Aquaretics and PCKD

One of the big stories at the ASN this year was the announcement of the results of the TEMPO trial which were simultaneously published in NEJM. It has been known for some time that ADH is implicated in cyst growth in patients with polycystic kidney disease (PCKD) and that suppression of ADH release with high water intake or vasopressin receptor blockade reduces cyst growth in animal models. The TEMPO trial was a 3-year, multicenter controlled trial involving 1445 patients with PCKD who were randomized to receive tolvaptan (a V2-receptor antagonist) or placebo. The primary outcome was the rate of change in total kidney volume while the rate of CKD progression was a secondary outcome.

There was a lower rate of kidney growth in the tolvaptan group (2.8% per year vs. 5.5% per year) and a slower decline in renal function also. These are fantastic results and they should be celebrated, especially considering the disappointment surrounding bardoxolone. However, there are a couple of significant issues which should be considered. All of these patients had normal renal function at the time of entry into the study. The majority of these would progress very slowly to end stage and the cost of treatment with tolvaptan over this period of time would be enormous. Also, about 23% of the participants dropped out due to adverse effects (although, it should be said that 14% of the placebo group also dropped out). The most important side effect was liver toxicity.

So the question arises – who are the patients that will benefit most from vaptan treatment. As the accompanying editorial states – “the development of comprehensive criteria for aquaretic treatment and appropriate patient selection are needed”.

So maybe a recent series of papers from a group in Holland may help provide the answer. Vasopressin is difficult to measure in vivo because of its short half-life and tendency to bind to platelets. However, one of the components of its precursor, copeptin, is stable in plasma and can be used as a surrogate for the serum vasopressin concentration. Last year, this group published a paper which found that, in a group of 102 patients with PCKD, serum copeptin levels were associated with markers of disease severity such as kidney size, GFR and albuminuria. The group published two follow-up longitudinal studies (using historic samples from previous studies) in NDT and AJKD. In a group of 79 patients, higher baseline copeptin levels were associated with more rapid decline in renal function over 11 years follow-up. 8 of the 9 patients that started hemodialysis over the course of the study had copeptin levels above the median. It should be pointed out that baseline copeptin levels were higher in patients with lower GFR at the time of entry to the study and this could have biased the results.

The last paper looked back at 241 patients with normal baseline renal function who were included in a longitudinal study of cyst growth (and measured GFR!) In these patients, higher baseline copeptin levels were associated with a greater change in kidney volume over 8 years follow-up. After full covariate adjustment, there was a trend towards a greater decline in renal function in the higher copeptin group but this was not statistically significant. Again, however, patients with larger kidneys at baseline also had higher copeptin levels. Because of the size of the molecule, there may be some element of reduced clearance in patients with lower GFRs and this could explain some of the differential. Higher copeptin levels have also been noted in patients with other renal diseases so this is not entirely specific. This needs to be further studied.

Still, although not definitive, these studies provide some rationale for a potential means of stratifying patients with PCKD and certainly give a route for further investigation. It would be interesting, perhaps, to go back and measure baseline copeptin levels in the patients in the tolvaptan study to determine if there was a difference in response to therapy based on this promising biomarker.