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

• ClinicalTrials.gov Identifier: NCT04472624
• Recruitment Status: Completed
• First Posted: July 15, 2020
• Last Update Posted: September 14, 2021
• Sponsor: University of Cologne
• Information provided by (Responsible Party): Roman Müller, University of Cologne

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.

Condition or disease	Intervention/treatment	Phase
ADPKD	Other: Fasting; Other: Ketogenic diet	Not Applicable

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 10 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Other
• Official Title: Short Term Induction of Ketosis in PKD
• Actual Study Start Date: July 1, 2020
• Actual Primary Completion Date: July 1, 2021
• Actual Study Completion Date: July 1, 2021

Arms and Interventions

Arm	Intervention/treatment
Experimental: Fasting arm; Participants will be fasting during 72 hours	Other: Fasting; Acute fasting for 72 hours
Experimental: Diet arm; Participants will be using ketogenic diet for 14 days	Other: Ketogenic diet; Intake of a ketogenic diet for 14 days

Outcome Measures

Primary Outcome Measures :

1. Relative difference of TKV immediately before and after the ketonic state [ Time Frame: Visit 2: 2-4 Weeks after enrolment; Visit 3: 3 - 21 days after Visit 2 ]
   MRI-based kidney volumetry at study visit 2 and study visit 3

Secondary Outcome Measures :

1. Absolute and relative difference of TKV [ Time Frame: Baseline visit (V1) and final study visit (V4) after at maximum 95 days ]
   assessed by MRI-based volumetry at all study visits
2. Absolute and relative difference of height-adjusted total kidney volume (htTKV) [ Time Frame: Baseline visit (V1) and final study visit (V4) after at maximum 95 days ]
   assessed by MRI-based volumetry at all study visits
3. Absolute and relative difference of total liver volume (TLV) [ Time Frame: Baseline visit (V1) and final study visit (V4) after at maximum 95 days ]
   assessed by MRI-based volumetry at all study visits
4. Absolute and relative difference of cystic burden of kidneys and liver [ Time Frame: Baseline visit (V1) and final study visit (V4) after at maximum 95 days ]
   assessed by MRI at all study visits
5. Absolute and relative change of Renal Function Panel [ 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 ]
   Measurement of creatinine, urea and uric acid in blood and urine samples (measurement unit mg/dl)
6. Absolute and relative change of electrolytes and minerals [ 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 ]
   Measurement of electrolyte and minerals (sodium, natrium, potassium, magnesium, chloride, phosphate) in blood (measurement unit mmol/L) and urine samples (measurement unit mmol/24h)
7. Absolute and relative change of albumin [ 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 ]
   Measurement in blood and urine samples
8. Absolute and relative change of glucose [ 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 ]
   Measurement in blood and urine samples
9. Absolute and relative change of Hepatic Function Panel [ 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 ]
   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)
10. Absolute and relative change of bilirubin [ 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 ]
    Measurement in blood samples
11. Absolute and relative change of lipid panel [ 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 ]
    Measurement of high density lipoprotein (HDL), low density lipoprotein (LDL), total cholesterol, triglycerides and lipoprotein(a) in blood samples
12. Absolute and relative change of inflammatory parameters [ 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 ]
    Measurement of c-reactive protein (CRP) and high sensitivity c-reactive protein (hsCRP) in blood samples ( measurement unit mg/L)
13. Absolute and relative change in blood count [ 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 ]
    Measurement of white blood cells, red blood cells, platelets in blood samples (measurement unit 10^9/L )
14. Absolute and relative change of hemoglobin [ 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 ]
    Measurement in blood samples
15. Absolute and relative change of hematokrit [ 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 ]
    Measurement in blood samples
16. Absolute and relative change of betahydroxybutyrate level [ 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 ]
    Measurement of betahydroxybutyrate level in blood samples for determination of ketosis
17. Absolute and relative change in blood gas analysis [ 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 ]
    Measurement with blood gas analyzer for determination of ketosis
18. Analysis of the ketonic state with betahydroxybutyrate level [ 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 ]
    Betahydroxybutyrate measurement from blood samples of the fingertip by patients at home
19. Analysis of the ketonic state with ketonuria [ 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 ]
    Ketonuria measured with urine stix by patients at home
20. Analysis of the ketonic state with acetoacetate in breath [ 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 ]
    determination of acetoacetate in breath by patients at home
21. Absolute and relative change 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 ]
    Determination of height
22. Absolute and relative change 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 ]
    Determination of weight
23. Absolute and relative change 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 ]
    Determination of waist circumference
24. Relative change of calorimetry [ 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 ]
    Could be determined instead of anthropometric parameters
25. Changes in Bioimpedance [ 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 ]
    Bioimpedance measurements on each visit
26. Feeling of hunger, discomforts and problems [ Time Frame: In between baseline visit (V1) and final study visit (V4) after at maximum 95 days ]
    measured and documented at home in a study dietary in between study visits
27. Acetoacetate-concentrations [ Time Frame: In between baseline visit (V1) and final study visit (V4) after at maximum 95 days ]
    measured and documented at home in a study dietary in between study visits

