Diet as a Potential Treatment for Autosomal Dominant Polycystic Kidney Disease

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.

Inclusion Criteria:

- Adults 18 to 60 years of age, who have ADPKD with an estimated glomerular filtration
rate (eGFR) of 60 ml/min/1.73m2 or above

Exclusion Criteria:

1. Patients on chronic use of medications known to affect AVP secretion (Serotonin
Specific Reuptake inhibitors (SSRI), Opioids, Tricyclic Antidepressants (TCA) and
Tolvaptan)

2. History of diseases influencing renal concentration capacity, such as, diabetes
insipidus, adrenal or thyroid deficiencies, present or prior use of lithium, or
kidney diseases other than ADPKD.

3. Baseline hyponatremia (Na below 135 mEq/l)

4. Inability to comply with dietary or fluid requirements

5. Have physical or cognitive impairments which prevent participation

6. Pregnant women