Blog entry by Meguid El Nahas
Tolvaptan in Patients with 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.,
Jared J. Grantham, M.D., Eiji Higashihara, M.D., Ph.D., Ronald D. Perrone, M.D., Holly B. Krasa, M.S., John Ouyang, Ph.D., and Frank S. Czerwiec, M.D., Ph.D., for the TEMPO 3:4 Trial Investigators*
The course of autosomal dominant polycystic kidney disease (ADPKD) is often associ-
ated with pain, hypertension, and kidney failure. Preclinical studies indicated that
vasopressin V -receptor antagonists inhibit cyst growth and slow the decline of kidney
In this phase 3, multicenter, double-blind, placebo-controlled, 3-year trial, we ran- domly assigned 1445 patients, 18 to 50 years of age, who had ADPKD with a total kidney volume of 750 ml or more and an estimated creatinine clearance of 60 ml per minute or more, in a 2:1 ratio to receive tolvaptan, a V2-receptor antagonist, at the high- est of three twice-daily dose regimens that the patient found tolerable, or placebo. The primary outcome was the annual rate of change in the total kidney volume. Sequential secondary end points included a composite of time to clinical progression (defined as worsening kidney function, kidney pain, hypertension, and albuminuria) and rate of kidney-function decline.
Over a 3-year period, the increase in total kidney volume in the tolvaptan group was 2.8% per year (95% confidence interval [CI], 2.5 to 3.1), versus 5.5% per year in the placebo group (95% CI, 5.1 to 6.0; P<0.001). The composite end point favored tolvaptan over placebo (44 vs. 50 events per 100 follow-up-years, P=0.01), with lower rates of worsening kidney function (2 vs. 5 events per 100 person-years of follow- up, P<0.001) and kidney pain (5 vs. 7 events per 100 person-years of follow-up, P=0.007). Tolvaptan was associated with a slower decline in kidney function (recip- rocal of the serum creatinine level, −2.61 [mg per milliliter]−1 per year vs. −3.81 [mg per milliliter]−1 per year; P<0.001). There were fewer ADPKD-related adverse events in the tolvaptan group but more events related to aquaresis (excretion of electrolyte-free water) and hepatic adverse events unrelated to ADPKD, contributing to a higher dis- continuation rate (23%, vs. 14% in the placebo group).
Tolvaptan, as compared with placebo, slowed the increase in total kidney volume and the decline in kidney function over a 3-year period in patients with ADPKD but was associated with a higher discontinuation rate, owing to adverse events. (Funded by Otsuka Pharmaceuticals and Otsuka Pharmaceutical Development and Commercial- ization; TEMPO 3:4 ClinicalTrials.gov number, NCT00428948.)
n engl j med nejm.org
The New England Journal of Medicine November 2012.
Very exciting and promising results on the slowing of the progression of ADPKD with preserved kidney function by a ADH V2 receptor antagonist; Tolavptan.
Previous interventions with mTOR antagonists (Sirolimus and Everolimus) have shown that kidney size increase can be pharmacologically manipulated, improved, in ADPKD. Tolvaptan is also effective in that respect.
However, the TEMPO study shows, that unlike mTOR antagonists, V2 blockage by Tolavptan can slow the progression of CKD in ADPKD.
Some reservations regarding the latter point:
1. The impact on kidney function was not a primary endpoint, so the study may not be fully powered to look at that variable?!
2. Glomerular filtration rate was NOT measured but instead calculated (eGFR). It was shown by Remuzzi and his colleagues that such analysis can be misleading in ADPKD :
3. The study was also conducted on ADPKD patients with normal kidney function where the estimated GFR tend to be at best inaccurate.
4. The effect of ADH antagonisms on tubular secretion of creatinine is unknown? Could the observed effect related to changes in tubular handling of creatinine rather than GFR. After all ADH impacts on tubular secretion of uric acid another OCT mediated tubular handled substance.
It is high time nephrologists and their sponsor who undertake multimillion pounds/dollars RCTs on CKD progression MEASURE CKD progression.....not serum creatinine!