Diet as a Potential Treatment for Autosomal Dominant Polycystic Kidney Disease
Condition: Autosomal Dominant Polycystic Kidney Disease (ADPKD)
MeSH terms: Kidney Diseases; Polycystic Kidney Diseases; Polycystic Kidney, Autosomal Dominant
Study type: Interventional
Phase: Phase 2/Phase 3

Summary: 
      The purpose of this study is to learn if dietary habits can affect vasopressin secretion in
      patients with autosomal dominant polycystic kidney disease. Vasopressin increases the growth
      of kidney cysts and accelerates disease progression. Understanding how to control secretion
      of this hormone based on dietary habits may help to develop treatments to control this
      disease. The study will include about 60 patients from Tufts Medical Center. The study will
      last for 2 weeks. Blood and urine tests will be done 3 times during the study period.
      Subjects will be randomly assigned (by chance like flipping a coin), to one of two study
      groups. Group 1 will be given instructions to adjust their diet. This will include adjusting
      the amount of water, protein, and salt intake. Group 2 will have no adjustment of diet or
      water. The project has tremendous public health relevance, given the large numbers of people
      affected by autosomal dominant polycystic kidney disease and the substantial impact of the
      disease on morbidity, mortality, hospitalizations,dialysis or transplant, and societal costs
      of caring for those patients.
    

Detailed description: 
      Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary kidney
      disease with an estimated 600,000 persons affected in the United States and 12.5 million
      persons worldwide. To date, no disease-modifying treatment has been approved for the
      treatment of ADPKD.

      Arginine vasopressin (AVP) is a key player in cyst enlargement and disease progression. It
      has been established that patients with ADPKD have higher levels of AVP as compared to
      healthy controls. Suppression, blockade or elimination of AVP slows cyst progression. AVP-V2
      receptor inhibition controls disease progression in both animal models and humans, as does
      genetic elimination of vasopressin in the Polycystic Kidney (PCK) rat. This evidence
      indicates that AVP could be a promising target for therapeutic intervention. Unfortunately,
      the only clinically tested medication that blocks the AVP-V2 receptor (Tolvaptan) is
      associated with side effects including hypernatremia, hyperuricemia and elevated liver
      enzymes. An ideal therapeutic approach to target AVP in patients with ADPKD would be safe,
      easy to administer and could be adopted early in the disease process to prevent permanent
      kidney damage. High fluid intake presents one such possible treatment, and has been shown to
      suppress plasma levels of AVP, and slow cyst progression in an animal model of polycystic
      kidney disease. However, adherence to a high fluid intake diet is difficult to maintain in
      clinical practice.

      To address this adherence challenge, The investigators have developed a stepwise approach of
      combining a low osmolar diet (low protein and salt) with adjusted water intake, with the goal
      of lowering the amount of water intake needed to suppress AVP secretion. The major objective
      of this proposal is to evaluate whether this intervention can suppress vasopressin secretion
      in patients with early ADPKD. Vasopressin suppression will be assessed by measuring copeptin
      levels, which have been shown to be a reliable surrogate marker for the circulating AVP
      concentration.

      The rationale for this proposal is based on the fact that part of the difficulty in
      sustaining a low AVP level with daily water ingestion is the consumption of a diet that
      generates a large number of osmoles; high osmolar load stimulates vasopressin secretion to
      maintain water homeostasis. Hence, combining a low osmolar diet with adjusted water intake
      might prove to be sufficient to suppress vasopressin secretion in the clinical setting. The
      investigators propose the following:

      Specific Aim: To conduct a randomized controlled trial to evaluate the effect of a low
      osmolar diet and high water intake intervention on vasopressin secretion, urine osmolality,
      and daily solute excretion in adult patients with ADPKD. The investigators hypothesize that a
      low osmolar diet combined with adjusted water intake will decrease serum copeptin level and
      total daily solute excretion in patients with ADPKD as compared to the control arm.

      To accomplish the research goals, the current proposal builds upon existing expertise at
      Tufts Medical Center in conducting controlled clinical trials in patients with ADPKD.

      The expected outcomes include the identification of a relevant, safe, easily tolerated and
      affordable intervention that can suppress vasopressin secretion in ADPKD patients early in
      the disease process; the proposed stepwise approach of combining a low osmolar diet and
      adjusted water intake carries the premise of lowering the amount of water needed to suppress
      AVP secretion and potentially slow the progression of this devastating disorder.

      The study long-term goal is to evaluate whether this therapeutic approach could be tolerated
      by patients over a longer period of time, and could impact clinical outcome measures such as
      kidney volume and kidney function progression.
    

Intervention name(s): Diet and water adjustment
Intervention type(s): Behavioral
Intervention description(s): The dietary intervention consisted of three elements: low sodium (1500 mg/day), low protein (daily protein dietary allowance of 0.8 gram/kg body weight), and low urea (avoidance of preservatives, food additives, bulking agents, and chewing gum). Protein was factored by measured body weight to mirror the estimated average requirement (EAR) of healthy adults which is set on a grams per kilogram basis
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: ADPKD; Copeptin; Vasopressin; Diet; Water