Tolvaptan, a vasopressin receptor 2 antagonist, shows promise in polycystic kidney disease (TEMPO trial)
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Image: PD/CDC. Cystic kidneys, gross pathology.
1. Tolvaptan can slow progression of autosomal dominant polycystic kidney disease both in terms of kidney volume and kidney function.
2. Side effects of tolvaptan are mainly related to water loss due to its function as a V2 receptor antagonist.
Tolvaptan appears to offer a promising option for the treatment of ADPKD. However, the authors note that the aquaretic side effects of the drug (e.g. thirst, polyuria) pose a barrier to patient tolerance of and adherence to the medication.
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Image: PD/CDC. Cystic kidneys, gross pathology.
1. Tolvaptan can slow progression of autosomal dominant polycystic kidney disease both in terms of kidney volume and kidney function.
2. Side effects of tolvaptan are mainly related to water loss due to its function as a V2 receptor antagonist.
Primer: Autosomal dominant Polycystic Kidney Disease (ADPKD) causes a progressive decline in kidney function associated with extensive formation of renal cysts. The vast majority of mutations are in the PKD1 locus on chromosome 16. Most of the remainder cases are due to mutations in the PKD2 locus on chromosome 4. The mechanism of cyst formation is not completely known, but appears to require loss of the wild-type copy of PKD1 in heterozygous cells (similar to the two-hit hypothesis of carcinogenesis).
Vasopressin (aka anti-diuretic hormone or ADH) mainly regulates water reabsorption in the collecting ducts. It mediates this through the vasopressin V2 receptor, a G-protein coupled receptor that works through adenylyl cyclase to increase cAMP levels. Through other receptors, vasopressin can also cause peripheral vasoconstriction and have effects within the brain.
Previous studies have shown that reduced vasopressin signaling in the collecting duct can slow progression of ADPKD. The mechanism is believed to involve reduced cAMP levels in the kidney. The TEMPO trial is a phase 3 study testing the efficacy and safety of using the V2-receptor antagonist tolvaptan in patients with ADPKD. Tolvaptan is already in use for treatment of conditions like hyponatremia.
Background reading:
- Up-to-date page on genetics of ADPKD and mechanisms of cyst growth
- Mouse model of ADPKD benefits from V2-receptor antagonist
This [phase 3 randomized controlled] study: 961 ADPKD patients were assigned to tolvaptan, while 484 were assigned to placebo as controls. The primary end point of the study was change in total kidney volume over a 3-year period (treatment goals being to minimize volume increase). In the tolvaptan group, total kidney volume increased by 2.8% per year versus 5.5% per year in the placebo group (P<0.001).
Using the reciprocal slope of mean serum creatinine levels as a proxy for rate of decline in kidney function, the tolvaptan group demonstrated significantly less functional decline vs. placebo. In addition, fewer ADPKD-related events per 100 persons years were observed in the tolvaptan vs. placebo group (44 vs. 50; P = 0.01) In short, the tolvaptan group had a slower decline in kidney function than the placebo group and this was reflected in a lower rate of disease-related events.
In sum: Tolvaptan appears to offer a promising option for the treatment of ADPKD. However, the authors note that the aquaretic side effects of the drug (e.g. thirst, polyuria) pose a barrier to patient tolerance of and adherence to the medication.
Click to read the study in NEJM
Click to read an accompanying editorial in NEJM
By [TJ] and [MS]
© 2012 2minutemedicine.com. All rights reserved. No works may be reproduced without written consent from 2minutemedicine.com. Disclaimer: We present factual information directly from peer reviewed medical journals. No post should be construed as medical advice and is not intended as such by the authors or by 2minutemedicine.com. PLEASE SEE A HEALTHCARE PROVIDER IN YOUR AREA IF YOU SEEK MEDICAL ADVICE OF ANY SORT.
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Tomi Jun: Tomi is a member of the class of 2015 in the Health Sciences and Technology program at HMS. He enjoys road biking and molecular biology.
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