“homocysteinylation” means a putative mechanism through which high total plasma
homocysteine levels exert a toxic effect. Homocysteinylation, imagined as similar to diabetic
protein glycation, occurs just on physiological levels of total plasma homocysteine and
depends on concentration and time of exposure. An interesting hypothesis suggests that
cysteine-rich repeated domains of proteins like fibrillin-1 [49], coagulation factors and low
density lipoprotein receptors are sites at risk of homocysteinylation. End-stage renal disease
patients on maintenance hemodialysis have significantly higher total plasma homocysteine
levels and protein-homocysteinylation values as compared to subjects with normal renal
function. It is known that long-term oral folic acid treatment significantly reduces the
alterations of protein functions. Moreover, another relevant toxic action of homocysteine is
DNA hypomethylation, which also can be reverted by folate therapy [50].
HOMOCYSTEINE, VITAMIN B THERAPY AND
Cardiovascular disease is the most important cause of morbidity and mortality not only in
the general population with normal renal function, but also in the end-stage renal disease
patients on dialysis [51,52]. In Italy, the overall mortality rate of end-stage renal disease
patients on dialysis is about 14% per year and cardiovascular events are responsible for up to
Epidemiological investigations and succeeding meta-analysis, related to these studies,
have underlined both that total plasma homocysteine concentrations are responsible for 10%
of the cardiovascular disease, and that the homocysteine-reduction net value of 5 micromoles
per liter lowers 25% of cardiovascular events [55,56].
Recently, both the large observational study Dialysis Outcomes and Practice Pattern
Study (DOPPS) showed [57] an association between the regular use of water-soluble
vitamins and lower overall and cardiovascular mortality rate, and our small single-centre
prospective study [58] displayed that homocysteine-lowering vitamin B therapy decreases
cardiovascular events in end-stage renal disease patients on hemodialysis. On the contrary,
two recent papers [59,60] told us that high, rather than low plasma homocysteine levels are
related to lower mortality rate in end-stage renal disease patients on hemodialysis, suggesting
the hypothesis of an inverse epidemiology for homocysteine. These trials had two important
methodological bias, because first the close direct relationship between plasma homocysteine
levels and serum albumin values may simply reflect a malnutrition with an amino-acid pool
reduction and in these two trials either adjustment for albumin levels was not performed, or
when it was done the reverse epidemiology disappeared. Moreover, in both cases, diabetic
end-stage renal disease patients on dialysis were a significant part of enrolled patients, and
they should be analyzed separately because they showed significantly lower homocysteine
levels as compared with non-diabetic end-stage renal disease patients on hemodialysis.
Consequently, the issue of reverse epidemiology between plasma homocysteine levels and
cardiovascular mortality in end-stage renal disease patients is not settled [61]. Moreover, our
last paper and above all Suliman M et al. [62] recently observed that the paradoxical reverse
puzzling factors on total plasma homocysteine levels, including inflammatory and wasting
markers. Therefore, these works strongly support the theory that the influence of malnutrition
and inflammation on total plasma homocysteine levels should be taken into consideration
when evaluating homocysteine as a risk factor for cardiovascular morbidity and mortality in
end-stage renal disease patients on hemodialysis.
According to my data, supporting the beneficial effect of homocysteine-lowering folic
acid therapy on cardiovascular events also if vitamin B treatment does not normalize plasma
total homocysteine levels in a large part of treated patients, Yap S et al. [63] showed that
long-term treatment with betaine, vitamin B, and low-methionine diet, is effective in
lowering the potentially life-threatening vascular risk in homocystinuric patients, without
population with slight increase of total plasma homocysteine levels. It has been recently
published by Yang Q et al. [64] that, after a food fortification program with folic acid, US
and Canada population showed a highly significant decrease of fatal stroke as compared both
with a similar population before the beginning of this program, and with the contemporary
populations of England and Wales not submitted to a food fortification with folate. The same
differences observed with vascular events were obtained considering the effects of food
fortification on neural tube defects. These data are very impressive; also if the intervention
model is not a randomized controlled study which represents the gold standard, but often it is
prevention of cardiovascular disease in randomized controlled studies, found no significant
benefit or harm of folate treatment on the risk of cardiovascular disease, or all-cause
mortality. In contrast they observed, excluding VISP trial by Toole et al [66], a significant
protective effect of folic acid supplementation on stroke (RR, 0.76; 95% CI, 0.63-0.93), and
consequently, they concluded that several ongoing trials might provide a definitive answer to
this important clinical and public health question. VISP trial, also if shows that vitamin B
therapy is ineffective to lower cardiovascular events rate, had two essential methodological
bias: the absence of a placebo group and the food fortification with folate which lowered
homocysteine values in both patients’ groups with, as result, a low difference for
homocysteine levels in the two groups. Therefore the authors decided to renew their data
analysis [67], showing that, if they choose two well-splitted patients’ subgroups for the
vitamin B status, they observe a significant risk reduction for composite cardiovascular
events in patients with both high vitamin B12 levels and high doses of vitamins. Also in the
Norwegian Vitamin Trial (NORVIT) [68] the homocysteine levels are similar in the treated
and untreated groups, and these latter patients show an unexpected increase of folate values
during the study. Moreover, homocysteine levels were not an inclusion criteria, and therefore
Vitamin B Treatment and Cardiovascular Events in Hyperhomocysteinemic Patients 131
a large part of patients had baseline homocysteine levels in the normal range or slightly
increased. Hope-2 trial [69] was published with NORVIT in the same issue of the New
England Journal of Medicine, and it was characterized by the same methodological defects.
