relative change of hematokrit
Description
Measurement in blood samples
Time Frame
Baseline visit (V1), study visit 2 (V2): 2-4 Weeks after enrolment; Visit 3: 3 - 21 days after Visit 2, and final study visit (V4) after at maximum 95 days
Title
Absolute and relative change of betahydroxybutyrate level
Description
Measurement of betahydroxybutyrate level in blood samples for determination of ketosis
Time Frame
Baseline visit (V1), study visit 2 (V2): 2-4 Weeks after enrolment; Visit 3: 3 - 21 days after Visit 2, and final study visit (V4) after at maximum 95 days
Title
Absolute and relative change in blood gas analysis
Description
Measurement with blood gas analyzer for determination of ketosis
Time Frame
Baseline visit (V1), study visit 2 (V2): 2-4 Weeks after enrolment; Visit 3: 3 - 21 days after Visit 2, and final study visit (V4) after at maximum 95 days
Title
Analysis of the ketonic state with betahydroxybutyrate level
Description
Betahydroxybutyrate measurement from blood samples of the fingertip by patients at home
Time Frame
Baseline visit (V1), during 14 days of ketogenic diet or 3 days fasting and final study visit (V4) after at maximum 95 days
Title
Analysis of the ketonic state with ketonuria
Description
Ketonuria measured with urine stix by patients at home
Time Frame
Baseline visit (V1), during 14 days of ketogenic diet or 3 days fasting and final study visit (V4) after at maximum 95 days
Title
Analysis of the ketonic state with acetoacetate in breath
Description
determination of acetoacetate in breath by patients at home
Time Frame
Baseline visit (V1), during 14 days of ketogenic diet or 3 days fasting and final study visit (V4) after at maximum 95 days
Title
Absolute and relative change of height
Description
Determination of height
Time Frame
Baseline visit (V1), V2 (2-4 Weeks after enrolment); Visit 3 (3 - 21 days after Visit 2 ) and final study visit (V4) after at maximum 95 days
Title
Absolute and relative change of weight
Description
Determination of weight
Time Frame
Baseline visit (V1), V2 (2-4 Weeks after enrolment); Visit 3 (3 - 21 days after Visit 2 ) and final study visit (V4) after at maximum 95 days
Title
Absolute and relative change of waist circumference
Description
Determination of waist circumference
Time Frame
Baseline visit (V1), V2 (2-4 Weeks after enrolment); Visit 3 (3 - 21 days after Visit 2 ) and final study visit (V4) after at maximum 95 days
Title
Relative change of calorimetry
Description
Could be determined instead of anthropometric parameters
Time Frame
Baseline visit (V1), V2 (2-4 Weeks after enrolment); Visit 3 (3 - 21 days after Visit 2 ) and final study visit (V4) after at maximum 95 days
Title
Changes in Bioimpedance
Description
Bioimpedance measurements on each visit
Time Frame
Baseline visit (V1), V2 (2-4 Weeks after enrolment); Visit 3 (3 - 21 days after Visit 2 ) and final study visit (V4) after at maximum 95 days
Title
Feeling of hunger, discomforts and problems
Description
measured and documented at home in a study dietary in between study visits
Time Frame
In between baseline visit (V1) and final study visit (V4) after at maximum 95 days
Title
Acetoacetate-concentrations
Description
measured and documented at home in a study dietary in between study visits
Time Frame
In between baseline visit (V1) and final study visit (V4) after at maximum 95 days
Other Pre-specified Outcome Measures:
Title
Changes of renal functional panel in 24-h-urine
Description
Urin samples will be collected before and during the dietary intervention for the determination of creatinine, uric acid and urea (measurement unit mg/24h)
Time Frame
Baseline and during 14 days of ketogenic diet or 3 days fasting
Title
Changes of electrolytes and minerals in 24-h-urine
Description
Urin samples will be collected before and during the dietary intervention for the determination of sodium, natrium, potassium, magnesium, chloride, phosphate (measurement unit mmol/24h )
Time Frame
Baseline and during 14 days of ketogenic diet or 3 days fasting
Title
Changes of glucose in 24-h-urine
Description
Urin samples will be collected before and during the dietary intervention
Time Frame
Baseline and during 14 days of ketogenic diet or 3 days fasting
Title
Changes of albumin in 24-h-urine
Description
Urin samples will be collected before and during the dietary intervention
Time Frame
Baseline and during 14 days of ketogenic diet or 3 days fasting
Title
Analysis of stool samples
Description
Stool samples will be collected before and during the dietary intervention and analysed
Time Frame
Baseline and during 14 days of ketogenic diet or 3 days fasting
Title
Changes of renal functional panel in spot urine
Description
Urin samples will be collected before and during the dietary intervention for the determination of creatinine, uric acid and urea (measurement unit g/24h)
Time Frame
Baseline and during 14 days of ketogenic diet or 3 days fasting
Title
Changes of electrolytes and minerals in spot urine
Description
Urin samples will be collected before and during the dietary intervention for the determination of sodium, natrium, potassium, magnesium, chloride, phosphate (measurement unit mmol/24h)
Time Frame
Baseline and during 14 days of ketogenic diet or 3 days fasting
Title
Changes of albumin in spot urine
Description
Urin samples will be collected before and during the dietary intervention
Time Frame
Baseline and during 14 days of ketogenic diet or 3 days fasting
Title
Changes of glucose in spot urine
Description
Urin samples will be collected before and during the dietary intervention
Time Frame
Baseline and during 14 days of ketogenic diet or 3 days fasting
Title
Changes in urinary doubly refractile lipid bodies
Description
Urin samples will be collected before and during the dietary intervention
Time Frame
Baseline and during 14 days of ketogenic diet or 3 days fasting

