Short Term Induction of Ketosis in PKD
试验速览
- 阶段
- 不适用
- 状态
- 已完成
- 入组人数
- 10
- 试验地点
- 2
- 主要终点
- Relative difference of TKV immediately before and after the ketonic state
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Other
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 60 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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
结局指标
主要结局
Relative difference of TKV immediately before and after the ketonic state
时间窗: 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
次要结局
- Absolute and relative difference of TKV(Baseline visit (V1) and final study visit (V4) after at maximum 95 days)
- Absolute and relative difference of height-adjusted total kidney volume (htTKV)(Baseline visit (V1) and final study visit (V4) after at maximum 95 days)
- Absolute and relative difference of total liver volume (TLV)(Baseline visit (V1) and final study visit (V4) after at maximum 95 days)
- Absolute and relative difference of cystic burden of kidneys and liver(Baseline visit (V1) and final study visit (V4) after at maximum 95 days)
- Absolute and relative change of Renal Function Panel(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)
- Absolute and relative change of electrolytes and minerals(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)
- Absolute and relative change of albumin(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)
- Absolute and relative change of glucose(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)
- Absolute and relative change of Hepatic Function Panel(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)
- Absolute and relative change of bilirubin(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)
- Absolute and relative change of hemoglobin(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)
- Absolute and relative change of lipid panel(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)
- Absolute and relative change of inflammatory parameters(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)
- Absolute and relative change in blood count(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)
- Absolute and relative change of hematokrit(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)
- Absolute and relative change of betahydroxybutyrate level(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)
- Absolute and relative change in blood gas analysis(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)
- Analysis of the ketonic state with betahydroxybutyrate level(Baseline visit (V1), during 14 days of ketogenic diet or 3 days fasting and final study visit (V4) after at maximum 95 days)
- Analysis of the ketonic state with ketonuria(Baseline visit (V1), during 14 days of ketogenic diet or 3 days fasting and final study visit (V4) after at maximum 95 days)
- Analysis of the ketonic state with acetoacetate in breath(Baseline visit (V1), during 14 days of ketogenic diet or 3 days fasting and final study visit (V4) after at maximum 95 days)
- Absolute and relative change of height(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)
- Absolute and relative change of weight(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)
- Absolute and relative change of waist circumference(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)
- Relative change of calorimetry(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)
- Changes in Bioimpedance(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)
- Feeling of hunger, discomforts and problems(In between baseline visit (V1) and final study visit (V4) after at maximum 95 days)
- Acetoacetate-concentrations(In between baseline visit (V1) and final study visit (V4) after at maximum 95 days)
研究者
Roman Müller
Department II of Internal Medicine
University of Cologne