We now have an effective medication for autosomal dominant polycystic kidney disease. Tolvaptan, the oral vaptan approved for hyponatremia, was effective at slowing cyst growth and loss of GFR in the TEMPO 3:4 trial.

TEMPO stands for Tolvaptan Efficacy and safety in Management of Polycystic kidney disease and its Outcomes.

The data was presented by the lead author, Vicente E. Torres  of the Mayo clinic.

Torres begins by showing how vasopressin has a important role in stimulating cyclic AMP which via PKA causes cytogenesis by multiple mechanisms (disrupted tubulogenesis, increased fluid secretion, and stimulating cell proliferation). So the V2R is located at an important place in the pathogenesis of ADPKD but also, since it is limited to selective sites in the kidney, there are relatively few side effects.

Preclinical trials show that vasopressin antagonists decrease cyst growth in animals. Additionally, other mechanisms for decreasing vasopressin, such as increased water intake and knock out mice likewise decrease cyst growth. Data such as this led to the design of the TEMPO trial.

TEMPO 3:4 trial was a randomized, multinational, placebo controlled, parallel arm, three year trial.

129 sites in 15 countries.

Patients were randomized 2:1 to tolvaptan:placebo. Patients started on 45 mg in the morning and 15 mg at night and were pushed to the target dose of 90 mg in the morning and 30 mg at night as tolerated. Titration occurred for 1-3 weeks and then patients were maintained for 36 months with clinic visits every 4 months and yearly MRIs.

Entry criteria was a total kidney volume of 750 mL, age 18-50 years and a CrCl ≥60 mL/min.

Primary endpoint was annualized percent change in kidney volume. Secondary endpoints included:

• time to 25% decline in reciprocal serum creatinine
• time to intervention for kidney pain
• time to worsening of hypertension
• time to worsening albuminuria

961 were randomized to Tolvaptan and 484 to placebo. Average GFR was 81 mL/min. The groups were well matched. 23% of patients on tolvaptan withdrew from the trial versus 13.8% of the placebo arm. 55% of the tolvaptan group was able to tolerate the target dose of 90 mg in the morning and 30 mg at night.

Primary end point: Tolvaptan kidney grew 2.8% a year and placebo grew 5.5% a year. They looked at 10 sub-groups and each sub-group demonstrated significant slowing of kidney growth. Win for tolvaptan.

The biggest difference was in the first year of treatment but there was continued separation of kidney sizes at 24 and 36 months too.

In terms of secondary end-points, there was a 61% lower risk of 1/cr decreasing 25%. The decreased loss of renal function was seen across all sub-groups, except it did not reach significance among patients without hypertension, age < 35, and kidney volume < 1,500 mL. The trends were all in the direction of benefit for tolvaptan.

36% lower risk of kidney pain requiring intervention, P=0.007.

Adverse events were ubiquitous, with 97.9% of the tolvaptan group experiencing them, and 97.1% of the placebo group. Adverse events that occurred in more than 10% of the patients and were more common with tolvaptan were all related to diuresis: thirst, polyuria, nocturia and pollakiuria (frequency). The adverse events significantly more common in the placebo group included: renal pain, hematuria, and urinary tract infection.

Liver enzymes were >3x the upper limits of normal in 4.7% of the patients on tolvaptan, compared to 1.7% in the placebo.

This is a major breakthrough. The first drug proven to slow cyst growth in humans. Torres pointed out that the drug is not approved for this indication and that there are many questions to be answered regarding the duration of therapy, and the optimal time to initiate therapy, but it does feel like we finally have some traction for this condition.

The study is now available at the New England Journal of Medicine website.

Post by Dr. Joel Topf, eAJKD Advisory Board Member

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