In a recent edition of Vascular Health and Risk Management, Kirmizis and Chatzidimitriou
have published a review article, “Antiatherogenic effects of vitamin E: the search
for the Holy Grail”.
Beside a general evaluation of the literature on vitamin E and CVD prevention, the
authors pointed out the possibility that vitamin E therapy may have particular efficacy
in kidney patients. In this sense, they may represent an elective population with
high susceptibility to such a secondary prevention effect, that was not identified
in other cardiovascular (CVD) patient populations studied in the largest randomized
controlled trials. The SPACE study,1 indeed, provided one of the most striking findings
in support of this assumption.
The reason for this could be inherent to a defect in the levels and metabolism of
vitamin E in kidney patients documented in previous studies,2,3 but also in the higher
demand of vitamin E that these patients may have as a consequence of the exposure
to chronic inflammation and uremic toxicity. This higher than normal demand of vitamin
E may translate into a higher need for antioxidant protection, but also of other biological
functions of this vitamin that include homeostatic effects on genes involved in immuno-inflammatory
and vascular protection pathways.4
The authors have highlighted the unconventional vitamin E therapy that some of these
patients follow while treated with extracorporeal hemodialysis therapy (HD). This
consists of the use of a special biomaterial developed to produce hollow-fiber hemodialysesrs
that are coated on the blood surface with a layer of all-rac-α-tocopherol, ie, the
synthetic form of vitamin E that predominates in our tissues and body fluids.4,5 These
hemodialyser membranes, also known as vitamin E-modified membranes, were developed
in the 1980s in Japan as cellulosic membranes that were introduced in the clinical
practice in the early 1990s in Japan and then in Europe. The first clinical observation
on these innovative membranes was published in a peer-reviewed journal on 1997.6 In
recent years, this cellulosic prototype has been substituted with a new generation
of vitamin E-modified (or -interactive) membranes that possess the highest depurative
and biocompatibility standards in HD being produced using a polysulfone-like fiber
backbone with an advanced filtration geometry. Other than biocompatible, these synthetic
membranes have now a well characterized antioxidant activity profile that was recent
described and quantitated in vitro.7
However, this should not lead to consider the antioxidant activity of these dialysers
as fully available for an antioxidant effect in vivo, during the extracorporeal circulation.
Actually, since from the first researches by us and other groups in the late 1990s,
it was clear that the clinical effects of these membranes could not be explained simply
with the concept that the chromanols bound to the dialysis membrane surface may produce
an in vivo scavenging effect on peroxyl radicals, ie, producing an antioxidant therapy
effect.
In other words, the antioxidant activity as well as the other beneficial properties
of this vitamin E (bound to the dialyser membranes), are probably different from those
of the vitamin E form introduced with the diet or supplements, which is present in
the circulation within the lipoprotein particles and in the cell membranes.
Thus, the interpretation of possible therapeutic mechanisms by these modified membranes
needs more careful dissection and further studies aimed to verify underlying events.
To explain the benefical effects of these membranes reported in literature, they have
used expressions such as “pharmacokinetic factors”, “the type of the α-T molecule
used”, “form of the drug” or “pharmacokinetic conditions”, which are obviously inappropriate
in this context and may generate confusion in the readers.
In the case of these membranes, indeed, the form of vitamin E that should be taken
into account is exclusively that present in synthetic coating on the blood surface
of the hollow fiber, ie, all-rac-α-tocopherol, and this vitamin E form does not seem
to be released even under drastic in vitro recirculation conditions.7 Thus, there
is no reason to discuss clinical effects of vitamin E-modified membrane dialysers
in terms of “pharmacokinetics”.
As Kirmizis and Chatzidimitriou briefly discussed in their review paper, the antioxidation
and anti-inflammatory protection claimed in several studies on these membranes are
probably the result of a complex series of effects. According to the available evidence
in literature already reviewed by us8,9 and others,10 even the previous generations
of less biocompatible (cellulosic) vitamin E-modified hemodialyser membranes were
observed to produce a better control of antioxidant parameters and lowered oxidative
stress markers,11–14 but at the same time these membranes were found to provide a
better control of leukocyte activation and apoptotic death,8,15,16 of erythrocyte
integrity and lifespan,17,18,a and to afford higher protection of low-density lipoproteins
and endothelial cells.19,20 Probably, the interaction of all these effects is responsible
for the improved CVD outcome observed in a series of promising small clinical studies
that examined aortic calcifications,21 carotid atherosclerosis17,22 and the nitric
oxide-dependent vasodilation response during HD.23
In conclusion, it is my belief that all these effects and the efforts made by the
authors to explain them in this review paper can be summarized in the concept of “superior
biocompatibility” that these vitamin E-modified membranes may have with respect to
several other dialyser membranes particularly in the recent interactive polysulfone-based
version.