Other Outcome Measures:

1. Changes of renal functional panel in 24-h-urine [ Time Frame: Baseline and during 14 days of ketogenic diet or 3 days fasting ]
   Urin samples will be collected before and during the dietary intervention for the determination of creatinine, uric acid and urea (measurement unit mg/24h)
2. Changes of electrolytes and minerals in 24-h-urine [ Time Frame: Baseline and during 14 days of ketogenic diet or 3 days fasting ]
   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 )
3. Changes of glucose in 24-h-urine [ Time Frame: Baseline and during 14 days of ketogenic diet or 3 days fasting ]
   Urin samples will be collected before and during the dietary intervention
4. Changes of albumin in 24-h-urine [ Time Frame: Baseline and during 14 days of ketogenic diet or 3 days fasting ]
   Urin samples will be collected before and during the dietary intervention
5. Analysis of stool samples [ Time Frame: Baseline and during 14 days of ketogenic diet or 3 days fasting ]
   Stool samples will be collected before and during the dietary intervention and analysed
6. Changes of renal functional panel in spot urine [ Time Frame: Baseline and during 14 days of ketogenic diet or 3 days fasting ]
   Urin samples will be collected before and during the dietary intervention for the determination of creatinine, uric acid and urea (measurement unit g/24h)
7. Changes of electrolytes and minerals in spot urine [ Time Frame: Baseline and during 14 days of ketogenic diet or 3 days fasting ]
   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)
8. Changes of albumin in spot urine [ Time Frame: Baseline and during 14 days of ketogenic diet or 3 days fasting ]
   Urin samples will be collected before and during the dietary intervention
9. Changes of glucose in spot urine [ Time Frame: Baseline and during 14 days of ketogenic diet or 3 days fasting ]
   Urin samples will be collected before and during the dietary intervention
10. Changes in urinary doubly refractile lipid bodies [ Time Frame: Baseline and during 14 days of ketogenic diet or 3 days fasting ]
    Urin samples will be collected before and during the dietary intervention

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 60 Years (Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

  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

Contacts and Locations

Locations

Germany

Department II of Internal Medicine, University Hospital Cologne

Cologne, Germany, 50937

Sponsors and Collaborators

University of Cologne

Investigators

• Principal Investigator: Roman-Ulrich Müller, Prof.; Department II of Internal Medicine, University of Cologne

More Information

Additional Information:

Clinical and Translational Report 

Publications:

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.

• Responsible Party: Roman Müller, Department II of Internal Medicine, University of Cologne
• ClinicalTrials.gov Identifier: NCT04472624
• Other Study ID Numbers: 20-1040
• First Posted: July 15, 2020
• Last Update Posted: September 14, 2021
• Last Verified: September 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Roman Müller, University of Cologne:

ADPKD; dietary intervention; ketosis; fasting; ketogenic diet

Additional relevant MeSH terms:

Ketosis; Acidosis; Acid-Base Imbalance; Metabolic Diseases