Dietary Intervention in ADPKD on Tolvaptan

Overview

Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited renal disorder. Tolvaptan has been approved in Canada as a treatment for ADPKD. Tolvaptan is an arginine vasopressin receptor antagonist which has been shown to decrease the progression of ADPKD. The main side effect of this treatment is increased urine output which leads to cessation of therapy in about 20% of patients. Low solute (low sodium, low protein) diet may alleviate this side effect. This is a single arm before / after study of dietary intervention on urine output and quality of life in ADPKD patients on a stable dose of tolvaptan.

Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited renal disorder affecting 12.5 million persons worldwide, and impacting approximately 35,000-66,000 Canadians. An estimated 45% to 70% of patients with ADPKD progress to end-stage renal disease by age 65 years. Tolvaptan has been approved in Canada as a treatment for ADPKD. Tolvaptan was discovered in Japan by Otsuka Pharmaceutical and was first approved there for ADPKD in 2014. The Health Canada approval of Tolvaptan is based on the results of the pivotal Phase 3 randomized, double-blind and placebo-controlled TEMPO 3:4 Trial, the largest study conducted to date in adults with ADPKD. The treatment of ADPKD had previously been symptomatic with the aim of reducing morbidity and mortality associated with disease manifestations. This changed with the publication of the TEMPO 3:4 trial, which proved the efficacy of the arginine vasopressin (AVP) V2 receptor antagonist tolvaptan in decreasing the progression of CKD. In this trial, 1445 patients with ADPKD eGFR \> 60 were randomized to receive either placebo or tolvaptan in a split-dose regimen of 45 mg in the morning and 15 mg in the afternoon, up titrated to 90/30 mg as tolerated. The REPRISE study investigated the value of tolvaptan in 1300 patients with lower levels of eGFR (25-65 mL/min/1.73 m2). AVP plays a major role in the pathogenesis of cysts in ADPKD via cAMP stimulation. The AVP antagonist blocks V2 receptors in collecting ducts and therefore blocks the concentrating ability of the tubule. This leads to increased urine volume. Recently, it has been demonstrated that this increased urine volume is related to solute excretion. Therefore, it seems possible that dietary modification to decrease solute intake (salt, protein) would decrease the urine volume in patients taking tolvaptan. The most common side effect of AVP antagonist is increased renal water excretion which presents as polyuria, nocturia, increased thirst, and dry mouth. The daily urine volumes 5 days after starting different split doses of tolvaptan (15/15, 30/0, 30/15, 30/30 mg) in a preliminary phase 2 study were 4 to 6 L. In the treatment of hyponatremia and heart failure (another indication for tolvaptan therapy), a meta-analysis found an average increase in water clearance of only 68 mL/h after tolvaptan treatment. This more modest increase in urine output may be related to the low sodium diet most of these patients should be adhering to.