SAN DIEGO—Tolvaptan, a drug approved by the FDA for treating hyponatremia, may inhibit cyst growth and slow kidney function decline in patients with autosomal dominant polycystic kidney disease (ADPKD), according to a new study presented at Kidney Week 2012 and published online in the New England Journal of Medicine.

In a phase 3, double-blind, placebo-controlled study, the medication slowed the pace of kidney cyst growth over the three years of the study, but was associated with a higher discontinuation rate (23%) compared with placebo (14%) due to aquaresis-related events and liver enzyme abnormalities.

“ADPKD is the most common inherited and the fourth most common overall cause of kidney failure worldwide,” said lead investigator Vicente Torres, MD, a nephrologist at the Mayo Clinic in Rochester, Minn. “In many patients with this disease, relentless cyst growth within the kidneys destroys the tissue, causes hypertension and painful complications, and negatively impacts the quality of life. The results of this study reveal a potential treatment that blunts kidney growth, lessens associated symptoms, and slows kidney function decline when given over three years.”

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The trial included 1,445 ADPKD patients aged 18-50 years. Each patient had a total kidney volume of 750 mL or more and an estimated creatinine clearance of 60 mL per minute or greater. The patients were randomized to receive tolvaptan at the highest of three twice daily split dose regimens that the patient deemed tolerable (45/15, 60/30 or 90/30 mg) or placebo. The primary outcome was the yearly rate of change in total kidney volume. Secondary endpoints included a composite of time to clinical progression events: pre-specified kidney function decline, kidney pain requiring intervention, and development or progression of hypertension and albuminuria.

Over the three-year study period, the increase in total kidney volume in the tolvaptan arm was 2.8% per year compared with 5.5% per year in the placebo arm. The composite endpoint favored the medication over placebo: 44 vs. 50 events per 100 person-years of follow-up. The researchers observed lower rates of worsening kidney function and kidney pain events with tolvaptan. The rate of decline of kidney function was also less in the tolvaptan-treated patients.

The tolvaptan arm had fewer ADPKD-related adverse events compared with the placebo group. The most common adverse effects in patients who received tolvaptan were anticipated and related to high urine output with more frequent voiding. Investigators observed unexpected liver test abnormalities in approximately 5% of patients and led to the discontinuation of the study drug in 1.8% of tolvaptan-treated patients.

“The hope is that this drug can significantly delay the need for dialysis or transplantation and maybe in some cases prevent it,” Dr. Torres told Renal & Urology News.  “Clinically significant elevations of liver enzymes were an unexpected adverse event. Close monitoring of liver function will be required when patients are placed on the drug. At present, tolvaptan is not approved for the treatment of ADPKD. Although the trial results are encouraging, further analyses of benefits and risks of this potential therapy need to be performed by the sponsor and regulatory agencies. For now, patients with ADPKD should not be treated with tolvaptan outside of approved research studies.”

Commenting on the study findings, nephrologist Josef Coresh, MD, PhD, a clinical epidemiologist at Johns Hopkins University in Baltimore, observed: “Polycystic kidney disease can be diagnosed early but so far rigorous evidence about treatments which slow down progression has been limited.”

The new study is important because it shows a consistent protective effect with respect to multiple outcomes, Dr. Coresh said. Still, he said, challenges remain because it is not easy to recognize when treatment should be started and to quantify the benefit for an individual patient.

“It will be important to find ways to estimate the long term benefit since patients need to slow progression for decades and the trial focused on the first three years on treatment,” he said.