Tolvaptan in Later-Stage Autosomal Dominant Polycystic Kidney Disease

Explanation of terms:

Total Kidney Volume (TKV) is calculated from measurements made at an MRI scan and is known to relate to kidney function. As the TKV increases so the function falls, or larger kidneys tend to have lower function.

Estimated glomerular filtration rate (eGFR) is calculated from measurements of the creatinine in the blood and it is an approximation of how well the kidneys are working – a low eGFR equates to a low kidney function. It is measured in units ml/minute/1.73m2.

Vasopressin is a hormone that causes cyst cells to increase in number and to secrete more fluid into the cyst. It does this through a messenger called cAMP.

Tolvaptan is a drug that blocks the actions of vasopressin.


Tolvaptan in Later-Stage Autosomal Dominant Polycystic Kidney Disease


The authors of this paper have previously shown that Tolvaptan is effective in slowing the growth of the TKV and in slowing the decline in eGFR. However that trial focussed on patients in the early stages of their disease process. Now they have evidence that Tolvaptan also works in patients at the later stages of the disease.


This new trial is described in the paper as “phase 3, randomised withdrawal, multicentre, placebo-controlled, double-blind trial”. In essence that means that patients started off taking Tolvaptan and then, after a period, were randomly selected to take either a placebo in its place or to continue with Tolvaptan. Neither doctors nor patients knew whether they were taking the active drug or the placebo which avoids bias.


The study was carried out in several centres across US, UK and Europe.


The patients in this trial were between 18 and 65 years old, analysed in two groups (18-55yrs and 56-65yrs. )
The younger group had an eGFR from 65 down to 25 (ml/minute/1.73m2).
The older group had an eGFR from 44 down to 25.
For each patent who continued to receive Tolvaptan there was one who was on the placebo. They continued with the treatment for 12 months.
The important end point measurement was the change in eGFR from the baseline at the start of the trial to the end of the trial.


For those patients taking Tolvaptan the drop in eGFR was significantly smaller than for those patients on the placebo. Over the year the controls, or placebo group, had an average drop in eGFR of 3.61 ml/minute/1.73m2 while in the Tolvaptan group the drop was 2.34 ml/minute/1.73m2.
This difference is statistically significant.


From the safety aspect a few patients had slight rises in the liver enzymes ALT and bilirubin, but they fell back to normal on stopping Tolvaptan. Indeed some of the people in the placebo group also had rises.

The conclusion from this trial is that Tolvaptan results in a slower decline in the eGFR for patients in the later stages of the disease process. So it is effective even for patients who already have a reduced eGFR, as low as 25. Now it may take a while for the study results to be implemented into clinical practice and currently Tolvaptan is limited in its licence to certain patients with higher eGFR, but this is certainly good news for the whole of the ADPKD patient group.



Tolvaptan in Later-Stage Autosomal Dominant Polycystic Kidney Disease
Vicente E. Torres, M.D., Ph.D., Arlene B. Chapman, M.D., Olivier Devuyst, M.D., Ph.D., Ron T. Gansevoort, M.D., Ph.D., Ronald D. Perrone, M.D., Gary Koch, Ph.D., John Ouyang, Ph.D., Robert D. McQuade, Ph.D., Jaime D. Blais, Ph.D., Frank S. Czerwiec, M.D., Ph.D., and Olga Sergeyeva, M.D., M.P.H., for the REPRISE Trial Investigators*
N Engl J Med 2017; 377:1930-1942November 16, 2017DOI: 10.1056/NEJMoa1710030


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