Tolvaptan Trial Shows Benefit in Slowing Progression of Autosomal Dominant Polycystic Kidney Disease

A phase III clinical trial of tolvaptan for autosomal dominant polycystic kidney disease (ADPKD) demonstrated the drug slowed the rate of disease progression by almost half over the study period compared with placebo. While encouraging, the trial results presented at Kidney Week 2012 are investigative and have yet to be evaluated by the FDA. The 3-year multicenter, double-blind, placebo-controlled study (the TEMPO 3/4 Trial) found that patients with ADPKD who took tolvaptan experienced an average increase in total kidney volume of 2.8 percent per year compared with 5.51 percent for those in the placebo group (1). Given these results, how could this trial expand our understanding of ADPKD and change the investigative approach to the fourth leading cause of ESRD?

Prior to this study, physicians caring for patients with ADPKD were limited “to treating its complications (strict blood pressure control, dietary protein restriction, a low salt diet, and statin use for cardiovascular effects), since no treatment capable of inhibiting the development and progression of the cysts has been available,” said Vicente Torres, MD, PhD, of the Mayo Clinic and first author of the TEMPO trial. “In many patients, the growth of numerous cysts within the kidneys is accompanied by painful complications (such as bleeding into cysts or into the urinary tract, cyst infections, and passage of kidney stones), hypertension, and kidney failure.”

Vasopressin has been a pathway of interest to investigators in the ADPKD community, and has included research into the therapeutic use of water intake as a method to reduce vasopressin levels (2). A vasopressin V2 receptor antagonist, tolvaptan is currently indicated for hypervolemic and euvolemic hyponatremia. “Vasopressin causes production of the molecule cyclic adenosine monophosphate (cAMP), which is thought to accelerate the progression of ADPKD by stimulating proliferation of the cells lining the cysts and fluid secretion into the cysts,” said Torres. “By blocking the production of cAMP, it was expected that tolvaptan would slow the progression of ADPKD.”

Initiated in 2007, TEMPO 3/4 trial (Tolvaptan Efficacy and Safety in Management of Polycystic Kidney Disease and Its Outcomes) involved 1445 adult patients with ADPKD from 15 countries who were randomized to receive either tolvaptan (one of three dosages as tolerated) or placebo. The study’s primary end point was reduction of total kidney volume over the course of the study. Secondary end points included the rate of decline in kidney function and time to clinical progression events, including hypertension and pain.

At the end of the 3-year study, the annual increase in total kidney volume (2.8 percent per year for tolvaptan versus 5.51 percent for placebo) and the slope of renal function decline (–2.61 [mg/mL]–1/year for tolvaptan versus –3.81 [mg/mL]–1/year for placebo) were significantly reduced in the tolvaptan group (both p < 0.001). Patients taking tolvaptan also demonstrated significant reductions in risk for secondary end points including worsening kidney function (61 percent) and pain requiring intervention (36 percent).

“The trial results show that Tolvaptan, given over 3 years, slowed the increase in kidney volume and the decline in kidney function,” said Torres. “If these results are sustained beyond 3 years, tolvaptan would substantially extend the time before patients with ADPKD would need renal replacement therapy. Kidney pain, hematuria, and urinary tract infections, complications associated with ADPKD, occurred less frequently in the patients treated with tolvaptan compared to those treated with placebo. By reducing the rate of these complications, tolvaptan may lead to an improvement in quality of life.”

Yet Torres cautions that tolvaptan is not without risks. “The most common adverse effects were anticipated and related to high urine output with more frequent voiding. Unexpected liver test abnormalities were observed in approximately 5 percent of patients and led to the discontinuation of tolvaptan in 1.8 percent of the patients.” Adverse events led to a higher discontinuation rate in the tolvaptan group (23 percent) than in the placebo arm (14 percent).

“Although tolvaptan is already approved for treatment of other medical conditions, it is not approved for the treatment of ADPKD. The doses of tolvaptan used in the TEMPO trial were higher than used in previous studies of other diseases,” Torres said. “In addition, ADPKD patients are a unique patient population. Further analysis of the benefits and risks of this potential therapy will need to be performed by the sponsor (Otsuka Pharmaceuticals) and regulatory agencies. Therefore, although the results are encouraging, at the present time, patients with ADPKD should not be treated with tolvaptan outside of approved research studies.”

Terry Watnick, MD, of the University of Maryland School of Medicine and an investigator in the TEMPO trial, found the results of the trial’s primary end point very encouraging. But Watnick added that “it is still important that we control blood pressure and other cardiovascular risk factors in ADPKD patients since this population may still require renal replacement therapy. While tolvaptan may delay disease progression, it will not completely prevent or reverse established disease based on the data presented.”

There are other important questions with respect to tolvaptan that remain to be answered, Watnick said. For example she wondered if tolvaptan would be more beneficial if the drug was initiated earlier in the course of disease when patients had fewer cysts or smaller kidneys. In addition, the applicability of treatment in patients with milder disease severity, or the consequences of longer-term drug administration remain to be defined. She also pointed to a need for more basic research into the mechanisms underlying ADPKD pathogenesis. “Blocking the V2 receptor improves the disease course, but it doesn’t completely stop progression. ADPKD is a complicated disorder, and the PKD community has invested a lot in research over the past 15 years. The signaling pathways involved in cyst formation are complex, and we still don’t know everything we need to know about this disease. Blocking the V2 receptor provides one therapeutic approach, but I believe that there are likely to be others.”


1. Torres VE, et al. Tolvaptan in patients with autosomal dominant polycystic kidney disease. N Engl J Med 2012; doi: 10.1056/NEJMoa1205511.

2. Torres VE, et al. A case for water in the treatment of polycystic kidney disease. Clin J Am Soc Nephrol 2009; 4:1140–1150.