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
60 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Male and female ADPKD-patients (diagnosed by genetics / typical MRI / ultrasound) With evidence of fast progression, at least one of the following criteria Mayo Class 1C-1E Truncating PKD1-mutation Hypertension < 35 years Urological complications < 35 years ≥ 1 first class or second class family member with need of renal replacement therapy < 60 years eGFR loss > 2,5 ml/min/1,73m2 per year PROPKD-Score > 6 Age ≥ 18 and ≤ 60 years CKD stage 1-3a according to eGFR Signed written informed consent Exclusion Criteria: Currently under tolvaptan BMI < 18 or > 35 Diabetes mellitus (Type I, Type II, MODY, LADA) Active alcoholism Vegan or vegetarian lifestyle Inability to sign or understand written informed consent Anamnestically known circumstances which forbid the induction of a ketonic state by ketogenic diet or acute fasting (Liver damage (AST/ALT > 3x upper limit of normal, alkaline phosphatase > 6x upper limit of normal , Bilirubin ≥ 3 mg/dl), Diabetes mellitus, Pyruvate carboxylase deficiency, defects of gluconeogenesis, defects of ketolysis / ketogenesis, hyperinsulinism, defects of fatty acid oxidation ) Allergies or food intolerance against components of a ketogenic diet Eating disorders (Anorexia nervosa / Bulimia) Participation in a weight loss program (e.g. Optifast) or intake of medication to promote weight loss within the last six months Ketogenic Diet > 1 month within the last 12 months Chronic renal replacement therapy Previous history of kidney transplantation Uncontrolled local or systemic infection (according to clinical assessment) Simultaneous participation in other interventional studies Pregnant or breastfeeding women Persons who are dependent of or employed by the study investigators Contraindications against MRI examinations (stents, pacemakers or other metal inserts, claustrophobia) Persons living in an establishment by court order or official instructions
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Roman-Ulrich Müller, Prof.
Organizational Affiliation
Department II of Internal Medicine, University of Cologne
Official's Role
Principal Investigator
Facility Information:
Facility Name
Department II of Internal Medicine, University Hospital Cologne
City
Cologne
ZIP/Postal Code
50937
Country
Germany

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
31631001
Citation
Torres JA, Kruger SL, Broderick C, Amarlkhagva T, Agrawal S, Dodam JR, Mrug M, Lyons LA, Weimbs T. Ketosis Ameliorates Renal Cyst Growth in Polycystic Kidney Disease. Cell Metab. 2019 Dec 3;30(6):1007-1023.e5. doi: 10.1016/j.cmet.2019.09.012. Epub 2019 Oct 17.
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Short Term Induction of Ketosis in PKD

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