One of the big stories at the ASN this year was theannouncement 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.
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”.
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.
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.
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.
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.
Do you not think that there is a significant confounder here? Decreased concentrating ability is a potential early marker of renal disease and the increased output may just reflect higher fluid losses rather than any attempt to drink more in the patients with more renal function decline.
There was a study published in CJASN last year that looked at lowering urine osmolarity below that of serum to decrease ADH secretion in patients with PCKD. Increasing input to about 2.5L daily was sufficient to lower the osm. This was based on a previous rat study of PCKD that found lower cyst growth in rats given enough water to suppress ADH secretion.
I'm with you on then fact that water intake per se is not to be necessarily encouraged in patients with CKD but I think the evidence points towards a benefit in those with PCKD
Graham, check out figure 3 from this study of the MDRD data. It showed an increase progression of CKD with increased urine output (and this was also true for patients with ADPKD as diagnosis). Makes me skeptical that water alone would work. I have a pic of the fig on this post
Great post Gearoid.
A few more questions to chew on…
Can we achieve the same effects by simply increasing water intake?
I imagine vaptan therapy raises ADH levels as aquaresis leads to hypernatremia. As such, might increased water intake actually be a superior to vaptan therapy in a non-trial setting were more frequent missed doses might lead to intermittent renal exposure to high ADH levels?