One of the big stories at the ASN this year was theannouncement of the results of the TEMPO trial which were simultaneouslypublished in NEJM. It has been known for some time that ADH is implicated incyst growth in patients with polycystic kidney disease (PCKD) and thatsuppression of ADH release with high water intake or vasopressin receptorblockade reduces cyst growth in animal models. The TEMPO trial was a 3-year,multicenter controlled trial involving 1445 patients with PCKD who wererandomized to receive tolvaptan (a V2-receptor antagonist) or placebo. Theprimary outcome was the rate of change in total kidney volume while the rate ofCKD progression was a secondary outcome. There was a lower rate of kidney growth in the tolvaptangroup (2.8% per year vs. 5.5% per year) and a slower decline in renal functionalso. These are fantastic results and they should be celebrated, especially consideringthe disappointment surrounding bardoxolone. However, there are a couple ofsignificant issues which should be considered. All of these patients had normalrenal function at the time of entry into the study. The majority of these wouldprogress very slowly to end stage and the cost of treatment with tolvaptan overthis period of time would be enormous. Also, about 23% of the participantsdropped out due to adverse effects (although, it should be said that 14% of theplacebo group also dropped out). The most important side effect was livertoxicity.
So the question arises – who are the patients that willbenefit most from vaptan treatment. As the accompanying editorial states – “thedevelopment of comprehensive criteria for aquaretic treatment and appropriatepatient selection are needed”.
So maybe a recent series of papers from a group in Hollandmay help provide the answer. Vasopressin is difficult to measure in vivo becauseof its short half-life and tendency to bind to platelets. However, one of thecomponents of its precursor, copeptin, is stable in plasma and can be used as asurrogate for the serum vasopressin concentration. Last year, this grouppublished a paper which found that, in a group of 102 patients with PCKD, serumcopeptin levels were associated with markers of disease severity such as kidneysize, GFR and albuminuria. The group published two follow-up longitudinalstudies (using historic samples from previous studies) in NDT and AJKD. In a group of 79patients, higher baseline copeptin levels were associated with more rapiddecline in renal function over 11 years follow-up. 8 of the 9 patients thatstarted hemodialysis over the course of the study had copeptin levels above themedian. It should be pointed out that baseline copeptin levels were higher inpatients with lower GFR at the time of entry to the study and this could havebiased the results.
The last paper looked back at 241 patients with normal baselinerenal function who were included in a longitudinal study of cyst growth (andmeasured GFR!) In these patients, higher baseline copeptin levels wereassociated 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 highercopeptin levels. Because of the size of the molecule, there may be some elementof reduced clearance in patients with lower GFRs and this could explain some ofthe 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 somerationale for a potential means of stratifying patients with PCKD and certainlygive a route for further investigation. It would be interesting, perhaps, to goback and measure baseline copeptin levels in the patients in the tolvaptanstudy to determine if there was a difference in response to therapy based onthis promising biomarker.
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