Again, baseline homocysteine levels were not inclusion criteria, a large part of the study
population had not hyperhomocysteinemia and folate deficiency because both they originated
from fortification areas like US and Canada and had previously taken vitamin B therapy
before starting the trial. Also the authors of Hope-2 trial tell us that vitamin B therapy do not
reduce the cardiovascular events rate, but they unexpectedly set aside as irrelevant the lower
rate both of combined cardiovascular events (111 vs 147 cases) and of non-fatal
cerebrovascular events (84 vs 117 cases, RR 0.72, 95% CI, 0.54-0.95, p= 0.02) in the vitamin
B subgroup as compared with control group. I think that it is important to underline that all
these randomized controlled trials, excluding our paper, show a small reduction in
homocysteine levels from baseline that could mean a relatively too short follow-up time and,
thus, a powerlessness to show the protective effect of homocysteine-lowering folate therapy
on cardiovascular disease. Moreover, the greatest effect of vitamin B therapy is clearly
achieved when this treatment is assigned to hyperhomocysteinemic patients, as early as
possible, and for a long time.
Haemodialysis vascular access thrombosis is the most common cause of hospitalisation
among haemodialysis patients. In 1999 an observational prospective study by Shemin D et al
[70] showed that 47 of 84 (56%) haemodialysis patients had at least one access thrombosis
during a 18 months follow-up time, and baseline homocysteine values were directly related to
the development of vascular access thrombosis. They also observed that each 1 micromoles/L
increase in the total plasma homocysteine level was associated with a 4% increase in the risk
of vascular access thrombosis. Similar results were published by Mallamaci et al [71] in an
Italian hemodialysis population, because they detected that baseline total plasma
homocysteine values were an independent predictor of arteriovenous fistula outcome.
The retrospective analysis (personal data) of incident end-stage renal disease patients
submitted to hemodialysis from January 01 until now in Vimercate Hemodialysis Unit point
out no baseline biochemical and clinical variables linked to arterio-venous fistula failure, but
considering the parameters as repeated measurements during follow-up time, I discover that
dialysis patients with vascular access dysfunction have significantly higher homocysteine
levels and lower folate values as compared with events-free patients. Moreover, taking into
consideration the patients treated with folate, I detect a significant lower rate of vascular
access failure that it is not obtained when I consider our hemodialyis patients submitted to
In view of these interesting results, it is important to project randomized controlled
clinical trials evaluating the hypothesis that lowering total plasma homocysteine levels may
reduce the rate of haemodialysis vascular access thrombosis.
In the last years it has been observed that vitamin B therapy has other essential biological
properties. Folate supplementation has a basic function in one-carbon transfer, involving the
reactions [72]. Aberrant patterns and dysregulation of DNA methylation are mechanistically
related to cancers. Indeed, it has been observed an inverse association between folate status
and the risk of several malignancies, in particular colorectal cancer. Hence, modest doses of
vitamin B supplementation may give protection against serious diseases such as
cardiovascular disease and cancer [73] which represent the most important causes of
mortality in the general population and in end-stage renal disease patients submitted to
dialysis or renal transplantation.
Actually, long-term clinical trials have not shown harm from folate supplementation, and
we can affirm that folate therapy is inexpensive and has not actually apparent serious side
To summarize, I think that it is right to attend other ongoing randomized clinical trials for
give final statements and especially guidelines; but just nowadays, in view of a safe and
unexpensive therapy, it is important to:
a. check total plasma homocysteine levels both in patients with chronic renal failure,
and in patients with normal renal function but with previous cardiovascular events,
b. treat high total plasma homocysteine levels with vitamin B supplementation,
c. correct unbalanced and unrestricted diets because the “food as medicine” is the first
step to reduce the risk of cardiovascular morbidity and mortality.
Naturally, this last thought is not original, because it was first promoted by Hippocrates
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