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Effect of Long-term Epoetin Treatment on Serum Levels of High-density Lipoprotein
reduction in the atherogenic ratio of LDL cholesterol/HDL cholestrol (see
Figure 1: Effect of Epoetin Therapy on (A) High-density
Figure 1B).
20
The mechanism by which epoetin induces HDL cholesterol
Lipoprotein (HDL) Cholesterol Levels and (B) the Atherogenic Ratio
elevation remains to be established. Indeed, the biogenesis of HDL is a
of Low-density Lipoprotein (LDL) Cholesterol to HDL Cholesterol in
Patients with Chronic Kidney Disease Stages 3 and 4
complicated process in which several enzymes, lipid transporters and
receptors are involved.
21
Among them, cholesterol ester transfer protein
AB
(CETP) has a central role in HDL metabolism and in regulation of 70 7
HDL cholesterol levels in serum. CETP exchanges cholesterol esters with
p<0.001
triglycerides between HDL and apolipoprotein B (apoB)-containing 60 6
p<0.001
lipoproteins; thus, it significantly contributes to the reverse cholesterol
p<0.001
transport pathway. Increased CETP activity leads to a decrease in HDL
50 5
cholesterol levels and to an atherogenic lipoprotein profile.
22,23
40 4
According to our previously published results, baseline CETP activity
in patients with CKD was not influenced by epoetin treatment.
30 3
Consequently, CETP may not be involved in the increase in
HDL cholesterol levels observed in patients treated with epoetin.
20
In
20 2
CKD patients, epoetin-induced improvement in tissue oxygenation
10 1
could play a contributory role in increased HDL cholesterol levels. This
suggestion is supported by the positive correlation between the
0 0
increase in serum HDL cholesterol levels and the increase in Group I Group II Group I Group II
haemoglobin values observed in epoetin-treated patients.
20
Increased
Baseline 6 months 12 months
tissue oxygenation may lead to an increase in activity of several
enzymes and transferring proteins involved in HDL biogenesis as well
Group I: Epoetin-treated chronic kidney disease (CKD) patients; Group II: CKD patients not
as in HDL maturation, and lead to the increase in HDL cholesterol
receiving epoetin.
levels. Furthermore, the epoetin-induced improvement in tissue
oxygenation could also increase the exercise capacity of our patients. glomeruli of patients with glomerulonephritis and exhibits
Although the physical activity of our patients was not considered in pro-inflammatory activities.
29,30
Thus, by degrading PAF and oxidised
our previous study, we cannot exclude the possibility that it may have phospholipids, PAF-AH may not only play a role in atherogenesis, but
contributed to the increase in serum HDL cholesterol levels. It is well- may also be involved in renal pathology.
documented that an increase in physical activity leads to increased HDL
cholesterol levels and it is currently considered to be one of the most PAF-AH in plasma forms a complex with lipoproteins,
9
thus it is referred
important non-pharmacological strategies in increasing serum HDL to as lipoprotein-associated phospholipase A
2
(Lp-PLA
2
).
31
In human
cholesterol levels.
24
plasma, PAF-AH is mainly associated with apoB-containing lipoproteins
and primarily with LDL, whereas a small proportion of circulating
Effect of Epoetin on High-density Lipoprotein-associated enzyme activity is associated with HDL.
9
Data from large Caucasian
Antiatherogenic Enzymes population studies demonstrated an independent association between
HDL contains a variety of proteins and enzymes that play important plasma PAF-AH (primarily the LDL-associated enzyme) with CAD risk.
32
roles in its antiatherogenic activities.
8
Among them the enzymes In this regard, the role of the LDL-associated PAF-AH in atherogenesis
PAF-AH and PON1 may significantly contribute to HDL’s antioxidant is controversial. Thus, it is suggested that this enzyme may have an
and anti-inflammatory activities.
9,10
PAF-AH exhibits a Ca
2+
- anti-inflammatory role as it degrades and inactivates pro-inflammatory
independent phospholipase A
2
activity and degrades PAF and oxidised PAF and oxidised phospholipids. Other studies showed that PAF-AH
phospholipids by catalysing the hydrolysis of the ester bond at the may have a pro-inflammatory and pro-atherogenic role since it
sn-2 position.
9
Experimental studies in humans and animals generates lysophosphatidylcholine and bioactive oxidised fatty
indicate that PAF may be an important mediator of renal damage, residues.
9
In contrast to the LDL-associated enzyme, several lines of
suggesting that its production and action in the kidney may be evidence suggest that HDL-associated PAF-AH (HDL-PAF-AH), although
unregulated in a diseased state.
25
In the kidney, PAF is synthesised by at low levels, contributes substantially to the antiatherogenic effects of
infiltrating cells as well as by mesangial cells,
25
and plays an important this lipoprotein.
9
role in renal haemodynamic changes and in the recruitment of
inflammatory cells into glomeruli as observed in glomerular immune Human plasma PON1 is an esterase exclusively present in plasma
injury.
26,27
Oxidised phospholipids are also substrates for PAF-AH. associated with HDL. In vivo substrates for this enzyme are phospholipid
These phospolipids contain oxidatively fragmented residues at the sn- hydroperoxides and cholesteryl ester hydroperoxides (molecules that are
2 position and are produced during peroxidation of phospholipids formed during LDL oxidation). It has been shown that PON1 is able to
containing a polyunsaturated fatty acyl moiety esterified at the sn-2 retard LDL oxidation and to reduce the pro-inflammatory effects of
position of the glycerol backbone.
28
Such phospholipids are formed oxidised LDL. Furthermore, PON1 may inhibit HDL oxidation, thereby
during LDL oxidation and are thought to play key roles in inflammatory preserving its antiatherogenic functions.
33
reactions, particularly in vascular inflammation and atherosclerosis.
28
Although the role of these phospholipids in CKD remains to been In a recent study we examined whether epoetin has any influence on
established, it has been shown that oxidised LDL is localised in the HDL anti-inflammatory and antioxidant potency (activities of PAF-AH
EUROPEAN RENAL DISEASE 2007 35